WO2004002983A2 - Therapeutic piperazine derivatives useful for treating pain - Google Patents

Therapeutic piperazine derivatives useful for treating pain Download PDF

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Publication number
WO2004002983A2
WO2004002983A2 PCT/US2003/020509 US0320509W WO2004002983A2 WO 2004002983 A2 WO2004002983 A2 WO 2004002983A2 US 0320509 W US0320509 W US 0320509W WO 2004002983 A2 WO2004002983 A2 WO 2004002983A2
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WIPO (PCT)
Prior art keywords
compound
halo
animal
phenyl
alkyl
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PCT/US2003/020509
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French (fr)
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WO2004002983A3 (en
Inventor
Donald J. Kyle
Qun Sun
Laykea Tafesse
Chongwu Zhang
Xiaoming Zhou
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Euro-Celtique, S.A.
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Priority to AU2003247829A priority Critical patent/AU2003247829A1/en
Priority to NZ537292A priority patent/NZ537292A/en
Priority to MXPA04012748A priority patent/MXPA04012748A/en
Priority to DK03762220T priority patent/DK1556354T3/en
Priority to SI200331175T priority patent/SI1556354T1/en
Priority to EA200500114A priority patent/EA200500114A1/en
Priority to BR0312322-7A priority patent/BR0312322A/en
Priority to YU114804A priority patent/RS114804A/en
Application filed by Euro-Celtique, S.A. filed Critical Euro-Celtique, S.A.
Priority to EP03762220A priority patent/EP1556354B1/en
Priority to IL16586203A priority patent/IL165862A0/en
Priority to DE60318875T priority patent/DE60318875T2/en
Priority to CA2491079A priority patent/CA2491079C/en
Priority to JP2004549842A priority patent/JP4621502B2/en
Publication of WO2004002983A2 publication Critical patent/WO2004002983A2/en
Publication of WO2004002983A3 publication Critical patent/WO2004002983A3/en
Priority to NO20050371A priority patent/NO20050371L/en
Priority to HK06101088A priority patent/HK1082730A1/en

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    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom 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
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
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    • C07D237/06—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
    • C07D237/10—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-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
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    • C07D333/14—Radicals substituted by singly bound hetero atoms other than halogen
    • C07D333/16—Radicals substituted by singly bound hetero atoms other than halogen by oxygen atoms

Definitions

  • the present invention relates to Cyanoiminopiperazine Compounds, compositions comprising an effective amount of a Cyanoiminopiperazine Compound and methods for treating or preventing pain, urinary incontinence (UI), an ulcer, inflammatory- bowel disease (IBD), irritable-bowel syndrome (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, amyotrophic lateral sclerosis (ALS), dementia, retinopathy, a muscle spasm, a migraine, vomiting, dyskinesia or depression, comprising administering to an animal in need thereof an effective amount of a Cyanoiminopiperazine Compound.
  • UI urinary incontinence
  • IBD inflammatory- bowel disease
  • IBS irritable-bowel syndrome
  • an addictive disorder e.g., anxiety, epilepsy,
  • 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 andF. Plum eds., 20th ed. 1996)).
  • Nociceptive pain includes tissue injury-induced pain and inflammatory pain such as that associated with arthritis.
  • Neuropathic pain is caused by damage to the peripheral or cental nervous system and is maintained by aberrant somatosensory processing.
  • mGluRl metabotropic glutamate receptor 1
  • n ⁇ GluR5 metabotropic glutamate receptor 5
  • VR1 vanilloid receptors
  • Nociceptive pain has been traditionally managed by administering non-opioid analgesics, such as acetylsalicylic acid, choline magnesium trisalicylate, acetaminophen, ibuprofen, fenoprofen, difiusinal, and naproxen; or opioid analgesics, including morphine, hydromorphone, methadone, levorphanol, fentanyl, oxycodone, and oxymorphone.
  • opioid analgesics including morphine, hydromorphone, methadone, levorphanol, fentanyl, oxycodone, and oxymorphone.
  • NMDA antagonists e.g. ketamine, dextromethorphan
  • topical lidocaine for post-herpetic neuralgia
  • tricyclic antidepressants e.g. fluoxetine, sertraline and amitriptyline.
  • UI 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. At present, 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.
  • UI is associated with embarrassment, social stigmatization, depression and a risk of institutionalization (Herzo et al, Annu. Rev. Gerontol. Geriatr. 9:1 A (1989)). Economically, the costs of UI are great; in the United States alone, health-care costs associated with UI are over $15 billion per annum.
  • Physiologic bladder contraction results in large part from 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
  • sores are typically well-defined round or oval lesions primarily occurring in the stomach and duodenum. About 1 in 10 people develop an ulcer. 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”
  • 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 drags 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 Ff 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.
  • FT* " , K + - ATPase inhibitors inhibit the production of enzymes used by the stomach to secrete acid.
  • Side effects associated with H + , 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, however, 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.
  • 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 3 " , inhibit pepsin activity, and act as an antibacterial against H.
  • 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
  • IBD ulcerative colitis
  • Crohn's disease which can include regional enteritis, granulomatous ileitis, and ileocolitis, is a chronic inflammation ofthe 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 ofthe intestinal wall. Generally the disease affects the lowest portion ofthe small intestine (ileum) and the large intestine, but can occur in any part ofthe 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 ofthe 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 disease in which 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 ofthe intestine. The disease usually begins in the rectum and the sigmoid colon and eventually spreads partially or completely through out the large intestine. The cause of ulcerative colitis is unknown. Treatment of ulcerative colitis is directed to controlling inflammation, reducing symptoms, and replacing lost fluids and nutrients.
  • Anticholinergic drugs and low doses of diphenoxylate or loperamide are administered for treating mild diarrhea. For more intense diarrhea higher doses of diphenoxylate or loperamide, or deodorized opium tincture or codeine are administered.
  • Sulfasalazine, olsalazie, prednisone, or mesalamine can be used to reduce inflammation.
  • Azathioprine and mercaptopurine have been used to maintain remissions in ulcerative-colitis patients who would otherwise need long-term corticosteroid treatment, hi severe cases of ulcerative colitis the patient is hospitalized and given corticosteroids intravenously. People with severe rectal bleeding can require transfusions and intravenous fluids.
  • IBS is a disorder of motility ofthe entire gastrointestinal tract, causing abdominal pain, constipation, and/or diarrhea.
  • IBS affects three-times more women than men.
  • IBS stimuli such as stress, diet, drugs, hormones, or irritants can cause the gastrointestinal tract to contract abnormally.
  • IBS contractions ofthe gastrointestinal tract become stronger and more frequent, resulting in the rapid transit of food and feces through the small intestine, often leading to diarrhea.
  • Cramps result from the strong contractions ofthe large intestine and increased sensitivity of pain receptors in the large intestine.
  • 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 ofthe gastrointestinal tract are generally not effective for treating IBS.
  • Antidiarrheal drugs such as diphenoxylate and loperamide, help with diarrhea. The Merck Manual of Medical Information 525-526 (R. Berkow ed., 1997).
  • drugs can cause physical and/or psychological addiction.
  • Those most well known types of these drugs include opiates, such as heroin, opium, and morphine; sympathomimetics, including cocaine and amphetamines; sedative-hypnotics, including alcohol, benzodiazepines and barbiturates; and nicotine, which has effects similar to opioids and sympathomimetics.
  • Drug addiction is characterized by a craving or compulsion for taking the drug and an inability to limit its intake. Additionally, drug dependence is associated with drug tolerance, the loss of effect ofthe drug following repeated admimstration, and withdrawal, the appearance of physical and behavioral symptoms when the drug is not consumed. Sensitization occurs if repeated administration of a drug leads to an increased response to each dose.
  • 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 ofthe substance.
  • U.S. Patent No. 5,075,341 to Mendelson et al. discloses the use of a mixed opiate agonist/antagonist to treat cocaine and opiate addiction.
  • U.S. Patent No. 5,232,934 to Downs discloses administration of 3-phenoxypyridine to treat 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.
  • the features of Parkinson's disease are a loss of pigmented, dopaminergic neurons ofthe 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.
  • Other symptoms commonly associated with anxiety include depression, especially accompanied with dysthymic disorder (chronic "neurotic" depression); panic disorder; agoraphobia and other specific phobias; eating disorders; and many personality disorders.
  • anxiety is unattached to a clearly identified treatable primary illness. If a primary illness is found, however, it can be desirable to deal with the anxiety at the same time as the primary illness.
  • 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. The azapirones, however, are less useful for treating severe anxiety accompanied with panic attacks.
  • Epilepsy is a disorder characterized by the tendency to have recurring seizures.
  • the etiology commonly consists of lesions in some part ofthe cortex, such as a tumor; developmental malformation; or damage due to trauma or stroke. In some cases the etiology is genetic.
  • An epileptic seizure can be triggered by repetitive sounds, flashing lights, video games, or touching certain parts ofthe body.
  • Epilepsy is typically treated with anti-seizure drugs. In epilepsy cases, where anti-seizure drugs are ineffective, and the defect in the brain is isolated to a small area ofthe brain, surgical removal of that part ofthe brain can be helpful in alleviating the seizures. In patients who have several sources for the seizures or who have seizures that spread quickly to all parts ofthe brain, surgical removal ofthe nerve fibers that connect the two sides ofthe brain can be helpful.
  • Examples of drugs for treating a seizure and epilepsy include carbamazepine, ethosuximide, gabapentin, lamotrignine, phenobarbital, phenytoin, primidone, valproic acid, trimethadione, bemzodiaepines, ⁇ -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 hype ⁇ lasia; 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.
  • the Merck Manual of Medical Information 345-350 R. Berkow ed., 1997).
  • a seizure is the result of abnormal electrical discharge in the brain.
  • the discharge can involve a small area ofthe brain and lead to the person only noticing an odd taste or smell or it can involve a large area ofthe brain and lead to convulsions, i.e., a seizure that causes jerking and spasms ofthe muscles throughout the body. Convulsions can also result in brief attacks of altered consciousness and loss of consciousness, muscle control, or bladder control.
  • a seizures is often preceded by auras, i.e., unusual sensations of smell, taste, or vision or an intense feeling that a seizure is about to begin.
  • a seizure typically lasts for about 2 to 5 minutes. When the seizure ends the person can have headache, sore muscles, unusual sensations, confusion, and profound fatigue (postictal state). Usually the person cannot remember what happened during the seizure.
  • a stroke or cerebrovascular 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.
  • ischemic stroke blood supply to the brain is cut off because of athersclerosis or a blood clot that has blocked a blood vessel.
  • hemorrhagic stroke a blood vessel bursts preventing normal blood flow and allowing blood to leak into an area ofthe brain and destroying it. Most strokes develop rapidly and cause brain damage within minutes. In some cases, however, strokes can continue to worsen for several hours or days. Symptoms of strokes vary depending on what part ofthe brain is effected.
  • Symptoms include loss or abnormal sensations in an arm or leg or one side ofthe body, weakness or paralysis of an arm or leg or one side ofthe body, partial loss of vison or hearing, double vision, dizziness, slurred speech, difficulty in thinking ofthe appropriate word or saying it, inability to recognize parts ofthe body, unusual movements, loss of bladder control, imbalance, and falling, and fainting.
  • the symptoms can be permanent and can be associated with coma or stupor. Strokes can cause edema or swelling ofthe brain which can further damage brain tissue. For persons suffering from a stroke, intensive rehabilitation can help overcome the disability caused by impairment of brain tissue. Rehabilitation trains other parts ofthe brain to assume the tasks previously performed by the damaged part.
  • drugs for treating strokes include anticoagulants such as heparin, drags that break up clots such as streptokinase or tissue plasminogen activator, and drugs that reduce swelling such as mannitol or corticosteroids.
  • anticoagulants such as heparin
  • drags that break up clots such as streptokinase or tissue plasminogen activator
  • drugs that reduce swelling such as mannitol or corticosteroids.
  • Pruritus is an unpleasant sensation that prompts scratching. Pruritus can be attributed to dry skin, scabies, dermatitis, he ⁇ etiformis, 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. Conventionally, pruritus is treated by phototherapy with ultraviolet B or PUVA or with therapeutic agents such as naltrexone, nalmefene, danazol, tricyclics, and antidepressants.
  • therapeutic agents such as naltrexone, nalmefene, danazol, tricyclics, and antidepressants.
  • mGluR5 metabotropic glutamate receptor 5
  • Selective antagonists ofthe mGluR5 receptor have also been shown to exert anxiolytic and anti-depressant activity in in vivo animal models (E. Tatarczynska et al, Br. J. Pharmacol. 132(7): 1423-1430 (2001) and P.J.M. Will et al, Trends in Pharmacological Sciences 22(7):331-37 (2001)).
  • Selective antagonists ofthe mGluR5 receptor have also been shown to exert anti-Parkinson activity in vivo (K. J. Ossowska et al, Neuropharmacology 41(4):413-20 (2001) and P.J.M. Will et al, Trends in Pharmacological Sciences 22(7):331-37 (2001)).
  • the present invention encompasses compounds having the formula (I):
  • R 1 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:
  • each R 3 is independently:
  • R 6 is -phenyl, -naphthyl, -(C 3 -C 8 )cycloalkyl,-(C 14 )aryl, or -(C 5 -C 10 )heteroaryl, each of which is unsubstituted or substituted with one or more R 7 groups; each R 7 is independently -(C j -C ⁇ alkyl, -(C 2 -C 6 )alkenyl, -(C 2 -C 6 )alkynyl, -(C 3 -C 8 )cycloalkyl, -(C 5 -C 8 )cycloalkenyl, -phenyl, -(C 3 -C 5 )heterocycle, -C(halo) 3 , -CH 2 (halo), -CH(halo) 2 , -CN, -OH, -halo, -N 3 , -NO 2 , -N(R 8 )
  • each halo is independently -F, -CI, -Br or -I; n is an integer ranging from 0 to 3; and m is an integer ranging from 0 to 2.
  • the present invention encompasses compounds having the formula (la):
  • R 1 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:
  • each R 5 is independently -CN, -OH, -(C 1 -C 6 )alkyl, -(C 2 -C 6 )alkenyl, -
  • each R 7 is independently -(C 1 -C 6 )alkyl, -(C 2 -C 6 )alkenyl, -(C 2 -C 6 )alkynyl, -(C 3 -C 8 )cycloalkyl, -(C 5 -C 8 )cycloalkenyl, -phenyl, -(C 3 -C 5 )heterocycle, -C(halo) 3 , -CH 2 (halo), -CH(halo) 2 , -CN, -OH, -
  • each halo is independently -F, -CI, -Br or -I; n is an integer ranging from 0 to 3; and m is an integer ranging from 0 to 2.
  • the present invention encompasses compounds having the formula (lb):
  • R 1 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:
  • each R 3 is independently:
  • each halo is independently -F, -CI, -Br or -I; n is an integer ranging from 0 to 3; m is an integer ranging from 0 to 2; and p is an integer ranging from 0 to 4.
  • the present invention encompasses compounds having the formula (Ic):
  • R 6 is -phenyl, -naphthyl, -(C 3 -C 8 )cycloalkyl,-(C 14 )aryl, or -(C 5 -C 10 )heteroaryl, each of which is unsubstituted or substituted with one or more R 7 groups; each R 7 is independently -(C 1 -C 6 )alkyl, -(C 2 -C 6 )alkenyl, -(C 2 -C 6 )alkynyl, - (C 3 -C 8 )cycloalkyl, -(Cs-C ⁇ cycloalkenyl, -phenyl, -(C 3 -C 5 )heterocycle, -C(halo) 3 , -CH(halo) 2 , -CH 2 (halo), -CN, -OH, -halo, -N 3 , -NO 2 , -N(R 8 ) 2
  • R 11 is -hydrogen, -halo, -CH 3 , -NO 2 , -CN, -OH, -OCH 3 , -NH 2 , -C(halo) 3 , - CH(halo) 2 , or -CH 2 (halo); each R 12 is independently:
  • the present invention also encompasses compounds having the formula (fl):
  • A is -NR 4 -, -O-, or -S-;
  • R 1 is -halo, -CH 3 , -NO 2 , -CN, -OH, -OCH 3 , -NH 2 , -C(halo) 3 , -CH(halo) 2 , or -
  • each R 2 is independently:
  • each R 3 is independently:
  • R 6 is -phenyl, -naphthyl, -(C 3 -C 8 )cycloalkyl,-(C 14 )aryl, or -(C 5 -C ⁇ 0 )heteroaryl, each of which is unsubstituted or substituted with one or more R 7 groups; each R 7 is independently -(C j -C ⁇ alkyl, -(C 2 -C 6 )alkenyl, -(C 2 -C 6 )alkynyl, -(C 3 -C 8 )cycloalkyl, -(C 5 -C 8 )cycloalkenyl, -phenyl, -(C 3 -C 5 )heterocycle, -C(halo) 3 , -CH 2 (halo), -CH(halo) 2 , -CN, -OH, -halo, -N 3 , -NO 2 , -N(R 8
  • each halo is independently -F, -CI, -Br or -I; n 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 (lla):
  • R 6 is -phenyl, -naphthyl, -(C 3 -C 8 )cycloalkyl,-(C 14 )aryl, or -(C 5 -C 10 )heteroaryl, each of which is unsubstituted or substituted with one or more R 7 groups; each R 7 is independently -(C ⁇ -C 6 )alkyl, -(C 2 -C 6 )alkenyl, -(C 2 -C 6 )alkynyl, -(C 3 -C 3 )cycloalkyl, -(C 5 -C 8 )cycloalkenyl, -phenyl, -(C 3 -C 5 )heterocycle, -C(halo) 3 , -CH 2 (halo), -CH(halo) 2 , -CN, -OH, -halo, -N 3 , -NO 2 , -N(R 8 )
  • each R 12 is independently:
  • A is -NR 4 -, -O-, or -S-;
  • R 1 is -halo, -CH 3 , -NO 2 , -CN, -OH, -OCH 3 , -NH 2 , -C(halo) 3 , -CH(halo) 2 , or -
  • each R 2 is independently:
  • each R 3 is independently: (a) -halo, -CN, -OH, -NO 2 , or -NH 2 ;
  • R 4 is -(C r C 6 )alkyl, or -O-(C,-C 6 )alkyl; each R 5 is independently -CN, -OH, -(C ⁇ -C 6 )alkyl, -(C 2 -C 6 )alkenyl, -
  • R 6 is -phenyl, -naphthyl, -(C 3 -C 8 )cycloalkyl,-(C 14 )aryl, or -(C 5 -C 10 )heteroaryl, each of which is unsubstituted or substituted with one or more R 7 groups; each R 7 is independently -(C ⁇ -C 6 )alkyl, -(C 2 -C 6 )alkenyl, -(C 2 -C 6 )alkynyl,
  • R 1 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 6 is: (a), -nap
  • R 1 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:
  • each R 3 is independently:
  • each halo is independently -F, -CI, -Br or -I; n is an integer ranging from 0 to 2; m is an integer ranging from 0 to 2; and p is an integer ranging from 0 to 4.
  • the present invention also encompasses compounds having the formula (HIc):
  • R 6 is -phenyl, -naphthyl, -(C 3 -C 8 )cycloalkyl,-(C ⁇ 4 )aryl, or -(C 5 -C 10 )heteroaryl, each of which is unsubstituted or substituted with one or more R 7 groups; each R 7 is independently -(C 1 -C 6 )alkyl, -(C 2 -C 6 )alkenyl, -(C 2 -C 6 )alkynyl, -(C 3 -C 8 )cycloalkyl, -(C 5 -C 8 )cycloalkenyl, -phenyl, -(C 3 -C 5 )heterocycle, -C(halo) 3 ,
  • each R 8 is independently -H, -(C j -C ⁇ alkyl, -(C 2 -C 6 )alkenyl, -(C 2 -C 6 )alkynyl, -(C 3 -C 8 )cycloalkyl, -(C 5 -C 8 )cycloalkenyl, -phenyl, -(C 3 -C 5 )heterocycle, -
  • R u is -hydrogen, -halo, -CH 3 , -NO 2 , -CN, -OH, -OCH 3 , -NH 2 , -C(halo) 3 , -CH(halo) 2 , or -CH 2 (halo); each R 12 is independently:
  • the present invention also encompasses compounds having the formula (IV):
  • R 1 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: (a) -halo, -CN, -OH, -NO 2 , or -NH 2 ;
  • each R 3 is independently:
  • R 6 is -phenyl, -naphthyl, -(C 3 -C 8 )cycloalkyl,-(C ⁇ 4 )aryl, or -(C 5 -C )0 )heteroaryl, each of which is unsubstituted or substituted with one or more R 7 groups; each R 7 is independently -( -C ⁇ alkyl, -(C 2 -C 6 )alkenyl, -(C 2 -C 6 )alkynyl, -(C 3 -C 8 )cycloalkyl, -(C 5 -C 8 )cycloalkenyl, -phenyl, -(C 3 -C 5 )heterocycle, -C(halo) 3 , -CH(halo) 2 , -CH 2 (halo), -CN, -OH, -halo, -N 3 , -NO 2 , -N(R 8 )
  • each R !2 is independently:
  • R 1 is -hydrogen, -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:
  • R 6 is -phenyl, -naphthyl, -(C 3 -Cg)cycloalkyl,-(C 14 )aryl, or -(C 3 -C 10 )heteroaryl, each of which is unsubstituted or substituted with one or more R 7 groups; each R 7 is independently -(C j -C ⁇ alkyl, -(C 2 -C 6 )alkenyl, -(C 2 -C 6 )alkynyl, -(C 3 -C 8 )cycloalkyl, -(C 5 -C 8 )cycloalkenyl, -phenyl, -(C 3 -C 5 )heterocycle, -C(halo) 3 , -CH 2 (halo), -CH(halo) 2 , -CN, -OH, -halo, -N 3 , -NO 2 , -N(R 8 ) 2
  • each halo is independently -F, -CI, -Br or -I; and m is an integer ranging from 0 to 2.
  • the present invention encompasses compounds having the formula (VI):
  • R 1 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 , or -NH 2 ; (b) -(C 1 -C ]0 )alkyl, -(C 2 -C 10 )alkenyl, -(C 2 -C 10 )alkynyl, -(C 3 -C 10 )cycloalkyl,
  • each R 4 is independently -(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 , or CH 2 (halo); each R 5 is independently -CN, -OH, -(C j -C ⁇ alkyl, -(C 2 -C 6 )alkenyl, - (C 2 -C 6 )
  • R 1 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:
  • each R 4 is independently -(C,-C 6 )alkyl, -(C 2 -C 6 )alkenyl, -(C 2 -C 6 )alkynyl,
  • each R 5 is independently -CN, -OH, -(C 1 -C 6 )alkyl, -(C 2 -C 6 )alkenyl, -
  • each R 6 is independently -(C ⁇ -C 6 )alkyl, -(C 2 -C 6 )alkenyl, -(C 2 -C 6 )alkynyl,
  • each R 7 is independently -H, -( -C ⁇ alkyl, -(C 2 -C 6 )alkenyl, -(C 2 -C 6 )alkynyl,
  • each R 8 is independently -(C j -C ⁇ alkyl, -(C 2 -C 6 )alkenyl, -(C 2 -C 6 )alkynyl,
  • a compound of formula (I), (la), (lb), (Ic), (H), (Ha), (HI), (Hla), (HTb), (IHc), (IV), (IVa), (V), (VI), or (VH), or a pharmaceutically 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 Cyanoiminopiperazine Compound and a pharmaceutically acceptable carrier or excipient.
  • the compositions are useful for treating or
  • the invention further relates to methods for treating a Condition, comprising administering to an animal in need thereof an effective amount of a Cyanoiminopiperazine Compound.
  • the invention further relates to methods for preventing a Condition, comprising administering to an animal in need thereof an effective amount of a Cyanoiminopiperazine Compound.
  • the invention still further relates to methods for inhibiting Vanilloid Receptor 1 ("VRl") function in a cell, comprising contacting a cell capable of expressing VRl with an effective amount of a Cyanoiminopiperazine Compound.
  • the invention still further relates to methods for inhibiting mGluR5 function in a cell, comprising contacting a cell capable of expressing mGluR5 with an effective amount of a Cyanoiminopiperazine 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 Cyanoiminopiperazine Compound.
  • mGluRl metabotropic glutamate receptor 1
  • the invention still further relates to a method for preparing a composition, comprising the step of admixing a Cyanoiminopiperazine 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 Cyanoiminopiperazine Compound.
  • n 3.
  • n 0.
  • n is 1. In another embodiment, m is 2.
  • A is -N((C r C 6 )alkyl)-.
  • A is -N(O(C,-C 6 )alkyl)-. h another embodiment, A is -O-.
  • A is -S-.
  • R 1 is halo.
  • R 1 is -CI.
  • R 1 is -Br.
  • R 1 is -I.
  • R 1 is -F. In another embodiment, R 1 is -CH 3 .
  • n is 1 and R 2 is -halo, -CN, -OH, -NO 2 , or -NH 2 .
  • n is 1 and R 2 is -(C j -C 10 )alkyl, -(C 2 -C ]0 )alkenyl, -(C 2 - C 10 )alkynyl, -(C 3 -C 10 )cycloalkyl, -(C 8 -C, 4 )bicycloalkyl, -(Cg-C 14 )tricycloalkyl, -(C 5 - C 10 )cycloalkenyl,-(C 8 -C 14 )bicycloalkenyl, -(Cg-C I4 )tricycloalkenyl, -(C 3 -C 7 )heterocycle, or - (C 7 -C ⁇ 0 )bicycloheterocycle, each of which is unsubstituted or substituted with one or more R 5 groups.
  • n is 1 and R 2 is -phenyl, -naphthyl, -(C 14 )aryl, or -(C 5 - C 10 )heteroaryl, each of which is unsubstituted or substituted with one or more R 7 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 10 )alkyl, -(C 2 -C 10 )alkenyl, -(C 2 -
  • R 6 is -phenyl, -naphthyl, -(C 3 -Cg)cycloalkyl,-(C 14 )aryl, or -(C 5 -C 10 )heteroaryl, each of which is unsubstituted or substituted with one or more R 7 groups.
  • R 6 is -phenyl.
  • 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.
  • m is 1, R 3 is -CH 3 , and the carbon atom to which the - R 3 is attached is in the (S)-configuration.
  • n and m are 0 and R 6 is -phenyl.
  • n is 0, m is 1, R 3 is methyl, and R 6 is phenyl.
  • the -phenyl is substituted with a -(C C 6 ) alkyl group, i another embodiment, the -(C r C 6 ) alkyl group is substituted at the 4-position ofthe -phenyl.
  • the -(C r C 6 ) alkyl group is a t-butyl group substituted at 4-position ofthe -phenyl.
  • the -(C r C 6 ) alkyl group is an w ⁇ -propyl group substituted at the 4-position ofthe -phenyl.
  • R 1 is -CF 3 or -CHF 2 .
  • n and m are 0 and R 6 is -phenyl substituted at its 4- position with a -CF 3 group.
  • n and m are 0, R 1 is -halo or methyl; and R 6 is -phenyl.
  • -halo is -CI.
  • the -phenyl is substituted with a -(C r C 6 ) alkyl group.
  • the -(C r C 6 ) alkyl group is substituted at the 4-position ofthe -phenyl.
  • the -(C r C 6 ) alkyl group is a t-butyl group or an tso-propyl group substituted at the 4-position ofthe -phenyl.
  • n and m are 0, R 1 is -halo or methyl; and R 6 is -phenyl substituted with -CF 3 .
  • -halo is -CI.
  • the -CF 3 is substituted at the 4-position ofthe -phenyl.
  • -halo is -CI and the -CF 3 is substituted at the 4-position ofthe -phenyl.
  • R 1 , R 2 , R 3 , R 6 , n, and m are defined above for the Cyanoiminopiperazine Compounds of formula (Ia).
  • R 1 is -halo.
  • R 1 is -CI.
  • R 1 is -Br.
  • R 1 is -I. In another embodiment, R 1 is -F. hi another embodiment, R 1 is -CH 3 .
  • n is 1 and R 2 is -halo, -CN, -OH, -NO 2 , or -NH 2 .
  • n is 1 and R 2 is -(C j -C 10 )alkyl, -(C 2 -C 10 )alkenyl, -(C 2 -
  • n is 1 and R 2 is -phenyl, -naphthyl, -(C 14 )aryl, or -(C 5 -
  • n is 1 and R 3 is -halo, -CN, -OH, -NO 2 , or -NH 2 .
  • m is 1 and R 3 is -(C 2 -C 10 )alkenyl, -(C 2 - C !0 )alkynyl, -(C 3 -C 10 )cycloalkyl, -(C 8 -C 14 )bicycloalkyl, -(C 8 -C 14 )tricycloalkyl, -(C 5 - C 10 )cycloalkenyl,-(C 8 -C 14 )bicycloalkenyl, -(C 8 -C l4 )tricycloalkenyl, -(C 3 -C 7 )heterocycle, or - (C 7 -C 10 )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 14 )aryl or -(C 5 - C 10 )heteroaryl, each of which is unsubstituted or substituted with one or more R 7 groups.
  • m is 1 and R 3 is -CH 3 .
  • m is 1
  • R 3 is -CH 3
  • the carbon atom to which the - R 3 is attached is in the (Reconfiguration.
  • m is 1, R 3 is -CH 3 , and the carbon atom to which the - R 3 is attached is in the (S)-configuration.
  • R 6 is -naphthyl, -(C 14 )aryl, or -(C 3 -C 8 )cycloalkyl each of which is unsubstituted or substituted with one or more R 7 groups.
  • R 6 is pyridyl, furyl, benzofuranyl, thiophenyl, benzothiophenyl, quinolinyl, indolyl, oxazolyl, benzoxazolyl, imidazolyl, benzimidazolyl, thiazolyl, benzothiazolyl, isoxazolyl, pyrazolyl, isothiazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, thiadiazolyl, triazinyl, cinnolinyl, phthalazinyl, or quinazolinyl, each of which is substituted with one or more R 7 groups.
  • R 6 is pyridyl, pyrazinyl, py ⁇ midinyl, pyridazinyl, or thiadiazolyl.
  • the present invention encompasses compounds having the formula (lb):
  • n is 1. In another embodiment, n is 2. In another embodiment, m is 0. In another embodiment m is 1. In another embodiment, m is 2.
  • R 1 is -halo, hi another embodiment, R 1 is -CI. In another embodiment, R 1 is -Br. In another embodiment, R 1 is -I. In another embodiment, R 1 is -F.
  • R is -CH 3 hi one embodiment, n is 1 and R 2 is - ⁇ h,a n lo, - rC>N ⁇ , - ⁇ Nv ⁇ rO 2 , or . -N H H iJ2
  • n is 1 and R is -(C r C ⁇ 0 )alkyl, -(C 2 -C 10 )alkenyl, -(C 2 C 10 )alkynyl. -(C 3 -C 10 )cycloalkyl, -(C 8 -C 14 )bicycloalkyl, -(C 8 -C, 4 )tricycloalkyl, -(C 5 - C 10 )cycloalkenyl, -(C 8 -C 14 )bicycloalkenyl, -(C 8 -C 14 )tricycloalkenyl, -(C 3 -C 7 )heterocycle, or -(C 7 -C 10 )bicycloheterocycle, each of which is unsubstituted or substituted with one or more R 5 groups.
  • n 1 and R 2 is -phenyl, -naphthyl, -(C 14 )aryl, or -(C 5 -C 10 )heteroaryl, each of which is unsubstituted or substituted with one or more R 7 groups.
  • m is land R 3 is -halo, -CN, -OH, -NO 2 , or
  • m is 1 and R 3 is-(C r C 10 )alkyl, -(C 2 -C 10 )alkenyl, -(C 2 -C 10 )alkynyl, -(C 3 -C 10 )cycloalkyl, -(C 8 -C 14 )bicycloalkyl, -(C 8 -C 14 )tricycloalkyl, -(C 5 -C 10 )cycloalkenyl,-(C 8 -C 14 )bicycloalkenyl, -(C 8 -C 14 )tricycloalkenyl, -(C 3 -C 7 )heterocycle, or -(C 7 -C 10 )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 14 )aryl or -(C 5 -C, 0 )heteroaryl, each of which is unsubstituted or substituted with one or more R 7 groups.
  • n 1 and R 3 is -CH 3 . 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 (Reconfiguration. hi 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 encompasses compounds having the formula (Ic):
  • m is 0.
  • n is 1. In another embodiment, m is 2.
  • q is 0.
  • q is 1. hi another embodiment, q is 2. hi another embodiment, q is 3. h another embodiment, A is -N((C r C 6 )alkyl)-. hi another embodiment, A is -N(O(C,-C 6 )alkyl)-.
  • A is -O-.
  • A is -S-.
  • m is 1 and R 3 is -halo, -CN, -OH, -NO 2 , or -NH 2 ; or hi another embodiment, m is 1 and R 3 is -(C j -C 10 )alkyl, -(C 2 -C 10 )alkenyl, -(C 2 -
  • 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.
  • R 6 is -phenyl, -naphthyl, -(C 3 -C 8 )cycloalkyl,-(C 14 )aryl, or -(C 5 -C 10 )heteroaryl, each of which is unsubstituted or substituted with one or more R 7 groups.
  • R 6 is -phenyl.
  • R ⁇ is -hydrogen, -halo, -CH 3 , -NO 2 , -CN, -OH, - OCH 3 , -NH 2 , -C(halo) 3 , -CH(halo) 2 , or -CH 2 (halo).
  • R 11 is -halo
  • R 11 is -CI. In another embodiment, R ⁇ is -Br.
  • R ⁇ is -F.
  • R 11 is -I.
  • R 11 is -CH 3 .
  • q is 1 and R 12 is -halo, -CN, -OH, -NO 2 , or -NH 2 .
  • q is 1 and R 12 is -(C r C 10 )alkyl, -(C 2 -C 10 )alkenyl, -(C 2 -
  • the present invention also encompasses compounds of formula (II)
  • n 0.
  • n 1.
  • n is 2.
  • n 0.
  • n is 1. In another embodiment, m is 2.
  • R 1 is -halo
  • R 1 is -CI.
  • R 1 is -Br.
  • R 1 is -I. In another embodiment, R 1 is -F.
  • R 1 is -CH 3 .
  • A is -NH-.
  • A is -N((C,-C 6 )alkyl)-.
  • A is -N(O(C 1 -C 6 )alkyl)-. In another embodiment, A is -O-.
  • A is -S-.
  • n is 1 and R 2 is -halo, -CN, -OH, -NO 2 , or -NH 2 .
  • n is 1 and R 2 is -(C 1 -C 10 )alkyl, -(C 2 -C 10 )alkenyl, -(C 2 - C 10 )alkynyl, -(C 3 -C 10 )cycloalkyl, -(C 8 -C, 4 )bicycloalkyl, -(C 8 -C 14 )tricycloalkyl, -(C 5 - C 10 )cycloalkenyl,-(C 8 -C ⁇ 4 )bicycloalkenyl, -(C 8 -C ]4 )tricycloalkenyl, -(C 3 -C 7 )heterocycle, or - (C 7 -C 10 )bicycloheterocycle, each of which is unsubstituted or substituted with one or more R 5 groups.
  • n is 1 and R 2 is -phenyl, -naphthyl, -(C 14 )aryl, or -(C 5 - C t0 )heteroaryl, each of which is unsubstituted or substituted with one or more R 7 groups.
  • m is 1 and R 3 is -halo, -CN, -OH, -NO 2 , or -NH 2 .
  • m is 1 and R 3 is -(C 1 -C 10 )alkyl, -(C 2 -C 10 )alkenyl, -(C 2 - C 10 )alkynyl, -(C 3 -C 10 )cycloalkyl, -(C 8 -C ⁇ 4 )bicycloalkyl, -(C 8 -C 14 )tricycloalkyl, -(C 5 - C 10 )cycloalkeny],-(C 8 -C 14 )bicycloalkenyl, -(C 8 -C 14 )tricycloalkenyl, -(C 3 -C 7 )heterocycle, or - (C 7 -C 10 )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 14 )aryl or -(C 5 - C 10 )heteroaryl, each of which is unsubstituted or substituted with one or more R 7 groups.
  • m is 1 and R 3 is -CH 3 .
  • m is 1
  • R 3 is -CH 3
  • the carbon atom to which the - R 3 is attached is in the (Reconfiguration.
  • m is 1
  • R 3 is -CH 3
  • the carbon atom to which the - R 3 is attached is in the (S)-configuration.
  • R 6 is -phenyl, -naphthyl, -(C 3 -C 8 )cycloalkyl,-(C 14 )aryl, or -(C 5 -C 10 )heteroaryl, each of which is unsubstituted or substituted with one or more R 7 groups.
  • R 6 is -phenyl.
  • n and m are 0 and R 6 is -phenyl.
  • n is 0, m is 1, R 3 is methyl, and R 6 is phenyl.
  • the -phenyl is substituted with a -(C r C 6 ) alkyl group, hi another embodiment, the -(C,-C 6 ) alkyl group is substituted at the 4-position ofthe -phenyl. In another embodiment, the -(C r C 6 ) alkyl group is a t-butyl group substituted at 4-position ofthe -phenyl. In another embodiment, the -(C j - C 6 ) alkyl group is an is ⁇ -propyl group substituted at the 4-position ofthe -phenyl.
  • R 1 is -CF 3 or -CHF 2 .
  • n and m are 0 and R 6 is -phenyl substituted at its 4- position with a -CF 3 group.
  • n and m are 0, R 1 is -halo or methyl; and R 6 is -phenyl.
  • -halo is -CI.
  • the -phenyl is substituted with a -(C r C 6 ) alkyl group.
  • the -(C,-C 6 ) alkyl group is substituted at the 4-position ofthe -phenyl.
  • the -(C ] -C 6 ) alkyl group is a t-butyl group or an wo-propyl group substituted at the 4-position ofthe -phenyl.
  • n and m are 0, R 1 is -halo or methyl; and R 6 is -phenyl substituted with -CF 3 .
  • -halo is -CI.
  • the -CF 3 is substituted at the 4-position ofthe -phenyl.
  • -halo is -CI and the -CF 3 is substituted at the 4-position ofthe -phenyl.
  • the present invention also encompasses compounds having the formula (IIa):
  • q is 0. In another embodiment q is 1.
  • q is 2.
  • m is 0.
  • n 1
  • m is 2. In another embodiment, A is -N((C ! -C 6 )alkyl)-.
  • A is -N(O(C r C 6 )alkyl)-.
  • A is -O-.
  • A is -S-.
  • m is 1 and R 3 is -halo, -CN, -OH, -NO 2 , or -NH 2 .
  • m is 1 and R 3 is -(C ⁇ -C 10 )alkyl, -(C 2 -C 10 )alkenyl, -(C 2 -
  • (C 7 -C 10 )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 14 )aryl or -(C 5 -
  • C 10 C 10 )heteroaryl, each of which is unsubstituted or substituted with one or more R 7 groups.
  • m is 1 and R 3 is -CH 3 .
  • m is 1
  • R 3 is -CH 3
  • the carbon atom to which the - R 3 is attached is in the (Reconfiguration.
  • m is 1
  • R 3 is -CH 3
  • the carbon atom to which the - R 3 is attached is in the (Reconfiguration.
  • R 6 is -phenyl, -naphthyl, -(C 3 -C 8 )cycloalkyl,-(C ]4 )aryl, or -(C 5 -C 10 )heteroaryl, each of which is unsubstituted or substituted with one or more R 7 groups.
  • R 6 is -phenyl.
  • R 11 is -hydrogen, -halo, -CH 3 , -NO 2 , -CN, -OH, -
  • R 11 is -halo
  • R 11 is -CI.
  • R 11 is -Br. In another embodiment, R n is -F.
  • R 11 is -I.
  • R n is -CH 3 .
  • q is 1 and R 12 is -halo, -CN, -OH, -NO 2 , or -NH 2 .
  • R 12 is -(C r C 10 )alkyl, -(C 2 -C 10 )alkenyl, -(C 2 - C 10 )alkynyl, -(C 3 -C 10 )cycloalkyl, -(C 8 -C 14 )bicycloalkyl, -(C 8 -C 14 )tricycloalkyl, -(C 5 -
  • q is 1 and R 12 is -phenyl, -naphthyl, -(C 14 )aryl, or -(C 5 - C 10 )heteroaryl, each of which is unsubstituted or substituted with one or more R 7 groups.
  • the present invention also encompasses compounds of formula (HT)
  • n 0.
  • n 1
  • n is 2. In one embodiment, m is 0.
  • m is 1.
  • n is 2.
  • A is -N((C j -C 6 )alkyl)-.
  • A is -N(O(C r C 6 )alkyl)-. Li one embodiment, A is -O-.
  • A is -S-. .
  • R 1 is -halo
  • R 1 is -CI.
  • R 1 is -Br. In one embodiment, R 1 is -I.
  • R 1 is -F.
  • R 1 is -CH ⁇ 3 3.'
  • n is 1 and R 2 . is -halo, -CN, -OH, -NO 2 , or -NH 2 .
  • n is 1 and R 2 is -(C 1 -C 10 )alkyl, -(C 2 -C 10 )alkenyl, -(C 2 - C ]0 )alkynyl, -(C 3 -C 10 )cycloalkyl, -(C 8 -C 14 )bicycloalkyl, -(C 8 -C l4 )tricycloalkyl, -(C 5 -
  • n is 1 and R 2 is -phenyl, -naphthyl, -(C ]4 )aryl, or -(C 5 - Ci 0 )heteroaryl, each of which is unsubstituted or substituted with one or more R 7 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 10 )alkyl, -(C 2 -C ⁇ 0 )alkenyl, -(C 2 - C 10 )alkynyl, -(C 3 -C 10 )cycloalkyl, -(C 8 -C ⁇ 4 )bicycloalkyl, -(C 8 -C 14 )tricycloalkyl, -(C 5 - Ci 0 )cycloalkenyl,-(C 8 -C 14 )bicycloalkenyl, -(C 8 -C 14 )tricycloalkenyl, -(C 3 -C 7 )heterocycle, or - (C 7 -C I0 )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 14 )aryl or -(C 5 - C 10 )heteroaryl, each of which is unsubstituted or substituted with one or more R 7 groups.
  • m is 1 and R 3 is -CH 3 .
  • m is 1
  • R 3 is -CH 3
  • the carbon atom to which the - R 3 is attached is in the (Reconfiguration.
  • m is 1
  • R 3 is -CH 3
  • the carbon atom to which the - R 3 is attached is in the (S)-configuration.
  • R 6 is -phenyl, -naphthyl, -(C 3 -C 8 )cycloalkyl,-(C 14 )aryl, or - (C 5 -C 10 )heteroaryl, each of which is unsubstituted or substituted with one or more R 7 groups. In one embodiment, R 6 is -phenyl.
  • n and m are 0 and R 6 is -phenyl. In another embodiment, n is 0, m is 1, R 3 is methyl, and R 6 is phenyl. In another embodiment, the -phenyl is substituted with a -(C r C 6 ) alkyl group, hi another embodiment, the -(C r C 6 ) alkyl group is substituted at the 4-position ofthe -phenyl. In another embodiment, the -( - ) alkyl group is a t-butyl group substituted at 4-position ofthe -phenyl. In another embodiment, the -(C r C 6 ) alkyl group is an zso-propyl group substituted at the 4-position ofthe -phenyl.
  • R 1 is -CF 3 or -CHF 2 .
  • n and m are 0 and R 6 is -phenyl substituted at its 4- position with a -CF 3 group.
  • n and m are 0, R 1 is -halo or methyl; and R 6 is -phenyl.
  • -halo is -CI.
  • the -phenyl is substituted with a -(C,-C 6 ) alkyl group.
  • the -(C r C 6 ) alkyl group is substituted at the 4-position ofthe -phenyl.
  • the -(C,-C 6 ) alkyl group is a t-butyl group or an ⁇ o-propyl group substituted at the 4-position ofthe -phenyl.
  • n and m are 0, R 1 is -halo or methyl; and R 6 is -phenyl substituted with -CF 3 .
  • -halo is -CI.
  • the -CF 3 is substituted at the 4-position ofthe -phenyl.
  • -halo is -CI and the -CF 3 is substituted at the 4-position ofthe -phenyl.
  • the present invention also encompasses compounds of formula (Dla)
  • n 0.
  • n is 1. ⁇ In another embodiment, n is 2. h another embodiment, m is 0.
  • n 1
  • m is 2. hi another embodiment, R 1 is -halo. In another embodiment, R 1 is -CI.
  • R 1 is -Br. hi another embodiment, R 1 is -I. hi another embodiment, R 1 is -F. hi another embodiment, R 1 is -CH 3 .
  • n is 1 and R 2 is -halo, -CN, -OH, -NO 2 , or -NH 2 ;
  • n is 1 and R 2 is -(C r C 10 )alkyl, -(C 2 -C ⁇ 0 )alkenyl, -(C 2 -
  • n is 1 and R 2 is -phenyl, -naphthyl, -(C ⁇ aryl, or -(C 5 -
  • m is 1 and R 3 is -halo, -CN, -OH, -NO 2 , or -NH 2 ; or
  • m is 1 and R 3 is -(C r C 10 )alkyl, -(C 2 -C 10 )alkenyl, -(C 2 - C 10 )alkynyl, -(C 3 -C 10 )cycloalkyl, -(C 8 -C 14 )bicycloalkyl, -(C 8 -C 14 )tricycloalkyl, -(C 5 - C ⁇ 0 )cycloalkenyl,-(C 8 -C 14 )bicycloalkenyl, -(C 8 -C ⁇ 4 )tricycloalkenyl, -(C 3 -C 7 )heterocycle, or - (C 7 -C 10 )bicycloheterocycle, each of which is unsubstituted or substituted with one or more R 5 groups; or
  • m is 1 and R 3 is -phenyl, -naphthyl, -(C 14 )aryl or -(C 5 - C )0 )heteroaryl, each of which is unsubstituted or substituted with one or more R 7 groups.
  • m is 1 and R 3 is -CH 3 .
  • m is 1
  • R 3 is -CH 3
  • the carbon atom to which the - R 3 is attached is in the (Reconfiguration.
  • m is 1, R 3 is -CH 3 , and the carbon atom to which the - R J is attached is in the (S)-configuration.
  • R 6 is -naphthyl, -(C I4 )aryl, or -(C 3 -C 8 )cycloalkyl each of which is unsubstituted or substituted with one or more R 7 groups.
  • R 6 is pyridyl, furyl, benzofuranyl, thiophenyl, benzothiophenyl, quinolinyl, indolyl, oxazolyl, benzoxazolyl, imidazolyl, benzimidazolyl, thiazolyl, benzothiazolyl, isoxazolyl, pyrazolyl, isothiazolyl, pyridazinyl, pyrimidinyl. pyrazinyl, thiadiazolyl, triazinyl, cinnolinyl, phthalazinyl, or quinazolinyl, each of which is substituted with one or more R 7 groups.
  • the present invention encompasses compounds having the formula (nib):
  • n 0.
  • n is 1. In another embodiment, n is 2.
  • m is 0.
  • n 1
  • n 2
  • p is 0. In another embodiment, p is 1.
  • p is 2.
  • p is 3.
  • p is 4.
  • R 1 is -halo. In another embodiment, R 1 is -CI.
  • R 1 is -Br. In another embodiment, R 1 is -I. In another embodiment, R 1 is -F. In another embodiment, R 1 is -CH 3 .
  • n is 1 and R 2 is -halo, -CN, -OH, -NO 2 , or -NH 2 .
  • n is 1 and R 2 is -(C r C 10 )alkyl, -(C 2 -C 10 )alkenyl, -(C 2 -
  • n is 1 and R 2 is -phenyl, -naphthyl, -(C 14 )aryl, or -(C 5 -
  • Ci 0 heteroaryl, each of which is unsubstituted or substituted with one or more R 7 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 10 )alkyl, -(C 2 -C ]0 )alkenyl, -(C 2 - C 10 )alkynyl, -(C 3 -C 10 )cycloalkyl, -(C 8 -C 14 )bicycloalkyl, -(C 5 - C 10 )cycloalkenyl,-(Cg-C 14 )bicycloalkenyl, -(C 8 -C 14 )tricycloalkenyl, -(C 3 -C 7 )heterocycle, or - (C 7 -C, 0 )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 14 )aryl or -(C 5 - C, G )heteroaryl, each of which is unsubstituted or substituted with one or more R 7 groups.
  • m is 1 and R 3 is -CH 3 .
  • m is 1
  • R 3 is -CH 3
  • the carbon atom to which the - R 3 is attached is in the (Reconfiguration.
  • m is 1
  • R 3 is -CH 3
  • the carbon atom to which the - R 3 is attached is in the (S)-configuration.
  • m is 1. In another embodiment, m is 2. In another embodiment, A is -N ⁇ C j -C ⁇ alkyi)-. hi another embodiment, A is -N(O(C r C 6 )alkyl)-. In another embodiment, A is -O-. lh another embodiment, A is -S-.
  • m is 1 and R 3 is -halo, -CN, -OH, -NO 2 , or -NH 2 .
  • m is 1 and R 3 is -(C r C 10 )alkyl, -(C 2 -C 10 )alkenyl, -(C 2 - Ci 0 )alkynyl, -(C 3 -C 10 )cycloalkyl, -(C 8 -C 14 )tricycloalkyl, -(C 5 - C ]0 )cycloalkenyl,-(C 8 -C 14 )bicycloalkenyl, -(Cg-C j4 )tricycloalkenyl, -(C 3 -C 7 )heterocycle, or - (C 7 -C 10 )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 14 )aryl or -(C 5 - C 10 )heteroaryl, each of which is unsubstituted or substituted with one or more R 7 groups.
  • 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.
  • R 6 is -phenyl, -naphthyl, -(C 3 -C 8 )cycloalkyl,-(C ⁇ 4 )aryl, or -(C 5 -C 10 )heteroaryl, each of which is unsubstituted or substituted with one or more R 7 groups.
  • R 6 is -phenyl.
  • R ⁇ is -hydrogen, -halo, -CH 3 , -NO 2 , -CN, -OH, - OCFI 3 , -NH 2 , -C(halo) 3 , -CH(halo) 2 , or -CH 2 (halo).
  • R n is -halo
  • R n is -CI.
  • R 11 is -Br.
  • R n is -F. In another embodiment, R 11 is -I.
  • R 11 is -CH 3 .
  • q is 1 and R 12 is -halo, -CN, -OH, -NO 2 , or -NH 2 .
  • q is 1 and R 12 is -(C r C ⁇ 0 )alkyl, -(C 2 -C, 0 )alkenyl, -(C 2 - C ]0 )alkynyl, -(C 3 -C 10 )cycloalkyl, -(C 8 -C 14 )bicycloalkyl, -(C 8 -C 14 )tricycloalkyl, -(C 5 - C ]0 )cycloalkenyl,-(C 8 -C 14 )bicycloalkenyl, -(C 8 -C 14 )tricycloalkenyl, -(C 3 -C 7 )heterocycle, or - (C 7 -C I0 )bicycloheterocycle, each of which is
  • q is 1 and R 12 is -phenyl, -naphthyl, -(C I4 )aryl, or -(C 5 - C 10 )heteroaryl, each of which is unsubstituted or substituted with one or more R 7 groups.
  • the present invention also encompasses compounds of formula (IV):
  • n 0.
  • n 1
  • n is 2. In another embodiment, n is 0.
  • n 1
  • n 2
  • A is -NH-.
  • A is -N((Ci-C 6 )alkyl)-. In another embodiment, A is -N(O(C r C 6 )alkyl)-.
  • A is -O-.
  • A is -S-.
  • R 1 is -halo
  • R 1 is -CI. In another embodiment, R 1 is -Br.
  • R 1 is -I.
  • R 1 is -F.
  • R 1 is -CH 3 .
  • n is one and R ? is -halo, -CN, -OH, -NO 2 , or -NH 2 ; In another embodiment, n is 1 and R 9 ' is -(C r C, 0 )alkyl, -(C 2 -C 10 )alkenyl, -(C 2 -
  • n is 1 and R 2 is -phenyl, -naphthyl, -(C ⁇ 4 )aryl, or -(C 5 - C 10 )heteroaryl, each of which is unsubstituted or substituted with one or more R 7 groups;
  • m is 1 and R 3 is -halo, -CN, -OH, -NO 2 , or -NH 2 .
  • m is 1 and R 3 is -(C r C 10 )alkyl, -(C 2 -C 10 )alkenyl, -(C 2 - C 10 )alkynyl, -(C 3 -C 10 )cycloalkyl, -(C 8 -C 14 )bicycloalkyl, -(C 8 -C ⁇ 4 )tricycloalkyl, -(C 5 - C 10 )cycloalkenyl,-(C 8 -C 14 )bicycloalkenyl, -(C 8 -C 14 )tricycloalkenyl, -(C 3 -C 7 )heterocycle, or - (C 7 -C ⁇ 0 )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 14 )aryl or -(C 5 - C ]0 )heteroaryl, each of which is unsubstituted or substituted with one or more R 7 groups.
  • n 1 and R 3 is -CH 3 . 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 (Reconfiguration.
  • m is 1
  • R 3 is -CH 3
  • the carbon atom to which the - R 3 is attached is in the (S)-configuration.
  • R 6 is -phenyl, -naphthyl, -(C 3 -C 8 )cycloalkyl,-(C 14 )aryl, or -(C 5 -'C 10 )heteroaryl, each of which is unsubstituted or substituted with one or more R 7 groups.
  • R 6 is -phenyl.
  • n and m are 0 and R 6 is -phenyl. In another embodiment, n is 0, m is 1, R 3 is methyl, and R 6 is phenyl.
  • the -phenyl is substituted with a -(C r C 6 ) alkyl group, hi another embodiment, the -(C r C 6 ) alkyl group is substituted at the 4-position ofthe -phenyl.
  • the -(C r C 6 ) alkyl group is a t-butyl group substituted at 4-position ofthe -phenyl.
  • the -(C r C 6 ) alkyl group is an iso-p ⁇ opyl group substituted at the 4-position ofthe -phenyl.
  • R 1 is -CF 3 or -CHF 2 .
  • n and m are 0 and R 6 is -phenyl substituted at its 4- position with a -CF 3 group.
  • n and m are 0, R 1 is -halo or methyl; and R 6 is -phenyl.
  • -halo is -CI.
  • the -phenyl is substituted with a -(C r C 6 ) alkyl group, hi another embodiment, the -(C r C 6 ) alkyl group is substituted at the 4-position ofthe -phenyl.
  • the -(C C 6 ) alkyl group is a t-butyl group or an wo-propyl group substituted at the 4-position ofthe -phenyl.
  • n and m are 0, R 1 is -halo or methyl; and R 6 is -phenyl substituted with -CF 3 .
  • -halo is -CI.
  • the -CF 3 is substituted at the 4-position ofthe -phenyl.
  • -halo is -CI and the -CF 3 is substituted at the 4-position ofthe -phenyl.
  • A is -N(O(C r C 6 )alkyl)-.
  • A is -O-. h another embodiment, A is -S-. In another embodiment, m is 1 and R 3 is -halo, -CN, -OH, -NO 2 , or -NH 2 .
  • m is 1 and R 3 is -(C r C 10 )alkyl, -(C 2 -C ⁇ 0 )alkenyl, -(C 2 - C ⁇ o)alkynyl, -(C 3 -C 10 )cycloalkyl, -(C 8 -C 14 )bicycloalkyl, -(C 8 -C 14 )tricycloalkyl, -(C 5 - C 1 o)cycloalkenyl,-(C 8 -C ]4 )bicycloalkenyl, -(C 8 -C ]4 )tricycloalkenyl, -(C 3 -C 7 )heterocycle, or - (C 7 -C ⁇ 0 )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 14 )aryl or -(C 5 - C, 0 )heteroaryl, each of which is unsubstituted or substituted with one or more R 7 groups.
  • m is 1 and R 3 is -CH 3 .
  • m is 1
  • R 3 is -CH 3
  • the carbon atom to which the - R 3 is attached is in the (Reconfiguration.
  • m is 1
  • R 3 is -CH 3
  • the carbon atom to which the - R 3 is attached is in the (S)-configuration.
  • R 6 is -phenyl, -naphthyl, -(C 3 -C 8 )cycloalkyl,-(C 14 )aryl, or -(C 5 -C 10 )heteroaryl, each of which is unsubstituted or substituted with one or more R 7 groups.
  • R 6 is -phenyl.
  • R 11 is -hydrogen, -halo, -CH 3 , -NO 2 , -CN, -OH, - OCH 3 , -NH 2 , -C(halo) 3 , -CH(halo) 2 , or -CH 2 (halo).
  • R 11 is -halo. In another embodiment, R u is -CI.
  • R 11 is -Br.
  • R n is -F.
  • R ⁇ is -I. h another embodiment, R ⁇ is -CH 3 .
  • R 12 is -halo, -CN, -OH, -NO 2 , or -NH 2 .
  • R 12 is -(C 1 -C 10 )alkyl, -(C 2 -C 10 )alkenyl, -(C 2 - C 10 )alkynyl, -(C 3 -C 10 )cycloalkyl, -(C 8 -Ci 4 )tricycloalkyl, -(C 5 - C 10 )cycloalkenyl,-(C 8 -C 14 )bicycloalkenyl, -(C 3 -C 7 )heterocycle, or - (C 7 -C ]0 )bicycloheterocycle, each of which is unsubstituted or substituted with one or more R 5 groups.
