# Patent

## Title
Therapeutic agents useful for treating pain

## Abstract

The present invention discloses a compound of formula:




where Ar1, Ar2, X, Z1, Z2, R3, and m are as disclosed herein or a pharmaceutically acceptable salt thereof (a “Pyridylene Compound”); compositions comprising an effective amount of a Pyridylene Compound; and methods for treating or preventing pain or other conditions in an animal comprising administering to an animal in need thereof an effective amount of a Pyridylene Compound.

## Background
This application is a continuation of and claims the benefit of International patent application no. PCT/US2004/030825, filed Sep. 21, 2004, which claims the benefit of U.S. provisional application No. 60/504,730, filed Sep. 22, 2003, the disclosure of each application being incorporated by reference herein in its entirety.


1. FIELD OF THE INVENTION
The present invention relates to Pyridylene Compounds, compositions comprising an effective amount of a Pyridylene Compound and methods for treating or preventing a Condition such as pain comprising administering to an animal in need thereof an effective amount of a Pyridylene 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 and F. 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 mGluRs (mGluR1 and mGluR5) (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 mGluR1 or mGluR5 reduces pain, as shown by in vivo treatment with antibodies selective for either mGluR1 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 mGluR1 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, Biochemistry & 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, diflusinal, 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, phenyloin), NMDA antagonists (e.g., ketamine, dextromethorphan), topical lidocaine (for post-herpetic neuralgia), and tricyclic antidepressants (e.g., fluoxetine, sertraline and amitriptyline).
Pain has been traditionally managed by administering non-opioid analgesics, such as acetylsalicylic acid, choline magnesium trisalicylate, acetaminophen, ibuprofen, fenoprofen, diflusinal, and naproxen; or opioid analgesics, including morphine, hydromorphone, methadone, levorphanol, fentanyl, oxycodone, and oxymorphone. Id.
Urinary incontinence (“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. 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. 22:557-577 (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 of the existing commercial drug treatments for UI 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).
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 drugs 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 H2 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. H+, 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. Ingestion of bismuth compounds, however, can lead to elevated plasma concentrations of Bi+3 and can interfere with the absorption of other drugs.
Prostaglandin analogues, such as misoprostal, inhibit secretion of acid and stimulate the secretion of mucous and bicarbonate and are also used to treat ulcers, especially ulcers in patients who require nonsteroidal anti-inflammatory drugs. Effective oral doses of prostaglandin analogues, however, can cause diarrhea and abdominal cramping. In addition, some prostaglandin analogues are abortifacients.
Carbenoxolone, a mineral corticoid, 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 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).
Inflammatory-bowel disease (“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 of the intestinal wall. Crohn's disease occurs equally in both sexes and is more common in Jews of eastern-European ancestry. Most cases of Crohn's disease begin before age 30 and the majority start between the ages of 14 and 24. The disease typically affects the full thickness of the intestinal wall. Generally the disease affects the lowest portion of the small intestine (ileum) and the large intestine, but can occur in any part of the digestive tract.
Early symptoms of Crohn's disease are chronic diarrhea, crampy abdominal pain, fever, loss of appetite, and weight loss. Complications associated with Crohn's disease include the development of intestinal obstructions, abnormal connecting channels (fistulas), and abscesses. The risk of cancer of the large intestine is increased in people who have Crohn's disease. 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 drug 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 of the 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 of the intestine. Surgery, however, does not cure the disease, and inflammation tends to recur where the intestine is rejoined. In 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 of the intestine. The disease usually begins in the rectum and the sigmoid colon and eventually spreads partially or completely throughout 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.
Irritable-bowel syndrome (“IBS”) is a disorder of motility of the entire gastrointestinal tract, causing abdominal pain, constipation, and/or diarrhea. IBS affects three-times more men than women.
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 of the 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).
Certain pharmaceutical agents have been administered for treating addiction. U.S. Pat. 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. Pat. No. 5,574,052 to Rose et al. discloses co-administration of an addictive substance with an antagonist to partially block the pharmacological effects of the addictive substance. U.S. Pat. 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. Pat. No. 5,232,934 to Downs discloses administration of 3-phenoxypyridine to treat addiction. U.S. Pat. Nos. 5,039,680 and 5,198,459 to Imperato et al. disclose using a serotonin antagonist to treat chemical addiction. U.S. Pat. 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. Pat. 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. Pat. No. 6,204,284 to Beer et al. discloses racemic (±)-1-(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.
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 drugs 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. 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. Examples of drugs for treating a seizure and epilepsy include carbamazepine, ethosuximide, gabapentin, lamotrigine, phenobarbital, phenyloin, primidone, valproic acid, trimethadione, benzodiazepines, 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 hyperplasia; gastrointestinal disturbances such as nausea, vomiting, epigastric pain, and anorexia; endocrine effects such as inhibition of antidiuretic hormone, hyperglycemia, glycosuria, osteomalacia; and hypersensitivity such as scarlatiniform rash, morbilliform rash, Stevens-Johnson syndrome, systemic lupus erythematosus, and hepatic necrosis; and hematological reactions such as red-cell aplasia, agranulocytosis, thrombocytopenia, aplastic anemia, and megaloblastic anemia. The Merck Manual of Medical Information 345-350 (R. Berkow ed., 1997).
Symptoms of strokes vary depending on what part of the brain is affected. Symptoms include loss or abnormal sensations in an arm or leg or one side of the body, weakness or paralysis of an arm or leg or one side of the body, partial loss of vison or hearing, double vision, dizziness, slurred speech, difficulty in thinking of the appropriate word or saying it, inability to recognize parts of the 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. Examples of drugs for treating strokes include anticoagulants such as heparin, drugs that break up clots such as streptokinase or tissue plasminogen activator, and drugs that reduce swelling such as mannitol or corticosteroids. The Merck Manual of Medical Information 352-355 (R. Berkow ed., 1997).
Pruritus is an unpleasant sensation that prompts scratching. 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 of the 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 of the 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 of the 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 of the mGluR5 receptor have also been shown to exert anti-dependence activity in vivo (C. Chiamulera et al., Nature Neuroscience 4(9):873-74 (2001)).
U.S. Pat. No. 6,495,550 to McNaughton-Smith et al. discloses pyridine substituted benzanilides useful as openers of potassium ion channels.
International publication no. WO 94/05153 discloses substituted benzene compounds useful as herbicides.
International publication no. WO 04/058762 discloses substituted 9-membered bicyclic compounds useful as MK-2 inhibitors.
United Kingdom Application No. GB 2 276 162 discloses aniline and benzanilide compounds useful for treating disorders of the central nervous system, endocrine disorders, and sexual dysfunction.
United Kingdom Application No. GB 2 276 163 discloses pyridine compounds useful for treating disorders of the central nervous system, endocrine disorders, and sexual dysfunction.
European Application No. EP 533267 discloses benzanilide compounds useful as 5-HT1D antagonists.
There remains a need in the art for compounds 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, amyotrophic lateral sclerosis, dementia, retinopathy, a muscle spasm, a migraine, vomiting, dyskinesia, or depression in an animal.
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 of formula (I):




and pharmaceutically acceptable salts thereof, where

Ar1 is




Ar2 is




X is O or S;
R1 is -halo, —CH3, —C(halo)3, —CH(halo)2, or —CH2(halo);
each R2 is independently:

    
    
        (a) -halo, —OH, —NH2, —CN, or —NO2;
        (b) —(C1-C10)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, -(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 R3 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, —(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
        (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 R5 is independently —CN, —OH, —(C1-C6)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 R6 is independently —(C1-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, 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 R7 is independently —H, —(C1-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 —(C1-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, —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 R11 is independently —(C1-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, —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, —Cl, —Br, or —I;
m is an integer ranging from 0 to 3;
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; and
s is an integer ranging from 0 to 4.
The invention further encompasses compounds of formula (II):




and pharmaceutically acceptable salts thereof, where

Ar1 is




Ar2 is




X is O or S;
R1 is -halo, —CH3, —C(halo)3, —CH(halo)2, or —CH2(halo);
each R2 is independently:

    
    
        (a) -halo, —OH, —NH2, —CN, or —NO2;
        (b) —(C1-C10)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, -(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 R3 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, —(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
        (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 R5 is independently —CN, —OH, —(C1-C6)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 R6 is independently —(C1-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, 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 R7 is independently —H, —(C1-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 —(C1-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, —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 R11 is independently —(C1-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, —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, —Cl, —Br, or —I;
m is an integer ranging from 0 to 3;
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; and
s is an integer ranging from 0 to 4.
A compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof (a “Pyridylene 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 Pyridylene 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 Pyridylene Compound.
The invention further relates to methods for preventing a Condition, comprising administering to an animal in need thereof an effective amount of a Pyridylene Compound.
The invention still further relates to methods for inhibiting Vanilloid Receptor 1 (“VR1”) function in a cell, comprising contacting a cell capable of expressing VR1 with an effective amount of a Pyridylene 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 Pyridylene Compound.
The invention still further relates to methods for inhibiting metabotropic glutamate receptor 1 (“mGluR1”) function in a cell, comprising contacting a cell capable of expressing mGluR1 with an effective amount of a Pyridylene Compound.
The invention still further relates to methods for preparing a composition, comprising the step of admixing a Pyridylene 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 Pyridylene Compound.
The present invention can be understood more fully by reference to the following detailed description and illustrative examples, which are intended to exemplify non-limiting embodiments of the invention.


4. DETAILED DESCRIPTION OF THE INVENTION
4.1 Pyridylene Compounds of Formula (I)
As stated above, the present invention encompasses compounds of Formula (I)




    
    
        (I)

and pharmaceutically acceptable salts thereof, where Ar1, Ar2, R3, X, and m are defined above for the Pyridylene Compounds of formula (I).

    
    


In one embodiment, Art is a pyridyl group;
In another embodiment, Ar1 is a pyrimidinyl group.
In another embodiment, Ar1 is a pyrazinyl group.
In another embodiment, Ar1 is a pyridazinyl group.
In another embodiment, Ar1 is a thiadiazolyl group.
In another embodiment, X is O.
In another embodiment, X is S.
In another embodiment, Ar2 is a benzoimidazolyl group.
In another embodiment, Ar2 is a benzothiazolyl group.
In another embodiment, Ar2 is a benzooxazolyl group.
In another embodiment, Ar2 is




In another embodiment, Ar2 is




In another embodiment, Ar2 is




In another embodiment, Ar2 is




In another embodiment, m is 0.
In another embodiment, m is 1.
In another embodiment, m is 2.
In another embodiment, m is 3.
In another embodiment, p is 0.
In another embodiment, p is 1.
In another embodiment, p is 2.
In another embodiment, n is 0.
In another embodiment, n is 1.
In another embodiment, n is 2.
In another embodiment, n is 3.
In another embodiment, o is 0.
In another embodiment, o is 1.
In another embodiment, o is 2.
In another embodiment, o is 3.
In another embodiment, o is 4.
In another embodiment, q is 0.
In another embodiment, q is 1.
In another embodiment, q is 2.
In another embodiment, q is 3.
In another embodiment, q is 4.
In another embodiment, q is 5.
In another embodiment, q is 6.
In another embodiment, r is 0.
In another embodiment, r is 1.
In another embodiment, r is 2
In another embodiment, r is 3
In another embodiment, r is 4
In another embodiment, r is 5
In another embodiment, s is 0.
In another embodiment, s is 1.
In another embodiment, s is 2.
In another embodiment, s is 3.
In another embodiment, s is 4.
In another embodiment, R1 is -halo.
In another embodiment, R1 is —Cl.
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, R1 is —C(halo)3.
In another embodiment, R1 is —CH(halo)2.
In another embodiment, R1 is —CH2(halo).
In another embodiment, n or p is 1 and R2 is -halo, —OH, —NH2, —CN, or —NO2.
In another embodiment, n or p is 1 and R2 is —(C1-C10)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, -(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, n or p is 1 and R2 is -phenyl, -naphthyl, —(C14)aryl or -(5- to 10-membered)heteroaryl, each of which is unsubstituted or substituted with one or more R6 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 -(C1-C10)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, -(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, m is 1 and R3 is -phenyl, -naphthyl, —(C14)aryl or -(5- to 10-membered)heteroaryl, each of which is unsubstituted or substituted with one or more R6 groups.
In another embodiment, m is 1 and R3 is —(C1-C10)alkyl.
In another embodiment, m is 1 and R3 is —CH3.
In another embodiment, m is 1 and R3 is -halo.
In another embodiment, m is 1 and R3 is —Cl.
In another embodiment, m is 1 and R3 is —Br.
In another embodiment, m is 1 and R3 is —I.
In another embodiment, m is 1 and R3 is —F.
In another embodiment, Ar2 is a benzothiazolyl group and s is 1.
In another embodiment, Ar2 is a benzoimidazolyl group and s is 1.
In another embodiment, Ar2 is a benzooxazolyl group and s is 1.
In another embodiment, Ar2 is




and o is 1.

In another embodiment, Ar2 is




and o is 1.

In another embodiment, Ar2 is




and q is 1.

In another embodiment, Ar2 is




and r is 1.

In another embodiment, Ar2 is a benzothiazolyl group, s is 1, and R8 is -halo or —(C1-C6)alkyl.
In another embodiment, Ar2 is a benzoimidazolyl group, s is 1, and R8 is -halo or —(C1-C6)alkyl.
In another embodiment, Ar2 is a benzooxazolyl group, s is 1, and R8 is -halo or —(C1-C6)alkyl.
In another embodiment, Ar2 is




o is 1, and R8 is -halo or —(C1-C6)alkyl.

In another embodiment, Ar2 is




o is 1, and R8 is -halo or —(C1-C6)alkyl.

In another embodiment, Ar2 is




r is 1, and R8 is -halo or —(C1-C6)alkyl.

In another embodiment, Ar2 is




q is 1, and R11 is -halo or —(C1-C6)alkyl.

In another embodiment, Ar2 is




r is 1, and R8 is at the para-position of the phenyl ring.

In another embodiment, Ar1 is a pyridyl group, X is O, m is 0, and Ar2 is a benzothiazolyl group.
In another embodiment, Ar1 is a pyridyl group, X is O, m is 0, and Ar2 is a benzooxazolyl group.
In another embodiment, Ar1 is a pyridyl group, X is O, m is 0, and Ar2 is a benzoimidazolyl group.
In another embodiment, Ar1 is a pyridyl group, X is O, m is 0, and Ar2 is




In another embodiment, Ar1 is a pyridyl group, X is O, m is 0, and Ar2 is




In another embodiment, Ar1 is a pyridyl group, X is O, m is 0, Ar2 is




and R8 is a —(C1-C6)alkyl. In another embodiment, r is 1, the —(C1-C6)alkyl is substituted at the phenyl group's para-position. In another embodiment, r is 1, the —(C1-C6)alkyl is a tert-butyl group. In another embodiment, r is 1, the —(C1-C6)alkyl is a tert-butyl group and is substituted at the phenyl group's para-position. In another embodiment, r is 1, the —(C1-C6)alkyl is an iso-propyl group. In another embodiment, the —(C1-C6)alkyl is a iso-propyl group and is substituted at the phenyl group's para-position.

In another embodiment, Ar1 is a pyridyl group, X is O, m is 0, Ar2 is




r is 1, and R8 is —CF3. In another embodiment, r is 1 and the —CF3 is substituted at the phenyl group's para-position.

In another embodiment, Ar1 is a pyridyl group, X is O, m is 0, Ar2 is




r is 1, and R8 is -halo. In another embodiment, r is 1 and the -halo is substituted at the phenyl group's para-position. In another embodiment, r is 1 and -halo is —Cl. In another embodiment, r is 1 and -halo is —Cl and is substituted at the phenyl group's para-position. In another embodiment, r is 1 and -halo is —Br. In another embodiment, r is 1 and -halo is —Br and is substituted at the phenyl group's para-position. In another embodiment, r is 1 and -halo is —I. In another embodiment, r is 1 and -halo is —I and is substituted at the phenyl group's para-position. In another embodiment, r is 1 and -halo is —F. In another embodiment, r is 1 and -halo is —F and is substituted at the phenyl group's para-position.

In another embodiment, Ar1 is a pyrazinyl group, X is O, m is 0, and Ar2 is a benzothiazolyl group.
In another embodiment, Ar1 is a pyrazinyl group, X is O, m is 0, and Ar2 is a benzooxazolyl group.
In another embodiment, Ar1 is a pyrazinyl group, X is O, m is 0, and Ar2 is a benzoimidazolyl group.
In another embodiment, Ar1 is a pyrazinyl group, X is O, m is 0, and Ar2 is




In another embodiment, Ar1 is a pyrazinyl group, X is O, m is 0, and Ar2 is




In another embodiment, Ar1 is a pyrazinyl group, X is O, m is 0, Ar2 is




r is 1, and R8 is a —(C1-C6)alkyl. In another embodiment, r is 1 and the —(C1-C6)alkyl is substituted at the phenyl group's para-position. In another embodiment, r is 1 and the —(C1-C6)alkyl is a tert-butyl group. In another embodiment, r is 1, the —(C1-C6)alkyl is a tert-butyl group, and is substituted at the phenyl group's para-position. In another embodiment, r is 1 and the —(C1-C6)alkyl is an iso-propyl group. In another embodiment, r is 1, the —(C1-C6)alkyl is a iso-propyl group and is substituted at the phenyl group's para-position.

In another embodiment, Ar1 is a pyrazinyl group, X is O, m is 0, Ar2 is




r is 1, and R8 is —CF3. In another embodiment, the —CF3 is substituted at the phenyl group's para-position.

In another embodiment, Ar1 is a pyrazinyl group, X is O, m is 0, Ar2 is




r is 1, and R8 is -halo. In another embodiment, r is 1 and the -halo is substituted at the phenyl group's para-position. In another embodiment, r is 1 and -halo is —Cl. In another embodiment, r is 1 and -halo is —Cl and is substituted at the phenyl group's para-position. In another embodiment, r is 1 and -halo is —Br. In another embodiment, r is 1 and -halo is —Br and is substituted at the phenyl group's para-position. In another embodiment, r is 1 and -halo is —I. In another embodiment, r is 1, -halo is —I and is substituted at the phenyl group's para-position. In another embodiment, r is 1 and -halo is —F. In another embodiment, r is 1, -halo is —F and is substituted at the phenyl group's para-position.

In another embodiment, Ar1 is a pyrimidinyl group, X is O, m is 0, and Ar2 is a benzothiazolyl group.
In another embodiment, Ar1 is a pyrimidinyl group, X is O, m is 0, and Ar2 is a benzooxazolyl group.
In another embodiment, Ar1 is a pyrimidinyl group, X is O, m is 0, and Ar2 is a benzoimidazolyl group.
In another embodiment, Ar1 is a pyrimidinyl group, X is O, m is 0, and Ar2 is




In another embodiment, Ar1 is a pyrimidinyl group, X is O, m is 0, and Ar2 is




In another embodiment, Ar1 is a pyrimidinyl group, X is O, m is 0, Ar2 is




r is 1, and R8 is a —(C1-C6)alkyl. In another embodiment, r is 1 and the —(C1-C6)alkyl is substituted at the phenyl group's para-position. In another embodiment, r is 1 and the —(C1-C6)alkyl is a tert-butyl group. In another embodiment, r is 1 and the —(C1-C6)alkyl is a tert-butyl group and is substituted at the phenyl group's para-position. In another embodiment, r is 1 and the —(C1-C6)alkyl is an iso-propyl group. In another embodiment, r is 1 and the —(C1-C6)alkyl is a iso-propyl group and is substituted at the phenyl group's para-position.

In another embodiment, Ar1 is a pyrimidinyl group, X is O, m is 0, Ar2 is




r is 1, and R8 is —CF3. In another embodiment, the —CF3 is substituted at the phenyl group's para-position.

In another embodiment, Ar1 is a pyrimidinyl group, X is O, m is 0, Ar2 is




r is 1, and R8 is -halo. In another embodiment, r is 1 and the -halo is substituted at the phenyl group's para-position. In another embodiment, r is 1 and -halo is —Cl. In another embodiment, r is 1 and -halo is —Cl and is substituted at the phenyl group's para-position. In another embodiment, r is 1 and -halo is —Br. In another embodiment, r is 1 and -halo is —Br and is substituted at the phenyl group's para-position. In another embodiment, r is 1 and -halo is —I. In another embodiment, r is 1 and -halo is —I and is substituted at the phenyl group's para-position. In another embodiment, r is 1 and -halo is —F. In another embodiment, r is 1 and -halo is —F and is substituted at the phenyl group's para-position.

In another embodiment, Ar1 is a pyridazinyl group, X is O, m is 0, and Ar2 is a benzothiazolyl group.
In another embodiment, Ar1 is a pyridazinyl group, X is O, m is 0, and Ar2 is a benzooxazolyl group.
In another embodiment, Ar1 is a pyridazinyl group, X is O, m is 0, and Ar2 is a benzoimidazolyl group.
In another embodiment, Ar1 is a pyridazinyl group, X is O, m is 0, and Ar2 is




In another embodiment, Ar1 is a pyridazinyl group, X is O, m is 0, and Ar2 is




In another embodiment, Ar1 is a pyridazinyl group, X is O, m is 0, Ar2 is




r is 1, and R8 is a —(C1-C6)alkyl. In another embodiment, r is 1 and the —(C1-C6)alkyl is substituted at the phenyl group's para-position. In another embodiment, r is 1 and the —(C1-C6)alkyl is a tert-butyl group. In another embodiment, r is 1 and the —(C1-C6)alkyl is a tert-butyl group and is substituted at the phenyl group's para-position. In another embodiment, r is 1 and the —(C1-C6)alkyl is an iso-propyl group. In another embodiment, r is 1 and the —(C1-C6)alkyl is a iso-propyl group and is substituted at the phenyl group's para-position.

In another embodiment, Ar1 is a pyridazinyl group, X is O, m is 0, Ar2 is




r is 1, and R8 is —CF3. In another embodiment, the —CF3 is substituted at the phenyl group's para-position.

In another embodiment, Ar1 is a pyridazinyl group, X is O, m is 0, Ar2 is




r is 1, and R8 is -halo. In another embodiment, r is 1 and the -halo is substituted at the phenyl group's para-position. In another embodiment, r is 1 and -halo is —Cl. In another embodiment, r is 1 and -halo is —Cl and is substituted at the phenyl group's para-position. In another embodiment, r is 1 and -halo is —Br. In another embodiment, r is 1 and -halo is —Br and is substituted at the phenyl group's para-position. In another embodiment, r is 1 and -halo is —I. In another embodiment, r is 1 and -halo is —I and is substituted at the phenyl group's para-position. In another embodiment, r is 1 and -halo is —F. In another embodiment, r is 1 and -halo is —F and is substituted at the phenyl group's para-position.

In another embodiment, Ar1 is a thiadiazolyl group, X is O, m is 0, and Ar2 is a benzothiazolyl group.
In another embodiment, Ar1 is a thiadiazolyl group, X is O, m is 0, and Ar2 is a benzooxazolyl group.
In another embodiment, Ar1 is a thiadiazolyl group, X is O, m is 0, and Ar2 is a benzoimidazolyl group.
In another embodiment, Ar1 is a thiadiazolyl group, X is O, m is 0, and Ar2 is




In another embodiment, Ar1 is a thiadiazolyl group, X is O, m is 0, Ar2 is




r is 1, and R8 is a —(C1-C6)alkyl. In another embodiment, r is 1 and the —(C1-C6)alkyl is substituted at the phenyl group's para-position. In another embodiment, r is 1 and the —(C1-C6)alkyl is a tert-butyl group. In another embodiment, r is 1 and the —(C1-C6)alkyl is a tert-butyl group and is substituted at the phenyl group's para-position. In another embodiment, r is 1 and the —(C1-C6)alkyl is an iso-propyl group. In another embodiment, r is 1 and the —(C1-C6)alkyl is a iso-propyl group and is substituted at the phenyl group's para-position.

In another embodiment, Ar1 is a thiadiazolyl group, X is O, m is 0, Ar2 is




r is 1, and R8 is —CF3. In another embodiment, the —CF3 is substituted at the phenyl group's para-position.

In another embodiment, Ar1 is a thiadiazolyl group, X is O, m is 0, Ar2 is




r is 1, and R8 is -halo. In another embodiment, r is 1 and the -halo is substituted at the phenyl group's para-position. In another embodiment, r is 1 and -halo is —Cl. In another embodiment, r is 1 and -halo is —Cl and is substituted at the phenyl group's para-position. In another embodiment, r is 1 and -halo is —Br. In another embodiment, r is 1 and -halo is —Br and is substituted at the phenyl group's para-position. In another embodiment, r is 1 and -halo is —I. In another embodiment, r is 1 and -halo is —I and is substituted at the phenyl group's para-position. In another embodiment, r is 1 and -halo is —F. In another embodiment, r is 1 and -halo is —F and is substituted at the phenyl group's para-position.

4.2 Pyridylene Compounds of Formula (II)
The invention also relates to Pyridylene Compounds of formula (II)




and pharmaceutically acceptable salts thereof, where Ar1, Ar2, X, R3, and m are defined above for the Pyridylene Compounds of formula (II).

In one embodiment, Ar1 is a pyridyl group;
In another embodiment, pyrimidinyl group.
In another embodiment, Ar1 is a pyrazinyl group.
In another embodiment, Ar1 is a pyridazinyl group.
In another embodiment, Ar1 is a thiadiazolyl group.
In another embodiment, X is O.
In another embodiment, X is S.
In another embodiment, Ar2 is a benzoimidazolyl group.
In another embodiment, Ar2 is a benzothiazolyl group.
In another embodiment, Ar2 is a benzooxazolyl group.
In another embodiment, Ar2 is




In another embodiment, Ar2 is




In another embodiment, Ar2 is




In another embodiment, Ar2 is




In another embodiment, m is 0.
In another embodiment, m is 1.
In another embodiment, m is 2.
In another embodiment, m is 3.
In another embodiment, p is 0.
In another embodiment, p is 1.
In another embodiment, p is 2.
In another embodiment, n is 0.
In another embodiment, n is 1.
In another embodiment, n is 2.
In another embodiment, n is 3.
In another embodiment, o is 0.
In another embodiment, o is 1.
In another embodiment, o is 2.
In another embodiment, o is 3.
In another embodiment, o is 4.
In another embodiment, q is 0.
In another embodiment, q is 1.
In another embodiment, q is 2.
In another embodiment, q is 3.
In another embodiment, q is 4.
In another embodiment, q is 5.
In another embodiment, q is 6.
In another embodiment, r is 0.
In another embodiment, r is 1.
In another embodiment, r is 2
In another embodiment, r is 3
In another embodiment, r is 4
In another embodiment, r is 5
In another embodiment, s is 0.
In another embodiment, s is 1.
In another embodiment, s is 2.
In another embodiment, s is 3.
In another embodiment, s is 4.
In another embodiment, R1 is -halo.
In another embodiment, R1 is —Cl.
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, R1 is —C(halo)3.
In another embodiment, R1 is —CH(halo)2.
In another embodiment, R1 is —CH2(halo).
In another embodiment, n or p is 1 and R2 is -halo, —OH, —NH2, —CN, or —NO2.
In another embodiment, n or p is 1 and R2 is —(C1-C10)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, -(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, n or p is 1 and R2 is -phenyl, -naphthyl, —(C14)aryl or -(5- to 10-membered)heteroaryl, each of which is unsubstituted or substituted with one or more R6 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 —(C1-C10)alkyl, —(C2-C10)alkenyl, —(C2-C10)alkynyl, —(C3-C10)cycloalkyl, —(C8-C4)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.
In another embodiment, m is 1 and R3 is -phenyl, -naphthyl, —(C14)aryl or -(5- to 10-membered)heteroaryl, each of which is unsubstituted or substituted with one or more R6 groups.
In another embodiment, m is 1 and R3 is —(C1-C10)alkyl.
In another embodiment, m is 1 and R3 is —CH3.
In another embodiment, m is 1 and R3 is -halo.
In another embodiment, m is 1 and R3 is —Cl.
In another embodiment, m is 1 and R3 is —Br.
In another embodiment, m is 1 and R3 is —I.
In another embodiment, m is 1 and R3 is —F.
In another embodiment, Ar2 is a benzothiazolyl group and s is 1.
In another embodiment, Ar2 is a benzoimidazolyl group and s is 1.
In another embodiment, Ar2 is a benzooxazolyl group and s is 1.
In another embodiment, Ar2 is




and o is 1.

In another embodiment, Ar2 is




and o is 1.

In another embodiment, Ar2 is




and q is 1.

In another embodiment, Ar2 is




and r is 1.

In another embodiment, Ar2 is a benzothiazolyl group, s is 1, and R8 is -halo or —(C1-C6)alkyl.
In another embodiment, Ar2 is a benzoimidazolyl group, s is 1, and R8 is -halo or —(C1-C6)alkyl.
In another embodiment, Ar2 is a benzooxazolyl group, s is 1, and R8 is -halo or —(C1-C6)alkyl.
In another embodiment, Ar2 is




o is 1, and R8 is -halo or —(C1-C6)alkyl.

In another embodiment, Ar2 is




o is 1, and R8 is -halo or —(C1-C6)alkyl.

In another embodiment, Ar2 is




r is 1, and R8 is -halo or —(C1-C6)alkyl.

In another embodiment, Ar2 is




q is 1, and R11 is -halo or —(C1-C6)alkyl.

In another embodiment, Ar2 is




r is 1, and R8 is at the para-position of the phenyl ring.

In another embodiment, Ar1 is a pyridyl group, X is O, m is 0, and Ar2 is a benzothiazolyl group.
In another embodiment, Ar1 is a pyridyl group, X is O, m is 0, and Ar2 is a benzooxazolyl group.
In another embodiment, Ar1 is a pyridyl group, X is O, m is 0, and Ar2 is a benzoimidazolyl group.
In another embodiment, Ar1 is a pyridyl group, X is O, m is 0, and Ar2 is




In another embodiment, Ar1 is a pyridyl group, X is O, m is 0, and Ar2 is




In another embodiment, Ar1 is a pyridyl group, X is O, m is 0, Ar2 is




r is 1, and R8 is a —(C1-C6)alkyl. In another embodiment, r is 1 and the —(C1-C6)alkyl is substituted at the phenyl group's para-position. In another embodiment, r is 1 and the —(C1-C6)alkyl is a tert-butyl group. In another embodiment, r is 1 and the —(C1-C6)alkyl is a tert-butyl group and is substituted at the phenyl group's para-position. In another embodiment, r is 1 and the —(C1-C6)alkyl is an iso-propyl group. In another embodiment, r is 1 and the —(C1-C6)alkyl is a iso-propyl group and is substituted at the phenyl group's para-position.

In another embodiment, Ar1 is a pyridyl group, X is O, m is 0, Ar2 is




r is 1, and R8 is —CF3. In another embodiment, the —CF3 is substituted at the phenyl group's para-position.

In another embodiment, Ar1 is a pyridyl group, X is O, m is 0, Ar2 is




r is 1, and R8 is -halo. In another embodiment, r is 1 and the -halo is substituted at the phenyl group's para-position. In another embodiment, r is 1 and -halo is —Cl. In another embodiment, r is 1 and -halo is —Cl and is substituted at the phenyl group's para-position. In another embodiment, r is 1 and -halo is —Br. In another embodiment, r is 1 and -halo is —Br and is substituted at the phenyl group's para-position. In another embodiment, r is 1 and -halo is —I. In another embodiment, r is 1 and -halo is —I and is substituted at the phenyl group's para-position. In another embodiment, r is 1 and -halo is —F. In another embodiment, r is 1 and -halo is —F and is substituted at the phenyl group's para-position.

In another embodiment, Ar1 is a pyrazinyl group, X is O, m is 0, and Ar2 is a benzothiazolyl group.
In another embodiment, Ar1 is a pyrazinyl group, X is O, m is 0, and Ar2 is a benzooxazolyl group.
In another embodiment, Ar1 is a pyrazinyl group, X is O, m is 0, and Ar2 is a benzoimidazolyl group.
In another embodiment, Ar1 is a pyrazinyl group, X is O, m is 0, and Ar2 is




In another embodiment, Ar1 is a pyrazinyl group, X is O, m is 0, and Ar2 is




In another embodiment, Ar1 is a pyrazinyl group, X is O, m is 0, Ar2 is




r is 1, and R8 is a —(C1-C6)alkyl. In another embodiment, r is 1 and the —(C1-C6)alkyl is substituted at the phenyl group's para-position. In another embodiment, r is 1 and the —(C1-C6)alkyl is a tert-butyl group. In another embodiment, r is 1 and the —(C1-C6)alkyl is a tert-butyl group and is substituted at the phenyl group's para-position. In another embodiment, r is 1 and the —(C1-C6)alkyl is an iso-propyl group. In another embodiment, r is 1 and the —(C1-C6)alkyl is a iso-propyl group and is substituted at the phenyl group's para-position.