  • R 12 is -phenyl, -naphthyl, -(C 14 )aryl, or -(C 5 - C 10 )heteroaryl, each of which is unsubstituted or substituted with one or more R 7 groups.
  • A is -O-.
  • A is -S-.
  • R ! is -hydrogen.
  • R 1 is -halo, -CH 3 , -NO 2 , -CN, -OH, -OCH 3 , -NH 2 , - C(halo) 3 , -CH(halo) 2 , or -CH 2 (halo).
  • R 1 is -halo
  • R 1 is -CI. In another embodiment, R 1 is -Br.
  • R 1 is -I.
  • R 1 is -F.
  • R 1 is -CH 3 .
  • m is 1 and R 3 is -halo, -CN, -OH, -NO 2 , or -NH 2 .
  • m is 1 and R 3 is -(C r C 10 )alkyl, -(C 2 -C 10 )alkenyl, -(C 2 -
  • C 10 C 10 )heteroaryl, each of which is unsubstituted or substituted with one or more R 7 groups.
  • 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.
  • R 6 is -phenyl, -naphthyl, -(C 3 -C 8 )cycloalkyl,-(C, 4 )aryl, or -(C 5 -C 10 )heteroaryl, each of which is unsubstituted or substituted with one or more R 7 groups.
  • R 6 is -phenyl.
  • m is 0 and R 6 is -phenyl.
  • m is 1, R 3 is methyl, and R 6 is phenyl.
  • the -phenyl is substituted with a -(C r C 6 ) alkyl group.
  • the -(C r C 6 ) alkyl group is substituted at the 4- position ofthe -phenyl.
  • the -(C,-C 6 ) alkyl group is a t-butyl group substituted at 4-position ofthe -phenyl.
  • the -(C r C 6 ) alkyl group is an iso-propyl group substituted at the 4-position ofthe -phenyl.
  • R 1 is -CF 3 or -CHF 2 .
  • m is 0 and R 6 is -phenyl substituted at its 4-position with a -CF 3 group.
  • m is 0, R 1 is -halo or methyl; and R 6 is -phenyl.
  • -halo is -CI.
  • the -phenyl is substituted with a -(C r C 6 ) alkyl group.
  • the -(C r C 6 ) alkyl group is substituted at the 4-position ofthe -phenyl.
  • the -(C,-C 6 ) alkyl group is a t-butyl group or an ⁇ o-propyl group substituted at the 4-position ofthe -phenyl.
  • m is 0, R 1 is -halo or methyl; and R 6 is -phenyl sxxbstituted with -CF 3 .
  • -halo is -CI.
  • the -CF 3 is substituted at the 4-position ofthe -phenyl.
  • -halo is -CI and the -CF 3 is substituted at the 4-position ofthe -phenyl.
  • the present invention also encompasses compounds of formula (VI):
  • AT J is a pyrazinyl group. !!, procedure., II...1I , tedious labor, ll. preparationll "3"
  • AT J is a thiadiazolyl group.
  • Ar 2 is a benzothiazolyl group, hi another embodiment, Ar 2 is a benzoimidazolyl group. In another embodiment, Ar 2 is a benzooxazolyl group. In another embodiment, 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 ⁇ nautically > ⁇ .
  • 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
  • a - r "r, 2 is
  • R j is • H.
  • R is -halo.
  • R ! is -CI.
  • R ! is -Br.
  • R is -I.
  • R is -F.
  • R j is • CH 3 .
  • R is ⁇ NO 2 .
  • Ri is ⁇ •CN.
  • R ( is ⁇ ⁇ OH.
  • R] is • OCH 3 .
  • R j is • NH 2 .
  • R j is ⁇ C(halo) 3 .
  • R j is -CH(halo) 2 .
  • R ⁇ is -CH 2 (halo).
  • R 2 is -halo, -CN, -OH, -NO 2 , or -NH 2 .
  • R 2 is -(C,-C 10 )alkyl, -(C 2 -C 10 )alkenyl, -(C 2 - C j0 )alkynyl, -(C 3 -C 10 )cycloalkyl, -(C 8 -C 14 )bicycloalkyl, -(C 8 -C 14 )tricycloalkyl, -(C 5 - C 10 )cycloalkenyl, -(C 8 -C 14 )bicycloalkenyl, -(C 8 -C 14 )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
  • R 3 is -halo, -CN, -OH, -NO 2 , or -NH 2 .
  • R 3 is -(C r C 10 )alkyl, -(C 2 -C 10 )alkenyl, -(C 2 - C 10 )alkynyl, -(C 3 -C ⁇ 0 )cycloalkyl, -(C 8 -C, 4 )bicycloalkyl, -(C 8 -C, 4 )tricycloalkyl, -(C 5 - C 10 )cycloalkenyl, -(C 8 -C, 4 )bicycloalkenyl, -(C 8 -C 14 )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 groxxps.
  • R 3 is -phenyl, -naphthyl, -(C 14 )aryl or -(5- to 10- membered) heteroaryl, each of which is unsubstituted or substituted with one or more R 5 groups.
  • R 3 is -CH 3 .
  • m is 1
  • R 3 is -CH 3
  • the carbon atom to which the - R 3 is attached is in the (Reconfiguration.
  • m is 1
  • R 3 is -CH 3
  • the carbon atom to which the - R 3 is attached is in the (S)-configuration.
  • the present invention also encompasses compounds of formula (VH): .
  • vomer 't,., ⁇ ,!' ,. • ⁇ ;;;;, II leverage.II ;;;;ii ⁇ t taste.
  • AT J is a pyridyl group.
  • Ar j is a pyrimidinyl group.
  • A is a pyridazinyl group.
  • Ar is a pyrazinyl group.
  • Ar is a thiadiazolyl group.
  • Ar 2 is a benzothiazolyl group.
  • Ar 2 is a benzoimidazolyl group. In another embodiment, 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
  • 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
  • R, s -CH(halo) 2 In another embodiment, R, s -CH 2 (halo). In another embodiment, R 2 s -halo, -CN, -OH, -NO 2 , or -NH 2 ;.
  • R 2 s -(C 1 -C 10 )alkyl, -(C 2 -C 10 )alkenyl, -(C 2 - C ]0 )alkynyl, -(C 3 -C 10 )cycloalkyl, -(C 8 -C 14 )bi cycloalkyl, -(Cg-C j4 )tricycloalkyl, -(C 5 - C ]0 )cycloalkenyl, -(C 8 -C 14 )bicycloalkenyl, -(C 8 -C 14 )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; or
  • R 2 is -phenyl, -naphthyl, -(C 14 )aryl or -(5- to 10- membered)heteroaryl, each of which is unsubstitute or substituted with one or more R 6 groups;
  • R 3 is -halo, -CN, -OH, -NO 2 , or -NH 2 .
  • R 3 is -(C I -C 10 )alkyl, -(C 2 -C 10 )alkenyl, -(C 2 - C 10 )alkynyl, -(C 3 -C 10 )cycloalkyl, -(C 8 -C 14 )bicycloalkyl, -(C 8 -C 14 )tricycloalkyl, -(C 5 - C 10 )cycloalkenyl, -(C 8 -C ]4 )bicycloalkenyl, -(C 8 -C 14 )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
  • 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 6 groups.
  • 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.
  • m is 1
  • R 3 is -CH 3
  • the carbon atom to which the - R 3 is attached is in the (S)-configuration.
  • Cyanoiminopiperazine Compounds may have asymmetric centers and therefore exist in different enantiomeric and diastereomic forms.
  • This invention relates to the use of all optical isomers and stereoisomers ofthe Cyanoiminopiperazine Compounds, and mixtures thereof, and to all pharmaceutical compositions and methods of treatment that may employ or contain them.
  • each R 3 can be on any carbon ofthe piperazine ring.
  • the Cyanoiminopiperazine Compounds have only one R 3 group, and that R 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 a single atom ofthe piperazine ring.
  • the Cyanoiminopiperazine Compound has two R 3 groups, each being attached to a different carbon atom adjacent to a nitrogen atom attached to the pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, or thiadiazolyl group.
  • the Cyanoiminopiperazine Compound has one or two R 3 groups
  • the carbon atom to which an R 3 group is attached has the (R) configuration.
  • the Cyanoiminopiperazine Compound has one or two R 3 groups
  • the carbon atom to which the R 3 group is attached has the (S) configuration
  • the Cyanoiminopiperazine Compound has one or two R 3 groups, and at least one ofthe carbon atoms to which an R 3 group is attached has the (R) configuration
  • the Cyanoiminopiperazine Compound has one or two R 3 groups, and at least one ofthe carbon atoms to which an R 3 group is attached has the (S) configuration.
  • the Cyanoiminopiperazine Compound has one or two R 3 groups, an R 3 group is attached to a carbon atom adjacent to a nitrogen atom attached to the pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, or thiadiazolyl group, and the carbon to which the R ? group is attached is in the (R) configuration.
  • the Cyanoiminopiperazine Compound has one or two R 3 groups, an R 3 group is attached to a carbon atom adjacent to a 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, hi another embodiment, the Cyanoiminopiperazine Compound has one or two R 3 groups, an R 3 group is attached to a carbon atom adjacent to a 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 Cyanoiminopiperazine Compound has one or two R 3 groups, an R 3 group is attached to a carbon atom adjacent to a 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 Cyanoiminopiperazine Compoimd has one or two R 3 groups, an R 3 group is attached to a carbon atom adjacent to a 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 .
  • R 3 groups an R 3 group is attached to a carbon atom adjacent to a 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 Cyanoiminopiperazine Compound has one or two R 3 groups, an R 3 group is attached to a carbon atom adjacent to a 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 r C 4 )alkyl unsubstituted or substituted with one or more halo groups.
  • the Cyanoiminopiperazine Compound has one or two R 3 groups, an R 3 group is attached to a carbon atom adjacent to a 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 Cyanoiminopiperazine Compound has one or two R 3 groups, an R 3 group is attached to a carbon atom adjacent to a 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 Cyanoiminopiperazine Compound has one or two R 3 groups, an R 3 group is attached to a carbon atom adjacent to a 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 2 CH 3 .
  • the carbon to which the R 3 group is attached is in the (S) configuration
  • R 3 is -CF 3 .
  • the Cyanoiminopiperazine Compound has only one R 3 group, the R 3 group is attached to a carbon atom adjacent to a 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 Cyanoiminopiperazine Compound has only one R 3 group, the R 3 group is attached to a carbon atom adjacent to a 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 1 -C 4 )alkyl unsubstituted or substituted with one or more halo groups.
  • the Cyanoiminopiperazine Compound has only one R 3 group, the R 3 group is attached to a carbon atom adjacent to a 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 Cyanoiminopiperazine Compound has only one R 3 group, the R 3 group is attached to a carbon atom adjacent to a 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 Cyanoiminopiperazine Compound has only one R 3 group, the R 3 group is attached to a carbon atom adjacent to a 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 Cyanoiminopiperazine Compound has only one R 3 group, the R 3 group is attached to a carbon atom adjacent to a 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 Cyanoiminopiperazine Compound has only one R 3 group, the R 3 group is attached to a carbon atom adjacent to a 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 Cyanoiminopiperazine Compound has only one R 3 group, the R 3 group is attached to a carbon atom adjacent to a 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 Cyanoiminopiperazine Compound has only one R 3 group, the R 3 group is attached to a carbon atom adjacent to a 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 Cyanoiminopiperazine Compound has only one R 3 group, the R 3 group is attached to a carbon atom adjacent to a 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 2 CH 3 .
  • the present invention includes the Cyanoiminopiperazine Compounds, and the phannaceutically acceptable salts thereof, wherein one or more hydrogen, carbon or other atoms are replaced by isotopes thereof.
  • Such compounds may be useful as research and diagnostic tools in metabolism pharmacokinetic studies and in binding assays.
  • Illustrative Cyanoiminopiperazine Compounds are listed below in Tables 1-8: Table 1
  • -(C,-C] 0 )alkyl means a straight chain or branched non-cyclic hydrocarbon having from 1 to 10 carbon atoms.
  • Representative straight chain -(C r C 10 )alkyls include -methyl, -ethyl, -n-propyl, -n-butyl, -n-pentyl, -n-hexyl, -n-heptyl, -n-octyl, -n-nonly and -n- decyl.
  • Representative branched -(C 1 -C 10 )alkyls include -isopropyl, -sec-butyl, -isobutyl, -tert-butyl, -isopentyl, -neopentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, J ,l "dimethylpropyl, 1 ,2-dimethylpropyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl,.
  • -(C,-C 6 )alkyl means a straight chain or branched non-cyclic hydrocarbon having from 1 to 6 carbon atoms.
  • Representative straight chain -(C r C ⁇ )aIkyls include -methyl, -ethyl, -n-propyl, -n-butyl, -n-pentyl and -n-hexyl.
  • Representative branched -(C,- C 6 )alkyls include -isopropyl, -sec-butyl, -isobutyl, -tert-butyl, -isopentyl, -neopentyl, l-ructhylburyl, 2-rnethylbutyl, 3-methyib ⁇ tyl, ,1-dimethylpropyl, 1 ,2-dimethylpropyl, i-methylpentyl, 2-methylpentyl, 3- ⁇ nethylpentyl, 4-methylpentyl, 1 -ethylbutyl, 2-ethylbutyl, 3-ethylbutyl, 1,1-dimethtylbutyl, 1,2-dm ⁇ ethylbutyl, 1,3-dimethylbutyl, 2,2-dimethylbutyl. 2.3-dirnethylbutyl and 3,3-dimethylbutyl.
  • -(C 2 -C ]0 )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 -C 10 )alkenyls include -vinyl, -allyl, -1-butenyl, -2-buienyi, -isobutylenyl, -1 -pentenyl, -2-pentenyl, -3 -methyl- 1-butenyl, -2-methyl-2-butenyl, -2,3-c ⁇ imethyl-2-butenyl, -1-hexenyl, -2-hexenyl, -3-hexenyl, -1-heptenyl, -2-heptenyl, -3- heptenyl.
  • -(C 2 -C 6 )alkenyT 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 -C 6 )alkenyls include -vinyl, -allyl, -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 10 )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 10 )alkynyls include -acetylenyl, -propynyl, -1-butynyl, -2-butynyl, -1-pentynyl, -2-pentynyl, -3-methyl-l -butynyl, -4-pentynyl, -1- hexy ⁇ yl, -2-hexynyl, -5-hexynyl, -1-heptynyl, -2-heptynyl, -6-heptynyl, -1-octynyl, -2-octynyl, -7-octynyl, -1-nonynyl, -2-nonynyl, -8-nonynyl, -l decynyl, -2-decynyl, -9-dec
  • -(C 2 -C 6 )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 -C 6 )alkynyls include -acetylenyl, -propynyl, -1-butynyl, -2-butynyl, -1-pentynyl, -2-pentynyl, ⁇ 3-methy!- 1-butynyl, -4-pentynyl, -1- H bexynyl, -2-hexynyl, -5-hexynyl and the like.
  • -(C 3 -C 10 )cycloalky ⁇ means a saturated cyclic hydrocarbon having from 3 to 0 carbon atoms.
  • Representative (C 3 -C 10 )cycloalkyls are -cyclopropyl, -cyclobutyl, -cyclopentyl, -cyclohexyl, -cycloheptyl, -cyclooctyl, -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, -cyclohexyl, -cycloheptyl and -cyclooctyl.
  • -(C 8 -C j4 )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 14 )bicycloalkyls include -indanyl, -l.,2,3,4-tet ⁇ -ahydronaphthyl, -5,6,7,8-tetrahydronaphthyl, - perhydronaphthyl and the like.
  • Representative -(C 8 - Ci 4 )iricycloalkyls include -pyrenyl, -1,2,3,4-tetrahydroanthracenyl, -perhydroanthracenyl -aceantbren ⁇ yl, -1 ,2,3,4-tetrahydropenanthrenyl, -5,6,7,8-tetrahydrophenanthrenyl, -perhydrophenanthrenyl and the like.
  • -(C 5 -C 10 )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 10 )cycloalkenyls include -cyclopentenyl, -cyclopentadienyl, -cyclohexenyl, -cyclohexadienyl,-cycloheptenyl, -cycloheptadienyl, -cycloheptatrienyl,
  • -(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,
  • -(C 8 -C 14 )bicycloalkenyl means a bi-cyclic hydrocarbon ring system having at least one carbon-carbon double bond in each ring and from 8 to 14 carbon atoms. Representative include -indenyl, -pentalenyl, -naphthalenyl,
  • -azulenyl -heptalenyl, -1,2,7,8-tetrahydronaphthalenyl and the like.
  • Representative -(Cg-C j tricycloalkeriyls include -anthracenyl, -phenanthrenyl, -phenalenyl, -acenaphthalenyl, s-indacenyl, s-indacenyl and the like.
  • a 3-membered -(C 3 -C 7 )heterocycle can contain up to 3 heteroatoms, and a 4- to 7-membered
  • -(C 3 -C 7 )hete3Ocycle can contain up to 4 heteroatoms. Each heteroatom is independently selected from nitrogen, which can be quatemized; oxygen; and sulfur, including sulfoxide and sulfone.
  • the -(C 3 -C 7 )heterocycle can be attached via a nitrogen, sulfur, or carbon atom.
  • Representative -(C 3 -C 7 )heterocycles include pyridyl, furyl, thiophenyl, pyrrolyl, oxazolyl, . imidazolyl, thiazolyl, thiadiazolyl, isoxazolyl, pyrazolyl, isothiazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, mo holinyl, pyn'olidinonyl, pyrrolidinyl, piperidinyl, piperazinyl, hydantoinyl, valerolactamyl, oxiranyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydropyrindinyl, tetrahydropyrimidinyl, tetrahydrothiophenyl, tetrahydrothiopyranyl
  • -(C 3 -C 5 )heterocycle or "-(C 3 -C 5 )heterocyclo” means a 3- to 5-membered monocyclic heterocyclic ring which is either saturated, unsaturated non-aromatic, or aromatic.
  • a 3-membered -(C 3 -C 7 )heterocycle can contain up to 3 heteroatoms, and a 4- to 5-membered -(C 3 -C 5 )heterocycle can contain up to 4 heteroatoms.
  • Each heteroatom is independently selected from nitrogen, which can be quatemized; oxygen; and sulfur, including sulfoxide and sulfone.
  • the -(C 3 -C 5 )heterocycle can be attached via a nitrogen, sulfur, or carbon atom.
  • Representative -(C 3 -C 5 )heterocycles include furyl, thiophenyl, pyrrolyl, oxazolyl, imidazolyl, thiazolyl, isoxazolyl, pyrazolyl, isothiazolyl, triazinyl, pyrrolidinonyl, pyrrolidinyl, hydantoinyl, oxiranyl, oxetanyl, tetrahydrofuranyl, tetrahydrothiophenyl and the like,
  • -(C 7 -C 10 )bicycloheterocycle or "-(C 7 -C 10 )bicycloheterocyclo” means a 7- to 10-membered bicyclic, heterocyclic ring which is either saturated, unsaturated non-aromatic, or aromatic.
  • a -(C 7 -C 10 )bicycloheterocycle contains from 1 to 4 heteroatoms independently : selected from nitrogen, which can be quatemized; oxygeu; and sulfur, including sulfoxide and ; sulfone.
  • the (C 7 -C 10 )bicycloheterocycle can be attached via a nitrogen, sulfur, or carbon atom.
  • Representative -(C 7 -C 10 )bicycloheterocycles include -quinolinyl, -isoquinolinyl, - chromonyl, -coumarinyl, -indolyl, -indoJizinyl, -benzo[b]furanyl, -benzo[b]thiopbenyl, - iudazolyl, -purinyl, -4H-quinolizinyl, -isoquinolyl, -quinolyl, -phthalazinyl, -naphthyridinyl, - carbazolyl, - ?-carbolinyl and the like.
  • -(C 14 )aryl means a 14-membered aromatic carbocyclic moiety such as -anthryl or -phenanthryl.
  • ''-(C j -C j c ⁇ eteroaryl" 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 ofthe -(C 5 -C ]0 )heteroaryrs rings contain at least one carbon atom.
  • C 5 -C 10 )heteroaryls include pyridyl, furyl, benzofuianyl, thiophenyl, benzothiophenyl, quinolinyl, pyrrolyl, indolyl, oxazolyl, benzoxazolyl, imidazolyl, benzimidazolyl, thiazolyl, benzothiazolyl, isoxazolyl, pyrazolyl, isothiazolyl, pyridazinyl, pyrimidinyl, pyrazinyl. thiadiazolyl, triazinyl, cinnolinyl, phthalazinyl, and qumazolinyl.
  • - Halogen or "-Halo" means -F, -CI, -Br or -I.
  • the phrase "2-(3 -chloropyridyl)" means
  • R b R 2 , and n are defined above for the Cyanoiminopiperazine Compounds of fonnula (IV).
  • R 8 and s are defined above for the Cyanoiminopiperazine Compounds of fonnulas (VI) and (VTO.
  • phenethyl group means an ethylene group attached to a terminal Ar 2 group, wherein one or each of two hydrogens ofthe ethylene group can optionally be substituted with an R 4 group.
  • a phenethyl group is depicted below t ⁇
  • phenpropyl group an n-propylene group attached to a terminal Ar 2 group, wherein one or each of two hydrogens ofthe n-propylene group can optionally be substituted with an R 4 group.
  • a phenpropyl group is depicted below
  • R 4 , Ar 2 , and t are defined above for the Cyanoiminopiperazine Compounds of formula (VH).
  • salt is a salt formed from an acid and a basic nitrogen group of one ofthe Cyanoiminopiperazine 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, fonnate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, yp-toluenesulfonate, and pamoate (i.e.,
  • pharmaceutically acceptable salt also refers to a salt prepared frorri a Cyanoiminopiperazine Compound having an acidic functional group, such as a carboxylic acid functional group, and a phannaceutically acceptable 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-(hydiOxymethyl)methylamine, N, N,-di-lower alkyl-N-(hydroxy lower alkyl) ' -amines, t such as N,
  • 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, hi another embodiment, each carbon atom of a first group is independently substituted with only one second group.
  • the tenn “UI” means urinary incontinence.
  • the term “IBD” means inflammatory-bowel disease.
  • the tenn “IBS” means irritable-bowel syndrome.
  • DIEA means diisopropylethylamine.
  • DMSO means dimethyl sulfoxide.
  • DMF means dimethyl formamide.
  • DCM means dichloromethane.
  • treatment of and “treating” includes the amelioration or cessation of a Condition or a symptom thereof.
  • prevention of and "preventing” includes the avoidance ofthe onset of a Condition or a symptom thereof.
  • the Cyanoiminopiperazine Compounds can be made using conventional organic synthesis or by the following illustrative methods shown in the schemes below.
  • the Cyanoiminopiperazine Compounds wherein A is NR 4 can be obtained by the following illustrative methods shown below in Scheme A:
  • R 1 , R 2 and n are defined above.
  • a compound of formula A is reacted with a compound of formula B in an aprotic organic solvent such as diethyl ether, di-n-propyl ether, tefrahydiofuran, methylene chloride, or toluene at a temperature ranging from about room temperature to about the reflux temperature ofthe solvent for a period of about 0.5 h to about 24 h to provide a Cyanoiminopiperazine Compound wherein A is NR 4 .
  • the aprotic organic solvent is di-n-propyl ether.
  • a reaction mixture of di-n-propyl ether, compound of formula A and a compound of formula B is heated at a temperature of about 70° to about 80° C.
  • the reaction mixture of di-n-propyl ether, a compound of fo ⁇ nula A and a compound of formula B is heated at a temperature of about at 75 °C for about 12 h.
  • the aprotic solvent is DCM and the reaction mixture of NHR b R 4 and ,- . diphenylcyanocabonimidate is allowed to react at about room temperature.
  • the aprotic solvent is toluene and the reaction mixture of NHR 6 R 4 and diphenylcyanocabonimidate is allowed to react at about 110°C.
  • the NHR 6 R 4 and diphenylcyanocaboniinidate is typically allowed to react for a period of about 0.5 h to about
  • a compound of formula C1-C5 is reacted with a compound of formula D in an aprotic solvent in the presence of DIEA or triethylamine, optionally with heating, to provide compound B.
  • Compound B is isolated from the reaction mixture and purified. In one embodiment, the reaction is purified using column chromatography or recrystalhzation.
  • Compounds of formula C1-C5 and D are commercially available or can be prepared by methods well known to those skilled in the art.
  • the compound of formula D.. wherein m is 0 is commercially available from Sigma-Aldrich, St. Louis, MO (www.sigma- aldrich.com).
  • the compound of formula E can be obtained by reacting a compound of formula F with cyanamide. Representative procedures for obtaining a compound of formula E from a compound of formula F are provided in R.L. Webb et al., J. Heterocycl. Chem. . 19(5): 1205-1206 (1982) and U.S. Patent No. 4,285,878 to Labaw et al. 15 The compound of formula F can be obtained as shown below in Scheme F.
  • the compound of formula F can be obtained by reacting a compound of formula G with PC1 5 .
  • a representative procedure for obtaining a compound of formula F from a compound of fonnula G is provided in. R.L. Webb et al., J. Heterocyc Chem.
  • the compound of formula G can be obtained by reacting a compound of formula R 6 -OH with COCl 2 , triphosgene, or CO and a Pd catalyst as described in U.S. Patent No. 6,175,017 to H. Buyschi et al.; A. Gode et al., Chemistry-A European Journal 6(19):3522-30 (2000); or H. Yasuda et a Orga ometallics, 21(6):1216-20 (2002),
  • a compound of formula B is reacted with a compound of formula H to provide the Cyanoiminopiperazine Compoxmds wherein A is -S-.
  • Representative procedures for reacting a compound of formula B with a compound of formula H are provided in T.D. Aicher et al., J. Med. Chem. 43(2);236-49 (2000) and Ger. Patent No. 3336409. The compound of formula H can be obtained as shown below in Scheme H.
  • a thiol of formula R 6 SH is reacted with a compound of formula J to provide the compound of formula H.
  • Representative procedures for obtaining compounds of formula J and for obtaining the compound of formula H by reacting a thiol with a compound of formula J are provided in R.L. Webb et al., J. Heterocycl. Chem., 24(l):275-78 (1.987); I.
  • the amine of formula I or the amine of formula J and diphenylcyanocabonimidate is typically allowed to react for a period of about 0.5 h to about 24 h.
  • the compound of formula K or the compound of formula L is used without further purification.
  • the Cyanoiminopiperazine Compounds are administered to an animal in need of treatment or prevention of 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.
  • an effective amount of a Cyanoiminopiperazine is administered to an animal in need of treatment or prevention of 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
  • Compound can be used to heat or prevent any condition treatable or preventable by inhibiting VRl.
  • conditions that are treatable or preventable by inhibiting VRl include, but are not limited to, pain, UI, an ulcer, IBD, and IBS.
  • an effective amoixnt of a Cyanoiminopiperazine Compound can be used to treat or prevent any condition treatable or preventable by inhibitiug 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 Cyanoiminopiperazine 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 Cyanoiminopiperazine Compounds can be used to treat or prevent acute or chronic pain.
  • Examples of pain treatable or preventable using the Cyanoiminopiperazine 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, pain associated with intensive care, arthritic pain, neuropathic pain, and pain associated with a periodontal disease, including gingivitis and periodontitis.
  • the Cyanoiminopiperazine Compounds can also be used for inhibiting, preventing, or treating pain associated with inflammation or with an inflammatory disease in an animal.
  • the pain to be inhibited, treated or prevented may be associated with inflammation associated with an inflammatory disease, which can arise where there is an inflammation ofthe body tissue, and which can be a local inflammatory response and/or a systemic inflammation.
  • the Cyanoiminopiperazine Compounds car. be used to inhibit, treat, or prevent pain associated with inflammatory diseases including, but not limited to: organ transplant rejection; reoxygenation injury resulting from organ transplantation (see Grupp et al., J. Mol Cell Cardiol.
  • autoimmune diseases including comeal dystrophy trachoma, oncnocerciasis, uveitis, sympathetic ophthalmitis and endophthalmitis; chronic inflammatory diseases ofthe gum, including gingivitis and periodontitis; tuberculosis; leprosy; inflammatory diseases ofthe kidney, including uremic complications, glomenilonephritis and nephrosis; inflammatory diseases ofthe skin, including sclerodemiatitis, psoriasis and eczema; inflammatory diseases ofthe central nervous system, including chronic demyelinating diseases of the nervous system, multiple sclerosis, AIDS- related neurodegeneration and Alzheimer s disease, infectious meningitis, encephalomyelitis, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis and viral or autoimmune encephalitis; autoimmune diseases, including Type I and Type H diabetes mellitus; diabetic complications, including, but not limited to, diabetic cataract, glaucoma
  • the Cyanoiminopiperazine Compounds can also be used for inhibiting, treating, or preventing pain associated with inflammatory disease that can, for example, be a systemic inflammation ofthe 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. Such shock can be induced, e.g., by a chemotherapeutic agent that is adminstered as a treatment for cancer.
  • the Cyanoiminopiperazine Compounds can be used to treat or prevent UI.
  • Examples of UI treatable or preventable using the Cyanoiminopiperazine Compounds include, ut are not limited to, urge incontinence, stress incontinence, overflow incontinence, neurogenic incontinence, and total incontinence.
  • the Q'anoiminopiperazine Compounds can be used to treat or prevent an ulcer. Examples of ulcers treatable or preventable using the Cyanoiminopiperazine
  • Compounds include, but are not limited to, a duodenal ulcer, a gastric ulcer, a marginal ulcer, an esophageal ulcer, or a stress ulcer.
  • the Cyanoiminopiperazine Compounds can be used to treat or prevent IBD, including Crohn's disease and ulcerative colitis.
  • the Cyauoiminopiperazine Compounds can be used to treat or prevent IBS.
  • Examples of IBS treatable or preventable using the Cyanoiminopiperazine Compounds include, but are not limited to, spastic-colon-type IBS and constipation-predominant IBS.
  • the Cyanoiminopiperazine 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
  • Impulse control disorders include, but are not limited to, Intermittent
  • Alcohol-related disorders include, but are not limited to, Alcohol-Induced Psychotic Disorder with delusions, Alcohol Abuse, Alcohol Intoxication, Alcohol
  • 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 ⁇ ' ⁇ ⁇
  • Nicotine-related disorders include, but are not limi ted to, Nicotine
  • Amphetamine-related disorders include, but are not limited to, Amphetamine
  • Amphetamine Intoxication Delirium, Amphetamine-Induced Psychotic Disorder with delusions, Amphetamine-Induced Psychotic Disorders with hallucinations,
  • Amphetamine-Induced Mood Disorder Amphetamine-Induced Anxiety Disorder, Aniphetamine- ⁇ nduced Sexual Dysfunction, Amphetamine-Induced Sleep Disorder,
  • Cannabis-related disorders include, but are not limited to., Cannabis
  • 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-hiduced Mood Disorder, Cocaine-Induced 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-hiduced Sleep Disorder, Halhxcinogen Related Disorder not otherwise specified (NOS), Hallucinogen Intoxication, and Halluciuogen Persisting Perception Disorder (Flashbacks).
  • Lnhaiant-rulated disorders include, but aie not limited to, Inhalant Dependence, Inhalant Abuse, Inhalant Intoxication, Inhalant Intoxication Delirium, Inhalant-Induced Psychotic Disorder with delusions, ialant- ⁇ nduced 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 wi ! h delusions, Opioid-Induced Psychotic Disorder with hallucinations, Opioid-Induced Anxiety Disorder, Opioid Related Disorder not otherwise specified (NOS), Opioid Intoxication, and Opioid Withdrawal.
  • the Cyanoiminopiperazine 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, bradykin ⁇ sia, muscular rigidity, resting tremor, and impairment of postural balance.
  • the Cyanoiminopiperazine 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 Cyanoiminopiperazine 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 Cyanoiminopiperazine Compounds can be used to treat or prevent strokes, including but. not limited to, ischemic strokes and hemorrhagic strokes.
  • the Cyanoiminopiperazine Compounds can be used to treat or prevent a seizure, including but not limited to, infantile spasms, febrile seizures, and epileptic seizures.
  • the Cyanoiminopiperazine Compounds can be used to treat or prevent a pruritic condition, including but not limited to, prurihxs caused by dry skin, scabies, dermatitis, herpetifonnis, atopic dermatitis, pruritus vulvae et ani, miliaria, insect bites.
  • pediculosis contact dermatitis, drug reactions, urticaria, urticarial enxptions of pregnancy, psoriasis, lichen planus, lichen simplex chronicus, exfoliative dermatitis, folliculitis, bullous pe phigoid, or fiberglass dermatitis.
  • the Cyanoiminopiperazine 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 subtype 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 subtype 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
  • the Cyanoiminopiperazine Compoxmds 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.
  • the Cyanoiminopiperazine Compounds can be used to treat or prevent a memory deficiency, including but not limited to, dissociative amnesia and dissociative fugue.
  • the Cyanoiminopiperazine Compounds can be used to heat or prevent restricted brain function, including but not limited to, that caused by surgery or an organ tiunsplant, restricted blood supply to the brain, a spinal cord injury, a head injury, hypoxia, cardiac arrest, or hypoglycemia.
  • the Cyanoiminopiperazine Compounds can be used to treat or prevent HuBtington's chorea.
  • the Cyanoiminopiperazine Compounds can be used to treat or prevent ALS.
  • the Cyanoiminopiperazine 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 Cyanoiminopiperazine Compounds can be used to treat or prevent a muscle spasm.
  • the Cyanoiminopiperazine Compounds can be used to treat or prevent a migraine.
  • the Cyanoiminopiperazine Compounds can be used to inhibit, treat or prevent vomiting, including but not limited to, nausea vomiting, dry vomiting (retching), and regurgitation.
  • the Cyanoiminopiperazine Compounds can be used to treat or prevent dyskinesia, including but not limited to, tardive dyskinesia and biliary dyskinesia.
  • the Cyanoiminopiperazine Compounds can be used to treat or prevent depression, including but not limited to, major depression and bipolar disorder. Applicants believe that the Cyanoiminopiperazine 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 effective amount of a Cyanoim nopiperazine Compound.
  • 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, a human in one embodiment, by contacting a cell, in an animal, with an effective amount of a Cyanoiminopiperazine Compound.
  • the method is useful for treating or preventing pain in an animal.
  • the method is useful for treating or preventing UI in an animal. In another embodiment, the method is useful for treating or preventing an ulcer in an animal. In another embodiment, the method is useful for treating or preventing IBD in an animal. In another embodiment, the method is useful for treating or preventing IBS in an animal.
  • tissue comprising cells capable of expressing VRl include, but are not limited to, neuronal, brain, kidney, urotheliuni, and bladder tissue. Methods for assaying cells that express VRl are well known in the art.
  • the invention also relates to methods for inhibiting mGluR5 function in a cell, ,?. comprising contacting a cell capable of expressing mGluRS with an amount of a
  • Cyanoiminopiperazine Compound effective to inhibit mGluR5 function in the cell can be used in vitro, for example, as an assay to select cells that express mGhxR5 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 mGluR5 function in a cell in vivo, in an animal, a human in one embodiment, by contacting a cell, in an animal, with an amount of a Cyanoiminopiperazine 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 heating or preventing psychosis in an animal in need thereof.
  • Examples of cells capable of expressing mGluRS are neuronal and glial cells ofthe 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 invention also relates to methods for inhibiting mGluRl function in a cell, comprising contacting a cell capable of expressing mGluRl with an amount of a Cyanoiminopiperazine 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, a human in one embodiment, by contacting a cell, in an animal, with an amount of a Cyanoiminopiperazine Compound effective to inhibit mGluRl function in the cell, hi one embodiment, the method is useful for treating or preventing pain in an animal in need thereof. In another embodiment, 1he method is useful for treating or preventing UI in an animal in need thereof. In another embodiment. the method is useful for treating or preventing an addictive disorder in an animal in need thereof, hi another embodiment, 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, hi another embodiment, 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 heating or preventing stroke in an animal in need thereof. In another embodiment, the method is useful for treating or preventing a seizure in an animal in need thereof, hi 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, hi another embodiment, the method is useful for treating or preventing a cognitive disorder in an animal in need thereof.
  • the method is useful for treating or preventing a memory deficit in an animal in need thereof. In another embodiment, the method is useful for heating or preventing restricted brain function in an animal in need thereof. In another embodiment, the method is useful for treating or preventing Huntington's 5 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, hi another embodiment, the method is useful for treating or preventing a muscle
  • the method is useful for treating or preventing a migraine in an animal in need thereof.
  • the method is useful for treating or preventing vomiting in an animal in need thereof.
  • the method is useful for treating or preventing dyskinesia in an animal in need thereof.
  • the method is useful for treating or preventing depression in
  • Examples of cells capable of expressing mGluRl include, but are not limited to, cerebe ⁇ ar Puirkinje neuron cells.
  • Purkinje cell bodies punctate
  • cells of spine(s) ofthe. cerebellut neurons and neurophil cells of olfactory-bulb glomeruli; cells ofthe superficial ; layer of the cerebral cortex; hippocampus cells; thalamus cells; superior colliculus cells; and
  • the Cyanoiminopiperazine Compounds are advantageously useful in veterinary and human medicine. As described above, the Cyanoiminopiperazine Compounds are useful for heating 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
  • the Cyanoiminopiperazine Compounds are administered as a component of a composition that comprises a pharmaceutically acceptable can ⁇ er or ⁇ xcipient.
  • the present compositions, which comprise a Cyanoiminopiperazine Compound can be administered orally.
  • the Cyanoimmopiperazine Compounds ofthe 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. dminisnation 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 Cyanoiminopiperazine Compound.
  • Methods of administration include, but are not limited to, intradermal, intramuscular, inhaperitoneal, intravenous, subcutaneous, intranasal. epidural, oral, sublfngual, 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 o the practitioner. In most instauces, administration will result in the elease of the Cyanoiminopiperazine Compounds into the bloodstream.
  • This can be achieved, for example, and not by of limitation, by local infusion during surgery, topical application, e.g., in conjunction with a wound dressing after surgery, by injection, by means of a catheter, by means of a supposi tory or enema, or by means of an implant, said implant being of a porous, non-porous, or gelatinous material, including membranes, such as sialastic membranes, or fibers.
  • Cyonoiminopiperazine Compounds info the central nervous system or gastrointestinal tract by an ⁇ ' suitable route, including intraventricular, intrathecal. and epidural injection, and enema. Jnfruyerjtric ⁇ lar injection can be facilitated by an intraventricular catheter, for example, attached to a reservoir, such as an Ommaya 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 fluoiocarbon or synthetic pulmonary surfactant.
  • the Cyanoiminopiperazine Compounds can be formulated as a suppository, with traditional binders and excipients such as triglycerides.
  • the Cyanoiminopiperazine 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
  • Cyanoiminopiperazine Compounds can be delivered in a controlled-release system or sustained-release system (see, e.g., Goodson, in
  • a pump can be used (Langer,
  • polymeric materials can be used (see Medical Applications of Controlled Release (Langer and Wise eds., 1974); Controlled Drug Bioavailability ' , Drug
  • a controlled- or sustained-release system can be placed in proximity of a target ofthe Cyanoiminopiperazme Compounds, e.g., the spinal column, brain, or gastrointestinal tract, thus requiring only a fraction ofthe systemic dose.
  • compositions can optionally comprise a suitable amount of a pharmaceutically acceptable excipient so as to provide the form for proper administration to die acimai.
  • a pharmaceutically acceptable excipient can be liquids, such as water and oils, including those of petroleum, animal, vegetable, oi synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil and the like.
  • the pharmaceutical excipients can be saline, girn acacia, gelatin, starch paste, talc, keratin, colloidal silica, urea and the like, hi addition, aixxiliary, stabilizing, thickening, lubricating, and coloring agents can be used, h one embodiment, the pharmaceutically acceptable excipients are sterile when administered to an animal.
  • Water is a particularly useful excipient when the Cyanoiminopiperazine 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 5 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 fonn of solutions, suspensions, emulsion, tablets, pills, pellets, capsules, capsules containing liquids, powders.
  • compositions 0 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 's Pharmaceutical Sciences 1AA1-1616 (Alfonso R. Gennaro ed., 19th ed. 1995), incorporated herein by reference.
  • the Cyanoiminopiperazine Compounds are formulated in accordance with routine procedures as a composition adapted for oral administration to human beings.
  • Compositions for oral delivery can be in e fonn of tablets, lozenges, aqueous or oily suspensions, granules, powders, emulsions, capsules, syrups, or elixirs, foi example.
  • Orally administered compositions can contain one or more agents, for example,
  • compositions can be coated to delay disintegration and absorption in the gastrointestinal tract thereby providing a sustained action over an extended period of time.
  • 25 menibianes suiTounding an osmotically active driving compound are also suitable for orally administered compositions, hi these latter platforms, fluid from the environment surrounding the capsule is imbibed by the driving compound, which swells to displace the agent or agent composition tlirough an aperture.
  • These delivery platforms can provide an essentially zero order deliveiy profile as opposed to the spiked profiles of immediate release formulations.
  • time-delay material such as glycerol monostearate or glycerol stearate can also be used.
  • Oral compositions can include standard excipients such as mannitol, lactose, starch, magnesium stearate, sodium saccharin, cellulose, and magnesium carbonate. In one embodiment, the excipients are of pharmaceutical grade.
  • compositions for intravenous administration comprise sterile isotonic aqueous buffer. Where necessary, 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 ofthe injection.
  • a local anesthetic such as lignocaine to lessen pain at the site ofthe 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.
  • Cyanoiminopiperazine Compounds are to be administered by infusion, they can be dispensed, for example, with an infusion bottle containing sterile pharmaceutical grade " water or saline. Where the Cyanoiminopiperazine Compounds are administered by injection, an ampule of sterile water for injection cr saline can be provided so that the ingredients can be mixed prior to administration.
  • Cyanoiminopiperazine Compounds can be administered by controlied- 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; 3,508,123; 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, hydropropylmethyl 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 ordinaiy skill in the an. including those described herein, can be readily selected for use with the active ingredients ofthe invention.
  • the invention thus encompasses single unit dosage fonns 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 counterparts.
  • a controlled- or sustained-release composition comprises a minimal amount of a Cyanoiminopiperazine Compound to cure or control the condition in a minimum amount of time.
  • Advantages of controlled- or sustained-release compositions include extended activity ofthe drug, reduced dosage frequency, and increased 5 patient compliance.
  • controlled- or sustained-release compositions can favorably affect the time of onset of action or other characteristics, such as blood levels ofthe Cyanoiminopiperazine Compound, and can thus reduce the occurrence of adverse side
  • Controlled- or sustained-release compositions can initially release an amount
  • Cyanoiminopiperazine Compound that promptly produces the desired therapeutic or , prophylactic effect, and gradually and continually release other amounts ofthe Cyanoiminopiperazine Compound to maintain this level of therapeutic or prophylactic effect over an extended period of time.
  • the Cyanoiminopiperazine Compound can be released from the * '•;;
  • ⁇ ⁇ ingredient can be stim ⁇ lated by various conditions, including but not limited to, changes in % pH, changes in temperature, concentration or availability ofenzym.es, concentration or - availability of water, or other physiological conditions or compounds.
  • Cyanoiminopiperazine C mpou ⁇ :d that is effective in the •. treatment or prevention of 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 and
  • 25 can be determined by standard clinical techniques.
  • in vitro or in vivo assays can optionally be employed to help identify optimal dosage ranges.
  • dosage amounts range from about 10 micrograms to about 2500 milligrams about every 4 h, although they are typically about 100 mg or less.
  • the effective dosage amount ranges from about 0.01 milligrams to about 100 milligrams of a Cyanoiminopiperazine Compound about every 4 h, in another embodiment, about 0.020 milligrams to about 50 milligrams about every 4 h, and in another embodiment, about 0.025 milligrams to about 20 milligrams about every 4 h.
  • the effective dosage amounts described 5 herein refer to total amounts administered; that is, if more than one Cyanoiminopiperazine ⁇ Compound is administered, the effective dosage amounts correspond to the total amount administered.
  • 1.0 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 is from about 1 ⁇ L to about I mL. hi .
  • the volume of solution or suspension is about 200 ⁇ L.
  • the amount effective foi inhibiting the receptor fimction in a cell will typically range from about 0.01 mg to about 100 mg/kg of body weight, per day, in one embodiment, from about 0.1 mg to about 50 mg/kg body weight 0 per day, and in another embodiment, from about 1 mg to about 20 mg kg of body weight per day. • '
  • the Cyanoiminopiperazine 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. 5 The present methods 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 in an animal in need thereof can further comprise administering to 0 the animal being administered a Cyanoiminopiperazine 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 mGluR5 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 non-opioid analgesic, a non-steroid anti-inflammatory agent, an antimigraine agent, a Cox-H inhibitor, an antiemetic, a ⁇ -adrenergic blocker, an anticonvulsant, an antidepressant, a Ca2+-channel blocker, an anticancer agent, an agent for treating or preventing UI, an agent for heating or preventing an ulcer, an agent for treating 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 treating anxiety, an agent for treating opi' ⁇ psy, an agent for treating a stroke, an agent for treating a seizure, an agent for heating a pruritic condition, an
  • Effective amounts ofthe 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, hi one embodiment ofthe invention, where another therapeutic agent is administered to an animal, the effective amount of the Cyanoiminopiperazine Compound is less than its effective amount would be where the other therapeutic agent is not administered.
  • the Cyanoiminopiperazine Compounds and the other therapeutic agent act syrergistically to treat or prevent 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, re ⁇ tricted brain function, Huntington's chorea, ALS, dementia, retinopathy, a muscle spasm, a migraine, vomiting, dyskinesia, or depression.
  • Examples of useful opioid agonists include, but are not limited to, alfentanil, allylprodine, alphaprodine, anileridine, benzyhnorphine, bezitramide, buprenorphine, butorphanol, clonitazene, codeine, desomorphine, dexhomoramide, dezocine, diamprornide, diamorphone, dihydrocodeine, dihydromorphine, dimenoxadol, dimepheptanol, dimethylthiambutene, dioxaphetyl butyrate, dipipanone, eptazocine, ethoheptazine, ethylmethylthiambutene, ethylmo ⁇ hine, etonitazene fentanyl, heroin, hydrocodone.
  • the opioid agonist is selected from codeine, hydromo ⁇ houe, hydrocodone, oxycodone, dihydrocodeine, dihydromorphine, mo ⁇ hine, tramadol, oxymo ⁇ hone, pharmaceutically acceptable salts thereof, and mixtures thereof.
  • useful nou-opioid analgesics include non-steroidal anti-inflammatory agents, such as aspirin, ibuprofen, diclofenac, naproxen, benoxaprofen, flurbiptofen, fenoprofen, flubufen, ketoprofen, indoprofen, piroprofen, ca ⁇ rofen, oxaprozin.
  • analgesic, antipyretic, nonsteroidal anti-inflammatory drugs include salicylic acid derivatives, including aspirin, sodium salicylate, choline magnesium trisalicylate, salsalate, diflunisal, sali ⁇ ylsalicyiic 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 pyrazolidinedione
  • useful antimigraine agents include, but are not limited to, alpiropride, dihydroergotamine, dolasetron, ergocornine. ergoco iinine, ergocryptiiie, ergot, ergotamine, flumedroxone acetate, fonazine, lisuride, lomerizine, methysergide oxetoron ⁇ , pizotyline, and mixtures thereof.
  • the other therapeutic agent can also be an agent useful for reducing any potential side effects of a Cyanoiminopiperazine Compounds.
  • the other therapeutic agent can be an antiemetic agent.
  • useful antiemetic agents include, but are not limited to, metoclopromide, domperidone, prochlo ⁇ erazine, promethazine, chlo ⁇ Oinazine, tiimethobenzamide, ondansetron, granisetron, hydioxyzine, acetylleucine monoethanolamine, alizapride, azasetron, benzquinamide, bietanautine, bromopride, buclizine, clebopride, cyclizine, dimenhydrinate, diphenidol, dolasetron, meclizine, methallatal, metopimazine, nabilone, oxyperndyl, pipamazine, scopolamine, sulphide, tetrahydrocannabmol, thiethylperazine, thioproperazine, tropisetron, and mixtures thereof.
  • ⁇ -adrenergic blockers include, but are not limited to, acebutolol, alprenolol, amosulabol, arotinolol, atenolol, befunolol, betaxolol, bevantolol, bisoprolol, bopind lol, bucumolol, bufetolol, bufuralol, buniholol, bupranolol, butidrine hydrochloride, butofilolol, carazolol, carteolol, carvedilol, celiprolol, cetamolol, cloranolol, dilevalol, epanolol, esmolol, indenolol, labetalol, levobimolol, mepindolol, metipranolol, metoprolol, moprolol, nado
  • 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.
  • useful antidepressants include, but. are not limited to, binedaline, caroxazone, citalopram, dimethazan, fencamine, indalpine, indeloxazine hydrocholoride, nefopam, nomifensine, oxitriptan, oxypertine, paroxetine, sertraline, thiazesim, trazodone, benmoxine, iprocJozide, iproniazid, isocarboxazid, nialamide, octamoxin, phenelzine, cotinine, rolicyprine, rolipram, maprotiline, metralindole, mianserin, mirtazepine, adinazolam, amitriptyline, amitiiptylinoxide, amoxapine, butriptyline, clomipramine, demexiptiline, desipramine
  • Ca2+-channel blockers examples include, but are not limited to, bepridil, clentiazem, diltiazem, fendiline. gallopamil, mibefradil, prenylamine, semotiadil, terodiline, verapamil, amlodipine, aranidipine, hassledipine, benidipine, cilnidipine, efonidipine, elgodipine, felodipine, isradipine, lacidipine, lercanidipine.
  • manidipine nicardipine, nifedipine, nilvadipine, nimodipine, nisoldipine, nitrendipine, cinnarizine, fjunarizine, iidoflazine, lomerizine. bencyclane, etafenone, fantofarone, and perhexiline.
  • useful anticancer agents include, but are not limited to, acivicin, aelambicin, acodazole hydrochloride, acronine, adozelesin, aldesleukin, altretamine, • ambomycin, ametantrone acetate, aminoglutethimide.
  • cisplatin cladribine, crisnatol mesylate, cyclophosphamide.
  • cytarabine dacarbazine, dactinomycin, daunorubicin hydrochloride, decitabine, dexormaplatin, dezaguanine, dezaguanine mesylate, diaziquone, docetaxel, doxorubicin, doxon ⁇ icin hydrochloride, droloxifene, droloxifene citrate, dromostanolone propionate, duazomycin, edahexate, eflomithine hydrochloride, elsamitracin, enloplatin, enpromate, epipropidine, epirubicin hydrochloride, erbulozole, esorubicin hydrochloride, estramustine, estramustine phosphate sodium, etanidazole, etoposide, etoposide
  • meturedepa mitindomide, mitocarcin, mitocromin, mitogillin, mitomalcin, mitomycin, mitosper, mitotane, mitoxantrone hydrochloride, mycophenolic acid, nocodazole, nogalamycin, ormaplatin, oxisuran, paclitaxel, pegaspargase, pebomycin, pentamustine, peplomycin sulfate, perfosfamide, pipobroman, piposulfan, piroxantrone hydrochloride, plicamycin, plomestane, porfimer sodium, porfiromycin, prednimustine, procarbazine hydrochloride, puromycin, puromycin hydrochloride, pyrazofurin, riboprine, rogletimide, safingol, safingol hydrochloride, semustine, suppressrazene, sparfosate sodium, sparsomycin, spi
  • talisomycin tecogalan sodium, tegafur, teloxantrone hydrochloride, temoporfm, teniposide, teroxirone, testolacione, thiamiprine, thioguanine, thiotepa, tiazo ⁇ xrin, tirapazanxine, toremifene citrate, trestolone acetate, triciribine phosphate, trimehexate, trimetrexate glucuronate, triptorelin, hxbulozole hydrochloride, uracil mustard, uredepa, vapreotide, verteporfm, vinblastine sulfate, vincristine sulfate, vindesine, vindesine sulfate, vinepidine sulfate, vinglycinate sulfate, vinleurosine sulfate, vinorelbine tartrate. vinrosidine sulfate, vin
  • anti-cancer drugs include, but are not limited to, 20-epi-l,25 dibydroxyvitamin D3; 5-ethynyl ⁇ racil; abiraterone; aclarubicin; acylfuJvene; adecypenol; adozelesin; aldesleukin: ALL-TK antagonists; altretamine; ambamustine; amidox; amifostine; aminolevulinic acid; anirubicin; amsacrine; anagrelide; anastrozole: andrographolide; angiogenesis inhibitors; antagonist D; antagonist G; antarelix; anti-dorsalizing mo ⁇ hogenetic protein- 1; antiandrogen, prostatic carcinoma; antiestrogen; antmeoplaston; antisense oligonucleotides; apliidicolin glycinate; apoptosis gene modulators; apoptosis regulators; apurinic acid
  • protein tyrosine phosphatase inhibitors purine nucleoside phosphorylase inhibitors; purpurfns; pyrazoloacridine; pyridoxylated hemoglobin polyoxyethylene conjugate; raf antagonists; raltihexed; ramosetron; ras famesyl protein hansferase inhibitors; ras inhibitors: ras-GAP inhibitor; retelliptine demethylated; rhenium Re 186 etidronate; rhizoxin; ribozymes; RH retinamide; rogletimide; rohitukine; romurtide; roquinimex; rubiginone Bl; ruboxyl; safingol; saintopin; SarCNU; sarcophytol A; sargramostim; Sdi 1 mimetics; semustine; senescence derived inhibitor 1: sense oligonucleo
  • ⁇ but are not limited to, propantheiine, 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 subcihate; H 2 antagonists such as cimetidine, ranitidine, famotidine, and nizatidine;
  • K " - ATPase inhibitors such as omeprazole, iansoprazole, and lansoprazole; carberxoxolone; misprostol; and antibiotics such as tetracyclme, mehonidazole, timidazole, claritlirouiycin, and amoxicillin.
  • Examples of 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, propantheiine; muscarine receptor antogonists such as pirenzapine, methoctramine, ipratropium, tiotropium, scopolamine, methscopolamine, homatropine, homatropiue methyibromide, 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, " b ⁇ prenorphine, an opiate agonist, 3-phenoxypyridine, levomethadyl acetate hydrochloride, and serotonin antagonists.
  • 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 trihexyphenidy] 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 iriazolam; non-benzodiazepine agents, such as buspirone, gepirone, ipsaprione, tiospirone, zolpicone, zolpidem, and zaleplon; tranq ⁇ ilizers, such as barbituates, e.g., amobarbital, aprobarbital, butabarbital,
  • 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 GAB A, 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 streptokina ⁇ e or tissue plasminogen activator, agents that reduce swelling such as mannitol or corticosteroids, and acetylsalicylic acid.
  • anticoagulants such as heparin
  • agents that break up clots such as streptokina ⁇ e or tissue plasminogen activator
  • agents that 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, pbenothiazines such as chlo ⁇ romazine hydrochloride, mesoridazine besylate, and thoridazine hydrochloride; thioxanthenes such as chloToprothixene and thiothixene hydrochloride; clozapine risperidone; olanzapine; quetiapine; quetiapine fumarate; haloperidol; haloperidol decanoate; loxapine succinate; molindone hydrochloride; pimozide; and ziprasidone.
  • pbenothiazines such as chlo ⁇ romazine hydrochloride, mesoridazine besylate, and thoridazine hydrochloride
  • thioxanthenes such as chloToprothixene and
  • Examples of useful therapeutic agents for heating or preventing Huntington's chorea include, but are not limited to, haloperidol and pimozide.
  • Examples of useful therapeutic agents for treating or preventing ALS include, but are not limited to, baclofen, n ⁇ urotrophic 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 treating or preventing dementia such as tacrine; donepezil; ibuprofen; antipsychotic drags such as thioridazine and haloperidol; and antidepressant drugs such as those given below.
  • Examples of useful therapeutic agents for heating or preventing a migraine include, but are not limited to, sumatriptan; methysergide; ergotamine; caffeine; and beta- blockers such as propranolol, veraparnil, and divalproex.
  • Examples of useful therapeutic agents for treating or preventing vomiting include, but are not limited to, 5-HT j receptor antagonists such as ondansetron, dolasetron, granisetron, and tropisetron; dopamine receptor antagonists such as prochlo ⁇ erazine, thiethylperazine, chlo ⁇ romazin, metoclopramide, and domperidone; glucocorticoid?.
  • 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.
  • ciomipraniine desipramine, doxepin, imipramine, maprotilinr, nefazadone, norhiptyhne, 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
  • psychostimulants such as dexhOamphetamine and methylphenidate.
  • a Cyanoiminopiperazine Compound and the other therapeutic agent can act additively r, in one embodiment, synergistically. hi one embodiment, a
  • Cyanohninopiperazine Compound is administered concunently with another therapeutic agent, h one embodiment, a composition comprising an effective amount of a Cyanoiminopiperazine Compound and an effective amount of another therapeutic agent can be administered. Alternatively, a composition comprising an effective amount of a Cyanoiminopiperazine Compound and a different composition comprising an effective amount of another therapeutic agent can be concurrently administered.
  • an effective amoxxnt of a Cyanoiminopiperazine Compound is administered prior or subsequent to administration of an effective amount of another therapeutic agent, hi ⁇ his embodiment, the Cyanoiminopiperazine Compound is administered while the other therapeutic agent exerts its therapeutic effect, or the other therapeutic agent is administered while the Cyanoiminopiperazine Compound exerts its preventative or therapeutic effect for treating or preventing a Condition.
  • a composition ofthe invention is prepared by a method comprising admixing a Cyanoiminopiperazine Compound or a pharmaceutically acceptable salt and a pharmaceutically acceptable carrier or excipient.
  • A.dmixing can be accomplished using methods well known for admixing a compound (or salt) and a phannaceutically acceptable cairier or excipient.
  • the Cyanoimiuopiperazine Compound or the pharmaceutically acceptable salt o the Compound is present in the composition in an effective amoun
  • the invention encompasses kits that can simplify the administration of a Cyanoiminopiperazine Compound to an animal.
  • a typical kit ofthe invention comprises a unit dosage fonn of a Cyanoinhnopipe ⁇ tzine Compound.
  • the unit dosage form is a container, which can be sterile, containing an effective amount of a Cyanoiminopiperazine Compound and s pharmaceutically acceptable carrier or excipient.
  • the kit can further comprise a label or printed instiuctions instructing the use ofthe Cyanoiminopiperazine Compound to treat pain, UI, an ulcet, 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 muscie spasm, a migraine- vomiting, dyskinesia, or depression.
  • the kit can also further comprise a unit dosage form of another therapeutic agent, for example, a container containing an effective amount ofthe other therapeutic agent.
  • the kit comprises a container containing an effective amount of a Cyanoiminopiperazine Compound and an effective amount of another therapeutic agent. Examples of other therapeutic agents include, but are not limited to, those listed above.
  • Kits ofthe 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.
  • 2,3-Dichloropyridine (15.0 g, 101.6 mmol), piperazine(9.78 g, 113.70 mmol), and triethylamine (14.36 g, 141.95 mmol) were dissolved in 300 mL of DMSO and the resulting mixture was heated at about 80 °C for about 24 h. The reaction mixture was then cooled to room temperature and extracted with a saturated aqueous sodium bicarbonate 5 solution.

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Abstract

A compound of formula (I): wherein A, Ar, R3, R6, and m are disclosed herein, or a pharmaceutically acceptable salt thereof (a 'Cyanoiminopiperazine Compound'), cornposition, comprising an effective amount of a Cyanoiminopiperazine Compound, and methods for treating or preventing pain, urinary incontinence, an ulcer, inflammatory-bowel disease, irritable-bowel syndi-oine, an addictive disorder, Parkinson's disease, parkinsonism, anxiety, epilepsy, stroke. a sc z,are, a prurifc condition, psychosis, a cognitive disorder;`a memory deficit, restricted brain function. R rnfington's chorea., arsiyotrophic lateral sclerosis, dementia, retinopathy, a muscie ,spasm„ a migraine, vomiting, dyskinesia or depression in an animal comprising administek-irgT.b ati animal in need thereof an effective amount of a Cyanoi:irinopiperazine Compound are disclosed.

Description

THERAPEUTIC AGENTS USEFUL FOR TREATING PAIN
This application claims the benefit of U.S. Provisional Application No. 60/391,962, filed June 28, 2002; U.S. Provisional Application No. 60/411,030, filed
September 17, 2002; U.S. Provisional Application No. 60/413,148, filed September 25, 2002; and U.S. Provisional Application No. 60/416,582, filed October 8, 2002, each of which is incorporated herein by reference in its entirety.
1. FIELD OF THE INVENTION
The present invention relates to Cyanoiminopiperazine Compounds, compositions comprising an effective amount of a Cyanoiminopiperazine Compound and methods for treating or preventing pain, urinary incontinence (UI), an ulcer, inflammatory- bowel disease (IBD), irritable-bowel syndrome (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, amyotrophic lateral sclerosis (ALS), dementia, retinopathy, a muscle spasm, a migraine, vomiting, dyskinesia or depression, comprising administering to an animal in need thereof an effective amount of a Cyanoiminopiperazine Compound.
2. BACKGROUND OF THE INVENTION 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 andF. Plum eds., 20th ed. 1996)).
Moreover, chronic pain can be classified as either nociceptive or neuropathic. Nociceptive pain includes tissue injury-induced pain and inflammatory pain such as that associated with arthritis. Neuropathic pain is caused by damage to the peripheral or cental nervous system and is maintained by aberrant somatosensory processing. There is a large body of evidence relating activity at both Group I metabotropic glutamate receptors, i.e., metabotropic glutamate receptor 1 ("mGluRl") and metabotropic glutamate receptor 5 ("nιGluR5") (M.E. Fundytus, CNS Drugs 15:29-58 (2001)), and vanilloid receptors ("VR1") (V. Di Marzo et al, Current Opinion in Neurobiology 12:372-379 (2002)) to pain processing. Inhibiting mGluRl or mGluR5 reduces pain, as shown by in vivo treatment with antibodies selective for either mGluRl or mGluR5, where neuropathic pain in rats was attenuated (M.E. Fundytus et al, NeuroReport 9:731-735 (1998)). It has also been shown that antisense oligonucleotide knockdown of mGluRl alleviates both neuropathic and inflammatory pain (M.E. Fundytus et al, British Journal of Pharmacology 132:354-367 (2001); M.E. Fundytus et al, Pharmacology, Biochemsitry & Behavior 73:401-410 (2002)). Small molecule antagonists for mGluR5-attenuated pain in in vivo animal models are disclosed in, e.g., K. Walker et al, Neuropharmacology 40 : 1 -9 (2000) and A. Dogrul et al, Neuroscience Letters 292:115-118 (2000)).
Nociceptive pain has been traditionally managed by administering non-opioid analgesics, such as acetylsalicylic acid, choline magnesium trisalicylate, acetaminophen, ibuprofen, fenoprofen, difiusinal, and naproxen; or opioid analgesics, including morphine, hydromorphone, methadone, levorphanol, fentanyl, oxycodone, and oxymorphone. Id. In addition to the above-listed treatments, neuropathic pain, which can be difficult to treat, has also been treated with anti-epileptics (e.g. gabapentin, carbamazepine, valproic acid, topiramate, phenytoin), NMDA antagonists (e.g. ketamine, dextromethorphan), topical lidocaine (for post-herpetic neuralgia), and tricyclic antidepressants (e.g. fluoxetine, sertraline and amitriptyline).
UI 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. At present, 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. 9:1 A (1989)). Economically, the costs of UI are great; in the United States alone, health-care costs associated with UI are over $15 billion per annum. Physiologic bladder contraction results in large part from 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. For example, anticholinergics such as propantheline bromide and glycopyrrolate, and combinations of smooth-muscle relaxants such as a combination of racemic oxybutynin and dicyclomine or an anticholinergic, have been used to treat UI (See, e.g., A.J. Wein, Urol Clin. N. Am. 22:551-511 (1995); Levin et al, J. Urol. 128:396-398 (1982); Cooke et al, S. Afr. Med. J. 63:3 (1983); R.K. Mirakhur et al, Anaesthesia 38:1195-1204 (1983)). These drugs are not effective, however, in all patients having uninhibited bladder contractions. Administration of anticholinergic medications represent the mainstay of this type of treatment.
None ofthe existing commercial drug treatments for UI, however, has achieved complete success in all classes of UI patients, nor has treatment occurred without significant adverse side effects. For example, drowsiness, dry mouth, constipation, blurred vision, headaches, tachycardia, and cardiac arrhythmia, which are related to the anticholinergic activity of traditional anti-UI drugs, can occur frequently and adversely affect patient compliance. Yet despite the prevalence of unwanted anticholinergic effects in many patients, anticholinergic drugs are currently prescribed for patients having UI. The Merck Manual of Medical Information 631-634 (R. Berkow ed., 1997). Ulcers are sores occurring where the lining ofthe digestive tract has been eroded by stomach acids or digestive juices. The sores are typically well-defined round or oval lesions primarily occurring in the stomach and duodenum. About 1 in 10 people develop an ulcer. 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.
Treatment of ulcers typically involves reducing or inhibiting the aggressive factors. For example, 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 drags into the blood stream and cause diarrhea. H2 antagonists, such as cimetidine, ranitidine, famotidine, and nizatidine, are also used to treat ulcers. H2 antagonists promote ulcer healing by reducing gastric acid and digestive-enzyme secretion elicited by histamine and other Ff2 agonists in the stomach and duodenum. H2 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. FT*", K+ - ATPase inhibitors inhibit the production of enzymes used by the stomach to secrete acid. Side effects associated with H+, 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, however, 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 HCO3 ", inhibit pepsin activity, and act as an antibacterial against H. pylori, ϊngestion of bismuth compounds, however, can lead to elevated plasma concentrations of Bi+3 and can interfere with the absoφtion of other drags. 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, can also be used to treat ulcers. Carbenoxolone appears to alter the composition and quantity of mucous, thereby enhancing the mucosal barrier. Carbenoxolone, however, 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
-A- 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., 9th ed. 1996). IBD is a chronic disorder in which the bowel becomes inflamed, often causing recurring abdominal cramps and diarrhea. The two types of IBD are Crohn's disease and ulcerative colitis.
Crohn's disease, which can include regional enteritis, granulomatous ileitis, and ileocolitis, is a chronic inflammation ofthe 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 ofthe intestinal wall. Generally the disease affects the lowest portion ofthe small intestine (ileum) and the large intestine, but can occur in any part ofthe digestive tract. Early symptoms of Crohn's disease are chronic diarrhea, crampy abdominal pain, fever, loss of appetite, and weight loss. Complications associated with Crohn's disease include the development of intestinal obstructions, abnormal connecting channels (fistulas), and abscesses. The risk of cancer ofthe large intestine is increased in people who have Crohn's disease. Often 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. There is no known cure for Crohn's disease.
Cramps and diarrhea, side effects associated with Crohn's disease, can be relieved by anticholinergic drugs, diphenoxylate, loperamide, deodorized opium tincture, or codeine. Generally, the drag is taken orally before a meal.
Broad-spectrum 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, however, 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. Long-term corticosteroid therapy, however, invariably results in serious side effects such as high blood-sugar levels, increased risk of infection, osteoporosis, water retention, and fragility ofthe skin. Drugs such as azathioprine and mercaptourine can compromise the immune system and are often effective for Crohn's disease in patients that do not respond to other drugs. These drugs, however, usually need 3 to 6 months before they produce benefits and can cause serious side effects such as allergy, pancreatitis, and low white-blood-cell count.
When Crohn's disease causes the intestine to be obstructed or when abscesses or fistulas do not heal, surgery can be necessary to remove diseased sections ofthe intestine. Surgery, however, does not cure the disease, and inflammation tends to recur where the intestine is rejoined, h almost half of the cases a second operation is needed. The Merck Manual of Medical Information 528-530 (R. Berkow ed., 1997).
Ulcerative colitis is a chronic disease in which 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 ofthe intestine. The disease usually begins in the rectum and the sigmoid colon and eventually spreads partially or completely through out the large intestine. The cause of ulcerative colitis is unknown. Treatment of ulcerative colitis is directed to controlling inflammation, reducing symptoms, and replacing lost fluids and nutrients. Anticholinergic drugs and low doses of diphenoxylate or loperamide are administered for treating mild diarrhea. For more intense diarrhea higher doses of diphenoxylate or loperamide, or deodorized opium tincture or codeine are administered. Sulfasalazine, olsalazie, prednisone, or mesalamine can be used to reduce inflammation. Azathioprine and mercaptopurine have been used to maintain remissions in ulcerative-colitis patients who would otherwise need long-term corticosteroid treatment, hi severe cases of ulcerative colitis the patient is hospitalized and given corticosteroids intravenously. People with severe rectal bleeding can require transfusions and intravenous fluids. If toxic colitis develops and treatments fail, surgery to remove the large intestine can be necessary. Non-emergency surgery can be performed if cancer is diagnosed, precancerous legions are detected, or unremitting chronic disease would otherwise make the person an invalid or dependent on high doses of corticosteroids. Complete removal ofthe large intestine and rectum permanently cures ulcerative colitis. The Merck Manual of Medical Information 530-532 (R. Berkow ed., 1997) and Goodman and Gilman 's The Pharmacological Basis of Therapeutics (J. Hardman and L. Limbird eds., 9th ed. 1996). IBS is a disorder of motility ofthe entire gastrointestinal tract, causing abdominal pain, constipation, and/or diarrhea. IBS affects three-times more women than men. In IBS stimuli such as stress, diet, drugs, hormones, or irritants can cause the gastrointestinal tract to contract abnormally. During an episode of IBS contractions ofthe gastrointestinal tract become stronger and more frequent, resulting in the rapid transit of food and feces through the small intestine, often leading to diarrhea. Cramps result from the strong contractions ofthe large intestine and increased sensitivity of pain receptors in the large intestine.
There are two major types of IBS. The first type, 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.
Treatment of IBS typically involves modification of an IBS-patient's diet. Often it is recommended that 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 ofthe gastrointestinal tract are generally not effective for treating IBS. Antidiarrheal drugs, such as diphenoxylate and loperamide, help with diarrhea. The Merck Manual of Medical Information 525-526 (R. Berkow ed., 1997).
Many drugs can cause physical and/or psychological addiction. Those most well known types of these drugs include opiates, such as heroin, opium, and morphine; sympathomimetics, including cocaine and amphetamines; sedative-hypnotics, including alcohol, benzodiazepines and barbiturates; and nicotine, which has effects similar to opioids and sympathomimetics. Drug addiction is characterized by a craving or compulsion for taking the drug and an inability to limit its intake. Additionally, drug dependence is associated with drug tolerance, the loss of effect ofthe drug following repeated admimstration, and withdrawal, the appearance of physical and behavioral symptoms when the drug is not consumed. Sensitization occurs if repeated administration of a drug leads to an increased response to each dose. Tolerance, sensitization, and withdrawal are phenomena evidencing a change in the central nervous system resulting from continued use ofthe drug. This change can motivate the addicted individual to continue consuming the drug despite serious social, legal, physical and/or professional consequences. (See, e.g., U.S. Patent No. 6,109,269 to Rise et al).
Certain pharmaceutical agents have been administered for treating addiction. 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 ofthe substance. U.S. Patent No. 5,075,341 to Mendelson et al. discloses the use of a mixed opiate agonist/antagonist to treat cocaine and opiate addiction. U.S. Patent No. 5,232,934 to Downs discloses administration of 3-phenoxypyridine to treat addiction. U.S. Patents No. 5,039,680 and 5,198,459 to hnperato 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. U.S. Patent No. 6,204,284 to Beer et al. discloses racemic (±)-l-(3,4-dichlorophenyl)-3- azabicyclo[3.1.0]hexane for use in the prevention or relief of a withdrawal syndrome resulting from addiction to drugs and for the treatment of chemical dependencies.
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. The features of Parkinson's disease are a loss of pigmented, dopaminergic neurons ofthe substantia nigra pars compacta and the appearance of intracellular inclusions known as Lewy bodies (Goodman and Gillman 's The Pharmaceutical Basis of Therapeutics 506 (9th 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. There remains, however, a need for drags useful for the treatment of Parkinson's disease and having an improved therapeutic profile.
Anxiety is a fear, apprehension, or dread of impending danger often accompanied by restlessness, tension, tachycardia, and dyspnea. Other symptoms commonly associated with anxiety include depression, especially accompanied with dysthymic disorder (chronic "neurotic" depression); panic disorder; agoraphobia and other specific phobias; eating disorders; and many personality disorders. Often anxiety is unattached to a clearly identified treatable primary illness. If a primary illness is found, however, it can be desirable to deal with the anxiety at the same time as the primary illness.
Currently, 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. The azapirones, however, are less useful for treating severe anxiety accompanied with panic attacks. Epilepsy is a disorder characterized by the tendency to have recurring seizures.
The etiology commonly consists of lesions in some part ofthe cortex, such as a tumor; developmental malformation; or damage due to trauma or stroke. In some cases the etiology is genetic. An epileptic seizure can be triggered by repetitive sounds, flashing lights, video games, or touching certain parts ofthe body. Epilepsy is typically treated with anti-seizure drugs. In epilepsy cases, where anti-seizure drugs are ineffective, and the defect in the brain is isolated to a small area ofthe brain, surgical removal of that part ofthe brain can be helpful in alleviating the seizures. In patients who have several sources for the seizures or who have seizures that spread quickly to all parts ofthe brain, surgical removal ofthe nerve fibers that connect the two sides ofthe brain can be helpful.
Examples of drugs for treating a seizure and epilepsy include carbamazepine, ethosuximide, gabapentin, lamotrignine, phenobarbital, phenytoin, primidone, valproic acid, trimethadione, bemzodiaepines, γ-vinyl GABA, acetazolamide, and felbamate. Anti-seizure drugs, however, 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 hypeφlasia; 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. The Merck Manual of Medical Information 345-350 (R. Berkow ed., 1997).
A seizure is the result of abnormal electrical discharge in the brain. The discharge can involve a small area ofthe brain and lead to the person only noticing an odd taste or smell or it can involve a large area ofthe brain and lead to convulsions, i.e., a seizure that causes jerking and spasms ofthe muscles throughout the body. Convulsions can also result in brief attacks of altered consciousness and loss of consciousness, muscle control, or bladder control. A seizures is often preceded by auras, i.e., unusual sensations of smell, taste, or vision or an intense feeling that a seizure is about to begin. A seizure typically lasts for about 2 to 5 minutes. When the seizure ends the person can have headache, sore muscles, unusual sensations, confusion, and profound fatigue (postictal state). Usually the person cannot remember what happened during the seizure.
A stroke or cerebrovascular 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. In an ischemic stroke, blood supply to the brain is cut off because of athersclerosis or a blood clot that has blocked a blood vessel. In a hemorrhagic stroke, a blood vessel bursts preventing normal blood flow and allowing blood to leak into an area ofthe brain and destroying it. Most strokes develop rapidly and cause brain damage within minutes. In some cases, however, strokes can continue to worsen for several hours or days. Symptoms of strokes vary depending on what part ofthe brain is effected. Symptoms include loss or abnormal sensations in an arm or leg or one side ofthe body, weakness or paralysis of an arm or leg or one side ofthe body, partial loss of vison or hearing, double vision, dizziness, slurred speech, difficulty in thinking ofthe appropriate word or saying it, inability to recognize parts ofthe body, unusual movements, loss of bladder control, imbalance, and falling, and fainting. The symptoms can be permanent and can be associated with coma or stupor. Strokes can cause edema or swelling ofthe brain which can further damage brain tissue. For persons suffering from a stroke, intensive rehabilitation can help overcome the disability caused by impairment of brain tissue. Rehabilitation trains other parts ofthe brain to assume the tasks previously performed by the damaged part.
Examples of drugs for treating strokes include anticoagulants such as heparin, drags 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, heφetiformis, 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. Conventionally, pruritus is treated by phototherapy with ultraviolet B or PUVA or with therapeutic agents such as naltrexone, nalmefene, danazol, tricyclics, and antidepressants.
Selective antagonists ofthe metabotropic glutamate receptor 5 ("mGluR5") have been shown to exert analgesic activity in in vivo animal models (K. Walker et al, Neuropharmacology 40:1-9 (2000) and A. Dogrul et al, Neuroscience Letters, 292(2):115- 118 (2000)).
Selective antagonists ofthe mGluR5 receptor have also been shown to exert anxiolytic and anti-depressant activity in in vivo animal models (E. Tatarczynska et al, Br. J. Pharmacol. 132(7): 1423-1430 (2001) and P.J.M. Will et al, Trends in Pharmacological Sciences 22(7):331-37 (2001)). Selective antagonists ofthe mGluR5 receptor have also been shown to exert anti-Parkinson activity in vivo (K. J. Ossowska et al, Neuropharmacology 41(4):413-20 (2001) and P.J.M. Will et al, Trends in Pharmacological Sciences 22(7):331-37 (2001)).
Selective antagonists ofthe mGluR5 receptor have also been shown to exert anti-dependence activity in vivo (C. Chiamulera et al, Nature Neuroscience 4(9):873-74 (2001)).
International publication no. WO 02/16318 discloses a class of N-cyanoimines allegedly useful for treating a acute pain, urinary bladder hypersensitiveness, an ulcer, IBD, and IBS. There remains, however, a clear need in the art for new drags 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. Citation of any reference in Section 2 of this application is not to be construed as an admission that such reference is prior art to the present application
3. SUMMARY OF THE INVENTION
The present invention encompasses compounds having the formula (I):
Figure imgf000013_0001
(D and pharmaceutically acceptable salts thereof, wherein: A is -NR4-, -O-, or -S-;
R1 is -halo, -CH3, -NO2, -CN, -OH, -OCH3, -NH2, -C(halo)3, -CH(halo)2, or -CH2(halo); each R2 is independently:
(a) -halo, -CN, -OH, -NO2, or -NH2;
(b) -(CrC10)alkyl, -(C2-C10)alkenyl, -(C2-C10)alkynyl, -(C3- C10)cycloalkyl, -(C8-C14)bicycloalkyl, -(C8-C14)tricycloalkyl, -(C5-
C10)cycloalkenyl,-(C8-C14)bicycloalkenyl, -(C8-C14)tricycloalkenyl, -(C3- C7)heterocycle, or -(C7-C10)bicycloheterocycle, each of which is unsubstituted or substituted with one or more R5 groups; or
(c) -phenyl, -naphthyl, -(C14)aryl, or -(C5-C10)heteroaryl, each of which is unsubstituted or substituted with one or more R7 groups; each R3 is independently:
(a) -halo, -CN, -OH, -NO2, or -NH2; or
(b) -(CrC10)alkyl, -(C2-C10)alkenyl, -(C2-C10)alkynyl, -(C3- C10)cycloalkyl, -(C8-C14)bicycloalkyl, -(C8-C14)tricycloalkyl, -(C5- C10)cycloalkenyl,-(C8-C14)bicycloalkenyl, -(C8-C14)tricycloalkenyl, -(C3-
C7)heterocycle, or -(C7-C10)bicycloheterocycle, each of which is unsubstituted or substituted with one or more R5 groups; or
(c) -phenyl, -naphthyl, -(Cι4)aryl or -(C5-C10)heteroaryl, each of which is unsubstituted or substituted with one or more R7 groups; R4 is -(CrC6)alkyl, or -O-(CrC6)alkyl; each R5 is independently -CN, -OH, -(Cj-C^alkyl, -(C2-C6)alkenyl, - (C2-C6)alkenyl, -halo, -N3, -NO2, -N(R8)2, -CH=NR8, -NR8OH, -OR8, -COR8' -C(O)OR8, -OC(O)R8, -OC(O)OR8, -SR8, -S(O)R8, or -S(O)2R8;
R6 is -phenyl, -naphthyl, -(C3-C8)cycloalkyl,-(C14)aryl, or -(C5-C10)heteroaryl, each of which is unsubstituted or substituted with one or more R7 groups; each R7 is independently -(Cj-C^alkyl, -(C2-C6)alkenyl, -(C2-C6)alkynyl, -(C3-C8)cycloalkyl, -(C5-C8)cycloalkenyl, -phenyl, -(C3-C5)heterocycle, -C(halo)3, -CH2(halo), -CH(halo)2, -CN, -OH, -halo, -N3, -NO2, -N(R8)2, -CH=NR8, -NR8OH, -OR8, -COR8, -C(O)OR8, -OC(O)R8, -OC(O)OR8, -SR8, -S(O)R8, or -S(O)2R8; each R8 is independently -H, -( -C^alkyl, -(C2-C6)alkenyl, -(C2-C6)alkynyl,
-(C3-C8)cycloalkyl, -(C5-C8)cycloalkenyl, -phenyl, -(C3-C5)heterocycle, -C(halo)3, -CH2(halo), or -CH(halo)2; each halo is independently -F, -CI, -Br or -I; n is an integer ranging from 0 to 3; and m is an integer ranging from 0 to 2. The present invention encompasses compounds having the formula (la):
Figure imgf000015_0001
(la) and pharmaceutically acceptable salts thereof, wherein:
R1 is -halo, -CH3, -NO2, -CN, -OH, -OCH3, -NH2, -C(halo)3, -CH(halo)2, or -CH2(halo); each R2 is independently:
(a) -halo, -CN, -OH, -NO2, or -NH2; (b) -(CrC10)alkyl, -(C2-C10)alkenyl, -(C2-C10)alkynyl, -(C3-
C10)cycloalkyl, -(C8-C14)bicycloalkyl,
Figure imgf000015_0002
-(C5- C10)cycloalkenyl,-(C8-C14)bicycloalkenyl, -(C8-Cι4)tricycloalkenyl, -(C3- C7)heterocycle, or -(C7-C10)bicycloheterocycle, each of which is unsubstituted or substituted with one or more R5 groups; or (c) -phenyl, -naphthyl, -(C14)aryl, or -(C5-C10)heteroaryl, each of which is unsubstituted or substituted with one or more R7 groups; each R3 is independently:
(a) -halo, -CN, -OH, -NO2, or -NH2; or
(b) -(CrC10)alkyl, -(C2-C10)alkenyl, -(C2-C10)alkynyl, -(C3- C10)cycloalkyl, -(C8-C14)bicycloalkyl, -(C8-Ci4)tricycloalkyl, -(C5-
C10)cycloalkenyl, -(C8-C14)bicycloalkenyl, -(Cg-C14)tricycloalkenyl, -(C3- C7)heterocycle, or -(C7-C10)bicycloheterocycle, each of which is unsubstituted or substituted with one or more R5 groups; or
(c) -phenyl, -naphthyl, -(C^aryl or -(C5-C10)heteroaryl, each of which is unsubstituted or substituted with one or more R7 groups; each R5 is independently -CN, -OH, -(C1-C6)alkyl, -(C2-C6)alkenyl, -
(C2-C6)alkenyl, -halo, -N3, -NO2, -N(R8)2, -CH=NR8, -NR8OH, -OR8, -COR8' -C(O)OR8, -OC(O)R8, -OC(O)OR8, -SR8, -S(O)R8, or -S(O)2R8; R6 is:
(a) -naphthyl, -(C14)aryl, or -(C3-Cg)cycloalkyl each of which is unsubstituted or substituted with one or more R7 groups; or
(b) pyridyl, furyl, benzofuranyl, thiophenyl, benzothiophenyl, quinolinyl, indolyl, oxazolyl, benzoxazolyl, imidazolyl, benzimidazolyl. thiazolyl, benzothiazolyl, isoxazolyl, pyrazolyl, isothiazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, thiadiazolyl, triazinyl, cinnolinyl, phthalazinyl, or quinazolinyl, each of which is substituted with one or more R7 groups; each R7 is independently -(C1-C6)alkyl, -(C2-C6)alkenyl, -(C2-C6)alkynyl, -(C3-C8)cycloalkyl, -(C5-C8)cycloalkenyl, -phenyl, -(C3-C5)heterocycle, -C(halo)3, -CH2(halo), -CH(halo)2, -CN, -OH, -halo, -N3, -NO2, -N(R8)2, -CH=NR8, -NR8OH, -OR8, -COR8, -C(O)OR8, -OC(O)R8, -OC(O)OR8, -SR8, -S(O)R8, or -S(O)2R8; each R8 is independently -H, -(Cι-C6)alkyl, -(C2-C6)alkenyl, -(C2-C6)alkynyl, .
-(C3-C8)cycloalkyl, -(C5-C8)cycloalkenyl, -phenyl, -(C3-C5)heterocycle, -C(halo)3, -CH2(halo), or -CH(halo)2; each halo is independently -F, -CI, -Br or -I; n is an integer ranging from 0 to 3; and m is an integer ranging from 0 to 2.
The present invention encompasses compounds having the formula (lb):
Figure imgf000017_0001
(lb) and pharmaceutically acceptable salts thereof, wherein:
R1 is -halo, -CH3, -NO2, -CN, -OH, -OCH3, -NH2, -C(halo)3, -CH(halo)2, or -CH2(halo); each R2 is independently:
(a) -halo, -CN, -OH, -NO2, or -NH2;
(b) -(CrC10)alkyl, -(C2-C10)alkenyl, -(C2-C10)alkynyl, -(C3- C10)cycloalkyl, -(Cg-Cι4)bicycloalkyl, -(C8-C14)tricycloalkyl, -(C5- C10)cycloalkenyl,-(C8-C14)bicycloalkenyl, -(Cg-C14)tricycloalkenyl, -(C3-
C7)heterocycle, or -(C7-C10)bicycloheterocycle, each of which is unsubstituted or substituted with one or more R5 groups; or
(c) -phenyl, -naphthyl, -(C14)aryl, or -(C5-C10)heteroaryl, each of which is unsubstituted or substituted with one or more R7 groups; each R3 is independently:
(a) -halo, -CN, -OH, -NO2, or -NH2; or
(b) -(CrC10)alkyl, -(C2-C10)alkenyl, -(C2-C10)alkynyl, -(C3- C10)cycloalkyl, -(C8-C14)bicycloalkyl, -(C8-C14)tricycloalkyl, -(C5- C10)cycloalkenyl,-(C8-C14)bicycloalkenyl, -(C8-C14)tricycloalkenyl, -(C3- C7)heterocycle, or -(C7-C10)bicycloheterocycle, each of which is unsubstituted or substituted with one or more R5 groups; or (c) -phenyl, -naphthyl, -(C14)aryl or -(C5-C10)heteroaryl, each of which is unsubstituted or substituted with one or more R7 groups; each R5 is independently -CN, -OH, -( -C^alkyl, -(C2-C6)alkenyl, - (C2-C6)alkenyl, -halo, -N3, -NO2, -N(R8)2, -CH=NR8, -NR8OH, -OR8, -COR8' -C(O)OR8, -OC(O)R8, -OC(O)OR8, -SR8, -S(O)R8, or -S(O)2R8; each R7, R9, and R10 is independently -(C,-C6)alkyl, -(C2-C6)alkenyl, - (C2-C6)alkynyl, -(C3-C8)cycloalkyl, -(C5-C8)cycloalkenyl, -phenyl, -(C3-C5)heterocycle, - C(halo)3, -CH(halo)2, -CH2(halo), -CN, -OH, -halo, -N3, -NO2, -N(R8)2, -CH=NR8, -NR8OH, -OR8, -COR8, -C(O)OR8, -OC(O)R8, -OC(O)OR8, -SR8, -S(O)R8, or -S(O)2R8; each R8 is independently -H,
Figure imgf000018_0001
-(C2-C6)alkenyl, -(C2-C6)alkynyl,
-(C3-C8)cycloalkyl, -(C5-C8)cycloalkenyl, -phenyl, -(C3-C5)heterocycle, -C(halo)3, -CH2(halo), or -CH(halo)2; each halo is independently -F, -CI, -Br or -I; n is an integer ranging from 0 to 3; m is an integer ranging from 0 to 2; and p is an integer ranging from 0 to 4. The present invention encompasses compounds having the formula (Ic):
Figure imgf000018_0002
(Ic) and pharmaceutically acceptable salts thereof, wherein: A is -NR4-, -O-, or -S-; each R3 is independently:
(a) -halo, -CN, -OH, -NO2, or -NH2; or (b) -(CrC10)alkyl, -(C2-C10)alkenyl, -(C2-C10)alkynyl, -(C3- C10)cycloalkyl, -(C8-C14)bicycloalkyl, -(C8-Cι4)tricycloalkyl, -(C5- C10)cycloalkenyl,-(C8-C14)bicycloalkenyl, -(C8-C14)tricycloalkenyl, -(C3- C7)heterocycle, or -(C7-C10)bicycloheterocycle, each of which is unsubstituted or substituted with one or more R5 groups; or
(c) -phenyl, -naphthyl, -(C14)aryl or -(C5-C10)heteroaryl, each of which is unsubstituted or substituted with one or more R7 groups;
R4 is -(CrC6)alkyl, or -O-(CrC6)alkyl; each R5 is independently -CN, -OH,
Figure imgf000019_0001
-(C2-C6)alkenyl, - (C2-C6)alkenyl, -halo, -N3, -NO2, -N(R8)2, -CH=NR8, -NR8OH, -OR8, -COR8' -C(O)OR8, -OC(O)R8, -OC(O)OR8, -SR8, -S(O)R8, or -S(O)2R8;
R6 is -phenyl, -naphthyl, -(C3-C8)cycloalkyl,-(C14)aryl, or -(C5-C10)heteroaryl, each of which is unsubstituted or substituted with one or more R7 groups; each R7 is independently -(C1-C6)alkyl, -(C2-C6)alkenyl, -(C2-C6)alkynyl, - (C3-C8)cycloalkyl, -(Cs-C^cycloalkenyl, -phenyl, -(C3-C5)heterocycle, -C(halo)3, -CH(halo)2, -CH2(halo), -CN, -OH, -halo, -N3, -NO2, -N(R8)2, -CH=NR8, -NR8OH, -OR8, -COR8, -C(O)OR8, -OC(O)R8, -OC(O)OR8, -SR8, -S(O)R8, or -S(O)2R8; each R8 is independently -H, -(Cj-C^alkyl, -(C2-C6)alkenyl, -(C2-C6)alkynyl, -(C3-C8)cycloalkyl, -(C5-C8)cycloalkenyl, -phenyl, -(C3-C5)heterocycle, -C(halo)3, -CH2(halo), or -CH(halo)2;
R11 is -hydrogen, -halo, -CH3, -NO2, -CN, -OH, -OCH3, -NH2, -C(halo)3, - CH(halo)2, or -CH2(halo); each R12 is independently:
(a) -halo, -CN, -OH, -NO2, or -NH2; (b) -(CrC10)alkyl, -(C2-C10)alkenyl, -(C2-C10)alkynyl, -(C3-
C10)cycloalkyl, -(C8-C]4)bicycloalkyl, -(C8-C14)tricycloalkyl, -(C5- C10)cycloalkenyl,-(C8-C14)bicycloalkenyl, -(C8-CM)tricycloalkenyl, -(C3- C7)heterocycle, or -(C7-Cι0)bicycloheterocycle, each of which is unsubstituted or substituted with one or more R5 groups; or (c) -phenyl, -naphthyl, -(C14)aryl, or -(C5-C10)heteroaryl, each of which is unsubstituted or substituted with one or more R7 groups; m is an integer ranging from 0 to 2; and q is an integer ranging from 0 to 3.
The present invention also encompasses compounds having the formula (fl):
Figure imgf000020_0001
(π) and pharmaceutically acceptable salts thereof, wherein:
A is -NR4-, -O-, or -S-; R1 is -halo, -CH3, -NO2, -CN, -OH, -OCH3, -NH2, -C(halo)3, -CH(halo)2, or -
CH2(halo); each R2 is independently:
(a) -halo, -CN, -OH, -NO2, or -NH2;
(b) -(CrC10)alkyl, -(C2-C10)alkenyl, -(C2-C10)alkynyl, -(C3- C10)cycloalkyl, -(C8-Cι4)bicycloalkyl, -(C8-C14)tricycloalkyl, -(C5-
C10)cycloalkenyl,-(C8-C14)bicycloalkenyl, -(C8-C14)tricycloalkenyl, -(C3- C7)heterocycle, or -(C7-C10)bicycloheterocycle, each of which is unsubstituted or substituted with one or more R5 groups; or
(c) -phenyl, -naphthyl, -(C14)aryl, or -(C5-CI0)heteroaryl, each of which is unsubstituted or substituted with one or more R7 groups; each R3 is independently:
(a) -halo, -CN, -OH, -NO2, or -NH2;
(b) -(CrC10)alkyl- -(C2-C10)alkenyl, -(C2-C10)alkynyl, -(C3- C10)cycloalkyl, -(C8-C14)bicycloalkyl, -(C8-C14)tricycloalkyl, -(C5- C10)cycloalkenyl,-(C8-C14)bicycloalkenyl, -(C8-C14)tricycloalkenyl, -(C3- C7)heterocycle, or -(C7-Cι0)bicycloheterocycle, each of which is unsubstituted or substituted with one or more R5 groups; or
(c) -phenyl, -naphthyl, -(C14)aryl or -(C5-C10)heteroaryl, each of which is unsubstituted or substituted with one or more R7 groups; R4 is hydrogen, -(C,-C6)alkyl, or -O-(CrC6)alkyl; each R5 is independently -CN, -OH, -( -C^alkyl, -(C2-C6)alkenyl, - (C2-C6)alkenyl, -halo, -N3, -NO2, -N(R8)2, -CH=NR8, -NR8OH, -OR8, -COR8' -C(O)OR8, -OC(O)R8, -OC(O)OR8, -SR8, -S(O)R8, or -S(O)2R8;
R6 is -phenyl, -naphthyl, -(C3-C8)cycloalkyl,-(C14)aryl, or -(C5-Cι0)heteroaryl, each of which is unsubstituted or substituted with one or more R7 groups; each R7 is independently -(Cj-C^alkyl, -(C2-C6)alkenyl, -(C2-C6)alkynyl, -(C3-C8)cycloalkyl, -(C5-C8)cycloalkenyl, -phenyl, -(C3-C5)heterocycle, -C(halo)3, -CH2(halo), -CH(halo)2, -CN, -OH, -halo, -N3, -NO2, -N(R8)2, -CH=NR8, -NR8OH, -OR8, -COR8, -C(O)OR8, -OC(O)R8, -OC(O)OR8, -SR8, -S(O)R8, or -S(O)2R8; each R8 is independently -H, -(Cι-C6)alkyl, -(C2-C6)alkenyl, -(C2-C6)alkynyl,
-(C3-C3)cycloalkyl, -(C5-C8)cycloalkenyl, -phenyl, -(C3-C5)heterocycle, -C(halo)3, -CH2(halo), or -CH(halo)2; each halo is independently -F, -CI, -Br or -I; n 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 (lla):
Figure imgf000021_0001
(fla) and pharmaceutically acceptable salts thereof, wherein: A is -NR4-, -O-, or -S-; each R3 is independently:
(a) -halo, -CN, -OH, -NO2, or -NH2; (b) -(CrC10)alkyl, -(C2-C10)alkenyl, -(C2-C]0)alkynyl, -(C3-
C10)cycloalkyl, -(C8-C14)bicycloalkyl, -(C8-Cj4)tricycloalkyl, -(C5- Cι0)cycloalkenyl,-(C8-C14)bicycloalkenyl, -(C8-CM)tricycloalkenyl, -(C3- C7)heterocycle, or -(C7-C]0)bicycloheterocycle, each of which is unsubstituted or substituted with one or more R5 groups; or (c) -phenyl, -naphthyl, -(C14)aryl or -(C5-Cι0)heteroaryl, each of which is unsubstituted or substituted with one or more R7 groups; R4 is hydrogen, -(C,-C6)alkyl, or -O-(CrC6)alkyl; each R5 is independently -CN, -OH, -( - alkyl, -(C2-C6)alkenyl, - (C2-C6)alkenyl, -halo, -N3, -NO2, -N(R8)2, -CH=NR8, -NR8OH, -OR8, -COR8- -C(O)OR8, -OC(O)R8, -OC(O)OR8, -SR8, -S(O)R8, or -S(O)2R8;
R6 is -phenyl, -naphthyl, -(C3-C8)cycloalkyl,-(C14)aryl, or -(C5-C10)heteroaryl, each of which is unsubstituted or substituted with one or more R7 groups; each R7 is independently -(Cι~-C6)alkyl, -(C2-C6)alkenyl, -(C2-C6)alkynyl, -(C3-C3)cycloalkyl, -(C5-C8)cycloalkenyl, -phenyl, -(C3-C5)heterocycle, -C(halo)3, -CH2(halo), -CH(halo)2, -CN, -OH, -halo, -N3, -NO2, -N(R8)2, -CH=NR8, -NR8OH, -OR8, -COR8, -C(O)OR8, -OC(O)R8, -OC(O)OR8, -SR8, -S(O)R8, or -S(O)2R8; each R8 is independently -H, -(C1-C6)alkyl, -(C2-C6)alkenyl, -(C2-C6)alkynyl, -(C3-C8)cycloalkyl, -(C5-C8)cycloalkenyl, -phenyl, -(C3-C5)heterocycle, -C(halo)3, -CH2(halo), or -CH(halo)2; R11 is -hydrogen, -halo, -CH3, -NO2, -CN, -OH, -OCH3, -NH2, -C(halo)3, -
CH(halo)2, or -CH2(halo); each R12 is independently:
(a) -halo, -CN, -OH, -NO2, or -NH2;
(b) -(CrC10)alkyl, -(C2-C10)alkenyl, -(C2-C10)alkynyl, -(C3- C,0)cycloalkyl, -(C8-C,4)bicycloalkyl, -(Cs-Cι4)tricycloalkyl, -(C5-
CI0)cycloalkenyl,-(C8-C14)bicycloalkenyl,
Figure imgf000022_0001
-(C3- C7)heterocycle, or -(C7-C10)bicycloheterocycle, each of which is unsubstituted or substituted with one or more R5 groups; or
(c) -phenyl, -naphthyl, -(C14)aryl, or -(C5-C10)heteroaryl, each of which is unsubstituted or substituted with one or more R7 groups; and each halo is independently -F, -CI, -Br or -I; q 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 (HT):
Figure imgf000023_0001
(IH) and pharmaceutically acceptable salts thereof, wherein: A is -NR4-, -O-, or -S-; R1 is -halo, -CH3, -NO2, -CN, -OH, -OCH3, -NH2, -C(halo)3, -CH(halo)2, or -
CH2(halo); each R2 is independently:
(a) -halo, -CN, -OH, -NO2, or -NH2;
(b) -(CrCI0)alkyl, -(C2-C10)alkenyl, -(C2-C10)alkynyl, -(C3- C10)cycloalkyl, -(C8-Cι4)bicycloalkyl, -(C8-C14)tricycloalkyl, -(C5-
C10)cycloalkenyl,-(C8-C14)bicycloalkenyl, -(Cg-C14)tricycloalkenyl, -(C3- C7)heterocycle, or -(C7-C]0)bicycloheterocycle, each of which is unsubstituted or substituted with one or more R5 groups; or
(c) -phenyl, -naphthyl, -(C14)aryl, or -(C5-C10)heteroaryl, each of which is unsubstituted or substituted with one or more R7 groups; each R3 is independently: (a) -halo, -CN, -OH, -NO2, or -NH2;
(b) -(CrC10)alkyl, -(C2-C10)alkenyl, -(C2-C10)alkynyl, -(C3- C10)cycloalkyl, -(C8-Cι4)bicycloalkyl, -(C8-C14)tricycloalkyl, -(C5- C10)cycloalkenyl,-(C8-C14)bicycloalkenyl, -(C8-C14)tricycloalkenyl, -(C3- C7)heterocycle, or -(C7-C10)bicycloheterocycle, each of which is unsubstituted or substituted with one or more R5 groups; or
(c) -phenyl, -naphthyl, -(C14)aryl or -(C5-C10)heteroaryl, each of which is unsubstituted or substituted with one or more R7 groups;
R4 is -(CrC6)alkyl, or -O-(C,-C6)alkyl; each R5 is independently -CN, -OH, -(Cι-C6)alkyl, -(C2-C6)alkenyl, -
(C2-C6)alkenyl, -halo, -N3, -NO2, -N(R8)2, -CH=NR8, -NR8OH, -OR8, -COR8' -C(O)OR8, -OC(O)R8, -OC(O)OR8, -SR8, -S(O)R8, or -S(O)2R8;
R6 is -phenyl, -naphthyl, -(C3-C8)cycloalkyl,-(C14)aryl, or -(C5-C10)heteroaryl, each of which is unsubstituted or substituted with one or more R7 groups; each R7 is independently -(Cι-C6)alkyl, -(C2-C6)alkenyl, -(C2-C6)alkynyl,
-(C3-C8)cycloalkyl, -(C5-C8)cycloalkenyl, -phenyl, -(C3-C5)heterocycle, -C(halo)3, -CH(halo)2, -CH2(halo), -CN, -OH, -halo, -N3, -NO2, -N(R8)2, -CH=NR8, -NR8OH, -OR8, -COR8, -C(O)OR8, -OC(O)R8, -OC(O)OR8, -SR8, -S(O)R8, or -S(O)2R8; each R8 is independently -H, -(C]-C6)alkyl, -(C2-C6)alkenyl, -(C2-C6)alkynyl, -(C3-C8)cycloalkyl, -(C5-C8)cycloalkenyl, -phenyl, -(C3-C5)heterocycle, -C(halo)3, -CH2(halo), or -CH(halo)2; each halo is independently -F, -CI, -Br or -I; n is an integer ranging from 0 to 2; and m is an integer ranging from 0 to 2. The present invention encompasses compounds having the formula (HTa):
Figure imgf000025_0001
(ma) and pharmaceutically acceptable salts thereof, wherein:
R1 is -halo, -CH3, -NO2, -CN, -OH, -OCH3, -NH2, -C(halo)3, -CH(halo)2, or -CH2(halo); each R2 is independently:
(a) -halo, -CN, -OH, -NO2, or -NH2; (b) -(C1-C10)alkyl, -(C2-C10)alkenyl, -(C2-C10)alkynyl, -(C3-
C10)cycloalkyl, -(C8-C14)bicycloalkyl,
Figure imgf000025_0002
-(C5-
Cι0)cycloalkenyl,-(C8-C,4)bicycloalkenyl, -(C8-C14)tricycloalkenyl, -(C3-
C7)heterocycle, or -(C7-C10)bicycloheterocycle, each of which is unsubstituted or substituted with one or more R5 groups; or (c) -phenyl, -naphthyl, -(CI4)aryl, or -(C5-Cι0)heteroaryl, each of which is unsubstituted or substituted with one or more R7 groups; each R3 is independently:
(a) -halo, -CN, -OH, -NO2, or -NH2; or
(b) -(CrC10)alkyl, -(C2-C10)alkenyl, -(C2-C10)alkynyl, -(C3- C10)cycloalkyl, -(C8-Cι4)bicycloalkyl, -(C8-C14)tricycloalkyl, -(C5-
C10)cycloalkenyl,-(C8-CM)bicycloalkenyl, -(C8-C14)tricycloalkenyl, -(C3- C7)heterocycle, or -(C7-C10)bicycloheterocycle, each of which is unsubstituted or substituted with one or more R5 groups; or
(c) -phenyl, -naphthyl, -(C14)aryl or -(C5-C)0)heteroaryl, each of which is unsubstituted or substituted with one or more R7 groups; each R5 is independently -CN, -OH, -(C1-C6)alkyl, -(C2-C6)alkenyl, - (C2-C6)alkenyl, -halo, -N3, -NO2, -N(R8)2, -CH=NR8, -NR8OH, -OR8, -COR8' -C(O)OR8, -OC(O)R8, -OC(O)OR8, -SR8, -S(O)R8, or -S(O)2R8; R6 is: (a), -naphthyl, -(C14)aryl, or -(C3-C8)cycloalkyl each of which is unsubstituted or substituted with one or more R7 groups; or
(b) pyridyl, furyl, benzofiiranyl, thiophenyl, benzothiophenyl, quinolinyl, indolyl, oxazolyl, benzoxazolyl, imidazolyl, benzimidazolyl, thiazolyl, benzothiazolyl, isoxazolyl, pyrazolyl, isothiazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, thiadiazolyl, triazinyl, cinnolinyl, phthalazinyl, or quinazolinyl, each of which is substituted with one or more R7 groups; each R7 is independently -( -C^alkyl, -(C2-C6)alkenyl, -(C2-C6)alkynyl, -(C3-C8)cycloalkyl, -(C5-C8)cycloalkenyl, -phenyl, -(C3-C5)heterocycle, -C(halo)3, -CH(halo)2, -CH2(halo), -CN, -OH, -halo, -N3, -NO2, -N(R8)2, -CH=NR8, -NR8OH, -OR8, -COR8, -C(O)OR8, -OC(O)R8, -OC(O)OR8, -SR8, -S(O)R8, or -S(O)2R8; each R8 is independently -H, -( -C^alkyl, -(C2-C6)alkenyl, -(C2-C6)alkynyl, -(C3-C8)cycloalkyl, -(C5-C8)cycloalkenyl, -phenyl, -(C3-C5)heterocycle, -C(halo)3 -CH2(halo), or -CH(halo)2; each halo is independently -F, -CI, -Br or -I; n is an integer ranging from 0 to 2; and m is an integer ranging from 0 to 2. The present invention encompasses compounds having the formula (DTD):
Figure imgf000027_0001
(mb) and pharmaceutically acceptable salts thereof, wherein:
R1 is -halo, -CH3, -NO2, -CN, -OH, -OCH3, -NH2, -C(halo)3, -CH(halo)2, or -CH2(halo); each R2 is independently:
(a) -halo, -CN, -OH, -NO2, or -NH2;
(b) -(CrC10)alkyl, -(C2-C10)alkenyl, -(C2-C10)alkynyl, -(C3- Ci0)cycloalkyl, -(C8-Cι4)bicycloalkyl,
Figure imgf000027_0002
-(C5- C10)cycloalkenyl,-(C8-C,4)bicycloalkenyl, -(C8-C14)tricycloalkenyl, -(C3- C7)heterocycle, or -(C7-C10)bicycloheterocycle, each of which is unsubstituted or substituted with one or more R5 groups; or
(c) -phenyl, -naphthyl, -(C14)aryl, or -(C5-C10)heteroaryl, each of which is unsubstituted or substituted with one or more R7 groups; each R3 is independently:
(a) -halo, -CN, -OH, -NO2, or -NH2; or
(b) -(C1-C10)alkyl, -(C2-C10)alkenyl, -(C2-C10)alkynyl, -(C3- C10)cycloalkyl, -(C8-C14)bicycloalkyl, -(C8-C14)tricycloalkyl, -(C5- C10)cycloaιkenyl,-(Cg-C14)bicycloalkenyl, -(C8-C14)tricycloalkenyl, -(C3- C7)heterocycle, or -(C7-C10)bicycloheterocycle, each of which is unsubstituted or substituted with one or more R5 groups; or (c) -phenyl, -naphthyl, -(C14)aryl or -(C5-Cι0)heteroaryl, each of which is unsubstituted or substituted with one or more R7 groups; each R5 is independently -CN, -OH, -(C1-C6)alkyl, -(C2-C6)alkenyl, - (C2-C6)alkenyl, -halo, -N3, -NO2, -N(R8)2, -CH=NR8, -NR8OH, -OR8, -COR8' -C(O)OR8, -OC(O)R8, -OC(O)OR8, -SR8, -S(O)R8, or -S(O)2R8; each R7, R9, and R10 is independently -( -C^alkyl, -(C2-C6)alkenyl, - (C2-C6)alkynyl, -(C3-C8)cycloalkyl, -(C5-C8)cycloalkenyl, -phenyl, -(C3-C5)heterocycle, - C(halo)3, -CH(halo)2, -CH2(halo), -CN, -OH, -halo, -N3, -NO2, -N(R8)2, -CH=NR8, -NR8OH, -OR8, -COR8, -C(O)OR8, -OC(O)R8, -OC(O)OR8, -SR8, -S(O)R8, or -S(O)2R8; each R8 is independently -H, -(Cj-C6)alkyl, -(C2-C6)alkenyl, -(C2-C6)alkynyl,
-(C3-C8)cycloalkyl, -(C5-C8)cycloalkenyl, -phenyl, -(C3-C5)heterocycle, -C(halo)3, -CH2(halo), or -CH(halo)2; each halo is independently -F, -CI, -Br or -I; n is an integer ranging from 0 to 2; m is an integer ranging from 0 to 2; and p is an integer ranging from 0 to 4. The present invention also encompasses compounds having the formula (HIc):
Figure imgf000028_0001
(mc) and pharmaceutically acceptable salts thereof, wherein: A is -NR4-, -O-, or -S-; each R3 is independently:
(a) -halo, -CN, -OH, -NO2, or -NH2; (b) -(CrC10)alkyl, -(C2-C10)alkenyl, -(C2-C10)alkynyl, -(C3- Cι0)cycloalkyl, -(Cg-C14)bicycloalkyl,
Figure imgf000029_0001
-(C5- Cιo)cycloalkenyl,-(C8-Cι4)bicycloalkenyl, -(C8-C14)tricycloalkenyl, -(C3- C7)heterocycle, or -(C7-C10)bicycloheterocycle, each of which is unsubstituted or substituted with one or more R5 groups; or
(c) -phenyl, -naphthyl, -(CI4)aryl or -(C5-C10)heteroaryl, each of which is unsubstituted or substituted with one or more R7 groups;
R4 is -(CrC6)alkyl, or -O-(CrC6)alkyl; each R5 is independently -CN, -OH, -( -C^alkyl, -(C2-C6)alkenyl, - (C2-C6)alkenyl, -halo, -N3, -NO2, -N(R8)2, -CH=NR8, -NR8OH, -OR8, -COR8' -C(O)OR8, -OC(O)R8, -OC(O)OR8, -SR8, -S(O)R8, or -S(O)2R8;
R6 is -phenyl, -naphthyl, -(C3-C8)cycloalkyl,-(Cι4)aryl, or -(C5-C10)heteroaryl, each of which is unsubstituted or substituted with one or more R7 groups; each R7 is independently -(C1-C6)alkyl, -(C2-C6)alkenyl, -(C2-C6)alkynyl, -(C3-C8)cycloalkyl, -(C5-C8)cycloalkenyl, -phenyl, -(C3-C5)heterocycle, -C(halo)3,
-CH(halo)2, -CH2(halo), -CN, -OH, -halo, -N3, -NO2, -N(R8)2, -CH=NR8, -NR8OH, -OR8, -COR8, -C(O)OR8, -OC(O)R8, -OC(O)OR8, -SR8, -S(O)R8, or -S(O)2R8; each R8 is independently -H, -(Cj-C^alkyl, -(C2-C6)alkenyl, -(C2-C6)alkynyl, -(C3-C8)cycloalkyl, -(C5-C8)cycloalkenyl, -phenyl, -(C3-C5)heterocycle, -C(halo)3, -CH2(balo), or -CH(halo)2;
Ru is -hydrogen, -halo, -CH3, -NO2, -CN, -OH, -OCH3, -NH2, -C(halo)3, -CH(halo)2, or -CH2(halo); each R12 is independently:
(a) -halo, -CN, -OH, -NO2, or -NH2; (b) -(CrC10)alkyl, -(C2-C10)alkenyl, -(C2-C10)alkynyl, -(C3-
C10)cycloalkyl, -(C8-C,4)bicycloalkyl, -(C8-C14)tricycloalkyl, -(C5- C]0)cycloalkenyl,-(C8-C14)bicycloalkenyl, -(C8-C14)tricycloalkenyl, -(C3- C7)heterocycle, or -(C7-C10)bicycloheterocycle, each of which is unsubstituted or substituted with one or more R5 groups; or (c) -phenyl, -naphthyl, -(C14)aryl, or -(C5-C10)heteroaryl, each of which is unsubstituted or substituted with one or more R7 groups; each halo is independently -F, -CI, -Br or -I; q 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 (IV):
Figure imgf000030_0001
(IV) and pharmaceutically acceptable salts thereof, wherein: A is -NR4-, -O-, or -S-;
R1 is -halo, -CH3, -NO2, -CN, -OH, -OCH3, -NH2, -C(halo)3, -CH(halo)2, or - CH2(halo); each R2 is independently: (a) -halo, -CN, -OH, -NO2, or -NH2;
(b) -(CrC10)alkyl, -(C2-C10)alkenyl, -(C2-C10)alkynyl, -(C3- C]0)cycloalkyl, -(Cg-C14)bicycloalkyl, -(C8-C]4)tricycloalkyl, -(C5- CI0)cycloalkenyl,-(C8-C14)bicycloalkenyl, -(C8-CI4)tricycloalkenyl, -(C3- C7)heterocycle, or -(C7-C10)bicycloheterocycle, each of which is unsubstituted or substituted with one or more R5 groups; or
(c) -phenyl, -naphthyl, -(C14)aryl, or -(C5-C10)heteroaryl, each of which is unsubstituted or substituted with one or more R7 groups; each R3 is independently:
(a) -halo, -CN, -OH, -NO2, or -NH2; (b) -(CrC10)alkyl, -(C2-C!0)alkenyl, -(C2-C10)alkynyl, -(C3-
Cι0)cycloalkyl, -(Cg-C]4)bicycloalkyl, -(C8-C14)tricycloalkyl, -(C5- Cι0)cycloalkenyl,-(Cg-C14)bicycloalkenyl, -(C8-C14)tricycloalkenyl, -(C3- C7)heterocycle, or -(C7-C10)bicycloheterocycle, each of which is unsubstituted or substituted with one or more R5 groups; or
(c) -phenyl, -naphthyl, -(C14)aryl or -(C5-C10)heteroaryl, each of which is unsubstituted or substituted with one or more R7 groups;
R4 is hydrogen, -(CrC6)alkyl, or -O-(CrC6)alkyl; each R5 is independently -CN, -OH,
Figure imgf000031_0001
-(C2-C6)alkenyl, - (C2-C6)alkenyl, -halo, -N3, -NO2, -N(R8)2, -CH=NR8, -NR8OH, -OR8, -COR8' -C(O)OR8, -OC(O)R8, -OC(O)OR8, -SR8, -S(O)R8, or -S(O)2R8; R6 is -phenyl, -naphthyl, -(C3-C8)cycloalkyl,-(C14)aryl, or -(C5-C10)heteroaryl, each of which is unsubstituted or substituted with one or more R7 groups; each R7 is independently -(Cι-C6)alkyl, -(C2-C6)alkenyl, -(C2-C6)alkynyl, -(C3-C8)cycloalkyl, -(C5-C8)cycloalkenyl, -phenyl, -(C3-C5)heterocycle, -C(halo)3, -CH(halo)2, -CH2(halo), -CN, -OH, -halo, -N3, -NO2, -N(R8)2, -CH=NR8, -NR8OH, -OR8, -COR8, -C(O)OR8, -OC(O)R8, -OC(O)OR8, -SR8, -S(O)R8, or -S(O)2R8; each R8 is independently -H,
Figure imgf000031_0002
-(C2-C6)alkenyl, -(C2-C6)alkynyl, -(C3-C8)cycloalkyl, -(C5-Cg)cycloalkenyl, -phenyl, -(C3-C5)heterocycle, -C(halo)3, -CH2(halo), or -CH(halo)2; each halo is independently -F, -CI, -Br or -I; n 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 (IVa):
Figure imgf000031_0003
(IVa) and pharmaceutically acceptable salts thereof, wherein: A is -NR4-, -O-, or -S-; each R3 is independently:
(a) -halo, -CN, -OH, -NO2, or -NH2; (b) -(CrC10)alkyl, -(C2-C10)alkenyl, -(C2-C10)alkynyl, -(C3-
C10)cycloalkyl, -(C8-C14)bicycloalkyl, -(C8-Cι4)tricycloalkyl, -(C5- C10)cycloalkenyl,-(C8-C14)bicycloalkenyl, -(C8-C14)tricycloalkenyl, -(C3- C7)heterocycle, or -(C7-C10)bicycloheterocycle, each of which is unsubstituted or substituted with one or more R5 groups; or (c) -phenyl, -naphthyl, -(C14)aryl or -(C5-C10)heteroaryl, each of which is unsubstituted or substituted with one or more R7 groups; R4 is hydrogen, -(CrC6)alkyl, or -O-(CrC6)alkyl; each R5 is independently -CN, -OH, -(Cj-C6)alkyl, -(C2-C6)alkenyl, - (C2-C6)alkenyl, -halo, -N3, -NO2, -N(R8)2, -CH=NR8, -NR8OH, -OR8, -COR8' -C(O)OR8, -OC(O)R8, -OC(O)OR8, -SR8, -S(O)R8, or -S(O)2R8;
R6 is -phenyl, -naphthyl, -(C3-C8)cycloalkyl,-(Cι4)aryl, or -(C5-C)0)heteroaryl, each of which is unsubstituted or substituted with one or more R7 groups; each R7 is independently -( -C^alkyl, -(C2-C6)alkenyl, -(C2-C6)alkynyl, -(C3-C8)cycloalkyl, -(C5-C8)cycloalkenyl, -phenyl, -(C3-C5)heterocycle, -C(halo)3, -CH(halo)2, -CH2(halo), -CN, -OH, -halo, -N3, -NO2, -N(R8)2, -CH=NR8, -NR8OH, -OR8, -COR8, -C(O)OR8, -OC(O)R8, -OC(O)OR8, -SR8, -S(O)R8, or -S(O)2R8; each R8 is independently -H,
Figure imgf000032_0001
-(C2-C6)alkenyl, -(C2-C6)alkynyl, -(C3-C8)cycloalkyl, -(C5-C8)cycloalkenyl, -phenyl, -(C3-C5)heterocycle, -C(halo)3, -CH2(halo), or -CH(halo)2; Rn is -hydrogen, -halo, -CH3, -NO2, -CN, -OH, -OCH3, -NH2, -C(halo)3, -
CH(halo)2, or -CH2(halo); each R!2 is independently:
(a) -halo, -CN, -OH, -NO2, or -NH2;
(b) -(CrC10)alkyl, -(C2-C10)alkenyl, -(C2-C10)alkynyl, -(C3- C10)cycloalkyl, -(C8-C14)bicycloalkyl, -(C8-C14)tricycloalkyl, -(C5-
C10)cycloalkenyl,-(Cg-C14)bicycloalkenyl, -(C8-C14)tricycloalkenyl, -(C3- C7)heterocycle, or -(C7-C10)bicycloheterocycle, each of which is unsubstituted or substituted with one or more R5 groups; or
(c) -phenyl, -naphthyl, -(C14)aryl, or -(C5-C10)heteroaryl, each of which is unsubstituted or substituted with one or more R7 groups; each halo is independently -F, -CI, -Br or -I; q 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 (V):
Figure imgf000033_0001
(V) and pharmaceutically acceptable salts thereof, wherein: A is -NR4-, -O-, or -S-;
R1 is -hydrogen, -halo, -CH3, -NO2, -CN, -OH, -OCH3, -NH2, -C(halo)3, - CH(halo)2, or -CH2(halo); each R3 is independently:
(a) -halo, -CN, -OH, -NO2, or -NH2;
(b) -(CrC10)alkyl, -(C2-C10)alkenyl, -(C2-C10)alkynyl, -(C3- C10)cycloalkyl, -(C8-C14)bicycloalkyl, -(C8-C]4)tricycloalkyl, -(C5- C10)cycloalkenyl,-(C8-C14)bicycloalkenyl,
Figure imgf000033_0002
-(C3-
C7)heterocycle, or -(C7-C10)bicycloheterocycle, each of which is unsubstituted or substituted with one or more R5 groups; or
(c) -phenyl, -naphthyl, -(C14)aryl or -(C5-C10)heteroaryl, each of which is unsubstituted or substituted with one or more R7 groups; R4 is hydrogen, -(CrC6)alkyl, or -O-(CrC6)alkyl; each R5 is independently -CN, -OH, -(Cj-C6)alkyl, -(C2-C6)alkenyl, - (C2-C6)alkenyl, -halo, -N3, -NO2, -N(R8)2, -CH=NR8, -NR8OH, -OR8, -COR8' -C(O)OR8, -OC(O)R8, -OC(O)OR8, -SR8, -S(0)R8, or -S(O)2R8;
R6 is -phenyl, -naphthyl, -(C3-Cg)cycloalkyl,-(C14)aryl, or -(C3-C10)heteroaryl, each of which is unsubstituted or substituted with one or more R7 groups; each R7 is independently -(Cj-C^alkyl, -(C2-C6)alkenyl, -(C2-C6)alkynyl, -(C3-C8)cycloalkyl, -(C5-C8)cycloalkenyl, -phenyl, -(C3-C5)heterocycle, -C(halo)3, -CH2(halo), -CH(halo)2, -CN, -OH, -halo, -N3, -NO2, -N(R8)2, -CH=NR8, -NR8OH, -OR8, -COR8, -C(O)OR8, -OC(O)R8, -OC(O)OR8, -SR8, -S(O)R8, or -S(O)2R8; each R8 is independently -H, -( -C^alkyl, -(C2-C6)alkenyl, -(C2-C6)alkynyl,
-(C3-C8)cycloalkyl, -(C5-C8)cycloalkenyl, -phenyl, -(C3-C5)heterocycle, -C(halo)3, -CH2(halo), or -CH(halo)2; each halo is independently -F, -CI, -Br or -I; and m is an integer ranging from 0 to 2. The present invention encompasses compounds having the formula (VI):
(VI) and pharmaceutically acceptable salts thereof, wherein: Ar, is
Figure imgf000035_0001
Ar, is
Figure imgf000035_0002
Figure imgf000035_0003
Figure imgf000035_0004
R1 is -H, -halo, -CH3, -NO2, -CN, -OH, -OCH3, -NH2, C(halo)3, -CH(halo)2, or -CH2(halo); each R2 is independently: (a) -halo, -CN, -OH, -NO2, or -NH2; (b) -(C1-C]0)alkyl, -(C2-C10)alkenyl, -(C2-C10)alkynyl, -(C3-C10)cycloalkyl,
-(C8-C14)bicycloalkyl, -(C8-C,4)tricycloalkyl, -(C5-C10)cycloalkenyl, -(C8- C14)bicycloalkenyl, -(C8-C14)tricycloalkenyl, -(3- to 7-membered)heterocycle, or -(1- to 10-membered)bicycloheterocycle, each of which is unsubstituted or substituted with one or more R5 groups; or (c) -phenyl, -naphthyl, -(Cι4)aryl or -(5- to 10-membered)heteroaryl, each of which is unsubstitute or substituted with one or more R6 groups; each R3 is independently:
(a) -halo, -CN, -OH, -NO2, or -NH2;
( ) -(CrC10)alkyl, -(C2-C10)alkenyl, -(C2-C ^alkynyl, -(C3-C10)cycloalkyl, -(C8-Cι4)bicycloalkyl, -(C8-Cj4)tricycloalkyl, -(C5-C10)cycloalkenyl, -(C8-
Cι4)bicycloalkenyl, -(C8-C14)tricycloalkenyl, -(3- to 7-membered)heterocycle, or -(7- to 10-membered)bicycloheterocycle, each of which is unsubstituted or substituted with one or more R5 groups; or
(c) -phenyl, -naphthyl, -(C14)aryl or -(5- to 10-membered) heteroaryl, each of which is unsubstituted or substituted with one or more R6 groups; each R4 is independently -(C,-C6)alkyl, -(C2-C6)alkenyl, -(C2-C6)alkynyl, -(C3-C8)cycloalkyl, -(C5-C8)cycloalkenyl, -phenyl, -(3- to 5-membered)heterocycle, - C(halo)3, -CH(halo)2, or CH2(halo); each R5 is independently -CN, -OH, -(Cj-C^alkyl, -(C2-C6)alkenyl, - (C2-C6)alkenyl, -halo, -N3, -NO2, -N(R8)2, -CH=NR8, -NR8OH, -OR8, -COR8' -C(O)OR8, -OC(O)R8, -OC(O)OR8, -SR8, -S(O)R8, or -S(O)2R8; each R6 is independently -( -C^alkyl, -(C2-C6)alkenyl, -(C2-C6)alkynyl, -(C3-C8)cycloalkyl, -(C5-C8)cycloalkenyl, -phenyl, -(3- to 5-membered)heterocycle, -C(halo)3, -CH(halo)2, -CH2(halo), -CN, -OH, -halo, -N3, -NO2, -CH=NR7, -NR7OH, -OR7, -COR7, -C(O)OR7, -OC(O)R7, -OC(O)OR7, -SR7, -S(O)R7, or -S(O)2R7; each R7 is independently -H, -(Cι-C6)alkyl, -(C2-C6)alkenyl, -(C2-C6)alkynyl, -(C3-C8)cycloalkyl, -(C5-C8)cycloalkenyl, -phenyl, -(3- to 5-membered)heterocycle, - C(halo)3, -CH(halo)2, or CH2(halo); each R8 is independently -(Cj-C6)alkyl, -(C2-C6)alkenyl, -(C2-C6)alkynyl, -(C3-C8)cycloalkyl, -(C5-C8)cycloalkenyl, -phenyl, -C(halo)3, -CH(halo)2, -CH2(halo), -CN, -OH, -halo, -N3, -NO2, -CH=NR7, -NR7OH, -OR7, -COR7, -C(O)OR7, -OC(O)R7, -OC(O)OR7, -SR7, -S(O)R7, or -S(O)2R7; each R" is independently -CN, -OH, -(Cj-C^alkyl, -(C2-C6)alkenyl, -halo, -N3, -NO2, -N(R7)2, -CH=NR7, -NR7OH, -OR7, -COR7, -C(O)OR7, -OC(O)R7, -OC(O)OR7, -SR7, -S(O)R7, or -S(O)2R7; each halo is independently -F, -CI, -Br, or -I; m is O or 1; n is an integer ranging from 0 to 3; o is an integer ranging from 0 to 4; p is an integer ranging from 0 to 2; q is an integer ranging from 0 to 6; r is an integer ranging from 0 to 5; s is an integer ranging from 0 to 4; and t is an integer ranging from 0 to 2. The present invention encompasses compounds having the formula (VH):
Figure imgf000037_0001
(VH) and pharmaceutically acceptable salts thereof, wherein:
Arj is
Figure imgf000038_0001
Ar, is
Figure imgf000038_0002
Figure imgf000038_0003
Figure imgf000038_0004
R1 is -H, -halo, -CH3, -NO2, -CN, -OH, -OCH3, -NH2, C(halo)3, -CH(halo)2, or -CH2(halo); each R2 is independently:
(a) -halo, -CN, -OH, -NO2, or -NH2;
(b) -(CrC10)alkyl, -(C2-C10)alkenyl, -(C2-C10)alkynyl, -(C3-C10)cycloalkyl,
Figure imgf000038_0005
-(C8-C14)tricycloalkyl, -(C5-C,0)cycloalkenyl, -(C8- C14)bicycloalkenyl, -(C8-C14)tricycloalkenyl, -(3- to 7-membered)heterocycle, or -(7- to 10-membered)bicycloheterocycle, each of which is unsubstituted or substituted with one or more R5 groups; or
(c) -phenyl, -naphthyl, -(C14)aryl or -(5- to 10~membered)heteroaryl, each of which is unsubstitute or substituted with one or more R6 groups; each R3 is independently:
(a) -halo, -CN, -OH, -NO2, or -NH2;
(b) -(CrC10)alkyl, -(C2-C10)alkenyl, -(C2-C10)alkynyl, -(C3-C10)cycloalkyl, -(C8-C14)bicycloalkyl, -(C8-C14)tricycloalkyl, -(C5-C10)cycloalkenyl, -(C8- C,4)bicycloalkenyl, -(C8-Ci4)tricycloalkenyl, -(3- to 7-membered)heterocycle, or -(1- to 10-membered)bicycloheterocycle, each of which is unsubstituted or substituted with one or more R5 groups; or
(c) -phenyl, -naphthyl, -(C14)aryl or -(5- to 10-membered) heteroaryl, each of which is unsubstituted or substituted with one or more R6 groups; each R4 is independently -(C,-C6)alkyl, -(C2-C6)alkenyl, -(C2-C6)alkynyl,
-(C3-C8)cycloalkyl, -(C5-C8)cycloalkenyl, -phenyl, -(3- to 5-membered)heterocycle, -
C(halo)3; -CH(halo)2, or CH2(halo); each R5 is independently -CN, -OH, -(C1-C6)alkyl, -(C2-C6)alkenyl, -
(C2-C6)alkenyl, -halo, -N3, -NO2, -N(R8)2, -CH=NR8, -NR8OH, -OR8, -COR8' -C(O)OR8, -OC(O)R8, -OC(O)OR8, -SR8, -S(O)R8, or -S(O)2R8; each R6 is independently -(Cι-C6)alkyl, -(C2-C6)alkenyl, -(C2-C6)alkynyl,
-(C3-C8)cycloalkyl, -(C5-C8)cycloalkenyl, -phenyl, -(3- to 5-membered)heterocycle,
-C(halo)3, -CH(halo)2, -CH2(halo), -CN, -OH, -halo, -N3, -NO2, -CH=NR7, -NR7OH, -OR7,
-COR7, -C(O)OR7, -OC(O)R7, -OC(O)OR7, -SR7, -S(O)R7, or -S(O)2R7; each R7 is independently -H, -( -C^alkyl, -(C2-C6)alkenyl, -(C2-C6)alkynyl,
-(C3-C8)cycloalkyl, -(C5-C8)cycloalkenyl, -phenyl, -(3- to 5-membered)heterocycle, -
C(halo)3, -CH(halo)2, or CH2(halo); each R8 is independently -(Cj-C^alkyl, -(C2-C6)alkenyl, -(C2-C6)alkynyl,
-(C3-C8)cycloalkyl, -(C5-C8)cycloalkenyl, -phenyl, -C(halo)3, -CH(halo)2, -CH2(halo), -CN, -OH, -halo, -N3, -NO,, -CH=NR7, -NR7OH, -OR7, -COR7, -C(O)OR7, -OC(O)R7, -OC(O)OR7,
-SR7, -S(O)R7, or -S(O)2R7; each Rn is independently -CN, -OH, -( -C^alkyl, -(C2-C6)alkenyl, -halo, -N3, -NO2, -N(R7)2, -CH=NR7, -NR7OH, -OR7, -COR7, -C(O)OR7, -OC(O)R7, -OC(O)OR7, -SR7, -S(O)R7, or -S(O)2R7; each halo is independently -F, -CI, -Br, or -I; m is 0 or 1 ; n is an integer ranging from 0 to 3; o is an integer ranging from 0 to 4; p is an integer ranging from 0 to 2; q is an integer ranging from 0 to 6; r is an integer ranging from 0 to 5; s is an integer ranging from 0 to 4; and t is an integer ranging from 0 to 2.