In another embodiment, Ar1 is a pyrazinyl group, X is O, m is 0, Ar2 is




r is 1, and R8 is —CF3. In another embodiment, the —CF3 is substituted at the phenyl group's para-position.

In another embodiment, Ar1 is a pyrazinyl group, X is O, m is 0, Ar2 is




r is 1, and R8 is -halo. In another embodiment, r is 1 and the -halo is substituted at the phenyl group's para-position. In another embodiment, r is 1 and -halo is —Cl. In another embodiment, r is 1 and -halo is —Cl and is substituted at the phenyl group's para-position. In another embodiment, r is 1 and -halo is —Br. In another embodiment, r is 1 and -halo is —Br and is substituted at the phenyl group's para-position. In another embodiment, r is 1 and -halo is —I. In another embodiment, r is 1 and -halo is —I and is substituted at the phenyl group's para-position. In another embodiment, r is 1 and -halo is —F. In another embodiment, r is 1 and -halo is —F and is substituted at the phenyl group's para-position.

In another embodiment, Ar1 is a pyrimidinyl group, X is O, m is 0, and Ar2 is a benzothiazolyl group.
In another embodiment, Ar1 is a pyrimidinyl group, X is O, m is 0, and Ar2 is a benzooxazolyl group.
In another embodiment, Ar1 is a pyrimidinyl group, X is O, m is 0, and Ar2 is a benzoimidazolyl group.
In another embodiment, Ar1 is a pyrimidinyl group, X is O, m is 0, and Ar2 is




In another embodiment, Ar1 is a pyrimidinyl group, X is O, m is 0, and Ar2 is




In another embodiment, Ar1 is a pyrimidinyl group, X is O, m is 0, Ar2 is




r is 1, and R9 is a —(C1-C6)alkyl. In another embodiment, r is 1 and the —(C1-C6)alkyl is substituted at the phenyl group's para-position. In another embodiment, r is 1 and the —(C1-C6)alkyl is a tert-butyl group. In another embodiment, r is 1 and the —(C1-C6)alkyl is a tert-butyl group substituted at the phenyl group's para-position. In another embodiment, r is 1 and the —(C1-C6)alkyl is an iso-propyl group. In another embodiment, r is 1 and the —(C1-C6)alkyl is a iso-propyl group substituted at the phenyl group's para-position.

In another embodiment, Ar1 is a pyrimidinyl group, X is O, m is 0, Ar2 is




r is 1, and R8 is —CF3. In another embodiment, the —CF3 is substituted at the phenyl group's para-position.

In another embodiment, Ar1 is a pyrimidinyl group, X is O, m is 0, Ar2 is




r is 1, and R8 is -halo. In another embodiment, r is 1 and the -halo is substituted at the phenyl group's para-position. In another embodiment, r is 1 and -halo is —Cl. In another embodiment, r is 1 and -halo is —Cl and is substituted at the phenyl group's para-position. In another embodiment, r is 1 and -halo is —Br. In another embodiment, r is 1 and -halo is —Br and is substituted at the phenyl group's para-position. In another embodiment, r is 1 and -halo is —I. In another embodiment, r is 1 and -halo is —I and is substituted at the phenyl group's para-position. In another embodiment, r is 1 and -halo is —F. In another embodiment, r is 1 and -halo is —F and is substituted at the phenyl group's para-position.

In another embodiment, Ar1 is a pyridazinyl group, X is O, m is 0, and Ar2 is a benzothiazolyl group.
In another embodiment, Ar1 is a pyridazinyl group, X is O, m is 0, and Ar2 is a benzooxazolyl group.
In another embodiment, Ar1 is a pyridazinyl group, X is O, m is 0, and Ar2 is a benzoimidazolyl group.
In another embodiment, Ar1 is a pyridazinyl group, X is O, m is 0, and Ar2 is




In another embodiment, Ar1 is a pyridazinyl group, X is O, m is 0, and Ar2 is




In another embodiment, Ar1 is a pyridazinyl group, X is O, m is 0, Ar2 is




r is 1, and R8 is a —(C1-C6)alkyl. In another embodiment, r is 1 and the —(C1-C6)alkyl is substituted at the phenyl group's para-position. In another embodiment, r is 1 and the —(C1-C6)alkyl is a tert-butyl group. In another embodiment, r is 1 and the —(C1-C6)alkyl is a tert-butyl group and is substituted at the phenyl group's para-position. In another embodiment, r is 1 and the —(C1-C6)alkyl is an iso-propyl group. In another embodiment, r is 1 and the —(C1-C6)alkyl is a iso-propyl group and is substituted at the phenyl group's para-position.

In another embodiment, Ar1 is a pyridazinyl group, X is O, m is 0, Ar2 is




r is 1, and R8 is —CF3. In another embodiment, the —CF3 is substituted at the phenyl group's para-position.

In another embodiment, Ar1 is a pyridazinyl group, X is O, m is 0, Ar2 is




r is 1, and R8 is -halo. In another embodiment, r is 1 and the -halo is substituted at the phenyl group's para-position. In another embodiment, r is 1 and -halo is —Cl. In another embodiment, r is 1 and -halo is —Cl and is substituted at the phenyl group's para-position. In another embodiment, r is 1 and -halo is —Br. In another embodiment, r is 1 and -halo is —Br and is substituted at the phenyl group's para-position. In another embodiment, r is 1 and -halo is —I. In another embodiment, r is 1 and -halo is —I and is substituted at the phenyl group's para-position. In another embodiment, r is 1 and -halo is —F. In another embodiment, r is 1 and -halo is —F and is substituted at the phenyl group's para-position.

In another embodiment, Ar1 is a thiadiazolyl group, X is O, m is 0, and Ar2 is a benzothiazolyl group.
In another embodiment, Ar1 is a thiadiazolyl group, X is O, m is 0, and Ar2 is a benzooxazolyl group.
In another embodiment, Ar1 is a thiadiazolyl group, X is O, m is 0, and Ar2 is a benzoimidazolyl group.
In another embodiment, Ar1 is a thiadiazolyl group, X is O, m is 0, and Ar2 is




In another embodiment, Ar1 is a thiadiazolyl group, X is O, m is 0, Ar2 is




r is 1, and R8 is a —(C1-C6)alkyl. In another embodiment, r is 1 and the —(C1-C6)alkyl is substituted at the phenyl group's para-position. In another embodiment, r is 1 and the —(C1-C6)alkyl is a tert-butyl group. In another embodiment, r is 1 and the —(C1-C6)alkyl is a tert-butyl group and is substituted at the phenyl group's para-position. In another embodiment, r is 1 and the —(C1-C6)alkyl is an iso-propyl group. In another embodiment, r is 1 and the —(C1-C6)alkyl is a iso-propyl group and is substituted at the phenyl group's para-position.

In another embodiment, Ar1 is a thiadiazolyl group, X is O, m is 0, Ar2 is




r is 1, and R8 is —CF3. In another embodiment, the —CF3 is substituted at the phenyl group's para-position.

In another embodiment, Ar1 is a thiadiazolyl group, X is O, m is 0, Ar2 is




r is 1, and R8 is -halo. In another embodiment, r is 1 and the -halo is substituted at the phenyl group's para-position. In another embodiment, r is 1 and -halo is —Cl. In another embodiment, r is 1 and -halo is —Cl and is substituted at the phenyl group's para-position. In another embodiment, r is 1 and -halo is —Br. In another embodiment, r is 1 and -halo is —Br and is substituted at the phenyl group's para-position. In another embodiment, r is 1 and -halo is −I. In another embodiment, r is 1 and -halo is —I and is substituted at the phenyl group's para-position. In another embodiment, r is 1 and -halo is —F. In another embodiment, r is 1 and -halo is —F and is substituted at the phenyl group's para-position.

4.3 Pyridylene Compounds of Formula (I) and (II)
In the Pyridylene Compounds that have an R3 group, the R3 group can be attached to the carbon atom at the 3-, 4-, or 6-position of the pyridylene ring of the Pyridylene Compound of formula (I) or (II). In one embodiment, the R3 group is attached to the carbon at the 3-position of the pyridylene ring of the Pyridylene Compound of formula (I) or (II). In another embodiment, the R3 group is attached to the carbon at the 4-position of the pyridylene ring of the Pyridylene Compound of formula (I) or (II). In another embodiment, the R3 group is attached to the carbon at the 6-position of the pyridylene ring of the Pyridylene Compound of formula (I) or (II).
In another embodiment, the R3 group is —CH3 and the R3 group is attached to the carbon at the 3-position of the pyridylene ring of the Pyridylene Compound of formula (I) or (II). In another embodiment, the R3 group is —CH3 and the R3 group is attached to the carbon at the 4-position of the pyridylene ring of the Pyridylene Compound of formula (I) or (II). In another embodiment, the R3 group is —CH3 and the R3 group is attached to the carbon at the 6-position of the pyridylene ring of the Pyridylene Compound of formula (I) or (II).
In another embodiment, the R3 group is -halo and the R3 group is attached to the carbon at the 3-position of the pyridylene ring of the Pyridylene Compound of formula (I) or (II). In another embodiment, the R3 group is -halo and the R3 group is attached to the carbon at the 4-position of the pyridylene ring of the Pyridylene Compound of formula (I) or (II). In another embodiment, the R3 group is -halo and the R3 group is attached to the carbon at the 6-position of the pyridylene ring of the Pyridylene Compound of formula (I) or (II).
In another embodiment, the R3 group is —Cl and the R3 group is attached to the carbon at the 3-position of the pyridylene ring of the Pyridylene Compound of formula (I) or (II). In another embodiment, the R3 group is —Cl and the R3 group is attached to the carbon at the 4-position of the pyridylene ring of the Pyridylene Compound of formula (I) or (II). In another embodiment, the R3 group is —Cl and the R3 group is attached to the carbon at the 6-position of the pyridylene ring of the Pyridylene Compound of formula (I) or (II).
In another embodiment, the R3 group is —Br and the R3 group is attached to the carbon at the 3-position of the pyridylene ring of the Pyridylene Compound of formula (I) or (II). In another embodiment, the R3 group is —Br and the R3 group is attached to the carbon at the 4-position of the pyridylene ring of the Pyridylene Compound of formula (I) or (II). In another embodiment, the R3 group is —Br and the R3 group is attached to the carbon at the 6-position of the pyridylene ring of the Pyridylene Compound of formula (I) or (II).
In another embodiment, the R3 group is —F and the R3 group is attached to the carbon at the 3-position of the pyridylene ring of the Pyridylene Compound of formula (I) or (II). In another embodiment, the R3 group is —F and the R3 group is attached to the carbon at the 4-position of the pyridylene ring of the Pyridylene Compound of formula (I) or (II). In another embodiment, the R3 group is —F and the R3 group is attached to the carbon at the 6-position of the pyridylene ring of the Pyridylene Compound of formula (I) or (II).
In another embodiment, the R3 group is —I and the R3 group is attached to the carbon at the 3-position of the pyridylene ring of the Pyridylene Compound of formula (I) or (II). In another embodiment, the R3 group is —I and the R3 group is attached to the carbon at the 4-position of the pyridylene ring of the Pyridylene Compound of formula (I) or (II). In another embodiment, the R3 group is —I and the R3 group is attached to the carbon at the 6-position of the pyridylene ring of the Pyridylene Compound of formula (I) or (II).
Optical isomers of the Pyridylene Compounds can be obtained by known techniques such as chiral chromatography or formation of diastereomeric salts from an optically active acid or base.
In addition, one or more hydrogen, carbon or other atoms of a Pyridylene Compound can be replaced by an isotope of the hydrogen, carbon or other atoms. Such compounds, which are encompassed by the present invention, are useful as research and diagnostic tools in metabolism pharmacokinetic studies and in binding assays.
Illustrative Pyridylene Compounds are listed below in Tables 1-10.
For the chemical structure depicted, e.g., at the head of each of Tables 1-5, a is independently 0 or 1. When a=0, the group at the “a” position is —H. When a=1, the group at the “a” position (R8a) is other than —H, i.e., is R8.
For the chemical structure depicted, e.g., at the head of each of Tables 6-10, a is independently 0 or 1. When a=0, the group at the “a” position is —H. When a=1, the group at the “a” position ((R8)a) is other than —H, i.e., is R8.
For the chemical structure depicted, e.g., at the head of each of Tables 6-10, b is independently 0 or 1. When b=0, the group at the “b” position is —H. When b=1, the group at the “b” position ((R8)b) is other than —H, i.e., is R8.








TABLE 1








(III)








 







and pharmaceutically acceptable salts thereof, where:









Compound
R1
R8a





 A1(a and b)
—Cl
—H


 A2(a and b)
—Cl
-tert-butyl


 A3(a and b)
—Cl
-iso-butyl


 A4(a and b)
—Cl
-sec-butyl


 A5(a and b)
—Cl
-iso-propyl


 A6(a and b)
—Cl
-n-propyl


 A7(a and b)
—Cl
-cyclohexyl


 A8(a and b)
—Cl
-tert-butoxy


 A9(a and b)
—Cl
-iso-propoxy


A10(a and b)
—Cl
—CF3


A11(a and b)
—Cl
—OCF3


A12(a and b)
—Cl
—Cl


A13(a and b)
—Cl
—Br


A14(a and b)
—Cl
—I


A15(a and b)
—Cl
-n-butyl


A16(a and b)
—Cl
-n-propyl


A17(a and b)
—F
—H


A18(a and b)
—F
-tert-butyl


A19(a and b)
—F
-iso-butyl


A20(a and b)
—F
-sec-butyl


A21(a and b)
—F
-iso-propyl


A22(a and b)
—F
-n-propyl


A23(a and b)
—F
-cyclohexyl


A24(a and b)
—F
-tert-butoxy


A25(a and b)
—F
-iso-propoxy


A26(a and b)
—F
—CF3


A27(a and b)
—F
—OCF3


A28(a and b)
—F
—Cl


A29(a and b)
—F
—Br


A30(a and b)
—F
—I


A31(a and b)
—F
-n-butyl


A32(a and b)
—F
-n-propyl


A33(a and b)
—CH3
—H


A34(a and b)
—CH3
-iso-butyl


A35(a and b)
—CH3
-tert-butyl


A36(a and b)
—CH3
-sec-butyl


A37(a and b)
—CH3
-iso-propyl


A38(a and b)
—CH3
-n-propyl


A39(a and b)
—CH3
-cyclohexyl


A40(a and b)
—CH3
-tert-butoxy


A41(a and b)
—CH3
-iso-propoxy


A42(a and b)
—CH3
—CF3


A43(a and b)
—CH3
—OCF3


A44(a and b)
—CH3
—Cl


A45(a and b)
—CH3
—Br


A46(a and b)
—CH3
—I


A47(a and b)
—CH3
-n-butyl


A48(a and b)
—CH3
-n-propyl


A49(a and b)
—CF3
—H


A50(a and b)
—CF3
-tert-butyl


A51(a and b)
—CF3
-iso-butyl


A52(a and b)
—CF3
-sec-butyl


A53(a and b)
—CF3
-iso-propyl


A54(a and b)
—CF3
-n-propyl


A55(a and b)
—CF3
-cyclohexyl


A56(a and b)
—CF3
-tert-butoxy


A57(a and b)
—CF3
-iso-propoxy


A58(a and b)
—CF3
—CF3


A59(a and b)
—CF3
—OCF3


A60(a and b)
—CF3
—Cl


A61(a and b)
—CF3
—Br


A62(a and b)
—CF3
—I


A63(a and b)
—CF3
-n-butyl


A64(a and b)
—CF3
-n-propyl


A65(a and b)
—CHF2
-tert-butyl


A66(a and b)
—CHF2
—H


A67(a and b)
—CHF2
-iso-butyl


A68(a and b)
—CHF2
-sec-butyl


A69(a and b)
—CHF2
-iso-propyl


A70(a and b)
—CHF2
-n-propyl


A71(a and b)
—CHF2
-cyclohexyl


A72(a and b)
—CHF2
-tert-butoxy


A73(a and b)
—CHF2
-iso-propoxy


A74(a and b)
—CHF2
—CF3


A75(a and b)
—CHF2
—OCF3


A76(a and b)
—CHF2
—Cl


A77(a and b)
—CHF2
—Br


A78(a and b)
—CHF2
—I


A79(a and b)
—CHF2
-n-butyl


A80(a and b)
—CHF2
-n-propyl


A81(a and b)
—Br
—H


A82(a and b)
—Br
-tert-butyl


A83(a and b)
—Br
-iso-butyl


A84(a and b)
—Br
-sec-butyl


A85(a and b)
—Br
-iso-propyl


A86(a and b)
—Br
-n-propyl


A87(a and b)
—Br
-cyclohexyl


A88(a and b)
—Br
-tert-butoxy


A89(a and b)
—Br
-iso-propoxy


A90(a and b)
—Br
—CF3


A91(a and b)
—Br
—OCF3


A92(a and b)
—Br
—Cl


A93(a and b)
—Br
—Br


A94(a and b)
—Br
—I


A95(a and b)
—Br
-n-butyl


A96(a and b)
—Br
-n-propyl


A97(a and b)
—I
-tert-butyl


A98(a and b)
—I
—H


A99(a and b)
—I
-iso-butyl


A100(a and b) 
—I
-sec-butyl


A101(a and b) 
—I
-iso-propyl


A102(a and b) 
—I
-n-propyl


A103(a and b) 
—I
-cyclohexyl


A104(a and b) 
—I
-tert-butoxy


A105(a and b) 
—I
-iso-propoxy


A106(a and b) 
—I
—CF3


A107(a and b) 
—I
—OCF3


A108(a and b) 
—I
—Cl


A109(a and b) 
—I
—Br


A110(a and b) 
—I
—I


A111(a and b) 
—I
-n-butyl


A112(a and b) 
—I
-n-propyl





In the column labeled “Compound”:


(a) means Z1 is CH and Z2 is N; and


(b) means Z1 is N and Z2 is CH.














TABLE 2








(IV)








 







and pharmaceutically acceptable salts thereof, where:









Compound
R1
R8a





 B1(a and b)
—Cl
—H


 B2(a and b)
—Cl
-tert-butyl


 B3(a and b)
—Cl
-iso-butyl


 B4(a and b)
—Cl
-sec-butyl


 B5(a and b)
—Cl
-iso-propyl


 B6(a and b)
—Cl
-n-propyl


 B7(a and b)
—Cl
-cyclohexyl


 B8(a and b)
—Cl
-tert-butoxy


 B9(a and b)
—Cl
-iso-propoxy


B10(a and b)
—Cl
—CF3


B11(a and b)
—Cl
—OCF3


B12(a and b)
—Cl
—Cl


B13(a and b)
—Cl
—Br


B14(a and b)
—Cl
—I


B15(a and b)
—Cl
-n-butyl


B16(a and b)
—Cl
-n-propyl


B17(a and b)
—F
—H


B18(a and b)
—F
-tert-butyl


B19(a and b)
—F
-iso-butyl


B20(a and b)
—F
-sec-butyl


B21(a and b)
—F
-iso-propyl


B22(a and b)
—F
-n-propyl


B23(a and b)
—F
-cyclohexyl


B24(a and b)
—F
-tert-butoxy


B25(a and b)
—F
-iso-propoxy


B26(a and b)
—F
—CF3


B27(a and b)
—F
—OCF3


B28(a and b)
—F
—Cl


B29(a and b)
—F
—Br


B30(a and b)
—F
—I


B31(a and b)
—F
-n-butyl


B32(a and b)
—F
-n-propyl


B33(a and b)
—CH3
—H


B34(a and b)
—CH3
-iso-butyl


B35(a and b)
—CH3
-tert-butyl


B36(a and b)
—CH3
-sec-butyl


B37(a and b)
—CH3
-iso-propyl


B38(a and b)
—CH3
-n-propyl


B39(a and b)
—CH3
-cyclohexyl


B40(a and b)
—CH3
-tert-butoxy


B41(a and b)
—CH3
-iso-propoxy


B42(a and b)
—CH3
—CF3


B43(a and b)
—CH3
—OCF3


B44(a and b)
—CH3
—Cl


B45(a and b)
—CH3
—Br


B46(a and b)
—CH3
—I


B47(a and b)
—CH3
-n-butyl


B48(a and b)
—CH3
-n-propyl


B49(a and b)
—CF3
—H


B50(a and b)
—CF3
-tert-butyl


B51(a and b)
—CF3
-iso-butyl


B52(a and b)
—CF3
-sec-butyl


B53(a and b)
—CF3
-iso-propyl


B54(a and b)
—CF3
-n-propyl


B55(a and b)
—CF3
-cyclohexyl


B56(a and b)
—CF3
-tert-butoxy


B57(a and b)
—CF3
-iso-propoxy


B58(a and b)
—CF3
—CF3


B59(a and b)
—CF3
—OCF3


B60(a and b)
—CF3
—Cl


B61(a and b)
—CF3
—Br


B62(a and b)
—CF3
—I


B63(a and b)
—CF3
-n-butyl


B64(a and b)
—CF3
-n-propyl


B65(a and b)
—CHF2
-tert-butyl


B66(a and b)
—CHF2
—H


B67(a and b)
—CHF2
-iso-butyl


B68(a and b)
—CHF2
-sec-butyl


B69(a and b)
—CHF2
-iso-propyl


B70(a and b)
—CHF2
-n-propyl


B71(a and b)
—CHF2
-cyclohexyl


B72(a and b)
—CHF2
-tert-butoxy


B73(a and b)
—CHF2
-iso-propoxy


B74(a and b)
—CHF2
—CF3


B75(a and b)
—CHF2
—OCF3


B76(a and b)
—CHF2
—Cl


B77(a and b)
—CHF2
—Br


B78(a and b)
—CHF2
—I


B79(a and b)
—CHF2
-n-butyl


B80(a and b)
—CHF2
-n-propyl


B81(a and b)
—Br
—H


B82(a and b)
—Br
-tert-butyl


B83(a and b)
—Br
-iso-butyl


B84(a and b)
—Br
-sec-butyl


B85(a and b)
—Br
-iso-propyl


B86(a and b)
—Br
-n-propyl


B87(a and b)
—Br
-cyclohexyl


B88(a and b)
—Br
-tert-butoxy


B89(a and b)
—Br
-iso-propoxy


B90(a and b)
—Br
—CF3


B91(a and b)
—Br
—OCF3


B92(a and b)
—Br
—Cl


B93(a and b)
—Br
—Br


B94(a and b)
—Br
—I


B95(a and b)
—Br
-n-butyl


B96(a and b)
—Br
-n-propyl


B97(a and b)
—I
-tert-butyl


B98(a and b)
—I
—H


B99(a and b)
—I
-iso-butyl


B100(a and b) 
—I
-sec-butyl


B101(a and b) 
—I
-iso-propyl


B102(a and b) 
—I
-n-propyl


B103(a and b) 
—I
-cyclohexyl


B104(a and b) 
—I
-tert-butoxy


B105(a and b) 
—I
-iso-propoxy


B106(a and b) 
—I
—CF3


B107(a and b) 
—I
—OCF3


B108(a and b) 
—I
—Cl


B109(a and b) 
—I
—Br


B110(a and b) 
—I
—I


B111(a and b) 
—I
-n-butyl


B112(a and b) 
—I
-n-propyl





In the column labeled “Compound”:


(a) means Z1 is CH and Z2 is N; and


(b) means Z1 is N and Z2 is CH.














TABLE 3








(V)








 







and pharmaceutically acceptable salts thereof, where:









Compound
R1
R8a





 C1(a and b)
—Cl
—H


 C2(a and b)
—Cl
-tert-butyl


 C3(a and b)
—Cl
-iso-butyl


 C4(a and b)
—Cl
-sec-butyl


 C5(a and b)
—Cl
-iso-propyl


 C6(a and b)
—Cl
-n-propyl


 C7(a and b)
—Cl
-cyclohexyl


 C8(a and b)
—Cl
-tert-butoxy


 C9(a and b)
—Cl
-iso-propoxy


C10(a and b)
—Cl
—CF3


C11(a and b)
—Cl
—OCF3


C12(a and b)
—Cl
—Cl


C13(a and b)
—Cl
—Br


C14(a and b)
—Cl
—I


C15(a and b)
—Cl
-n-butyl


C16(a and b)
—Cl
-n-propyl


C17(a and b)
—F
—H


C18(a and b)
—F
-tert-butyl


C19(a and b)
—F
-iso-butyl


C20(a and b)
—F
-sec-butyl


C21(a and b)
—F
-iso-propyl


C22(a and b)
—F
-n-propyl


C23(a and b)
—F
-cyclohexyl


C24(a and b)
—F
-tert-butoxy


C25(a and b)
—F
-iso-propoxy


C26(a and b)
—F
—CF3


C27(a and b)
—F
—OCF3


C28(a and b)
—F
—Cl


C29(a and b)
—F
—Br


C30(a and b)
—F
—I


C31(a and b)
—F
-n-butyl


C32(a and b)
—F
-n-propyl


C33(a and b)
—CH3
—H


C34(a and b)
—CH3
-iso-butyl


C35(a and b)
—CH3
-tert-butyl


C36(a and b)
—CH3
-sec-butyl


C37(a and b)
—CH3
-iso-propyl


C38(a and b)
—CH3
-n-propyl


C39(a and b)
—CH3
-cyclohexyl


C40(a and b)
—CH3
-tert-butoxy


C41(a and b)
—CH3
-iso-propoxy


C42(a and b)
—CH3
—CF3


C43(a and b)
—CH3
—OCF3


C44(a and b)
—CH3
—Cl


C45(a and b)
—CH3
—Br


C46(a and b)
—CH3
—I


C47(a and b)
—CH3
-n-butyl


C48(a and b)
—CH3
-n-propyl


C49(a and b)
—CF3
—H


C50(a and b)
—CF3
-tert-butyl


C51(a and b)
—CF3
-iso-butyl


C52(a and b)
—CF3
-sec-butyl


C53(a and b)
—CF3
-iso-propyl


C54(a and b)
—CF3
-n-propyl


C55(a and b)
—CF3
-cyclohexyl


C56(a and b)
—CF3
-tert-butoxy


C57(a and b)
—CF3
-iso-propoxy


C58(a and b)
—CF3
—CF3


C59(a and b)
—CF3
—OCF3


C60(a and b)
—CF3
—Cl


C61(a and b)
—CF3
—Br


C62(a and b)
—CF3
—I


C63(a and b)
—CF3
-n-butyl


C64(a and b)
—CF3
-n-propyl


C65(a and b)
—CHF2
-tert-butyl


C66(a and b)
—CHF2
—H


C67(a and b)
—CHF2
-iso-butyl


C68(a and b)
—CHF2
-sec-butyl


C69(a and b)
—CHF2
-iso-propyl


C70(a and b)
—CHF2
-n-propyl


C71(a and b)
—CHF2
-cyclohexyl


C72(a and b)
—CHF2
-tert-butoxy


C73(a and b)
—CHF2
-iso-propoxy


C74(a and b)
—CHF2
—CF3


C75(a and b)
—CHF2
—OCF3


C76(a and b)
—CHF2
—Cl


C77(a and b)
—CHF2
—Br


C78(a and b)
—CHF2
—I


C79(a and b)
—CHF2
-n-butyl


C80(a and b)
—CHF2
-n-propyl


C81(a and b)
—Br
—H


C82(a and b)
—Br
-tert-butyl


C83(a and b)
—Br
-iso-butyl


C84(a and b)
—Br
-sec-butyl


C85(a and b)
—Br
-iso-propyl


C86(a and b)
—Br
-n-propyl


C87(a and b)
—Br
-cyclohexyl


C88(a and b)
—Br
-tert-butoxy


C89(a and b)
—Br
-iso-propoxy


C90(a and b)
—Br
—CF3


C91(a and b)
—Br
—OCF3


C92(a and b)
—Br
—Cl


C93(a and b)
—Br
—Br


C94(a and b)
—Br
—I


C95(a and b)
—Br
-n-butyl


C96(a and b)
—Br
-n-propyl


C97(a and b)
—I
-tert-butyl


C98(a and b)
—I
—H


C99(a and b)
—I
-iso-butyl


C100(a and b) 
—I
-sec-butyl


C101(a and b) 
—I
-iso-propyl


C102(a and b) 
—I
-n-propyl


C103(a and b) 
—I
-cyclohexyl


C104(a and b) 
—I
-tert-butoxy


C105(a and b) 
—I
-iso-propoxy


C106(a and b) 
—I
—CF3


C107(a and b) 
—I
—OCF3


C108(a and b) 
—I
—Cl


C109(a and b) 
—I
—Br


C110(a and b) 
—I
—I


C111(a and b) 
—I
-n-butyl


C112(a and b) 
—I
-n-propyl





In the column labeled “Compound”:


(a) means Z1 is CH and Z2 is N; and


(b) means Z1 is N and Z2 is CH.














TABLE 4








(VI)








 







and pharmaceutically acceptable salts thereof, where:









Compound
R1
R8a





 D1(a and b)
—Cl
—H


 D2(a and b)
—Cl
-tert-butyl


 D3(a and b)
—Cl
-iso-butyl


 D4(a and b)
—Cl
-sec-butyl


 D5(a and b)
—Cl
-iso-propyl


 D6(a and b)
—Cl
-n-propyl


 D7(a and b)
—Cl
-cyclohexyl


 D8(a and b)
—Cl
-tert-butoxy


 D9(a and b)
—Cl
-iso-propoxy


D10(a and b)
—Cl
—CF3


D11(a and b)
—Cl
—OCF3


D12(a and b)
—Cl
—Cl


D13(a and b)
—Cl
—Br


D14(a and b)
—Cl
—I


D15(a and b)
—Cl
-n-butyl


D16(a and b)
—Cl
-n-propyl


D17(a and b)
—F
—H


D18(a and b)
—F
-tert-butyl


D19(a and b)
—F
-iso-butyl


D20(a and b)
—F
-sec-butyl


D21(a and b)
—F
-iso-propyl


D22(a and b)
—F
-n-propyl


D23(a and b)
—F
-cyclohexyl


D24(a and b)
—F
-tert-butoxy


D25(a and b)
—F
-iso-propoxy


D26(a and b)
—F
—CF3


D27(a and b)
—F
—OCF3


D28(a and b)
—F
—Cl


D29(a and b)
—F
—Br


D30(a and b)
—F
—I


D31(a and b)
—F
-n-butyl


D32(a and b)
—F
-n-propyl


D33(a and b)
—CH3
—H


D34(a and b)
—CH3
-iso-butyl


D35(a and b)
—CH3
-tert-butyl


D36(a and b)
—CH3
-sec-butyl


D37(a and b)
—CH3
-iso-propyl


D38(a and b)
—CH3
-n-propyl


D39(a and b)
—CH3
-cyclohexyl


D40(a and b)
—CH3
-tert-butoxy


D41(a and b)
—CH3
-iso-propoxy


D42(a and b)
—CH3
—CF3


D43(a and b)
—CH3
—OCF3


D44(a and b)
—CH3
—Cl


D45(a and b)
—CH3
—Br


D46(a and b)
—CH3
—I


D47(a and b)
—CH3
-n-butyl


D48(a and b)
—CH3
-n-propyl


D49(a and b)
—CF3
—H


D50(a and b)
—CF3
-tert-butyl


D51(a and b)
—CF3
-iso-butyl


D52(a and b)
—CF3
-sec-butyl


D53(a and b)
—CF3
-iso-propyl


D54(a and b)
—CF3
-n-propyl


D55(a and b)
—CF3
-cyclohexyl


D56(a and b)
—CF3
-tert-butoxy


D57(a and b)
—CF3
-iso-propoxy


D58(a and b)
—CF3
—CF3


D59(a and b)
—CF3
—OCF3


D60(a and b)
—CF3
—Cl


D61(a and b)
—CF3
—Br


D62(a and b)
—CF3
—I


D63(a and b)
—CF3
-n-butyl


D64(a and b)
—CF3
-n-propyl


D65(a and b)
—CHF2
-tert-butyl


D66(a and b)
—CHF2
—H


D67(a and b)
—CHF2
-iso-butyl


D68(a and b)
—CHF2
-sec-butyl


D69(a and b)
—CHF2
-iso-propyl


D70(a and b)
—CHF2
-n-propyl


D71(a and b)
—CHF2
-cyclohexyl


D72(a and b)
—CHF2
-tert-butoxy


D73(a and b)
—CHF2
-iso-propoxy


D74(a and b)
—CHF2
—CF3


D75(a and b)
—CHF2
—OCF3


D76(a and b)
—CHF2
—Cl


D77(a and b)
—CHF2
—Br


D78(a and b)
—CHF2
—I


D79(a and b)
—CHF2
-n-butyl


D80(a and b)
—CHF2
-n-propyl


D81(a and b)
—Br
—H


D82(a and b)
—Br
-tert-butyl


D83(a and b)
—Br
-iso-butyl


D84(a and b)
—Br
-sec-butyl


D85(a and b)
—Br
-iso-propyl


D86(a and b)
—Br
-n-propyl


D87(a and b)
—Br
-cyclohexyl


D88(a and b)
—Br
-tert-butoxy


D89(a and b)
—Br
-iso-propoxy


D90(a and b)
—Br
—CF3


D91(a and b)
—Br
—OCF3


D92(a and b)
—Br
—Cl


D93(a and b)
—Br
—Br


D94(a and b)
—Br
—I


D95(a and b)
—Br
-n-butyl


D96(a and b)
—Br
-n-propyl


D97(a and b)
—I
-tert-butyl


D98(a and b)
—I
—H


D99(a and b)
—I
-iso-butyl


D100(a and b) 
—I
-sec-butyl


D101(a and b) 
—I
-iso-propyl


D102(a and b) 
—I
-n-propyl


D103(a and b) 
—I
-cyclohexyl


D104(a and b) 
—I
-tert-butoxy


D105(a and b) 
—I
-iso-propoxy


D106(a and b) 
—I
—CF3


D107(a and b) 
—I
—OCF3


D108(a and b) 
—I
—Cl


D109(a and b) 
—I
—Br


D110(a and b) 
—I
—I


D111(a and b) 
—I
-n-butyl


D112(a and b) 
—I
-n-propyl





In the column labeled “Compound”:


(a) means Z1 is CH and Z2 is N; and


(b) means Z1 is N and Z2 is CH.