A compound of formula (I), (la), (lb), (Ic), (H), (Ha), (HI), (Hla), (HTb), (IHc), (IV), (IVa), (V), (VI), or (VH), or a pharmaceutically acceptable salt thereof (a "Cyanoiminopiperazine Compound") 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 Cyanoiminopiperazine 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 Cyanoiminopiperazine Compound.
The invention further relates to methods for preventing a Condition, comprising administering to an animal in need thereof an effective amount of a Cyanoiminopiperazine Compound.
The invention still further relates to methods for inhibiting Vanilloid Receptor 1 ("VRl") function in a cell, comprising contacting a cell capable of expressing VRl with an effective amount of a Cyanoiminopiperazine Compound. The invention still further relates to methods for inhibiting mGluR5 function in a cell, comprising contacting a cell capable of expressing mGluR5 with an effective amount of a Cyanoiminopiperazine 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 Cyanoiminopiperazine Compound.
The invention still further relates to a method for preparing a composition, comprising the step of admixing a Cyanoiminopiperazine 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 Cyanoiminopiperazine Compound.
The present invention may be understood more fully by reference to the following detailed description and illustrative examples, which are intended to exemplify non-limiting embodiments ofthe invention.
4. DETAILED DESCRIPTION OF THE INVENTION 4.1 CYANOIMINOPIPERAZINE COMPOUNDS OF FORMULA (I) As stated above, the present invention encompasses compounds of Formula (I)
Figure imgf000041_0001
(I) and pharmaceutically acceptable salts thereof, where A, R1, R2, R3, R6, n, and m are defined above for the Cyanoiminopiperazine Compounds of formula (I). In one embodiment n is 0. another embodiment, n is 1. In another embodiment, n is 2.
In another embodiment, n is 3.
In another embodiment, m is 0.
In another embodiment, m is 1. In another embodiment, m is 2.
In another embodiment, A is -N((CrC6)alkyl)-.
In another embodiment, A is -N(O(C,-C6)alkyl)-. h another embodiment, A is -O-.
In another embodiment, A is -S-. In another embodiment, R1 is halo.
In another embodiment, R1 is -CI.
In another embodiment, R1 is -Br.
In another embodiment, R1 is -I.
In another embodiment, R1 is -F. In another embodiment, R1 is -CH3.
In another embodiment, n is 1 and R2 is -halo, -CN, -OH, -NO2, or -NH2.
In another embodiment, n is 1 and R2 is -(Cj-C10)alkyl, -(C2-C]0)alkenyl, -(C2- C10)alkynyl, -(C3-C10)cycloalkyl, -(C8-C,4)bicycloalkyl, -(Cg-C14)tricycloalkyl, -(C5- C10)cycloalkenyl,-(C8-C14)bicycloalkenyl, -(Cg-CI4)tricycloalkenyl, -(C3-C7)heterocycle, or - (C7-Cι0)bicycloheterocycle, each of which is unsubstituted or substituted with one or more R5 groups.
In another embodiment, n is 1 and R2 is -phenyl, -naphthyl, -(C14)aryl, or -(C5- C10)heteroaryl, each of which is unsubstituted or substituted with one or more R7 groups;
In another embodiment, m is 1 and R3 is -halo, -CN, -OH, -NO2, or -NH2. In another embodiment, m is 1 and R3 is -(C,-C10)alkyl, -(C2-C10)alkenyl, -(C2-
Ct0)alkynyl, -(C3-C10)cycloalkyl, -(C8-C14)bicycloalkyl, -(C8-C14)tricycloalkyl, -(C5- C10)cycloalkenyl,-(Cg-C14)bicycloalkenyl, -(C8-C14)tricycloalkenyl, -(C3-C7)heterocycle, or - (C7-C10)bicycloheterocycle, each of which is unsubstituted or substituted with one or more R5 groups. In another embodiment, m is 1 and R3 is -phenyl, -naphthyl, -(C14)aryl or -(C5-
C10)heteroaryl, each of which is unsubstituted or substituted with one or more R7 groups. In another embodiment, R6 is -phenyl, -naphthyl, -(C3-Cg)cycloalkyl,-(C14)aryl, or -(C5-C10)heteroaryl, each of which is unsubstituted or substituted with one or more R7 groups. hi another embodiment, R6 is -phenyl. hi another embodiment, m is 1 and R3 is -CH3. hi another embodiment, m is 1, R3 is -CH3, and the carbon atom to which the - R3 is attached is in the (Reconfiguration.
In another embodiment, m is 1, R3 is -CH3, and the carbon atom to which the - R3 is attached is in the (S)-configuration. In one embodiment, n and m are 0 and R6 is -phenyl. In another embodiment, n is 0, m is 1, R3 is methyl, and R6 is phenyl. In another embodiment, the -phenyl is substituted with a -(C C6) alkyl group, i another embodiment, the -(CrC6) alkyl group is substituted at the 4-position ofthe -phenyl. In another embodiment, the -(CrC6) alkyl group is a t-butyl group substituted at 4-position ofthe -phenyl. hi another embodiment, the -(Cr C6) alkyl group is an wø-propyl group substituted at the 4-position ofthe -phenyl.
In another embodiment, R1 is -CF3 or -CHF2.
In another embodiment, n and m are 0 and R6 is -phenyl substituted at its 4- position with a -CF3 group.
In another embodiment, n and m are 0, R1 is -halo or methyl; and R6 is -phenyl. In one embodiment, -halo is -CI. In another embodiment, the -phenyl is substituted with a -(CrC6) alkyl group. In another embodiment, the -(CrC6) alkyl group is substituted at the 4-position ofthe -phenyl. In another embodiment, the -(CrC6) alkyl group is a t-butyl group or an tso-propyl group substituted at the 4-position ofthe -phenyl.
In another embodiment, n and m are 0, R1 is -halo or methyl; and R6 is -phenyl substituted with -CF3. hi another embodiment, -halo is -CI. In another embodiment, the -CF3 is substituted at the 4-position ofthe -phenyl. In another embodiment, -halo is -CI and the -CF3 is substituted at the 4-position ofthe -phenyl.
4.2 CYANOIMINOPIPERAZINE COMPOUNDS OF FORMULA (IA) The present invention also encompasses compounds of formula (Ia)
Figure imgf000044_0001
(Ia) and pharmaceutically acceptable salts thereof, wherein R1, R2, R3, R6, n, and m are defined above for the Cyanoiminopiperazine Compounds of formula (Ia). In one embodiment, R1 is -halo. In another embodiment, R1 is -CI. In another embodiment, R1 is -Br.
In another embodiment, R1 is -I. In another embodiment, R1 is -F. hi another embodiment, R1 is -CH3.
In another embodiment, n is 1 and R2 is -halo, -CN, -OH, -NO2, or -NH2. In another embodiment, n is 1 and R2 is -(Cj-C10)alkyl, -(C2-C10)alkenyl, -(C2-
C10)alkynyl, -(C3-C10)cycloalkyl, -(C8-Cι4)bicycloalkyl, -(C8-C14)tricycloalkyl, -(C5- CI0)cycloalkenyl,-(C8-C14)bicycloalkenyl, -(C8-C14)tricycloalkenyl, -(C3-C7)heterocycle, or - (C7-C]0)bicycloheterocycle, each of which is unsubstituted or substituted with one or more R5 groups. In another embodiment, n is 1 and R2 is -phenyl, -naphthyl, -(C14)aryl, or -(C5-
C10)heteroaryl, each of which is unsubstituted or substituted with one or more R7 groups. In another embodiment, m is 1 and R3 is -halo, -CN, -OH, -NO2, or -NH2. In another embodiment, m is 1 and R3 is
Figure imgf000044_0002
-(C2-C10)alkenyl, -(C2- C!0)alkynyl, -(C3-C10)cycloalkyl, -(C8-C14)bicycloalkyl, -(C8-C14)tricycloalkyl, -(C5- C10)cycloalkenyl,-(C8-C14)bicycloalkenyl, -(C8-Cl4)tricycloalkenyl, -(C3-C7)heterocycle, or - (C7-C10)bicycloheterocycle, each of which is unsubstituted or substituted with one or more R5 groups.
In another embodiment, m is 1 and R3 is -phenyl, -naphthyl, -(C14)aryl or -(C5- C10)heteroaryl, each of which is unsubstituted or substituted with one or more R7 groups. In another embodiment, m is 1 and R3 is -CH3.
In another embodiment, m is 1, R3 is -CH3, and the carbon atom to which the - R3 is attached is in the (Reconfiguration.
In another embodiment, m is 1, R3 is -CH3, and the carbon atom to which the - R3 is attached is in the (S)-configuration. In another embodiment, R6 is -naphthyl, -(C14)aryl, or -(C3-C8)cycloalkyl each of which is unsubstituted or substituted with one or more R7 groups.
In another embodiment, R6 is pyridyl, furyl, benzofuranyl, thiophenyl, benzothiophenyl, quinolinyl, indolyl, oxazolyl, benzoxazolyl, imidazolyl, benzimidazolyl, thiazolyl, benzothiazolyl, isoxazolyl, pyrazolyl, isothiazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, thiadiazolyl, triazinyl, cinnolinyl, phthalazinyl, or quinazolinyl, each of which is substituted with one or more R7 groups.
In another embodiment, R6 is pyridyl, pyrazinyl, pyαmidinyl, pyridazinyl, or thiadiazolyl.
4.3 CYANOIMINOPIPERAZINE COMPOUNDS OF FORMULA (IB)
The present invention encompasses compounds having the formula (lb):
Figure imgf000046_0001
(lb) and pharmaceutically acceptable salts thereof, wherein R1, R2, R3, R9, R10, n, m, p and halo are defined above for the Cyanoiminopiperazine Compounds of formula (lb). In one embodiment, n is 0.
In another embodiment, n is 1. In another embodiment, n is 2. In another embodiment, m is 0. In another embodiment m is 1. In another embodiment, m is 2.
In another embodiment, R1 is -halo, hi another embodiment, R1 is -CI. In another embodiment, R1 is -Br. In another embodiment, R1 is -I. In another embodiment, R1 is -F.
In another embodiment, R is -CH3 hi one embodiment, n is 1 and R2 is - ιh,anlo, - rC>Nτ,
Figure imgf000046_0002
- ιNvτrO2, or . -NHHiJ2
In another embodiment, n is 1 and R is -(CrCι0)alkyl, -(C2-C10)alkenyl, -(C2 C10)alkynyl. -(C3-C10)cycloalkyl, -(C8-C14)bicycloalkyl, -(C8-C,4)tricycloalkyl, -(C5- C10)cycloalkenyl, -(C8-C14)bicycloalkenyl, -(C8-C14)tricycloalkenyl, -(C3-C7)heterocycle, or -(C7-C10)bicycloheterocycle, each of which is unsubstituted or substituted with one or more R5 groups.
In another embodiment, n is 1 and R2 is -phenyl, -naphthyl, -(C14)aryl, or -(C5-C10)heteroaryl, each of which is unsubstituted or substituted with one or more R7 groups. In another embodiment, m is land R3 is -halo, -CN, -OH, -NO2, or
-NH2.
In another embodiment, m is 1 and R3 is-(CrC10)alkyl, -(C2-C10)alkenyl, -(C2-C10)alkynyl, -(C3-C10)cycloalkyl, -(C8-C14)bicycloalkyl, -(C8-C14)tricycloalkyl, -(C5-C10)cycloalkenyl,-(C8-C14)bicycloalkenyl, -(C8-C14)tricycloalkenyl, -(C3-C7)heterocycle, or -(C7-C10)bicycloheterocycle, each of which is unsubstituted or substituted with one or more R5 groups.
In another embodiment, m is 1 and R3 is-phenyl, -naphthyl, -(C14)aryl or -(C5-C,0)heteroaryl, each of which is unsubstituted or substituted with one or more R7 groups.
In another embodiment, m is 1 and R3 is -CH3. In another embodiment, m is 1, R3 is -CH3, and the carbon atom to which the -
R3 is attached is in the (Reconfiguration. hi another embodiment, m is 1. R3 is -CH3, and the carbon atom to which the - R3 is attached is in the (S)-configuration.
4.4 CYANOIMINOPIPERAZINE COMPOUNDS OF FORMULA (IC)
The present invention encompasses compounds having the formula (Ic):
Figure imgf000047_0001
(Ic) and pharmaceutically acceptable salts thereof, wherein A, R3, R6, Rn, R12, m, and q are defined above for the Cyanoiminopiperazine Compounds of formula (Ic).
In one embodiment, m is 0.
In another embodiment, m is 1. In another embodiment, m is 2.
In another embodiment, q is 0.
In another embodiment, q is 1. hi another embodiment, q is 2. hi another embodiment, q is 3. h another embodiment, A is -N((CrC6)alkyl)-. hi another embodiment, A is -N(O(C,-C6)alkyl)-.
In another embodiment, A is -O-.
In another embodiment, A is -S-. hi another embodiment, m is 1 and R3 is -halo, -CN, -OH, -NO2, or -NH2; or hi another embodiment, m is 1 and R3 is -(Cj-C10)alkyl, -(C2-C10)alkenyl, -(C2-
C10)alkynyl, -(C3-C10)cycloalkyl, -(C8-C]4)bicycloalkyl, -(Cg-C^tricycloalkyl, -(C5- C10)cycloalkenyl,-(Cg-C]4)bicycloalkenyl, -(C8-C14)tricycloalkenyl, -(C3-C7)heterocycle, or - (C7-C10)bicycloheterocycle, each of which is unsubstituted or substituted with one or more R5 groups. In another embodiment, m is 1 and R3 is -phenyl, -naphthyl, -(C14)aryl or -(C5-
C10)heteroaryl, each of which is unsubstituted or substituted with one or more R7 groups.
In another embodiment, m is 1 and R3 is -CH3.
In another embodiment, m is 1, R3 is -CH3, and the carbon atom to which the - R3 is attached is in the (Reconfiguration. In another embodiment, m is 1, R3 is -CH3, and the carbon atom to which the -
R3 is attached is in the (S)-configuration.
In another embodiment, R6 is -phenyl, -naphthyl, -(C3-C8)cycloalkyl,-(C14)aryl, or -(C5-C10)heteroaryl, each of which is unsubstituted or substituted with one or more R7 groups. In another embodiment, R6 is -phenyl. In another embodiment, Rπ is -hydrogen, -halo, -CH3, -NO2, -CN, -OH, - OCH3, -NH2, -C(halo)3, -CH(halo)2, or -CH2(halo).
In another embodiment, R11 is -halo.
In another embodiment, R11 is -CI. In another embodiment, Rπ is -Br.
In another embodiment, Rπ is -F.
In another embodiment, R11 is -I.
In another embodiment, R11 is -CH3.
In another embodiment, q is 1 and R12 is -halo, -CN, -OH, -NO2, or -NH2. In another embodiment, q is 1 and R12 is -(CrC10)alkyl, -(C2-C10)alkenyl, -(C2-
Cj0)alkynyl, -(C3-C10)cycloalkyl, -(C8-Cι4)bicycloalkyl, -(C8-C14)tricycloalkyl, -(C5- C10)cycloalkenyl,-(C8-C14)bicycloalkenyl, -(C8-CI4)tricycloalkenyl, -(C3-C7)heterocycle, or - (C7-C10)bicycloheterocycle, each of which is unsubstituted or substituted with one or more R5 groups. In one embodiment, q is 1 and R12 is -phenyl, -naphthyl, -(C14)aryl, or -(C5-
C]0)heteroaryl, each of which is unsubstituted or substituted with one or more R7 groups.
4.5 CYANOIMINOPIPERAZINE COMPOUNDS OF FORMULA (II)
The present invention also encompasses compounds of formula (II)
Figure imgf000049_0001
0D and pharmaceutically acceptable salts thereof, wherein A, R1, R2, R3, R6, n, and m are defined above for the Cyanoiminopiperazine Compounds of fonnula (II). In one embodiment, n is 0. hi another embodiment, n is 1.
In another embodiment, n is 2.
In another embodiment, m is 0.
In another embodiment, m is 1. In another embodiment, m is 2.
In another embodiment, R1 is -halo.
In another embodiment, R1 is -CI.
In another embodiment, R1 is -Br.
In another embodiment, R1 is -I. In another embodiment, R1 is -F.
In another embodiment, R1 is -CH3.
In another embodiment, A is -NH-.
In another embodiment, A is -N((C,-C6)alkyl)-.
In another embodiment, A is -N(O(C1-C6)alkyl)-. In another embodiment, A is -O-.
In another embodiment, A is -S-.
In another embodiment, n is 1 and R2 is -halo, -CN, -OH, -NO2, or -NH2.
In another embodiment, n is 1 and R2 is -(C1-C10)alkyl, -(C2-C10)alkenyl, -(C2- C10)alkynyl, -(C3-C10)cycloalkyl, -(C8-C,4)bicycloalkyl, -(C8-C14)tricycloalkyl, -(C5- C10)cycloalkenyl,-(C8-Cι4)bicycloalkenyl, -(C8-C]4)tricycloalkenyl, -(C3-C7)heterocycle, or - (C7-C10)bicycloheterocycle, each of which is unsubstituted or substituted with one or more R5 groups. hi another embodiment, n is 1 and R2 is -phenyl, -naphthyl, -(C14)aryl, or -(C5- Ct0)heteroaryl, each of which is unsubstituted or substituted with one or more R7 groups. In another embodiment, m is 1 and R3 is -halo, -CN, -OH, -NO2, or -NH2. hi another embodiment, m is 1 and R3 is -(C1-C10)alkyl, -(C2-C10)alkenyl, -(C2- C10)alkynyl, -(C3-C10)cycloalkyl, -(C8-Cι4)bicycloalkyl, -(C8-C14)tricycloalkyl, -(C5- C10)cycloalkeny],-(C8-C14)bicycloalkenyl, -(C8-C14)tricycloalkenyl, -(C3-C7)heterocycle, or - (C7-C10)bicycloheterocycle, each of which is unsubstituted or substituted with one or more R5 groups. In another embodiment, m is 1 and R3 is -phenyl, -naphthyl, -(C14)aryl or -(C5- C10)heteroaryl, each of which is unsubstituted or substituted with one or more R7 groups.
In another embodiment, m is 1 and R3 is -CH3.
In another embodiment, m is 1, R3 is -CH3, and the carbon atom to which the - R3 is attached is in the (Reconfiguration.
In another embodiment, m is 1, R3 is -CH3, and the carbon atom to which the - R3 is attached is in the (S)-configuration.
In another embodiment, R6 is -phenyl, -naphthyl, -(C3-C8)cycloalkyl,-(C14)aryl, or -(C5-C10)heteroaryl, each of which is unsubstituted or substituted with one or more R7 groups. hi another embodiment, R6 is -phenyl. hi one embodiment, n and m are 0 and R6 is -phenyl. hi another embodiment, n is 0, m is 1, R3 is methyl, and R6 is phenyl. In another embodiment, the -phenyl is substituted with a -(CrC6) alkyl group, hi another embodiment, the -(C,-C6) alkyl group is substituted at the 4-position ofthe -phenyl. In another embodiment, the -(CrC6) alkyl group is a t-butyl group substituted at 4-position ofthe -phenyl. In another embodiment, the -(Cj- C6) alkyl group is an isø-propyl group substituted at the 4-position ofthe -phenyl.
In another embodiment, R1 is -CF3 or -CHF2.
In another embodiment, n and m are 0 and R6 is -phenyl substituted at its 4- position with a -CF3 group.
In another embodiment, n and m are 0, R1 is -halo or methyl; and R6 is -phenyl. In one embodiment, -halo is -CI. hi another embodiment, the -phenyl is substituted with a -(CrC6) alkyl group. In another embodiment, the -(C,-C6) alkyl group is substituted at the 4-position ofthe -phenyl. In another embodiment, the -(C]-C6) alkyl group is a t-butyl group or an wo-propyl group substituted at the 4-position ofthe -phenyl.
In another embodiment, n and m are 0, R1 is -halo or methyl; and R6 is -phenyl substituted with -CF3. In another embodiment, -halo is -CI. In another embodiment, the -CF3 is substituted at the 4-position ofthe -phenyl. hi another embodiment, -halo is -CI and the -CF3 is substituted at the 4-position ofthe -phenyl. 4.6 CYANOIMINOPIPERAZINE COMPOUNDS OF FORMULA (IIA)
The present invention also encompasses compounds having the formula (IIa):
Figure imgf000052_0001
(Ha) and pharmaceutically acceptable salts thereof, wherein A, R3, R6, Rn, R12, m, and q are defined above for the Cyanoiminopiperazine Compounds of formula (Ha).
In one embodiment, q is 0. In another embodiment q is 1.
In another embodiment q is 2.
In one embodiment, m is 0.
In another embodiment, m is 1.
In another embodiment, m is 2. In another embodiment, A is -N((C!-C6)alkyl)-.
In another embodiment, A is -N(O(CrC6)alkyl)-.
In another embodiment, A is -O-.
In another embodiment, A is -S-.
In another embodiment, m is 1 and R3 is -halo, -CN, -OH, -NO2, or -NH2. In another embodiment, m is 1 and R3 is -(Cι-C10)alkyl, -(C2-C10)alkenyl, -(C2-
C10)alkynyl, -(C3-Cι0)cycloalkyl, -(C8-C14)bicycloalkyl, -(C8-C14)tricycloalkyl, -(C5-
C10)cycloalkenyl,-(C8-C14)bicycloalkenyl, -(C8-CM)tricycloalkenyl, -(C3-C7)heterocycle, or -
(C7-C10)bicycloheterocycle, each of which is unsubstituted or substituted with one or more R5 groups. In another embodiment, m is 1 and R3 is -phenyl, -naphthyl, -(C14)aryl or -(C5-
C10)heteroaryl, each of which is unsubstituted or substituted with one or more R7 groups. In another embodiment, m is 1 and R3 is -CH3.
In another embodiment, m is 1, R3 is -CH3, and the carbon atom to which the - R3 is attached is in the (Reconfiguration.
In another embodiment, m is 1, R3 is -CH3, and the carbon atom to which the - R3 is attached is in the (Reconfiguration.
In another embodiment, R6 is -phenyl, -naphthyl, -(C3-C8)cycloalkyl,-(C]4)aryl, or -(C5-C10)heteroaryl, each of which is unsubstituted or substituted with one or more R7 groups.
In another embodiment, R6 is -phenyl. lh another embodiment, R11 is -hydrogen, -halo, -CH3, -NO2, -CN, -OH, -
OCH3, -NH2, -C(halo)3, -CH(halo)2, or -CH2(halo).
In another embodiment, R11 is -halo.
In another embodiment, R11 is -CI.
In another embodiment, R11 is -Br. In another embodiment, Rn is -F.
In another embodiment, R11 is -I.
In another embodiment, Rn is -CH3.
In another embodiment, q is 1 and R12 is -halo, -CN, -OH, -NO2, or -NH2.
In another embodiment, q is 1 and R12 is -(CrC10)alkyl, -(C2-C10)alkenyl, -(C2- C10)alkynyl, -(C3-C10)cycloalkyl, -(C8-C14)bicycloalkyl, -(C8-C14)tricycloalkyl, -(C5-
Cι0)cycloalkenyl,-(C8-C14)bicycloalkenyl, -(C8-Cι4)tricycloalkenyl, -(C3-C7)heterocycle, or - (C7-C10)bicycloheterocycle, each of which is unsubstituted or substituted with one or more R5 groups.
In another embodiment, q is 1 and R12 is -phenyl, -naphthyl, -(C14)aryl, or -(C5- C10)heteroaryl, each of which is unsubstituted or substituted with one or more R7 groups.
4.7 CYANOIMINOPIPERAZINE COMPOUNDS OF FORMULA (III)
The present invention also encompasses compounds of formula (HT)
Figure imgf000054_0001
(in) and pharmaceutically acceptable salts thereof, wherein A.R1, R2, R3, R6, m, and nare defined above for the Cyanoiminopiperazine Compounds of formula (1TI).
In one embodiment, n is 0.
In one embodiment, n is 1.
In one embodiment, n is 2. In one embodiment, m is 0.
In one embodiment, m is 1.
In one embodiment, m is 2.
In another embodiment, A is -N((Cj-C6)alkyl)-.
In another embodiment, A is -N(O(CrC6)alkyl)-. Li one embodiment, A is -O-.
In one embodiment, A is -S-. .
In one embodiment, R1 is -halo.
In one embodiment, R1 is -CI.
In one embodiment, R1 is -Br. In one embodiment, R1 is -I.
In one embodiment, R1 is -F.
In one embodiment, R1 is -CH ■ 33.'
In one embodiment, n is 1 and R 2 . is -halo, -CN, -OH, -NO2, or -NH2. In one embodiment, n is 1 and R2 is -(C1-C10)alkyl, -(C2-C10)alkenyl, -(C2- C]0)alkynyl, -(C3-C10)cycloalkyl, -(C8-C14)bicycloalkyl, -(C8-Cl4)tricycloalkyl, -(C5-
C10)cycloalkenyl,-(C8-C14)bicycloalkenyl, -(C8-C14)tricycloalkenyl, -(C3-C7)heterocycle, or • (C7-C10)bicycloheterocycle, each of which is unsubstituted or substituted with one or more R5 groups.
In one embodiment, n is 1 and R2 is -phenyl, -naphthyl, -(C]4)aryl, or -(C5- Ci0)heteroaryl, each of which is unsubstituted or substituted with one or more R7 groups. In one embodiment, m is 1 and R3 is -halo, -CN, -OH, -NO2, or -NH2.
In one embodiment, m is 1 and R3 is -(C,-C10)alkyl, -(C2-Cι0)alkenyl, -(C2- C10)alkynyl, -(C3-C10)cycloalkyl, -(C8-Cι4)bicycloalkyl, -(C8-C14)tricycloalkyl, -(C5- Ci0)cycloalkenyl,-(C8-C14)bicycloalkenyl, -(C8-C14)tricycloalkenyl, -(C3-C7)heterocycle, or - (C7-CI0)bicycloheterocycle, each of which is unsubstituted or substituted with one or more R5 groups. h one embodiment, m is 1 and R3 is -phenyl, -naphthyl, -(C14)aryl or -(C5- C10)heteroaryl, each of which is unsubstituted or substituted with one or more R7 groups.
In another embodiment, m is 1 and R3 is -CH3.
In another embodiment, m is 1, R3 is -CH3, and the carbon atom to which the - R3 is attached is in the (Reconfiguration.
In another embodiment, m is 1, R3 is -CH3, and the carbon atom to which the - R3 is attached is in the (S)-configuration.
In one embodiment, R6 is -phenyl, -naphthyl, -(C3-C8)cycloalkyl,-(C14)aryl, or - (C5-C10)heteroaryl, each of which is unsubstituted or substituted with one or more R7 groups. In one embodiment, R6 is -phenyl.
In one embodiment, n and m are 0 and R6 is -phenyl. In another embodiment, n is 0, m is 1, R3 is methyl, and R6 is phenyl. In another embodiment, the -phenyl is substituted with a -(CrC6) alkyl group, hi another embodiment, the -(CrC6) alkyl group is substituted at the 4-position ofthe -phenyl. In another embodiment, the -( - ) alkyl group is a t-butyl group substituted at 4-position ofthe -phenyl. In another embodiment, the -(Cr C6) alkyl group is an zso-propyl group substituted at the 4-position ofthe -phenyl.
In another embodiment, R1 is -CF3 or -CHF2.
In another embodiment, n and m are 0 and R6 is -phenyl substituted at its 4- position with a -CF3 group. In another embodiment, n and m are 0, R1 is -halo or methyl; and R6 is -phenyl. In one embodiment, -halo is -CI. hi another embodiment, the -phenyl is substituted with a -(C,-C6) alkyl group. In another embodiment, the -(CrC6) alkyl group is substituted at the 4-position ofthe -phenyl. hi another embodiment, the -(C,-C6) alkyl group is a t-butyl group or an ώo-propyl group substituted at the 4-position ofthe -phenyl. In another embodiment, n and m are 0, R1 is -halo or methyl; and R6 is -phenyl substituted with -CF3. In another embodiment, -halo is -CI. In another embodiment, the -CF3 is substituted at the 4-position ofthe -phenyl. In another embodiment, -halo is -CI and the -CF3 is substituted at the 4-position ofthe -phenyl.
4.8 CYANOIMINOPIPERAZINE COMPOUNDS OF FORMULA (IIIA)
The present invention also encompasses compounds of formula (Dla)
Figure imgf000056_0001
(ma) and pharmaceutically acceptable salts thereof, wherein R1, R2, R3, R6, n, and m are defined above for the Cyanoiminopiperazine Compounds of formula (IHa).
In one embodiment, n is 0.
In another embodiment, n is 1. ■ In another embodiment, n is 2. h another embodiment, m is 0.
In another embodiment, m is 1.
In another embodiment, m is 2. hi another embodiment, R1 is -halo. In another embodiment, R1 is -CI.
In another embodiment, R1 is -Br. hi another embodiment, R1 is -I. hi another embodiment, R1 is -F. hi another embodiment, R1 is -CH3. h another embodiment, n is 1 and R2 is -halo, -CN, -OH, -NO2, or -NH2; hi another embodiment, n is 1 and R2 is -(CrC10)alkyl, -(C2-Cι0)alkenyl, -(C2-
C10)alkynyl, -(C3-C10)cycloalkyl, -(C8-C14)bicycloalkyl, -(C8-Ci4)tricycloalkyl, -(C5- C10)cycloalkenyl,-(C8-C14)bicycloalkenyl, -(C8-C14)tricycloalkenyl, -(C3-C7)heterocycle, or - (C7-C10)bicycloheterocycle, each of which is unsubstituted or substituted with one or more R5 groups; or In another embodiment, n is 1 and R2 is -phenyl, -naphthyl, -(C^aryl, or -(C5-
C10)heteroaryl, each of which is unsubstituted or substituted with one or more R7 groups;
In another embodiment, m is 1 and R3 is -halo, -CN, -OH, -NO2, or -NH2; or
In another embodiment, m is 1 and R3 is -(CrC10)alkyl, -(C2-C10)alkenyl, -(C2- C10)alkynyl, -(C3-C10)cycloalkyl, -(C8-C14)bicycloalkyl, -(C8-C14)tricycloalkyl, -(C5- Cι0)cycloalkenyl,-(C8-C14)bicycloalkenyl, -(C8-Cι4)tricycloalkenyl, -(C3-C7)heterocycle, or - (C7-C10)bicycloheterocycle, each of which is unsubstituted or substituted with one or more R5 groups; or
In another embodiment, m is 1 and R3 is -phenyl, -naphthyl, -(C14)aryl or -(C5- C)0)heteroaryl, each of which is unsubstituted or substituted with one or more R7 groups. In another embodiment, m is 1 and R3 is -CH3.
In another embodiment, m is 1, R3 is -CH3, and the carbon atom to which the - R3 is attached is in the (Reconfiguration.
In another embodiment, m is 1, R3 is -CH3, and the carbon atom to which the - RJ is attached is in the (S)-configuration. In another embodiment, R6 is -naphthyl, -(CI4)aryl, or -(C3-C8)cycloalkyl each of which is unsubstituted or substituted with one or more R7 groups. h another embodiment, R6 is pyridyl, furyl, benzofuranyl, thiophenyl, benzothiophenyl, quinolinyl, indolyl, oxazolyl, benzoxazolyl, imidazolyl, benzimidazolyl, thiazolyl, benzothiazolyl, isoxazolyl, pyrazolyl, isothiazolyl, pyridazinyl, pyrimidinyl. pyrazinyl, thiadiazolyl, triazinyl, cinnolinyl, phthalazinyl, or quinazolinyl, each of which is substituted with one or more R7 groups. 4.9 CYANOIMINOPIPERAZINE COMPOUNDS OF FORMULA (IIIB)
The present invention encompasses compounds having the formula (nib):
Figure imgf000058_0001
and pharmaceutically acceptable salts thereof, wherein R1, R2, R3, R9, R10, n, m, and p are defined above for the Cyanoiminopiperazine Compounds of formula (lTIb).
In one embodiment, n is 0.
In another embodiment, n is 1. In another embodiment, n is 2.
In one embodiment, m is 0.
In another embodiment, m is 1.
In another embodiment, m is 2.
In one embodiment, p is 0. In another embodiment, p is 1.
In another embodiment, p is 2.
In another embodiment, p is 3.
In another embodiment, p is 4.
In another embodiment, R1 is -halo. In another embodiment, R1 is -CI.
In another embodiment, R1 is -Br. In another embodiment, R1 is -I. In another embodiment, R1 is -F. In another embodiment, R1 is -CH3.
In another embodiment, n is 1 and R2 is -halo, -CN, -OH, -NO2, or -NH2. In another embodiment, n is 1 and R2 is -(CrC10)alkyl, -(C2-C10)alkenyl, -(C2-
C10)alkynyl, -(C3-Cι0)cycloalkyl, -(Cg-C14)bicycloalkyl, -(C8-C14)tricycloalkyl, -(C5- C10)cycloalkenyl,-(C8-C14)bicycloalkenyl, -(C8-C14)tricycloalkenyl, -(C3-C7)heterocycle, or - (C7-C10)bicycloheterocycle, each of which is unsubstituted or substituted with one or more R5 groups. In another embodiment, n is 1 and R2 is -phenyl, -naphthyl, -(C14)aryl, or -(C5-
Ci0)heteroaryl, each of which is unsubstituted or substituted with one or more R7 groups. In another embodiment, m is 1 and R3 is -halo, -CN, -OH, -NO2, or -NH2. In another embodiment, m is 1 and R3 is -(C,-C10)alkyl, -(C2-C]0)alkenyl, -(C2- C10)alkynyl, -(C3-C10)cycloalkyl, -(C8-C14)bicycloalkyl,
Figure imgf000059_0001
-(C5- C10)cycloalkenyl,-(Cg-C14)bicycloalkenyl, -(C8-C14)tricycloalkenyl, -(C3-C7)heterocycle, or - (C7-C,0)bicycloheterocycle, each of which is unsubstituted or substituted with one or more R5 groups.
In another embodiment, m is 1 and R3 is -phenyl, -naphthyl, -(C14)aryl or -(C5- C,G)heteroaryl, each of which is unsubstituted or substituted with one or more R7 groups. In another embodiment, m is 1 and R3 is -CH3.
In another embodiment, m is 1, R3 is -CH3, and the carbon atom to which the - R3 is attached is in the (Reconfiguration.
In another embodiment, m is 1, R3 is -CH3, and the carbon atom to which the - R3 is attached is in the (S)-configuration.
4.10 CYANOIMINOPIPERAZINE COMPOUNDS OF FORMULA (IIIc) The present invention encompasses compounds having the formula (IIIc):
Figure imgf000060_0001
(mc) and pharmaceutically acceptable salts thereof, wherein A, R3, R6, Rπ, R12, m, and q are defined above for the Cyanoiminopiperazine Compounds of formula (πic). In one embodiment, q is 0. In another embodiment, q is 1. In another embodiment, q is 2. In one embodiment, m is 0.
In another embodiment, m is 1. In another embodiment, m is 2. In another embodiment, A is -N^Cj-C^alkyi)-. hi another embodiment, A is -N(O(CrC6)alkyl)-. In another embodiment, A is -O-. lh another embodiment, A is -S-.
In another embodiment, m is 1 and R3 is -halo, -CN, -OH, -NO2, or -NH2. hi another embodiment, m is 1 and R3 is -(CrC10)alkyl, -(C2-C10)alkenyl, -(C2- Ci0)alkynyl, -(C3-C10)cycloalkyl,
Figure imgf000060_0002
-(C8-C14)tricycloalkyl, -(C5- C]0)cycloalkenyl,-(C8-C14)bicycloalkenyl, -(Cg-Cj4)tricycloalkenyl, -(C3-C7)heterocycle, or - (C7-C10)bicycloheterocycle, each of which is unsubstituted or substituted with one or more R5 groups.
In another embodiment, m is 1 and R3 is -phenyl, -naphthyl, -(C14)aryl or -(C5- C10)heteroaryl, each of which is unsubstituted or substituted with one or more R7 groups. In another embodiment, m is 1 and R3 is -CH3. In another embodiment, m is 1, R3 is -CH3, and the carbon atom to which the - R3 is attached is in the (Reconfiguration.
In another embodiment, m is 1, R3 is -CH3, and the carbon atom to which the - R3 is attached is in the (S)-configuration. In another embodiment, R6 is -phenyl, -naphthyl, -(C3-C8)cycloalkyl,-(Cι4)aryl, or -(C5-C10)heteroaryl, each of which is unsubstituted or substituted with one or more R7 groups. hi another embodiment, R6 is -phenyl.
In another embodiment, Rπ is -hydrogen, -halo, -CH3, -NO2, -CN, -OH, - OCFI3, -NH2, -C(halo)3, -CH(halo)2, or -CH2(halo).
In another embodiment, Rn is -halo.
In another embodiment, Rn is -CI.
In another embodiment, R11 is -Br.
In another embodiment, Rn is -F. In another embodiment, R11 is -I.
In another embodiment, R11 is -CH3.
In another embodiment, q is 1 and R12 is -halo, -CN, -OH, -NO2, or -NH2. n another embodiment, q is 1 and R12 is -(CrCι0)alkyl, -(C2-C,0)alkenyl, -(C2- C]0)alkynyl, -(C3-C10)cycloalkyl, -(C8-C14)bicycloalkyl, -(C8-C14)tricycloalkyl, -(C5- C]0)cycloalkenyl,-(C8-C14)bicycloalkenyl, -(C8-C14)tricycloalkenyl, -(C3-C7)heterocycle, or - (C7-CI0)bicycloheterocycle, each of which is unsubstituted or substituted with one or more R5 groups.
In another embodiment, q is 1 and R12 is -phenyl, -naphthyl, -(CI4)aryl, or -(C5- C10)heteroaryl, each of which is unsubstituted or substituted with one or more R7 groups.
4.11 CYANOIMINOPIPERAZINE COMPOUNDS OF FORMULA (IV)
The present invention also encompasses compounds of formula (IV):
Figure imgf000062_0001
(IV) and pharmaceutically acceptable salts thereof, where A, R1, R2, R3, R6, n, and m are defined above for the Cyanoiminopiperazine Compounds of formula (IV).
In one embodiment, n is 0.
In another embodiment, n is 1.
In another embodiment, n is 2. In one embodiment, m is 0.
In another embodiment, m is 1.
In another embodiment, m is 2.
In another embodiment, A is -NH-.
In another embodiment, A is -N((Ci-C6)alkyl)-. In another embodiment, A is -N(O(CrC6)alkyl)-.
In another embodiment, A is -O-.
In another embodiment, A is -S-.
In another embodiment, R1 is -halo.
In another embodiment, R1 is -CI. In another embodiment, R1 is -Br.
In another embodiment, R1 is -I.
In another embodiment, R1 is -F.
In another embodiment, R1 is -CH3.
In another embodiment, n is one and R? is -halo, -CN, -OH, -NO2, or -NH2; In another embodiment, n is 1 and R9' is -(CrC,0)alkyl, -(C2-C10)alkenyl, -(C2-
Ci0)alkynyl, -(C3-Cι0)cycloalkyl, -(C8-C]4)bicycloalkyl, -(C8-C14)tricycloalkyl, -(C5- C10)cycloalkenyl,-(C8-Cι4)bicycloalkenyl, -(C8-C14)tricycloalkenyl, -(C3-C7)heterocycle, or - (C7-C10)bicycloheterocycle, each of which is unsubstituted or substituted with one or more R5 groups. hi another embodiment, n is 1 and R2 is -phenyl, -naphthyl, -(Cι4)aryl, or -(C5- C10)heteroaryl, each of which is unsubstituted or substituted with one or more R7 groups;
In another embodiment, m is 1 and R3 is -halo, -CN, -OH, -NO2, or -NH2.
In another embodiment, m is 1 and R3 is -(CrC10)alkyl, -(C2-C10)alkenyl, -(C2- C10)alkynyl, -(C3-C10)cycloalkyl, -(C8-C14)bicycloalkyl, -(C8-Cι4)tricycloalkyl, -(C5- C10)cycloalkenyl,-(C8-C14)bicycloalkenyl, -(C8-C14)tricycloalkenyl, -(C3-C7)heterocycle, or - (C7-Cι0)bicycloheterocycle, each of which is unsubstituted or substituted with one or more R5 groups. hi another embodiment, m is 1 and R3 is -phenyl, -naphthyl, -(C14)aryl or -(C5- C]0)heteroaryl, each of which is unsubstituted or substituted with one or more R7 groups.
In another embodiment, m is 1 and R3 is -CH3. In another embodiment, m is 1, R3 is -CH3, and the carbon atom to which the -
R3 is attached is in the (Reconfiguration.
In another embodiment, m is 1, R3 is -CH3, and the carbon atom to which the - R3 is attached is in the (S)-configuration.
In another embodiment, R6 is -phenyl, -naphthyl, -(C3-C8)cycloalkyl,-(C14)aryl, or -(C5-'C10)heteroaryl, each of which is unsubstituted or substituted with one or more R7 groups. hi another embodiment, R6 is -phenyl.
In one embodiment, n and m are 0 and R6 is -phenyl. In another embodiment, n is 0, m is 1, R3 is methyl, and R6 is phenyl. hi another embodiment, the -phenyl is substituted with a -(CrC6) alkyl group, hi another embodiment, the -(CrC6) alkyl group is substituted at the 4-position ofthe -phenyl. hi another embodiment, the -(CrC6) alkyl group is a t-butyl group substituted at 4-position ofthe -phenyl. hi another embodiment, the -(Cr C6) alkyl group is an iso-pτopyl group substituted at the 4-position ofthe -phenyl.