TABLE 5








(VII)








 







and pharmaceutically acceptable salts thereof, where:









Compound
R1
R8a





 E1(a and b)
—Cl
—H


 E2(a and b)
—Cl
-tert-butyl


 E3(a and b)
—Cl
-iso-butyl


 E4(a and b)
—Cl
-sec-butyl


 E5(a and b)
—Cl
-iso-propyl


 E6(a and b)
—Cl
-n-propyl


 E7(a and b)
—Cl
-cyclohexyl


 E8(a and b)
—Cl
-tert-butoxy


 E9(a and b)
—Cl
-iso-propoxy


E10(a and b)
—Cl
—CF3


E11(a and b)
—Cl
—OCF3


E12(a and b)
—Cl
—Cl


E13(a and b)
—Cl
—Br


E14(a and b)
—Cl
—I


E15(a and b)
—Cl
-n-butyl


E16(a and b)
—Cl
-n-propyl


E17(a and b)
—F
—H


E18(a and b)
—F
-tert-butyl


E19(a and b)
—F
-iso-butyl


E20(a and b)
—F
-sec-butyl


E21(a and b)
—F
-iso-propyl


E22(a and b)
—F
-n-propyl


E23(a and b)
—F
-cyclohexyl


E24(a and b)
—F
-tert-butoxy


E25(a and b)
—F
-iso-propoxy


E26(a and b)
—F
—CF3


E27(a and b)
—F
—OCF3


E28(a and b)
—F
—Cl


E29(a and b)
—F
—Br


E30(a and b)
—F
—I


E31(a and b)
—F
-n-butyl


E32(a and b)
—F
-n-propyl


E33(a and b)
—CH3
—H


E34(a and b)
—CH3
-iso-butyl


E35(a and b)
—CH3
-tert-butyl


E36(a and b)
—CH3
-sec-butyl


E37(a and b)
—CH3
-iso-propyl


E38(a and b)
—CH3
-n-propyl


E39(a and b)
—CH3
-cyclohexyl


E40(a and b)
—CH3
-tert-butoxy


E41(a and b)
—CH3
-iso-propoxy


E42(a and b)
—CH3
—CF3


E43(a and b)
—CH3
—OCF3


E44(a and b)
—CH3
—Cl


E45(a and b)
—CH3
—Br


E46(a and b)
—CH3
—I


E47(a and b)
—CH3
-n-butyl


E48(a and b)
—CH3
-n-propyl


E49(a and b)
—CF3
—H


E50(a and b)
—CF3
-tert-butyl


E51(a and b)
—CF3
-iso-butyl


E52(a and b)
—CF3
-sec-butyl


E53(a and b)
—CF3
-iso-propyl


E54(a and b)
—CF3
-n-propyl


E55(a and b)
—CF3
-cyclohexyl


E56(a and b)
—CF3
-tert-butoxy


E57(a and b)
—CF3
-iso-propoxy


E58(a and b)
—CF3
—CF3


E59(a and b)
—CF3
—OCF3


E60(a and b)
—CF3
—Cl


E61(a and b)
—CF3
—Br


E62(a and b)
—CF3
—I


E63(a and b)
—CF3
-n-butyl


E64(a and b)
—CF3
-n-propyl


E65(a and b)
—CHF2
-tert-butyl


E66(a and b)
—CHF2
—H


E67(a and b)
—CHF2
-iso-butyl


E68(a and b)
—CHF2
-sec-butyl


E69(a and b)
—CHF2
-iso-propyl


E70(a and b)
—CHF2
-n-propyl


E71(a and b)
—CHF2
-cyclohexyl


E72(a and b)
—CHF2
-tert-butoxy


E73(a and b)
—CHF2
-iso-propoxy


E74(a and b)
—CHF2
—CF3


E75(a and b)
—CHF2
—OCF3


E76(a and b)
—CHF2
—Cl


E77(a and b)
—CHF2
—Br


E78(a and b)
—CHF2
—I


E79(a and b)
—CHF2
-n-butyl


E80(a and b)
—CHF2
-n-propyl


E81(a and b)
—Br
—H


E82(a and b)
—Br
-tert-butyl


E83(a and b)
—Br
-iso-butyl


E84(a and b)
—Br
-sec-butyl


E85(a and b)
—Br
-iso-propyl


E86(a and b)
—Br
-n-propyl


E87(a and b)
—Br
-cyclohexyl


E88(a and b)
—Br
-tert-butoxy


E89(a and b)
—Br
-iso-propoxy


E90(a and b)
—Br
—CF3


E91(a and b)
—Br
—OCF3


E92(a and b)
—Br
—Cl


E93(a and b)
—Br
—Br


E94(a and b)
—Br
—I


E95(a and b)
—Br
-n-butyl


E96(a and b)
—Br
-n-propyl


E97(a and b)
—I
-tert-butyl


E98(a and b)
—I
—H


E99(a and b)
—I
-iso-butyl


E100(a and b) 
—I
-sec-butyl


E101(a and b) 
—I
-iso-propyl


E102(a and b) 
—I
-n-propyl


E103(a and b) 
—I
-cyclohexyl


E104(a and b) 
—I
-tert-butoxy


E105(a and b) 
—I
-iso-propoxy


E106(a and b) 
—I
—CF3


E107(a and b) 
—I
—OCF3


E108(a and b) 
—I
—Cl


E109(a and b) 
—I
—Br


E110(a and b) 
—I
—I


E111(a and b) 
—I
-n-butyl


E112(a and b) 
—I
-n-propyl





In the column labeled “Compound”:


(a) means Z1 is CH and Z2 is N; and


(b) means Z1 is N and Z2 is CH.














TABLE 6








(VIII)








 







and pharmaceutically acceptable salts thereof, where:











Compound
Y
R1
(R8)a
(R8)b





 F1(a and b)
S
—Cl
—Cl
—H


 F2(a and b)
S
—Cl
—Br
—H


 F3(a and b)
S
—Cl
—F
—H


 F4(a and b)
S
—Cl
—CH3
—H


 F5(a and b)
S
—Cl
—CF3
—H


 F6(a and b)
S
—Cl
—OCH3
—H


 F7(a and b)
S
—Cl
—OCH2CH3
—H


 F8(a and b)
S
—Cl
—OCF3
—H


 F9(a and b)
S
—Cl
-tert-butyl
—H


 F10(a and b)
S
—Cl
-iso-propyl
—H


 F11(a and b)
S
—Cl
—CH3
—CH3


 F12(a and b)
S
—Cl
—H
—H


 F13(a and b)
S
—Cl
—H
—Cl


 F14(a and b)
S
—Cl
—H
—Br


 F15(a and b)
S
—Cl
—H
—F


 F16(a and b)
S
—Cl
—H
—CH3


 F17(a and b)
S
—Cl
—H
—CF3


 F18(a and b)
S
—Cl
—H
—OCH3


 F19(a and b)
S
—Cl
—H
—OCH2CH3


 F20(a and b)
S
—Cl
—H
—OCF3


 F21(a and b)
S
—Cl
—H
-tert-butyl


 F22(a and b)
S
—Cl
—H
-iso-propyl


 F23(a and b)
S
—CH3
—Cl
—H


 F24(a and b)
S
—CH3
—Br
—H


 F25(a and b)
S
—CH3
—F
—H


 F26(a and b)
S
—CH3
—CH3
—H


 F27(a and b)
S
—CH3
—CF3
—H


 F28(a and b)
S
—CH3
—OCH3
—H


 F29(a and b)
S
—CH3
—OCH2CH3
—H


 F30(a and b)
S
—CH3
—OCF3
—H


 F31(a and b)
S
—CH3
-tert-butyl
—H


 F32(a and b)
S
—CH3
-iso-propyl
—H


 F33(a and b)
S
—CH3
—CH3
—CH3


 F34(a and b)
S
—CH3
—H
—H


 F35(a and b)
S
—CH3
—H
—Cl


 F36(a and b)
S
—CH3
—H
—Br


 F37(a and b)
S
—CH3
—H
—F


 F38(a and b)
S
—CH3
—H
—CH3


 F39(a and b)
S
—CH3
—H
—CF3


 F40(a and b)
S
—CH3
—H
—OCH3


 F41(a and b)
S
—CH3
—H
—OCH2CH3


 F42(a and b)
S
—CH3
—H
—OCF3


 F43(a and b)
S
—CH3
—H
-tert-butyl


 F44(a and b)
S
—CH3
—H
-iso-propyl


 F45(a and b)
S
—CF3
—Cl
—H


 F46(a and b)
S
—CF3
—Br
—H


 F47(a and b)
S
—CF3
—F
—H


 F48(a and b)
S
—CF3
—CH3
—H


 F49(a and b)
S
—CF3
—CF3
—H


 F50(a and b)
S
—CF3
—OCH3
—H


 F51(a and b)
S
—CF3
—OCH2CH3
—H


 F52(a and b)
S
—CF3
—OCF3
—H


 F53(a and b)
S
—CF3
-tert-butyl
—H


 F54(a and b)
S
—CF3
-iso-propyl
—H


 F55(a and b)
S
—CF3
—CH3
—CH3


 F56(a and b)
S
—CF3
—H
—H


 F57(a and b)
S
—CF3
—H
—Cl


 F58(a and b)
S
—CF3
—H
—Br


 F59(a and b)
S
—CF3
—H
—F


 F60(a and b)
S
—CF3
—H
—CH3


 F61(a and b)
S
—CF3
—H
—CF3


 F62(a and b)
S
—CF3
—H
—OCH3


 F63(a and b)
S
—CF3
—H
—OCH2CH3


 F64(a and b)
S
—CF3
—H
—OCF3


 F65(a and b)
S
—CF3
—H
-tert-butyl


 F66(a and b)
S
—CF3
—H
-iso-propyl


 F67(a and b)
S
—CHF2
—Cl
—H


 F68(a and b)
S
—CHF2
—Br
—H


 F69(a and b)
S
—CHF2
—F
—H


 F70(a and b)
S
—CHF2
—CH3
—H


 F71(a and b)
S
—CHF2
—CF3
—H


 F72(a and b)
S
—CHF2
—OCH3
—H


 F73(a and b)
S
—CHF2
—OCH2CH3
—H


 F74(a and b)
S
—CHF2
—OCF3
—H


 F75(a and b)
S
—CHF2
-tert-butyl
—H


 F76(a and b)
S
—CHF2
-iso-propyl
—H


 F77(a and b)
S
—CHF2
—CH3
—CH3


 F78(a and b)
S
—CHF2
—H
—H


 F79(a and b)
S
—CHF2
—H
—Cl


 F80(a and b)
S
—CHF2
—H
—Br


 F81(a and b)
S
—CHF2
—H
—F


 F82(a and b)
S
—CHF2
—H
—CH3


 F83(a and b)
S
—CHF2
—H
—CF3


 F84(a and b)
S
—CHF2
—H
—OCH3


 F85(a and b)
S
—CHF2
—H
—OCH2CH3


 F86(a and b)
S
—CHF2
—H
—OCF3


 F87(a and b)
S
—CHF2
—H
-tert-butyl


 F88(a and b)
S
—CHF2
—H
-iso-propyl


 F89(a and b)
S
—Br
—Br
—H


 F90(a and b)
S
—Br
—Cl
—H


 F91(a and b)
S
—Br
—F
—H


 F92(a and b)
S
—Br
—CH3
—H


 F93(a and b)
S
—Br
—CF3
—H


 F94(a and b)
S
—Br
—OCH3
—H


 F95(a and b)
S
—Br
—OCH2CH3
—H


 F96(a and b)
S
—Br
—OCF3
—H


 F97(a and b)
S
—Br
-tert-butyl
—H


 F98(a and b)
S
—Br
-iso-propyl
—H


 F99(a and b)
S
—Br
—CH3
—CH3


F100(a and b)
S
—Br
—H
—H


F101(a and b)
S
—Br
—H
—Cl


F102(a and b)
S
—Br
—H
—Br


F103(a and b)
S
—Br
—H
—F


F104(a and b)
S
—Br
—H
—CH3


F105(a and b)
S
—Br
—H
—CF3


F106(a and b)
S
—Br
—H
—OCH3


F107(a and b)
S
—Br
—H
—OCH2CH3


F108(a and b)
S
—Br
—H
—OCF3


F109(a and b)
S
—Br
—H
-tert-butyl


F110(a and b)
S
—Br
—H
-iso-propyl


F111(a and b)
S
—I
—Cl
—H


F112(a and b)
S
—I
—Br
—H


F113(a and b)
S
—I
—F
—H


F114(a and b)
S
—I
—CH3
—H


F115(a and b)
S
—I
—CF3
—H


F116(a and b)
S
—I
—OCH3
—H


F117(a and b)
S
—I
—OCH2CH3
—H


F118(a and b)
S
—I
—OCF3
—H


F119(a and b)
S
—I
-tert-butyl
—H


F120(a and b)
S
—I
-iso-propyl
—H


F121(a and b)
S
—I
—CH3
—CH3


F122(a and b)
S
—I
—H
—H


F123(a and b)
S
—I
—H
—Cl


F124(a and b)
S
—I
—H
—Br


F125(a and b)
S
—I
—H
—F


F126(a and b)
S
—I
—H
—CH3


F127(a and b)
S
—I
—H
—CF3


F128(a and b)
S
—I
—H
—OCH3


F129(a and b)
S
—I
—H
—OCH2CH3


F130(a and b)
S
—I
—H
—OCF3


F131(a and b)
S
—I
—H
-tert-butyl


F132(a and b)
S
—I
—H
-iso-propyl


F133(a and b)
O
—Cl
—Cl
—H


F134(a and b)
O
—Cl
—Br
—H


F135(a and b)
O
—Cl
—F
—H


F136(a and b)
O
—Cl
—CH3
—H


F137(a and b)
O
—Cl
—CF3
—H


F138(a and b)
O
—Cl
—OCH3
—H


F139(a and b)
O
—Cl
—OCH2CH3
—H


F140(a and b)
O
—Cl
—OCF3
—H


F141(a and b)
O
—Cl
-tert-butyl
—H


F142(a and b)
O
—Cl
-iso-propyl
—H


F143(a and b)
O
—Cl
—CH3
—CH3


F144(a and b)
O
—Cl
—H
—H


F145(a and b)
O
—Cl
—H
—CH3


F146(a and b)
O
—Cl
—H
—Cl


F147(a and b)
O
—Cl
—H
—Br


F148(a and b)
O
—Cl
—H
—F


F149(a and b)
O
—Cl
—H
—CF3


F150(a and b)
O
—Cl
—H
—OCH3


F151(a and b)
O
—Cl
—H
—OCH2CH3


F152(a and b)
O
—Cl
—H
—OCF3


F153(a and b)
O
—Cl
—H
-tert-butyl


F154(a and b)
O
—Cl
—H
-iso-propyl


F155(a and b)
O
—CH3
—Cl
—H


F156(a and b)
O
—CH3
—Br
—H


F157(a and b)
O
—CH3
—F
—H


F158(a and b)
O
—CH3
—CH3
—H


F159(a and b)
O
—CH3
—CF3
—H


F160(a and b)
O
—CH3
—OCH3
—H


F161(a and b)
O
—CH3
—OCH2CH3
—H


F162(a and b)
O
—CH3
—OCF3
—H


F163(a and b)
O
—CH3
-tert-butyl
—H


F164(a and b)
O
—CH3
-iso-propyl
—H


F165(a and b)
O
—CH3
—CH3
—CH3


F166(a and b)
O
—CH3
—H
—H


F167(a and b)
O
—CH3
—H
—Cl


F168(a and b)
O
—CH3
—H
—Br


F169(a and b)
O
—CH3
—H
—F


F170(a and b)
O
—CH3
—H
—CH3


F171(a and b)
O
—CH3
—H
—CF3


F172(a and b)
O
—CH3
—H
—OCH3


F173(a and b)
O
—CH3
—H
—OCH2CH3


F174(a and b)
O
—CH3
—H
—OCF3


F175(a and b)
O
—CH3
—H
-tert-butyl


F176(a and b)
O
—CH3
—H
-iso-propyl


F177(a and b)
O
—CF3
—Cl
—H


F178(a and b)
O
—CF3
—Br
—H


F179(a and b)
O
—CF3
—F
—H


F180(a and b)
O
—CF3
—CH3
—H


F181(a and b)
O
—CF3
—CF3
—H


F182(a and b)
O
—CF3
—OCH3
—H


F183(a and b)
O
—CF3
—OCH2CH3
—H


F184(a and b)
O
—CF3
—OCF3
—H


F185(a and b)
O
—CF3
-tert-butyl
—H


F186(a and b)
O
—CF3
-iso-propyl
—H


F187(a and b)
O
—CF3
—CH3
—CH3


F188(a and b)
O
—CF3
—H
—H


F189(a and b)
O
—CF3
—H
—Cl


F190(a and b)
O
—CF3
—H
—Br


F191(a and b)
O
—CF3
—H
—F


F192(a and b)
O
—CF3
—H
—CH3


F193(a and b)
O
—CF3
—H
—CF3


F194(a and b)
O
—CF3
—H
—OCH3


F195(a and b)
O
—CF3
—H
—OCH2CH3


F196(a and b)
O
—CF3
—H
—OCF3


F197(a and b)
O
—CF3
—H
-tert-butyl


F198(a and b)
O
—CF3
—H
-iso-propyl


F199(a and b)
O
—CHF2
—Cl
—H


F200(a and b)
O
—CHF2
—Br
—H


F201(a and b)
O
—CHF2
—F
—H


F202(a and b)
O
—CHF2
—CH3
—H


F203(a and b)
O
—CHF2
—CF3
—H


F204(a and b)
O
—CHF2
—OCH3
—H


F205(a and b)
O
—CHF2
—OCH2CH3
—H


F206(a and b)
O
—CHF2
—OCF3
—H


F207(a and b)
O
—CHF2
-tert-butyl
—H


F208(a and b)
O
—CHF2
-iso-propyl
—H


F209(a and b)
O
—CHF2
—CH3
—CH3


F210(a and b)
O
—CHF2
—H
—H


F211(a and b)
O
—CHF2
—H
—Cl


F212(a and b)
O
—CHF2
—H
—Br


F213(a and b)
O
—CHF2
—H
—F


F214(a and b)
O
—CHF2
—H
—CH3


F215(a and b)
O
—CHF2
—H
—CF3


F216(a and b)
O
—CHF2
—H
—OCH3


F217(a and b)
O
—CHF2
—H
—OCH2CH3


F218(a and b)
O
—CHF2
—H
—OCF3


F219(a and b)
O
—CHF2
—H
-tert-butyl


F220(a and b)
O
—CHF2
—H
-iso-propyl


F221(a and b)
O
—Br
—Br
—H


F222(a and b)
O
—Br
—Cl
—H


F223(a and b)
O
—Br
—F
—H


F224(a and b)
O
—Br
—CH3
—H


F225(a and b)
O
—Br
—CF3
—H


F226(a and b)
O
—Br
—OCH3
—H


F227(a and b)
O
—Br
—OCH2CH3
—H


F228(a and b)
O
—Br
—OCF3
—H


F229(a and b)
O
—Br
-tert-butyl
—H


F230(a and b)
O
—Br
-iso-propyl
—H


F231(a and b)
O
—Br
—CH3
—CH3


F232(a and b)
O
—Br
—H
—H


F233(a and b)
O
—Br
—H
—Cl


F234(a and b)
O
—Br
—H
—Br


F235(a and b)
O
—Br
—H
—F


F236(a and b)
O
—Br
—H
—CH3


F237(a and b)
O
—Br
—H
—CF3


F238(a and b)
O
—Br
—H
—OCH3


F239(a and b)
O
—Br
—H
—OCH2CH3


F240(a and b)
O
—Br
—H
—OCF3


F241(a and b)
O
—Br
—H
-tert-butyl


F242(a and b)
O
—Br
—H
-iso-propyl


F243(a and b)
O
—I
—Cl
—H


F244(a and b)
O
—I
—Br
—H


F245(a and b)
O
—I
—F
—H


F246(a and b)
O
—I
—CH3
—H


F247(a and b)
O
—I
—CF3
—H


F248(a and b)
O
—I
—OCH3
—H


F249(a and b)
O
—I
—OCH2CH3
—H


F250(a and b)
O
—I
—OCF3
—H


F251(a and b)
O
—I
-tert-butyl
—H


F252(a and b)
O
—I
-iso-propyl
—H


F253(a and b)
O
—I
—CH3
—CH3


F254(a and b)
O
—I
—H
—H


F255(a and b)
O
—I
—H
—Cl


F256(a and b)
O
—I
—H
—Br


F257(a and b)
O
—I
—H
—F


F258(a and b)
O
—I
—H
—CH3


F259(a and b)
O
—I
—H
—CF3


F260(a and b)
O
—I
—H
—OCH3


F261(a and b)
O
—I
—H
—OCH2CH3


F262(a and b)
O
—I
—H
—OCF3


F263(a and b)
O
—I
—H
-tert-butyl


F264(a and b)
O
—I
—H
-iso-propyl


F265(a and b)
NH
—Cl
—Cl
—H


F266(a and b)
NH
—Cl
—Br
—H


F267(a and b)
NH
—Cl
—F
—H


F268(a and b)
NH
—Cl
—CH3
—H


F269(a and b)
NH
—Cl
—CF3
—H


F270(a and b)
NH
—Cl
—OCH3
—H


F271(a and b)
NH
—Cl
—OCH2CH3
—H


F272(a and b)
NH
—Cl
—OCF3
—H


F273(a and b)
NH
—Cl
-tert-butyl
—H


F274(a and b)
NH
—Cl
-iso-propyl
—H


F275(a and b)
NH
—Cl
—CH3
—CH3


F276(a and b)
NH
—Cl
—H
—H


F277(a and b)
NH
—Cl
—H
—CH3


F278(a and b)
NH
—Cl
—H
—Cl


F279(a and b)
NH
—Cl
—H
—Br


F280(a and b)
NH
—Cl
—H
—F


F281(a and b)
NH
—Cl
—H
—CF3


F282(a and b)
NH
—Cl
—H
—OCH3


F283(a and b)
NH
—Cl
—H
—OCH2CH3


F284(a and b)
NH
—Cl
—H
—OCF3


F285(a and b)
NH
—Cl
—H
-tert-butyl


F286(a and b)
NH
—Cl
—H
-iso-propyl


F287(a and b)
NH
—CH3
—Cl
—H


F288(a and b)
NH
—CH3
—Br
—H


F289(a and b)
NH
—CH3
—F
—H


F290(a and b)
NH
—CH3
—CH3
—H


F291(a and b)
NH
—CH3
—CF3
—H


F292(a and b)
NH
—CH3
—OCH3
—H


F293(a and b)
NH
—CH3
—OCH2CH3
—H


F294(a and b)
NH
—CH3
—OCF3
—H


F295(a and b)
NH
—CH3
-tert-butyl
—H


F296(a and b)
NH
—CH3
-iso-propyl
—H


F297(a and b)
NH
—CH3
—CH3
—CH3


F298(a and b)
NH
—CH3
—H
—H


F299(a and b)
NH
—CH3
—H
—Cl


F300(a and b)
NH
—CH3
—H
—Br


F301(a and b)
NH
—CH3
—H
—F


F302(a and b)
NH
—CH3
—H
—CH3


F303(a and b)
NH
—CH3
—H
—CF3


F304(a and b)
NH
—CH3
—H
—OCH3


F305(a and b)
NH
—CH3
—H
—OCH2CH3


F306(a and b)
NH
—CH3
—H
—OCF3


F307(a and b)
NH
—CH3
—H
-tert-butyl


F308(a and b)
NH
—CH3
—H
-iso-propyl


F309(a and b)
NH
—CF3
—Cl
—H


F310(a and b)
NH
—CF3
—Br
—H


F311(a and b)
NH
—CF3
—F
—H


F312(a and b)
NH
—CF3
—CH3
—H


F313(a and b)
NH
—CF3
—CF3
—H


F314(a and b)
NH
—CF3
—OCH3
—H


F315(a and b)
NH
—CF3
—OCH2CH3
—H


F316(a and b)
NH
—CF3
—OCF3
—H


F317(a and b)
NH
—CF3
-tert-butyl
—H


F318(a and b)
NH
—CF3
-iso-propyl
—H


F319(a and b)
NH
—CF3
—CH3
—CH3


F320(a and b)
NH
—CF3
—H
—H


F321(a and b)
NH
—CF3
—H
—Cl


F322(a and b)
NH
—CF3
—H
—Br


F323(a and b)
NH
—CF3
—H
—F


F324(a and b)
NH
—CF3
—H
—CH3


F325(a and b)
NH
—CF3
—H
—CF3


F326(a and b)
NH
—CF3
—H
—OCH3


F327(a and b)
NH
—CF3
—H
—OCH2CH3


F328(a and b)
NH
—CF3
—H
—OCF3


F329(a and b)
NH
—CF3
—H
-tert-butyl


F330(a and b)
NH
—CF3
—H
-iso-propyl


F331(a and b)
NH
—CHF2
—Cl
—H


F332(a and b)
NH
—CHF2
—Br
—H


F333(a and b)
NH
—CHF2
—F
—H


F334(a and b)
NH
—CHF2
—CH3
—H


F335(a and b)
NH
—CHF2
—CF3
—H


F336(a and b)
NH
—CHF2
—OCH3
—H


F337(a and b)
NH
—CHF2
—OCH2CH3
—H


F338(a and b)
NH
—CHF2
—OCF3
—H


F339(a and b)
NH
—CHF2
-tert-butyl
—H


F340(a and b)
NH
—CHF2
-iso-propyl
—H


F341(a and b)
NH
—CHF2
—CH3
—CH3


F342(a and b)
NH
—CHF2
—H
—H


F343(a and b)
NH
—CHF2
—H
—Cl


F344(a and b)
NH
—CHF2
—H
—Br


F345(a and b)
NH
—CHF2
—H
—F


F346(a and b)
NH
—CHF2
—H
—CH3


F347(a and b)
NH
—CHF2
—H
—CF3


F348(a and b)
NH
—CHF2
—H
—OCH3


F349(a and b)
NH
—CHF2
—H
—OCH2CH3


F350(a and b)
NH
—CHF2
—H
—OCF3


F351(a and b)
NH
—CHF2
—H
-tert-butyl


F352(a and b)
NH
—CHF2
—H
-iso-propyl


F353(a and b)
NH
—Br
—Br
—H


F354(a and b)
NH
—Br
—Cl
—H


F355(a and b)
NH
—Br
—F
—H


F356(a and b)
NH
—Br
—CH3
—H


F357(a and b)
NH
—Br
—CF3
—H


F358(a and b)
NH
—Br
—OCH3
—H


F359(a and b)
NH
—Br
—OCH2CH3
—H


F360(a and b)
NH
—Br
—OCF3
—H


F361(a and b)
NH
—Br
-tert-butyl
—H


F362(a and b)
NH
—Br
-iso-propyl
—H


F363(a and b)
NH
—Br
—CH3
—CH3


F364(a and b)
NH
—Br
—H
—H


F365(a and b)
NH
—Br
—H
—Cl


F366(a and b)
NH
—Br
—H
—Br


F367(a and b)
NH
—Br
—H
—F


F368(a and b)
NH
—Br
—H
—CH3


F369(a and b)
NH
—Br
—H
—CF3


F370(a and b)
NH
—Br
—H
—OCH3


F371(a and b)
NH
—Br
—H
—OCH2CH3


F372(a and b)
NH
—Br
—H
—OCF3


F373(a and b)
NH
—Br
—H
-tert-butyl


F374(a and b)
NH
—Br
—H
-iso-propyl


F375(a and b)
NH
—I
—Cl
—H


F376(a and b)
NH
—I
—Br
—H


F377(a and b)
NH
—I
—F
—H


F378(a and b)
NH
—I
—CH3
—H


F379(a and b)
NH
—I
—CF3
—H


F380(a and b)
NH
—I
—OCH3
—H


F381(a and b)
NH
—I
—OCH2CH3
—H


F382(a and b)
NH
—I
—OCF3
—H


F383(a and b)
NH
—I
-tert-butyl
—H


F384(a and b)
NH
—I
-iso-propyl
—H


F385(a and b)
NH
—I
—CH3
—CH3


F386(a and b)
NH
—I
—H
—H


F387(a and b)
NH
—I
—H
—Cl


F388(a and b)
NH
—I
—H
—Br


F389(a and b)
NH
—I
—H
—F


F390(a and b)
NH
—I
—H
—CH3


F391(a and b)
NH
—I
—H
—CF3


F392(a and b)
NH
—I
—H
—OCH3


F393(a and b)
NH
—I
—H
—OCH2CH3


F394(a and b)
NH
—I
—H
—OCF3


F395(a and b)
NH
—I
—H
-tert-butyl


F396(a and b)
NH
—I
—H
-iso-propyl





In the column labeled “Compound”:


(a) means Z1 is CH and Z2 is N; and


(b) means Z1 is N and Z2 is CH.