In another embodiment, R1 is -CF3 or -CHF2. hi another embodiment, n and m are 0 and R6 is -phenyl substituted at its 4- position with a -CF3 group. In another embodiment, n and m are 0, R1 is -halo or methyl; and R6 is -phenyl. In one embodiment, -halo is -CI. In another embodiment, the -phenyl is substituted with a -(CrC6) alkyl group, hi another embodiment, the -(CrC6) alkyl group is substituted at the 4-position ofthe -phenyl. In another embodiment, the -(C C6) alkyl group is a t-butyl group or an wo-propyl group substituted at the 4-position ofthe -phenyl.
In another embodiment, n and m are 0, R1 is -halo or methyl; and R6 is -phenyl substituted with -CF3. In another embodiment, -halo is -CI. In another embodiment, the -CF3 is substituted at the 4-position ofthe -phenyl. In another embodiment, -halo is -CI and the -CF3 is substituted at the 4-position ofthe -phenyl.
4.12 CYANOIMINOPIPERAZINE COMPOUNDS OF FORMULA (TVA) The present invention also encompasses compounds having the formula (IVa):
Figure imgf000064_0001
(IVa) and pharmaceutically acceptable salts thereof, wherein A, R3, R6, Rn, R12, m and q are defined above for the Cyanoiminopiperazine Compounds of formula (IVa). In one embodiment, q is 0. hi another embodiment, q is 1. In another embodiment, q is 2. In one embodiment, m is 0. hi another embodiment, is 1. In another embodiment, m is 2. hϊ another embodiment, A is -NH-. In another embodiment, A is -N((C1-C6)alkyl)-.
In another embodiment, A is -N(O(CrC6)alkyl)-.
In another embodiment, A is -O-. h another embodiment, A is -S-. In another embodiment, m is 1 and R3 is -halo, -CN, -OH, -NO2, or -NH2.
In another embodiment, m is 1 and R3 is -(CrC10)alkyl, -(C2-Cι0)alkenyl, -(C2- Cιo)alkynyl, -(C3-C10)cycloalkyl, -(C8-C14)bicycloalkyl, -(C8-C14)tricycloalkyl, -(C5- C1o)cycloalkenyl,-(C8-C]4)bicycloalkenyl, -(C8-C]4)tricycloalkenyl, -(C3-C7)heterocycle, or - (C7-Cι0)bicycloheterocycle, each of which is unsubstituted or substituted with one or more R5 groups.
In another embodiment, m is 1 and R3 is -phenyl, -naphthyl, -(C14)aryl or -(C5- C,0)heteroaryl, each of which is unsubstituted or substituted with one or more R7 groups.
In another embodiment, m is 1 and R3 is -CH3.
In another embodiment, m is 1, R3 is -CH3, and the carbon atom to which the - R3 is attached is in the (Reconfiguration.
In another embodiment, m is 1, R3 is -CH3, and the carbon atom to which the - R3 is attached is in the (S)-configuration.
In another embodiment, R6 is -phenyl, -naphthyl, -(C3-C8)cycloalkyl,-(C14)aryl, or -(C5-C10)heteroaryl, each of which is unsubstituted or substituted with one or more R7 groups. hi another embodiment, R6 is -phenyl.
In another embodiment, R11 is -hydrogen, -halo, -CH3, -NO2, -CN, -OH, - OCH3, -NH2, -C(halo)3, -CH(halo)2, or -CH2(halo).
In another embodiment, R11 is -halo. In another embodiment, Ru is -CI.
In another embodiment, R11 is -Br.
In another embodiment, Rn is -F.
In another embodiment, Rπ is -I. h another embodiment, Rπ is -CH3. In another embodiment, R12 is -halo, -CN, -OH, -NO2, or -NH2. In another embodiment, R12 is -(C1-C10)alkyl, -(C2-C10)alkenyl, -(C2- C10)alkynyl, -(C3-C10)cycloalkyl,
Figure imgf000066_0001
-(C8-Ci4)tricycloalkyl, -(C5- C10)cycloalkenyl,-(C8-C14)bicycloalkenyl,
Figure imgf000066_0002
-(C3-C7)heterocycle, or - (C7-C]0)bicycloheterocycle, each of which is unsubstituted or substituted with one or more R5 groups.
In another embodiment, R12 is -phenyl, -naphthyl, -(C14)aryl, or -(C5- C10)heteroaryl, each of which is unsubstituted or substituted with one or more R7 groups.
4.13 CYANOIMINOPIPERAZINE COMPOUNDS OF FORMULA (V) The present invention also encompasses compounds of formula (V)
Figure imgf000066_0003
(V) and pharmaceutically acceptable salts thereof, wherein A, R1, R3, R6, and m are defined above for the Cyanoiminopiperazine Compounds of formula (V). i one embodiment, m is 0. h another embodiment, m is 1. hi another embodiment, m is 2. In another embodiment, A is -NH- h another embodiment, A is -N((CrC6)alkyl)-.- i another embodiment, A is -N(O(C1-C6)alkyl)-.
In another embodiment, A is -O-.
In another embodiment, A is -S-. hi another embodiment, R! is -hydrogen. hi another embodiment, R1 is -halo, -CH3, -NO2, -CN, -OH, -OCH3, -NH2, - C(halo)3, -CH(halo)2, or -CH2(halo).
In another embodiment, R1 is -halo.
In another embodiment, R1 is -CI. In another embodiment, R1 is -Br.
In another embodiment, R1 is -I.
In another embodiment, R1 is -F.
In another embodiment, R1 is -CH3.
In another embodiment, m is 1 and R3 is -halo, -CN, -OH, -NO2, or -NH2. h another embodiment, m is 1 and R3 is -(CrC10)alkyl, -(C2-C10)alkenyl, -(C2-
C10)alkynyl, -(C3-C10)cycloalkyl, -(C8-C14)bicycloalkyl, -(C8-C14)tricycloalkyl, -(C5- C10)cycloalkenyl,-(C8-C14)bicycloalkenyl, -(C8-C14)tricycloalkenyl, -(C3-C7)heterocycle, or - (C7-C,0)bicycloheterocycle, each of which is unsubstituted or substituted with one or more R5 groups. hi another embodiment, rn is 1 and R3 is -phenyl, -naphthyl, -(C14)aryl or -(C5-
C10)heteroaryl, each of which is unsubstituted or substituted with one or more R7 groups. hi another embodiment, m is 1 and R3 is -CH3.
In another embodiment, m is 1, R3 is -CH3, and the carbon atom to which the - R3 is attached is in the (Reconfiguration. In another embodiment, m is 1 , R3 is -CH3, and the carbon atom to which the -
R3 is attached is in the (S)-configuration.
In another embodiment, R6 is -phenyl, -naphthyl, -(C3-C8)cycloalkyl,-(C,4)aryl, or -(C5-C10)heteroaryl, each of which is unsubstituted or substituted with one or more R7 groups. In another embodiment, R6 is -phenyl. hi one embodiment, m is 0 and R6 is -phenyl. hi another embodiment, m is 1, R3 is methyl, and R6 is phenyl. In another embodiment, the -phenyl is substituted with a -(Cr C6) alkyl group. In another embodiment, the -(CrC6) alkyl group is substituted at the 4- position ofthe -phenyl. In another embodiment, the -(C,-C6) alkyl group is a t-butyl group substituted at 4-position ofthe -phenyl. In another embodiment, the -(CrC6) alkyl group is an iso-propyl group substituted at the 4-position ofthe -phenyl. In another embodiment, R1 is -CF3 or -CHF2. hi another embodiment, m is 0 and R6 is -phenyl substituted at its 4-position with a -CF3 group. hi another embodiment, m is 0, R1 is -halo or methyl; and R6 is -phenyl. In one embodiment, -halo is -CI. In another embodiment, the -phenyl is substituted with a -(CrC6) alkyl group. In another embodiment, the -(CrC6) alkyl group is substituted at the 4-position ofthe -phenyl. In another embodiment, the -(C,-C6) alkyl group is a t-butyl group or an ώo-propyl group substituted at the 4-position ofthe -phenyl.
In another embodiment, m is 0, R1 is -halo or methyl; and R6 is -phenyl sxxbstituted with -CF3. In another embodiment, -halo is -CI. In another embodiment, the -CF3 is substituted at the 4-position ofthe -phenyl. In another embodiment, -halo is -CI and the -CF3 is substituted at the 4-position ofthe -phenyl.
4.14 CYANOIMINOPIPERAZINE COMPOUNDS OF FORMULA (VI)
The present invention also encompasses compounds of formula (VI):
Figure imgf000068_0001
(VI) and pharmaceutically acceptable salts thereof, wherein Arl5 Ar2 R3, R4, m, and t are defined above for the Cyanoiminopiperazine Compound of formula (VI). In one embodiment ATJ is a pyridyl group, hi another embodiment, Ar, is a pyrimidinyl group. In another embodiment, Ar, is a pyridazinyl group.
In another embodiment, ATJ is a pyrazinyl group. !!,„., II...1I ,„„il ll.„ll "3"
In another embodiment, ATJ is a thiadiazolyl group. In another embodiment, Ar2 is a benzothiazolyl group, hi another embodiment, Ar2 is a benzoimidazolyl group. In another embodiment, Ar2 is a benzooxazolyl group. In another embodiment, Ar2 is
Figure imgf000069_0001
In another embodiment, Ar2 is
Figure imgf000069_0002
In another embodiment, Ar2 is
Figure imgf000069_0003
In another embodiment, Ar2 is
Figure imgf000069_0004
In another embodiment, Ar2 is ιι„... >ι.„ιι ,„..ιι iι,„ιι •:«»
Figure imgf000070_0001
In another embodiment, Ar2 is
Figure imgf000070_0002
In another embodiment >, A -r"r,2 is
Figure imgf000070_0003
hi another embodiment, Rj is • H.
In another embodiment, R is -halo. hi another embodiment, R! is -CI. h another embodiment, R! is -Br.
In another embodiment, R is -I.
In another embodiment, R, is -F.
In another embodiment, Rj is • CH3.
In another embodiment, R, is ■ NO2.
In another embodiment, Ri is ■ •CN.
In another embodiment, R( is ■ ■OH.
In another embodiment, R] is • OCH3. hi another embodiment, Rj is • NH2.
In another embodiment, Rj is ■ C(halo)3. h another embodiment, Rj is -CH(halo)2. hi another embodiment, Rλ is -CH2(halo).
In another embodiment, R2 is -halo, -CN, -OH, -NO2, or -NH2. h another embodiment, R2 is -(C,-C10)alkyl, -(C2-C10)alkenyl, -(C2- Cj0)alkynyl, -(C3-C10)cycloalkyl, -(C8-C14)bicycloalkyl, -(C8-C14)tricycloalkyl, -(C5- C10)cycloalkenyl, -(C8-C14)bicycloalkenyl, -(C8-C14)tricycloalkenyl, -(3- to 7- membered)heterocycle, or -(7- to 10-membered)bicycloheterocycle, each of which is unsubstituted or substituted with one or more R5 groups; or hi another embodiment, R2 is -phenyl, -naphthyl, -(C14)aryl or -(5- to 10- membered)heteroaryl, each of which is unsubstitute or substituted with one or more R6 groups;
In another embodiment, R3 is -halo, -CN, -OH, -NO2, or -NH2.
In another embodiment, R3 is -(CrC10)alkyl, -(C2-C10)alkenyl, -(C2- C10)alkynyl, -(C3-Cι0)cycloalkyl, -(C8-C,4)bicycloalkyl, -(C8-C,4)tricycloalkyl, -(C5- C10)cycloalkenyl, -(C8-C,4)bicycloalkenyl, -(C8-C14)tricycloalkenyl, -(3- to 7- membered)heterocycle, or -(7- to 10-membered)bicycloheterocycle, each of which is unsubstituted or substituted with one or more R5 groxxps.
In another embodiment, R3 is -phenyl, -naphthyl, -(C14)aryl or -(5- to 10- membered) heteroaryl, each of which is unsubstituted or substituted with one or more R5 groups.
In another embodiment, R3 is -CH3.
In another embodiment, m is 1, R3 is -CH3, and the carbon atom to which the - R3 is attached is in the (Reconfiguration.
In another embodiment, m is 1, R3 is -CH3, and the carbon atom to which the - R3 is attached is in the (S)-configuration.
4.15 CYANOIMINOPIPERAZINE COMPOUNDS OF FORMULA (VII)
The present invention also encompasses compounds of formula (VH): .„" 't,.,ι ,!' ,.• ιι;;;;, II„.II ;;;;;ii ιt„.|i. ":;;n
Figure imgf000072_0001
(VH) and pharmaceutically acceptable salts thereof, wherein Arl5 Ar2 R3, R4, m, and t are defined above for formula (VI).
In one embodiment ATJ is a pyridyl group.
In another embodiment, Arj is a pyrimidinyl group. In another embodiment, A is a pyridazinyl group.
In another embodiment, Ar, is a pyrazinyl group.
In another embodiment, Ar, is a thiadiazolyl group.
In another embodiment, Ar2 is a benzothiazolyl group.
In another embodiment, Ar2 is a benzoimidazolyl group. In another embodiment, Ar2 is a benzooxazolyl group.
In another embodiment, Ar2 is
Figure imgf000072_0002
In another embodiment, Ar2 is
Figure imgf000072_0003
In another embodiment, Ar2 is
Figure imgf000073_0001
In another embodiment, Ar2 is
Figure imgf000073_0002
hi another embodiment, Ar2 is
Figure imgf000073_0003
In another embodiment, Ar2 is
Figure imgf000073_0004
In another embodiment, Ar2 is
Figure imgf000073_0005
In another embodiment, Rx s -H. In another embodiment, R, s -halo. In another embodiment, Rj s -CI. In another embodiment, Rj s -Br. In another embodiment, Rj s -I. In another embodiment, Rj s -F. In another embodiment, Rj s -CH3. hi another embodiment, Rj s -NO2. In another embodiment, R, s -CN. In another embodiment, R, s -OH. i another embodiment, R, s -OCH, hi another embodiment, Rj s -NH2. In another embodiment, Rj s -C(halo)3. In another embodiment, R, s -CH(halo)2. In another embodiment, R, s -CH2(halo). In another embodiment, R2 s -halo, -CN, -OH, -NO2, or -NH2;.
In another embodiment, R2 s -(C1-C10)alkyl, -(C2-C10)alkenyl, -(C2- C]0)alkynyl, -(C3-C10)cycloalkyl, -(C8-C14)bi cycloalkyl, -(Cg-Cj4)tricycloalkyl, -(C5- C]0)cycloalkenyl, -(C8-C14)bicycloalkenyl, -(C8-C14)tricycloalkenyl, -(3- to 7- membered)heterocycle, or -(7- to 10-membered)bicycloheterocycle, each of which is unsubstituted or substituted with one or more R5 groups; or
In another embodiment, R2 is -phenyl, -naphthyl, -(C14)aryl or -(5- to 10- membered)heteroaryl, each of which is unsubstitute or substituted with one or more R6 groups;
In another embodiment, R3 is -halo, -CN, -OH, -NO2, or -NH2. In another embodiment, R3 is -(CI-C10)alkyl, -(C2-C10)alkenyl, -(C2- C10)alkynyl, -(C3-C10)cycloalkyl, -(C8-C14)bicycloalkyl, -(C8-C14)tricycloalkyl, -(C5- C10)cycloalkenyl, -(C8-C]4)bicycloalkenyl, -(C8-C14)tricycloalkenyl, -(3- to 7- membered)heterocycle, or -(7- to 10-membered)bicycloheterocycle, each of which is unsubstituted or substituted with one or more R5 groups. In another embodiment, R3 is -phenyl, -naphthyl, -(C,4)aryl or -(5- to 10- membered) heteroaryl, each of which is unsubstituted or substituted with one or more R6 groups.
In another embodiment, R3 is -CH3. In another embodiment, m is 1 , R3 is -CH3, and the carbon atom to which the -
R3 is attached is in the (Reconfiguration.
In another embodiment, m is 1, R3 is -CH3, and the carbon atom to which the - R3 is attached is in the (S)-configuration.
4.16 CYANOIMINOPIPERAZINE COMPOUNDS OF FORMULA (I). (IA). (IB). (II). (IIA), (III).
Figure imgf000075_0001
Certain Cyanoiminopiperazine Compounds may have asymmetric centers and therefore exist in different enantiomeric and diastereomic forms. This invention relates to the use of all optical isomers and stereoisomers ofthe Cyanoiminopiperazine Compounds, and mixtures thereof, and to all pharmaceutical compositions and methods of treatment that may employ or contain them.
In the Cyanoiminopiperazine Compounds each R3 can be on any carbon ofthe piperazine ring. In one embodiment, the Cyanoiminopiperazine Compounds have only one R3 group, and that R3 group is attached to a carbon atom adjacent to the nitrogen atom attached to the pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, or thiadiazolyl group. In another embodiment, the Cyanoiminopiperazine Compound has only one R3 group, and that R3 group is attached to a carbon atom adjacent to the nitrogen atom attached to the -C(=N-CN)-A-R6 group, -C(=N-CN)-NH-phenethyl group, -C(=N-CN)-NH-phenpropyl group, or -C(=N-CN)- NH-(R9)-phenyl. In another embodiment, two R3 groups are on a single atom ofthe piperazine ring. In another embodiment, an R3 group is attached to a carbon atom adjacent to the nitrogen atom attached to the pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, or thiadiazolyl group and another R3 group is attached to a carbon atom adjacent to the nitrogen atom attached to the -C(=N-CN)-A-R6 group, -C(=N-CN)-NH-phenethyl group, -C(=N-CN)-NH- phenpropyl group, or -C(=N-CN)-NH-(R9)-phenyl.
In another embodiment, the Cyanoiminopiperazine Compound has two R3 groups, each being attached to a different carbon atom adjacent to a nitrogen atom attached to the pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, or thiadiazolyl group. In another embodiment, the Cyanoiminopiperazine Compound has two R3 groups, each being attached to a different carbon atom adjacent to a nitrogen atom attached to the -C(=N-CN)-A-R6 group, -C(=N-CN)-NH-phenethyl group, -C(=N-CN)-NH-phenpropyl group, or -C(=N-CN)- NH-(R9)-phenyl.
In one embodiment, wherein the Cyanoiminopiperazine Compound has one or two R3 groups, the carbon atom to which an R3 group is attached has the (R) configuration. In another embodiment, wherein the Cyanoiminopiperazine Compound has one or two R3 groups, the carbon atom to which the R3 group is attached has the (S) configuration, hi another embodiment, the Cyanoiminopiperazine Compound has one or two R3 groups, and at least one ofthe carbon atoms to which an R3 group is attached has the (R) configuration, h another embodiment, the Cyanoiminopiperazine Compound has one or two R3 groups, and at least one ofthe carbon atoms to which an R3 group is attached has the (S) configuration.
In another embodiment, the Cyanoiminopiperazine Compound has one or two R3 groups, an R3 group is attached to a carbon atom adjacent to a nitrogen atom attached to the pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, or thiadiazolyl group, and the carbon to which the R? group is attached is in the (R) configuration. In another embodiment, the Cyanoiminopiperazine Compound has one or two R3 groups, an R3 group is attached to a carbon atom adjacent to a nitrogen attached to the pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, or thiadiazolyl group, the carbon to which the R3 group is attached is in the (R) configuration, and R3 is -(C C4)alkyl unsubstituted or substituted with one or more halo groups, hi another embodiment, the Cyanoiminopiperazine Compound has one or two R3 groups, an R3 group is attached to a carbon atom adjacent to a nitrogen attached to the pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, or thiadiazolyl group, the carbon to which the R3 group is attached is in the (R) configuration, and R3 is -CH3. In another embodiment, the Cyanoiminopiperazine Compound has one or two R3 groups, an R3 group is attached to a carbon atom adjacent to a nitrogen attached to the pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, or thiadiazolyl group, the carbon to which the R3 group is attached is in the (R) configuration, and R3 is -CF3. In another embodiment, the Cyanoiminopiperazine Compoimd has one or two R3 groups, an R3 group is attached to a carbon atom adjacent to a nitrogen attached to the pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, or thiadiazolyl group, the carbon to which the R3 group is attached is in the (R) configuration, and R3 is -CH2CH3.
In another embodiment, the Cyanoiminopiperazine Compound has one or two R3 groups, an R3 group is attached to a carbon atom adjacent to a nitrogen atom attached to the -C(=N-CN)-A-R6 group, -C(=N-CN)-NH-phenethyl group, -C(=N-CN)-NH-phenpropyl group, or -C(=N-CN)-NH-(R9)-phenyl, and the carbon to which the R3 group is attached is in the (R) configuration. In another embodiment, the Cyanoiminopiperazine Compound has one or two R3 groups, an R3 group is attached to a carbon atom adjacent to a nitrogen attached to the -C(=N-CN)-A-R6 group,-C(=N-CN)-NH-phenethyl group, -C(=N-CN)-NH-phenpropyl group, or -C(=N-CN)-NH-(R9)-phenyl, the carbon to which the R3 group is attached is in the (R) configuration, and R3 is -(C1-C4)alkyl unsubstituted or substituted with one or more halo groups. In another embodiment, the Cyanoiminopiperazine Compound has one or two R3 groups, an R3 group is attached to a carbon atom adjacent to a nitrogen attached to the -C(=N- CN)-A-R6 group, -C(=N-CN)-NH-ρhenethyl group, -C(=N-CN)-NH-ρhenρroρyl group, or - C(=N-CN)-NH-(R9)-phenyl, the carbon to which the R3 group is attached is in the (R) configuration, and R3 is -CH3. In another embodiment, the Cyanoiminopiperazine Compound has one or two R3 groups, an R3 group is attached to a carbon atom adjacent to a nitrogen attached to the -C(=N-CN)-A-R6 group, -C(=N-CN)-NH-phenethyl group, -C(=N- CN)-NH-phenpropyl group, or -C(=N-CN)-NH-(R9)-phenyl, the carbon to which the R3 group is attached is in the (R) configuration, and R3 is -CF3. hi another embodiment, the
Cyanoiminopiperazine Compound has one or two R3 groups, an R3 group is attached to a carbon atom adjacent to a nitrogen attached to the -C(=N-CN)-A-R6 group,-C(=N-CN)-NH- phenethyl group, -C(=N-CN)-NH-phenpropyl group, or -C(=N-CN)-NH-(R9)-phenyl, the carbon to which the R3 group is attached is in the (R) configuration, and R3 is -CH2CH3. h another embodiment, the Cyanoiminopiperazine Compound has one or two
R3 groups, an R3 group is attached to a carbon atom adjacent to a nitrogen atom attached to the pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, or thiadiazolyl group, and the carbon to which the R3 group is attached is in the (S) configuration. In another embodiment, the Cyanoiminopiperazine Compound has one or two R3 groups, an R3 group is attached to a carbon atom adjacent to a nitrogen attached to the pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, or thiadiazolyl group, the carbon to which the R3 group is attached is in the (S) configuration, and R3 is -(CrC4)alkyl unsubstituted or substituted with one or more halo groups. In another embodiment, the Cyanoiminopiperazine Compound has one or two R3 groups, an R3 group is attached to a carbon atom adjacent to a nitrogen attached to the pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, or thiadiazolyl group, the carbon to which the R3 group is attached is in the (S) configuration, and R3 is -CH3. In another embodiment, the Cyanoiminopiperazine Compound has one or two R3 groups, an R3 group is attached to a carbon atom adjacent to a nitrogen attached to the pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, or thiadiazolyl group, the carbon to which the R3 group is attached is in the (S) configuration, and R3 is -CF3. In another embodiment, the Cyanoiminopiperazine Compound has one or two R3 groups, an R3 group is attached to a carbon atom adjacent to a nitrogen attached to the pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, or thiadiazolyl group, the carbon to which the R3 group is attached is in the (S) configuration, and R3 is -CH2CH3.
In another embodiment, the Cyanoiminopiperazine Compound has one or two R3 groups, an R3 group is attached to a carbon atom adjacent to a nitrogen atom attached to the -C(=N-CN)-A-R6 group, -C(=N-CN)-NH-phenethyl group, -C(=N-CN)-NH-phenpropyl group, or -C(=N-CN)-NH-(R9)-phenyl, and the carbon to which the R3 group is attached is in the (S) configuration. In another embodiment, the Cyanoiminopiperazine Compound has one or two R3 groups, an R3 group is attached to a carbon atom adjacent to a nitrogen attached to the -C(=N-CN)-A-R6 group, -C(=N-CN)-NH-phenethyl group, -C(=N-CN)-NH-phenpropyl group, or -C(=N-CN)-NH-(R9)-phenyl, the carbon to which the R3 group is attached is in the (S) configuration, and R3 is -(Cι-C4)alkyl unsubstituted or substituted with one or more halo groups. In another embodiment, the Cyanoiminopiperazine Compound has one or two R3 groups, an R3 group is attached to a carbon atom adjacent to a nitrogen attached to the -C(=N- CN)-A-R6 group, -C(=N-CN)-NH-phenethyl group, -C(=N-CN)-NH-phenpropyl group, or - C(=N-CN)-NH-(R9)-phenyl, the carbon to which the R3 group is attached is in the (S) configuration, and R3 is -CH3. In another embodiment, the Cyanoiminopiperazine Compound has one or two R3 groups, an R3 group is attached to a carbon atom adjacent to a nitrogen attached to the -C(=N-CN)-A-R6 group, -C(=N-CN)-NH-phenethyl group, -C(=N- CN)-NH-phenpropyl group, or -C(=N-CN)-NH-(R9)-phenyl, the carbon to which the R3 group is attached is in the (S) configuration, and R3 is -CF3. In another embodiment, the
Cyanoiminopiperazine Compound has one or two R3 groups, an R3 group is attached to a carbon atom adjacent to a nitrogen attached to the -C(=N-CN)-A-R6 group, -C(=N-CN)-NH- phenethyl group, -C(=N-CN)-NH-phenpropyl group, or -C(=N-CN)-NH-(R9)-phenyl, the carbon to which the R3 group is attached is in the (S) configuration, and R3 is -CH2CH3.
In another embodiment, the Cyanoiminopiperazine Compound has only one R3 group, the R3 group is attached to a carbon atom adjacent to a nitrogen atom attached to the pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, or thiadiazolyl group, and the carbon to which the R3 group is attached is in the (R) configuration. In another embodiment, the Cyanoiminopiperazine Compound has only one R3 group, the R3 group is attached to a carbon atom adjacent to a nitrogen attached to the pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, or thiadiazolyl group, the carbon to which the R3 group is attached is in the (R) configuration, and R3 is -(C1-C4)alkyl unsubstituted or substituted with one or more halo groups. In another embodiment, the Cyanoiminopiperazine Compound has only one R3 group, the R3 group is attached to a carbon atom adjacent to a nitrogen attached to the pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, or thiadiazolyl group, the carbon to which the R3 group is attached is in the (R) configuration, and R3 is -CH3. In another embodiment, the Cyanoiminopiperazine Compound has only one R3 group, the R3 group is attached to a carbon atom adjacent to a nitrogen attached to the pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, or thiadiazolyl group, the carbon to which the R3 group is attached is in the (R) configuration, and R3 is -CF3. hi another embodiment, the Cyanoiminopiperazine Compound has only one R3 group, the R3 group is attached to a carbon atom adjacent to a nitrogen attached to the pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, or thiadiazolyl group, the carbon to which the R3 group is attached is in the (R) configuration, and R3 is -CH2CH3.
In another embodiment, the Cyanoiminopiperazine Compound has only one R3 group, the R3 group is attached to a carbon atom adjacent to a nitrogen atom attached to the - C(=N-CN)-A-R6 group, -C(=N-CN)-NH-phenethyl group, -C(=N-CN)-NH-phenpropyl group, or -C(=N-CN)-NH-(R9)-phenyl, and the carbon to which the R3 group is attached is in the (R) configuration. In another embodiment, the Cyanoiminopiperazine Compound has only one R3 group, the R3 group is attached to a carbon atom adjacent to a nitrogen attached to the -C(=N-CN)-A-R6 group, -C(=N-CN)-NH-phenethyl group, -C(=N-CN)-NH- phenpropyl group, or -C(=N-CN)-NH-(R9)-phenyl, the carbon to which the R3 group is attached is in the (R) configuration, and R3 is -(Cj-C4)alkyl unsubstituted or substituted with one or more halo groups. In another embodiment, the Cyanoiminopiperazine Compound has only one R3 group, the R3 group is attached to a carbon atom adjacent to a nitrogen attached to the -C(=N-CN)-A-R6 group, -C(=N-CN)-NH-phenethyl group, -C(=N-CN)-NH- phenpropyl group, or -C(-N-CN)-NH-(R9)-phenyl, the carbon to which the R3 group is attached is in the (R) configuration, and R3 is -CH3. In another embodiment, the
Cyanoiminopiperazine Compound has only one R3 group, the R3 group is attached to a carbon atom adjacent to a nitrogen attached to the -C(=N-CN)-A-R6 group, -C(=N-CN)-NH- phenethyl group, -C(=N-CN)-NH-phenpropyl group, or -C(=N-CN)-NH-(R9)-phenyl, the carbon to which the R3 group is attached is in the (R) configuration, and R3 is -CF3. In another embodiment, the Cyanoiminopiperazine Compound has only one R3 group, the R3 group is attached to a carbon atom adjacent to a nitrogen attached to the -C(=N-CN)-A-R6 group, -C(=N-CN)-NH-ρhenethyl group, -C(=N-CN)-NH-phenρroρyl group, or -C(=N-CN)- NH-(R9)-phenyl, the carbon to which the R3 group is attached is in the (R) configuration, and R3 is -CH2CH3. In another embodiment, the Cyanoiminopiperazine Compound has only one R3 group, the R3 group is attached to a carbon atom adjacent to a nitrogen atom attached to the pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, or thiadiazolyl group, and the carbon to which the R3 group is attached is in the (S) configuration. In another embodiment, the Cyanoiminopiperazine Compound has only one R3 group, the R3 group is attached to a carbon atom adjacent to a nitrogen attached to the pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, or thiadiazolyl group, the carbon to which the R3 group is attached is in the (S) configuration, and R3 is -(C,-C4)alkyl unsubstituted or substituted with one or more halo groups, i another embodiment, the Cyanoiminopiperazine Compound has only one R3 group, the R3 group is attached to a carbon atom adjacent to a nitrogen attached to the pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, or thiadiazolyl group, the carbon to which the R3 group is attached is in the (S) configuration, and R3 is -CH3. In another embodiment, the Cyanoiminopiperazine Compound has only one R3 group, the R3 group is attached to a carbon atom adjacent to a nitrogen attached to the pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, or thiadiazolyl group, the carbon to which the R3 group is attached is in the (S) configuration, and R3 is -CF3. In another embodiment, the Cyanoiminopiperazine Compound has only one R3 group, the R3 group is attached to a carbon atom adjacent to a nitrogen attached to the pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, or thiadiazolyl group, the carbon to which the R3 group is attached is in the (S) configuration, and R3 is -CH2CH3.
In another embodiment, the Cyanoiminopiperazine Compound has only one R3 group, the R3 group is attached to a carbon atom adjacent to a nitrogen atom attached to the - C(=N-CN)-A-R6 group, -C(=N-CN)-NH-phenethyl group, -C(=N-CN)-NH-phenpropyl group, or -C(=N-CN)-NH-(R9)-phenyl, and the carbon to which the R3 group is attached is in the (S) configuration. In another embodiment, the Cyanoiminopiperazine Compound has only one R3 group, the R3 group is attached to a carbon atom adjacent to a nitrogen attached to the -C(=N-CN)-A-R6 group, -C(=N-CN)-NH-phenethyl group, -C(=N-CN)-NH- phenpropyl group, or -C(=N-CN)-NH-(R9)-phenyl, the carbon to which the R3 group is attached is in the (S) configuration, and R3 is -(CrC4)alkyl unsubstituted or substituted with one or more halo groups. In another embodiment, the Cyanoiminopiperazine Compound has only one R3 group, the R3 group is attached to a carbon atom adjacent to a nitrogen attached to the -C(=N-CN)-A-R6 group, -C(-N-CN)-NH-phenethyl group, -C(=N-CN)-NH- phenpropyl group, or -C(=N-CN)-NH-(R9)-phenyl, the carbon to which the R3 group is attached is in the (S) configuration, and R3 is -CH3. In another embodiment, the Cyanoiminopiperazine Compound has only one R3 group, the R3 group is attached to a carbon atom adjacent to a nitrogen attached to the -C(=N-CN)-A-R6 group, -C(=N-CN)-NH- phenethyl group, -C(=N-CN)-NH-phenpropyl group, or -C(=N-CN)-NH-(R9)-phenyl, the carbon to which the R3 group is attached is in the (S) configuration, and R3 is -CF3. In another embodiment, the Cyanoiminopiperazine Compound has only one R3 group, the R3 group is attached to a carbon atom adjacent to a nitrogen attached to the -C(=N-CN)-A-R6 group, -C(=N-CN)-NH-phenethyl group, -C(=N-CN)-NH-phenpropyl group, or -C(=N-CN)- NH-(R9)-phenyl, the carbon to which the R3 group is attached is in the (R) configuration, and R3 is -CH2CH3.
The present invention includes the Cyanoiminopiperazine Compounds, and the phannaceutically acceptable salts thereof, wherein one or more hydrogen, carbon or other atoms are replaced by isotopes thereof. Such compounds may be useful as research and diagnostic tools in metabolism pharmacokinetic studies and in binding assays. Illustrative Cyanoiminopiperazine Compounds are listed below in Tables 1-8: Table 1
Figure imgf000082_0001
VI and pharmaceutically acceptable salts thereof, wherein:
Figure imgf000082_0002
Figure imgf000083_0001
Figure imgf000084_0001
Figure imgf000085_0001
Figure imgf000086_0001
Figure imgf000087_0001
Figure imgf000088_0001
Figure imgf000089_0001
Figure imgf000090_0001
Figure imgf000091_0001
Figure imgf000092_0001
Figure imgf000093_0001
Table 2
Figure imgf000094_0001
vπ
and pharmaceutically acceptable salts thereof, wherein:
Figure imgf000094_0002
Figure imgf000095_0001
Figure imgf000096_0001
Figure imgf000099_0001
Figure imgf000100_0001
Figure imgf000101_0001
Figure imgf000102_0001
Figure imgf000103_0001
Figure imgf000104_0001
Figure imgf000105_0001
Table 3
Figure imgf000106_0001
vm
and pharmaceutically acceptable salts thereof, wherein:
Figure imgf000106_0002
Figure imgf000107_0001
Figure imgf000108_0001
Figure imgf000109_0001
Figure imgf000110_0001
Figure imgf000111_0001
Figure imgf000112_0001
Figure imgf000113_0001
Figure imgf000114_0001
Figure imgf000115_0001
Figure imgf000116_0001
Figure imgf000117_0001
Table 4
Figure imgf000118_0001
IX
and pharmaceutically acceptable salts thereof, wherein:
Figure imgf000118_0002
Figure imgf000119_0001
1.18-
Figure imgf000120_0001
Figure imgf000121_0001
Figure imgf000122_0001
Figure imgf000123_0001
Figure imgf000124_0001
Figure imgf000125_0001
Figure imgf000126_0001
Figure imgf000127_0001
Figure imgf000128_0001
Figure imgf000129_0001
wherein "a" means that the carbon atom ofthe piperazino group to which the methyl group is attached is in the R. configuration and "b" means that the carbon ofthe piperazino group to which the methyl group is attached is in the S configuration
Table 5
Figure imgf000130_0001
X
and pnaixnaceutically acceptable salts thereof, wherein:
Figure imgf000130_0002
Figure imgf000131_0001
Figure imgf000132_0001
Figure imgf000133_0001
Figure imgf000134_0001
Figure imgf000135_0001
Figure imgf000136_0001
Figure imgf000137_0001
Figure imgf000138_0001
Figure imgf000139_0001
Figure imgf000140_0001
Figure imgf000141_0001
wherein "a" means that the carbon atom ofthe piperazino group to which the methyl group is attached is in the R configuration and "b" means that the carbon ofthe : piperazino group to which the methyl group is attached is in the S configuration
Table 6
Figure imgf000142_0001
XI and pharmaceutically acceptable salts thereof, wherein:
Figure imgf000142_0002
Figure imgf000143_0001
Figure imgf000144_0001
Figure imgf000145_0001
Figure imgf000146_0001
Figure imgf000147_0001
Figure imgf000148_0001
Figure imgf000149_0001
Figure imgf000150_0001
Figure imgf000151_0001
Figure imgf000152_0001
Figure imgf000153_0001
Table 7
Figure imgf000154_0001
and pharmaceutically acceptable salts thereof, wherein:
Figure imgf000154_0002
-152
Figure imgf000155_0001
Figure imgf000156_0001
Figure imgf000157_0001
Figure imgf000158_0001
Figure imgf000159_0001
Figure imgf000160_0001
Figure imgf000161_0001
Figure imgf000162_0001
Figure imgf000163_0001
-16:
Figure imgf000164_0001
Table 8
Figure imgf000165_0001
and pharmaceutically acceptable salts thereof, wherein:
Figure imgf000165_0002
Figure imgf000166_0001
4.17 DEFINITIONS
As used herein, the terms used above having following meaning: "-(C,-C]0)alkyl" means a straight chain or branched non-cyclic hydrocarbon having from 1 to 10 carbon atoms. Representative straight chain -(CrC10)alkyls include -methyl, -ethyl, -n-propyl, -n-butyl, -n-pentyl, -n-hexyl, -n-heptyl, -n-octyl, -n-nonly and -n- decyl. Representative branched -(C1-C10)alkyls include -isopropyl, -sec-butyl, -isobutyl, -tert-butyl, -isopentyl, -neopentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, J ,l "dimethylpropyl, 1 ,2-dimethylpropyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl,. 4-methylpentyl, 1 -ethylbutyl, 2-ethylbutyl, 3-ethylbutyl, 1,1-dimethtylbutyl, 1,2-diιnetlrylbutyl, 1,3-dimethylbutyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl and
3,3-dimethylbutyl. -isopropyl, -sec-butyl, -isobutyl, 1-methylhexyl, 2-methylhexyl, 3- methylhexyl, 4-methylhexyl, 5-methylhexyl, 1,2-dimethylpentyl, 1,3-dimethylpentyl, 1,2- dimethylhexyl, 1,3-dimethylhexyl, 3,3-dimethylhexyl, 1,2-dimethylheptyl, 1,3- dimeihylheptyl, and 3,3-dimethylheptyl. "-(C,-C6)alkyl" means a straight chain or branched non-cyclic hydrocarbon having from 1 to 6 carbon atoms. Representative straight chain -(CrCύ)aIkyls include -methyl, -ethyl, -n-propyl, -n-butyl, -n-pentyl and -n-hexyl. Representative branched -(C,- C6)alkyls include -isopropyl, -sec-butyl, -isobutyl, -tert-butyl, -isopentyl, -neopentyl, l-ructhylburyl, 2-rnethylbutyl, 3-methyibυtyl, ,1-dimethylpropyl, 1 ,2-dimethylpropyl, i-methylpentyl, 2-methylpentyl, 3-ιnethylpentyl, 4-methylpentyl, 1 -ethylbutyl, 2-ethylbutyl, 3-ethylbutyl, 1,1-dimethtylbutyl, 1,2-dmιethylbutyl, 1,3-dimethylbutyl, 2,2-dimethylbutyl. 2.3-dirnethylbutyl and 3,3-dimethylbutyl.
"-(C2-C]0)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 (C2-C10)alkenyls include -vinyl, -allyl, -1-butenyl, -2-buienyi, -isobutylenyl, -1 -pentenyl, -2-pentenyl, -3 -methyl- 1-butenyl, -2-methyl-2-butenyl, -2,3-cιimethyl-2-butenyl, -1-hexenyl, -2-hexenyl, -3-hexenyl, -1-heptenyl, -2-heptenyl, -3- heptenyl. - L-octenyl, -2-octenyl, -3-octenyl, -1-nonenyl, -2-nqnenyl. -3-nonen3 , -l~decenyl, ■■2-ά& ^,ιyl, -3-decenyl and the like. "-(C2-C6)alkenyT 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 (C2-C6)alkenyls include -vinyl, -allyl, -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. -(C2-C10)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 -(C2-C10)alkynyls include -acetylenyl, -propynyl, -1-butynyl, -2-butynyl, -1-pentynyl, -2-pentynyl, -3-methyl-l -butynyl, -4-pentynyl, -1- hexyπyl, -2-hexynyl, -5-hexynyl, -1-heptynyl, -2-heptynyl, -6-heptynyl, -1-octynyl, -2-octynyl, -7-octynyl, -1-nonynyl, -2-nonynyl, -8-nonynyl, -l decynyl, -2-decynyl, -9-decynyl and the like.
"-(C2-C6)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 (C2-C6)alkynyls include -acetylenyl, -propynyl, -1-butynyl, -2-butynyl, -1-pentynyl, -2-pentynyl, ~3-methy!- 1-butynyl, -4-pentynyl, -1- H bexynyl, -2-hexynyl, -5-hexynyl and the like.
"-(C3-C10)cycloalkyι" means a saturated cyclic hydrocarbon having from 3 to 0 carbon atoms. Representative (C3-C10)cycloalkyls are -cyclopropyl, -cyclobutyl, -cyclopentyl, -cyclohexyl, -cycloheptyl, -cyclooctyl, -cyclononyl and -cyclodecyl.
"-(C3-C8)cycloalkyl" means a saturated cyclic hydrocarbon having from 3 to 8 carbon atoms. Representative (C3-C8)cycloalkyls include -cyclopropyl, -cyclobutyl, ' -cyclopentyl, -cyclohexyl, -cycloheptyl and -cyclooctyl.
"-(C8-Cj4)bicycloalkyl" means a bi-cyclic hydrocarbon ring system having from 8 to 14 carbon atoms and at least one saturated cyclic alkyl ring. Representative -(C8- C14)bicycloalkyls include -indanyl, -l.,2,3,4-tetι-ahydronaphthyl, -5,6,7,8-tetrahydronaphthyl, - perhydronaphthyl and the like.
Figure imgf000168_0001
means a tri-cyclic hydrocarbon ring system having from 8 to 14 carbon atoms and at least one saturated ring. Representative -(C8- Ci4)iricycloalkyls include -pyrenyl, -1,2,3,4-tetrahydroanthracenyl, -perhydroanthracenyl -aceantbrenεyl, -1 ,2,3,4-tetrahydropenanthrenyl, -5,6,7,8-tetrahydrophenanthrenyl, -perhydrophenanthrenyl and the like.
"-(C5-C10)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 (C5-C10)cycloalkenyls include -cyclopentenyl, -cyclopentadienyl, -cyclohexenyl, -cyclohexadienyl,-cycloheptenyl, -cycloheptadienyl, -cycloheptatrienyl,
-cyclooctenyl, -cyclooctadienyl, -cyclooctatrienyl, -cyclooctatetraenyl, -cyclononenyl
-cyclononadienyl, -cyclodecenyl, -cyclodecadienyl and the like.
"-(C5-C8)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-(C5-C8)cycloalkenyls include -cyclopentenyl, -cyclopentadienyl,
-cyclohexenyl, -cyclohexadienyl, -cycloheptenyl, -cycloheptadienyl, -cycloheptatrienyl,
-cyclooctenyl, -cyclooctadienyl, -cyclooctatrienyl, -cyclooctatetraenyl and the like.
"-(C8-C14)bicycloalkenyl" means a bi-cyclic hydrocarbon ring system having at least one carbon-carbon double bond in each ring and from 8 to 14 carbon atoms. Representative
Figure imgf000169_0001
include -indenyl, -pentalenyl, -naphthalenyl,
-azulenyl, -heptalenyl, -1,2,7,8-tetrahydronaphthalenyl and the like.
Figure imgf000169_0002
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 -(Cg-Cj tricycloalkeriyls include -anthracenyl, -phenanthrenyl, -phenalenyl, -acenaphthalenyl, s-indacenyl, s-indacenyl and the like.
"-(C3-C7)heterocycle" or "-(C3-C7)heterocyclo" means a 3- to 7-membered monocyclic heterocyclic ring which is either saturated, unsaturated non-aromatic, or aromatic.
A 3-membered -(C3-C7)heterocycle can contain up to 3 heteroatoms, and a 4- to 7-membered
-(C3-C7)hete3Ocycle can contain up to 4 heteroatoms. Each heteroatom is independently selected from nitrogen, which can be quatemized; oxygen; and sulfur, including sulfoxide and sulfone. The -(C3-C7)heterocycle can be attached via a nitrogen, sulfur, or carbon atom.
Representative -(C3-C7)heterocycles include pyridyl, furyl, thiophenyl, pyrrolyl, oxazolyl, . imidazolyl, thiazolyl, thiadiazolyl, isoxazolyl, pyrazolyl, isothiazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, mo holinyl, pyn'olidinonyl, pyrrolidinyl, piperidinyl, piperazinyl, hydantoinyl, valerolactamyl, oxiranyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydropyrindinyl, tetrahydropyrimidinyl, tetrahydrothiophenyl, tetrahydrothiopyranyl and the like.
"-(C3-C5)heterocycle" or "-(C3-C5)heterocyclo" means a 3- to 5-membered monocyclic heterocyclic ring which is either saturated, unsaturated non-aromatic, or aromatic. A 3-membered -(C3-C7)heterocycle can contain up to 3 heteroatoms, and a 4- to 5-membered -(C3-C5)heterocycle can contain up to 4 heteroatoms. Each heteroatom is independently selected from nitrogen, which can be quatemized; oxygen; and sulfur, including sulfoxide and sulfone. The -(C3-C5)heterocycle can be attached via a nitrogen, sulfur, or carbon atom. Representative -(C3-C5)heterocycles include furyl, thiophenyl, pyrrolyl, oxazolyl, imidazolyl, thiazolyl, isoxazolyl, pyrazolyl, isothiazolyl, triazinyl, pyrrolidinonyl, pyrrolidinyl, hydantoinyl, oxiranyl, oxetanyl, tetrahydrofuranyl, tetrahydrothiophenyl and the like,
"-(C7-C10)bicycloheterocycle" or "-(C7-C10)bicycloheterocyclo" means a 7- to 10-membered bicyclic, heterocyclic ring which is either saturated, unsaturated non-aromatic, or aromatic. A -(C7-C10)bicycloheterocycle contains from 1 to 4 heteroatoms independently : selected from nitrogen, which can be quatemized; oxygeu; and sulfur, including sulfoxide and ; sulfone. The (C7-C10)bicycloheterocycle can be attached via a nitrogen, sulfur, or carbon atom. Representative -(C7-C10)bicycloheterocycles include -quinolinyl, -isoquinolinyl, - chromonyl, -coumarinyl, -indolyl, -indoJizinyl, -benzo[b]furanyl, -benzo[b]thiopbenyl, - iudazolyl, -purinyl, -4H-quinolizinyl, -isoquinolyl, -quinolyl, -phthalazinyl, -naphthyridinyl, - carbazolyl, - ?-carbolinyl and the like.
"-(C14)aryl" means a 14-membered aromatic carbocyclic moiety such as -anthryl or -phenanthryl.
''-(Cj-Cjc^eteroaryl" 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 ofthe -(C5-C]0)heteroaryrs rings contain at least one carbon atom. - Representative (C5-C10)heteroaryls include pyridyl, furyl, benzofuianyl, thiophenyl, benzothiophenyl, quinolinyl, pyrrolyl, indolyl, oxazolyl, benzoxazolyl, imidazolyl, benzimidazolyl, thiazolyl, benzothiazolyl, isoxazolyl, pyrazolyl, isothiazolyl, pyridazinyl, pyrimidinyl, pyrazinyl. thiadiazolyl, triazinyl, cinnolinyl, phthalazinyl, and qumazolinyl. - "-Halogen" or "-Halo" means -F, -CI, -Br or -I. The phrase "2-(3 -chloropyridyl)" means
Figure imgf000171_0001
The phrase "2-(3 -fluoropyridyl)" means
Figure imgf000171_0002
The phrase "2-(3- methylpyridyl)" means
Figure imgf000171_0003
The phrase 4 .-(3-CF3-methylpyridyi means
Figure imgf000171_0004
The phrase "2-(3-CHF2-methylpyridyl>" means
Figure imgf000171_0005
The phrase "2-(3-hydroxypyridyl)" means
Figure imgf000171_0006
The phrase "2-(3 -nitropyridyl)" means
Figure imgf000172_0001
The phrase "2-(3 -cyanopyridyl)" means
Figure imgf000172_0002
The phrase "2-(3 -bromopyridyl)" means!
Figure imgf000172_0003
The phrase 'X (3 -iodopyridyl)5' meari
Figure imgf000172_0004
The phrase "4-(5-chloropyrimidinyl)" means
Figure imgf000172_0005
The phrase "4-(5- methylpyrimidinyl)" means
Figure imgf000172_0006
The phrase "4-(5 -fluoropyrimidinyl)" means
Figure imgf000173_0001
The plirase "2-(3-chloropyrazinyl)" means
Figure imgf000173_0002
The phrase "2-(3 -methylpyrazinyl)" means
Figure imgf000173_0003
The phrase "2-(3-fiuorepyrazinyl)" means
Figure imgf000173_0004
The phrase "3-(4-chlorσpyridazinyl)" means
Figure imgf000173_0005
The plirase "3 -(4-methylpyridazinyl)" means
Figure imgf000173_0006
The phrase "3 -(4-fluoropyridazinyl)" means
Figure imgf000174_0001
The phrase "5-(4-chlorothiadiazolyl)" means
Figure imgf000174_0002
The phrase "5 -(4-methylthiadiazolyl)" means
Figure imgf000174_0003
The phrase "5-(4-fluorothiadiazolyl)" means
Figure imgf000174_0004
The phrase "pyridyl group" in connection with the Cyanoiminopiperazine Compounds of formula (I), (Ia), and (lb) means
Figure imgf000174_0005
wherein R;, R2, and n are defined above for the Cyanoiminopiperazine Compounds of formula (ϊ), (la), and (lb). The plirase "pyridyl group" in connection with the Cyanoiminopiperazine Compounds of formula (Ic) means
Figure imgf000175_0001
wherein Rπ, R12, and q are defined above for the Cyanoiminopiperazine Compounds of formula (Ic).
The plirase "pyrazinyl group" in connection with the Cyanoiminopiperazine Compounds of formula (If) means
Figure imgf000175_0002
wherein Rj, R2, and n are defined above for the Cyaτιoiminopipeιazine Compounds of fof mula (II).
The phrase "pyrazinyl group" in connection with the Cyanoiminopiperazine Compounds of formula (Ha) means
Figure imgf000175_0003
wherein R,, R2, and q are defined above for the Cyanoiminopiperazine Compounds of formula (ila). The phrase, "pyrimidinyl group" in connection with the Cyanoiminopiperazine
Compounds of formula (lit), (ilia), and (lTϊb) means
Figure imgf000175_0004
wherein R,, R2, and n are defined above for the Cyanoiminopiperazine Compounds of formula (IH), (Hla), and (lTIb).
The phrase "pyrimidinyl group" in connection with the Cyanoiminopiperazine Compounds of formula (Hie) means
Figure imgf000176_0001
- v/herein Rn, Rϊ2, and. q are defined above for the Cyanoiminopiperazine Compounds of formula (ILIc).
The plirase "pyridizanyl group" in connection with the Cyanoiminopiperazine Compounds of formula (IV) means
Figure imgf000176_0002
wherein Rb R2, and n are defined above for the Cyanoiminopiperazine Compounds of fonnula (IV).
The phrase "pyridizanyl group" in connection with the Cyanoiminopiperazine Compounds of formula (IVa) means
Figure imgf000176_0003
wherein Rπ, R12, and q are defined above for the Cyanoiminopiperazine Compounds of formula (IVa).
The phrase "thiadiazolyl group" means
Figure imgf000176_0004
wherein R, is defined above for the Cyanoiminopiperazine Compounds of formula (V). The phrase "benzothiazolyl group" means
Figure imgf000177_0001
wherein R& and s are defined above for the Cyanoiminopiperazine Compounds of formulas (VI) and (VH).
The phrase "benzoimidazolyl group" means
Figure imgf000177_0002
wherein R8 and s are defined above for the Cyanoiminopiperazine Compounds of fonnulas (VI) and (VTO.
The phrase "benzcoxazolyl group" rneans
Figure imgf000177_0003
wherein R8 and s are defined above for the Cyanoiminopiperazine Compounds of formulas (Vl) and (VH).
The phrase "(R9)-phenyl group" means
Figure imgf000178_0001
The phrase "phenethyl group" means an ethylene group attached to a terminal Ar2 group, wherein one or each of two hydrogens ofthe ethylene group can optionally be substituted with an R4 group. A phenethyl group is depicted below tΛΛΛ
(R4)t
Ar2
wherein R , Ar2, and t are defined above for the Cyanoiminopiperazine Compounds of formula (VI).
The phrase "phenpropyl group" an n-propylene group attached to a terminal Ar2 group, wherein one or each of two hydrogens ofthe n-propylene group can optionally be substituted with an R4 group. A phenpropyl group is depicted below
Figure imgf000178_0002
wherem R4, Ar2, and t are defined above for the Cyanoiminopiperazine Compounds of formula (VH). The term "animal," includes, but is not limited to, a cow, monkey, horse, sheep, pig, chicken, turkey, quail, cat, dog, mouse, rat, rabbit, guinea pig and human.
The phrase "pharmaceutically acceptable salt," as used herein, is a salt formed from an acid and a basic nitrogen group of one ofthe Cyanoiminopiperazine 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, fonnate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, yp-toluenesulfonate, and pamoate (i.e., 1,1 '-methylene-bis-(2-hydroxy-3-naphthoate)) salts. The term "pharmaceutically acceptable salt" also refers to a salt prepared frorri a Cyanoiminopiperazine Compound having an acidic functional group, such as a carboxylic acid functional group, and a phannaceutically acceptable 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 Λ 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-(hydiOxymethyl)methylamine, N, N,-di-lower alkyl-N-(hydroxy lower alkyl)'-amines, t such as N,N,-dimethyl-N-(2-hydroxyethyl)amine, or tri-(2-hydroxyethyl)amine; N-methyl-D-glucamine; and amino acids such as arginine, lysine, and the like.
When 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. In one embodiment, each carbon atom of a first group is independently substituted with one or two second groups, hi another embodiment, each carbon atom of a first group is independently substituted with only one second group.
The tenn "UI" means urinary incontinence. The term "IBD" means inflammatory-bowel disease. The tenn "IBS" means irritable-bowel syndrome.
The term "DIEA" means diisopropylethylamine. The term "DMSO" means dimethyl sulfoxide. The term "DMF" means dimethyl formamide. The term "DCM" means dichloromethane.
The phrase "treatment of and "treating" includes the amelioration or cessation of a Condition or a symptom thereof.
The phrase "prevention of and "preventing" includes the avoidance ofthe onset of a Condition or a symptom thereof.
4.18 METHODS FOR MAKING THE CYANOIMINOPIPERAZINE COMPOUNDS The Cyanoiminopiperazine Compounds can be made using conventional organic synthesis or by the following illustrative methods shown in the schemes below. The Cyanoiminopiperazine Compounds wherein A is NR4 can be obtained by the following illustrative methods shown below in Scheme A:
Figure imgf000180_0001
B
A
Figure imgf000180_0002
Scheme A wherein R3, R4, R6, and m are defined above for the Cyanoiminopiperazine Compounds and Ar is:
Figure imgf000181_0001
wherein R1, R2 and n are defined above.
A compound of formula A is reacted with a compound of formula B in an aprotic organic solvent such as diethyl ether, di-n-propyl ether, tefrahydiofuran, methylene chloride, or toluene at a temperature ranging from about room temperature to about the reflux temperature ofthe solvent for a period of about 0.5 h to about 24 h to provide a Cyanoiminopiperazine Compound wherein A is NR4. hi one embodiment, the aprotic organic solvent is di-n-propyl ether. In another embodiment, a reaction mixture of di-n-propyl ether, compound of formula A and a compound of formula B is heated at a temperature of about 70° to about 80° C. In another embodiment, the reaction mixture of di-n-propyl ether, a compound of foπnula A and a compound of formula B is heated at a temperature of about at 75 °C for about 12 h.
Compounds of formula A can be obtained as shown below in Scheme B:
Figure imgf000182_0001
solvent, heat
Figure imgf000182_0002
1
Figure imgf000182_0003
15 Scheme B
An amine of formula NHR6R4, wherein R4 and R6 are defined above, is reacted with diphenylcyanocabonimidate (commercially available from Sigma-Aldrich, St. Louis, MO (www. sigma-aldrich.com)) in an aprotic solvent such as diethyl ether, di-n-propyl ether, tetrahydro aran, methylene chloride, or toluene to provide the compound of formula A. In
20 one embodiment, the aprotic solvent is DCM and the reaction mixture of NHRbR4 and ,- . diphenylcyanocabonimidate is allowed to react at about room temperature. In another embodiment, the aprotic solvent is toluene and the reaction mixture of NHR6R4 and diphenylcyanocabonimidate is allowed to react at about 110°C. The NHR6R4 and diphenylcyanocaboniinidate is typically allowed to react for a period of about 0.5 h to about
25 24 h. Typically the compound of formula A is used without further purification.