TABLE 7








(IX)








 







and pharmaceutically acceptable salts thereof, where:











Compound
Y
R1
(R8)a
(R8)b





 G1(a and b)
S
—Cl
—Cl
—H


 G2(a and b)
S
—Cl
—Br
—H


 G3(a and b)
S
—Cl
—F
—H


 G4(a and b)
S
—Cl
—CH3
—H


 G5(a and b)
S
—Cl
—CF3
—H


 G6(a and b)
S
—Cl
—OCH3
—H


 G7(a and b)
S
—Cl
—OCH2CH3
—H


 G8(a and b)
S
—Cl
—OCF3
—H


 G9(a and b)
S
—Cl
-tert-butyl
—H


 G10(a and b)
S
—Cl
-iso-propyl
—H


 G11(a and b)
S
—Cl
—CH3
—CH3


 G12(a and b)
S
—Cl
—H
—H


 G13(a and b)
S
—Cl
—H
—Cl


 G14(a and b)
S
—Cl
—H
—Br


 G15(a and b)
S
—Cl
—H
—F


 G16(a and b)
S
—Cl
—H
—CH3


 G17(a and b)
S
—Cl
—H
—CF3


 G18(a and b)
S
—Cl
—H
—OCH3


 G19(a and b)
S
—Cl
—H
—OCH2CH3


 G20(a and b)
S
—Cl
—H
—OCF3


 G21(a and b)
S
—Cl
—H
-tert-butyl


 G22(a and b)
S
—Cl
—H
-iso-propyl


 G23(a and b)
S
—CH3
—Cl
—H


 G24(a and b)
S
—CH3
—Br
—H


 G25(a and b)
S
—CH3
—F
—H


 G26(a and b)
S
—CH3
—CH3
—H


 G27(a and b)
S
—CH3
—CF3
—H


 G28(a and b)
S
—CH3
—OCH3
—H


 G29(a and b)
S
—CH3
—OCH2CH3
—H


 G30(a and b)
S
—CH3
—OCF3
—H


 G31(a and b)
S
—CH3
-tert-butyl
—H


 G32(a and b)
S
—CH3
-iso-propyl
—H


 G33(a and b)
S
—CH3
—CH3
—CH3


 G34(a and b)
S
—CH3
—H
—H


 G35(a and b)
S
—CH3
—H
—Cl


 G36(a and b)
S
—CH3
—H
—Br


 G37(a and b)
S
—CH3
—H
—F


 G38(a and b)
S
—CH3
—H
—CH3


 G39(a and b)
S
—CH3
—H
—CF3


 G40(a and b)
S
—CH3
—H
—OCH3


 G41(a and b)
S
—CH3
—H
—OCH2CH3


 G42(a and b)
S
—CH3
—H
—OCF3


 G43(a and b)
S
—CH3
—H
-tert-butyl


 G44(a and b)
S
—CH3
—H
-iso-propyl


 G45(a and b)
S
—CF3
—Cl
—H


 G46(a and b)
S
—CF3
—Br
—H


 G47(a and b)
S
—CF3
—F
—H


 G48(a and b)
S
—CF3
—CH3
—H


 G49(a and b)
S
—CF3
—CF3
—H


 G50(a and b)
S
—CF3
—OCH3
—H


 G51(a and b)
S
—CF3
—OCH2CH3
—H


 G52(a and b)
S
—CF3
—OCF3
—H


 G53(a and b)
S
—CF3
-tert-butyl
—H


 G54(a and b)
S
—CF3
-iso-propyl
—H


 G55(a and b)
S
—CF3
—CH3
—CH3


 G56(a and b)
S
—CF3
—H
—H


 G57(a and b)
S
—CF3
—H
—Cl


 G58(a and b)
S
—CF3
—H
—Br


 G59(a and b)
S
—CF3
—H
—F


 G60(a and b)
S
—CF3
—H
—CH3


 G61(a and b)
S
—CF3
—H
—CF3


 G62(a and b)
S
—CF3
—H
—OCH3


 G63(a and b)
S
—CF3
—H
—OCH2CH3


 G64(a and b)
S
—CF3
—H
—OCF3


 G65(a and b)
S
—CF3
—H
-tert-butyl


 G66(a and b)
S
—CF3
—H
-iso-propyl


 G67(a and b)
S
—CHF2
—Cl
—H


 G68(a and b)
S
—CHF2
—Br
—H


 G69(a and b)
S
—CHF2
—F
—H


 G70(a and b)
S
—CHF2
—CH3
—H


 G71(a and b)
S
—CHF2
—CF3
—H


 G72(a and b)
S
—CHF2
—OCH3
—H


 G73(a and b)
S
—CHF2
—OCH2CH3
—H


 G74(a and b)
S
—CHF2
—OCF3
—H


 G75(a and b)
S
—CHF2
-tert-butyl
—H


 G76(a and b)
S
—CHF2
-iso-propyl
—H


 G77(a and b)
S
—CHF2
—CH3
—CH3


 G78(a and b)
S
—CHF2
—H
—H


 G79(a and b)
S
—CHF2
—H
—Cl


 G80(a and b)
S
—CHF2
—H
—Br


 G81(a and b)
S
—CHF2
—H
—F


 G82(a and b)
S
—CHF2
—H
—CH3


 G83(a and b)
S
—CHF2
—H
—CF3


 G84(a and b)
S
—CHF2
—H
—OCH3


 G85(a and b)
S
—CHF2
—H
—OCH2CH3


 G86(a and b)
S
—CHF2
—H
—OCF3


 G87(a and b)
S
—CHF2
—H
-tert-butyl


 G88(a and b)
S
—CHF2
—H
-iso-propyl


 G89(a and b)
S
—Br
—Br
—H


 G90(a and b)
S
—Br
—Cl
—H


 G91(a and b)
S
—Br
—F
—H


 G92(a and b)
S
—Br
—CH3
—H


 G93(a and b)
S
—Br
—CF3
—H


 G94(a and b)
S
—Br
—OCH3
—H


 G95(a and b)
S
—Br
—OCH2CH3
—H


 G96(a and b)
S
—Br
—OCF3
—H


 G97(a and b)
S
—Br
-tert-butyl
—H


 G98(a and b)
S
—Br
-iso-propyl
—H


 G99(a and b)
S
—Br
—CH3
—CH3


G100(a and b)
S
—Br
—H
—H


G101(a and b)
S
—Br
—H
—Cl


G102(a and b)
S
—Br
—H
—Br


G103(a and b)
S
—Br
—H
—F


G104(a and b)
S
—Br
—H
—CH3


G105(a and b)
S
—Br
—H
—CF3


G106(a and b)
S
—Br
—H
—OCH3


G107(a and b)
S
—Br
—H
—OCH2CH3


G108(a and b)
S
—Br
—H
—OCF3


G109(a and b)
S
—Br
—H
-tert-butyl


G110(a and b)
S
—Br
—H
-iso-propyl


G111(a and b)
S
—I
—Cl
—H


G112(a and b)
S
—I
—Br
—H


G113(a and b)
S
—I
—F
—H


G114(a and b)
S
—I
—CH3
—H


G115(a and b)
S
—I
—CF3
—H


G116(a and b)
S
—I
—OCH3
—H


G117(a and b)
S
—I
—OCH2CH3
—H


G118(a and b)
S
—I
—OCF3
—H


G119(a and b)
S
—I
-tert-butyl
—H


G120(a and b)
S
—I
-iso-propyl
—H


G121(a and b)
S
—I
—CH3
—CH3


G122(a and b)
S
—I
—H
—H


G123(a and b)
S
—I
—H
—Cl


G124(a and b)
S
—I
—H
—Br


G125(a and b)
S
—I
—H
—F


G126(a and b)
S
—I
—H
—CH3


G127(a and b)
S
—I
—H
—CF3


G128(a and b)
S
—I
—H
—OCH3


G129(a and b)
S
—I
—H
—OCH2CH3


G130(a and b)
S
—I
—H
—OCF3


G131(a and b)
S
—I
—H
-tert-butyl


G132(a and b)
S
—I
—H
-iso-propyl


G133(a and b)
O
—Cl
—Cl
—H


G134(a and b)
O
—Cl
—Br
—H


G135(a and b)
O
—Cl
—F
—H


G136(a and b)
O
—Cl
—CH3
—H


G137(a and b)
O
—Cl
—CF3
—H


G138(a and b)
O
—Cl
—OCH3
—H


G139(a and b)
O
—Cl
—OCH2CH3
—H


G140(a and b)
O
—Cl
—OCF3
—H


G141(a and b)
O
—Cl
-tert-butyl
—H


G142(a and b)
O
—Cl
-iso-propyl
—H


G143(a and b)
O
—Cl
—CH3
—CH3


G144(a and b)
O
—Cl
—H
—H


G145(a and b)
O
—Cl
—H
—CH3


G146(a and b)
O
—Cl
—H
—Cl


G147(a and b)
O
—Cl
—H
—Br


G148(a and b)
O
—Cl
—H
—F


G149(a and b)
O
—Cl
—H
—CF3


G150(a and b)
O
—Cl
—H
—OCH3


G151(a and b)
O
—Cl
—H
—OCH2CH3


G152(a and b)
O
—Cl
—H
—OCF3


G153(a and b)
O
—Cl
—H
-tert-butyl


G154(a and b)
O
—Cl
—H
-iso-propyl


G155(a and b)
O
—CH3
—Cl
—H


G156(a and b)
O
—CH3
—Br
—H


G157(a and b)
O
—CH3
—F
—H


G158(a and b)
O
—CH3
—CH3
—H


G159(a and b)
O
—CH3
—CF3
—H


G160(a and b)
O
—CH3
—OCH3
—H


G161(a and b)
O
—CH3
—OCH2CH3
—H


G162(a and b)
O
—CH3
—OCF3
—H


G163(a and b)
O
—CH3
-tert-butyl
—H


G164(a and b)
O
—CH3
-iso-propyl
—H


G165(a and b)
O
—CH3
—CH3
—CH3


G166(a and b)
O
—CH3
—H
—H


G167(a and b)
O
—CH3
—H
—Cl


G168(a and b)
O
—CH3
—H
—Br


G169(a and b)
O
—CH3
—H
—F


G170(a and b)
O
—CH3
—H
—CH3


G171(a and b)
O
—CH3
—H
—CF3


G172(a and b)
O
—CH3
—H
—OCH3


G173(a and b)
O
—CH3
—H
—OCH2CH3


G174(a and b)
O
—CH3
—H
—OCF3


G175(a and b)
O
—CH3
—H
-tert-butyl


G176(a and b)
O
—CH3
—H
-iso-propyl


G177(a and b)
O
—CF3
—Cl
—H


G178(a and b)
O
—CF3
—Br
—H


G179(a and b)
O
—CF3
—F
—H


G180(a and b)
O
—CF3
—CH3
—H


G181(a and b)
O
—CF3
—CF3
—H


G182(a and b)
O
—CF3
—OCH3
—H


G183(a and b)
O
—CF3
—OCH2CH3
—H


G184(a and b)
O
—CF3
—OCF3
—H


G185(a and b)
O
—CF3
-tert-butyl
—H


G186(a and b)
O
—CF3
-iso-propyl
—H


G187(a and b)
O
—CF3
—CH3
—CH3


G188(a and b)
O
—CF3
—H
—H


G189(a and b)
O
—CF3
—H
—Cl


G190(a and b)
O
—CF3
—H
—Br


G191(a and b)
O
—CF3
—H
—F


G192(a and b)
O
—CF3
—H
—CH3


G193(a and b)
O
—CF3
—H
—CF3


G194(a and b)
O
—CF3
—H
—OCH3


G195(a and b)
O
—CF3
—H
—OCH2CH3


G196(a and b)
O
—CF3
—H
—OCF3


G197(a and b)
O
—CF3
—H
-tert-butyl


G198(a and b)
O
—CF3
—H
-iso-propyl


G199(a and b)
O
—CHF2
—Cl
—H


G200(a and b)
O
—CHF2
—Br
—H


G201(a and b)
O
—CHF2
—F
—H


G202(a and b)
O
—CHF2
—CH3
—H


G203(a and b)
O
—CHF2
—CF3
—H


G204(a and b)
O
—CHF2
—OCH3
—H


G205(a and b)
O
—CHF2
—OCH2CH3
—H


G206(a and b)
O
—CHF2
—OCF3
—H


G207(a and b)
O
—CHF2
-tert-butyl
—H


G208(a and b)
O
—CHF2
-iso-propyl
—H


G209(a and b)
O
—CHF2
—CH3
—CH3


G210(a and b)
O
—CHF2
—H
—H


G211(a and b)
O
—CHF2
—H
—Cl


G212(a and b)
O
—CHF2
—H
—Br


G213(a and b)
O
—CHF2
—H
—F


G214(a and b)
O
—CHF2
—H
—CH3


G215(a and b)
O
—CHF2
—H
—CF3


G216(a and b)
O
—CHF2
—H
—OCH3


G217(a and b)
O
—CHF2
—H
—OCH2CH3


G218(a and b)
O
—CHF2
—H
—OCF3


G219(a and b)
O
—CHF2
—H
-tert-butyl


G220(a and b)
O
—CHF2
—H
-iso-propyl


G221(a and b)
O
—Br
—Br
—H


G222(a and b)
O
—Br
—Cl
—H


G223(a and b)
O
—Br
—F
—H


G224(a and b)
O
—Br
—CH3
—H


G225(a and b)
O
—Br
—CF3
—H


G226(a and b)
O
—Br
—OCH3
—H


G227(a and b)
O
—Br
—OCH2CH3
—H


G228(a and b)
O
—Br
—OCF3
—H


G229(a and b)
O
—Br
-tert-butyl
—H


G230(a and b)
O
—Br
-iso-propyl
—H


G231(a and b)
O
—Br
—CH3
—CH3


G232(a and b)
O
—Br
—H
—H


G233(a and b)
O
—Br
—H
—Cl


G234(a and b)
O
—Br
—H
—Br


G235(a and b)
O
—Br
—H
—F


G236(a and b)
O
—Br
—H
—CH3


G237(a and b)
O
—Br
—H
—CF3


G238(a and b)
O
—Br
—H
—OCH3


G239(a and b)
O
—Br
—H
—OCH2CH3


G240(a and b)
O
—Br
—H
—OCF3


G241(a and b)
O
—Br
—H
-tert-butyl


G242(a and b)
O
—Br
—H
-iso-propyl


G243(a and b)
O
—I
—Cl
—H


G244(a and b)
O
—I
—Br
—H


G245(a and b)
O
—I
—F
—H


G246(a and b)
O
—I
—CH3
—H


G247(a and b)
O
—I
—CF3
—H


G248(a and b)
O
—I
—OCH3
—H


G249(a and b)
O
—I
—OCH2CH3
—H


G250(a and b)
O
—I
—OCF3
—H


G251(a and b)
O
—I
-tert-butyl
—H


G252(a and b)
O
—I
-iso-propyl
—H


G253(a and b)
O
—I
—CH3
—CH3


G254(a and b)
O
—I
—H
—H


G255(a and b)
O
—I
—H
—Cl


G256(a and b)
O
—I
—H
—Br


G257(a and b)
O
—I
—H
—F


G258(a and b)
O
—I
—H
—CH3


G259(a and b)
O
—I
—H
—CF3


G260(a and b)
O
—I
—H
—OCH3


G261(a and b)
O
—I
—H
—OCH2CH3


G262(a and b)
O
—I
—H
—OCF3


G263(a and b)
O
—I
—H
-tert-butyl


G264(a and b)
O
—I
—H
-iso-propyl


G265(a and b)
NH
—Cl
—Cl
—H


G266(a and b)
NH
—Cl
—Br
—H


G267(a and b)
NH
—Cl
—F
—H


G268(a and b)
NH
—Cl
—CH3
—H


G269(a and b)
NH
—Cl
—CF3
—H


G270(a and b)
NH
—Cl
—OCH3
—H


G271(a and b)
NH
—Cl
—OCH2CH3
—H


G272(a and b)
NH
—Cl
—OCF3
—H


G273(a and b)
NH
—Cl
-tert-butyl
—H


G274(a and b)
NH
—Cl
-iso-propyl
—H


G275(a and b)
NH
—Cl
—CH3
—CH3


G276(a and b)
NH
—Cl
—H
—H


G277(a and b)
NH
—Cl
—H
—CH3


G278(a and b)
NH
—Cl
—H
—Cl


G279(a and b)
NH
—Cl
—H
—Br


G280(a and b)
NH
—Cl
—H
—F


G281(a and b)
NH
—Cl
—H
—CF3


G282(a and b)
NH
—Cl
—H
—OCH3


G283(a and b)
NH
—Cl
—H
—OCH2CH3


G284(a and b)
NH
—Cl
—H
—OCF3


G285(a and b)
NH
—Cl
—H
-tert-butyl


G286(a and b)
NH
—Cl
—H
-iso-propyl


G287(a and b)
NH
—CH3
—Cl
—H


G288(a and b)
NH
—CH3
—Br
—H


G289(a and b)
NH
—CH3
—F
—H


G290(a and b)
NH
—CH3
—CH3
—H


G291(a and b)
NH
—CH3
—CF3
—H


G292(a and b)
NH
—CH3
—OCH3
—H


G293(a and b)
NH
—CH3
—OCH2CH3
—H


G294(a and b)
NH
—CH3
—OCF3
—H


G295(a and b)
NH
—CH3
-tert-butyl
—H


G296(a and b)
NH
—CH3
-iso-propyl
—H


G297(a and b)
NH
—CH3
—CH3
—CH3


G298(a and b)
NH
—CH3
—H
—H


G299(a and b)
NH
—CH3
—H
—Cl


G300(a and b)
NH
—CH3
—H
—Br


G301(a and b)
NH
—CH3
—H
—F


G302(a and b)
NH
—CH3
—H
—CH3


G303(a and b)
NH
—CH3
—H
—CF3


G304(a and b)
NH
—CH3
—H
—OCH3


G305(a and b)
NH
—CH3
—H
—OCH2CH3


G306(a and b)
NH
—CH3
—H
—OCF3


G307(a and b)
NH
—CH3
—H
-tert-butyl


G308(a and b)
NH
—CH3
—H
-iso-propyl


G309(a and b)
NH
—CF3
—Cl
—H


G310(a and b)
NH
—CF3
—Br
—H


G311(a and b)
NH
—CF3
—F
—H


G312(a and b)
NH
—CF3
—CH3
—H


G313(a and b)
NH
—CF3
—CF3
—H


G314(a and b)
NH
—CF3
—OCH3
—H


G315(a and b)
NH
—CF3
—OCH2CH3
—H


G316(a and b)
NH
—CF3
—OCF3
—H


G317(a and b)
NH
—CF3
-tert-butyl
—H


G318(a and b)
NH
—CF3
-iso-propyl
—H


G319(a and b)
NH
—CF3
—CH3
—CH3


G320(a and b)
NH
—CF3
—H
—H


G321(a and b)
NH
—CF3
—H
—Cl


G322(a and b)
NH
—CF3
—H
—Br


G323(a and b)
NH
—CF3
—H
—F


G324(a and b)
NH
—CF3
—H
—CH3


G325(a and b)
NH
—CF3
—H
—CF3


G326(a and b)
NH
—CF3
—H
—OCH3


G327(a and b)
NH
—CF3
—H
—OCH2CH3


G328(a and b)
NH
—CF3
—H
—OCF3


G329(a and b)
NH
—CF3
—H
-tert-butyl


G330(a and b)
NH
—CF3
—H
-iso-propyl


G331(a and b)
NH
—CHF2
—Cl
—H


G332(a and b)
NH
—CHF2
—Br
—H


G333(a and b)
NH
—CHF2
—F
—H


G334(a and b)
NH
—CHF2
—CH3
—H


G335(a and b)
NH
—CHF2
—CF3
—H


G336(a and b)
NH
—CHF2
—OCH3
—H


G337(a and b)
NH
—CHF2
—OCH2CH3
—H


G338(a and b)
NH
—CHF2
—OCF3
—H


G339(a and b)
NH
—CHF2
-tert-butyl
—H


G340(a and b)
NH
—CHF2
-iso-propyl
—H


G341(a and b)
NH
—CHF2
—CH3
—CH3


G342(a and b)
NH
—CHF2
—H
—H


G343(a and b)
NH
—CHF2
—H
—Cl


G344(a and b)
NH
—CHF2
—H
—Br


G345(a and b)
NH
—CHF2
—H
—F


G346(a and b)
NH
—CHF2
—H
—CH3


G347(a and b)
NH
—CHF2
—H
—CF3


G348(a and b)
NH
—CHF2
—H
—OCH3


G349(a and b)
NH
—CHF2
—H
—OCH2CH3


G350(a and b)
NH
—CHF2
—H
—OCF3


G351(a and b)
NH
—CHF2
—H
-tert-butyl


G352(a and b)
NH
—CHF2
—H
-iso-propyl


G353(a and b)
NH
—Br
—Br
—H


G354(a and b)
NH
—Br
—Cl
—H


G355(a and b)
NH
—Br
—F
—H


G356(a and b)
NH
—Br
—CH3
—H


G357(a and b)
NH
—Br
—CF3
—H


G358(a and b)
NH
—Br
—OCH3
—H


G359(a and b)
NH
—Br
—OCH2CH3
—H


G360(a and b)
NH
—Br
—OCF3
—H


G361(a and b)
NH
—Br
-tert-butyl
—H


G362(a and b)
NH
—Br
-iso-propyl
—H


G363(a and b)
NH
—Br
—CH3
—CH3


G364(a and b)
NH
—Br
—H
—H


G365(a and b)
NH
—Br
—H
—Cl


G366(a and b)
NH
—Br
—H
—Br


G367(a and b)
NH
—Br
—H
—F


G368(a and b)
NH
—Br
—H
—CH3


G369(a and b)
NH
—Br
—H
—CF3


G370(a and b)
NH
—Br
—H
—OCH3


G371(a and b)
NH
—Br
—H
—OCH2CH3


G372(a and b)
NH
—Br
—H
—OCF3


G373(a and b)
NH
—Br
—H
-tert-butyl


G374(a and b)
NH
—Br
—H
-iso-propyl


G375(a and b)
NH
—I
—Cl
—H


G376(a and b)
NH
—I
—Br
—H


G377(a and b)
NH
—I
—F
—H


G378(a and b)
NH
—I
—CH3
—H


G379(a and b)
NH
—I
—CF3
—H


G380(a and b)
NH
—I
—OCH3
—H


G381(a and b)
NH
—I
—OCH2CH3
—H


G382(a and b)
NH
—I
—OCF3
—H


G383(a and b)
NH
—I
-tert-butyl
—H


G384(a and b)
NH
—I
-iso-propyl
—H


G385(a and b)
NH
—I
—CH3
—CH3


G386(a and b)
NH
—I
—H
—H


G387(a and b)
NH
—I
—H
—Cl


G388(a and b)
NH
—I
—H
—Br


G389(a and b)
NH
—I
—H
—F


G390(a and b)
NH
—I
—H
—CH3


G391(a and b)
NH
—I
—H
—CF3


G392(a and b)
NH
—I
—H
—OCH3


G393(a and b)
NH
—I
—H
—OCH2CH3


G394(a and b)
NH
—I
—H
—OCF3


G395(a and b)
NH
—I
—H
-tert-butyl


G396(a and b)
NH
—I
—H
-iso-propyl





In the column labeled “Compound”:


(a) means Z1 is CH and Z2 is N; and


(b) means Z1 is N and Z2 is CH.














TABLE 8








(X)








 