Compounds of formula B can be obtained as shown below in Scheme C:
Figure imgf000183_0001
Figure imgf000183_0002
C2
B2
Figure imgf000183_0003
3 H
33
Figure imgf000183_0004
B4
Figure imgf000184_0001
B5 Scheme C wherein R1, R2, R3, m, and n are defined above and X is a halogen. In one embodiment, X is bromide, chloride or iodide.
A compound of formula C1-C5 is reacted with a compound of formula D in an aprotic solvent in the presence of DIEA or triethylamine, optionally with heating, to provide compound B. Compound B is isolated from the reaction mixture and purified. In one embodiment, the reaction is purified using column chromatography or recrystalhzation. Compounds of formula C1-C5 and D are commercially available or can be prepared by methods well known to those skilled in the art. The compound of formula D.. wherein m is 0 is commercially available from Sigma-Aldrich, St. Louis, MO (www.sigma- aldrich.com).
The Cyanoiminopiperazine Compounds wherem A is -O- can be obtained as shown below in Scheme D. - '
Figure imgf000184_0002
Scheme D wherein R", R6, m, and Ar are defined above for the Cyanoiminopiperazine Compounds. A compound of formula B is reacted with a compound of formula E to provide the Cyanoiminopiperazine Compounds wherein A is -O-. Representative procedures for reacting a compound of formula B with a compound of formula E are provided in T.D. Aicher et al.; J. Med. Chem. 43(2):236-49 (2000) and German Patent No. 3336409.
The compound of formula E can be obtained as shown below in Scheme E.
Figure imgf000185_0001
Scheme E 10 wherein R6 is defined above.
The compound of formula E can be obtained by reacting a compound of formula F with cyanamide. Representative procedures for obtaining a compound of formula E from a compound of formula F are provided in R.L. Webb et al., J. Heterocycl. Chem. .19(5): 1205-1206 (1982) and U.S. Patent No. 4,285,878 to Labaw et al. 15 The compound of formula F can be obtained as shown below in Scheme F.
Figure imgf000185_0002
20 Scheme wherein R6 is defined above.
The compound of formula F can be obtained by reacting a compound of formula G with PC15. A representative procedure for obtaining a compound of formula F from a compound of fonnula G is provided in. R.L. Webb et al., J. Heterocyc Chem.
25 19(5):1205-1206 (1982).
The compound of formula G can be obtained by reacting a compound of formula R6-OH with COCl2, triphosgene, or CO and a Pd catalyst as described in U.S. Patent No. 6,175,017 to H. Buyschi et al.; A. Gode et al., Chemistry-A European Journal 6(19):3522-30 (2000); or H. Yasuda et a Orga ometallics, 21(6):1216-20 (2002),
30 respectively. Compounds of formula Rb-OH are commercially available or can be prepared by methods well known to those skilled in the art. The Cyanoiminopiperazine Compounds wherein A is -S- can be obtained as shown below in Scheme G.
Figure imgf000186_0001
Scheme G wherein RG, R\ m, and Ar are defined above and R10 is -SCH3 or -O- Hj.
A compound of formula B is reacted with a compound of formula H to provide the Cyanoiminopiperazine Compoxmds wherein A is -S-. Representative procedures for reacting a compound of formula B with a compound of formula H are provided in T.D. Aicher et al., J. Med. Chem. 43(2);236-49 (2000) and Ger. Patent No. 3336409. The compound of formula H can be obtained as shown below in Scheme H.
Figure imgf000186_0002
H
Scheme H wherein R5 and R10 are defined above. : '
A thiol of formula R6SH is reacted with a compound of formula J to provide the compound of formula H. Representative procedures for obtaining compounds of formula J and for obtaining the compound of formula H by reacting a thiol with a compound of formula J are provided in R.L. Webb et al., J. Heterocycl. Chem., 24(l):275-78 (1.987); I.
Reid et al., Liebigs Ann. Chem. 6:599-601 (1988); and L.S. Wittenbrook et al., J. Heterocycl.
Chem. 12(1): 37-42 (1975). Compounds of formula R6-SH are commercially available or can be prepared by methods well known to those skilled in the art. The Cyanoirninopiperazine Compounds of formula VI and VH can be obtained as described below in Scheme I. .
Figure imgf000187_0001
solvent, heat
Figure imgf000187_0002
K
wherein Ar2, R4. and t are defined above.
Scheme I An amine of formula I or an amine of formula J is reacted with diphenylcyanocabonimidate (commercially available from Sigma-Aldrich, St. Louis, MO (v ww.sigma-aldrich.com)) in an aprotic solvent such as diethyl ether, di-n-propyl ether, tetrahydrofuran, methylene chloride, or toluene to provide the compound of formula K or a compound of formula L, respectively. In one embodiment, the aprotic solvent is DCM and the reaction mixture ofthe amine of formula I or the amine of formula J and diphenylcyanocabonimidate is allowed to react at about room temperature. In another embodiment, the aprotic solvent is toluene and the reaction mixture ofthe amine of formula 1 or the amine of formula J and diphenylcyanocabonimidate is allowed to react at about
1 10X. The amine of formula I or the amine of formula J and diphenylcyanocabonimidate is typically allowed to react for a period of about 0.5 h to about 24 h. Typically the compound of formula K or the compound of formula L is used without further purification.
The compound of formula K or the compound of formula L is then reacted with a compound of formula B, obtained as described above in Scheme B, according to the procedure described above in Scheme A to provide the Cyanoiminopiperazine Compound of formula (VI) or (VH) , respectively.
4.19 THERAPEUTIC USES OF THE CYANOIMI OPIPERAZINE COMPOUNDS
In accordance with the invention, the Cyanoiminopiperazine Compounds are administered to an animal in need of treatment or prevention of 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. hi one embodiment, an effective amount of a Cyanoiminopiperazine
Compound can be used to heat or prevent any condition treatable or preventable by inhibiting VRl. Examples of conditions that are treatable or preventable by inhibiting VRl include, but are not limited to, pain, UI, an ulcer, IBD, and IBS. hi another embodiment, an effective amoixnt of a Cyanoiminopiperazine Compound can be used to treat or prevent any condition treatable or preventable by inhibitiug mGluR5. Examples of 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.
In another embodiment, an effective amount of a Cyanoiminopiperazine Compound can be used to treat or prevent any condition treatable or preventable by inhibiting mGluRl . Examples of 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 Cyanoiminopiperazine Compounds can be used to treat or prevent acute or chronic pain. Examples of pain treatable or preventable using the Cyanoiminopiperazine 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, pain associated with intensive care, arthritic pain, neuropathic pain, and pain associated with a periodontal disease, including gingivitis and periodontitis.
The Cyanoiminopiperazine Compounds can also be used for inhibiting, preventing, or treating pain associated with inflammation or with an inflammatory disease in an animal. The pain to be inhibited, treated or prevented may be associated with inflammation associated with an inflammatory disease, which can arise where there is an inflammation ofthe body tissue, and which can be a local inflammatory response and/or a systemic inflammation. For example, the Cyanoiminopiperazine Compounds car. be used to inhibit, treat, or prevent pain associated with inflammatory diseases including, but not limited to: organ transplant rejection; reoxygenation injury resulting from organ transplantation (see Grupp et al., J. Mol Cell Cardiol. 31:297-303 (1999)) including, but not limited to, transplantation of the heart, lung, liver, or kidney; chronic inflammatory diseases of the joints, including arthritis, rheumatoid arthritis, osteoarthritis and bone diseases associated with increased bone resorption; inflammatory lung diseases, such as asthma, adult respiratory distress syndrome, and chronic obstructive airway disease; inflammatory diseases ofthe eye. including comeal dystrophy trachoma, oncnocerciasis, uveitis, sympathetic ophthalmitis and endophthalmitis; chronic inflammatory diseases ofthe gum, including gingivitis and periodontitis; tuberculosis; leprosy; inflammatory diseases ofthe kidney, including uremic complications, glomenilonephritis and nephrosis; inflammatory diseases ofthe skin, including sclerodemiatitis, psoriasis and eczema; inflammatory diseases ofthe central nervous system, including chronic demyelinating diseases of the nervous system, multiple sclerosis, AIDS- related neurodegeneration and Alzheimer s disease, infectious meningitis, encephalomyelitis, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis and viral or autoimmune encephalitis; autoimmune diseases, including Type I and Type H diabetes mellitus; diabetic complications, including, but not limited to, diabetic cataract, glaucoma, retinopathy, nephropathy (such as microaiuminuria and progressive diabetic nephropathy), polyneuropathy, mononeuropathies, autonomic neuropathy, gangrene ofthe feet, atherosclerotic coronary arterial disease, peripheral arterial disease, nonketotic hyperglycemic-hyperosmolar coma, foot ulcers, joint problems, and a, skin or mucous membrane complication (such as an infection, a shin spot, a candidal infection or necrobiosis lipoidica diabeticorum); immune-complex vasculitis, and systemic lupus erythematosus (SLE); inflammatory diseases ofthe heart, such as cardiomyopathy, ischemic heart disease hypercholesterolemia, and atherosclerosis; as well as various other diseases that can have significant inflammatory components, including preeclampsia, chronic liver failure, brain and spinal cord trauma, and cancer. The Cyanoiminopiperazine Compounds can also be used for inhibiting, treating, or preventing pain associated with inflammatory disease that can, for example, be a systemic inflammation ofthe 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. Such shock can be induced, e.g., by a chemotherapeutic agent that is adminstered as a treatment for cancer. The Cyanoiminopiperazine Compounds can be used to treat or prevent UI.
Examples of UI treatable or preventable using the Cyanoiminopiperazine Compounds include, ut are not limited to, urge incontinence, stress incontinence, overflow incontinence, neurogenic incontinence, and total incontinence.
The Q'anoiminopiperazine Compounds can be used to treat or prevent an ulcer. Examples of ulcers treatable or preventable using the Cyanoiminopiperazine
Compounds include, but are not limited to, a duodenal ulcer, a gastric ulcer, a marginal ulcer, an esophageal ulcer, or a stress ulcer. •
The Cyanoiminopiperazine Compounds can be used to treat or prevent IBD, including Crohn's disease and ulcerative colitis. The Cyauoiminopiperazine Compounds can be used to treat or prevent IBS.
Examples of IBS treatable or preventable using the Cyanoiminopiperazine Compounds include, but are not limited to, spastic-colon-type IBS and constipation-predominant IBS. The Cyanoiminopiperazine 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. X
Nicotine-related disorders include, but are not limi ted to, Nicotine
Dependence, Nicotine Withdrawal, and Nicotine-Related Disorder not otherwise specified "
(NOS). . . 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, Aniphetamine-ϊnduced Sexual Dysfunction, Amphetamine-Induced Sleep Disorder,
Amphetamine Related Disorder not otherwise specified (NOS), Amphetamine Intoxication, and Amphetamine Withdrawal.
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-hiduced Mood Disorder, Cocaine-Induced 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-hiduced Sleep Disorder, Halhxcinogen Related Disorder not otherwise specified (NOS), Hallucinogen Intoxication, and Halluciuogen Persisting Perception Disorder (Flashbacks).
Lnhaiant-rulated disorders include, but aie not limited to, Inhalant Dependence, Inhalant Abuse, Inhalant Intoxication, Inhalant Intoxication Delirium, Inhalant-Induced Psychotic Disorder with delusions, ialant-ϊnduced 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 wi!h delusions, Opioid-Induced Psychotic Disorder with hallucinations, Opioid-Induced Anxiety Disorder, Opioid Related Disorder not otherwise specified (NOS), Opioid Intoxication, and Opioid Withdrawal.
The Cyanoiminopiperazine 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, bradykinεsia, muscular rigidity, resting tremor, and impairment of postural balance. The Cyanoiminopiperazine 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 Cyanoiminopiperazine 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 Cyanoiminopiperazine Compounds can be used to treat or prevent strokes, including but. not limited to, ischemic strokes and hemorrhagic strokes.
The Cyanoiminopiperazine Compounds can be used to treat or prevent a seizure, including but not limited to, infantile spasms, febrile seizures, and epileptic seizures. The Cyanoiminopiperazine Compounds can be used to treat or prevent a pruritic condition, including but not limited to, prurihxs caused by dry skin, scabies, dermatitis, herpetifonnis, atopic dermatitis, pruritus vulvae et ani, miliaria, insect bites. pediculosis, contact dermatitis, drug reactions, urticaria, urticarial enxptions of pregnancy, psoriasis, lichen planus, lichen simplex chronicus, exfoliative dermatitis, folliculitis, bullous pe phigoid, or fiberglass dermatitis.
The Cyanoiminopiperazine 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 subtype schizophrenia, and non-deficit schizophrenia; a delusional disorder, including erotomanic subtype delusional disorder, grandiose subtype delusional disorder, jealous subtype delusional disorder, persecutory subtype delusional disorder, and somatic subtype delusional disorder; and brief psychosis.
The Cyanoiminopiperazine Compoxmds 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. The Cyanoiminopiperazine Compounds can be used to treat or prevent a memory deficiency, including but not limited to, dissociative amnesia and dissociative fugue.
The Cyanoiminopiperazine Compounds can be used to heat or prevent restricted brain function, including but not limited to, that caused by surgery or an organ tiunsplant, restricted blood supply to the brain, a spinal cord injury, a head injury, hypoxia, cardiac arrest, or hypoglycemia.
The Cyanoiminopiperazine Compounds can be used to treat or prevent HuBtington's chorea.
The Cyanoiminopiperazine Compounds can be used to treat or prevent ALS. The Cyanoiminopiperazine 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 Cyanoiminopiperazine Compounds can be used to treat or prevent a muscle spasm.
The Cyanoiminopiperazine Compounds can be used to treat or prevent a migraine.
The Cyanoiminopiperazine Compounds can be used to inhibit, treat or prevent vomiting, including but not limited to, nausea vomiting, dry vomiting (retching), and regurgitation.
The Cyanoiminopiperazine Compounds can be used to treat or prevent dyskinesia, including but not limited to, tardive dyskinesia and biliary dyskinesia.
The Cyanoiminopiperazine Compounds can be used to treat or prevent depression, including but not limited to, major depression and bipolar disorder. Applicants believe that the Cyanoiminopiperazine 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 effective amount of a Cyanoim nopiperazine Compound. 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, a human in one embodiment, by contacting a cell, in an animal, with an effective amount of a Cyanoiminopiperazine Compound. In one embodiment, the method is useful for treating or preventing pain in an animal. In another embodiment, the method is useful for treating or preventing UI in an animal. In another embodiment, the method is useful for treating or preventing an ulcer in an animal. In another embodiment, the method is useful for treating or preventing IBD in an animal. In another embodiment, the method is useful for treating or preventing IBS in an animal.
Examples of tissue comprising cells capable of expressing VRl include, but are not limited to, neuronal, brain, kidney, urotheliuni, and bladder tissue. Methods for assaying cells that express VRl are well known in the art.
Applicants believe that the Cyanoiminopiperazine Compounds are antagonists for mGluR5.
The invention also relates to methods for inhibiting mGluR5 function in a cell, ,?. comprising contacting a cell capable of expressing mGluRS with an amount of a
Cyanoiminopiperazine Compound effective to inhibit mGluR5 function in the cell. This V method can be used in vitro, for example, as an assay to select cells that express mGhxR5 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 mGluR5 function in a cell in vivo, in an animal, a human in one embodiment, by contacting a cell, in an animal, with an amount of a Cyanoiminopiperazine Compound effective to inhibit mGluR5 function in the cell. In one embodiment, the method is useful for treating or preventing pain in an animal in need thereof. In another embodiment, the method is useful for treating or preventing an addictive disorder in an animal in need thereof. In another embodiment, the method is useful for treating or preventing Parkinson's disease in an animal in need thereof. In another embodiment, the method is useful for treating or preventing parkinsonism in an animal in need thereof. In another embodiment, 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 a pruritic condition in an animal in need thereof, hi another embodiment, the method is useful for heating or preventing psychosis in an animal in need thereof. Examples of cells capable of expressing mGluRS are neuronal and glial cells ofthe central nervous system, particularly the brain, especially in the nucleus accumbens. Methods for assaying cells that express mGluR5 are well known in the art.
Applicants believe that the Cyanoiminopiperazine Compounds are antagonists for mGluRl.
The invention also relates to methods for inhibiting mGluRl function in a cell, comprising contacting a cell capable of expressing mGluRl with an amount of a Cyanoiminopiperazine 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, a human in one embodiment, by contacting a cell, in an animal, with an amount of a Cyanoiminopiperazine Compound effective to inhibit mGluRl function in the cell, hi one embodiment, the method is useful for treating or preventing pain in an animal in need thereof. In another embodiment, 1he method is useful for treating or preventing UI in an animal in need thereof. In another embodiment. the method is useful for treating or preventing an addictive disorder in an animal in need thereof, hi another embodiment, the method is useful for treating or preventing Parkinson's disease in an animal in need thereof. In another embodiment, the method is useful for treating or preventing parkinsonism in an animal in need thereof, hi another embodiment, 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 heating or preventing stroke in an animal in need thereof. In another embodiment, the method is useful for treating or preventing a seizure in an animal in need thereof, hi 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, hi another embodiment, the method is useful for treating or preventing a cognitive disorder in an animal in need thereof. In another embodiment, the method is useful for treating or preventing a memory deficit in an animal in need thereof. In another embodiment, the method is useful for heating or preventing restricted brain function in an animal in need thereof. In another embodiment, the method is useful for treating or preventing Huntington's 5 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, hi another embodiment, the method is useful for treating or preventing a muscle
,10 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 or preventing vomiting in an animal in need thereof. In another embodiment, the method is useful for treating or preventing dyskinesia in an animal in need thereof. In another embodiment, the method is useful for treating or preventing depression in
15 an animal in need thereof.
Examples of cells capable of expressing mGluRl include, but are not limited to, cerebeϋar Puirkinje neuron cells. Purkinje cell bodies (punctate), cells of spine(s) ofthe. cerebellut ; neurons and neurophil cells of olfactory-bulb glomeruli; cells ofthe superficial ; layer of the cerebral cortex; hippocampus cells; thalamus cells; superior colliculus cells; and
20 spinal trigeminal nucleus cells. Methods for assaying cells that express mGhiRl are well known, in the art.
4.19.1 THERAPEUTIC/PROPHYLACTIC ADMINISTRATION AND COMPOSITIONS OF THE INVENTION
25 Due to their activity, the Cyanoiminopiperazine Compounds are advantageously useful in veterinary and human medicine. As described above, the Cyanoiminopiperazine Compounds are useful for heating 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
30 brain function, Huntingtons chorea, ALS, dementia, retinopathy, a muscle spasm, a migraine, vomiting, dyskinesia, or depression in an animal in need thereof. When administered to an animal, the Cyanoiminopiperazine Compounds are administered as a component of a composition that comprises a pharmaceutically acceptable canϊer or εxcipient. The present compositions, which comprise a Cyanoiminopiperazine Compound, can be administered orally. The Cyanoimmopiperazine Compounds ofthe 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. dminisnation 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 Cyanoiminopiperazine Compound.
Methods of administration include, but are not limited to, intradermal, intramuscular, inhaperitoneal, intravenous, subcutaneous, intranasal. epidural, oral, sublfngual, 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 o the practitioner. In most instauces, administration will result in the elease of the Cyanoiminopiperazine Compounds into the bloodstream.
In specific embodiments, it can be desirable to administer the Cyanoiminopiperazine Compounds locally. This can be achieved, for example, and not by of limitation, by local infusion during surgery, topical application, e.g., in conjunction with a wound dressing after surgery, by injection, by means of a catheter, by means of a supposi tory or enema, or by means of an implant, said implant being of a porous, non-porous, or gelatinous material, including membranes, such as sialastic membranes, or fibers.
In certain embodiments, it can be desirable to introduce the Cyonoiminopiperazine Compounds info the central nervous system or gastrointestinal tract by an}' suitable route, including intraventricular, intrathecal. and epidural injection, and enema. Jnfruyerjtricυlar injection can be facilitated by an intraventricular catheter, for example, attached to a reservoir, such as an Ommaya 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 fluoiocarbon or synthetic pulmonary surfactant. In certain embodiments, the Cyanoiminopiperazine Compounds can be formulated as a suppository, with traditional binders and excipients such as triglycerides. hi another embodiment, the Cyanoiminopiperazine 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)). hi yet another embodiment, the Cyanoiminopiperazine Compounds can be delivered in a controlled-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. In one embodiment, 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. 321:51A (1989)).
[n another embodiment, 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. 23:61 (1983): Levy et al. Science 228:190 (1985): et σl.,Ann. Neurol. 25:351 (1989); and Howard et al., J. Neurosurg. 71:105 (1989;,;.
In yet another embodiment, a controlled- or sustained-release system can be placed in proximity of a target ofthe Cyanoiminopiperazme Compounds, e.g., the spinal column, brain, or gastrointestinal tract, thus requiring only a fraction ofthe systemic dose.
The present compositions can optionally comprise a suitable amount of a pharmaceutically acceptable excipient so as to provide the form for proper administration to die acimai. Such pharmaceutical excipients can be liquids, such as water and oils, including those of petroleum, animal, vegetable, oi synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil and the like. The pharmaceutical excipients can be saline, girn acacia, gelatin, starch paste, talc, keratin, colloidal silica, urea and the like, hi addition, aixxiliary, stabilizing, thickening, lubricating, and coloring agents can be used, h one embodiment, the pharmaceutically acceptable excipients are sterile when administered to an animal. Water is a particularly useful excipient when the Cyanoiminopiperazine 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 5 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.
The present compositions can take the fonn of solutions, suspensions, emulsion, tablets, pills, pellets, capsules, capsules containing liquids, powders.
) 0 sustained-release formulations, .suppositories, emulsions, aerosols, sprays, suspensions, or any other form suitable for use. In one embodiment, the composition is in the form of a capsule (see e.g.. U.S. Patent No. 5,698,155). Other examples of suitable pharmaceutical excipients are described in Remington 's Pharmaceutical Sciences 1AA1-1616 (Alfonso R. Gennaro ed., 19th ed. 1995), incorporated herein by reference.
15 In one embodiment, the Cyanoiminopiperazine Compounds are formulated in accordance with routine procedures as a composition adapted for oral administration to human beings. Compositions for oral delivery can be in e fonn of tablets, lozenges, aqueous or oily suspensions, granules, powders, emulsions, capsules, syrups, or elixirs, foi example. Orally administered compositions can contain one or more agents, for example,
20 sweetening agenls 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. Moreover, where in tablet or pill form, the 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
25 menibianes suiTounding an osmotically active driving compound are also suitable for orally administered compositions, hi these latter platforms, fluid from the environment surrounding the capsule is imbibed by the driving compound, which swells to displace the agent or agent composition tlirough an aperture. These delivery platforms can provide an essentially zero order deliveiy profile as opposed to the spiked profiles of immediate release formulations. A
30 time-delay material such as glycerol monostearate or glycerol stearate can also be used. Oral compositions can include standard excipients such as mannitol, lactose, starch, magnesium stearate, sodium saccharin, cellulose, and magnesium carbonate. In one embodiment, the excipients are of pharmaceutical grade.
In another embodiment, the Cyanoiminopiperazine Compounds can be formulated for intravenous administration. Typically, compositions for intravenous administration comprise sterile isotonic aqueous buffer. Where necessary, 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 ofthe injection. Generally, 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. Where the Cyanoiminopiperazine Compounds are to be administered by infusion, they can be dispensed, for example, with an infusion bottle containing sterile pharmaceutical grade" water or saline. Where the Cyanoiminopiperazine Compounds are administered by injection, an ampule of sterile water for injection cr saline can be provided so that the ingredients can be mixed prior to administration.
The Cyanoiminopiperazine Compounds can be administered by controlied- 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; 3,508,123; 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, hydropropylmethyl 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 ordinaiy skill in the an. including those described herein, can be readily selected for use with the active ingredients ofthe invention. The invention thus encompasses single unit dosage fonns 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 counterparts. In one embodiment, a controlled- or sustained-release composition comprises a minimal amount of a Cyanoiminopiperazine Compound to cure or control the condition in a minimum amount of time. Advantages of controlled- or sustained-release compositions include extended activity ofthe drug, reduced dosage frequency, and increased 5 patient compliance. In addition, controlled- or sustained-release compositions can favorably affect the time of onset of action or other characteristics, such as blood levels ofthe Cyanoiminopiperazine Compound, and can thus reduce the occurrence of adverse side
• . effects.
Controlled- or sustained-release compositions can initially release an amount
10 of a Cyanoiminopiperazine Compound that promptly produces the desired therapeutic or , prophylactic effect, and gradually and continually release other amounts ofthe Cyanoiminopiperazine Compound to maintain this level of therapeutic or prophylactic effect over an extended period of time. To maintain a constant level ofthe Cyanoiminopiperazine Compound in the body, the Cyanoiminopiperazine Compound can be released from the *'•;;,
15 dosage form at. a rate that will replace the amount of Cyanoiminopiperazine Compound bein Xf metabolized and excreted from the body. Controlled- or sustained-release of an active X
■■ ingredient can be stimμlated by various conditions, including but not limited to, changes in % pH, changes in temperature, concentration or availability ofenzym.es, concentration or - availability of water, or other physiological conditions or compounds.
20 The amount of the Cyanoiminopiperazine C mpouι:d that is effective in the •. treatment or prevention of 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 and
25 can be determined by standard clinical techniques. In addition, 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 ofthe condition being treated and should be decided according to the judgment o the practitioner and each patient's circumstances in view of, e.g.. published clinical studies. Suitable effective
30 dosage amounts, however, range from about 10 micrograms to about 2500 milligrams about every 4 h, although they are typically about 100 mg or less. In one embodiment, the effective dosage amount ranges from about 0.01 milligrams to about 100 milligrams of a Cyanoiminopiperazine Compound about every 4 h, in another embodiment, about 0.020 milligrams to about 50 milligrams about every 4 h, and in another embodiment, about 0.025 milligrams to about 20 milligrams about every 4 h. The effective dosage amounts described 5 herein refer to total amounts administered; that is, if more than one Cyanoiminopiperazine ■ Compound is administered, the effective dosage amounts correspond to the total amount administered.
Where a cell capable of expressing VRl, mGluRS, or mGluRl is contacted with a Cyanoiminopiperazine Compound in vitro, the amount effective for inhibiting the
1.0 receptor function in a cell will typically range from about 0.01 μg/L to about 5 mg/L, in one embodiment, from about 0.01 μg/L to about 2.5 mg/L, in another embodiment, from about 0.01 μg/L to about 0.5 mg/L, and in another embodiment, from about 0.01 μg/L to about 0.25 mg/L of a solution or suspension of a pharmaceutically acceptable carrier or excipient. In one embodiment, the volume of solution or suspension is from about 1 μL to about I mL. hi .
15 another embodiment, the volume of solution or suspension is about 200 μL. :
Where a cell capable of expressing VRl, nιGluR5, or mGluRl it? contacted with a Cyanoiminopiperazine Compound in vivo, the amount effective foi inhibiting the receptor fimction in a cell will typically range from about 0.01 mg to about 100 mg/kg of body weight, per day, in one embodiment, from about 0.1 mg to about 50 mg/kg body weight 0 per day, and in another embodiment, from about 1 mg to about 20 mg kg of body weight per day. • '
The Cyanoiminopiperazine 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. 5 The present methods 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 in an animal in need thereof can further comprise administering to 0 the animal being administered a Cyanoiminopiperazine Compound another therapeutic agent. In one embodiment, 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 mGluR5 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 non-opioid analgesic, a non-steroid anti-inflammatory agent, an antimigraine agent, a Cox-H inhibitor, an antiemetic, a β-adrenergic blocker, an anticonvulsant, an antidepressant, a Ca2+-channel blocker, an anticancer agent, an agent for treating or preventing UI, an agent for heating or preventing an ulcer, an agent for treating 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 treating anxiety, an agent for treating opi'εpsy, an agent for treating a stroke, an agent for treating a seizure, an agent for heating a pruritic condition, an agent for treating psychosis, an agent for treating Huntington's chorea, ar agent for treating ALS, an agent for treating a cognitive disorder, an agent for heating a migraine, an agent for treating vomiting, n agent for treating dyskinesia, or an agent for heating depression, and mixtures thereof.
Effective amounts ofthe 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, hi one embodiment ofthe invention, where another therapeutic agent is administered to an animal, the effective amount of the Cyanoiminopiperazine Compound is less than its effective amount would be where the other therapeutic agent is not administered. In this case, without being bound by theory, it is believed thnt the Cyanoiminopiperazine Compounds and the other therapeutic agent act syrergistically to treat or prevent 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, reεtricted brain function, Huntington's chorea, ALS, dementia, retinopathy, a muscle spasm, a migraine, vomiting, dyskinesia, or depression.
Examples of useful opioid agonists include, but are not limited to, alfentanil, allylprodine, alphaprodine, anileridine, benzyhnorphine, bezitramide, buprenorphine, butorphanol, clonitazene, codeine, desomorphine, dexhomoramide, dezocine, diamprornide, diamorphone, dihydrocodeine, dihydromorphine, dimenoxadol, dimepheptanol, dimethylthiambutene, dioxaphetyl butyrate, dipipanone, eptazocine, ethoheptazine, ethylmethylthiambutene, ethylmoφhine, etonitazene fentanyl, heroin, hydrocodone. hydromorphone, hydroxypethidine, isomethadone, ketobemidone, levoiphanol, levophenacylmoφhan, Jofentanil, eperidine, meptazinol, ήietazocine, methadone, metopon, moφhine, myrophine, nalbuphine, narceine, nicomoφhine, norlevoφhanol, normethadone, naloφhiiie, normoφhine, noφipanone, opium, oxycodone, oxymoφhone, papaveretum, pentazocine, phenadoxone, phenomoφhan, phenazocine, phenoperidine, piminodine, piritramide, proheptazine, piomedol, properidine, propiram, propoxypheαe, sufentanil, tilidine, tramadol, pharmaceutically acceptable salts thereof, and mixtures thereof. In certain embodiments, the opioid agonist is selected from codeine, hydromoφhoue, hydrocodone, oxycodone, dihydrocodeine, dihydromorphine, moφhine, tramadol, oxymoφhone, pharmaceutically acceptable salts thereof, and mixtures thereof. Examples of useful nou-opioid analgesics include non-steroidal anti-inflammatory agents, such as aspirin, ibuprofen, diclofenac, naproxen, benoxaprofen, flurbiptofen, fenoprofen, flubufen, ketoprofen, indoprofen, piroprofen, caφrofen, oxaprozin. pramoprofen, muroprofen, trioxaprofen, suprofen, aminoprofen, tiaprofenic acid, fluprofen, bucloxic acid, indomethacin, sulindac, tolmetin, zo epirac, tiopinac, zidometacin, acemetacin. fεntiazac, clidanac, oxpinac, mefenamic acid, meclofenamic acid, flufenamic acid, niflumic acid, tolfenamic acid, diflurisal, flufenisai, piroxicam, sudoxicam, isoxicam, and pharmaceutically acceptable salts thereof, and mixtures thereof. Other suitable non-opioid analgesics inchxde 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, saliσylsalicyiic 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 (phenylbutazone, oxyphenthartazone); and alkanones, including nabumetone. For a more detailed description ofthe NSAIDs, see Paul A. Insel, Analgesic-Antipyretic and Anti-inflammatory Agents and Drugs Employed in the Treatment of Gout, in Goodman & Gilman 's The Pharmacological Basis of Therapeutics 617-57 (Perry B. Molinhoff and Raymond W. Ruddon eds., 9th ed 1.996) and Glen R. Hanson, Analgesic, Antipyretic and Anti-Inflammatory Drugs in Remington: The Science and Practice of Pharmacy Vol II 1196-1221 (A.R. Gennaro ed. 19th ed. 1995) which are hereby incoφorated by reference in their entireties.
Examples of useful Cox-H inhibitors and 5-lipoxygenase inhibitors, as well as combinations thereof, are described in U.S. Patent No. 6,136,839, which is hereby incoφorated by reference in its entirety. Examples of useful Cox-H inhibitors include, but are not limited to, rofecoxib and celecoxib.
Examples of useful antimigraine agents include, but are not limited to, alpiropride, dihydroergotamine, dolasetron, ergocornine. ergoco iinine, ergocryptiiie, ergot, ergotamine, flumedroxone acetate, fonazine, lisuride, lomerizine, methysergide oxetoronε, pizotyline, and mixtures thereof. The other therapeutic agent can also be an agent useful for reducing any potential side effects of a Cyanoiminopiperazine Compounds. For example, the other therapeutic agent can be an antiemetic agent. Examples of useful antiemetic agents include, but are not limited to, metoclopromide, domperidone, prochloφerazine, promethazine, chloφλOinazine, tiimethobenzamide, ondansetron, granisetron, hydioxyzine, acetylleucine monoethanolamine, alizapride, azasetron, benzquinamide, bietanautine, bromopride, buclizine, clebopride, cyclizine, dimenhydrinate, diphenidol, dolasetron, meclizine, methallatal, metopimazine, nabilone, oxyperndyl, pipamazine, scopolamine, sulphide, tetrahydrocannabmol, thiethylperazine, thioproperazine, tropisetron, and mixtures thereof. Examples of useful β-adrenergic blockers include, but are not limited to, acebutolol, alprenolol, amosulabol, arotinolol, atenolol, befunolol, betaxolol, bevantolol, bisoprolol, bopind lol, bucumolol, bufetolol, bufuralol, buniholol, bupranolol, butidrine hydrochloride, butofilolol, carazolol, carteolol, carvedilol, celiprolol, cetamolol, cloranolol, dilevalol, epanolol, esmolol, indenolol, labetalol, levobimolol, mepindolol, metipranolol, metoprolol, moprolol, nadolol, nadoxolol, nebivalol, nifenaloϊ, nipradilol, oxprenolol, penbutolol, pindolol, practolol, pronethalol, propranolol, sotalol, sulfinalol, talinolol, tertatolol, tilisolol, fimolol, toliprolol, and xibenolol.
Examples of 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. doxenitroin, eterobarb, ethadione, ethosuximide, ethotoin, felbamate, fluoresone, gabapentiti, 5-hydroxytryptophan, lamotrigine, magnesium bromide, magnesium sulfate, mephenytoin, mephobarbital, metharbital, methetoin, inethsuximide, 5-methyl-5-(3-phenanthryl)-hydantoin, 3-methyl-5-phenylhydantoin, narcobarbital, nimetazepam, nitrazepam, oxcarbazepine, paramethadione, phenacemide, phenetharbital, pheneturide, phenobarbital, pheusuximide, pbenylmethylbarbituric acid, phenytoin, phethenylate sodixxm, potassium bromide, pregabaline, primidone, progabide, sodium bromide, soianum, strontium bromide, suclofenide, sulthiame, tetrantoin, tiagabine, topiramate, trimeihadioue, valproic acid, valpromide, vigabatrin, and zonisamide.
Examples of useful antidepressants include, but. are not limited to, binedaline, caroxazone, citalopram, dimethazan, fencamine, indalpine, indeloxazine hydrocholoride, nefopam, nomifensine, oxitriptan, oxypertine, paroxetine, sertraline, thiazesim, trazodone, benmoxine, iprocJozide, iproniazid, isocarboxazid, nialamide, octamoxin, phenelzine, cotinine, rolicyprine, rolipram, maprotiline, metralindole, mianserin, mirtazepine, adinazolam, amitriptyline, amitiiptylinoxide, amoxapine, butriptyline, clomipramine, demexiptiline, desipramine, dibenzepin, dimetacrine, dothiepin, doxepin, fluacizine, imip amine, imipramine N-oxide, iprindole, lofepramine, melitracen, metapramine, υortriptyline, noxiptilin, opipramol, pizotyline, propizepine, protriptyline, quinupramine, tianeptine, trimipramine, adrafiml, benactyzine, bupropion, butacetin, dioxadrol, duloxetine, etoperidone, febarbamate, femoxetine, fenpentadiol, fluoxetine, fluvoxamine, hematopoφhyrin, hypericin, levophacetoperane, medifoxamms, milnacipran, minaprine, moclobemide, nefazodone, oxaflozane, piberaline, prolintane, pyrisuccideanol, ritanserin, roxindole, rubidium chloride, sulphide, tandospirone, thozalinone, tofenacin, toloxatone, tranylcypromine, L-tryptophan, venlafaxine, viloxazine, and zimeldine.
Examples of useful Ca2+-channel blockers include, but are not limited to, bepridil, clentiazem, diltiazem, fendiline. gallopamil, mibefradil, prenylamine, semotiadil, terodiline, verapamil, amlodipine, aranidipine, baniidipine, benidipine, cilnidipine, efonidipine, elgodipine, felodipine, isradipine, lacidipine, lercanidipine. manidipine, nicardipine, nifedipine, nilvadipine, nimodipine, nisoldipine, nitrendipine, cinnarizine, fjunarizine, iidoflazine, lomerizine. bencyclane, etafenone, fantofarone, and perhexiline.
Examples of useful anticancer agents include, but are not limited to, acivicin, aelambicin, acodazole hydrochloride, acronine, adozelesin, aldesleukin, altretamine, • ambomycin, ametantrone acetate, aminoglutethimide. amsacrine, anastrozole, anthramyciiϊ, asparaginase, asperlin, azacixidine, azetepa, azocomycin, batimastat, benzodepa, bicaixxtamide, bisantrene hydrochloride, bisnafide dimesylate, bizelesin, bleomycin sulfate, brequinar sodium, bropirimine, busulfan, cactinomycin, calusteιone; caracemide, carbetimer, caiboplatin, carmustine, carubicin hydrochloride, carzelesin, cedefingol, chlorambucil, cirolemycin. cisplatin, cladribine, crisnatol mesylate, cyclophosphamide. cytarabine, dacarbazine, dactinomycin, daunorubicin hydrochloride, decitabine, dexormaplatin, dezaguanine, dezaguanine mesylate, diaziquone, docetaxel, doxorubicin, doxonώicin hydrochloride, droloxifene, droloxifene citrate, dromostanolone propionate, duazomycin, edahexate, eflomithine hydrochloride, elsamitracin, enloplatin, enpromate, epipropidine, epirubicin hydrochloride, erbulozole, esorubicin hydrochloride, estramustine, estramustine phosphate sodium, etanidazole, etoposide, etoposide phosphate, etoprine, fadrozole hydrochloride. fazarabine, fenretinide, floxuridine, fludarabine phosphate, fluorouracil, flu ocitabine, fos uidone. fostrieein sodium, gemcitabine, geracitabiue hydrochloride, hydroxvurea, idarubicin hydrochloride, ifosfamide, ihnofosine, interleukin H (including recombinant interleukin H or rJL2), interferon alfa-2a, interferon alfa-2b, interferon alfa-nl interferon alfa-n3, interferon beta-I a, interferon gamma-I b, iproplatin, irinotecan hydrochloride, lanreotide acetate, letrozole, leuprolide acetate, liarozole hydrochloride, lometrexol sodiimi, lomustiue, losoxantrone hydrochloride, masoprocol, maytansine, mechlorethamine hydrochloride, megestrol acetate, melengestrol acetate, melphalan, menogaril, mercaptopurine, methofrexate, methohexate sodium, metoprine. meturedepa, mitindomide, mitocarcin, mitocromin, mitogillin, mitomalcin, mitomycin, mitosper, mitotane, mitoxantrone hydrochloride, mycophenolic acid, nocodazole, nogalamycin, ormaplatin, oxisuran, paclitaxel, pegaspargase, pebomycin, pentamustine, peplomycin sulfate, perfosfamide, pipobroman, piposulfan, piroxantrone hydrochloride, plicamycin, plomestane, porfimer sodium, porfiromycin, prednimustine, procarbazine hydrochloride, puromycin, puromycin hydrochloride, pyrazofurin, riboprine, rogletimide, safingol, safingol hydrochloride, semustine, simtrazene, sparfosate sodium, sparsomycin, spirogermanium hydrochloride, spiromustine, spiroplatin, streptonigrin, streptozocin, sulofenur. talisomycin, tecogalan sodium, tegafur, teloxantrone hydrochloride, temoporfm, teniposide, teroxirone, testolacione, thiamiprine, thioguanine, thiotepa, tiazoήxrin, tirapazanxine, toremifene citrate, trestolone acetate, triciribine phosphate, trimehexate, trimetrexate glucuronate, triptorelin, hxbulozole hydrochloride, uracil mustard, uredepa, vapreotide, verteporfm, vinblastine sulfate, vincristine sulfate, vindesine, vindesine sulfate, vinepidine sulfate, vinglycinate sulfate, vinleurosine sulfate, vinorelbine tartrate. vinrosidine sulfate, vinzolidine sulfate, vorozole, zeniplatin, zinostatin, zorubicin hydrochloride.
Examples of other anti-cancer drugs include, but are not limited to, 20-epi-l,25 dibydroxyvitamin D3; 5-ethynylυracil; abiraterone; aclarubicin; acylfuJvene; adecypenol; adozelesin; aldesleukin: ALL-TK antagonists; altretamine; ambamustine; amidox; amifostine; aminolevulinic acid; anirubicin; amsacrine; anagrelide; anastrozole: andrographolide; angiogenesis inhibitors; antagonist D; antagonist G; antarelix; anti-dorsalizing moφhogenetic protein- 1; antiandrogen, prostatic carcinoma; antiestrogen; antmeoplaston; antisense oligonucleotides; apliidicolin glycinate; apoptosis gene modulators; apoptosis regulators; apurinic acid; ara-CDP-DL-PTBA; arginine deaminase; asulacrine; atamestane; atriinustine; axinastatin 1; axinastatin 2; axinastatin 3; azasetron; azatoxin; azatyrosine; baccalin HI derivatives; balanol; batimastat; BCR/ABL antagonists; beuzocblorins; benzovlstaurosporine; beta lactam derivatives; beta-alethine; betaclamycin B; betulinic acid; bFGF inhibitor; bicalutamide; bisantrene; bisaziridinylspermine; bisnafide: bistratene A; bizelesin; breflate; bropirimine; budotitane; buthionine sulfoximine; calcipotriol; calphostin C; camptothecin derivatives; canarypox IL-2; capecitabine; carboxamide-amino-tiiazoie; carboxyamidotriazole; CaRest M3; CΛRN 700; cartilage derived inhibitor; carzelesin; casein kinase inhibitors (ICOS); castanospermine; cecropin B; cetrorelix; chlorlns; chloroquinoxaline sulfonamide; cicaprost; cis-poφhyrin; cladribine; clomifene analogues; clotrimazole; collismycin A; collismycin B; combretastatin A4; combretastatin analogue; conagenin; crambescidin 816; crisnatol; cryptophycin 8; cryptophycin A derivatives; curacin A; cyclopentanthraquinones; cycloplatam; cypemycin; cytarabine ocfosfate; cytofytic factor; cytostatin; dacliximab; decitabine; dehydrodidemiiin B; deslorelin; dexamethasone; dexifosfamide; dexrazoxane; dexverapamil; diaziquone; didemnin B; didox; diethylnorspermine; dihydro-5-azacytidine; dihydrotaxol, 9-; dioxamycin; diphenyl spiromustine; docetaxel; docosanol; dolasetron; doxifluridine; droloxifene; dronabinol; duocarmycin SA; ebselen; ecomustine; edelfosine; edrecolomab; eflornithine: elemene; emitefur; epirubicin; epristeride; estramustine analogue; estrogen agonists; estrogen antagonists; etanidazole; etoposide phosphate; exemestane; fadrozole; fazarabine; fenretinide; filgrastim; finasteride; flavopiridol; flezelastine; fluasterone; fludarabine; fluorodaunorunicin hydrochloride; forfenimex; formestane; fostriecin;ibtemustine; gadolinium texaphyrin; gallium nitrate; galocitabine; ganirelix; gelatinase inhibitors; gemcitabine; glutathione inhibitors; hepsulfam; heregulin; hexamethylene bisacetamide; hypericin; ibandronic acid; * idarubicin; idoxifene; idramantone; ihnofosine; ilomastat; imidazoacridones; imiquimόd; immunostunulant peptides; insulin-like growth factor- 1 receptor inhibitor; interferon agonists; interferons; interleukins; iobenguane; iododoxorubicin; ipomeanol, 4-; iroplact; irsogladine; isobengazole; isohomohalicondrin B; itasetron; jasplakinolide; kahalalide F; iamellarin-N triacetate; lanreotide; leinamycin; lenograstim; lentinan sulfate; leptolstatin; lehozole; leukemia inhibiting factor; leukocyte alpha interferon; leuprolide estrogen+ρrogesterone; leuprorelin; levanii sole; liarozole; linear polyamine analogue; lipophilic disaccharide peptide; lipophilic platinum compounds; lissoclinamide 7; lobaplatin, lombricine; lometrexol; lonidamine; losoxantrone; lovastatin; loxoribine; liutotecan; lutetium texaphyrin; lysofylline; lytic peptides; maitansine; mannostatin A: marimastat; masoprocol; maspin; matrilysin inhibitors; matrix metalloproteinase inhibitors; menogaril; merbarone; meterelin; methioninase; metoclopramide; MIF inhibitor; mifepristone; miltefosine; mirimostim; mismatched double stranded RNA; mitoguazone; mitolactol; mitomycin analogues; mitonafide; mitotoxin fibroblast growth factor-saporin; mitoxantrone; mofarotene; molgramostim; monoclonal antibody, human chorionic gonadohOphin; monophosphoryl lipid A+myobacterixxm cell wall sk; mopidamol; multiple drug resistance gene inhibitor; multiple tumor suppressor 1 -based therapy; mustard anticancer agent; mycaperoxide B; mycobacterial cell wall extract; myriaporone; N-acetyldinaline;
N-substituted benzamides; nafarelin; nagrestip: naloxone+pentazocine; napavin; naphteφin; nartogi-astim; nedaplatin; nemorubicin; neridronic acid; neutral endopeptidase; nilutamide; πisamycin; nitric oxide modulators; nitroxide antioxidant; nitrαllyn; O6-benzyiguanine; octreotide; okicenone; oligonucleotides; onapristone; ondansetron; ondansetron; oracin; oral cytokine inducer; ormaplatin; osaterone; oxaliplatin; oxaunomycin;, paclitaxel; pachtaxel analogues; paclitaxel derivatives; palauamine; palmitoylrhizoxin; pamidronic acid; panaxytriol; panomifene; parabactin; pazelliptine; pegaspargase; peldesine; pentosan polysulfate sodium; pentostatin; pentrozole; perflubron; perfosfamide: perillyl alcohol; phenazinomycin; phenylacetate; phosphatase inhibitors; picibanil; pilocaφine hydrochloride; pirarubicin; piritrexim: placetin A; placetin B; plasminogen activator inhibitor; platinum complex; platinum compounds; platinum-triamine complex; porfϊmer 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; purpurfns; pyrazoloacridine; pyridoxylated hemoglobin polyoxyethylene conjugate; raf antagonists; raltihexed; ramosetron; ras famesyl protein hansferase inhibitors; ras inhibitors: ras-GAP inhibitor; retelliptine demethylated; rhenium Re 186 etidronate; rhizoxin; ribozymes; RH retinamide; rogletimide; rohitukine; romurtide; roquinimex; rubiginone Bl; ruboxyl; safingol; saintopin; SarCNU; sarcophytol A; sargramostim; Sdi 1 mimetics; semustine; senescence derived inhibitor 1: sense oligonucleotides; signal transduction , inhibitors; signal transduction modulators; single chain antigen binding protein; sizofiran; sobuzoxane; sodium borocaptate; sodium phenylacetate; solverol; somatomedin binding protein; sonennin; sparfosic acid; spicamycin D; spiromustine; splenopentin; spongistatin 1; squalamine; stem cell inhibitor; stem-cell division inhibitors; stipiamide; stromelysin inhibitors; sulfinosine; superactive vasoactive intestinal peptide antagonist; suradista; suramin; swainsonine; synthetic glycosaminoglycans; tallimustine; tamoxifen methiodide; tauromustine; tazεrotene; tecogalan sodium; tegafur; tellurapyrylium; telomerase inhibitors; temoporfm; temozolomide; teniposide; tetrachlorodecaoxide; tetrazomine; thaliblastine; thjocoralinε; thrombopoietin; thrombopoietin mimetic; thymalfasin; thymopoietin receptor agonist; thymotrinan; thyroid stimulating hormone; tin ethyl etiopuφurin; tirapazamine; titanocene bichloride; topsentin; toremifene; totipotent stem cell factor; hanslation inhibitors; tretinoin: triacetyluridine; triciribine; trimetrexate; triptorefin; tropisetron; turosteride; tyrosine kinase inhibitors; tyφhostins; UBC inhibitors; ubenimex; urogenital sinus-derived growth inhibitory factor; urokinase receptor antagonists; vapreotide; variolin B; vector system, erythrocyte gene therapy; velaresol; veramine; verdins; verteporfin; vinorelbine; vinxaltine; vitaxin; vorozole; zanoterone; zeniplatin; zilascorb; and zinostatin stimalamer. Examples of usefui therapeutic agents for treating or preventing LH include,
■but are not limited to, propantheiine, imipramine, hyoscyamine, oxybutynin, and dicyclomine. Examples of 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 subcihate; H2 antagonists such as cimetidine, ranitidine, famotidine, and nizatidine;
H"*, K " - ATPase inhibitors such as omeprazole, iansoprazole, and lansoprazole; carberxoxolone; misprostol; and antibiotics such as tetracyclme, mehonidazole, timidazole, claritlirouiycin, and amoxicillin.
Examples of 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.
Examples of useful therapeutic agents for treating or preventing IBS include, but are not limited to, propantheiine; muscarine receptor antogonists such as pirenzapine, methoctramine, ipratropium, tiotropium, scopolamine, methscopolamine, homatropine, homatropiue methyibromide, and methantheline; and antidiarrheal drugs such as diphenoxylate and loperamide.
Examples of useful therapeutic agents for treating or preventing an addictive disorder include, but are not limited to, methadone, desipramine, amantadine, fluoxetine," bυprenorphine, an opiate agonist, 3-phenoxypyridine, 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 trihexyphenidy] hydrochloride.
Examples of 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 iriazolam; non-benzodiazepine agents, such as buspirone, gepirone, ipsaprione, tiospirone, zolpicone, zolpidem, and zaleplon; tranqυilizers, such as barbituates, e.g., amobarbital, aprobarbital, butabarbital, butalbital, mεphobaibital, methohexital, pentobarbital, phenobarbital, secobarbital, and thiopental; and propanediol carbamates, such as meprobamate and tybamate.
Examples of 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, γ- vinyl GAB A, acetazolamide. and felbamate. ' ι<
Examples of 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 streptokinaεe or tissue plasminogen activator, agents that reduce swelling such as mannitol or corticosteroids, and acetylsalicylic acid. Examples of 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, γ-vinyl GABA, acetazolamide, and felbamate.
Examples of 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.
Examples of useful therapeutic agents for treating or preventing psychosis include, but are not limited to, pbenothiazines such as chloφromazine hydrochloride, mesoridazine besylate, and thoridazine hydrochloride; thioxanthenes such as chloToprothixene and thiothixene hydrochloride; clozapine risperidone; olanzapine; quetiapine; quetiapine fumarate; haloperidol; haloperidol decanoate; loxapine succinate; molindone hydrochloride; pimozide; and ziprasidone.
Examples of useful therapeutic agents for heating or preventing Huntington's chorea include, but are not limited to, haloperidol and pimozide. Examples of useful therapeutic agents for treating or preventing ALS include, but are not limited to, baclofen, nεurotrophic factors, riluzole, tizanidine, benzodiazepines such as clonazepan and dantrolene.
Examples of useful therapeutic agents for treating or preventing cognitive disorders include, but are not limited to, agents for treating or preventing dementia such as tacrine; donepezil; ibuprofen; antipsychotic drags such as thioridazine and haloperidol; and antidepressant drugs such as those given below.
Examples of useful therapeutic agents for heating or preventing a migraine include, but are not limited to, sumatriptan; methysergide; ergotamine; caffeine; and beta- blockers such as propranolol, veraparnil, and divalproex. Examples of useful therapeutic agents for treating or preventing vomiting include, but are not limited to, 5-HTj receptor antagonists such as ondansetron, dolasetron, granisetron, and tropisetron; dopamine receptor antagonists such as prochloφerazine, thiethylperazine, chloφromazin, metoclopramide, and domperidone; glucocorticoid?. such as dexamethasone: and benzodiazepines such as lorazepam and alprazolam. Examples of useful therapeutic agents for treating or preventing dyskinesia include, but are not limited to, reseφine and tetrabenazine. Examples of useful therapeutic agents for treating or preventing depression include, but are not limited to, tricyclic antidepressants such as amitryptyline, amoxapine, bupropion. ciomipraniine, desipramine, doxepin, imipramine, maprotilinr, nefazadone, norhiptyhne, 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 dexhOamphetamine and methylphenidate.
A Cyanoiminopiperazine Compound and the other therapeutic agent can act additively r, in one embodiment, synergistically. hi one embodiment, a
Cyanohninopiperazine Compound is administered concunently with another therapeutic agent, h one embodiment, a composition comprising an effective amount of a Cyanoiminopiperazine Compound and an effective amount of another therapeutic agent can be administered. Alternatively, a composition comprising an effective amount of a Cyanoiminopiperazine Compound and a different composition comprising an effective amount of another therapeutic agent can be concurrently administered. In another embodiment, an effective amoxxnt of a Cyanoiminopiperazine Compound is administered prior or subsequent to administration of an effective amount of another therapeutic agent, hi ϊhis embodiment, the Cyanoiminopiperazine Compound is administered while the other therapeutic agent exerts its therapeutic effect, or the other therapeutic agent is administered while the Cyanoiminopiperazine Compound exerts its preventative or therapeutic effect for treating or preventing a Condition.
A composition ofthe invention is prepared by a method comprising admixing a Cyanoiminopiperazine Compound or a pharmaceutically acceptable salt and a pharmaceutically acceptable carrier or excipient. A.dmixing can be accomplished using methods well known for admixing a compound (or salt) and a phannaceutically acceptable cairier or excipient. In one embodiment the Cyanoimiuopiperazine Compound or the pharmaceutically acceptable salt o the Compound is present in the composition in an effective amoun
4.19.2 Kits
The invention encompasses kits that can simplify the administration of a Cyanoiminopiperazine Compound to an animal.
A typical kit ofthe invention comprises a unit dosage fonn of a CyanoinhnopipeΛtzine Compound. In one embodiment, the unit dosage form is a container, which can be sterile, containing an effective amount of a Cyanoiminopiperazine Compound and s pharmaceutically acceptable carrier or excipient. The kit can further comprise a label or printed instiuctions instructing the use ofthe Cyanoiminopiperazine Compound to treat pain, UI, an ulcet, 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 muscie spasm, a migraine- vomiting, dyskinesia, or depression. The kit can also further comprise a unit dosage form of another therapeutic agent, for example, a container containing an effective amount ofthe other therapeutic agent. In one embodiment- the kit comprises a container containing an effective amount of a Cyanoiminopiperazine Compound and an effective amount of another therapeutic agent. Examples of other therapeutic agents include, but are not limited to, those listed above.
Kits ofthe invention can further comprise a device that is useful for administering the unit dosage forms. Examples of such a device includes, but are not limited to, a syringe, a drip bag, a patch, an inhaler, and an enema bag.
The following examples are set forth to assist in understanding the invention a.id should not, of course, be construed as specifically limiting the invention described and claimed herein. Such variations ofthe invention, including the substitution of all equivalents now iαiown or later developed, which would be within the purview of those skilled in the art, and changes in formulation or minor changes in experimental design, are to be considered to fall within the scope ofthe invention incorporated herein,
5. EXAMPLES Examples 1-3 relate to the synthesis of illustrative Cyanoiminopiperazine Compoxmds.
5.3. Example 1: Synthesis of Compound AAA
Figure imgf000217_0001
H
.
100°C
Figure imgf000217_0002
Figure imgf000217_0003
Figure imgf000217_0004
Compound AAA
2,3-Dichloropyridine (15.0 g, 101.6 mmol), piperazine(9.78 g, 113.70 mmol), and triethylamine (14.36 g, 141.95 mmol) were dissolved in 300 mL of DMSO and the resulting mixture was heated at about 80 °C for about 24 h. The reaction mixture was then cooled to room temperature and extracted with a saturated aqueous sodium bicarbonate 5 solution. The organic layer was dried, concentrated, and purified using a silica gel column eluted with a gradient elution from ethyl acetate to 2:1 ethyl acetate :rn ethanol to provide N- (3-chloropyridin-2-yl)-piperazine (compound 1) as a yellow liquid.
A solution diphenylcyanocarbodirnidate (Commercially available from Sigma- Aldrich, St. Louis, MO (www.sigma-aldrich.com)) (0.5 mmol) and 4-tert-butylaniline (0.5 1 mmol) in 1.5 mL of DCM was stirred at room temperature for about 12 h. The mixture was concentrated under reduced pressure to provide compound 2, which was used directly in the . nexϊ step* without further purification.
A solution of compound 2, prepared as described above, and compound 1 (0.5 mmol), prepared as described above, in 1.5 mL of 2-methoxymethylether was stirred at about 15 75 °C for about 12 h. The solution was cooled to room temperature and purified using direct flash chromatography on a silica gel column eluted with a gradient, elution from 1:10 ethyl acstate:bexaι,e to 1 :1 ethyl acetatε:hexane to provide Compound AAA (62 % yield). •
The identity of compound AAA was confirmed using !H NMR.