Compound
Y
R1
(R8)a
(R8)b





 H1 (a) and (b)
S
—Cl
—Cl
—H


 H2 (a) and (b)
S
—Cl
—Br
—H


 H3 (a) and (b)
S
—Cl
—F
—H


 H4 (a) and (b)
S
—Cl
—CH3
—H


 H5 (a) and (b)
S
—Cl
—CF3
—H


 H6 (a) and (b)
S
—Cl
—OCH3
—H


 H7 (a) and (b)
S
—Cl
—OCH2CH3
—H


 H8 (a) and (b)
S
—Cl
—OCF3
—H


 H9 (a) and (b)
S
—Cl
-tert-butyl
—H


 H10 (a) and (b)
S
—Cl
-iso-propyl
—H


 H11 (a) and (b)
S
—Cl
—CH3
—CH3


 H12 (a) and (b)
S
—Cl
—H
—H


 H13 (a) and (b)
S
—Cl
—H
—Cl


 H14 (a) and (b)
S
—Cl
—H
—Br


 H15 (a) and (b)
S
—Cl
—H
—F


 H16 (a) and (b)
S
—Cl
—H
—CH3


 H17 (a) and (b)
S
—Cl
—H
—CF3


 H18 (a) and (b)
S
—Cl
—H
—OCH3


 H19 (a) and (b)
S
—Cl
—H
—OCH2CH3


 H20 (a) and (b)
S
—Cl
—H
—OCF3


 H21 (a) and (b)
S
—Cl
—H
-tert-butyl


 H22 (a) and (b)
S
—Cl
—H
-iso-propyl


 H23 (a) and (b)
S
—CH3
—Cl
—H


 H24 (a) and (b)
S
—CH3
—Br
—H


 H25 (a) and (b)
S
—CH3
—F
—H


 H26 (a) and (b)
S
—CH3
—CH3
—H


 H27 (a) and (b)
S
—CH3
—CF3
—H


 H28 (a) and (b)
S
—CH3
—OCH3
—H


 H29 (a) and (b)
S
—CH3
—OCH2CH3
—H


 H30 (a) and (b)
S
—CH3
—OCF3
—H


 H31 (a) and (b)
S
—CH3
-tert-butyl
—H


 H32 (a) and (b)
S
—CH3
-iso-propyl
—H


 H33 (a) and (b)
S
—CH3
—CH3
—CH3


 H34 (a) and (b)
S
—CH3
—H
—H


 H35 (a) and (b)
S
—CH3
—H
—Cl


 H36 (a) and (b)
S
—CH3
—H
—Br


 H37 (a) and (b)
S
—CH3
—H
—F


 H38 (a) and (b)
S
—CH3
—H
—CH3


 H39 (a) and (b)
S
—CH3
—H
—CF3


 H40 (a) and (b)
S
—CH3
—H
—OCH3


 H41 (a) and (b)
S
—CH3
—H
—OCH2CH3


 H42 (a) and (b)
S
—CH3
—H
—OCF3


 H43 (a) and (b)
S
—CH3
—H
-tert-butyl


 H44 (a) and (b)
S
—CH3
—H
-iso-propyl


 H45 (a) and (b)
S
—CF3
—Cl
—H


 H46 (a) and (b)
S
—CF3
—Br
—H


 H47 (a) and (b)
S
—CF3
—F
—H


 H48 (a) and (b)
S
—CF3
—CH3
—H


 H49 (a) and (b)
S
—CF3
—CF3
—H


 H50 (a) and (b)
S
—CF3
—OCH3
—H


 H51 (a) and (b)
S
—CF3
—OCH2CH3
—H


 H52 (a) and (b)
S
—CF3
—OCF3
—H


 H53 (a) and (b)
S
—CF3
-tert-butyl
—H


 H54 (a) and (b)
S
—CF3
-iso-propyl
—H


 H55 (a) and (b)
S
—CF3
—CH3
—CH3


 H56 (a) and (b)
S
—CF3
—H
—H


 H57 (a) and (b)
S
—CF3
—H
—Cl


 H58 (a) and (b)
S
—CF3
—H
—Br


 H59 (a) and (b)
S
—CF3
—H
—F


 H60 (a) and (b)
S
—CF3
—H
—CH3


 H61 (a) and (b)
S
—CF3
—H
—CF3


 H62 (a) and (b)
S
—CF3
—H
—OCH3


 H63 (a) and (b)
S
—CF3
—H
—OCH2CH3


 H64 (a) and (b)
S
—CF3
—H
—OCF3


 H65 (a) and (b)
S
—CF3
—H
-tert-butyl


 H66 (a) and (b)
S
—CF3
—H
-iso-propyl


 H67 (a) and (b)
S
—CHF2
—Cl
—H


 H68 (a) and (b)
S
—CHF2
—Br
—H


 H69 (a) and (b)
S
—CHF2
—F
—H


 H70 (a) and (b)
S
—CHF2
—CH3
—H


 H71 (a) and (b)
S
—CHF2
—CF3
—H


 H72 (a) and (b)
S
—CHF2
—OCH3
—H


 H73 (a) and (b)
S
—CHF2
—OCH2CH3
—H


 H74 (a) and (b)
S
—CHF2
—OCF3
—H


 H75 (a) and (b)
S
—CHF2
-tert-butyl
—H


 H76 (a) and (b)
S
—CHF2
-iso-propyl
—H


 H77 (a) and (b)
S
—CHF2
—CH3
—CH3


 H78 (a) and (b)
S
—CHF2
—H
—H


 H79 (a) and (b)
S
—CHF2
—H
—Cl


 H80 (a) and (b)
S
—CHF2
—H
—Br


 H81 (a) and (b)
S
—CHF2
—H
—F


 H82 (a) and (b)
S
—CHF2
—H
—CH3


 H83 (a) and (b)
S
—CHF2
—H
—CF3


 H84 (a) and (b)
S
—CHF2
—H
—OCH3


 H85 (a) and (b)
S
—CHF2
—H
—OCH2CH3


 H86 (a) and (b)
S
—CHF2
—H
—OCF3


 H87 (a) and (b)
S
—CHF2
—H
-tert-butyl


 H88 (a) and (b)
S
—CHF2
—H
-iso-propyl


 H89 (a) and (b)
S
—Br
—Br
—H


 H90 (a) and (b)
S
—Br
—Cl
—H


 H91 (a) and (b)
S
—Br
—F
—H


 H92 (a) and (b)
S
—Br
—CH3
—H


 H93 (a) and (b)
S
—Br
—CF3
—H


 H94 (a) and (b)
S
—Br
—OCH3
—H


 H95 (a) and (b)
S
—Br
—OCH2CH3
—H


 H96 (a) and (b)
S
—Br
—OCF3
—H


 H97 (a) and (b)
S
—Br
-tert-butyl
—H


 H98 (a) and (b)
S
—Br
-iso-propyl
—H


 H99 (a) and (b)
S
—Br
—CH3
—CH3


H100 (a) and (b)
S
—Br
—H
—H


H101 (a) and (b)
S
—Br
—H
—Cl


H102 (a) and (b)
S
—Br
—H
—Br


H103 (a) and (b)
S
—Br
—H
—F


H104 (a) and (b)
S
—Br
—H
—CH3


H105 (a) and (b)
S
—Br
—H
—CF3


H106 (a) and (b)
S
—Br
—H
—OCH3


H107 (a) and (b)
S
—Br
—H
—OCH2CH3


H108 (a) and (b)
S
—Br
—H
—OCF3


H109 (a) and (b)
S
—Br
—H
-tert-butyl


H110 (a) and (b)
S
—Br
—H
-iso-propyl


H111 (a) and (b)
S
—I
—Cl
—H


H112 (a) and (b)
S
—I
—Br
—H


H113 (a) and (b)
S
—I
—F
—H


H114 (a) and (b)
S
—I
—CH3
—H


H115 (a) and (b)
S
—I
—CF3
—H


H116 (a) and (b)
S
—I
—OCH3
—H


H117 (a) and (b)
S
—I
—OCH2CH3
—H


H118 (a) and (b)
S
—I
—OCF3
—H


H119 (a) and (b)
S
—I
-tert-butyl
—H


H120 (a) and (b)
S
—I
-iso-propyl
—H


H121 (a) and (b)
S
—I
—CH3
—CH3


H122 (a) and (b)
S
—I
—H
—H


H123 (a) and (b)
S
—I
—H
—Cl


H124 (a) and (b)
S
—I
—H
—Br


H125 (a) and (b)
S
—I
—H
—F


H126 (a) and (b)
S
—I
—H
—CH3


H127 (a) and (b)
S
—I
—H
—CF3


H128 (a) and (b)
S
—I
—H
—OCH3


H129 (a) and (b)
S
—I
—H
—OCH2CH3


H130 (a) and (b)
S
—I
—H
—OCF3


H131 (a) and (b)
S
—I
—H
-tert-butyl


H132 (a) and (b)
S
—I
—H
-iso-propyl


H133 (a) and (b)
O
—Cl
—Cl
—H


H134 (a) and (b)
O
—Cl
—Br
—H


H135 (a) and (b)
O
—Cl
—F
—H


H136 (a) and (b)
O
—Cl
—CH3
—H


H137 (a) and (b)
O
—Cl
—CF3
—H


H138 (a) and (b)
O
—Cl
—OCH3
—H


H139 (a) and (b)
O
—Cl
—OCH2CH3
—H


H140 (a) and (b)
O
—Cl
—OCF3
—H


H141 (a) and (b)
O
—Cl
-tert-butyl
—H


H142 (a) and (b)
O
—Cl
-iso-propyl
—H


H143 (a) and (b)
O
—Cl
—CH3
—CH3


H144 (a) and (b)
O
—Cl
—H
—H


H145 (a) and (b)
O
—Cl
—H
—CH3


H146 (a) and (b)
O
—Cl
—H
—Cl


H147 (a) and (b)
O
—Cl
—H
—Br


H148 (a) and (b)
O
—Cl
—H
—F


H149 (a) and (b)
O
—Cl
—H
—CF3


H150 (a) and (b)
O
—Cl
—H
—OCH3


H151 (a) and (b)
O
—Cl
—H
—OCH2CH3


H152 (a) and (b)
O
—Cl
—H
—OCF3


H153 (a) and (b)
O
—Cl
—H
-tert-butyl


H154 (a) and (b)
O
—Cl
—H
-iso-propyl


H155 (a) and (b)
O
—CH3
—Cl
—H


H156 (a) and (b)
O
—CH3
—Br
—H


H157 (a) and (b)
O
—CH3
—F
—H


H158 (a) and (b)
O
—CH3
—CH3
—H


H159 (a) and (b)
O
—CH3
—CF3
—H


H160 (a) and (b)
O
—CH3
—OCH3
—H


H161 (a) and (b)
O
—CH3
—OCH2CH3
—H


H162 (a) and (b)
O
—CH3
—OCF3
—H


H163 (a) and (b)
O
—CH3
-tert-butyl
—H


H164 (a) and (b)
O
—CH3
-iso-propyl
—H


H165 (a) and (b)
O
—CH3
—CH3
—CH3


H166 (a) and (b)
O
—CH3
—H
—H


H167 (a) and (b)
O
—CH3
—H
—Cl


H168 (a) and (b)
O
—CH3
—H
—Br


H169 (a) and (b)
O
—CH3
—H
—F


H170 (a) and (b)
O
—CH3
—H
—CH3


H171 (a) and (b)
O
—CH3
—H
—CF3


H172 (a) and (b)
O
—CH3
—H
—OCH3


H173 (a) and (b)
O
—CH3
—H
—OCH2CH3


H174 (a) and (b)
O
—CH3
—H
—OCF3


H175 (a) and (b)
O
—CH3
—H
-tert-butyl


H176 (a) and (b)
O
—CH3
—H
-iso-propyl


H177 (a) and (b)
O
—CF3
—Cl
—H


H178 (a) and (b)
O
—CF3
—Br
—H


H179 (a) and (b)
O
—CF3
—F
—H


H180 (a) and (b)
O
—CF3
—CH3
—H


H181 (a) and (b)
O
—CF3
—CF3
—H


H182 (a) and (b)
O
—CF3
—OCH3
—H


H183 (a) and (b)
O
—CF3
—OCH2CH3
—H


H184 (a) and (b)
O
—CF3
—OCF3
—H


H185 (a) and (b)
O
—CF3
-tert-butyl
—H


H186 (a) and (b)
O
—CF3
-iso-propyl
—H


H187 (a) and (b)
O
—CF3
—CH3
—CH3


H188 (a) and (b)
O
—CF3
—H
—H


H189 (a) and (b)
O
—CF3
—H
—Cl


H190 (a) and (b)
O
—CF3
—H
—Br


H191 (a) and (b)
O
—CF3
—H
—F


H192 (a) and (b)
O
—CF3
—H
—CH3


H193 (a) and (b)
O
—CF3
—H
—CF3


H194 (a) and (b)
O
—CF3
—H
—OCH3


H195 (a) and (b)
O
—CF3
—H
—OCH2CH3


H196 (a) and (b)
O
—CF3
—H
—OCF3


H197 (a) and (b)
O
—CF3
—H
-tert-butyl


H198 (a) and (b)
O
—CF3
—H
-iso-propyl


H199 (a) and (b)
O
—CHF2
—Cl
—H


H200 (a) and (b)
O
—CHF2
—Br
—H


H201 (a) and (b)
O
—CHF2
—F
—H


H202 (a) and (b)
O
—CHF2
—CH3
—H


H203 (a) and (b)
O
—CHF2
—CF3
—H


H204 (a) and (b)
O
—CHF2
—OCH3
—H


H205 (a) and (b)
O
—CHF2
—OCH2CH3
—H


H206 (a) and (b)
O
—CHF2
—OCF3
—H


H207 (a) and (b)
O
—CHF2
-tert-butyl
—H


H208 (a) and (b)
O
—CHF2
-iso-propyl
—H


H209 (a) and (b)
O
—CHF2
—CH3
—CH3


H210 (a) and (b)
O
—CHF2
—H
—H


H211 (a) and (b)
O
—CHF2
—H
—Cl


H212 (a) and (b)
O
—CHF2
—H
—Br


H213 (a) and (b)
O
—CHF2
—H
—F


H214 (a) and (b)
O
—CHF2
—H
—CH3


H215 (a) and (b)
O
—CHF2
—H
—CF3


H216 (a) and (b)
O
—CHF2
—H
—OCH3


H217 (a) and (b)
O
—CHF2
—H
—OCH2CH3


H218 (a) and (b)
O
—CHF2
—H
—OCF3


H219 (a) and (b)
O
—CHF2
—H
-tert-butyl


H220 (a) and (b)
O
—CHF2
—H
-iso-propyl


H221 (a) and (b)
O
—Br
—Br
—H


H222 (a) and (b)
O
—Br
—Cl
—H


H223 (a) and (b)
O
—Br
—F
—H


H224 (a) and (b)
O
—Br
—CH3
—H


H225 (a) and (b)
O
—Br
—CF3
—H


H226 (a) and (b)
O
—Br
—OCH3
—H


H227 (a) and (b)
O
—Br
—OCH2CH3
—H


H228 (a) and (b)
O
—Br
—OCF3
—H


H229 (a) and (b)
O
—Br
-tert-butyl
—H


H230 (a) and (b)
O
—Br
-iso-propyl
—H


H231 (a) and (b)
O
—Br
—CH3
—CH3


H232 (a) and (b)
O
—Br
—H
—H


H233 (a) and (b)
O
—Br
—H
—Cl


H234 (a) and (b)
O
—Br
—H
—Br


H235 (a) and (b)
O
—Br
—H
—F


H236 (a) and (b)
O
—Br
—H
—CH3


H237 (a) and (b)
O
—Br
—H
—CF3


H238 (a) and (b)
O
—Br
—H
—OCH3


H239 (a) and (b)
O
—Br
—H
—OCH2CH3


H240 (a) and (b)
O
—Br
—H
—OCF3


H241 (a) and (b)
O
—Br
—H
-tert-butyl


H242 (a) and (b)
O
—Br
—H
-iso-propyl


H243 (a) and (b)
O
—I
—Cl
—H


H244 (a) and (b)
O
—I
—Br
—H


H245 (a) and (b)
O
—I
—F
—H


H246 (a) and (b)
O
—I
—CH3
—H


H247 (a) and (b)
O
—I
—CF3
—H


H248 (a) and (b)
O
—I
—OCH3
—H


H249 (a) and (b)
O
—I
—OCH2CH3
—H


H250 (a) and (b)
O
—I
—OCF3
—H


H251 (a) and (b)
O
—I
-tert-butyl
—H


H252 (a) and (b)
O
—I
-iso-propyl
—H


H253 (a) and (b)
O
—I
—CH3
—CH3


H254 (a) and (b)
O
—I
—H
—H


H255 (a) and (b)
O
—I
—H
—Cl


H256 (a) and (b)
O
—I
—H
—Br


H257 (a) and (b)
O
—I
—H
—F


H258 (a) and (b)
O
—I
—H
—CH3


H259 (a) and (b)
O
—I
—H
—CF3


H260 (a) and (b)
O
—I
—H
—OCH3


H261 (a) and (b)
O
—I
—H
—OCH2CH3


H262 (a) and (b)
O
—I
—H
—OCF3


H263 (a) and (b)
O
—I
—H
-tert-butyl


H264 (a) and (b)
O
—I
—H
-iso-propyl


H265 (a) and (b)
NH
—Cl
—Cl
—H


H266 (a) and (b)
NH
—Cl
—Br
—H


H267 (a) and (b)
NH
—Cl
—F
—H


H268 (a) and (b)
NH
—Cl
—CH3
—H


H269 (a) and (b)
NH
—Cl
—CF3
—H


H270 (a) and (b)
NH
—Cl
—OCH3
—H


H271 (a) and (b)
NH
—Cl
—OCH2CH3
—H


H272 (a) and (b)
NH
—Cl
—OCF3
—H


H273 (a) and (b)
NH
—Cl
-tert-butyl
—H


H274 (a) and (b)
NH
—Cl
-iso-propyl
—H


H275 (a) and (b)
NH
—Cl
—CH3
—CH3


H276 (a) and (b)
NH
—Cl
—H
—H


H277 (a) and (b)
NH
—Cl
—H
—CH3


H278 (a) and (b)
NH
—Cl
—H
—Cl


H279 (a) and (b)
NH
—Cl
—H
—Br


H280 (a) and (b)
NH
—Cl
—H
—F


H281 (a) and (b)
NH
—Cl
—H
—CF3


H282 (a) and (b)
NH
—Cl
—H
—OCH3


H283 (a) and (b)
NH
—Cl
—H
—OCH2CH3


H284 (a) and (b)
NH
—Cl
—H
—OCF3


H285 (a) and (b)
NH
—Cl
—H
-tert-butyl


H286 (a) and (b)
NH
—Cl
—H
-iso-propyl


H287 (a) and (b)
NH
—CH3
—Cl
—H


H288 (a) and (b)
NH
—CH3
—Br
—H


H289 (a) and (b)
NH
—CH3
—F
—H


H290 (a) and (b)
NH
—CH3
—CH3
—H


H291 (a) and (b)
NH
—CH3
—CF3
—H


H292 (a) and (b)
NH
—CH3
—OCH3
—H


H293 (a) and (b)
NH
—CH3
—OCH2CH3
—H


H294 (a) and (b)
NH
—CH3
—OCF3
—H


H295 (a) and (b)
NH
—CH3
-tert-butyl
—H


H296 (a) and (b)
NH
—CH3
-iso-propyl
—H


H297 (a) and (b)
NH
—CH3
—CH3
—CH3


H298 (a) and (b)
NH
—CH3
—H
—H


H299 (a) and (b)
NH
—CH3
—H
—Cl


H300 (a) and (b)
NH
—CH3
—H
—Br


H301 (a) and (b)
NH
—CH3
—H
—F


H302 (a) and (b)
NH
—CH3
—H
—CH3


H303 (a) and (b)
NH
—CH3
—H
—CF3


H304 (a) and (b)
NH
—CH3
—H
—OCH3


H305 (a) and (b)
NH
—CH3
—H
—OCH2CH3


H306 (a) and (b)
NH
—CH3
—H
—OCF3


H307 (a) and (b)
NH
—CH3
—H
-tert-butyl


H308 (a) and (b)
NH
—CH3
—H
-iso-propyl


H309 (a) and (b)
NH
—CF3
—Cl
—H


H310 (a) and (b)
NH
—CF3
—Br
—H


H311 (a) and (b)
NH
—CF3
—F
—H


H312 (a) and (b)
NH
—CF3
—CH3
—H


H313 (a) and (b)
NH
—CF3
—CF3
—H


H314 (a) and (b)
NH
—CF3
—OCH3
—H


H315 (a) and (b)
NH
—CF3
—OCH2CH3
—H


H316 (a) and (b)
NH
—CF3
—OCF3
—H


H317 (a) and (b)
NH
—CF3
-tert-butyl
—H


H318 (a) and (b)
NH
—CF3
-iso-propyl
—H


H319 (a) and (b)
NH
—CF3
—CH3
—CH3


H320 (a) and (b)
NH
—CF3
—H
—H


H321 (a) and (b)
NH
—CF3
—H
—Cl


H322 (a) and (b)
NH
—CF3
—H
—Br


H323 (a) and (b)
NH
—CF3
—H
—F


H324 (a) and (b)
NH
—CF3
—H
—CH3


H325 (a) and (b)
NH
—CF3
—H
—CF3


H326 (a) and (b)
NH
—CF3
—H
—OCH3


H327 (a) and (b)
NH
—CF3
—H
—OCH2CH3


H328 (a) and (b)
NH
—CF3
—H
—OCF3


H329 (a) and (b)
NH
—CF3
—H
-tert-butyl


H330 (a) and (b)
NH
—CF3
—H
-iso-propyl


H331 (a) and (b)
NH
—CHF2
—Cl
—H


H332 (a) and (b)
NH
—CHF2
—Br
—H


H333 (a) and (b)
NH
—CHF2
—F
—H


H334 (a) and (b)
NH
—CHF2
—CH3
—H


H335 (a) and (b)
NH
—CHF2
—CF3
—H


H336 (a) and (b)
NH
—CHF2
—OCH3
—H


H337 (a) and (b)
NH
—CHF2
—OCH2CH3
—H


H338 (a) and (b)
NH
—CHF2
—OCF3
—H


H339 (a) and (b)
NH
—CHF2
-tert-butyl
—H


H340 (a) and (b)
NH
—CHF2
-iso-propyl
—H


H341 (a) and (b)
NH
—CHF2
—CH3
—CH3


H342 (a) and (b)
NH
—CHF2
—H
—H


H343 (a) and (b)
NH
—CHF2
—H
—Cl


H344 (a) and (b)
NH
—CHF2
—H
—Br


H345 (a) and (b)
NH
—CHF2
—H
—F


H346 (a) and (b)
NH
—CHF2
—H
—CH3


H347 (a) and (b)
NH
—CHF2
—H
—CF3


H348 (a) and (b)
NH
—CHF2
—H
—OCH3


H349 (a) and (b)
NH
—CHF2
—H
—OCH2CH3


H350 (a) and (b)
NH
—CHF2
—H
—OCF3


H351 (a) and (b)
NH
—CHF2
—H
-tert-butyl


H352 (a) and (b)
NH
—CHF2
—H
-iso-propyl


H353 (a) and (b)
NH
—Br
—Br
—H


H354 (a) and (b)
NH
—Br
—Cl
—H


H355 (a) and (b)
NH
—Br
—F
—H


H356 (a) and (b)
NH
—Br
—CH3
—H


H357 (a) and (b)
NH
—Br
—CF3
—H


H358 (a) and (b)
NH
—Br
—OCH3
—H


H359 (a) and (b)
NH
—Br
—OCH2CH3
—H


H360 (a) and (b)
NH
—Br
—OCF3
—H


H361 (a) and (b)
NH
—Br
-tert-butyl
—H


H362 (a) and (b)
NH
—Br
-iso-propyl
—H


H363 (a) and (b)
NH
—Br
—CH3
—CH3


H364 (a) and (b)
NH
—Br
—H
—H


H365 (a) and (b)
NH
—Br
—H
—Cl


H366 (a) and (b)
NH
—Br
—H
—Br


H367 (a) and (b)
NH
—Br
—H
—F


H368 (a) and (b)
NH
—Br
—H
—CH3


H369 (a) and (b)
NH
—Br
—H
—CF3


H370 (a) and (b)
NH
—Br
—H
—OCH3


H371 (a) and (b)
NH
—Br
—H
—OCH2CH3


H372 (a) and (b)
NH
—Br
—H
—OCF3


H373 (a) and (b)
NH
—Br
—H
-tert-butyl


H374 (a) and (b)
NH
—Br
—H
-iso-propyl


H375 (a) and (b)
NH
—I
—Cl
—H


H376 (a) and (b)
NH
—I
—Br
—H


H377 (a) and (b)
NH
—I
—F
—H


H378 (a) and (b)
NH
—I
—CH3
—H


H379 (a) and (b)
NH
—I
—CF3
—H


H380 (a) and (b)
NH
—I
—OCH3
—H


H381 (a) and (b)
NH
—I
—OCH2CH3
—H


H382 (a) and (b)
NH
—I
—OCF3
—H


H383 (a) and (b)
NH
—I
-tert-butyl
—H


H384 (a) and (b)
NH
—I
-iso-propyl
—H


H385 (a) and (b)
NH
—I
—CH3
—CH3


H386 (a) and (b)
NH
—I
—H
—H


H387 (a) and (b)
NH
—I
—H
—Cl


H388 (a) and (b)
NH
—I
—H
—Br


H389 (a) and (b)
NH
—I
—H
—F


H390 (a) and (b)
NH
—I
—H
—CH3


H391 (a) and (b)
NH
—I
—H
—CF3


H392 (a) and (b)
NH
—I
—H
—OCH3


H393 (a) and (b)
NH
—I
—H
—OCH2CH3


H394 (a) and (b)
NH
—I
—H
—OCF3


H395 (a) and (b)
NH
—I
—H
-tert-butyl


H396 (a) and (b)
NH
—I
—H
-iso-propyl





In the column labeled “Compound”:


(a) means Z1 is CH and Z2 is N; and


(b) means Z1 is N and Z2 is CH.














TABLE 9








(XI)








 











Compound
Y
R1
(R8)a
(R8)b














 I1(a and b)
S
—Cl
—Cl
—H


 I2(a and b)
S
—Cl
—Br
—H


 I3(a and b)
S
—Cl
—F
—H


 I4(a and b)
S
—Cl
—CH3
—H


 I5(a and b)
S
—Cl
—CF3
—H


 I6(a and b)
S
—Cl
—OCH3
—H


 I7(a and b)
S
—Cl
—OCH2CH3
—H


 I8(a and b)
S
—Cl
—OCF3
—H


 I9(a and b)
S
—Cl
-tert-butyl
—H


 I10(a and b)
S
—Cl
-iso-propyl
—H


 I11(a and b)
S
—Cl
—CH3
—CH3


 I12(a and b)
S
—Cl
—H
—H


 I13(a and b)
S
—Cl
—H
—Cl


 I14(a and b)
S
—Cl
—H
—Br


 I15(a and b)
S
—Cl
—H
—F


 I16(a and b)
S
—Cl
—H
—CH3


 I17(a and b)
S
—Cl
—H
—CF3


 I18(a and b)
S
—Cl
—H
—OCH3


 I19(a and b)
S
—Cl
—H
—OCH2CH3


 I20(a and b)
S
—Cl
—H
—OCF3


 I21(a and b)
S
—Cl
—H
-tert-butyl


 I22(a and b)
S
—Cl
—H
-iso-propyl


 I23(a and b)
S
—CH3
—Cl
—H


 I24(a and b)
S
—CH3
—Br
—H


 I25(a and b)
S
—CH3
—F
—H


 I26(a and b)
S
—CH3
—CH3
—H


 I27(a and b)
S
—CH3
—CF3
—H


 I28(a and b)
S
—CH3
—OCH3
—H


 I29(a and b)
S
—CH3
—OCH2CH3
—H


 I30(a and b)
S
—CH3
—OCF3
—H


 I31(a and b)
S
—CH3
-tert-butyl
—H


 I32(a and b)
S
—CH3
-iso-propyl
—H


 I33(a and b)
S
—CH3
—CH3
—CH3


 I34(a and b)
S
—CH3
—H
—H


 I35(a and b)
S
—CH3
—H
—Cl


 I36(a and b)
S
—CH3
—H
—Br


 I37(a and b)
S
—CH3
—H
—F


 I38(a and b)
S
—CH3
—H
—CH3


 I39(a and b)
S
—CH3
—H
—CF3


 I40(a and b)
S
—CH3
—H
—OCH3


 I41(a and b)
S
—CH3
—H
—OCH2CH3


 I42(a and b)
S
—CH3
—H
—OCF3


 I43(a and b)
S
—CH3
—H
-tert-butyl


 I44(a and b)
S
—CH3
—H
-iso-propyl


 I45(a and b)
S
—CF3
—Cl
—H


 I46(a and b)
S
—CF3
—Br
—H


 I47(a and b)
S
—CF3
—F
—H


 I48(a and b)
S
—CF3
—CH3
—H


 I49(a and b)
S
—CF3
—CF3
—H


 I50(a and b)
S
—CF3
—OCH3
—H


 I51(a and b)
S
—CF3
—OCH2CH3
—H


 I52(a and b)
S
—CF3
—OCF3
—H


 I53(a and b)
S
—CF3
-tert-butyl
—H


 I54(a and b)
S
—CF3
-iso-propyl
—H


 I55(a and b)
S
—CF3
—CH3
—CH3


 I56(a and b)
S
—CF3
—H
—H


 I57(a and b)
S
—CF3
—H
—Cl


 I58(a and b)
S
—CF3
—H
—Br


 I59(a and b)
S
—CF3
—H
—F


 I60(a and b)
S
—CF3
—H
—CH3


 I61(a and b)
S
—CF3
—H
—CF3


 I62(a and b)
S
—CF3
—H
—OCH3


 I63(a and b)
S
—CF3
—H
—OCH2CH3


 I64(a and b)
S
—CF3
—H
—OCF3


 I65(a and b)
S
—CF3
—H
-tert-butyl


 I66(a and b)
S
—CF3
—H
-iso-propyl


 I67(a and b)
S
—CHF2
—Cl
—H


 I68(a and b)
S
—CHF2
—Br
—H


 I69(a and b)
S
—CHF2
—F
—H


 I70(a and b)
S
—CHF2
—CH3
—H


 I71(a and b)
S
—CHF2
—CF3
—H


 I72(a and b)
S
—CHF2
—OCH3
—H


 I73(a and b)
S
—CHF2
—OCH2CH3
—H


 I74(a and b)
S
—CHF2
—OCF3
—H


 I75(a and b)
S
—CHF2
-tert-butyl
—H


 I76(a and b)
S
—CHF2
-iso-propyl
—H


 I77(a and b)
S
—CHF2
—CH3
—CH3


 I78(a and b)
S
—CHF2
—H
—H


 I79(a and b)
S
—CHF2
—H
—Cl


 I80(a and b)
S
—CHF2
—H
—Br


 I81(a and b)
S
—CHF2
—H
—F


 I82(a and b)
S
—CHF2
—H
—CH3


 I83(a and b)
S
—CHF2
—H
—CF3


 I84(a and b)
S
—CHF2
—H
—OCH3


 I85(a and b)
S
—CHF2
—H
—OCH2CH3


 I86(a and b)
S
—CHF2
—H
—OCF3


 I87(a and b)
S
—CHF2
—H
-tert-butyl


 I88(a and b)
S
—CHF2
—H
-iso-propyl


 I89(a and b)
S
—Br
—Br
—H


 I90(a and b)
S
—Br
—Cl
—H


 I91(a and b)
S
—Br
—F
—H


 I92(a and b)
S
—Br
—CH3
—H


 I93(a and b)
S
—Br
—CF3
—H


 I94(a and b)
S
—Br
—OCH3
—H


 I95(a and b)
S
—Br
—OCH2CH3
—H


 I96(a and b)
S
—Br
—OCF3
—H


 I97(a and b)
S
—Br
-tert-butyl
—H


 I98(a and b)
S
—Br
-iso-propyl
—H


 I99(a and b)
S
—Br
—CH3
—CH3


I100(a and b)
S
—Br
—H
—H


I101(a and b)
S
—Br
—H
—Cl


I102(a and b)
S
—Br
—H
—Br


I103(a and b)
S
—Br
—H
—F


I104(a and b)
S
—Br
—H
—CH3


I105(a and b)
S
—Br
—H
—CF3


I106(a and b)
S
—Br
—H
—OCH3


I107(a and b)
S
—Br
—H
—OCH2CH3


I108(a and b)
S
—Br
—H
—OCF3


I109(a and b)
S
—Br
—H
-tert-butyl


I110(a and b)
S
—Br
—H
-iso-propyl


I111(a and b)
S
—I
—Cl
—H


I112(a and b)
S
—I
—Br
—H


I113(a and b)
S
—I
—F
—H


I114(a and b)
S
—I
—CH3
—H


I115(a and b)
S
—I
—CF3
—H


I116(a and b)
S
—I
—OCH3
—H


I117(a and b)
S
—I
—OCH2CH3
—H


I118(a and b)
S
—I
—OCF3
—H


I119(a and b)
S
—I
-tert-butyl
—H


I120(a and b)
S
—I
-iso-propyl
—H


I121(a and b)
S
—I
—CH3
—CH3


I122(a and b)
S
—I
—H
—H


I123(a and b)
S
—I
—H
—Cl


I124(a and b)
S
—I
—H
—Br


I125(a and b)
S
—I
—H
—F


I126(a and b)
S
—I
—H
—CH3


I127(a and b)
S
—I
—H
—CF3


I128(a and b)
S
—I
—H
—OCH3


I129(a and b)
S
—I
—H
—OCH2CH3


I130(a and b)
S
—I
—H
—OCF3


I131(a and b)
S
—I
—H
-tert-butyl


I132(a and b)
S
—I
—H
-iso-propyl


I133(a and b)
O
—Cl
—Cl
—H


I134(a and b)
O
—Cl
—Br
—H


I135(a and b)
O
—Cl
—F
—H


I136(a and b)
O
—Cl
—CH3
—H


I137(a and b)
O
—Cl
—CF3
—H


I138(a and b)
O
—Cl
—OCH3
—H


I139(a and b)
O
—Cl
—OCH2CH3
—H


I140(a and b)
O
—Cl
—OCF3
—H


I141(a and b)
O
—Cl
-tert-butyl
—H


I142(a and b)
O
—Cl
-iso-propyl
—H


I143(a and b)
O
—Cl
—CH3
—CH3


I144(a and b)
O
—Cl
—H
—H


I145(a and b)
O
—Cl
—H
—CH3


I146(a and b)
O
—Cl
—H
—Cl


I147(a and b)
O
—Cl
—H
—Br


I148(a and b)
O
—Cl
—H
—F


I149(a and b)
O
—Cl
—H
—CF3


I150(a and b)
O
—Cl
—H
—OCH3


I151(a and b)
O
—Cl
—H
—OCH2CH3


I152(a and b)
O
—Cl
—H
—OCF3


I153(a and b)
O
—Cl
—H
-tert-butyl


I154(a and b)
O
—Cl
—H
-iso-propyl


I155(a and b)
O
—CH3
—Cl
—H


I156(a and b)
O
—CH3
—Br
—H


I157(a and b)
O
—CH3
—F
—H


I158(a and b)
O
—CH3
—CH3
—H


I159(a and b)
O
—CH3
—CF3
—H


I160(a and b)
O
—CH3
—OCH3
—H


I161(a and b)
O
—CH3
—OCH2CH3
—H


I162(a and b)
O
—CH3
—OCF3
—H


I163(a and b)
O
—CH3
-tert-butyl
—H


I164(a and b)
O
—CH3
-iso-propyl
—H


I165(a and b)
O
—CH3
—CH3
—CH3


I166(a and b)
O
—CH3
—H
—H


I167(a and b)
O
—CH3
—H
—Cl


I168(a and b)
O
—CH3
—H
—Br


I169(a and b)
O
—CH3
—H
—F


I170(a and b)
O
—CH3
—H
—CH3


I171(a and b)
O
—CH3
—H
—CF3


I172(a and b)
O
—CH3
—H
—OCH3


I173(a and b)
O
—CH3
—H
—OCH2CH3


I174(a and b)
O
—CH3
—H
—OCF3


I175(a and b)
O
—CH3
—H
-tert-butyl


I176(a and b)
O
—CH3
—H
-iso-propyl


I177(a and b)
O
—CF3
—Cl
—H


I178(a and b)
O
—CF3
—Br
—H


I179(a and b)
O
—CF3
—F
—H


I180(a and b)
O
—CF3
—CH3
—H


I181(a and b)
O
—CF3
—CF3
—H


I182(a and b)
O
—CF3
—OCH3
—H


I183(a and b)
O
—CF3
—OCH2CH3
—H


I184(a and b)
O
—CF3
—OCF3
—H


I185(a and b)
O
—CF3
-tert-butyl
—H


I186(a and b)
O
—CF3
-iso-propyl
—H


I187(a and b)
O
—CF3
—CH3
—CH3


I188(a and b)
O
—CF3
—H
—H


I189(a and b)
O
—CF3
—H
—Cl


I190(a and b)
O
—CF3
—H
—Br


I191(a and b)
O
—CF3
—H
—F


I192(a and b)
O
—CF3
—H
—CH3


I193(a and b)
O
—CF3
—H
—CF3


I194(a and b)
O
—CF3
—H
—OCH3


I195(a and b)
O
—CF3
—H
—OCH2CH3


I196(a and b)
O
—CF3
—H
—OCF3


I197(a and b)
O
—CF3
—H
-tert-butyl


I198(a and b)
O
—CF3
—H
-iso-propyl


I199(a and b)
O
—CHF2
—Cl
—H


I200(a and b)
O
—CHF2
—Br
—H


I201(a and b)
O
—CHF2
—F
—H


I202(a and b)
O
—CHF2
—CH3
—H


I203(a and b)
O
—CHF2
—CF3
—H


I204(a and b)
O
—CHF2
—OCH3
—H


I205(a and b)
O
—CHF2
—OCH2CH3
—H


I206(a and b)
O
—CHF2
—OCF3
—H


I207(a and b)
O
—CHF2
-tert-butyl
—H


I208(a and b)
O
—CHF2
-iso-propyl
—H


I209(a and b)
O
—CHF2
—CH3
—CH3


I210(a and b)
O
—CHF2
—H
—H


I211(a and b)
O
—CHF2
—H
—Cl


I212(a and b)
O
—CHF2
—H
—Br


I213(a and b)
O
—CHF2
—H
—F


I214(a and b)
O
—CHF2
—H
—CH3


I215(a and b)
O
—CHF2
—H
—CF3


I216(a and b)
O
—CHF2
—H
—OCH3


I217(a and b)
O
—CHF2
—H
—OCH2CH3


I218(a and b)
O
—CHF2
—H
—OCF3


I219(a and b)
O
—CHF2
—H
-tert-butyl


I220(a and b)
O
—CHF2
—H
-iso-propyl


I221(a and b)
O
—Br
—Br
—H


I222(a and b)
O
—Br
—Cl
—H


I223(a and b)
O
—Br
—F
—H


I224(a and b)
O
—Br
—CH3
—H


I225(a and b)
O
—Br
—CF3
—H


I226(a and b)
O
—Br
—OCH3
—H


I227(a and b)
O
—Br
—OCH2CH3
—H


I228(a and b)
O
—Br
—OCF3
—H


I229(a and b)
O
—Br
-tert-butyl
—H


I230(a and b)
O
—Br
-iso-propyl
—H


I231(a and b)
O
—Br
—CH3
—CH3


I232(a and b)
O
—Br
—H
—H


I233(a and b)
O
—Br
—H
—Cl


I234(a and b)
O
—Br
—H
—Br


I235(a and b)
O
—Br
—H
—F


I236(a and b)
O
—Br
—H
—CH3


I237(a and b)
O
—Br
—H
—CF3


I238(a and b)
O
—Br
—H
—OCH3


I239(a and b)
O
—Br
—H
—OCH2CH3


I240(a and b)
O
—Br
—H
—OCF3


I241(a and b)
O
—Br
—H
-tert-butyl


I242(a and b)
O
—Br
—H
-iso-propyl


I243(a and b)
O
—I
—Cl
—H


I244(a and b)
O
—I
—Br
—H


I245(a and b)
O
—I
—F
—H


I246(a and b)
O
—I
—CH3
—H


I247(a and b)
O
—I
—CF3
—H


I248(a and b)
O
—I
—OCH3
—H


I249(a and b)
O
—I
—OCH2CH3
—H


I250(a and b)
O
—I
—OCF3
—H


I251(a and b)
O
—I
-tert-butyl
—H


I252(a and b)
O
—I
-iso-propyl
—H


I253(a and b)
O
—I
—CH3
—CH3


I254(a and b)
O
—I
—H
—H


I255(a and b)
O
—I
—H
—Cl


I256(a and b)
O
—I
—H
—Br


I257(a and b)
O
—I
—H
—F


I258(a and b)
O
—I
—H
—CH3


I259(a and b)
O
—I
—H
—CF3


I260(a and b)
O
—I
—H
—OCH3


I261(a and b)
O
—I
—H
—OCH2CH3


I262(a and b)
O
—I
—H
—OCF3


I263(a and b)
O
—I
—H
-tert-butyl


I264(a and b)
O
—I
—H
-iso-propyl


I265(a and b)
NH
—Cl
—Cl
—H


I266(a and b)
NH
—Cl
—Br
—H


I267(a and b)
NH
—Cl
—F
—H


I268(a and b)
NH
—Cl
—CH3
—H


I269(a and b)
NH
—Cl
—CF3
—H


I270(a and b)
NH
—Cl
—OCH3
—H


I271(a and b)
NH
—Cl
—OCH2CH3
—H


I272(a and b)
NH
—Cl
—OCF3
—H


I273(a and b)
NH
—Cl
-tert-butyl
—H


I274(a and b)
NH
—Cl
-iso-propyl
—H


I275(a and b)
NH
—Cl
—CH3
—CH3


I276(a and b)
NH
—Cl
—H
—H


I277(a and b)
NH
—Cl
—H
—CH3


I278(a and b)
NH
—Cl
—H
—Cl


I279(a and b)
NH
—Cl
—H
—Br


I280(a and b)
NH
—Cl
—H
—F


I281(a and b)
NH
—Cl
—H
—CF3


I282(a and b)
NH
—Cl
—H
—OCH3


I283(a and b)
NH
—Cl
—H
—OCH2CH3


I284(a and b)
NH
—Cl
—H
—OCF3


I285(a and b)
NH
—Cl
—H
-tert-butyl


I286(a and b)
NH
—Cl
—H
-iso-propyl


I287(a and b)
NH
—CH3
—Cl
—H


I288(a and b)
NH
—CH3
—Br
—H


I289(a and b)
NH
—CH3
—F
—H


I290(a and b)
NH
—CH3
—CH3
—H


I291(a and b)
NH
—CH3
—CF3
—H


I292(a and b)
NH
—CH3
—OCH3
—H


I293(a and b)
NH
—CH3
—OCH2CH3
—H


I294(a and b)
NH
—CH3
—OCF3
—H


I295(a and b)
NH
—CH3
-tert-butyl
—H


I296(a and b)
NH
—CH3
-iso-propyl
—H


I297(a and b)
NH
—CH3
—CH3
—CH3


I298(a and b)
NH
—CH3
—H
—H


I299(a and b)
NH
—CH3
—H
—Cl


I300(a and b)
NH
—CH3
—H
—Br


I301(a and b)
NH
—CH3
—H
—F


I302(a and b)
NH
—CH3
—H
—CH3


I303(a and b)
NH
—CH3
—H
—CF3


I304(a and b)
NH
—CH3
—H
—OCH3


I305(a and b)
NH
—CH3
—H
—OCH2CH3


I306(a and b)
NH
—CH3
—H
—OCF3


I307(a and b)
NH
—CH3
—H
-tert-butyl


I308(a and b)
NH
—CH3
—H
-iso-propyl


I309(a and b)
NH
—CF3
—Cl
—H


I310(a and b)
NH
—CF3
—Br
—H


I311(a and b)
NH
—CF3
—F
—H


I312(a and b)
NH
—CF3
—CH3
—H


I313(a and b)
NH
—CF3
—CF3
—H


I314(a and b)
NH
—CF3
—OCH3
—H


I315(a and b)
NH
—CF3
—OCH2CH3
—H


1316(a and b)
NH
—CF3
—OCF3
—H


I317(a and b)
NH
—CF3
-tert-butyl
—H


I318(a and b)
NH
—CF3
-iso-propyl
—H


I319(a and b)
NH
—CF3
—CH3
—CH3


I320(a and b)
NH
—CF3
—H
—H


I321(a and b)
NH
—CF3
—H
—Cl


I322(a and b)
NH
—CF3
—H
—Br


I323(a and b)
NH
—CF3
—H
—F


I324(a and b)
NH
—CF3
—H
—CH3


I325(a and b)
NH
—CF3
—H
—CF3


I326(a and b)
NH
—CF3
—H
—OCH3


I327(a and b)
NH
—CF3
—H
—OCH2CH3


I328(a and b)
NH
—CF3
—H
—OCF3


I329(a and b)
NH
—CF3
—H
-tert-butyl


I330(a and b)
NH
—CF3
—H
-iso-propyl


I331(a and b)
NH
—CHF2
—Cl
—H


I332(a and b)
NH
—CHF2
—Br
—H


I333(a and b)
NH
—CHF2
—F
—H


I334(a and b)
NH
—CHF2
—CH3
—H


I335(a and b)
NH
—CHF2
—CF3
—H


I336(a and b)
NH
—CHF2
—OCH3
—H


I337(a and b)
NH
—CHF2
—OCH2CH3
—H


I338(a and b)
NH
—CHF2
—OCF3
—H


I339(a and b)
NH
—CHF2
-tert-butyl
—H


I340(a and b)
NH
—CHF2
-iso-propyl
—H


I341(a and b)
NH
—CHF2
—CH3
—CH3


I342(a and b)
NH
—CHF2
—H
—H


I343(a and b)
NH
—CHF2
—H
—Cl


I344(a and b)
NH
—CHF2
—H
—Br


I345(a and b)
NH
—CHF2
—H
—F


I346(a and b)
NH
—CHF2
—H
—CH3


I347(a and b)
NH
—CHF2
—H
—CF3


I348(a and b)
NH
—CHF2
—H
—OCH3


I349(a and b)
NH
—CHF2
—H
—OCH2CH3


I350(a and b)
NH
—CHF2
—H
—OCF3


I351(a and b)
NH
—CHF2
—H
-tert-butyl


I352(a and b)
NH
—CHF2
—H
-iso-propyl


I353(a and b)
NH
—Br
—Br
—H


I354(a and b)
NH
—Br
—Cl
—H


I355(a and b)
NH
—Br
—F
—H


I356(a and b)
NH
—Br
—CH3
—H


I357(a and b)
NH
—Br
—CF3
—H


I358(a and b)
NH
—Br
—OCH3
—H


I359(a and b)
NH
—Br
—OCH2CH3
—H


I360(a and b)
NH
—Br
—OCF3
—H


I361(a and b)
NH
—Br
-tert-butyl
—H


I362(a and b)
NH
—Br
-iso-propyl
—H


I363(a and b)
NH
—Br
—CH3
—CH3


I364(a and b)
NH
—Br
—H
—H


I365(a and b)
NH
—Br
—H
—Cl


I366(a and b)
NH
—Br
—H
—Br


I367(a and b)
NH
—Br
—H
—F


I368(a and b)
NH
—Br
—H
—CH3


I369(a and b)
NH
—Br
—H
—CF3


I370(a and b)
NH
—Br
—H
—OCH3


I371(a and b)
NH
—Br
—H
—OCH2CH3


I372(a and b)
NH
—Br
—H
—OCF3


I373(a and b)
NH
—Br
—H
-tert-butyl


I374(a and b)
NH
—Br
—H
-iso-propyl


I375(a and b)
NH
—I
—Cl
—H


I376(a and b)
NH
—I
—Br
—H


I377(a and b)
NH
—I
—F
—H


I378(a and b)
NH
—I
—CH3
—H


I379(a and b)
NH
—I
—CF3
—H


I380(a and b)
NH
—I
—OCH3
—H


I381(a and b)
NH
—I
—OCH2CH3
—H


I382(a and b)
NH
—I
—OCF3
—H


I383(a and b)
NH
—I
-tert-butyl
—H


I384(a and b)
NH
—I
-iso-propyl
—H


I385(a and b)
NH
—I
—CH3
—CH3


I386(a and b)
NH
—I
—H
—H


I387(a and b)
NH
—I
—H
—Cl


I388(a and b)
NH
—I
—H
—Br


I389(a and b)
NH
—I
—H
—F


I390(a and b)
NH
—I
—H
—CH3


I391(a and b)
NH
—I
—H
—CF3


I392(a and b)
NH
—I
—H
—OCH3


I393(a and b)
NH
—I
—H
—OCH2CH3


I394(a and b)
NH
—I
—H
—OCF3


I395(a and b)
NH
—I
—H
-tert-butyl


I396(a and b)
NH
—I
—H
-iso-propyl





In the column labeled “Compound”:


(a) means Z1 is CH and Z2 is N; and


(b) means Z1 is N and Z2 is CH.














TABLE 10








(XII)








 











Compound
Y
R1
(R8)a
(R8)b





 J1(a and b)
S
—Cl
—Cl
—H


 J2(a and b)
S
—Cl
—Br
—H


 J3(a and b)
S
—Cl
—F
—H


 J4(a and b)
S
—Cl
—CH3
—H


 J5(a and b)
S
—Cl
—CF3
—H


 J6(a and b)
S
—Cl
—OCH3
—H


 J7(a and b)
S
—Cl
—OCH2CH3
—H


 J8(a and b)
S
—Cl
—OCF3
—H


 J9(a and b)
S
—Cl
-tert-butyl
—H


 J10(a and b)
S
—Cl
-iso-propyl
—H


 J11(a and b)
S
—Cl
—CH3
—CH3


 J12(a and b)
S
—Cl
—H
—H


 J13(a and b)
S
—Cl
—H
—Cl


 J14(a and b)
S
—Cl
—H
—Br


 J15(a and b)
S
—Cl
—H
—F


 J16(a and b)
S
—Cl
—H
—CH3


 J17(a and b)
S
—Cl
—H
—CF3


 J18(a and b)
S
—Cl
—H
—OCH3


 J19(a and b)
S
—Cl
—H
—OCH2CH3


 J20(a and b)
S
—Cl
—H
—OCF3


 J21(a and b)
S
—Cl
—H
-tert-butyl


 J22(a and b)
S
—Cl
—H
-iso-propyl


 J23(a and b)
S
—CH3
—Cl
—H


 J24(a and b)
S
—CH3
—Br
—H


 J25(a and b)
S
—CH3
—F
—H


 J26(a and b)
S
—CH3
—CH3
—H


 J27(a and b)
S
—CH3
—CF3
—H


 J28(a and b)
S
—CH3
—OCH3
—H


 J29(a and b)
S
—CH3
—OCH2CH3
—H


 J30(a and b)
S
—CH3
—OCF3
—H


 J31(a and b)
S
—CH3
-tert-butyl
—H


 J32(a and b)
S
—CH3
-iso-propyl
—H


 J33(a and b)
S
—CH3
—CH3
—CH3


 J34(a and b)
S
—CH3
—H
—H


 J35(a and b)
S
—CH3
—H
—Cl


 J36(a and b)
S
—CH3
—H
—Br


 J37(a and b)
S
—CH3
—H
—F


 J38(a and b)
S
—CH3
—H
—CH3


 J39(a and b)
S
—CH3
—H
—CF3


 J40(a and b)
S
—CH3
—H
—OCH3


 J41(a and b)
S
—CH3
—H
—OCH2CH3


 J42(a and b)
S
—CH3
—H
—OCF3


 J43(a and b)
S
—CH3
—H
-tert-butyl


 J44(a and b)
S
—CH3
—H
-iso-propyl


 J45(a and b)
S
—CF3
—Cl
—H


 J46(a and b)
S
—CF3
—Br
—H


 J47(a and b)
S
—CF3
—F
—H


 J48(a and b)
S
—CF3
—CH3
—H


 J49(a and b)
S
—CF3
—CF3
—H


 J50(a and b)
S
—CF3
—OCH3
—H


 J51(a and b)
S
—CF3
—OCH2CH3
—H


 J52(a and b)
S
—CF3
—OCF3
—H


 J53(a and b)
S
—CF3
-tert-butyl
—H


 J54(a and b)
S
—CF3
-iso-propyl
—H


 J55(a and b)
S
—CF3
—CH3
—CH3


 J56(a and b)
S
—CF3
—H
—H


 J57(a and b)
S
—CF3
—H
—Cl


 J58(a and b)
S
—CF3
—H
—Br


 J59(a and b)
S
—CF3
—H
—F


 J60(a and b)
S
—CF3
—H
—CH3


 J61(a and b)
S
—CF3
—H
—CF3


 J62(a and b)
S
—CF3
—H
—OCH3


 J63(a and b)
S
—CF3
—H
—OCH2CH3


 J64(a and b)
S
—CF3
—H
—OCF3


 J65(a and b)
S
—CF3
—H
-tert-butyl


 J66(a and b)
S
—CF3
—H
-iso-propyl


 J67(a and b)
S
—CHF2
—Cl
—H


 J68(a and b)
S
—CHF2
—Br
—H


 J69(a and b)
S
—CHF2
—F
—H


 J70(a and b)
S
—CHF2
—CH3
—H


 J71(a and b)
S
—CHF2
—CF3
—H


 J72(a and b)
S
—CHF2
—OCH3
—H


 J73(a and b)
S
—CHF2
—OCH2CH3
—H


 J74(a and b)
S
—CHF2
—OCF3
—H


 J75(a and b)
S
—CHF2
-tert-butyl
—H


 J76(a and b)
S
—CHF2
-iso-propyl
—H


 J77(a and b)
S
—CHF2
—CH3
—CH3


 J78(a and b)
S
—CHF2
—H
—H


 J79(a and b)
S
—CHF2
—H
—Cl


 J80(a and b)
S
—CHF2
—H
—Br


 J81(a and b)
S
—CHF2
—H
—F


 J82(a and b)
S
—CHF2
—H
—CH3


 J83(a and b)
S
—CHF2
—H
—CF3


 J84(a and b)
S
—CHF2
—H
—OCH3


 J85(a and b)
S
—CHF2
—H
—OCH2CH3


 J86(a and b)
S
—CHF2
—H
—OCF3


 J87(a and b)
S
—CHF2
—H
-tert-butyl


 J88(a and b)
S
—CHF2
—H
-iso-propyl


 J89(a and b)
S
—Br
—Br
—H


 J90(a and b)
S
—Br
—Cl
—H


 J91(a and b)
S
—Br
—F
—H


 J92(a and b)
S
—Br
—CH3
—H


 J93(a and b)
S
—Br
—CF3
—H


 J94(a and b)
S
—Br
—OCH3
—H


 J95(a and b)
S
—Br
—OCH2CH3
—H


 J96(a and b)
S
—Br
—OCF3
—H


 J97(a and b)
S
—Br
-tert-butyl
—H


 J98(a and b)
S
—Br
-iso-propyl
—H


 J99(a and b)
S
—Br
—CH3
—CH3


J100(a and b)
S
—Br
—H
—H


J101(a and b)
S
—Br
—H
—Cl


J102(a and b)
S
—Br
—H
—Br


J103(a and b)
S
—Br
—H
—F


J104(a and b)
S
—Br
—H
—CH3


J105(a and b)
S
—Br
—H
—CF3


J106(a and b)
S
—Br
—H
—OCH3


J107(a and b)
S
—Br
—H
—OCH2CH3


J108(a and b)
S
—Br
—H
—OCF3


J109(a and b)
S
—Br
—H
-tert-butyl


J110(a and b)
S
—Br
—H
-iso-propyl


J111(a and b)
S
—I
—Cl
—H


J112(a and b)
S
—I
—Br
—H


J113(a and b)
S
—I
—F
—H


J114(a and b)
S
—I
—CH3
—H


J115(a and b)
S
—I
—CF3
—H


J116(a and b)
S
—I
—OCH3
—H


J117(a and b)
S
—I
—OCH2CH3
—H


J118(a and b)
S
—I
—OCF3
—H


J119(a and b)
S
—I
-tert-butyl
—H


J120(a and b)
S
—I
-iso-propyl
—H


J121(a and b)
S
—I
—CH3
—CH3


J122(a and b)
S
—I
—H
—H


J123(a and b)
S
—I
—H
—Cl


J124(a and b)
S
—I
—H
—Br


J125(a and b)
S
—I
—H
—F


J126(a and b)
S
—I
—H
—CH3


J127(a and b)
S
—I
—H
—CF3


J128(a and b)
S
—I
—H
—OCH3


J129(a and b)
S
—I
—H
—OCH2CH3


J130(a and b)
S
—I
—H
—OCF3


J131(a and b)
S
—I
—H
-tert-butyl


J132(a and b)
S
—I
—H
-iso-propyl


J133(a and b)
O
—Cl
—Cl
—H


J134(a and b)
O
—Cl
—Br
—H


J135(a and b)
O
—Cl
—F
—H


J136(a and b)
O
—Cl
—CH3
—H


J137(a and b)
O
—Cl
—CF3
—H


J138(a and b)
O
—Cl
—OCH3
—H


J139(a and b)
O
—Cl
—OCH2CH3
—H


J140(a and b)
O
—Cl
—OCF3
—H


J141(a and b)
O
—Cl
-tert-butyl
—H


J142(a and b)
O
—Cl
-iso-propyl
—H


J143(a and b)
O
—Cl
—CH3
—CH3


J144(a and b)
O
—Cl
—H
—H


J145(a and b)
O
—Cl
—H
—CH3


J146(a and b)
O
—Cl
—H
—Cl


J147(a and b)
O
—Cl
—H
—Br


J148(a and b)
O
—Cl
—H
—F


J149(a and b)
O
—Cl
—H
—CF3


J150(a and b)
O
—Cl
—H
—OCH3


J151(a and b)
O
—Cl
—H
—OCH2CH3


J152(a and b)
O
—Cl
—H
—OCF3


J153(a and b)
O
—Cl
—H
-tert-butyl


J154(a and b)
O
—Cl
—H
-iso-propyl


J155(a and b)
O
—CH3
—Cl
—H


J156(a and b)
O
—CH3
—Br
—H


J157(a and b)
O
—CH3
—F
—H


J158(a and b)
O
—CH3
—CH3
—H


J159(a and b)
O
—CH3
—CF3
—H


J160(a and b)
O
—CH3
—OCH3
—H


J161(a and b)
O
—CH3
—OCH2CH3
—H


J162(a and b)
O
—CH3
—OCF3
—H


J163(a and b)
O
—CH3
-tert-butyl
—H


J164(a and b)
O
—CH3
-iso-propyl
—H


J165(a and b)
O
—CH3
—CH3
—CH3


J166(a and b)
O
—CH3
—H
—H


J167(a and b)
O
—CH3
—H
—Cl


J168(a and b)
O
—CH3
—H
—Br


J169(a and b)
O
—CH3
—H
—F


J170(a and b)
O
—CH3
—H
—CH3


J171(a and b)
O
—CH3
—H
—CF3


J172(a and b)
O
—CH3
—H
—OCH3


J173(a and b)
O
—CH3
—H
—OCH2CH3


J174(a and b)
O
—CH3
—H
—OCF3


J175(a and b)
O
—CH3
—H
-tert-butyl


J176(a and b)
O
—CH3
—H
-iso-propyl


J177(a and b)
O
—CF3
—Cl
—H


J178(a and b)
O
—CF3
—Br
—H


J179(a and b)
O
—CF3
—F
—H


J180(a and b)
O
—CF3
—CH3
—H


J181(a and b)
O
—CF3
—CF3
—H


J182(a and b)
O
—CF3
—OCH3
—H


J183(a and b)
O
—CF3
—OCH2CH3
—H


J184(a and b)
O
—CF3
—OCF3
—H


J185(a and b)
O
—CF3
-tert-butyl
—H


J186(a and b)
O
—CF3
-iso-propyl
—H


J187(a and b)
O
—CF3
—CH3
—CH3


J188(a and b)
O
—CF3
—H
—H


J189(a and b)
O
—CF3
—H
—Cl


J190(a and b)
O
—CF3
—H
—Br


J191(a and b)
O
—CF3
—H
—F


J192(a and b)
O
—CF3
—H
—CH3


J193(a and b)
O
—CF3
—H
—CF3


J194(a and b)
O
—CF3
—H
—OCH3


J195(a and b)
O
—CF3
—H
—OCH2CH3


J196(a and b)
O
—CF3
—H
—OCF3


J197(a and b)
O
—CF3
—H
-tert-butyl


J198(a and b)
O
—CF3
—H
-iso-propyl


J199(a and b)
O
—CHF2
—Cl
—H


J200(a and b)
O
—CHF2
—Br
—H


J201(a and b)
O
—CHF2
—F
—H


J202(a and b)
O
—CHF2
—CH3
—H


J203(a and b)
O
—CHF2
—CF3
—H


J204(a and b)
O
—CHF2
—OCH3
—H


J205(a and b)
O
—CHF2
—OCH2CH3
—H


J206(a and b)
O
—CHF2
—OCF3
—H


J207(a and b)
O
—CHF2
-tert-butyl
—H


J208(a and b)
O
—CHF2
-iso-propyl
—H


J209(a and b)
O
—CHF2
—CH3
—CH3


J210(a and b)
O
—CHF2
—H
—H


J211(a and b)
O
—CHF2
—H
—Cl


J212(a and b)
O
—CHF2
—H
—Br


J213(a and b)
O
—CHF2
—H
—F


J214(a and b)
O
—CHF2
—H
—CH3


J215(a and b)
O
—CHF2
—H
—CF3


J216(a and b)
O
—CHF2
—H
—OCH3


J217(a and b)
O
—CHF2
—H
—OCH2CH3


J218(a and b)
O
—CHF2
—H
—OCF3


J219(a and b)
O
—CHF2
—H
-tert-butyl


J220(a and b)
O
—CHF2
—H
-iso-propyl


J221(a and b)
O
—Br
—Br
—H


J222(a and b)
O
—Br
—Cl
—H


J223(a and b)
O
—Br
—F
—H


J224(a and b)
O
—Br
—CH3
—H


J225(a and b)
O
—Br
—CF3
—H


J226(a and b)
O
—Br
—OCH3
—H


J227(a and b)
O
—Br
—OCH2CH3
—H


J228(a and b)
O
—Br
—OCF3
—H


J229(a and b)
O
—Br
-tert-butyl
—H


J230(a and b)
O
—Br
-iso-propyl
—H


J231(a and b)
O
—Br
—CH3
—CH3


J232(a and b)
O
—Br
—H
—H


J233(a and b)
O
—Br
—H
—Cl


J234(a and b)
O
—Br
—H
—Br


J235(a and b)
O
—Br
—H
—F


J236(a and b)
O
—Br
—H
—CH3


J237(a and b)
O
—Br
—H
—CF3


J238(a and b)
O
—Br
—H
—OCH3


J239(a and b)
O
—Br
—H
—OCH2CH3


J240(a and b)
O
—Br
—H
—OCF3


J241(a and b)
O
—Br
—H
-tert-butyl


J242(a and b)
O
—Br
—H
-iso-propyl


J243(a and b)
O
—I
—Cl
—H


J244(a and b)
O
—I
—Br
—H


J245(a and b)
O
—I
—F
—H


J246(a and b)
O
—I
—CH3
—H


J247(a and b)
O
—I
—CF3
—H


J248(a and b)
O
—I
—OCH3
—H


J249(a and b)
O
—I
—OCH2CH3
—H


J250(a and b)
O
—I
—OCF3
—H


J251(a and b)
O
—I
-tert-butyl
—H


J252(a and b)
O
—I
-iso-propyl
—H


J253(a and b)
O
—I
—CH3
—CH3


J254(a and b)
O
—I
—H
—H


J255(a and b)
O
—I
—H
—Cl


J256(a and b)
O
—I
—H
—Br


J257(a and b)
O
—I
—H
—F


J258(a and b)
O
—I
—H
—CH3


J259(a and b)
O
—I
—H
—CF3


J260(a and b)
O
—I
—H
—OCH3


J261(a and b)
O
—I
—H
—OCH2CH3


J262(a and b)
O
—I
—H
—OCF3


J263(a and b)
O
—I
—H
-tert-butyl


J264(a and b)
O
—I
—H
-iso-propyl


J265(a and b)
NH
—Cl
—Cl
—H


J266(a and b)
NH
—Cl
—Br
—H


J267(a and b)
NH
—Cl
—F
—H


J268(a and b)
NH
—Cl
—CH3
—H


J269(a and b)
NH
—Cl
—CF3
—H


J270(a and b)
NH
—Cl
—OCH3
—H


J271(a and b)
NH
—Cl
—OCH2CH3
—H


J272(a and b)
NH
—Cl
—OCF3
—H


J273(a and b)
NH
—Cl
-tert-butyl
—H


J274(a and b)
NH
—Cl
-iso-propyl
—H


J275(a and b)
NH
—Cl
—CH3
—CH3


J276(a and b)
NH
—Cl
—H
—H


J277(a and b)
NH
—Cl
—H
—CH3


J278(a and b)
NH
—Cl
—H
—Cl


J279(a and b)
NH
—Cl
—H
—Br


J280(a and b)
NH
—Cl
—H
—F


J281(a and b)
NH
—Cl
—H
—CF3


J282(a and b)
NH
—Cl
—H
—OCH3


J283(a and b)
NH
—Cl
—H
—OCH2CH3


J284(a and b)
NH
—Cl
—H
—OCF3


J285(a and b)
NH
—Cl
—H
-tert-butyl


J286(a and b)
NH
—Cl
—H
-iso-propyl


J287(a and b)
NH
—CH3
—Cl
—H


J288(a and b)
NH
—CH3
—Br
—H


J289(a and b)
NH
—CH3
—F
—H


J290(a and b)
NH
—CH3
—CH3
—H


J291(a and b)
NH
—CH3
—CF3
—H


J292(a and b)
NH
—CH3
—OCH3
—H


J293(a and b)
NH
—CH3
—OCH2CH3
—H


J294(a and b)
NH
—CH3
—OCF3
—H


J295(a and b)
NH
—CH3
-tert-butyl
—H


J296(a and b)
NH
—CH3
-iso-propyl
—H


J297(a and b)
NH
—CH3
—CH3
—CH3


J298(a and b)
NH
—CH3
—H
—H


J299(a and b)
NH
—CH3
—H
—Cl


J300(a and b)
NH
—CH3
—H
—Br


J301(a and b)
NH
—CH3
—H
—F


J302(a and b)
NH
—CH3
—H
—CH3


J303(a and b)
NH
—CH3
—H
—CF3


J304(a and b)
NH
—CH3
—H
—OCH3


J305(a and b)
NH
—CH3
—H
—OCH2CH3


J306(a and b)
NH
—CH3
—H
—OCF3


J307(a and b)
NH
—CH3
—H
-tert-butyl


J308(a and b)
NH
—CH3
—H
-iso-propyl


J309(a and b)
NH
—CF3
—Cl
—H


J310(a and b)
NH
—CF3
—Br
—H


J311(a and b)
NH
—CF3
—F
—H


J312(a and b)
NH
—CF3
—CH3
—H


J313(a and b)
NH
—CF3
—CF3
—H


J314(a and b)
NH
—CF3
—OCH3
—H


J315(a and b)
NH
—CF3
—OCH2CH3
—H


J316(a and b)
NH
—CF3
—OCF3
—H


J317(a and b)
NH
—CF3
-tert-butyl
—H


J318(a and b)
NH
—CF3
-iso-propyl
—H


J319(a and b)
NH
—CF3
—CH3
—CH3


J320(a and b)
NH
—CF3
—H
—H


J321(a and b)
NH
—CF3
—H
—Cl


J322(a and b)
NH
—CF3
—H
—Br


J323(a and b)
NH
—CF3
—H
—F


J324(a and b)
NH
—CF3
—H
—CH3


J325(a and b)
NH
—CF3
—H
—CF3


J326(a and b)
NH
—CF3
—H
—OCH3


J327(a and b)
NH
—CF3
—H
—OCH2CH3


J328(a and b)
NH
—CF3
—H
—OCF3


J329(a and b)
NH
—CF3
—H
-tert-butyl


J330(a and b)
NH
—CF3
—H
-iso-propyl


J331(a and b)
NH
—CHF2
—Cl
—H


J332(a and b)
NH
—CHF2
—Br
—H


J333(a and b)
NH
—CHF2
—F
—H


J334(a and b)
NH
—CHF2
—CH3
—H


J335(a and b)
NH
—CHF2
—CF3
—H


J336(a and b)
NH
—CHF2
—OCH3
—H


J337(a and b)
NH
—CHF2
—OCH2CH3
—H


J338(a and b)
NH
—CHF2
—OCF3
—H


J339(a and b)
NH
—CHF2
-tert-butyl
—H


J340(a and b)
NH
—CHF2
-iso-propyl
—H


J341(a and b)
NH
—CHF2
—CH3
—CH3


J342(a and b)
NH
—CHF2
—H
—H


J343(a and b)
NH
—CHF2
—H
—Cl


J344(a and b)
NH
—CHF2
—H
—Br


J345(a and b)
NH
—CHF2
—H
—F


J346(a and b)
NH
—CHF2
—H
—CH3


J347(a and b)
NH
—CHF2
—H
—CF3


J348(a and b)
NH
—CHF2
—H
—OCH3


J349(a and b)
NH
—CHF2
—H
—OCH2CH3


J350(a and b)
NH
—CHF2
—H
—OCF3


J351(a and b)
NH
—CHF2
—H
-tert-butyl


J352(a and b)
NH
—CHF2
—H
-iso-propyl


J353(a and b)
NH
—Br
—Br
—H


J354(a and b)
NH
—Br
—Cl
—H


J355(a and b)
NH
—Br
—F
—H


J356(a and b)
NH
—Br
—CH3
—H


J357(a and b)
NH
—Br
—CF3
—H


J358(a and b)
NH
—Br
—OCH3
—H


J359(a and b)
NH
—Br
—OCH2CH3
—H


J360(a and b)
NH
—Br
—OCF3
—H


J361(a and b)
NH
—Br
-tert-butyl
—H


J362(a and b)
NH
—Br
-iso-propyl
—H


J363(a and b)
NH
—Br
—CH3
—CH3


J364(a and b)
NH
—Br
—H
—H


J365(a and b)
NH
—Br
—H
—Cl


J366(a and b)
NH
—Br
—H
—Br


J367(a and b)
NH
—Br
—H
—F


J368(a and b)
NH
—Br
—H
—CH3


J369(a and b)
NH
—Br
—H
—CF3


J370(a and b)
NH
—Br
—H
—OCH3


J371(a and b)
NH
—Br
—H
—OCH2CH3


J372(a and b)
NH
—Br
—H
—OCF3


J373(a and b)
NH
—Br
—H
-tert-butyl


J374(a and b)
NH
—Br
—H
-iso-propyl


J375(a and b)
NH
—I
—Cl
—H


J376(a and b)
NH
—I
—Br
—H


J377(a and b)
NH
—I
—F
—H


J378(a and b)
NH
—I
—CH3
—H


J379(a and b)
NH
—I
—CF3
—H


J380(a and b)
NH
—I
—OCH3
—H


J381(a and b)
NH
—I
—OCH2CH3
—H


J382(a and b)
NH
—I
—OCF3
—H


J383(a and b)
NH
—I
-tert-butyl
—H


J384(a and b)
NH
—I
-iso-propyl
—H


J385(a and b)
NH
—I
—CH3
—CH3


J386(a and b)
NH
—I
—H
—H


J387(a and b)
NH
—I
—H
—Cl


J388(a and b)
NH
—I
—H
—Br


J389(a and b)
NH
—I
—H
—F


J390(a and b)
NH
—I
—H
—CH3


J391(a and b)
NH
—I
—H
—CF3


J392(a and b)
NH
—I
—H
—OCH3


J393(a and b)
NH
—I
—H
—OCH2CH3


J394(a and b)
NH
—I
—H
—OCF3


J395(a and b)
NH
—I
—H
-tert-butyl


J396(a and b)
NH
—I
—H
-iso-propyl





In the column labeled “Compound”:


(a) means Z1 is CH and Z2 is N; and


(b) means Z1 is N and Z2 is CH.