Compound AAA: Η NMR (CDC13) δ 9.19(dd, J = 1.5, 4.7 Hz, IH), 6.62 (dd, 0 J = 1,5, 7.8 Hz, 1H)S 7.38 (d, J = 8.5 Hz, 2H), 7.18 (b, IH), 7.01 (d, J = 8.5 Hz, 2H), 6.91. (dd, J = 4.7, 7.8 Hz, IH), 3.58 (m, 4H), 3.34 (m, 4H), 1.33 (s, 9H) ppm.
5.2. Example 2; Synthesis of Compound AAI
Compound AAI was prepared by a procedure analogous to that used to 5 prepare Compound AAA except, that 4-trifluoromethoxyaniline was used in place of 4-tert- butylaniline (yield 78%).
The identity of compound AAI way confirmed using 'H NMR. Compound AAI: Η NMR (CDCL) δ 8.19(dd, J = 1.6, 4.7 Hz, IH), 7.62 (dd, J - 1.6, 7.8 Hz, IH), 7.26 (b, IH), 7.24 (d, J = 9.0 Hz, 2H), 7.12 (d, J - 9.0 Hz, 2H), 6.92 (dd, 30 J = 4.7 Hz, IH), 3.59 (m, 4H), 3.35 (m, 4H) ppm. 5.3. Example 3: Synthesis of Compound AAG
Compound AAG was prepared by a procedure analogous to that used to prepare Compound AAA except that 4-trifluoromethylaniline was used in place fA-tert- butylani line (yield 61%). The identity of compound AAG was confirmed using Η NMR.
Compound AAG: Η NMR (CDCLJ δ 8.19(dd, J = 1.6, 4.7 Hz, IH), 7.62 (dd, J = 1.6, 7.8 Hz, IH), 7.26 (b, IH), 7.24 (d, J = 9.0 Hz, 2H), 7.12 (d, J = 9.0 Hz, 2H), 6.92 (dd, J = 4.7 Hz, IH), 3.59 (m, 4H), 3.35 (m, 4H) ppm.
5.4. Example 4: Synthesis of Compound DEY
Figure imgf000219_0001
3
Figure imgf000219_0002
Figure imgf000220_0001
Compound DEY
15
To a solution of 2-(l-cyclohexenyl)-ethylamine 3 (125.2 mg, 1.0 mmol) in 2- ra.ethoxyethyl ether (2.0 mL) was added diphenylcyanocaibodimidate (commercially available from Sigma- Aldrich, St. Louis, MO (www.sigma-aldrich.com)) (238.2 mg, 1.0 mmol) at room t mperature. The resultant reaction mixture was heated to about 80° C and allowed to
.0 sstir at 80° C for about 5 h. (R)-l-(3-chloro-pyridin-2-yl)-3-methylpiperazine 4 (21 1.6 mg, 1.0 mmol) was added to the reaction mixture and the reaction mixture was heated to about 140° C and allowed to stir at about 140° C for about 12 h. The reaction mixture was then cooled to room temperature and purified using flash chromatography on a silica gel column eluted with ethyl acetate/hexane (10:90 to 50:50) to provide compound DEY as a slightly yellow product.
'JA
Compound 4 was prepared by a procedure analogous to that used to prepare Compound 1, as described above in Example 1, except that (R)-3-methylpiperazine (commercially available from Sigma-Aldrich, St. Louis, MO (www.sigma-aldrich.com)) was used in place of piperazine.
30 The identity of compound DEY was confirmed using lH NMR and mass spectroscopy (MS). Compound DEY: Η NMR (CDC13) δ 8.20 (dd, J = 1.8. 4.9 Hz, IH), 7.63 (dd, J - 1.8, 7.8 Hz, IH), 6.91 (dd, J= 4.9, 7.8 Hz, IH), 5.61 (br, s, IH), 4.80 (m, IH), 4,32 (m, IH), 3.80 (m, 3H), 3.63 (m, 2H), 3.42 (m, IH), 3.10 (m, IH), 3.00 (m, IH), 2.31 (m, IH), 2.05 (m, 2H), 1.96 (m, 2H), 1.64 (m, 5H), 1.43 (m, 3H) ppm. MS: m/e 387.6
5.5. Example 5: Binding of Cyanoiminopiperazine Compounds to mGluR5
The following assay can be used to demonstrates Cyanoiminopipereazine
Compounds that, bind to and modulate the activity of niGluRS. Cell cultures: Primary glial cultures are prepared from cortices of Sprague-Dawley 18 days oktembryos. 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 hie. of Franklin Lakes, NJ ) in Dulbelcco's Modified Eagle's Medium ("DMEM," pH 7.4), buffered with 25 inM 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% CO2. After 24 hours, FCS supplementation is reduced to 10%. On day six, oligodendrocytes and microgiia are removed by strongly tapping the sides ofthe flasks. One day following this purification step, secondary asfrocyte 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. After 24 hours, 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/n L epidermal . • growth factor ("EGF"), 1 mM sodium pyruvate, and IX penicillin/streptomycin at pH 7.5 for 3 to 5 days at 37σC and 5% CO? The procedure allows the expression ofthe mGluR.5 receptor by astrocytes, as demonstrated by S. Miller et al, J. Neuroscience 15(9):6103-6109 (1995).
A.ssay Protocol: After 3-5 days incubation with EGF, the astrocytes are washed with • 127 mM NaCl, 5 mM KC1, 2 mMMgC , 700 mM NaH2PO4, 2 mM CaCl2, 5 mM NaHCO3, . 8 mM HEPES, 10 mM Glucose at pH 7.4 ("Assay Buffer") and loaded with the dye Fluo-4 {co mer iaily available from Molecular Probes Inc. of Eugene, OR) using 0.1 mL of Assay Buffer containing Fluo-4 (3 mM final). After 90 minutes of dye loading, the cells are then washed twice with 0.2 mL Assay Buffer and resuspended in 0.1 mL of Assay Buffer. The plates containing the astrocytes are then transferred to a Fluorometric Imaging Plate reader (commercially available from Molecular Devices Coφoration of Sunnyvale, CA) for the assessment of calcium mobilization flux in the presence of glutamate and in the presence or absence of antagonist. After monitoring fluorescence for 15 seconds to establish a base line, DMSO solutions containing various concentrations of a Cyanoimmopipereazme Compound diluted in Assay Buffer (0.05 mL of 4X dilutions for competition curves) are added to the cell plate and 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 concentration in the assay is 1.0%. In each experiment, fluorescence is monitored as a function of time and the data analyzed using Microsoft Excel and GtaphPad Prism. Dose-response cuives are fit using a non-linear regression to determine IC50 value. In each experiment, each data point is determined two times. The assay results will demonstrate that Cyanoimmopipereazme Compounds bind to and modulate the activity ofmGluRS.
5.6 E MPLE 6: BINDING OF CYANOIMINOPIPERAZINE COMPOUNDS TO MGLUR5
Alternatively, the following assay can be used to demonstrate that a Cyanoiminopiperazine Compound binds to and modulates the activity of mGluRS.
40,000 CHO-rat mGluR5 cells/well are plated into 96 well plate (Costar 3409, Black, clear bottom, 96 well, tissue culture treated) for an overnight incubation in Dulbecco 's Modified Eagle's Medium (DMEM, pH 7.4) and supplemented with glutamine, 10% FBS, 1% Pen/Strep, and 500ug/mL Geneticin. CHO-rat mGluR5 cells are washed and treated with Optimem medium and were incubated for 1-4 hours prior to loading cells. Cell plates are washed with loading buffer (127 mM NaCl, 5 mM KC1, 2 mM MgCl2, 700 μM Na H2PO4, 2 mM CaCl2, 5 mM NaHCO3, 8 mM Hepes, and 10 mM glucose, pH 7.4) and incubated with 3μM Fluo 4 (commercially available from Molecular probes Inc. of Eugene, OR) in 0.1 mL of loading buffer. After 90 minutes of dye loading, the cells are washed twice with 0.2 mL ioad xg buffer and resuspended in 0.1 mL loading buffer. The plates containing the CHO-rat mGluR5 cells are transferred to a Fluorometric hnaging Plate Reader (FLIPR) (commercially available from Molecular Devices Corporation of Sunnyvale, CA) for the assessment of calcium mobilization flux in the presence of glutamate and in the presence or absence of test compounds. After monitoring fluorescence 5 for 15 seconds to establish a baseline, DMSO solutions containing various concentrations of the test compound diluted in loading buffer (0.05 mL of 4X dilutions for the competition curves) are added to the cell plate and fluorescence was monitored for 2 minutes. 0.05 mL of 4X glutamate solution (agonist) is then added to each well to provide a final glutamate concentration in each well of 10 uM. Plate fluorescence is then monitored for an additional
10 60 seconds after agonist addition. The final DMSO concentration in the assay is 1.0%. In each experiment, 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 the IC50 value. In each experiment, each data point is determined at least two times.
15
5.7. Example 7: In Vivo Assays for Prevention or Treatment of Pain 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 administration of a Cyanoiminopiperazine Compound when food is 0 removed for 16 hours before dosing. A control group acts as a comparison to rats treated with a Cyanoiminopiperazine Compound. The control group is administered the carrier for the Cyanoiminopiperazine Compound. The volume of carrier administered to the control group is the same as the volume of carrier and Cyanoiminopiperazine Compound administered to the test group. 5 Acute Pain: To assess the actions ofthe Cyanoiminopiperazine Compounds for the treatment or prevention of acute pain the rat tail flick test can be used. Rats are gently restrained by hand and the tail exposed to a focused beam of radiant heat at a point 5 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 ofthe thermal stimulus and
30 the flick ofthe tail. Animals not responding within 20 seconds are removed from the tail flick unit and assigned a withdrawal latency of 20 seconds. Tail flick latencies are measured
-22: immediately before (pre-treatment) and 1, 3, and 5 hours following administration of a Cyanoiminopiperazine Compound. Data are expressed as tail flick latency(s) and the percentage ofthe maximal possible effect (% MPE), t.e., 20 seconds, is calculated as follows:
[ (post administration latency) - (pre-administratiυn latency) ]
% MPE = X 100
(20 s pre-administration latency)
The rat tail flick test is described in F.E. D'Amoor et al, "A Method for Detennining Loss of Pain Sensation," J. Pharmacol. Exp. Ther. 72:1A-19 (1941). ihe results show that Cyanoiminopiperazine Compounds are useful for treating or preventing acute pain.
A-cute 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. Inflammatory Pain: To assess the actions of the Cyanoiminopiperazine Compounds for the treatment or prevention of inflammatory pain the Freund's complete adjuvant ("FCA") model of inflammatory pain is used. FCA-induced inflammation of the rat hind paw is associated with the development of persistent inflammatory mechanical hyperalg ia and provides reliable prediction ofthe anti-hyperalgeric action of clinically useful analgesic drugs (L. Bartho et al, "Involvement of Capsaicin-sensitive Neurones in Hyperalgesia and
Enhanced Opioid Antinociception in Inflammation," Naunyn-Schmiedeberg's Archives of Pharmacology 342:666-670 (1990)). The left hind paw of each animal is administered a 50 uL intraplantar injection of 50% FCA. 24 hour 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
Cyanoiminopiperazine Compound, 30 mg/Kg of a control selected from indomethacin, ■ Celebrex or naproxen or carrier. Responses to noxious mechanical stimuli are then determined 1, 3, 5, and 24 hours post administration. Percentage reversal of Iryperalgesia for each animal is defined as: [ (post administration PWT) - (pre-administration PWT) ]
% Reversal = X 10Q '
[(Baseline PWT) — (pre-administration PWT)]
The results show that the Cyanoiminopiperazine Compounds are useful for treating or preventing inflammatory pain.
Neuropathic Pain: To assess the actions ofthe Cyanoiminopiperazine Compounds for the treatment or prevention of neuropathic pain either the Seltzer model or the Chung model can be used. In the Seltzer model, 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 ofthe left sciatic uervs is performed under isoflurane/O, inhalation anaesthesia. Following induction of anesthesia, the left thigh ofthe rat is shaved and the sciatic nerve exposed at high, thigh level through a small incision and is carefully- cleared of sxuiOundixig connective tissues at a site near the hocantber 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 5 ofthe nerve thickness is held within the ligature. The wound is closed with a single muscle suture (4-0. nylon (Vicryl)) and a Vetbond surgical . glue. Following surgery, the wound area is dusted with antibiotic powder. Sham-treated rats undergo an identical surgical procedure except that the sciatic nerve is not manipulated. Following surgery, animals are weighed and placed on a warm pad until they recover from anesthesia. Animals are then returned to their home cages until behavioral testing begins. The animal is assessed for response to noxious mechanical stimuli by determining PWT, as described below, prior to surgery (baseline), then immediately prior to and 1, 3, and 5 hours after drag administration for the left rear paw ofthe animal. Percentage reversal of neuropathic hyperalgesia is defined as: [(post administration PWT) - (pre-administration PWT) ]
% Reversal = X 100
[(Baseline PWT) - (pre-administration PWT)]
In the Chung model, the spinal nerve ligation model of neuropathic pain is used to produce mechanical hyperalgesia, thermal hyperalgesia and tactile allodynia in rats. Surgery is performed under isoflurane/O2 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 - S2 levels. The L6 transverse process is carefully removed with a pair of small rongeurs to identify visually the L4 - L6 spinal nerves. The left L5 (or L5 and L6) 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 netve(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 returned to their home cages until behavioral testing begins. The animals are assessed for response to noxious mechanical stimuli by determining PWT, as described below, prior to surgery (baseline), then immediately prior to and 1, 3, and 5 hours after being administered a Cyanoiminopiperazine Compound for the left rear paw ofthe animal. The animal can also be assessed for response to noxious thennal stimuli or for tactile allodynia, 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 results will show that Cyanoiminopiperazine Compounds are useful for treating or preventing neuropathic pain.
Response to Mechanical Stimuli as an Assessment of Mechanical Hyperalgesia: The paw pressure assay can be used to assess mechanical hyperalgesia. For this assay, hind- paw withdrawal thresholds (PWT) to a noxious mechanical stimulus are determined using an aiαalgesymeter (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 ofthe paw. PWT is determined once for each rat at each time point and only the affected (ipsilateral) paw is tested.
5 Response to Thennal Stimuli as an Assessment of Thermal Hyperalgesia: The plantar test can be used to assess thermal hyperalgesia. For this test, 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 j 0 Hyperalgesia," Pain 32(l):77-88 (1988). The maximum exposure time is set at 32 seconds to avoid tissue damage and any directed 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.
Assessment of Tactile Allodynia: To assess tactile allodynia, rats are placed in clear, 15 plexiglass compartments with a wire mesh floor and allowed to habihxate for a period of at least 15 minutes. After habituation, a series of von Frey niαnoΛlanients. are presented to the plantar surface ofthe left (operated) foot of each rat. The series of von Frey monofi laments 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 20 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 are considered nociceptive behavioral responses.
5.8. Example 8: In Vivo Assays for Prevention or Treatment of Anxiety
25 The elevated plus maze test or the shock-probe burying test can be used to assess the anxiolytic activity of Cyanoimmopipereazme Compounds in rats or mice.
The Elevated Plus Maze Test: The elevated plus maze consists of a platform with 4 aims, two open and two closed (50x10x50 cm enclosed with an open roof). Rats (or mice) are placed in the center ofthe platform, at the crossroad ofthe 4 arms, facing one ofthe 30 closed aims. 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 admimstration and again after drug administration. Test results are expressed as the mean time spent in open aims and the mean number of entries into open arms. Known anxiolytic drugs increase both the time spent in open arms and number of open arm entries. The elevated plus maze test is described in D. Treit, "Animal Models for the Study of Anti-anxiety Agents: A .Review," Neuroscience & Biobehavioral Reviews 9(2):203-222 (1985).
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 Jitter) 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_ cαrtenl is administered. The current is set at 2 mA. 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 ofthe test chamber following drug administration. The piobe is not electrified until the rat touches it with its snout cr fore paws, at which point the rat receives a brief 2 mA shock. The 15 min testing period begms once the rat receives its first shock and the probe remains electrified for the remainder o the testing period. The shock elicits burying behavior by the rat. Following the first shock, the dixration of time the rat sounds spraying bedding material toward or over the probe with its snout or fote paws (burying behavior) 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. In addition, an index ofthe 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. 1 he shock -probe burying test is described in D. Treit, 1985, supra. The results υf this test ill demonstrate that Cyanoiminopipereazine Compounds are useful for treating or t'fελ ennπg anxiety.
5.9. Example 9: In Vivo Assays for Prevention or Treatment of an Addictive Disorder
The conditioned place preference test or drug self-administration test can be used to assess the ability of Cyanoiminopipereazine Compounds to attenuate the rewarding properties cf known drugs of abuse. The Conditioned 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 ofthe 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. During habituation, rats generally show no preference for either compartment.. Following habituation, rats are given 6 conditioning sessions. Rats are divided into 4 groups: carrier pre-freatment + carrier (control group), Cyanoiminopipereazine Compound pre-freatment + carrier, carrier pre-treatment + moφhine, Cyanoiminopipereazine Compound pre -treat ient + moφhine. During each conditioning session the rat is injected with one of the drug combinations and confined to one compartment for 30 min. On the following day, the rat receives a carrier + carrier treatment and is confined to the othe large compartment, 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. On the test day, rats are injected prior to testing (30 min to 1 hour) with either moφhine 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. If the. Cyanoiminopipereazine Compound blocks the acquisition of morphine . conditioned place preference (reward), there will be no difference in time spent in each side in rats pre -treated with a Cyanoiminopipereazine Compound and the group will not be . different from the group of rats that was given carrier + carrier in both compartments. Data will be analyzed as time spent in each compartment (drug combination-paired vs carrier- paired). Generally, the experiment is repeated with a minimum of 3 doses of a Cyanoiminopipereazine Compound. The Drug Self- Administration Test: The apparatus for the drug self- administration test is a standard commercially available operant conditioning chamber. Before drug trials begin rats are trained to press a lever for a food reward. After stable lever pressing behavior is acquired, rats are tested for acquisition of lever pressing for drug reward. Rats are implanted with chronically indwelling jugular catheters for i.v. administration of compounds and are allowed to recover for 7 days before training begins. Experimental sessions are conducted daily for 5 days in 3 hour sessions. Rats are trained to self-administer a known drug of abuse, such as moφhine. Rats are then presented with two levers, an "active" lever and an "inactive" lever. Pressing ofthe active lever results in drug infusion on a fixed ratio 1 (FR1) schedule (i.e., one lever press gives an infusion) followed by a 20 second time out period (signaled by illuminatiou of a light above the levers). Pressing of the inactive lever results in infusion of excipient. Training continues until the total number of moφhine infusions stabilizes to within ± 10% per session. Trained rats are then used to evaluate the effect of Cyanoiminopipereazine Compounds pre-treatment on drag self- administration. On test day, rats are pre-treated with a Cyanoiminopipereazine Compound or excipient and then are allowed to self-administer drug as usual. If the
Cyanoiminopipereazine Compound blocks the rewarding effects of moφhine, rats pre-treated with the Cyanoiminopipereazine Compound will show a lower rate of responding compared to their previous rate of responding and compared to excipient pre-treated rats. Data is analyzed as the change in number of drug infusions per testing session (number of infusions during test session - number of infusions during training session). The results will demonstrate that Cyanoiminopipereazine Compounds are useful for treating or preventing an addictive disorder.
5.10. Example 10: Functional Assay for Characterizing mGluR 1 Antagonistic Properties Functional assays for the characterization of mGluRl antagonistic properties are well known in the art. For example, the following procedure can be used. cDNA encoding rat mGluRl a receptor is obtained from, e.g., Prof. S. Nakanishi (Kyoto, Japan). It is transiently transfected into HEK-EBNA cells using a procedure described by Schlaeger et al , New Dev. New Appl Anim. Cell Techn., Proc. ESACT Meet., 15tha (1998), 105-112 and 117-120. [Ca2+] measurements are performed on mGluRl a transfected HEK-EBNA cells after incubation ofthe cells v/ith Fluo-3 AM (0.5 μM final concentration) for 1 hour at 37 °C followed by 4 washes with assay buffer (DMEM supplemented with Hank's salt and 20 mM HEPES. [Ca2+] measurements are done using a flurometric imaging plate reader, e.g., FLIPR from Molecular Devices Coφoration, La Jolla, CA. 1 μM glutamate as agonist is used to evaluate the potency ofthe antagonists. Increasing concentrations of antagonists are applied to the cells 5 minutes prior to application ofthe agonist. The inhibition (antagonists) curves are fitted with appropriate software, for example, the four- parameter logistic equation giving IC30 and Hill, coefficient using the iterative nonlinear curve fitting software Origin from Microcal Software Inc., Northampton, MA. The results of this assay will demonstrate that Cyanohninopipereazine Compounds bind to and modulate the activity of mGluR I .
5.11. Example 11: Binding of Cyanoiminopiperazine Compounds to VRl
Methods for assaying compounds capable of inhibiting VRl are well known to those skilled in the art. for example, those methods disclosed in U.S. Patent No. 6,239,267 to Duckworth et al.; U.S. Patent No. 6,406,908 to Mchityre et al.; or U.S. Patent No. 6,335,180 to Julius et al. The results of these assays will demonstrate that. Cyanoiminopiperazine Compounds bind to and modulate the activity of VRl .
Binding of Compound DEY to VRl : Assay Protocol
Human VRl cloning. Human spinal cord RNA (commercially available from Clontech, Palo Alto, CA) was used. Reverse transcription was conducted on 1.0 μg total RNA using Thermoscript Reverse Transcriptase (commercially available from Invitrogen, Carlsbad,. CA) and oligo dT primers as detailed in its product description. Reverse transcription reactions were incubated at 55 °C for 1 h. heat-inactivated at 85 °C for 5 min, and RNase H-treated at 37 °C for 20 min. Human VRl cDNA sequence was obtained by comparison ofthe human genomic sequence, prior to annotation, to the published rat sequence. Intron sequences were removed and flanking exonic sequences were joined to generate the hypothetical human cDNA. Primers flanking the coding region of human VRl were designed as follows: forward primer, GAAGATCTTCGCTGGTTGCACACTGGGCCACA; and reverse primer. GAAGATCTTCGGGGACAGTGACGGTTGGATGT.
PCR of VRl was performed on one tenth ofthe Reverse transcription reaction mixture using Expand Long Template Polymerase and Expand Buffer 2 in a final volume of 50 μL according to the manufacturer's instructions (Roche Applied Sciences, Indianapolis, -N). After denaturation at 94°C for 2 min PCR amplification was performed for 25 cycles at 94°C for 15 sec, 58°C for 30 sec, and 68°C for 3 min followed by a final incubation at 72°C for 7 min to complete the amplification. A PCR product of -2.8 kb was gel-isolated using a 1.0% agarose, Tris- Acetate gel containing 1.6 μg/mL of crystal violet and purified with a S.N.A.P. UV-Free Gel Purification Kit (commercially available from Invitrogen). The VRl PCR product was cloned into the pIND/V5-His-TOPO vector (commercially available from Invitrogen) according to the manufacturer's instructions. DNA preparations, restriction enzyme digestions, and preliminary DNA sequencing were performed according to standard protocols. Full-length sequencing confirmed ϋ\e identity ofthe human VRl .
Generation of inducible cell lines. Unless noted otherwise, cell culture reagents were purchased from Life Technologies of Rockville, MD. HEK293-EcR cells expressing the ecdysone receptor (commercially available from Invitrogen) were cultured in Growth Medium (Dulbecco 's Modified Eagles Medium containing 10% fetal bovine serum (commercially available from HYCLONE, Logan, LIT), lx penicillin/streptomycin, lx glutamine, 1 mM sodium pj'ruvate and 400 μg/mL Zeocm (commercially available from mviirogen)) The VRl-pIND constiucts were transfected into the HEK293-EcR cell line using Fugene transfection reagent (commercially available from Roche Applied Sciences, Basel, Switzerland). After 48 h, cells were transferred to Selection Medium (Growth Medium containing 300 μg/mL G418 (commercially available from Invitrogen)). Approximately 3 weeks later individual Zeocin/G418 resistant colonies were isolated and expanded. To identify functional clones, multiple colonies were plated into 96-well plates and expression was induced for 48 h using Selection Medium supplemented with 5 μM ponasterone A ("PonA") (commercially available from Invitrogen). On the day of assay, cells were loaded with Fluo-4 (a calcium-sensitive dye that is commercially available from Molecular Probes, Eugene, OR) and CAP-mediated calcium influx was measured using a Fluorometric Imaging Plate Reader ("FLIPR") (commercially available from Molecular Devices Coφ., Sunnyvale, CA) as described below. Functional clones were re-assayed, expanded, and cryopreserved. pH-Based Assay. Two days prior to performing this assay, cells were seeded on poly-D-lysine-coated 96-well clear-bottom black plates (commercially available from Becton-Dickinson) at 75,000 cells/well in growth media containing 5 μM PonA (commercially available from hivitrogen) to induce expression. On the day ofthe assay, the plates were washed with 0.2 mL lx Hank's Balanced Salt Solution (commercially available from Life Technologies) containing 1.6 mM CaCl2 and 20 mM HEPES, pH 7.4 ("wash buffer"), and loaded using 0.1 mL of wash buffer containing Fluo-4 (3 μM final concentration, commercially available from Molecular Probes). After 1 h, the cells were washed twice with 0.2 mL wash buffer and resuspended in 0.05 L lx Hank's Balanced Salt Solution (commercially available from Life Technologies) containing 3.5 mM CaCl2 and 10 rnM Citrate, pH 7.4 ("assay buffer"). Plates were then transferred to a FLIPR (commercially available from Molecular Devices) for assay. Compound DEY was diluted in assay buffer, and 50 mL o the resultant solution were added to the cell plates and the solution monitored for two minutes. The final concentration of Compound DEY ranged from about 50 pM to about 3 μM. Agonist buffer (wash buffer titrated with IN HCI to provide a solxxtion having a pH of 5.5 when mixed 1:1 with assay buffer) (0.1 mL) was then added to each well, and the plates were incubated for 1 additional minute. Data were collected over the entire time course and analyzed using Excel and Graph Pad Prism. Compound DEY when assayed according to this protocol had an IC50 of 196.7 ± 39.8 nM (n + 3).
Capsaicin-based Assay. Two days prior to performing this assay, cells were seeded in poly-D-lysine-coated 96-well clear-bottom black plates (50,000 cells/well) in growth media containing 5 μM PonA (commercially available from Invitrogen) to induce expiession. On the day ofthe assay, the plates were washed with 0.2 mL lx Hank's Balanced Salt Solution (commercially available from Life Technologies) containing 1 mM CaCl2 and 20 mM HEPES, pH 7.4, and cells were loaded using 0.1 mL of wash buffer containing Fluo-4 (3 μM final). After one hour, the cells were washed twice with 0.2 mL of wash buffer and resuspended in 0.1 mL of wash buffer. The plates were transferred to a FLIPR (commercially available from Molecular Devices) for assay. 50 μL of Compound DEY diluted with assay buffer were added to the cell plates and incubated for 2 min. The final concentration of Compound DEY ranged from about 50 pM to about 3 μM. Human VRl was activated by the addition of 50 μL of capsaicin (400 nM), and the plates were incubated for an additional 3 min. Data were collected over the entire time course and analyzed using Excel and GraphPad Prism. Compound DEY when assayed according to this protocol had an IC50 of 59.4 ± 13.1 nM (n ). The results ofthe pH -based assay and the capsaicin-based assay demonstrate that Compound DEY, an illustrative Cyanoiminopiperazine Compound, binds to and modulates the activity of human VRl. .
The present invention is not to be limited in scope by the specific embodiments disclosed in the examples, which are intended as illustrations of a few aspects of the invention and any embodiments that are functionally equivalent are within the scope of this invention. Indeed, various modifications ofthe invention in addition to those shown and described herein will become apparent to those skilled in the art and are intended to fall within the scope ofthe appended claims.
A number of references have been cited, the entire disclosures of which are incorporated herein by reference.

Claims

What is claimed is:
1. A compound of formula :
Figure imgf000235_0001
(I) or a pharmaceutically acceptable salt thereof, wherein
A is -NR4-, -O-, or -S-;
15 R1 is -halo, -CH3, -NO2, -CN, -OH, -OCH3, - H2, - C(halo)3, -CH(haio)2, or
-CH2(halo); each R2 is independently:
(a) -halo, -CN, -OH, -NO2, or -NH2;
(b) -(CrC10)alky], -(C2-C10)alkenyl, -(C C10)alkynyl, -(C5- 20 C10)cycloalkyl, -(C8-CI4)bicycloalkyl, -(CR-C14)tricycloalkyl, -(C5-
Cl0)cycloalkenyl,-(C8-Cι4)bicycloalkenyl, -(C8-C14)tricycloalkenyl, -(C3- C7)heterocycle, or -(C7-C1 )bicycioheterocycle, each of which is unsubstituted or substituted with one or more R5 groups; or
(c) -phenyl, -naphthyl, -(C14)aryl, or -(C5-C10)heteroaryl. each of 2.5 which is unsubstituted or substituted with one or more R7 groups; each R3 is independently:
(a) -halo, -CN, -OH, -NO2, or -NH2; or
(b) -(C,-C10)alkyl, -(C2-C10)alkenyl, -(C2-C10)alkynyl, -(C3- C10)cycioalkyl, -(C8-C!4)bicycloalkyl, -(C8-C14)tricycloalkyl, -(C5~
30 C10)cycloalkenyl,-(C8-CI4)bicycloalkenyl, -(C8-Cl4)tricycloalkenyl, -(C3- C7)heterocycle, or -(C7-C10)bicycloheterocycle, each of which is unsubstituted or substituted with one or more R5 groups; or
(c) -phenyl, -naphthyl. -(C14)aryl or -(C5-C!0)heteroaryl, each of which is unsubstituted or substituted with one or more R7 groups; 5 R4 is -(CrC6)alkyi, or -O-(C, -C6)alkyl; each R5 is independently -CN, -OH, -(Cr C6)alkyl, -(C2-C6)alkenyl, - (CVC6)alkenyl, -halo, -N3, -NO2, -N(R8)2, -CH=NR8, -NR8OH, -OR8, -COR8' -C(O)OR8, -OC(O)Rs, -OC(O)OR8 ; -SR8, -S(O)R8, or -S(O)2R8;,
R6 is -phenyl, -naphthyl, -(C3-C8)cycloalkyl,-(C14)aryl, or -(C5-C10)heteroaryl, 0 each of which is unsubstituted or substituted with on or more R' groups; ; each R7 is independently -(Cι-C6)alkyl, -( -C^alkenyl, -(C2-C6)alkynyl, -(C3-C8)cycloalkyl, -(CD—C8)cycloalkenyl, -phenyl, -(C,-C;)heterocycle, -C(halo)3, -CH(halo)2, -CH2(halo), -CN, -OH, -halo, -N3, -NO2, -N(R8)2, -CH=NR8, -NR8OH, -OR8, •COR8, -C(O)OR8, -OC(O)R8, -OC(O)OR8, -SR8, ~S(O)PΛ or -S(O)2R8; i 5 each R8 is independently -H, -(Ct -C jalkyl, -(C2~C6)alkenyl, -(C,-C6)alkynyl,
■(C3- C8)cycloalk} -(C5-C8)cyclo alkenyl, -phenyl, -(C;-C5)heterocycie, -C(halo)3, -CH2(halo); o -CH(halo)2; each halo is independently -F, -CI, -Br or -I; n is an integer ranging from 0 to 3; and 0 m is an integer ranging from 0 to 2,
2. The compound of claim 1 , wherein A is -NR4-.
3.. The compound of claim 2, wherein: 5 n is 0; m is 0; and R6 is phenyl.
4. The compound of claim 3. wherein the R6 phenyl is unsubstituted. 0
5. . The compound of claim 3, wherein the R6 phenyl is substituted at the 4-position.
6. The compound of claim 5, wherein the R6 phenyl is substituted with a -(CrC6) alkyl.
7. The compound of claim 6, wherein the -(C C6) alkyl is a tert-butyl group.
8. The compound of claim 6, wherein the -(C C6) alkyl is an z'sø-propyl group.
9. The compound of claim 5, wherein the R6 phenyl is substituted with a -CF3 group.
10. The compound, of claim 3, wherein RJ is chloro or methyl.
11. The compound of claim 10, wherein the R6 phenyl is unsubstituted.
12. The compound of claim 10, wherein the R6 phenyl is substituted at the 4-position.
13. The compound of claim 12, wherein the R6 phenyl is substituted with a -(C,-C6) alkyl.
14. The compound of claim 13, wherein the -(CrC6) alkyl is a, tert-butyl group.
15. The compound of claim 13, wherein the -(C]-C6) alkyl is an wo-propyl group.
16. The compound of claim 12, wherein the R6 phenyl is substituted with a
-CF3 group.
17. The compound of claim 1, wherein A is -O-.
18. The compound of claim 1 , wherein A is -S-.
19. A compound of formula :
Figure imgf000238_0001
(la) or a pharmaceutically acceptable salts thereof, wherein:
R l is -halo, -CH3, -NO2, -CN, -OH, -OCH3, -NH2, -C(halo)3, -CH(halo)2, or -CH2(halo); each R2 is independently:
(a) -halo, -CN, -OH. -NO2, or -NH2;
(b) -(CrC10)alkyl, -(C2-C10)alkenyl, -(C2-CI0)alkynyl, -(C3- C10)cycloalkyl, -(C8-C14)bicycloalkyl, -(C8-C14)tricycloalkyl, -(C5- C,0)cycloalkenyl,-(C8-C14)bicycloalkenyl, -(C8-Ci4)tricycloalkenyl. -(C3-
C7)he1erocycle, or -(C7-C10)bicycloheterocycle, each of which is unsubstituted or substituted with one or more R5 groups; or
(c) -phenyl, -naphthyl, -(C14)aryl, or -(C5-C10)heteroaryl, each of which is unsubstituted or substituted with one or more R7 groups; each R3 is independently:
(a) -halo, -CN, -OH. -NO2, or -NH2; or (b) -(CrC10)alkyl, -(C2-C10)alkenyl, -(C2-C10)alkynyl, -(C3- C-l0)cycloalkyl, -(C8-C14)bicycloalkyl, -(C8-C!4)tri.cycloalkyl, -(C5- Cι0)cycloalkenyl,-(C8-C]4)bicycloalkenyl, -(C8-C14)tricycloalkenyl, -(C3- C7)heterocycle, or -(C7-C,0)bicycloheterocycle, each of which is unsubstituted or substituted with one or more R5 groups; or
(c) -phenyl, -naphthyl, -(C14)aryl or -(C5-C10)heteroaryl, each of which is unsubstituted or substituted with one or more R7 groups; each R5 is independently -CN, - OH, -( -C alkyl, -(C2-C6)alkenyl, - (C2--C3)alkenyl, -halo, -N3, -NO2, -N(R8)2. -CH=NR8, -NR8OH, -OR8, -COR8' -C(O)OR8, -OC(O)R8, -OC(O)QR8, -SR8, -S(O)R8, or -S(O)2R8; R6 is:
(a), -naphthyl, -(C14)aryl. or -(C3-C8)cycloalkyl each of which is unsubstituted or substituted with one or more R7 groups; or
(b) pyridyl, furyl, benzofuranyl, thiophenyl, benzothiophenyl, quinolinyl, indolyl, oxazolyl, benzoxazolyl, imidazolyl, benzimidazolyl, thiazolyl. benzo thiazolyl isoxazolyl, pyrazolyl, isothiazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, thiadiazolyl, triazinyl, cinnolinyl, phthalazinyl, or quinazolinyl, each of which is substituted with one or more R7 groups; each R7 is independently -(C, -C6)alkyl, -(C2-C3)alkenyl, -(C2-C6)a1kyrjyl, -(C3-Cj;)cycloalkyl, -(C5-C8)cycloaikenyl, -phenyl, -(C3-C5)heterocycle, -C(halo)3,
-CH(halo)2, -CH2(halo), -CN, -OH, -halo, -N3, -NO2, -N(R8)2, -CH-NR8, -NR8OH, -OR8, -CORs, -C(O)OR8, ~OC(O)R8, -OC(O)OR8, -SR8, -S(O)R8, or -S(O)2R8; each R8 is independently -H, -(Cj-C^alkyl, -(C2-C6)alkenyl, -(C2-C6)alkynyl, -(C3-C8)cycloalkyl, -(C5-C8)cycloalkenyl, -phenyl, -(C3-C5)heterocycle, -C(halo)3, -CH2(halo), or -CH(ha!o)2; each halo is independently -F, -CI, -Br or -I; n is an integer ranging from 0 to 3; and m is an integer ranging from 0 to 2.
20. The compound of claim 19, wherein R6 is pyridyl, pyrazinyl, pyrimidiiryl, pyridazinyl, or thiadiazolyl.
21. A compound of formu la
Figure imgf000240_0001
(lb) or a pharmaceutically acceptable salts thereof, wherein:
R is -halo, -CH3, -NO2, -CN, -OH, -OCH3, -NH2, -C(halo)3, -CH(halo)2; or
Figure imgf000240_0002
each R2 is independently:
(a) -halo, -CN, -OH, -NO2, or -NH2; (b) -(CrC10)alkyl, -(C2-C10)alkenyl, -(CrC,0)alkynyl, -(C3-
C10)cycloalkyl, -(C8-C14)bicycloalkyl, -(C8-C14)tricycloalkyl, -(C5- Cj0)cycloalkenyl,-(C8-C14)bicycloalkenyl, -(C8-C14)tricycloalkenyl, -(C3- C7)heterocycle, or -(C7-C10)bicycloheterocycle, each of which is unsubstituted or substituted with one or more R5 groups; or (c) -phenyl, -naphthyl, -(C14)aryl, or -(C -Cι0)heteroaryl, each of which is unsubstituted or substituted with one or more R7 groups; each R3 is independently:
(a) -halo, -CN, -OH, -NO2, or -NH2; or
(b) -(Cr-C10)alkyl, -(C2-C10)alkenyl, -(C2-C10)alkynyl, -(C3- C10)cycloalkyl, -(C8-C14)bicycloalkyl, -(C8-C14)tricycloalkyl, -(C5-
C10)cycloalkenyl,-(C8-C14)bicycloalkenyl, -(C8-Cl4)tricycloalkeny], ~(C3- C7)heterocycle, or -(C7-C10)bicycloheterocycle, each of which is unsubstituted or substituted with one or more R5 groups; or
(c) -phenyl, -naphthyl, -(C14)aryl or -(C5-C10)heteroaryl, each of which is unsubstituted or substituted with one or more P.7 groups; each R5 is independently -CN, -OH, -(C,-C6)alkyl, -(C2-C6)alkenyl, -
(C2-C6)alkenyl, -halo, -N3, -NO2, -N(R8)2, -CH=NR8, -NR8OH, -OR8, -COR8' -C(O)OR8, -OC(O)R8, -OC(O)OR8, -SR8, -S(O)R8, or -S(O)2R8; each R7, R9, and R10 is independently -(C,-C6)alkyl, -(C2-C6)alkenyl, - (C -C6 kynyl, -(C3-C8)cycloalkyl, -(C5-C8)cycloalkenyl, -phenyl, -(C3-C5)heterocycle. - C(halo)3, -CH(halo)2 -CH2(halo), -CN, -OH, -halo, -N3, -NO2, -N(R8)2, -CH-NR8, -NR8OH, -OR8, -COR8, -C(O)OR8, -OC(O)R8, -OC(O)OR8, -SR8, -S(O)R8, or -S(O)2R8; each R8 is independently -H, -(C1-C6)allcyl, -(C2--C6)alkenyl, -(C2-C6)alkynyl, -(C3-C8)cycloalkyl, -(C5-C8)cycloalkenyl, -phenyl^(C3-C5)heterocycle, -C(halo)3, -CH2(halo): or -CH(halo)2; each halo is independem.lv -F, -CI, -Br or -ϊ; n is an integer ranging from 0 to 3; rn is an integer ranging from 0 to 2; and p is an inxeger ranging from 0 to 4.
22. A compound of formula :
Figure imgf000241_0001
(Ic) or a phannaceutically acceptable salts thereof, wherein: A is -NR4-, -O-, or -S-; each R3 is independently:
(a) -halo, -CN, -OH, -NO2, or -NH2; or
(b) -(C1-C10)alkyl, -(C2-C10)alkenyl, -(C2-C10)alkynyl, -(C3~ C10)cycloalkyl, -(C8-C14)bicycloalkyl, -(C8-C14)tricycloalkyl, -(C5-
■ 5 Cι0)cycloalkenyl,-(C8-C14)bicycloalkenyl, -(C8-C14)tricycloalkenyl, -(C3-
C7)heterocycle, or -(C7-C10)bicycloheterocycle, each of which is unsubstituted or substituted with one or more R5 groups; or
(c) -phenyl, -naphthyl, -(C14)aryl or -(C5-C10)heteroaryl, each of which is unsubstituted or substituted with one or more R7 groups;
10 R4.is -(CrC6)alkyl, or -O-(CrC6)alky]; each R5 is independently -CN, -OH, -( -C^alkyl, -(C2-C6)alkenyl, - (C2-C6)alkenyϊ, -halo, -N3, -NO2, -N(R8)2, -CH=NR8, -NR8OH, -OR8, -COR8'. -C(O)OR8, -OC(O)R8, -OC(O)OR8, -SR8, -S(O)R8, or -S(O)2R8;
R6 is -phenyl, -naphthyl, -(C3-C8)cycloalkyl,-(Cϊ4)aryl, or -(C -C10)heteroaryl, ,15 each of which is unsubstituted or substituted with one or more R7 groups; each R7 is independently -(C1-C6)alkyl, -(C2-C6)alkenyl, -( -C^alkynyl, - (C:~C.j)cycloalkyl5 -(C5~C?)cycJoalkeuyl, -phenyl, -(C3-C5)heterocycIe, -C(halo)3, -CH(halo)2, -CK2(halo), -CN, -OH, -halo, -N3, -NO2, -N(R8)2, -CH-NR8, -NR8OH, -OR8, -COR8, -C(O)OR8, -OC(O)R8, -OC(O)OR8, -SR8, -S(O)R8, or -S(O)2R8; 20 each R8 is independently -H, -(C Cs)alkyl, -(C2-C6)alkenyl, -(C2-C6)alkynyl,
-(C3-Cj,)cycloalkyl, -(C5-C8)cycloalkenyl, -phenyl, -(C3-C5)heterocycle, -C(halo)3, -CH,(haϊo): or -CH(halo)2;
R11 is -hydrogen, -halo, -CH3, -NO2, -CN, -OH, -OCH3, -NH2, -C(halo)3, - CH(halo)2, or -CH2(halo); 5 each R.12 is independently:
(a) -halo, -CN, -OH, -NO2, or -NH2;
(b) -(CrC10)alkyl, -(C2-C10)alkenyl, -(C2-C10)alkynyl, -(C3- C10)cycloalkyl, -(C8-C14)bicycloalkyl, -(C8-C14)tricycloalkyl, -(C5- Cι0)cycloalkenyl,-(C8-C14)bicycloalkenyl, -(C8-C14)tricycloalkenyl. ~(C3-
30 C7)heterocycle. or -(C7-Cl0)bicycloheterocycle, each of which is unsubstituted or substituted with one or more R5 groups; or (c) -phenyl, -naphthyl, -(C14)aryl, or -(C5-C10)heteroaryl, each of which is unsubstituted or substituted with one or more R7 groups; m is an integer ranging from 0 to 2; and q is an integer ranging from 0 to 3.
23. A compound of formula :
Figure imgf000243_0001
(II) and phannaceutically acceptable salts thereof, wherein: A is -NR4-, -O-, or -S-;
R1 is -halo, -CH3, -NO2, -CN, -OH, -OCH3, -NH2, -C(halo)3: -CH(hato)2, or - CH2(halo); each R2 is independently:
(a) -halo, -CN, -OFI, -NO2, or -NH2;
(b) -(A-C^alkyl, -(C2-CI0)alkenyl, -(C2-Cl0)alkynyl, -(C3- Cι0)cycloalkyl, -(C8-C14)bicycloalkyl, -(C8-C14)tricycloalkyl, -(C5- C10)cycloalkenyl,-(C8-C14)bicycloalkenyl, -(C8-C54)trieycloalkenyl, -(C3- C7)heterocycle, or -(C7-C]0)bicycloheterocycle, each of which is unsubstituted or substituted with one or more R5 groups; or
(c) -phenyl,. -naphthyl, -(C14)aryl, or -(C5-Cι0)heteroaryl, each of which is unsubstituted or substituted with one or more R7 groups; each R3 is independently: (a) -halo, -CN, -OH, -NO2, or -NH2; (b) -(CrC]0)alkyl; -(C2-C10)alkenyl, -(C2-C10)alkynyl, -(C3- C10)cycloalkyl, -(C8-C14)bicycloalkyl, -(C8-Cι4)tricycloalkyl, -(C5- C10)cycloalkenyl,-(C8-Cl4)bicycloalkenyl, -(C3-C14)tricycloalkenyl, -(C3- C7)heterocycle, or -(C7-C10)bicycloheterocycle, each, of which is unsubstituted or substituted with one or more R5 groups; or
(c) -phenyl, -naphthyl, -(C14)aryl or -(C5-C10)heteroaryl, each of which is unsubstituted or substituted with one or more R7 groups;
R4 is hydrogen, -(CrC6)alkyl, or -O-(CrC6)alkyl; each R5 is independently -CN, -OH, -(C,~C6)alkyl, -(C2-C6)alkenyl, - (C,-C6)alkenyl, -halo, -N3, -NO2, -N(R8)2, -CH-NR8, -NR8OH, -OR8, -COR8- -C(O)OR8, -OC(O)R8, -OC(O)OR8, -SR8, -S(O)R8, or -S(O)2R8;
R6 is -phenyl, -naphthyl, -(C3-C8)cycloalkyl,-(C ()aryl, or -(C5-C10)heteroaryl, each of which is unsubstituted or substituted with one or more R7 groups; each R7 is independently -(C^-C^a-kyl, -(C2-C6)alkenyl, -(C2-C6)alkynyl, -(Cj- ~C8}cycloalkyl, -(Gj-C^cyclo alkenyl, -phenyl, -(C3-C5)heterocycle, -C(halo)3,
-CH2(αalo), -CH(halo)2, -CN, -OH, -halo, -N3, -NO2, -N(R8)2, -CH-NR8, -NR8OH, -OR8, -COR8, -C(O)OR8, -OC(O)R8, -OC(O)OR8, -SR8, -S(O)R8, or -S(O)2R8;
, each R8 is independently -H, -(Cr-C6)alkyl, -(C2-C6)alkenyl, -(C2--C6)alkynyl, -(C3-C3)cycloalkyl, -(C5-C8)cycloalkenyl, -phenyl, -(C3-C5)heterocycle, -C(halo)3, -CH2(haiό). o -CH(halo)2; each halo is independently -F, -CI, -Br or -I; n is an integer ranging from 0 to 2; and ' m is an integer ranging from 0 to 2.
24. The compound of claim 23, wherein A is -NH-.
25. The compound of claim 24, wherein: is ; m is 0; and R6 is phenyl.
26. The compound of claim 25, wherein ti e R6 phenyl is unsubstituted.
27. The compound of claim 25, wherein the R6 phenyl is substituted at the 4-position.
28. The compound of claim 27, wherein the R6 phenyl is substituted with a -(CrC6) alkyl.
29. The compound of claim 28, wbeiein the -(Cj- alkyl is a tert-butyl group.
30. The compound of claim 28, wherein the -(Ct-C6) alkyl is an /-?o-propyl group.
31. The compound of claim 27, wherein the Rb phenyl is substituted with a
-CF3 group.
32. The compound of claim 25, wherein R1 is chloro or methyl.
33. The compound of claim 32. wherein the R6 phenyl is unsubstituted.
34- The compound of claim 32, wherein the R6 phenyl is substituted at the 4-position.
35. The compound of claim 34, wherein the R6 phenyl is substituted with a
-(C,-C6) alkyl.
36. The compound of claim 35, wherein the -(C]-C6) alkyl is a tert-butyl group.
37. The compound of claim 35, wherein the -(C,-C6) alkyl is an is o-pτopyl group.
38. The compound of claim 34, wherem the R6 phenyl is substituted with a -CF3 group.
39. The compound of claim 23, wherein A is -O-.
40. The compound of claim 23, wherein A is S-.
41. A compound of formula :
Figure imgf000246_0001
(Ha) or a pharmaceutically acceptable salts thereof, wherein: A is -NR4-, -O-, or -S-; each R3 is independently: (a) -halo, -CN, -OH, -NO2, or -NH2;
(b) -(CrC10)alkyl, - (C2-C10)alkenyl, -(C2-C10)alkynyl, -(C3- C,0)cycloalkyl, -(C8-C14)bicycloalkyl, -(C8-C14)tricycloalkyl, -(C5- Cj0)cyclcalkenyl,-(C8-CI4)bicycloalkenyl, -(C8-C14)tricycloalkenyl, -(C3- C7)heterocycle, or -(C7-C10)bicycloheterocycle, each of which is unsubstituted or substituted with one or more R5 groups; or (c) -phenyl, -naphthyl, -(C]4)aryl or
Figure imgf000247_0001
each of which is unsubstituted or substituted with one or more R7 groups; R4 is hydrogen, -(CrC6)alkyl, or -O-(CrC6)alkyl; each R5 is independently -CN, -OH, -( -C^alkyl, -(C2-C6)alkenyl, - (C2-C6)alkenyl, -halo, -N3, -NO2, -N(R8)2, -CH-NR8, -NR8OH, -OR8, -COR8' -C(O)OR8, -OC(O)R , -OC(O)OR8, -SR8, -S(O)R8, or -S(O)2R8;
R6 is -phenyl, -naphthyl, -(C3-C8)cycloalkyl,-(C14)aryl, or -(C5-C10)heteroaryl, each of which is unsubstituted or substituted with one or more R7 groups; each R7 is independently -( -C^alkyl, -(C2-Cδ)alkenyl, -(C2-C6)aikynyl, -(C3-C8)cycloalkyl, -(C5-C8)cycloalkenyl, -phenyl, -(C3-C5)heterocycle, -C(halo 3,
-CH2(halo), -CH(halo)2, -CN, -OH, -halo, -N„ -NO2, -N(R8)2, -CH=NR8, -NR8OH, -OR8, -COR8, -C(O)OR8, -OC(O)R8, -OC(O)OR8, -SR8, -S(O)R8, or -S(O)2R8; each R8 is independently -H, -(C1-C6)alkyl, -(C2-C6)alkenyl, -(C2-C6)alkynyl, -(C3- Cg)cycloalkyl, -(C5-C8)cycloalkenyl, -phenyl, -(C ~C5)heterocycle, -C(halo)3, -CH (halo), or -CH(halo)2,
R" is -hydrogen, -halo, -CH3, -NO2, -CN. -OH, -OCH3, -NH2, -C(halo),, - CH(haio)2, or -CH2(halo); each R12 is independently:
(a) -halo, -CN, -OH, -NO2, or -NH2; (b) -(CrCi )alkyl, -(C2-C10)alkenyl, -(C2-C10)alkynyl, -(C3-
C10)cycloalkyl, -(C8-C,4)bicycloalkyl, -(C8-C14)tricycloalkyl, -(C5- Cι0)c3'cloalkenyl,-(C8-C14)bicycloalkenyl, -(C8-Cι4)tricycloalkenyl, -(C3- C7)heterocycle, or -(C7-C10)bicycloheterocycle, each of which is unsubstituted or substituted with one or more R5 groups; or (c) -phenyl, -naphthyl, -(C14)aryl, or -(C5-C10)heteroaryl, each of which is unsubstituted or substituted with one or more R7 groups; and each halo is independently -F, -CI, -Br or -I; q is an integer ranging from 0 to 2; and m is an integer ranging from 0 to 2.
42. A compound of formula :
Figure imgf000248_0001
(IK) or a pharmaceutically acceptable salts thereof, wherein:
A is -NR4-, -O-, or -S-; x is -halo, -CH3, -NO2, -CN, -OH, -OCH3, ~NH2, -C(halo)3, -CH(halo)2, or - CH2(halo); each R2 is independently: (a) -halo, -CN, -OH, -NO2, or -NH2;
(b) -(CrC10)alkyl, -(C2-C10)alkenyl, -(C2-C10)alkynyl, -(C3- C10)cycloalkyl, -(C8-C14)bicycloalkyl, -(C3-Cι4)tricycloalkyl, -(C5- Cio)cycloalkenyl,-(C8-C14)bicycloalken} , -(C8-C14)tricycloalkenyl, -(C3- C7)heterocycle, or -(C7-Cι0)bicycloheterocycle, each of which is imsubstituted or substituted with one or more R5 groups; or
(c) -phenyl, -naphthyl, -(C14)aryl, or -(C5-C10)heteroaryl, each of which is unsubstituted or substituted with one or more R7 groups; each R3 is independently:
(a) -halo, -CN, -OH, -NO2, or -NH2: (b) -(CrC10)alkyl, -(C2-C10)alkenyl, -(C2-C,0)alkynyl, -(C3-
C10)cycloalkyl, -(C8-C]4)bicycloalkyl, -(C8-C14)tri cycloalkyl, -(C5- C10)cycloalkenyl,-(C8-C14)bicycloalkenyl, -(C8-C14)tricycloalkenyl, -(C3- C7)heterocycle, or -(C7-C10)bicycloheterocycle, each of which is unsubstituted or substituted with one or more R5 groups; or (c) -phenyl, -naphthyl, -(C14)aryl or -(C5-C10)heteroaryl, each of which is unsubstituted or substituted with one or more R7 groups; R4 is -(CrC6)alkyl, or -O-(CrC6)alkyI; each R5 is independently -CN, -OH, -( -C^alkyl, -(C2-C6)alkenyl, - (C2-C6)alkenyl, -halo, -N3, -NO2, -N(R8)2, -CH=NR8, -NR8OH, -OR8, -COR8' -C(O)OR8, -OC(O)R8, -OC(O)OR8, -SR8, -S(O)R8, or -S(O)2R8; 5 R6 is -phenyl, -naphthyl, -(C3-C8)cycloalkyl,-(C,4)aryl, or -(C5-C10)heteroaryl, each of which is unsubstituted or substituted with one or more R7 groups; each R7 is independently -(C,-C6)alkyl, -(C2-C6)alkenyl, -(C2-C6)alkynyl, -(C3--C8)cycioalkyl, -(C5-C8)cycloalkenyl, -phenyl, -(C3-C5)heterocycle, -C(halo)3, -CH(halo)2, -CH2(halo), -CN, -OH, -halo, -N3, -NO2, -N(R8)2, -CH=NR8. -NR8OH, -OR8, 10 -COR8, -C(O.)OR8, -OC(O)R8, -OC(O)OR8, -SR8, -S(O)R8, or -S(O)2R8; each R8 is independently -H, -(Ct--C6)alkyl, -(C2-C6)alkenyl, -(C2-C6)alkynyl, -(C3-C8)cycloalkyl, -(C5-C8)cycloalkenyl, -phenyl, -(C3-C5)heterocycle, -C(halo)3, -CH2(halo), or -CH(halo)2; each halo is independently -F, -CI, -Br or -I; 15 n is an integer ranging from 0 to 2; and is an integer ranging from 0 to 2.
43. The compound of claim 42, wherein A is -NR4-.
20 44. The compound of claim 43, therein: n is 0; m is 0; and R6 is phenyl.
25.
45. The compound of claim 44, wherein the R6 phenyl is unsubstituted.
46. The compound of claim 44, wherein the R6 phenyl is substituted at the 4-position.
30 47. The compound of claim 46, wherein the R6 phenyl is substituted with a
-(CrC6) alkyl.
48. The compound of claim 47, wherein the -(C,-C6) alkyl is a tert-butyl group.
49. The compound of claim 47, wherein the ~(CrC6) alkyl is an z-ϊø-propyl group.
50. The compound of claim 46, wherein the R6 phenyl is substituted with a -CF3 group.
51. The compound of claim 44, wherein R1 is chloro or methyl.
52. The compound of claim 51, wherein the R6 phenyl is unsubstituted.
53. The compound of claim 51 , wherein the R6 phenyl is substituted at the
4-ρosilion.