4.4 DEFINITIONS
As used in connection with the Pyridylene Compounds herein, the terms used above having following meaning:
“—(C1-C10)alkyl” means a straight chain or branched non-cyclic hydrocarbon having from 1 to 10 carbon atoms. Representative straight chain —(C1-C10)alkyls include -methyl, -ethyl, -n-propyl, -n-butyl, -n-pentyl, -n-hexyl, -n-heptyl, -n-octyl, -n-nonyl, and -n-decyl. Representative branched —(C1-C10)alkyls include -iso-propyl, -sec-butyl, -iso-butyl, -tert-butyl, -iso-pentyl, -neopentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 1-ethylbutyl, 2-ethylbutyl, 3-ethylbutyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl, 3,3-dimethylbutyl, 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-dimethylheptyl, and 3,3-dimethylheptyl.
“—(C1-C6)alkyl” means a straight chain or branched non-cyclic hydrocarbon having from 1 to 6 carbon atoms. Representative straight chain —(C1-C6)alkyls include -methyl, -ethyl, -n-propyl, -n-butyl, -n-pentyl, and -n-hexyl. Representative branched —(C1-C6)alkyls include -iso-propyl, -sec-butyl, -iso-butyl, -tert-butyl, -iso-pentyl, -neopentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 1-ethylbutyl, 2-ethylbutyl, 3-ethylbutyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl, and 3,3-dimethylbutyl.
“—(C1-C4)alkyl” means a straight chain or branched non-cyclic hydrocarbon having from 1 to 4 carbon atoms. Representative straight chain —(C1-C4)alkyls include -methyl, -ethyl, -n-propyl, and -n-butyl. Representative branched —(C1-C4)alkyls include -iso-propyl, -sec-butyl, -iso-butyl, and -tert-butyl.
“—(C2-C10)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-butenyl, -iso-butylenyl, -1-pentenyl, -2-pentenyl, -3-methyl-1-butenyl, -2-methyl-2-butenyl, -2,3-dimethyl-2-butenyl, -1-hexenyl, -2-hexenyl, -3-hexenyl, -1-heptenyl, -2-heptenyl, -3-heptenyl, -1-octenyl, -2-octenyl, -3-octenyl, -1-nonenyl, -2-nonenyl, -3-nonenyl, -1-decenyl, -2-decenyl, -3-decenyl and the like.
“—(C2-C6)alkenyl” means a straight chain or branched non-cyclic hydrocarbon having from 2 to 6 carbon atoms and including at least one carbon-carbon double bond. Representative straight chain and branched (C2-C6)alkenyls include -vinyl, -allyl, -1-butenyl, -2-butenyl, -iso-butylenyl, -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 least 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-1-butynyl, -4-pentynyl, -1-hexynyl, -2-hexynyl, -5-hexynyl, -1-heptynyl, -2-heptynyl, -6-heptynyl, -1-octynyl, -2-octynyl, -7-octynyl, -1-nonynyl, -2-nonynyl, -8-nonynyl, -1-decynyl, -2-decynyl, -9-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 least 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-methyl-1-butynyl, -4-pentynyl, -1-hexynyl, -2-hexynyl, -5-hexynyl and the like.
“—(C3-C10)cycloalkyl” means a saturated cyclic hydrocarbon having from 3 to 10 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-C14)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, -1,2,3,4-tetrahydronaphthyl, -5,6,7,8-tetrahydronaphthyl, -perhydronaphthyl and the like.
“—(C8-C14)tricycloalkyl” means a tri-cyclic hydrocarbon ring system having from 8 to 14 carbon atoms and at least one saturated cyclic alkyl ring. Representative —(C8-C14)tricycloalkyls include -pyrenyl, -1,2,3,4-tetrahydroanthracenyl, -perhydroanthracenyl -aceanthreneyl, -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 —(C8-C14)bicycloalkenyls include -indenyl, -pentalenyl, -naphthalenyl, -azulenyl, -heptalenyl, -1,2,7,8-tetrahydronaphthalenyl and the like.
“—(C8-C14)tricycloalkenyl” means a tri-cyclic hydrocarbon ring system having at least one carbon-carbon double bond in each ring and from 8 to 14 carbon atoms. Representative —(C8-C14)tricycloalkenyls include -anthracenyl, -phenanthrenyl, -phenalenyl, -acenaphthalenyl, as-indacenyl, s-indacenyl and the like.
“—(3- to 7-membered)heterocycle” or “-(3- to 7-membered)heterocyclo” means a 3- to 7-membered monocyclic heterocyclic ring which is either saturated, unsaturated non-aromatic, or aromatic. A 3- or a 4-membered heterocycle can contain up to 3 heteroatoms, a 5-membered heterocycle can contain up to 4 heteroatoms, a 6-membered heterocycle can contain up to 6 heteroatoms, and a 7-membered heterocycle can contain up to 7 heteroatoms. Each heteroatom is independently selected from nitrogen, which can be quaternized; oxygen; and sulfur, including sulfoxide and sulfone. The -(3- to 7-membered)heterocycle can be attached via a nitrogen or carbon atom. Representative -(3- to 7-membered)heterocycles include pyridyl, furyl, thiophenyl, pyrrolyl, oxazolyl, imidazolyl, thiazolyl, thiadiazolyl, isoxazolyl, pyrazolyl, isothiazolyl, pyridazinyl, pyrimidinyl, triazinyl, morpholinyl, pyrrolidinonyl, pyrrolidinyl, piperidinyl, piperazinyl, hydantoinyl, valerolactamyl, oxiranyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydropyrindinyl, tetrahydropyrimidinyl, tetrahydrothiophenyl, tetrahydrothiopyranyl and the like.
“-(3- to 5-membered)heterocycle” or “-(3- to 5-membered)heterocyclo” means a 3- to 5-membered monocyclic heterocyclic ring which is either saturated, unsaturated non-aromatic, or aromatic. A 3- or a 4-membered heterocycle can contain up to 3 heteroatoms, and a 5-membered heterocycle can contain up to 4 heteroatoms. Each heteroatom is independently selected from nitrogen, which can be quaternized; oxygen; and sulfur, including sulfoxide and sulfone. The -(3- to 5-membered)heterocycle can be attached via a nitrogen or carbon atom. Representative -(3- to 5-membered)heterocycles include furyl, thiophenyl, pyrrolyl, oxazolyl, imidazolyl, thiazolyl, isoxazolyl, pyrazolyl, isothiazolyl, triazinyl, pyrrolidinonyl, pyrrolidinyl, hydantoinyl, oxiranyl, oxetanyl, tetrahydrofuranyl, tetrahydrothiophenyl and the like.
“-(7- to 10-membered)bicycloheterocycle” or “-(7- to 10-membered)bicycloheterocyclo” means a 7- to 10-membered bicyclic, heterocyclic ring which is either saturated, unsaturated non-aromatic, or aromatic. A -(7- to 10-membered)bicycloheterocycle contains from 1 to 4 heteroatoms independently selected from nitrogen, which can be quaternized; oxygen; and sulfur, including sulfoxide and sulfone. The -(7- to 10-membered)bicycloheterocycle can be attached via a nitrogen or carbon atom. Representative -(7- to 10-membered)bicycloheterocycles include -quinolinyl, -isoquinolinyl, -chromonyl, -coumarinyl, -indolyl, -indolizinyl, -benzo[b]furanyl, -benzo[b]thiophenyl, -indazolyl, -purinyl, -4H-quinolizinyl, -isoquinolyl, -quinolyl, -phthalazinyl, -naphthyridinyl, -carbazolyl, -p-carbolinyl and the like.
“—(C14)aryl” means a 14-membered aromatic carbocyclic moiety such as -anthryl or -phenanthryl.
“-(5- to 10-membered)heteroaryl” means an aromatic heterocycle ring of 5 to 10 members, including both mono- and bicyclic ring systems, where at least one carbon atom of one or both of the rings is replaced with a heteroatom independently selected from nitrogen, oxygen, and sulfur. In one embodiment, one of the -(5- to 10-membered)heteroaryl's rings contain at least one carbon atom. In another embodiment, both of the -(5- to 10-membered)heteroaryl's rings contain at least one carbon atom. Representative -(5- to 10-membered)heteroaryls include pyridyl, furyl, benzofuranyl, thiophenyl, benzothiophenyl, quinolinyl, pyrrolyl, indolyl, oxazolyl, benzoxazolyl, imidazolyl, benzimidazolyl, thiazolyl, benzothiazolyl, isoxazolyl, pyrazolyl, isothiazolyl, pyridazinyl, pyrimidyl, pyrimidinyl, thiadiazolyl, triazinyl, cinnolinyl, phthalazinyl, and quinazolinyl.
“—CH2(halo)” means a methyl group where one of the hydrogens of the methyl group has been replaced with a halogen. Representative —CH2(halo) groups include —CH2F, —CH2Cl, —CH2Br, and —CH2I.
“—CH(halo)2” means a methyl group where two of the hydrogens of the methyl group have been replaced with a halogen. Representative —CH(halo)2 groups include —CHF2, —CHCl2, —CHBr2, —CHBrCl, —CHClI, and —CHI2.
“—C(halo)3” means a methyl group where each of the hydrogens of the methyl group has been replaced with a halogen. Representative —C(halo)3 groups include —CF3, —CCl3, —CBr3, and —CI3.
“-Halogen” or “-halo” means —F, —Cl, —Br, or —I.
The phrase “pyridyl group” means




where R1, R2, and n are defined above for the Pyridylene Compounds of formula (I) and (II).

The phrase “pyrazinyl group” means,




where R1, R2, and p are defined above for the Pyridylene Compounds of formula (I) and (II).

The phrase “pyrimidinyl group” means




where R1, R2, and p are defined above for the Pyridylene Compounds of formula (I) and (II).

The phrase “pyridazinyl group” means




where R1, R2, and p are defined above for the Pyridylene Compounds of formula (I) and (II).

The phrase “thiadiazolyl group” means




where R1 is defined above for the Pyridylene Compounds of formula (I) and (II).

The phrase “benzoimidiazolyl group” means




where R8 and s are defined above for the Pyridylene Compounds of formula (I) and (II).

The phrase “benzothiazolyl group” means




where R8 and s are defined above for the Pyridylene Compounds of formula (I) and (II).

The phrase “benzooxazolyl group” means




where R8 and s are defined above for the Pyridylene Compounds of formula (I) and (II).

The phrase “pyridylene ring” in connection with the Pyridylene Compounds of formula (I) means




where R3 and m are defined above for the Pyridylene Compounds of formula (I) and (II) and the numbers designate the position of each atom of the pyridylene ring of formula (I).

The phrase “pyridylene ring” in connection with the Pyridylene Compounds of formula (II) means




where R3 and m are defined above for the Pyridylene Compounds of formula (I) and (II) and the numbers designate the position of each atom of the pyridylene ring of formula (II).

The term “animal” includes, but is not limited to, a cow, monkey, baboon, chimpanzee, horse, sheep, pig, chicken, turkey, quail, cat, dog, mouse, rat, rabbit, guinea pig, and human.
The phrase “pharmaceutically acceptable salt,” as used herein, is any pharmaceutically acceptable salt that can be prepared from a Pyridylene Compound including a salt formed from an acid and a basic functional group, such as a nitrogen group, of one of the Pyridylene 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, glucoronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, and pamoate (i.e., 1,1′-methylene-bis-(2-hydroxy-3-naphthoate)) salts. The term “pharmaceutically acceptable salt” also includes a salt prepared from a Pyridylene Compound having an acidic functional group, such as a carboxylic acid functional group, and a pharmaceutically 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-(hydroxymethyl)methylamine, N,N-di-lower alkyl-N-(hydroxy lower alkyl)-amines, 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.
The phrase “effective amount,” when used in connection with a Pyridylene Compound means an amount effective for: (a) treating or preventing a Condition; or (b) inhibiting VR1, mGluR1, or mGluR5 function in a cell.
The phrase “effective amount,” when used in connection with the another therapeutic agent means an amount for providing the therapeutic effect of the therapeutic agent.
When a first group is “substituted with one or more” second groups, one or more hydrogen atoms of the first group is replaced with a corresponding number of second groups. When the number of second groups is two or greater, each second group can be the same or different. In one embodiment, the number of second groups is one or two. In another embodiment, the number of second groups is one.
The term “THF” means tetrahydrofuran.
The term “DMF” means dimethylformamide.
The term “HOBT” means 1-hydroxybenzotriazole hydrate.
The term “EDCI” means 1-ethyl-3-[3-(dimethylamino)propyl]carbodiimide.
The term “IBD” means inflammatory-bowel disease.
The term “IBS” means irritable-bowel syndrome.
The term “ALS” means amyotrophic lateral sclerosis.
The phrases “treatment of,” “treating” and the like include the amelioration or cessation of a Condition or a symptom thereof.
In one embodiment, treating includes inhibiting, for example, decreasing the overall frequency of episodes of a Condition or a symptom thereof.
The phrases “prevention of,” “preventing” and the like include the avoidance of the onset of a Condition or a symptom thereof.
4.5 Methods for Making the Pyridylene Compounds
The Pyridylene Compounds can be made using conventional organic synthesis or by the following illustrative methods shown in the schemes below.
4.5.1 Methods for Making the Pyridylene Compounds of Formula (I) where X is O
The Pyridylene Compounds of formula (I) where X is O can be obtained by the following illustrative method shown below in Scheme 1.