54. The compound of claim 53, wherein the R6 phenyl is substituted with a -(C\-C6) alkyl.
55. The compound of claim 54, wherein the -( - alkyl is a tert-butyl group.
56 The compound of claim 54, wherein the -(CrC6) alkyl is an z-vo-propyl group.
57. The compound of claim 53, wherein the R6 phenyl is substituted with a -CF3 group.
58. The compound of claim 42, wherein A is -C-.
59. The compound of claim 42, wherein A is -S-.
60. A compound of formula
Figure imgf000251_0001
(IHa) or a pharmaceutically acceptable salts thereof, wherein:
R1 is -halo, -CH3, -NO2, -CN, -OH, -OCH3, -NH2, -C(balo)3, -CH(halo)2, or -CH2(halo); each R2 is independently:
(a) -halo, -CN, -OH, -NO2, or -NH2;
(b) -(CrC10)alkyl, -(C2-C10)alkenyl, -(C2-C10)alkynyl, -(C3- C10)cycloalkyl, -(C8-C14)bicycloalkyi, -(C8-C14)tricycloalkyl, -(C5- C10)cycloalkenyl,-(C8-C14)bicycloalkenyl, -(C8-C14)tricycloalkenyl, -(C6-
C7)heterocycle, or -(C7-C]0)bicycloheterocycle, each of which is unsubstituted or substituted with one or more R5 groups; or
(c) -phenyl, -naphthyl, -(CM)aryl, or -(C5-Cιυ)heteroaryl, each of which is unsubstituted or substituted with one or more R7 groups; each R3 is independently:
(a) -halo, -CN, -OH, -NO2, or -NH2; or
(b) -(CrC10)alkyl, -(C2-C10)alkenyl, -(C2-C!0)alkynyl, -(C3- C10)cycloalkyl, -(C8-C14)bicycloalkyl, -(C8-Cι4)tricycloalkyl, -(C5- C10)cycloalkenyl,-(C8-C14)bicycloalkenyl, -(C8-C14)rricycloalkenyl, -(C3- C7)heterocycle, or -(C7-C,0)bicycloheterocycle, each of which is unsubstituted or substituted with one or more R5 groups; or (c) -phenyl, -naphthyl, -(C14)aryl or -(C5-C10)heteroaryl, each of which is unsubstituted or substituted with one or more R7 groups; each R5 is independently -CN, -OH, -(Cr-C0)alkyl, -(C2-C6)alkenyl, - (C2-C6)alkenyl, -halo, -N3, -NO2, -N(R.8)2,.-CH=NR8, -NR8OH, -OR8, -COR8' -C(O)OR8, -OC(O)R8, -OC(O)OR8, -SR8, -S(O)R8, or -S(O)2R8; R6 is:
(a), -naphthyl, -(C14)aryl, or -(C3-C8)cycloalkyl each of which is unsubstituted or substituted with one or more R7 groups; or
(b) pyridyl, furyl, benzofuranyl, thiophenyl, benzothiophenyl, quinolinyl, indolyl, oxazolyl, benzoxazolyl, imidazolyl, benzimidazolyl, thiazolyl, benzothiazolyl, isoxazolyl, pyrazolyl, isothiazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, thiadiazolyl, triazinyl, cinnolinyl, phthalazinyl, or quinazolinyl, each of which is substituted with one or more R7 groups; each R7 is independently -(Cj-C^alkyl, -(C2-C6)alkenyl, -(C2-C6)alkynyl, -(C3 -C3)cycioalkyl, -(C5-C8)cycloalkenyi, -phenyl, -(C3-C5)heterocycle, -C(halo)3,
-CH(halo)2, -CH2(halo), -CN, -OH, -halo, -N3, -NO2, -N(R8)2, -CH-NR8, -NR8OH, -OR', -COR3, -C(O)ORs, -OC(O)R8, -OC(O)OR\ -SR8, -S(O)R8, or -S(O)2R8; each R8 is independently -H, -(C;-C6)alkyl, -(C2-C6)alkenyl, -(C -C6)alkynyl. -(C3-C8)cycloaϊkyl, -(C5 -C8)cycloalkenyl, -phenyl, -(C3-C5)heterocycle. -C(halo)3 -CH2(ha!o), or -CH(halo)2; . each halo is independently -F, -CI, -Br or -I; n is an integer ranging from 0 to 2; and m is. an integer ranging from 0 to 2.
61. The compound of claim 60, wherein R° is pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, or thiadiazolyl.
62. A compound of formula :
Figure imgf000253_0001
(mb) or a pharmaceutically acceptable salts thereof, wherein:
R1 is -halo, -CH3, -NO2, -CN, -OH, -OCH3, -NH2, -C(halo)3, -CH(halo)2: or -CH2(halo); each R2 is independently:
(a) -halo, -CN, -OH, -NO2, or -NH2;
(b) -(CrCi0)alkyl, -(C2-C10)alkenyl, -(C2-C10)alkynyl, -(C3- C]0)cycloalkyl, -(C8-Cld)bicycloalkyl, -(C8-Cι4)tricycloalkyl, -(C5- C10)cycloalkenyl,-(C8-C14)bicycloalkenyl, -(C8-C14)tricycloalkenyl, -(C3-
C7)heterocycle, or -(C7-C10)bicycloheterocycle, each of which is unsubstituted or substituted with one or more R5 groups; or
(c) -phenyl, -naphthyl, -(C14)aryl, or -(C5-C10)heteroaryl, each of which is unsubstituted or substituted with one or more R7 groups; each R3 is independently:
(a) -halo, -CN, -OH, -NO2, or -NH2; or
(b) -(CrC10)alkyl, -(C2-C10)alkenyl, -(C2-C10)alkynyl, -(C3- Cι0)cycloalkyl, -(C8-C14)bicycloalkyl, -(C8-C14)tricycloalkyl, -(C5- Cio)cycloalkenyl.,-(C8-C14)bicycloalkenyl, -(C8-C14)tricycloalkenyl, -(C3- C7)heterocycle, or -(C7-CI0)bicycloheterocycle, each of which is unsubstituted or substituted with one or more R5 groups; or (c) -phenyl, -naphthyl, -(C14)aryl or -(C5-C10)heteroaryl, each of which is unsubstituted or substituted with one or more R7 groups; each R5 is independently -CN, -OH,
Figure imgf000254_0001
-(C2-C6)alkenyl, - (C2-C6)alkenyl, -halo, -N3, -NO2, -N(R8)2, -CH=NR8, -NR8OH, -OR8, -COR8' -C(O)OR8, -OC(O)R8, -OC(O)OR8, -SR8, -S(O)R8, or -S(O)2Rs; each R7, R9, and R10 is independently -( -C^alkyl, -(C2-C6)alkenyl, - (C2-C6)alkynyl, -(C3-C8)cycloalkyl, -(C5-C8)cycloalkenyl, -phenyl, -(C3-C5)heterocycle, - C(halo)3, -CH(halo)2, -CH2(halo), -CN, -OH, -halo, -N3, -NO2, -N(R8)2, -CH=NR8, -NR8OFL -OR8, -COR8, -C(O)OR8, -OC(O)R8, -OC(O)OR8, -SR8, -S(O)R8, or -S(O)2R8; each R8 is independently -H, - (C,-C6)alkyl, -(C2-C6)alkenyl -(C2 -C6)alkynyl,
-(C3-C8)cycloalkyl, -(Cs-C^cycloalkenyl, -phenyl, -(C3-C5)heterocycle, -C(halo)3, -CH2(halo), or -CH(halo)2; each halo is independently -F, -CI, -Br or -I; n is an integer ranging from 0 to 2; m is an integer ranging from 0 to 2; and p is an integer ranging from 0 to 4.
63. A compound of formula:
Figure imgf000254_0002
(Hie) or a pharmaceutically acceptable salts thereof, wherein: A is -NR4-, -O-, or -S-; each R3 is independently: (a) -halo, -CN, -OH, -NO2, or -NH2;
(b) -(CrC10)alkyl, -(C2-C10)alkenyl, -(C2-C10)alkynyl, -(C3- C10)cycloalkyl, -(C8-C14)bicycloalkyl, -(C8-Cκ)tricycloalkyl, -(C5- CI0)cycloalkenyl,-(C8-C14)bicycloalkenyl, -(C3-C14)tncycloalkenyl, -(C3- C7)heterocycle, or -(C7-C10)bicycloheterocycle, each of which is unsubstituted or substituted with one. or more R5 groups; or
(c) -phenyl, -naphthyl, -(CM)aryl or -(C5-C10)heteroaryl, each of which is unsubstituted or substituted with one or more R7 groups;
R4 is -(C,-C6)alkyl, or -O-(CrC6)alkyl; each R5 is independently -CN, -OH, -( -C alkyl, -(C6-C6)alkenyl, -
(C2-C6)alkenyl, -halo, -N3, -NO2, -N(R8)2, -CH=NR8, -NR8OH, -OR8, -COR8' -C(O)OR8, -OC(O)RVi, -OC(O)OR8, -SR8, -S(O)R8, or -S( )2R8;
R6 is -phenyl, -naphthyl, -(C3-C8)cycloalkyl,-(C14)aryl, or -(C5-C)0)heteroaryl, each of which is unsubstituted or substituted with one or more R7 groups; each R7 is independently - ■(C1-C6)alkyl, -(C2-C6)alkenyl, -(C2-C6)alkyn)4,
-(C:-C8)cyc1oalkyl, -(C5-C8)cycloalkenyl, -phenyl, -(C3-C5)hetεrocycle, -C(halo)3, -CH('halo)?, -CH2(halo), -CN, -OH, -halo, -N3, -NO-, -N(R8)2; -CH-NR8, -NR8OH, -OR8, -COR8, -C(O)OR8, -OC(O)R8, -OC(O)OR8, -SR8, -S(O)R8, or -S(O),R8; each R8 is independently -H, -(C,-C6)alkyl, -(C2-C6)alkenyl, -(C2~C6)alkynyl, -(C1--C3)cycloaikyl> -(C5-C8)cycloalkenyl, -phenyl, -(C3-C5)heterocycle, -C(halo)3, -CH2(haϊo), or -CH(halo)2;
Ru is -hydrogen, -halo, -CH3, -NO2, -CN, -OH, -OCH3, -NH2, -C(halo)3, -CH(halo)2, or -CH2(halo); each R12 is independently. (a) -halo, -CN, -OH, -NO2, or -NH2:
(b) -(CrC10)alkyl, -(C2-C10)alkenyl, -(C2-C10)alkynyl, -(C3- C10)cycloalkyl, -(C8-C14)bicycloalkyl, -(C8-C14)tricycloalkyl, -(C5- C,0)cycloalkenyl,-(C,rC14)bicycloalkenyl, -(C8-C]4)tricycloalkenyl, -(C3- C7)heterocycle, or -(C7-C10)bicycioheterocycle, each of which is unsubstituted or substituted with one or more R5 giOups; or (c) -phenyl, -naphthyl, ~(C14)aryl, or -(C5-C,0)heteroaryl, each of which is unsubstituted or substituted with one or more R7 groups; each halo is independently -F, -CI, -Br or -I; q is an integer ranging from 0 to 2; and m is an integer ranging from 0 to 2.
64. A compound of formula :
Figure imgf000256_0001
(IV) or a pharmaceutically acceptable salts thereof, wherein: A is -NR4-, -O-, or -S-: R! is -halo, -CH3, -NO2. -CN, -OH, -OCH:, -NH2, -C(halo)3, -CH(halo)2, or -
CH2(halo); each R2 is independently:
(a) -halo, -CN, -OH, -NO2, or -NH2;
(b) -(CrC10)alkyL -(C2-C10)alkenyL -(C2-C10)alkynyl, -(C3- C] )eycloalkyl, -(C8-C14)bicycloalkyl, -(C8-C14)tricycloalkyl, -(Cr
C]0)cycloalkenyl,-(C8-C14)bicycloalkenyl, -(C8-C14)tricycloalkenyl, -(C,- C7)heterocycle, or -(C7-C10)bicycioheterocycle, each of which is unsubstituted or substituted with one or more R5 groups; or
(c) -phenyl, -naphthyl, -(C14)aryl, or -(C -C]0)heteroaryl, each of which is unsubstituted or substituted with one or more R7 groups; each RJ is independently: (a) -halo, -CN, -OH, -NO2, or -NH2;
(b) -(CrC10)alkyl, -(C C10)alkenyl. -(C2-C10)alkynyl, -(C3- C10)cycloalkyl, -(C8-C1 )bicycloalkyl, -(C8-C14)tricycloalkyl, -(C5- C10)cycloalkenyl,-(C8-C14)bicycloalkenyl, -(C8-C14)tricycloalkenyl, -(C3- C7)heterocycle, or -(C7-C10)bicycloheterocycle, each of which is unsubstituted or substituted with one or more R5 groups; or
(c) -phenyl, -naphthyl, -(CH)aryl or -(C5-C10)heteroaryl, each of which is unsubstituted or substituted with one or more R7 groups;
R4 is hydrogen, -(C,-C6)alkyl, or -O-(CrC6)alkyl; each R5 is independently -CN, -OFI, -(C,-C6)alkyl, -(C2-C6)alkenyl, -
(C2-C6)alkenyl, -halo, -N3, -NO2, -N(R8)2, -CH=NR8, -NR8OH, -OR8, -COR8' -C(O)OR8, -OC(O)R8, -OC(O)OR8, -SR8, -S(O)R8, or -S(O)2R8;
R6 is -phenyl, -naphthyl, -(C3-C8)cycloalkyl,-(C14)aryl, or -(C5-C10)heteroaryl, each of which is unsubstituted or substituted with one or more R7 groups; each R7 is independently -(Cr-C6)alkyl, -(C2--C6)alkenyl, -(C2-C6)aikynyl,
-(C3-C8)cycloalkyl, -(C5-C8)cycloalkenyl, -phenyl, -(C3-C5)heterocycle, -C(halo)3, -CH(halo)2, -CH2(halo), -CN, -OH, -halo, -N3, -NO,, -N(R8)2, -C.H-NR8, -NRsOH, -OR8, -COR8, -C(O)OR8, -OC(O)Rs, -OC(O)OR8, -SR8, -S(O)R8, or -S(O)2R8; each R8 is independently -H, -(Cj -C6)alkyl, -(C2-C6)alken3d, -(C2-C6)a.lkynyl, -(C3-C8)cycIoalkyl, -(C5- Cs)cycloalkenyl, -phenyl, -(Cj-C5)heterocycle, -C(halo)3, -CH2(haIo), or -CH(halo)2; each halo is independently -F, -CI, -Br or -1; n is an integer ranging from 0 to 2; and m is an integer ranging from 0 to.2.
65. The compound of claim 64, wherein A is -NH-.
66. The compound of claim 65, wherein: n is 0; m is 0; and
R6 is phenyl.
67. The compound of claim 66, wherein the R6 phenyl is unsubstituted.
68. The compound of claim 66. wherein the R6 phenyl is substitiited at the 4-position.
69. The compound of claim 68, wherein the R6 phenyl is substituted with a -(CrC6) alkyl.
70. The compound of claim 69, wherein the -(C,-C6) alkyl is a tert-butyl group.
71. The compound of claim 69, wherein the -(C,-C6) alkyl is an iso-propyl group.
72. The compound of claim 63, wherein the R6 phenyl is substituted with a _,"'
-CPj group.
73. The compound of claim 66, wherein R1 is chloro or methyl. i
74. The compound pf claim 73, wherein the R° phenyl is unsπbstituted. ''
75. The compound of claim 73, wherein the R6 phenyl is substituted at the 4-position.
76. The compound of claim 75, wherein the R6 phenyl is substituted with a
-(CrCό) alkyl.
77. The compound of claim 76, wherein the -(CrC6) alkyl is a tert-butyl group.
78. The compound of claim 76, wherein the -(CrC6) alkyl is an wo-propy! group.
79. The compound of claim 75, wherein the R6 phenyl is substituted with a -CF3 group.
80. The compound of claim 64, wherein A is -O-
81. The compound of claim 64, wherein A is -S-
82. A compound of formula
Figure imgf000259_0001
(IVa) or a phannaceutically acceptable salts thereof, wherein: A is -NR4-, -O-, or -S-; each R3 is independently:
(a) -halo, -CN, -OH, -NO2, or -NH2; .
(b) -(CrC10)aUcyl, -(C2-C10)alkenyl, -(C2-CJ0)alkynyl, -(C3- Cι0)cycloalkyl, -(C8-C14)bicycloalkyl. -(C8-C]4)tricycloalkyl, -(C5- C;0)cycloalkenyl,-(C8-C14)bicycloalkenyl, -(C8-C14)tricycloalkenyl, -(C3- C7)heterocycle, or -(C7-C10)bicycloheterocycle, each of which is unsubstituted or substituted with one or more R5 groups; or (c) -phenyl, -naphthyl, -(C14)aryl or -(C5-C10)heteroaryl, each of which is unsubstituted or substituted with one or more R7 groups; R4 is hydrogen, -(CrC6)alkyl, or -O-(CrC6)alkyl; each R5 is independently -CN, -OH, -( - alkyl, -(C2-C6)alkenyl, - (C2-C6)alkenyl, -halo, -N3, -NO2, -N(R8)2, -CH=NR8, -NR8OH, -OR8, -COR8' -C(O)OR8, -OC(O)R8, -OC(O)OR8, -SR8, -S(O)R8, or -S(O)2R8;
R6 is -phenyl, -naphthyl, -(C3-C8)cycloalkyl,-(C14)aryl, or -(C5-C10)heteroaryl, each of which is unsubstituted or substituted with one or more R7 groups; each R7 is independently -(C1-C6)alkyl, -(C2-C6)alkenyl, -(C2-C6)alkynyl, -(C3-C3)cycloalkyl, -(C5-C8)cycloalkenyl, -phenyl, -(C3-C5)heteιocycle, -C(halo)3,
-CH(halo)2, -CH2(halo), -CN, -OH, -halo, -N3, -NO2, -N(R8)2, -CH=NR8, -NR8OH, -OR8, -COR8, -C(O)OR8, -OC(O)R8, -OC(O)OR8, -SRS, -S(O)R8, or -S(O)2R8; each R8 is independently -H, -(C1-C6)alkyl, -(C2-C6)alkenyl, -(C2-C6)alkynyl, -(C:-C8)cycloalkyl, -(C5-Cg)cycloalkenyl, -phenyl, -(C3-C5)heteroeycle, -C(halo)3, -CH2(halo), or -CH(halo)2;
R11 is -hydrogen, -halo, -CH3, -NO2, -CN, -OH, -OCH3, -NH2, -C(halo)3, - CH(halc)2, or -CH2(halo); each R12 is independently:
(a) -halo, -CN, -OH, -NO2, or -NH2; (b) -(C,-C10)alkyl, -(C2-C10)alkenyl, -(C2-C10)alkynyl, -(C3-
C10)cycloalkyl, -(C8-Cι4)bicycloalkyl, -(C8-C14)tricycloalkyl, -(C5- C10)cycloalkenyl,-(C8-C14)bicycloalkenyl, -(C8-C14)tricycloalkenyl, -(C3- C7)heterocycle, or -(C7-C10)bicycloheterocycle, each of which is unsubstituted or substituted with one or more R5 groups; or (c) -phenyl, -naphthyl, -(C,4)aryl, or -(C5-C10)heteroaryl, each of which is unsubstituted or substituted with one or more R7 groups; each halo is independently -F, -CI, -Br or -I; q is an integer ranging from 0 to 2; and m is an integer ranging from 0 to 2.
83. A compound of formul a :
Figure imgf000261_0001
(V) and phannaceutically acceptable salts thereof, wherein: A is -NR4-, -O-, or -S-;
R1 is -hydrogen, -halo, -CH3, -NO2, -CN, -OH, -OCH3, -NH2, -C(haio)3, - CH(halo)2, or -CH2(halo); each R3 is independently: (a) -halo, -CN, -OH, -NO2, or -NH2;
(b) -(CrC10)aιkyl, -(C2-Cl0)alkenyl, -(C2-C10)alkynyl, -(C3- C10)cycloalkyl, -(C8-C14)bicycloalkyl, -(C8-Cι4)tricycloalkyl, -(C5- C10)cycloalkenyl.-(C8-C14)bicycloalkenyl, -(C8-C14)tricycloalkenyl, -(C3- C7)heterocycle, or -(C;-C10)bicycloheterocycle, each of which is unsubstituted or substituted v/ith one or more R5 groups; or
(c) -phenyl, -naphthyl, -(C14)aryl or -(C5-Cι0)heteroaryl, each of which is unsubstituted or substituted with one or more R7 groups;
R4 is hydrogen, -(CrC6)alkyl, or -O-(CrC6)alkyl; each R5 is independently -CN, -OH, ~(C1-C6)alkyl, -(C2-C6)alkenyl, - (C2-C6)alkenyl, -halo, -N3. -NO2, -N(R8)2, -CH=NR8, -NR8OH, -OR8, -COR8' -C(O)OR8, -OC(O)R8 , -OC(O)OR8, -SR8, -S(O)R8, or -S(O)2R8;
R6 is -phenyl, -naphthyl, -(C3-C8)cycloalkyl,-(C14)aryl, or -(C5-C10)heteroaryl, each of which is unsubstituted or substituted with one or more R7 groups; each R7 is independently -(Cj-C6)alkyl, -(C2-C6)alkenyl, -(C2-C6)alkynyl, - C3- C8)cycloalkyl, -(C5-C8)cycloalkenyl, -phenyl, -(C3-C5)heterocycle, -C(halo)3, -CH2(halo), -CH(halo)2, -CN, -OH, -halo, -N3, -NO2, -N(R8)2, -CH=NR8, -NR8OH, -OR8, -COR8, -C(O)OR8, -OC(O)R8, -OC(O)OR8, -SR8, -S(O)R8, or -S(O)2R8; each R8 is independently -H, -(Cj-C^alkyl, -(C2-C6)alkenyl, -(C2-C6)alkynyl, -(C3-C8)cycloalkyl, -(C5-C8)cycloalkenyl, -phenyl, -(C3-C5)heterocycle, -C(halo)3, -CH2(halo), or -CH(halo)2; each halo is independently -F, -CI, -Br or -I; and m is an integer ranging from 0 to 2. The compound of claim 64, wherein A is -NH-.
84. The compound of claim 83, wherein: m is 0; and R6 is phenyl.
85. The compound of claim 84, wherein the R6 phenyl is xmsubstilnted.
86. The compound of claim 84, wherein the R6 phenyl is substituted at the , t
4-position.
87. The compoimd of claim 86, wherein the R6 phenyl is substituted with a ~: -(CrC6) alkyl.
88. The compound of claim 87, wherein the -(Cj- ) alkyl is a tert-butyl group.
89. The compound of claim 87, wherein the -(C^ ) alkyl is an ύ'c-propyl group.
90. The compound of claim 84, wherein the R6 phenyl is substituted with a
-CF3 group.
91. The compoimd of claim 84, wherein R is chloro or methyl.
92. The compound of claim 91, wherein the R6 phenyl is unsubstituted.
93. The compound of claim 91, wherein the R6 phenyl is substituted at the 4-position.
94. The compound of claim 93, wherein the R6 phenyl is substituted with a -(CrC6) alkyl.
95. The compound of claim 94, wherein the -(CrC6) alkyl is a tert-butyl group.
96. The compound of claim 94, wherein the -(CrCΛ_alkyl is an tsø-propyl group.
97. ' The compound of claim 93, whe ein the Rb phenyl is substituted with a -CF, group.
98. The compound of claim 83, wherein A is -O-.
99. The compound of claim 83, wherein A is -S-.
100. A compound of formula:
Figure imgf000264_0001
(VI) a pharmaceutically acceptable salts thereof, wherein: Art is
Figure imgf000264_0002
Ar, is
Figure imgf000265_0001
Figure imgf000265_0002
Figure imgf000265_0003
R1 is -H, -halo, -CH3, -NO2, -CN, -OH, -OCH3, -NH2, C(halo)3, -CH(halo)2, or -CH2(halo); each R2 is independently:
(a) -halo, -CN, -OH, -NO2, or -NH2;
(b) -(CrC10)alkyl, -(C2-C10)alkenyl, -(C2-C10)alkynyl, -(C3-C10)cycloalkyl, -(C8- C-l4)bicycloalkyl, -(C8-C14)tricycloalkyl, -(C5-C,0)cycloalkenyl, -(C8-C14)bicycloalkenyl, -(C8- Cj4)tricycioalkenyl, -(3- to 7-membered)heterocycle, or -(7- to 10- membered)bicycloheterocycle, each of which is unsubstituted or substituted with one or more R5 groups; or
(c) -phenyl, -naphthyl, -(C14)aryl or -(5- to 10-membered)heteroaryl, each of which is unsubstitute or substituted with one or more R6 groups; each R3 is independently: (a) -halo, -CN, -OH, -NO2, or -NH2; (b) -(CrC10)alkyl, -(C2-C10)alkenyl, -(C2-C10)alkynyl, -(C3-C10)cycloalkyl, -(C8- C]4)bicycloalkyl, -(C8-Ci4)tricycloalkyl, -(C5-C10)cycloalkenyl, -(C8-C14)bicycloalkenyl, -(C8- Ci4)tricycIoalkenyl, -(3- to 7-membered)heterocycle, or -(7- to 10- membered)bicycloheterocycle, each of which is imsubstituted or substituted with one or more RD groups; or
(c) -phenyl, -naphthyl, -(C14)aryl or -(5- to 10-membered) heteroaryl, each of which is unsubstituted or substituted with one or more. R6 groups; each R4 is independently -(C,-C6)alkyl, -(C2-C6)alkenyl, -(C2-C6)alkynyl. -(C3-C8)c3/cloalkyl, -(C5-C8)cycloalkenyl, -phenyl, -(3- to 5-mernbered)heterocycle, - C(balo)3, -CH(halo)2! or CH2(halo); each R5 is independently -CN, -OH, -(Cι-C6)alkyl, -(C2-C6)alkenyl, -(C2-C6)alkenyl, -halo, -N3, -NO2, -N(R8)2, -CH=NR8, -NR3OH, -OR8, -COR8' -C(O)OR8, -OC(O)Rs, -OC(O)OR8, -SR8, -S(O)R8, or -S(O)2R8; each R6 is independently -( - alkyl, -(C2-C6)alkenyl, -(C2-C6 alkynyl, -(C3--C8)cycioalkyl, -(C5--C8)cycloalkehyl, -phenyl, -(3- to 5-membered)heterocycle,
-C(halo)3, -CH(halo)2, -CH2(halo), -CN, -OH, -halo, -N3, -NO2, -CH- R7, -NR7OH -OR7, • COR7, -C(O)OR7, -OC(O)R7, -OC(O)OR7, -SR,, -S(O)R7, or -S(O)2R7; each R7 is independently -H, -( -C^alkyl, -(C2-C6)alkenyl, -(C2-C6)alk>nyl. -(C3-C8)cycloalkyl, -(C5-C8)cycloalkenyl, -phenyl, -(3- to 5-rnembered)heterocycle, - C(halo)3, -CH(halo)2, or CH2(halo); each R8 is independently -(Cj-C6)alkyl, -(C2-C6)alkenyl, -(C2-C6)alkynyl, -(C3-C8)cycloalkyl, -(C5-C8)cycloalkenyl, -phenyl, -C(halo)3, -CH(halo)2, -CH2(halo), -CN, -OH, -halo, -N3, -NO2, -CH=NR7, -NR7OH, -OR7, -COR7, -C(O)OR7, -OC(O)R7, -OC(O)OR7, -SR7, -S(O)R7, or -S(O)2R7; each R11 is independently -CN, -OH, -(C C6)aιkyl, -(C2-C6)alkenyl, -halo, -N3,
-NO2, -N(R.7)2, -CH-NR7, -NR7OH, -OR,, -COR7, -C(O)OR7s -OC(O)R7, -OC(O)OR7, -SR7, -S(O)R7, or -S(O)2R7; each halo is independently ~F, -CI, -Br, or -I; m is 0 or 1 ; n is an integer ranging from 0 to 3; o is an integerranging from 0 to 4; p is an integer ranging from 0 to 2; q is an integer ranging from 0 to 6; r is an integer ranging from 0 to 5; s is an integer ranging from 0 to 4; and t is an integer ranging from 0 to 2.
101. A compound of formula:
Figure imgf000267_0001
(VH) or a pharmaceutically acceptable salts thereof, wherein:
Atj is
Figure imgf000267_0002
:3
Ar2 is
Figure imgf000268_0001
Figure imgf000268_0002
Figure imgf000268_0003
R1 is -H, -halo, -CH3, -NO2, -CN, -OH, -OCH3, -NH2, C(halo)3, -CH(halo)2, or -CH2(halo); each R2 is independently:
(a) -halo, -CN, -OH, -NO2, or -NH2;
(b) -(CrC10)alkyl, -(C2-C10)alkenyl, -(C2-C10)alkynyl, -(C3-C10)cycloalkyl, -(C8- C14)bicycloalkyl, -(C8-C14)tricycloalkyl, -(C5-C10)cycloalkenyl. -(C8-C14)bicycloalkenyl, -(C8- C14)tri yclnalkenyl, -(3- to 7-membered)heterocycle, or -(7- to 10- membered)bicyclohetero cycle, each of which is unsubstituted or substituted with one or more R5 groups; or
(c) -phenyl, -naphthyl, -(C14)aryl or -(5- to 10-membered)heteroaryl, each of which is unsubstitute or substituted with one or more R6 groups; each R3 is independently: (a) -halo, -CN, -OH, -NO2, or -NH2: (b) -(CrC10)alkyl, -(C2-C10)alkenyl, -(C2-C10)alkynyl, -(C3-C10)cycloalkyl, -(C8- C14)bicycloalkyl, -(C8-C14)tri cycloalkyl, -(C5-Cι0)cycloalkeny , -(C8-CI4)bicycloalkenyl, -(C8- Ci4)tricycioalkenyl, -(3- to 7-membered)heterocycle, or -(7- to 10- membered)bicycloheterocycle, each of which is unsubstituted or substituted with one or more R5 groups; or
(c) -phenyl, -naphthyl, -(C14)aryl or -(5- to 10-membered) heteroaryl, each of which is unsubstituted or substituted with one or more R6 groups; each R4 is independently -(Cj-C^alkyl, -(C2-C6)alkenyi, -(C2-C6)alkynyl, -(C3-C8)cycioalkyl, -( - jcycloalkenyl, -phenyl, -(3- to 5-membered)heterocycle, - C(h lo)3, -CH(halo)2, or CH2(halo); each R5 is independently -CN, -OH, -(C1-C6)alkyl, -(C2-C6)alkenyl, -(C2-C6)alkenyl, -halo, -N3, -NO2, -N(R8)2, -CH=NR8, -NR8OH, -OR8, -COR8' -C(O)OR8, -OC(O)R8, -OC(O)OR8, -SR8, -S(O)R8. or -S(O)2R8; each R6 is independently -(Ci -C6)alkyl, -(C2~C6)alkenyl, -(C2-C6)alkynyl, -(C3-C8)cycloalkyl, -(C5-C8)cycloalkenyl, -phenyl, -(3- to 5-mernbered)heteroeycle,
-C(halo)5, -CH(halo)2! -CH2(halo), -CN, -OH, -halo, -N3, -NO2, -CH=NR7, -r-}R7OH, -OR7, -COR„ -C(O)OR7, -OC(O)R-;, -OC(O)OR7. -SR7, -S(O)R7, or -S(O 2R7; each R7 is independently -H, -(Cι-C6)alkyl, -(C2~C6)alkenyl, -(C2-C6)alkynyl. -(C3-C8)cycloalkyl, -(C5-C8)cycloalken3'l, -phenyl, -(3- to 5-membered)heterocycle. - C(halo)3, -CH(halo)2, or CH2(halo); each R8 is independently -( -C^alkyl, -(C2-C6)alkenyl, -(C2-C6)alkynyl, -(C3-C8)cycloalkyl, -(C5~Cg)cycloalkenyl, -phenyl, -C(halo)3, -CH(halo)2, -CH2(halo), -CN, -OH, -halo, -N3, -NO2, -CH=NR7, -NR7OH, -OR7, -COR7, -C(O)OR7, -OC(O)R7, -OC(O)OR7, -SR,, -S(O)R7, or -S(O)2R7; each R! ! is independently -CN, -OH, •-(C1-C6)alkyl, -(C2~C6)alkenyl, -halo, -N3,
-N02, -N(R7)2, -CH-NR7, -NR7OH, -OR7, -COR7, -C(O)OR7, -OC(O)R7, -OC(O)OR,. -SR7, -S(O)R7, or -S(O)2R7; each halo is independently -F, -CI, -Br, or -ϊ; rα is 0 or 1 ; n is an integer ranging from 0 to 3; o is an integer ranging from 0 to 4; p is an integer ranging from 0 to 2; q is an integer ranging from 0 to 6; r is an integer ranging from 0 to 5; s is an integer ranging from 0 to 4; and t is an integer ranging from 0 to 2.
102. A composition comprising an effective-amount ofthe compound or a pharmaceutically acceptable salt ofthe compound of claim 1 and a pharmaceutically acceptable carrier or excipient.
103. A composition comprising an effective amount ofthe compound or a pharmaceutically acceptable salt ofthe compound of claim 19 and a phannaceutically acceptable carrier or excipient.
104. A composition comprising an effective amount ofthe compound or a pharmaceutically acceptable salt ofthe compound of claim 21 and a phannaceutically acceptable earner or excipient.
105. A composition comprising an effective amount ofthe compound or a phannaceutically acceptable salt ofthe compound of claim 22 and a pharmaceutically acceptable carrier or excipient.
106. A composition comprising an effective amount ofthe compound or a pharmaceutically acceptable salt of the compound of claim 23 and a pharmaceutically acceptable canier or excipient.
107. A composition comprising an effective amount ofthe compound or a pharmaceutically acceptable salt ofthe compound of claim 41 and a pharmaceutically acceptable canier or excipient.
108. A composition comprising an effective amount ofthe compound or a pharmaceutically acceptable salt ofthe compound of claim 42 and a pharmaceutically acceptable canier or excipient.
109. A composition comprising an effective amount ofthe compound or a phannaceutically acceptable salt ofthe compound of claim 60 and a pharmaceutically acceptable carrier or excipient.
110. A composition comprising an effective amount ofthe compound or a phamiaceutically acceptable salt ofthe compound of claim 62 and a pharmaceutically acceptable carrier or excipient.
111. A composition comprising an effective amount ofthe compound or a pharmaceutically acceptable salt ofthe compound of claim 63 and a phannaceutically acceptable earner or excipient.
112. A composition comprising an effective amount ofthe compound or a phamiaceutically acceptable salt ofthe compound of claim 64 and a pharmaceutically acceptable canier or excipient.
113. A composition comprising an effective amount ofthe compound or a phannaceirtically acceptable salt ofthe compound of claim 82 and a pharmaceutically acceptable carrier or excipient.
114. A composition comprising an effective amount of the compound or a pharmaceutically acceptable salt of the compound of claim 83 and a pharmaceutically acceptable carrier or excipient.
115. A composition comprising an effective amounl ofthe compoimd or a phannaceutically acceptable salt ofthe compomid of claim 100 and a phamiaceutically acceptable carrier or excipient.
116. A composition comprising an effective amount ofthe compound or a phaimaceutically acceptable salt ofthe compound of claim. 101 and a pharmaceutically acceptable carrier or excipient.
117. A method for treating pain in an animal, comprising administering to an animal in need thereof an effective amount ofthe compound or a pharmaceutically acceptable salt of the compound of claim 1.
118. A method for treating pain in an animal, comprising administering to an animal in need thereof an effective amount ofthe compound or a phar aceutically acceptable salt ofthe compound of claim 19.
119. A method for treating pain in an animal, comprising administering to an animal in need thereof an effective amount ofthe compound or a pharmaceutically acceptable salt of the compound of claim 21.
120. A method for treating pain in an animal, comprising administering to an animal in need thereof an effective amount ofthe compoimd or a pharmaceutically acceptable salt ofthe compound of claim 22.
121. A method for treating pain in an animal, comprising administering to an animal in need thereof an effective amount ofthe compound or a pharmaceutically acceptable salt of the compound of claim 23.
122. A method for treating pain in an animal, comprising administering to an animal in need thereof an effective amount ofthe compound or a pharmaceutically acceptable salt of the compound of claim 41.
123. A method for treating pain in an animal, comprising administering to an animal in need thereof an effective amount ofthe compound or a pharmaceυ.ticaily acceptable salt ofthe compound of claim 42.
124. A method for treating pain in an animal, comprising administering to an animal in need thereof an effective amount ofthe compound or a pharmaceutically acceptable salt ofthe compound of claim 60.
125. A method for treating pain in an animal, comprising administering to an animal in need thereof an effective amount ofthe compound or a pharmaceutically acceptable salt of the compound of claim 62.
126. A method for treating pain in an animal, comprising administering to an animal in need thereof an effective amount of the compound or a pharmaceutically . acceptable salt ofthe compound of claim 63.
127. A method for treating pain in an animal, comprising administering to an animal in need thereof an effective amount ofthe compound or a pharmaceutically acceptable salt of the compoimd of claim 64.
128. A method for treating pain in an animal, comprising administering to an animal in need thereof an effective amount o the compoimd or a phannaceutically acceptable salt ofthe compound of claim 82.
129. A method for treating pain in an animal, comprising administering to an animal in need thereof an effective amount o the compoimd or a pharmaceutically acceptable salt of the compound of claim 83.
130. A method for treating pain in an animal, comprising administering to an. animal in need thereof an effective amount ofthe compound or a phatmaceixtically acceptable salt ofthe compound of claim 100.
131. A method for treating pain in an animal, comprising administering to an animal in need thereof an effective amount ofthe compound or a pharmaceutically acceptable salt ofthe compound of claim 101.
132. A method for treating urinary incontinence in an animal, comprising administering to an animal in need thereof an effective amount ofthe compound or a pharmaceutically acceptable salt ofthe compound of claim 1.
133. A method for treating urinary incontinence in an animal, comprising administering to an animal in need thereof an effective amount ofthe compound or a phannaceutically acceptable salt ofthe compound of claim 19.
134. A method for treating urinary incontinence in an animal, comprising administering to an animal in need thereof an effective amount of the compound or a pharmaceutically acceptable salt of the compound of claim 21.
135. A method for treating urinary incontinence in an animal, comprising administering to an animal in need thereof an effective amount ofthe compound or a pharmaceutically acceptable salt ofthe compoimd of claim 22.
136. A method for treating urinary incontinence in an animal, comprising administering to an animal in need thereof an effective amount of the compound or a pharmaceutically acceptable salt ofthe compoimd of claim 23.
137, A method for treating urinary incontinence in an animal, comprising administering to an animal in need thereof an effective amount ofthe compound or a pharmaceutically acceptable salt ofthe compound of claim 41.
138. A method for treating urinary incontinence in an animal, comprising administering to an animal in need thereof an effective amount ofthe compound or a pharmaceutically acceptable salt ofthe compound of claim 42.
139. A method for treating urinary incontinence in an animal, comprising administering to an animal in need thereof an effective amount ofthe compoimd or a pharmaceutically acceptable salt ofthe compound of claim 60.
140. A method for treating urinary incontinence in an animal, comprising administering to an animal in need thereof an effective amount ofthe compound or a phannaceutically acceptable salt ofthe compound of claim 62.
141. A method for treating urinary incontinence in an animal, comprising administering to an animal in need thereof an effective amount ofthe compound or a pharmaceutically acceptable salt ofthe compound of claim 63.
142. A method lor treating urinary incontinence in an animal, comprising administering to an animal in need thereof an effective amount ofthe compound or a pharmaceutically acceptable salt ofthe compound of claim 64.
143. A method for treating urinary incontinence in an animal, comprising administering to an animal in need thereof an effective amount ofthe compomid or a phannaceutically acceptable salt ofthe compound of claim 82.
144. A method for treating urinary incontinence in an animal, comprising administering to an animal in need thereof an effective amount ofthe compound or a pharmaceutically acceptable salt ofthe compound of claim 83.
145. A method for heating urinary incontinence in an animal, comprising administering to an animal in need thereof an effective amount ofthe compound or a pharmaceutically acceptable salt ofthe compoimd of claim 100.
146. A method for treating urinary incontinence in an animal, comprising administering to an animal in need thereof an effective amount ofthe compound or a phamiaceutically acceptable salt ofthe compound of claim 101.
5 147. A method for treating an ulcer in an animal, comprising administering to an aiiimalin need thereof an effective amount ofthe compound or a pharmaceutically , acceptable salt of the compound of claim 1.
148. A method for treating an ulcer in an animal, comprising administering to an anima). in need thereof an effective amount ofthe compound or a pharmaceutically . acceptable salt ofthe compound of claim 19.
149. A method for treating an ulcer in an animal, comprising administering to an animal hi need thereof an effective amoxmt of the compoun or a pharmaceutically 5 acceptable salt of the compound of claim 21.
150. A method for treating an ulcer in an animal, comprising administering to an animal in need thereof an effective amount ofthe compound or a pharmaceutically . acceptable salt of the compound of claim 22. 0 ■
151. A method for treating an ulcer in an animal, comprising administering , to an animal in need thereof an effective amoxmt of the compound or a pharmaceuti cally acceptable salt ofthe compound of claim 23.
5 152. A method for treating an ulcer in an animal, comprising administering to .m animal in need thereof an effective amoxxnt ofthe compoimd or a pharmaceutically acceptable salt of the compound of claim 41.
153. A method for treating an ulcer in an animal, comprising administering 0 to an animal in need thereof an effective amount ofthe compound or a pharmaceiuically acceptable salt ofthe compound of claim 42.
154. A method for treating an ulcer in an. animal, comprising administering to an animal in need thereof an effective amount ofthe compound or a pharmaceutically acceptable salt ofthe compound of claim 60.
155. A method for treating an ulcer in an animal, comprising administering to an animal in need thereof an effective amount of the compound or a pharmaceutically acceptable salt ofthe compound, of claim 62.
.156. A method for treating an ulcer in an animal, comprising administering to an animal in need thereof an effective amoimt ofthe compound or a pharmaceutically acceptable salt of the compound of claim 63.
.157. A method for treating an u leer in an animal, comprising administering to an animal in need thereof an effective amount ofthe compound or a pharmaceutically ■ acceptable salt ofthe compound of claim 64.
1.58. A method for heating an ulcer in an animal, comprising administering to an animal in need thereof an effective amount ofthe compound or a pharmaceutically ,, acceptable salt of the compound of claim 82. '$'■■
159. A method for treating an ulcer in an animal, .comprising administering to an animal in need thereof an effective amount ofthe compound or a pharmaceutically acceptable salt ofthe compound of claim 83.
160. A method for treating an ulcer in an animal, comprising administering to an animal in need thereof an effective amount ofthe compound or a pharmaceutically acceptable salt ofthe compound of claim 100.
161. A method foi treating an ulcer in an animal, comprising administering to an animal in need thereof an effective amontit ofthe compound or a pharmaceutically • acceptable salt ofthe compound of claim 101.
5 162. A method for treating irritable-bowel syndrome in an animal, comprising administering to an animal in need thereof an effective amount of the compound . or a pharmaceutically acceptable salt ofthe compound of claim 1.
163. A method for treating irritable-bowel syndrome in an animal, 0 comprising administering to an animal in need thereof an effective amount ofthe compoimd or a phannaceutically acceptable salt ofthe compound of claim 19.
164. A method for treating irritable-bowel syndrome in an animal, comprising administering to an animal in need thereof an effective amount ofthe compound VX cr a pharmaceuti cally acceptable salt of the compound of claim 21.
165. A method for treating irritable-bowel syndrome in an animal, I comprising administering to an animal in need thereof an effective amount of die compound ;' :. or a pharmaceutically acceptable salt ofthe compound of claim 22. 0
166. A method for treating irritable-bowel syndrome in an animal, comprising administering to an animal in need thereof an effective amount ofthe compoimd or a phamiaceutically acceptable salt ofthe compound of claim 23.
5 167. A method for treating irritable-bowel syndrome in an animal, comprising administering to an animal in need thereof an effective amount ofthe compound or a pharmaceutically acceptable salt of the compound of claim 41.
168. A method for treating irritable-bowel syndrome in an animal, 0 comprising administering to an animal in need thereof an effective amoimt ofthe compound ... or a pharmaceutically acceptable salt of the compound of claim 42.
.
169. A method for treating irritable-bowel syndrome in an animal, comprising administering to an animal in. need thereof an effective amount of the compound or a pharmaceutically acceptable salt ofthe compound of claim 60.
170. A method for treating irritable-bowel syndrome in an animal, comprising administering to an animal in need thereof an effective amoimt ofthe compound or a pharmaceutically acceptable salt ofthe compound of claim 62.
171. A method for treating irritable- owel syn drome in an animal, comprising administering to an animal in need thereof an effective amount ofthe compound or a pharmaceutically acceptable salt ofthe compound of claim 63.
172. A method for treating irritable-bowel syndrome in an animal, comprising administering to an animal in need thereof an effective amount of the compoundi or a pharmaceutically acceptable salt ofthe compound of claim 64.
173. A method for treating i itable-bowel syndrome in an animal, :-, comprising administering to an animal in need thereof an effective amount ofthe compound- or a pharmaceutically acceptable salt ofthe compound of claim 82. ;
174; A method for treating irritable-bowel syndrome in an animal, comprising administering to an animal in need thereof an effective amount ofthe compound or a phaimaceutically acceptable salt of the compound of claim 83.
175. , A method for treating hritable-bowel syndrome in an animal, comprising administering to an animal in need thereof an effective amount ofthe compound or a pharmaceutically acceptable salt ofthe compound of claim 100.
176. A method for treating irritable-bowel syndrome in an animal, comprising admimstering to an animal in need thereof an effective amoxmt ofthe compound or a pharm aceutically acceptable salt of the compound of claim 101.
177. A method for treating inflammatory-bowel disease in an animal, comprising administering to an animal in need thereof an effective amount of the compound or a phannaceutically acceptable salt of the compound of claim 1.
178. A method for treating inflammatory-bowel disease in an animal, comprising administering to an animal in need thereof an effective amount ofthe compound or a pharmaceutically acceptable salt ofthe compound of claim 19.
179. A method for treating inflammatory-bowel disease in an animal, comprising administering to an animal in need thereof an effective amount ofthe compound " . or a pharmaceutically acceptable salt ofthe compound of claim 21. ' ■
180. A method for treating inflammatory-bowel disease in an animal, x comprising administering to an animal in need thereof an effective amount ofthe compound or a pharmaceutically acceptable salt ofthe compound of claim 22, v
181. A method for treating inflammatory-bowel disease in an animal, con. prising administering to an animal in need thereof an effective amoimt ofthe compomid or a pharmaceutically acceptable salt of the compound of claim 23.
182. A method for treating inflanimatoiy-bowel disease in an animal, comprising administering to an animal in need thereof an effective amoimt ofthe compound •; or a pharmaceutically acceptable salt of the compound of claim 41. • .
183. A method for treating inflammatory-bowel disease in an animal, comprising administering to an animal in need thereof an effective amount ofthe compound or a pharmaceutically accepxable salt ofthe compound of claim 42.
184. A method for treating inflammatory-bowel disease in an animal, comprising administering to an animal, in need thereof an effective amount ofthe compound or a pharmaceutically acceptable salt ofthe compound of claim 60.
185. A method for treating inflammatory-bowel disease in an animal, comprising administering to an animal in need thereof an effective amount ofthe compound or a pharmaceutically acceptable salt ofthe compound of claim 62.
186. A method for treating inflammatory-bowel disease in an animal, comprising administering to an animal in need thereof an effective amount ofthe compound, or a phannaceutically acceptable salt ofthe compound of claim 63.
187. A method for heating inflammatory -bowel disease in an animal, -.;; comprising administering to an animal in need thereof an effective amount ofthe compound or a pharmaceutically acceptable salt of the compound of claim 64. .:
188. A method for treating inflammatory-bowel disease in an animal, ,, comprising administering to an animal in need thereof an effective amount ofthe compound or a pharmaceutically acceptable salt ofthe compound of claim 82. .«,
189: A method for treating inflammatory-bowel disease in an animal, comprising administering to an animal in need thereof an effective amount of the compound or a pharmaceutically acceptable salt ofthe compound of claim 83.
190. A method for treating inflammatory-bowel disease in an animal, comprising administering to an animal in need thereof an effective amount ofthe compoimd or a pharmaceutically acceptable salt ofthe compoimd of claim 100.
191. A method for treating inflammatory-bowel disease in an animal, comprising administering to an animal in need thereof an effective amount ofthe compound or a phannaceutically acceptable salt ofthe compomid of claim 101.
192. A method for inhibiting VRl function in a cell, comprising contacting a cell capable of expressing VRl with an effective amount ofthe compound or a pharmaceutically acceptable salt of the compound of claim 1.
193. A method for inhibiting VRl function in a cell, comprising contacting a cell capable of expressing VRl with an effective amount ofthe compound or a pharmaceutically acceptable salt ofthe compound of claim 19.
194. A method for inhibiting VRl function in. a cell, comprising contacting a cell capable of expressing V 1 with an effective amount ofthe compound or a X pharmaceutically acceptable salt of the compound of claim 21. *?
1 5. A method for inhibiting VRi function in a cell, comprising contacting a cell capable of expressing VRl with an effective amount ofthe compound or a ";• pharmaceutically acceptable salt ofthe compound of claim 22. ; ,<
196. A method for inhibiting VRl function in a cell, comprising contacting a cell capable of expressing VRl with an effective amoimt ofthe compound or a pharmaceutically acceptable salt ofthe compound of claim 23.
197. A method for inhibiting VRl function in. a cell, comprising contacting a cell capable of expressing VRl with an effective amount ofthe compound or a pharmaceutically acceptable salt ofthe compound of claim 41.
198. A method for inhibiting VRl function in. a cell, comprising contacting a cell capable of expressing VRl with an effective amomit oi* the compound or a pharmaceutically acceptable salt ofthe compoimd of claim 42.
199. A method for inhibiting VRl function in a cell, comprising contacting a cell capable of expressing VRl with an effective amoimt ofthe compoimd or a phaimaceutically acceptable salt ofthe compound of claim 60.
200. A. method for inhibiting VRl function in a cell, comprising contacting a cell capable of expressing VRl with an effective amount ofthe compound or a pharmaceutically acceptable salt ofthe compound of claim 62.
201. A. method for inhibiting VRl function in a cell, comprising contacting a cell capable of expressing VRl with an effective amount ofthe compound or a pharmaceutically acceptable salt ofthe compound of claim 63.
202. A method for inhibiting VRl function in a cell, comprising contacting a cell capable of expressing VRl. with an effective amount ofthe compound or a pharmaceutically acceptable salt of the compound of claim 64. ;'.
203. A method for inhibiting VRl function in a cell, comprising contacting a cell capable of expressing VRl with an effective amoimt ofthe compoimd or a . - ■> • ■ phaimaceutically acceptable salt ofthe compound of claim 82. - ;χ
204. A method for inhibiting VRl function in a cell, comprising contacting a cell capable of expressing VRl with an effective amount ofthe compound or a phamiaceutically acceptable salt ofthe compoimd of claim. 83.
205. A method for inhibiting VRl function in a cell, comprising contacting a cell capable of expressing VRl with an effective amoimt ofthe compound or a pharmaceutically acceptable salt of the compound of claim 100.
206. A method for inhibiting VRl function in a cell, comprising contacting a cell capable of expressing VRl with an effective amount ofthe compound or a phannaceutically acceptable salt ofthe compound of claim 101.
207. A kit comprising a container containing an effective amount of a compc und or a pharmaceutically acceptable salt of the compound of claim 1.
208. A kit comprising a container containing an effective amount of a compoimd or a phannaceutically acceptable salt of the compound of claim 19.
209. A kit comprising a container containing an effective amount of a compound or a pharmaceutically acceptable salt of the compoimd of claim 21.
210. A kit comprising a container containing an effective amount of a */ compound or a pharmaceutically acceptable salt, ofthe compound of claim 22. • •-:, ;-iS ft
211. A kit comprising a. container containing an effective amount of a , :. ; compound or a phaimaceutically acceptable salt of the compoimd of claim 23.
212. A kit comprising a container containing an effective amoimt of a » compound or a pharmaceutically acceptable salt of the compound of claim 41.
213. A kit comprising a container containing an effective amount of a compound or 3 phannaceutically acceptable salt ofthe compound of claim 42.
214. A lcit comprising a container containing an effective amount of a compound or a pharmaceutically acceptable salt ofthe compound of claim 60.
215. A kit comprising a container containing an effective amount of a compound or a pharmaceutically acceptable salt ofthe compoimd of claim 62.
216. A kit comprising a container containing an effective amount of a compound or a pharmaceutically acceptable salt ofthe compound of claim 63.
217. A kit comprising a container contaimng an effective amount of a 5 compound or a pharmaceutically acceptable salt ofthe compound of claim 64.
218. A kit comprising a container containing an effective amount of a compound or a pharmaceutically acceptable salt ofthe compound of claim 82.
10 219. A kit comprising a container containing an effective amount of a compound or a pharmaceutically acceptable salt ofthe compoimd of claim 83.
220. A kit comprising a container containing an effective amount of a compound or a pharmaceutically acceptable salt ofthe compound of claim 100. X ,
■ 15 • • 'l
221. A kit comprising a container containing an effective amount of a ;- compound or a pharmaceutically acceptable salt ofthe compound of claim 101. X,
222. A method for preparing a composition, the method comprising ■, ;: 20 admixing a compound or a pharmaceutically acceptable salt ofthe compound of claim 1 and a pharmaceutically acceptable canier or excipient.
223. A method for preparing a composition, the method comprising admixing a compoimd or a pharmaceutically acceptable salt ofthe compound of claim 19 and
25 a hannaceutically acceptable carrier or excipient.
224. A method for preparing a composition, the method comprising admixing a compound or a phannaceutically acceptable salt ofthe compoimd of claim 21 and a pharmaceutically acceptable carrier or excipient.
30
225. A method for preparing a composition, the method comprising admixing a compound or a phannaceutically acceptable salt ofthe compound of claim 22 and a pharmaceutically acceptable carrier or excipient.
5 226. A method for preparing a composition, the method comprising admixing a compound or a pharmaceutically acceptable salt ofthe compound of claim 23 and a pharmaceutically acceptable carrier or excipient.
227. A method for preparing a composition, the method comprising
10 admixing a compound or a pharmaceutically acceptable salt of the compound of claim 41 and- a pharmaceutically acceptable carrier or excipient.
228. A method for preparing a composition, the method comprising admixing a compound or a pharmaceutically acceptable salt of the compound of claim 42 and
1.5 a phannaceutically acceptable carrier or excipient. ' ■ • '^"* ■
,
229. A method for preparing a composition, the method comprising r: admixing a compound or a pharmaceutically acceptable salt ofthe compound of claim 60 and a pharrnaceutically acceptable carrier or excipient. ,. •
20 , .
230. A method for preparing a composition, the method comprising admixing a compound or a phaimaceutically acceptable salt ofthe compomid of claim 62 and , a pharmaceutically acceptable carrier or excipient.
25 231. A method for preparing a composition, the method comprising admixing a compoimd or a pharmaceutically acceptable salt o he compomid of claim 63 and a pharmaceutically acceptable carrier or excipient.
232. A method for preparing a composition, the method comprising 30 admixing a compound or a pharmaceutically acceptable salt ofthe compound of claim 64 and pharmaceutically acceptable carrier oi excipient.
233. A method for preparing a composition, the method comprising acbiixing a compound or a pharmaceutically acceptable salt ofthe compound of claim 82 and a pharmaceutically acceptable carrier or excipient.
234. A method for preparing a composition, the method comprising admixing a compound or a pharmaceutically acceptable salt ofthe compound of claim 83 and a pharmaceutically acceptable carrier or excipient.
235. A method for preparing a composition, the method comprising admixing a compound or a pharmaceutically acceptable salt ofthe compoimd of claim 100 and a pharmaceutically acceptable canier or excipient.
236. A method for preparing a composition, the method comprising admixing a compound or a pharmaceutically acceptable salt ofthe compound of claim" 101 and a pharmaceutically acceptable carrier or excipient.
PCT/US2003/020509 2002-06-28 2003-06-27 Therapeutic piperazine derivatives useful for treating pain WO2004002983A2 (en)

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EP03762220A EP1556354B1 (en) 2002-06-28 2003-06-27 Therapeutic piperazine derivates useful for treating pain
NZ537292A NZ537292A (en) 2002-06-28 2003-06-27 Therapeutic piperazine derivatives useful for treating pain
IL16586203A IL165862A0 (en) 2002-06-28 2003-06-27 Therapeutic piperazine derivatives useful for tre ating pain
SI200331175T SI1556354T1 (en) 2002-06-28 2003-06-27 Therapeutic piperazine derivates useful for treating pain
EA200500114A EA200500114A1 (en) 2002-06-28 2003-06-27 THERAPEUTIC AGENTS USED FOR THE TREATMENT OF PAINS
BR0312322-7A BR0312322A (en) 2002-06-28 2003-06-27 Compounds, compositions, methods for the treatment of pain in an animal, urinary incontinence in an animal, an ulcer in an animal, irritable bowel syndrome in an animal, inflammatory bowel disease in an animal, methods for inhibition of vr1 function in a cell, kits and methods for preparing a composition
YU114804A RS114804A (en) 2002-06-28 2003-06-27 Therapeutic agents useful for treating pain
AU2003247829A AU2003247829A1 (en) 2002-06-28 2003-06-27 Therapeutic piperazine derivatives useful for treating pain
MXPA04012748A MXPA04012748A (en) 2002-06-28 2003-06-27 Therapeutic piperazine derivatives useful for treating pain.
DK03762220T DK1556354T3 (en) 2002-06-28 2003-06-27 Therapeutic piperazine derivatives suitable for the treatment of pain
DE60318875T DE60318875T2 (en) 2002-06-28 2003-06-27 Therapeutic piperazine derivatives for the treatment of pain
CA2491079A CA2491079C (en) 2002-06-28 2003-06-27 Therapeutic piperazine derivatives useful for treating pain
JP2004549842A JP4621502B2 (en) 2002-06-28 2003-06-27 A therapeutic agent useful for the treatment of pain
NO20050371A NO20050371L (en) 2002-06-28 2005-01-24 Therapeutic piperazine derivatives suitable for pain management
HK06101088A HK1082730A1 (en) 2002-06-28 2006-01-24 Therapeutic piperazine derivatives useful for treating pain

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US41103002P 2002-09-17 2002-09-17
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US41314802P 2002-09-25 2002-09-25
US60/413,148 2002-09-25
US41658202P 2002-10-08 2002-10-08
US60/416,582 2002-10-08

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