To a solution of a halogenated benzoic acid 1 in DMF (0.33 M) is added about 1.1 equivalents of amine, Ar2—NH2, and the resulting solution is allowed to stir for about 5 min at a temperature of about 25° C. To the resulting solution is then added about 0.5 equivalent of HOBT and about 1 equivalent of EDCI and the resulting mixture is allowed to stir for about 2 h at about 25° C. The reaction mixture is then diluted with about 100 mL 2N aqueous sodium hydroxide and extracted with ethyl acetate (3 extractions, about 100 mL/extraction). The ethyl acetate layers are combined and the ethyl acetate is removed under reduced pressure to provide a compound of formula 2. The compound of formula 2 is dissolved in DMF (0.04M) and about 3 equivalents of zinc bromide 3a-e and about 0.05 equivalents of Pd(PPh3)4 are added to the suspension under a nitrogen atmosphere. The resulting reaction mixture is allowed to stir for about 2 h at a temperature of about 100° C. The solvent is then removed under reduced pressure to provide a Pyridylene Compound where X is O. The Pyridylene Compound where X is O can be purified by means known to those skilled in the art. Representative methods to purify the Pyridylene Compound where X is O include, but are not limited to column chromatography, preparative thin-layer chromatography, preparative high pressure liquid chromatography (HPLC), and recrystallization.
If the compound of formula 2 is substituted with a hydroxyl or amino group, the hydroxyl or amino group is protected using a suitable protecting group before being reacted with zinc bromide 3a-e. Similarly, if R2 is a hydroxyl or amino group, the hydroxyl or amino group is protected before forming the zinc bromide reagent. Suitable protecting groups for hydroxyl group include, but are not limited to, methyl ether, methoxymethyl ether, methoxythiomethyl ether, 2-methoxyethoxymethyl ether, bis(2-chloroethoxy)ethyl ether, tetrahydropyranyl ether, tetrahydrothiopyranyl ether, 4-methoxytetrahydropyranyl ether, methoxytetrahydrothiopyranyl ether, tetrahydrofuranyl ether, tetrahydrothiofuranyl ether, 1-ethoxyethyl ether, 1-methyl-1-methoxyethyl ether, 2-(phenylselenyl ether), tert-butyl ether, allyl ether, benzyl ether, o-nitrobenzyl ether, triphenylmethyl ether, o-napthyldiphenylmethyl ether, p-methoxydiphenylmethyl ether, 9-(9-phenyl-10-oxo)anthryl ether(tritylone), trimethylsilyl ether, iso-propyldimethylsilyl ether, tert-butyldimethylsilyl ether, tert-butyldiphenylsilyl ether, tribenzylsilyl ether, tri-iso-propylsilyl ether, formate ester, acetate ester, trichloroacetate ester, phenoxyacetate ester, iso-butyrate ester, pivaloate ester, adamantoate ester, benzoate ester, 2,4,6-trimethyl(mesitoate)ester, methyl carbonate, 2,2,2-trichlorocarbonate, allyl carbonate, p-nitrophenyl carbonate, benzyl carbonate, p-nitrobenzyl carbonate, S-benzylthiocarbonate, N-phenylcarbamate, nitrate ester, and 2,4-dinitrophenylsulfenate ester (See, e.g., T. W. Greene, Protective Groups in Organic Synthesis, John Wiley-Interscience Publication, New York, (1981)). Suitable protecting groups for an amino group include, but are not limited to, 1,1-dimethyl-2,2,2-trichloroethyl carbamate, 1-methyl-1-(4-biphenylyl)ethyl carbamate, 2-trimethylsilylethyl carbamate, 9-fluorenylmethyl carbamate, and tert-butyl carbamate (T. W. Greene et al., Protective Groups in Organic Synthesis, 309-405 (2d ed. 1991)).
The halo acids 1 and the amines of formula Ar2NH2 are commercially available or can be prepared by methods known to those skilled in the art. Compounds of formula 3a-e can be prepared by methods known to those skilled in the art (See M. B. Smith and J. March, March's Advanced Organic Chemistry: Reaction Mechanisms and Structure, 805-807 (5th ed. 2001); H. Fillon et al., Tett. Lett. 42:3843-46 (2001); M. Amadji et al., Tettrahedron 9:1657-60 (1998); and S. Billotte, Synlett. 379-380 (1998)).
4.5.2 Methods for Making the Pyridylene Compounds Where X is S
The Pyridylene Compounds where X is S can be obtained by reacting a Pyridylene Compound where X is O, prepared as described above in section 4.5.1, with Lawesson's reagent at a temperature of about 100° C. (See, e.g., J. March, Advanced Organic Chemistry, Reactions, Mechanisms, and Structure, 891-892 (4th ed. 1992)).
4.6 Therapeutic Uses of the Pyridylene Compounds
In accordance with the invention, the Pyridylene Compounds are administered to an animal in need of treatment or prevention of a Condition.
In one embodiment, an effective amount of a Pyridylene Compound can be used to treat or prevent any condition treatable or preventable by inhibiting VR1. Examples of conditions that are treatable or preventable by inhibiting VR1 include, but are not limited to, pain, UI, an ulcer, IBD, and IBS.
In another embodiment, an effective amount of a Pyridylene Compound can be used to treat or prevent any condition treatable or preventable by inhibiting 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 Pyridylene Compound can be used to treat or prevent any condition treatable or preventable by inhibiting mGluR1. Examples of conditions that are treatable or preventable by inhibiting mGluR1 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 Pyridylene Compounds can be used to treat or prevent acute or chronic pain. Examples of pain treatable or preventable using the Pyridylene Compounds include, but are not limited to, cancer pain, labor pain, myocardial infarction pain, pancreatic pain, colic pain, post-operative pain, headache pain, muscle pain, arthritic pain, and pain associated with a periodontal disease, including gingivitis and periodontitis.
The Pyridylene Compounds can also be used for treating or preventing pain associated with inflammation or with an inflammatory disease in an animal. Such pain can arise where there is an inflammation of the body tissue which can be a local inflammatory response and/or a systemic inflammation. For example, the Pyridylene Compounds can be used to 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 bowel diseases, such as ileitis, ulcerative colitis, Barrett's syndrome, and Crohn's disease; inflammatory lung diseases, such as asthma, adult respiratory distress syndrome, and chronic obstructive airway disease; inflammatory diseases of the eye, including corneal dystrophy, trachoma, onchocerciasis, uveitis, sympathetic ophthalmitis and endophthalmitis; chronic inflammatory disease of the gum, including gingivitis and periodontitis; tuberculosis; leprosy; inflammatory diseases of the kidney, including uremic complications, glomerulonephritis and nephrosis; inflammatory disease of the skin, including sclerodermatitis, psoriasis and eczema; inflammatory diseases of the 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 II diabetes mellitus; diabetic complications, including, but not limited to, diabetic cataract, glaucoma, retinopathy, nephropathy (such as microaluminuria and progressive diabetic nephropathy), polyneuropathy, mononeuropathies, autonomic neuropathy, gangrene of the 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 disease of the heart, such as cardiomyopathy, ischemic heart disease hypercholesterolemia, and artherosclerosis; 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 Pyridylene Compounds can also be used for treating or preventing pain associated with inflammatory disease that can, for example, be a systemic inflammation of the body, exemplified by gram-positive or gram negative shock, hemorrhagic or anaphylactic shock, or shock induced by cancer chemotherapy in response to pro-inflammatory cytokines, e.g., shock associated with pro-inflammatory cytokines. Such shock can be induced, e.g., by a chemotherapeutic agent that is administered as a treatment for cancer.
The Pyridylene Compounds can be used to treat or prevent UI. Examples of UI treatable or preventable using the Pyridylene Compounds include, but are not limited to, urge incontinence, stress incontinence, overflow incontinence, neurogenic incontinence, and total incontinence.
The Pyridylene Compounds can be used to treat or prevent an ulcer. Examples of ulcers treatable or preventable using the Pyridylene Compounds include, but are not limited to, a duodenal ulcer, a gastric ulcer, a marginal ulcer, an esophageal ulcer, and a stress ulcer.
The Pyridylene Compounds can be used to treat or prevent IBD, including Crohn's disease and ulcerative colitis.
The Pyridylene Compounds can be used to treat or prevent IBS. Examples of IBS treatable or preventable using the Pyridylene Compounds include, but are not limited to, spastic-colon-type IBS and constipation-predominant IBS.
The Pyridylene 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, and Alcohol-Related Disorder not otherwise specified (NOS).
Nicotine-related disorders include, but are not limited 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, Amphetamine-Induced Sexual Dysfunction, Amphetamine-Induced Sleep Disorder, and Amphetamine Related Disorder not otherwise specified (NOS).
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, and Cannabis Related Disorder not otherwise specified (NOS).
Cocaine-related disorders include, but are not limited to, Cocaine Dependence, Cocaine Abuse, Cocaine Intoxication, Cocaine Withdrawal, Cocaine Intoxication Delirium, Cocaine-Induced Psychotic Disorder with delusions, Cocaine-Induced Psychotic Disorders with hallucinations, Cocaine-Induced Mood Disorder, Cocaine-Induced Anxiety Disorder, Cocaine-Induced Sexual Dysfunction, Cocaine-Induced Sleep Disorder, and Cocaine Related Disorder not otherwise specified (NOS).
Hallucinogen-related disorders include, but are not limited to, Hallucinogen Dependence, Hallucinogen Abuse, Hallucinogen Intoxication, Hallucinogen Withdrawal, Hallucinogen Intoxication Delirium, Hallucinogen Persisting Perception Disorder (Flashbacks), Hallucinogen-Induced Psychotic Disorder with delusions, Hallucinogen-Induced Psychotic Disorders with hallucinations, Hallucinogen-Induced Mood Disorder, Hallucinogen-Induced Anxiety Disorder, Hallucinogen-Induced Sexual Dysfunction, Hallucinogen-Induced Sleep Disorder, Hallucinogen Related Disorder not otherwise specified (NOS).
Inhalant-related disorders include, but are not limited to, Inhalant Dependence, Inhalant Abuse, Inhalant Intoxication, Inhalant Intoxication Delirium, Inhalant-Induced Psychotic Disorder with delusions, Inhalant-Induced Psychotic Disorder with hallucinations, Inhalant-Induced Anxiety Disorder, and Inhalant Related Disorder not otherwise specified (NOS).
Opioid-related disorders include, but are not limited to, Opioid Dependence, Opioid Abuse, Opioid Withdrawal, Opioid Intoxication, Opioid Intoxication Delirium, Opioid-Induced Psychotic Disorder with delusions, Opioid-Induced Psychotic Disorder with hallucinations, Opioid-Induced Anxiety Disorder, and Opioid Related Disorder not otherwise specified (NOS).
The Pyridylene Compounds can be used to treat or prevent Parkinson's disease and parkinsonism and the symptoms associated with Parkinson's disease and parkinsonism, including but not limited to, bradykinesia, muscular rigidity, resting tremor, and impairment of postural balance.
The Pyridylene 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 Pyridylene 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 Pyridylene Compounds can be used to treat or prevent strokes, including but not limited to, ischemic strokes and hemorrhagic strokes.
The Pyridylene Compounds can be used to treat or prevent a seizure, including but not limited to, infantile spasms, febrile seizures, and epileptic seizures.
The Pyridylene Compounds can be used to treat or prevent a pruritic condition, including but not limited to, pruritus caused by dry skin, scabies, dermatitis, herpetiformis, atopic dermatitis, pruritus vulvae et ani, miliaria, insect bites, pediculosis, contact dermatitis, drug reactions, urticaria, urticarial eruptions of pregnancy, psoriasis, lichen planus, lichen simplex chronicus, exfoliative dermatitis, folliculitis, bullous pemphigoid, or fiberglass dermatitis.
The Pyridylene 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 Pyridylene Compounds can be used to treat or prevent a cognitive disorder, including but not limited to, delirium and dementia such as multi-infarct dementia, dementia pugilistica, dementia caused by AIDS, and dementia caused by Alzheimer's disease.
The Pyridylene Compounds can be used to treat or prevent a memory deficiency, including but not limited to, dissociative amnesia and dissociative fugue.
The Pyridylene Compounds can be used to treat or prevent restricted brain function, including but not limited to, that caused by surgery or an organ transplant, restricted blood supply to the brain, a spinal cord injury, a head injury, hypoxia, cardiac arrest, or hypoglycemia.
The Pyridylene Compounds can be used to treat or prevent Huntington's chorea.
The Pyridylene Compounds can be used to treat or prevent ALS.
The Pyridylene 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 Pyridylene Compounds can be used to treat or prevent a muscle spasm.
The Pyridylene Compounds can be used to treat or prevent a migraine including, but not limited to, migraine without aura (“common migraine”), migraine with aura (“classic migraine”), migraine without headache, basilar migraine, familial hemiplegic migraine, migrainous infarction, and migraine with prolonged aura.
The Pyridylene Compounds can be used to treat or prevent vomiting, including but not limited to, nausea vomiting, dry vomiting (retching), and regurgitation.
The Pyridylene Compounds can be used to treat or prevent dyskinesia, including but not limited to, tardive dyskinesia and biliary dyskinesia.
The Pyridylene Compounds can be used to treat or prevent depression, including but not limited to, major depression and bipolar disorder.
Applicants believe that the Pyridylene Compounds are antagonists for VR1.
The invention also relates to methods for inhibiting VR1 function in a cell, comprising contacting a cell capable of expressing VR1 with an amount of a Pyridylene Compound effective to inhibit VR1 function in a cell. This method can be used in vitro, for example, as an assay to select cells that express VR1 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 VR1 function in a cell in vivo, in an animal (e.g., a human), by contacting a cell of the animal with an effective amount of a Pyridylene Compound. 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 UI in an animal in need thereof. In another embodiment, the method is useful for treating or preventing an ulcer in an animal in need thereof. In another embodiment, the method is useful for treating or preventing IBD in an animal in need thereof. In another embodiment, the method is useful for treating or preventing IBS in an animal in need thereof.
Examples of tissue comprising cells capable of expressing VR1 include, but are not limited to, neuronal, brain, kidney, urothelium, and bladder tissue. Methods for assaying cells that express VR1 are known in the art.
Applicants believe that the Pyridylene Compounds are antagonists for mGluR5.
The invention further relates to methods for inhibiting mGluR5 function in a cell, comprising contacting a cell capable of expressing mGluR5 with an amount of a Pyridylene Compound effective to inhibit mGluR5 function in the cell. This method can be used in vitro, for example, as an assay to select cells that express mGluR5 and, accordingly, are useful as part of an assay to select compounds useful for treating or preventing pain, an addictive disorder, Parkinson's disease, parkinsonism, anxiety, a pruritic condition, or psychosis. The method is also useful for inhibiting mGluR5 function in a cell in vivo, in an animal (e.g., a human), by contacting a cell, in an animal, with an amount of a Pyridylene 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. In another embodiment, the method is useful for treating or preventing psychosis in an animal in need thereof.
Examples of cells capable of expressing mGluR5 are neuronal and glial cells of the central nervous system, particularly the brain, especially in the nucleus accumbens. Methods for assaying cells that express mGluR5 are known in the art.
Applicants believe that the Pyridylene Compounds are antagonists for mGluR1.
The invention also relates to methods for inhibiting mGluR1 function in a cell, comprising contacting a cell capable of expressing mGluR1 with an amount of a Pyridylene Compound effective to inhibit mGluR1 function in the cell. This method can be used in vitro, for example, as an assay to select cells that express mGluR1 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 mGluR1 function in a cell in vivo, in an animal (e.g., a human), by contacting a cell in an animal with an effective amount of a Pyridylene Compound. 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 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. 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 epilepsy in an animal in need thereof. In another embodiment, the method is useful for treating or preventing stroke in an animal in need thereof. In another embodiment, the method is useful for treating or preventing a seizure in an animal in need thereof. In another embodiment, the method is useful for treating or preventing a pruritic condition in an animal in need thereof. In another embodiment, the method is useful for treating or preventing psychosis in an animal in need thereof. In 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 treating or preventing restricted brain function in an animal in need thereof. In another embodiment, the method is useful for treating or preventing Huntington's chorea in an animal in need thereof. In another embodiment, the method is useful for treating or preventing ALS in an animal in need thereof. In another embodiment, the method is useful for treating or preventing dementia in an animal in need thereof. In another embodiment, the method is useful for treating or preventing retinopathy in an animl in need thereof. In another embodiment, the method is useful for treating or preventing a muscle spasm in an animal in need thereof. In another embodiment, the method is useful for treating or preventing a migraine in an animal in need thereof. In another embodiment, the method is useful for treating 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 an animal in need thereof.
Examples of cells capable of expressing mGluR1 include, but are not limited to, cerebellar Purkinje neuron cells, Purkinje cell bodies (punctate), cells of spine(s) of the cerebellum; neurons and neurophil cells of olfactory-bulb glomeruli; cells of the superficial layer of the cerebral cortex; hippocampus cells; thalamus cells; superior colliculus cells; and spinal trigeminal nucleus cells. Methods for assaying cells that express mGluR1 are known in the art.
4.7 Therapeutic/Prophylactic Administration and Compositions of the Invention
Due to their activity, the Pyridylene Compounds are advantageously useful in veterinary and human medicine. As described above, the Pyridylene Compounds are useful for treating or preventing a Condition in an animal in need thereof.
When administered to an animal, the Pyridylene Compounds are administered as a component of a composition that comprises a pharmaceutically acceptable carrier or excipient. The present compositions, which comprise a Pyridylene Compound, can be administered orally. The Pyridylene Compounds of the invention can also be administered by any other convenient route, for example, by infusion or bolus injection, by absorption through epithelial or mucocutaneous linings (e.g., oral, rectal, and intestinal mucosa, etc.) and can be administered together with another therapeutically active agent. Administration can be systemic or local. Various delivery systems are known, e.g., encapsulation in liposomes, microparticles, microcapsules, capsules, etc., and can be used to administer the Pyridylene Compound.
Methods of administration include, but are not limited to, intradermal, intramuscular, intraperitoneal, intravenous, subcutaneous, intranasal, epidural, oral, sublingual, intracerebral, intravaginal, transdermal, rectal, by inhalation, or topical, particularly to the ears, nose, eyes, or skin. The mode of administration is left to the discretion of the practitioner. In most instances, administration will result in the release of the Pyridylene Compounds into the bloodstream.
In specific embodiments, it can be desirable to administer the Pyridylene Compounds locally. This can be achieved, for example, and not by way 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 suppository 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 Pyridylene Compounds into the central nervous system or gastrointestinal tract by any suitable route, including intraventricular, intrathecal, and epidural injection, and enema. Intraventricular injection can be facilitated by an intraventricular catheter, for example, attached to a reservoir, such as an 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 fluorocarbon or synthetic pulmonary surfactant. In certain embodiments, the Pyridylene Compounds can be formulated as a suppository, with traditional binders and excipients such as triglycerides.
In another embodiment, the Pyridylene 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)).
In yet another embodiment, the Pyridylene 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. 321:574(1989)). In 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); During et al., 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 of the Pyridylene Compounds, e.g., the spinal column, brain, or gastrointestinal tract, thus requiring only a fraction of the systemic dose.
The present compositions can optionally comprise a suitable amount of a pharmaceutically acceptable excipient so as to provide the form for proper administration to the animal. Such a pharmaceutical excipient can be a liquid, such as water or an oil, including those of petroleum, animal, vegetable, or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil and the like. The pharmaceutical excipient can be saline, gum acacia, gelatin, starch paste, talc, keratin, colloidal silica, urea and the like. In addition, auxiliary, stabilizing, thickening, lubricating, and coloring agents can be used. In one embodiment, the pharmaceutically acceptable excipient is sterile when administered to an animal. Water is a particularly useful excipient when the Pyridylene Compound is administered intravenously. Saline solutions and aqueous dextrose and glycerol solutions can also be employed as liquid excipients, particularly for injectable solutions. Suitable pharmaceutical excipients also include starch, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, dried skim milk, glycerol, propylene, glycol, water, ethanol and the like. The present compositions, if desired, can also contain minor amounts of wetting or emulsifying agents, or pH buffering agents.
The present compositions can take the form of solutions, suspensions, emulsions, tablets, pills, pellets, capsules, capsules containing liquids, powders, sustained-release formulations, suppositories, emulsions, aerosols, sprays, suspensions, or any other form suitable for use. In one embodiment, the composition is in the form of a capsule (see, e.g., U.S. Pat. No. 5,698,155). Other examples of suitable pharmaceutical excipients are described in Remington's Pharmaceutical Sciences 1447-1676 (Alfonso R. Gennaro ed., 19th ed. 1995), incorporated herein by reference.
In one embodiment, the Pyridylene 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 the form of tablets, lozenges, aqueous or oily suspensions, granules, powders, emulsions, capsules, syrups, or elixirs, for example. Orally administered compositions can contain one or more agents, for example, sweetening agents such as fructose, aspartame or saccharin; flavoring agents such as peppermint, oil of wintergreen, or cherry; coloring agents; and preserving agents, to provide a pharmaceutically palatable preparation. 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 membranes surrounding an osmotically active driving compound are also suitable for orally administered compositions. In 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 through an aperture. These delivery platforms can provide an essentially zero order delivery profile as opposed to the spiked profiles of immediate release formulations. A time-delay material such as glycerol monostearate or glycerol stearate can also be used. 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 Pyridylene 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 lidocaine to lessen pain at the site of the 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 Pyridylene 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 Pyridylene Compounds are administered by injection, an ampule of sterile water for injection or saline can be provided so that the ingredients can be mixed prior to administration.
The Pyridylene Compounds can be administered by controlled-release or sustained-release means or by delivery devices that are known to those in the art. Examples include, but are not limited to, those described in U.S. Pat. Nos. 3,845,770; 3,916,899; 3,536,809; 3,598,123; 4,008,719; 5,674,533; 5,059,595; 5,591,767; 5,120,548; 5,073,543; 5,639,476; 5,354,556; and 5,733,566, each of which is incorporated herein by reference. Such dosage forms can be used to provide controlled- or sustained-release of one or more active ingredients using, for example, 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 in the art, including those described herein, can be readily selected for use with the active ingredients of the invention. The invention thus encompasses single unit dosage forms suitable for oral administration such as, but not limited to, tablets, capsules, gelcaps, and caplets that are adapted for controlled- or sustained-release.
Controlled- or sustained-release pharmaceutical compositions can have a common goal of improving drug therapy over that achieved by their non-controlled or non-sustained-release counterparts. In one embodiment, a controlled- or sustained-release composition comprises a minimal amount of a Pyridylene Compound to treat or prevent the Condition or a symptom thereof in a minimum amount of time. Advantages of controlled- or sustained-release compositions include extended activity of the drug, reduced dosage frequency, and increased patient compliance. In addition, controlled- or sustained-release compositions can favorably affect the time of onset of action or other characteristics, such as blood levels of the Pyridylene Compound, and can thus reduce the occurrence of adverse side effects.
Controlled- or sustained-release compositions can initially release an amount of a Pyridylene Compound that promptly produces the desired therapeutic or prophylactic effect, and gradually and continually release other amounts of the Pyridylene Compound to maintain this level of therapeutic or prophylactic effect over an extended period of time. To maintain a constant level of the Pyridylene Compound in the body, the Pyridylene Compound can be released from the dosage form at a rate that will replace the amount of Pyridylene Compound being metabolized and excreted from the body. Controlled- or sustained-release of an active ingredient can be stimulated by various conditions, including but not limited to, changes in pH, changes in temperature, concentration or availability of enzymes, concentration or availability of water, or other physiological conditions or compounds.
The amount of the Pryidylene Compound that is effective for the treatment or prevention of a condition 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 of the Condition and can be decided according to the judgment of a practitioner and/or each animal's circumstances. Suitable effective dosage amounts, however, range from about 0.01 mg/kg of body weight to about 2500 mg/kg of body weight, although they are typically about 100 mg/kg of body weight or less. In one embodiment, the effective dosage amount ranges from about 0.01 mg/kg of body weight to about 100 mg/kg of body weight of a Pyridylene Compound, in another embodiment, about 0.02 mg/kg of body weight to about 50 mg/kg of body weight, and in another embodiment, about 0.025 mg/kg of body weight to about 20 mg/kg of body weight. In one embodiment, an effective dosage amount is administered about every 24 h until the Condition is abated. In another embodiment, an effective dosage amount is administered about every 12 h until the Condition is abated. In another embodiment, an effective dosage amount is administered about every 8 h until the Condition is abated. In another embodiment, an effective dosage amount is administered about every 6 h until the Condition is abated. In another embodiment, an effective dosage amount is administered about every 4 h until the Condition is abated. The effective dosage amounts described herein refer to total amounts administered; that is, if more than one Pryidylene Compound is administered, the effective dosage amounts correspond to the total amount administered.
Where a cell capable of expressing VR1, mGluR5, or mGluR1 is contacted with a Pyridylene Compound in vitro, the amount effective for inhibiting the VR1, mGluR5, or mGluR1 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 comprising the Pyridylene Compound is from about 0.01 μL to about 1 mL. In another embodiment, the volume of solution or suspension is about 200 μL.
Where a cell capable of expressing VR1, mGluR5, or mGluR1 is contacted with a Pyridylene Compound in vivo, the amount effective for inhibiting the receptor function in a cell will typically range from about 0.01 mg/kg of body weight to about 2500 mg/kg of body weight, although it typically ranges from about 100 mg/kg of body weight or less. In one embodiment, the effective dosage amount ranges from about 0.01 mg/kg of body weight to about 100 mg/kg of body weight of a Pyridylene Compound, in another embodiment, about 0.02 mg/kg of body weight to about 50 mg/kg of body weight, and in another embodiment, about 0.025 mg/kg of body weight to about 20 mg/kg of body weight. In one embodiment, an effective dosage amount is administered about every 24 h. In another embodiment, an effective dosage amount is administered about every 12. In another embodiment, an effective dosage amount is administered about every 8. In another embodiment, an effective dosage amount is administered about every 6 h. In another embodiment, an effective dosage amount is administered about every 4 h.
The Pyridylene Compounds can be assayed in vitro or in vivo for the desired therapeutic or prophylactic activity prior to use in humans. Animal model systems can be used to demonstrate safety and efficacy.
The present methods for treating or preventing a Condition in an animal in need thereof can further comprise administering to the animal being administered a Pyridylene Compound another therapeutic agent. In one embodiment, the other therapeutic agent is administered in an effective amount.
The present methods for inhibiting VR1 function in a cell capable of expressing VR1 can further comprise contacting the cell with an effective amount of another therapeutic agent that may or may not inhibit VR1.
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 that may or may not inhibit mGluR5.
The present methods for inhibiting mGluR1 function in a cell capable of expressing mGluR1 can further comprise contacting the cell with an effective amount of another therapeutic agent that may or may not inhibit mGluR1.
Effective amounts of the other therapeutic agents are known to those skilled in the art. However, it is well within the skilled artisan's purview to determine the other therapeutic agent's optimal effective-amount range. In one embodiment of the invention, where another therapeutic agent is administered to an animal, the minimal effective amount of the Pyridylene Compound is less than its minimal effective amount would be where the other therapeutic agent is not administered. In this embodiment, without being bound by theory, it is believed that the Pyridylene Compounds and the other therapeutic agent act synergistically to treat or prevent a Condition.
The other therapeutic agent can be, but is not limited to, an opioid agonist, a non-opioid analgesic, a non-steroidal anti-inflammatory agent, an antimigraine agent, a Cox-II 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 treating 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 epilepsy, an agent for treating a stroke, an agent for treating a seizure, an agent for treating a pruritic condition, an agent for treating psychosis, an agent for treating Huntington's chorea, an agent for treating ALS, an agent for treating a cognitive disorder, an agent for treating a migraine, an agent for inhibiting vomiting, an agent for treating dyskinesia, or an agent for treating depression, and mixtures thereof.
Examples of useful opioid agonists include, but are not limited to, alfentanil, allylprodine, alphaprodine, anileridine, benzylmorphine, bezitramide, buprenorphine, butorphanol, clonitazene, codeine, desomorphine, dextromoramide, dezocine, diampromide, diamorphone, dihydrocodeine, dihydromorphine, dimenoxadol, dimepheptanol, dimethylthiambutene, dioxaphetyl butyrate, dipipanone, eptazocine, ethoheptazine, ethylmethylthiambutene, ethylmorphine, etonitazene fentanyl, heroin, hydrocodone, hydromorphone, hydroxypethidine, isomethadone, ketobemidone, levorphanol, levophenacylmorphan, lofentanil, meperidine, meptazinol, metazocine, methadone, metopon, morphine, myrophine, nalbuphine, narceine, nicomorphine, norlevorphanol, normethadone, nalorphine, normorphine, norpipanone, opium, oxycodone, oxymorphone, papaveretum, pentazocine, phenadoxone, phenomorphan, phenazocine, phenoperidine, piminodine, piritramide, proheptazine, promedol, properidine, propiram, propoxyphene, sufentanil, tilidine, tramadol, pharmaceutically acceptable salts thereof, and mixtures thereof.
In certain embodiments, the opioid agonist is selected from codeine, hydromorphone, hydrocodone, oxycodone, dihydrocodeine, dihydromorphine, morphine, tramadol, oxymorphone, pharmaceutically acceptable salts thereof, and mixtures thereof.
Examples of useful non-opioid analgesics include non-steroidal anti-inflammatory agents, such as aspirin, ibuprofen, diclofenac, naproxen, benoxaprofen, flurbiprofen, fenoprofen, flubufen, ketoprofen, indoprofen, piroprofen, carprofen, oxaprozin, pramoprofen, muroprofen, trioxaprofen, suprofen, aminoprofen, tiaprofenic acid, fluprofen, bucloxic acid, indomethacin, sulindac, tolmetin, zomepirac, tiopinac, zidometacin, acemetacin, fentiazac, clidanac, oxpinac, mefenamic acid, meclofenamic acid, flufenamic acid, niflumic acid, tolfenamic acid, diflurisal, flufenisal, piroxicam, sudoxicam, isoxicam, and pharmaceutically acceptable salts thereof, and mixtures thereof. Other suitable non-opioid analgesics include the following, non-limiting, chemical classes of analgesic, antipyretic, nonsteroidal anti-inflammatory drugs: salicylic acid derivatives, including aspirin, sodium salicylate, choline magnesium trisalicylate, salsalate, diflunisal, salicylsalicylic acid, sulfasalazine, and olsalazin; para-aminophenol 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 of the 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 1996); 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 incorporated by reference in their entireties.
Examples of useful Cox-II inhibitors and 5-lipoxygenase inhibitors, as well as combinations thereof, are described in U.S. Pat. No. 6,136,839, which is hereby incorporated by reference in its entirety. Examples of useful Cox-II inhibitors include, but are not limited to, rofecoxib and celecoxib.
Examples of useful antimigraine agents include, but are not limited to, alpiropride, bromocriptine, dihydroergotamine, dolasetron, ergocornine, ergocorninine, ergocryptine, ergonovine, ergot, ergotamine, flumedroxone acetate, fonazine, ketanserin, lisuride, lomerizine, methylergonovine, methysergide, metoprolol, naratriptan, oxetorone, pizotyline, propranolol, risperidone, rizatriptan, sumatriptan, timolol, trazodone, zolmitriptan, and mixtures thereof.
The other therapeutic agent can also be an antiemetic agent. Examples of useful antiemetic agents include, but are not limited to, metoclopromide, domperidone, prochlorperazine, promethazine, chlorpromazine, trimethobenzamide, odansteron, granisetron, hydroxyzine, acetylleucine monoethanolamine, alizapride, azasetron, benzquinamide, bietanautine, bromopride, buclizine, clebopride, cyclizine, dimenhydrinate, diphenidol, dolasetron, meclizine, methallatal, metopimazine, nabilone, oxyperndyl, pipamazine, scopolamine, sulpiride, tetrahydrocannabinol, 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, bopindolol, bucumolol, bufetolol, bufuralol, bunitrolol, bupranolol, butidrine hydrochloride, butofilolol, carazolol, carteolol, carvedilol, celiprolol, cetamolol, cloranolol, dilevalol, epanolol, esmolol, indenolol, labetalol, levobunolol, mepindolol, metipranolol, metoprolol, moprolol, nadolol, nadoxolol, nebivalol, nifenalol, nipradilol, oxprenolol, penbutolol, pindolol, practolol, pronethalol, propranolol, sotalol, sulfinalol, talinolol, tertatolol, tilisolol, timolol, 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, gabapentin, 5-hydroxytryptophan, lamotrigine, magnesium bromide, magnesium sulfate, mephenyloin, mephobarbital, metharbital, methetoin, methsuximide, 5-methyl-5-(3-phenanthryl)-hydantoin, 3-methyl-5-phenylhydantoin, narcobarbital, nimetazepam, nitrazepam, oxcarbazepine, paramethadione, phenacemide, phenetharbital, pheneturide, phenobarbital, phensuximide, phenylmethylbarbituric acid, phenyloin, phethenylate sodium, potassium bromide, pregabaline, primidone, progabide, sodium bromide, solanum, strontium bromide, suclofenide, sulthiame, tetrantoin, tiagabine, topiramate, trimethadione, valproic acid, valpromide, vigabatrin, and zonisamide.
Examples of useful antidepressants include, but are not limited to, binedaline, caroxazone, citalopram, (S)-citalopram, dimethazan, fencamine, indalpine, indeloxazine hydrocholoride, nefopam, nomifensine, oxitriptan, oxypertine, paroxetine, sertraline, thiazesim, trazodone, benmoxine, iproclozide, iproniazid, isocarboxazid, nialamide, octamoxin, phenelzine, cotinine, rolicyprine, rolipram, maprotiline, metralindole, mianserin, mirtazepine, adinazolam, amitriptyline, amitriptylinoxide, amoxapine, butriptyline, clomipramine, demexiptiline, desipramine, dibenzepin, dimetacrine, dothiepin, doxepin, fluacizine, imipramine, imipramine N-oxide, iprindole, lofepramine, melitracen, metapramine, nortriptyline, noxiptilin, opipramol, pizotyline, propizepine, protriptyline, quinupramine, tianeptine, trimipramine, adrafinil, benactyzine, bupropion, butacetin, dioxadrol, duloxetine, etoperidone, febarbamate, femoxetine, fenpentadiol, fluoxetine, fluvoxamine, hematoporphyrin, hypericin, levophacetoperane, medifoxamine, milnacipran, minaprine, moclobemide, nefazodone, oxaflozane, piberaline, prolintane, pyrisuccideanol, ritanserin, roxindole, rubidium chloride, sulpiride, tandospirone, thozalinone, tofenacin, toloxatone, tranylcypromine, L-tryptophan, venlafaxine, viloxazine, and zimelidine.
Examples of useful Ca2+-channel blockers include, but are not limited to, bepridil, clentiazem, diltiazem, fendiline, gallopamil, mibefradil, prenylamine, semotiadil, terodiline, verapamil, amlodipine, aranidipine, barnidipine, benidipine, cilnidipine, efonidipine, elgodipine, felodipine, isradipine, lacidipine, lercanidipine, manidipine, nicardipine, nifedipine, nilvadipine, nimodipine, nisoldipine, nitrendipine, cinnarizine, flunarizine, lidoflazine, lomerizine, bencyclane, etafenone, fantofarone, and perhexiline.
Examples of useful anticancer agents include, but are not limited to, acivicin, aclarubicin, acodazole hydrochloride, acronine, adozelesin, aldesleukin, altretamine, ambomycin, ametantrone acetate, aminoglutethimide, amsacrine, anastrozole, anthramycin, asparaginase, asperlin, azacitidine, azetepa, azotomycin, batimastat, benzodepa, bicalutamide, bisantrene hydrochloride, bisnafide dimesylate, bizelesin, bleomycin sulfate, brequinar sodium, bropirimine, busulfan, cactinomycin, calusterone, caracemide, carbetimer, carboplatin, 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, doxorubicin hydrochloride, droloxifene, droloxifene citrate, dromostanolone propionate, duazomycin, edatrexate, eflornithine hydrochloride, elsamitrucin, 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, flurocitabine, fosquidone, fostriecin sodium, gemcitabine, gemcitabine hydrochloride, hydroxyurea, idarubicin hydrochloride, ifosfamide, ilmofosine, interleukin II (including recombinant interleukin II or rIL2), interferon alpha-2a, interferon alpha-2b, interferon alpha-n1, interferon alpha-n3, interferon beta-I a, interferon gamma-I b, iproplatin, irinotecan hydrochloride, lanreotide acetate, letrozole, leuprolide acetate, liarozole hydrochloride, lometrexol sodium, lomustine, losoxantrone hydrochloride, masoprocol, maytansine, mechlorethamine hydrochloride, megestrol acetate, melengestrol acetate, melphalan, menogaril, mercaptopurine, methotrexate, methotrexate sodium, metoprine, meturedepa, mitindomide, mitocarcin, mitocromin, mitogillin, mitomalcin, mitomycin, mitosper, mitotane, mitoxantrone hydrochloride, mycophenolic acid, nocodazole, nogalamycin, ormaplatin, oxisuran, paclitaxel, pegaspargase, peliomycin, pentamustine, peplomycin sulfate, perfosfamide, pipobroman, piposulfan, piroxantrone hydrochloride, plicamycin, plomestane, porfimer sodium, porfiromycin, prednimustine, procarbazine hydrochloride, puromycin, puromycin hydrochloride, pyrazoftirin, riboprine, rogletimide, safingol, safingol hydrochloride, semustine, simtrazene, sparfosate sodium, sparsomycin, spirogermanium hydrochloride, spiromustine, spiroplatin, streptonigrin, streptozotocin, sulofenur, talisomycin, tecogalan sodium, tegafur, teloxantrone hydrochloride, temoporfin, teniposide, teroxirone, testolactone, thiamiprine, thioguanine, thiotepa, tiazofurin, tirapazamine, toremifene citrate, trestolone acetate, triciribine phosphate, trimetrexate, trimetrexate glucuronate, triptorelin, tubulozole hydrochloride, uracil mustard, uredepa, vapreotide, verteporfin, 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-1,25 dihydroxyvitamin D3; 5-ethynyluracil; abiraterone; aclarubicin; acylfulvene; adecypenol; adozelesin; aldesleukin; ALL-TK antagonists; altretamine; ambamustine; amidox; amifostine; aminolevulinic acid; amrubicin; amsacrine; anagrelide; anastrozole; andrographolide; angiogenesis inhibitors; antagonist D; antagonist G; antarelix; anti-dorsalizing morphogenetic protein-1; antiandrogen, prostatic carcinoma; antiestrogen; antineoplaston; antisense oligonucleotides; aphidicolin glycinate; apoptosis gene modulators; apoptosis regulators; apurinic acid; ara-CDP-DL-PTBA; arginine deaminase; asulacrine; atamestane; atrimustine; axinastatin 1; axinastatin 2; axinastatin 3; azasetron; azatoxin; azatyrosine; baccatin III derivatives; balanol; batimastat; BCR/ABL antagonists; benzochlorins; benzoylstaurosporine; 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-triazole; carboxyamidotriazole; CaRest M3; CARN 700; cartilage derived inhibitor; carzelesin; casein kinase inhibitors (ICOS); castanospermine; cecropin B; cetrorelix; chlorlns; chloroquinoxaline sulfonamide; cicaprost; cis-porphyrin; 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; cytolytic factor; cytostatin; dacliximab; decitabine; dehydrodidemnin B; deslorelin; dexamethasone; dexifosfamide; dexrazoxane; dexverapamil; diaziquone; didemnin B; didox; diethylnorspermine; dihydro-5-azacytidine; 9-dihydrotaxol; 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; fotemustine; gadolinium texaphyrin; gallium nitrate; galocitabine; ganirelix; gelatinase inhibitors; gemcitabine; glutathione inhibitors; hepsulfam; heregulin; hexamethylene bisacetamide; hypericin; ibandronic acid; idarubicin; idoxifene; idramantone; ilmofosine; ilomastat; imidazoacridones; imiquimod; immunostimulant peptides; insulin-like growth factor-1 receptor inhibitor; interferon agonists; interferons; interleukins; iobenguane; iododoxorubicin; 4-ipomeanol; iroplact; irsogladine; isobengazole; isohomohalicondrin B; itasetron; jasplakinolide; kahalalide F; lamellarin-N triacetate; lanreotide; leinamycin; lenograstim; lentinan sulfate; leptolstatin; letrozole; leukemia inhibiting factor; leukocyte alpha interferon; leuprolide+estrogen+progesterone; leuprorelin; levamisole; liarozole; linear polyamine analogue; lipophilic disaccharide peptide; lipophilic platinum compounds; lissoclinamide 7; lobaplatin; lombricine; lometrexol; lonidamine; losoxantrone; lovastatin; loxoribine; lurtotecan; 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 gonadotrophin; monophosphoryl lipid A+myobacterium 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; naphterpin; nartograstim; nedaplatin; nemorubicin; neridronic acid; neutral endopeptidase; nilutamide; nisamycin; nitric oxide modulators; nitroxide antioxidant; nitrullyn; O6-benzylguanine; octreotide; okicenone; oligonucleotides; onapristone; odansteron; oracin; oral cytokine inducer; ormaplatin; osaterone; oxaliplatin; oxaunomycin; paclitaxel; paclitaxel 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; pilocarpine hydrochloride; pirarubicin; piritrexim; placetin A; placetin B; plasminogen activator inhibitor; platinum complex; platinum compounds; platinum-triamine complex; porfimer sodium; porfiromycin; prednisone; propyl bis-acridone; prostaglandin J2; proteasome inhibitors; protein A-based immune modulator; protein kinase C inhibitor; protein kinase C inhibitors, microalgal; protein tyrosine phosphatase inhibitors; purine nucleoside phosphorylase inhibitors; purpurins; pyrazoloacridine; pyridoxylated hemoglobin polyoxyethylene conjugate; raf antagonists; raltitrexed; ramosetron; ras farnesyl protein transferase inhibitors; ras inhibitors; ras-GAP inhibitor; retelliptine demethylated; rhenium Re 186 etidronate; rhizoxin; ribozymes; RII retinamide; rogletimide; rohitukine; romurtide; roquinimex; rubiginone B1; 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; sonermin; 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; tazarotene; tecogalan sodium; tegafur; tellurapyrylium; telomerase inhibitors; temoporfin; temozolomide; teniposide; tetrachlorodecaoxide; tetrazomine; thaliblastine; thiocoraline; thrombopoietin; thrombopoietin mimetic; thymalfasin; thymopoietin receptor agonist; thymotrinan; thyroid stimulating hormone; tin ethyl etiopurpurin; tirapazamine; titanocene bichloride; topsentin; toremifene; totipotent stem cell factor; translation inhibitors; tretinoin; triacetyluridine; triciribine; trimetrexate; triptorelin; tropisetron; turosteride; tyrosine kinase inhibitors; tyrphostins; 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 useful therapeutic agents for treating or preventing UI include, but are not limited to, propantheline, 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 subcitrate; H2 antagonists such as cimetidine, ranitidine, famotidine, and nizatidine; H+, K+-ATPase inhibitors such as omeprazole, iansoprazole, and lansoprazole; carbenoxolone; misprostol; and antibiotics such as tetracycline, metronidazole, timidazole, clarithromycin, 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; olsalazine; mesalamine; prednisone; azathioprine; mercaptopurine; and methotrexate.
Examples of useful therapeutic agents for treating or preventing IBS include, but are not limited to, propantheline; muscarine receptor antogonists such as pirenzapine, methoctramine, ipratropium, tiotropium, scopolamine, methscopolamine, homatropine, homatropine methylbromide, 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, buprenorphine, 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 trihexyphenidyl 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 triazolam; non-benzodiazepine agents, such as buspirone, gepirone, ipsapirone, tiospirone, zolpicone, zolpidem, and zaleplon; tranquilizers, such as barbituates, e.g., amobarbital, aprobarbital, butabarbital, butalbital, mephobarbital, 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, lamotrigine, phenobarbital, phenyloin, primidone, valproic acid, trimethadione, benzodiazepines, γ-vinyl GABA, acetazolamide, and felbamate.
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 streptokinase 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, lamotrigine, phenobarbital, phenyloin, primidone, valproic acid, trimethadione, benzodiazepines, 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, phenothiazines such as chlorpromazine hydrochloride, mesoridazine besylate, and thoridazine hydrochloride; thioxanthenes such as chloroprothixene 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 treating 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, neurotrophic 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 drugs such as thioridazine and haloperidol; and antidepressant drugs such as those given below.
Examples of useful therapeutic agents for treating or preventing a migraine include, but are not limited to, sumatriptan; methysergide; ergotamine; caffeine; and beta-blockers such as propranolol, verapamil, and divalproex.
Examples of useful therapeutic agents for treating, inhibiting, or preventing vomiting include, but are not limited to, 5-HT3 receptor antagonists such as odansteron, dolasetron, granisetron, and tropisetron; dopamine receptor antagonists such as prochlorperazine, thiethylperazine, chlorpromazin, metoclopramide, and domperidone; glucocorticoids 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, reserpine 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, clomipramine, desipramine, doxepin, imipramine, maprotiline, nefazadone, nortriptyline, protriptyline, trazodone, trimipramine, and venlafaxine; selective serotonin reuptake inhibitors such as citalopram, (S)-citalopram, fluoxetine, fluvoxamine, paroxetine, and setraline; monoamine oxidase inhibitors such as isocarboxazid, pargyline, phenelzine, and tranylcypromine; and psychostimulants such as dextroamphetamine and methylphenidate.
A Pyridylene Compound and the other therapeutic agent combined can act additively or, in one embodiment, synergistically. In one embodiment, a Pyridylene Compound is administered concurrently with another therapeutic agent, for example, a composition comprising an effective amount of a Pyridylene Compound and an effective amount of another therapeutic agent can be administered. Alternatively, a composition comprising an effective amount of a Pyridylene Compound and a different composition comprising an effective amount of another therapeutic agent can be concurrently administered. In another embodiment, an effective amount of a Pyridylene Compound is administered prior or subsequent to administration of an effective amount of another therapeutic agent. In this embodiment, the Pyridylene Compound is administered while the other therapeutic agent exerts its therapeutic effect, or the other therapeutic agent is administered while the Pyridylene Compound exerts its therapeutic effect for treating or preventing a Condition.
A composition of the invention is prepared by a method comprising admixing a Pyridylene Compound or a pharmaceutically acceptable salt and a pharmaceutically acceptable carrier or excipient. Admixing can be accomplished using methods known for admixing a compound (or salt) and a pharmaceutically acceptable carrier or excipient. In one embodiment, the Pyridylene Compound is present in the composition in an effective amount.
4.8 Kits
The invention encompasses kits that can simplify the administration of a Pyridylene Compound to an animal.
A typical kit of the invention comprises a unit dosage form of a Pyridylene Compound. In one embodiment, the unit dosage form is a container, which can be sterile, containing an effective amount of a Pyridylene Compound and a pharmaceutically acceptable carrier or excipient. The kit can further comprise a label or printed instructions instructing the use of the Pyridylene Compound to treat or prevent a Condition. The kit can also further comprise a unit dosage form of another therapeutic agent, for example, a second container containing an effective amount of the other therapeutic agent and a pharmaceutically acceptable carrier or excipient. In another embodiment, the kit comprises a container containing an effective amount of a Pyridylene Compound, an effective amount of another therapeutic agent and a pharmaceutically acceptable carrier or excipient. Examples of other therapeutic agents include, but are not limited to, those listed above.
Kits of the invention can further comprise a device that is useful for administering the unit dosage forms. Examples of such a device include, 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 and should not be construed as specifically limiting the invention described and claimed herein. Such variations of the invention, including the substitution of all equivalents now known or later developed, which would be within the purview of those skilled in the art, and changes in formulation or changes in experimental design, are to be considered to fall within the scope of the invention incorporated herein.
5. EXAMPLES
5.1 Example 1
Synthesis of Pyridylene Compound E35(a)




To a solution of 5-bromopyridine-2-carbonitrile (commercially available from Sigma-Aldrich, St. Louis, Mo.) in ethanol (1.4 M) was added 3 equivalents of sodium hydroxide as a 1.5 M aqueous solution and the resulting solution was allowed to reflux at a temperature of about 85° C. until no further evolution of ammonia gas was detected. The resulting solution was then concentrated under reduced pressure to provide a residue. The residue was dissolved in water, acidified with acetic acid, and allowed to stir for about 16 h at a temperature of about 25° C. to provide a solid precipitate. The solid was collected by vacuum filtration and washed with acetone to provide 5-bromopyridine-2-carboxylic acid (Compound B) as a solid. 5-bromopyridine-2-carboxylic acid (Compound B), 0.5 equivalents of HOBT, and 1 equivalent of EDCI were dissolved in DMF and combined with about 1.1 equivalents of 4-tert-butylaniline (Compound C; commercially available from Sigma-Aldrich) dissolved in DMF (0.8 M) and the resulting mixture was allowed to stir for about 2 h at about 25° C. The reaction mixture was then diluted with about 80 mL of 2N aqueous sodium hydroxide and extracted with ethyl acetate (3 extractions, 80 mL/extraction). The ethyl acetate layers were combined and the ethyl acetate was removed under reduced pressure to provide a solid. The resulting solid was suspended in water and filtered using vacuum filtration to provide Compound D as a solid. Compound D was dissolved in DMF (0.04M) and about 3 equivalents of the zinc bromide Compound F (commercially available from Sigma-Aldrich) and about 0.05 equivalents of Pd(PPh3)4 (commercially available from Sigma-Aldrich) were added to the solution under a nitrogen atmosphere, and the resulting reaction mixture was allowed to stir for about 2 h at a temperature of about 100° C. The solvent was then removed under reduced pressure to provide Pyridylene Compound E35(a). Pyridylene Compound E35(a) was purified using preparative thin-layer chromatography with a 1:1 ethyl acetate:hexane mobile phase to provide purified Pyridylene Compound E35(a) as an off-white solid (yield 47%).
The identity of Pyridylene Compound E35(a) was confirmed using 1H NMR.
Compound E35(a): 1H NMR (CDCl3) δ: 10.000 (s, 1H), 8.807 (s, 1H), 8.596 (d, 1H), 8.389 (d, 1H), 8.094 (dd, 1H), 7.732 (d, 2H), 7.654 (d, 1H), 7.421 (d, 2H), 7.279 (m, 1H+CDCl3), 2.418 (s, 3H), 1.341 (s, 9H).
5.2 Example 2
Synthesis of Pyridylene Compound E35(b)
Pyridylene Compound E35(b) was made by a procedure analogous to that used to make Pyridylene Compound E35(a) in Example 1 except that 6-chloronicotinic acid (Compound G), shown below:




was used in place of 5-bromopyridine-2-carboxylic acid (Compound B). 6-Chloronicotinic acid (Compound G) was obtained by hydrolyzing 6-chloronicotinic acid ethyl ester (commercially available from Sigma-Aldrich).

Pyridylene Compound E35(b) was obtained as a white solid (yield 22%).
The identity of Pyridylene Compound E35(b) was confirmed using 1H NMR.
Compound E35(b): 1H NMR (CDCl3) δ: 9.167-9.128 (s, 1H), 8.588-8.546 (d, 1H), 8.322-8.277 (dd, 1H), 8.022-7.972 (d, 1H), 7.929-7.880 (s, 1H), 7.675-7.634 (d, 1H), 7.614-7.556 (d, 1H), 7.453-7.395 (d, 1H), 7.307-7.264 (m, 1H), 2.581-2.536 (s, 3H), 1.607-1.540 (s, 9H).
5.3 Example 3
Binding of Pyridylene Compounds to mGluR5
The following assay can be used to demonstrate that Pyridylene Compounds bind to and modulate the activity of mGluR5.
Cell Cultures: Primary glial cultures are prepared from cortices of Sprague-Dawley 18 days old embryos. The cortices are dissected and then dissociated by trituration. The resulting cell homogenate is plated onto poly-D-lysine precoated T175 flasks (BIOCOAT, commercially available from Becton Dickinson and Company Inc. of Franklin Lakes, N.J.) in Dulbecco's Modified Eagle's Medium (“DMEM,” pH 7.4), buffered with 25 mM HEPES, and supplemented with 15% fetal calf serum (“FCS,” commercially available from Hyclone Laboratories Inc. of Omaha, Nebr.), and incubated at 37° C. and 5% CO2. After 24 hours, FCS supplementation is reduced to 10%. On day six, oligodendrocytes and microglia are removed by strongly tapping the sides of the flasks. One day following this purification step, secondary astrocyte 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/mL epidermal growth factor (“EGF”), 1 mM sodium pyruvate, and 1× penicillin/streptomycin at pH 7.5 for 3 to 5 days at 37° C. and 5% CO2. The procedure allows the expression of the mGluR5 receptor by astrocytes, as demonstrated by S. Miller et al., J. Neuroscience 15(9):6103-6109 (1995).
Assay Protocol: After 3-5 days incubation with EGF, the astrocytes are washed with 127 mM NaCl, 5 mM KCl, 2 mM MgCl2, 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 (commercially available from Molecular Probes Inc. of Eugene, Oreg.) 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 (“FLIPR,” commercially available from Molecular Devices Corporation of Sunnyvale, Calif.) 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 baseline, DMSO solutions containing various concentrations of a Pyridylene Compound diluted in Assay Buffer (0.05 mL of 4× dilutions for competition curves) are added to the cell plate and fluorescence is monitored for 2 minutes. 0.05 mL of a 4× 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 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 two times.
5.4 Example 4
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 Pyridylene Compound when food is removed for 16 hours before dosing. A control group acts as a comparison to rats treated with a Pyridylene Compound. The control group is administered the carrier for the Pyridylene Compound. The volume of carrier administered to the control group is the same as the volume of carrier and Pyridylene Compound administered to the test group.
Acute Pain: To assess the actions of the Pyridylene 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 of the thermal stimulus and the flick of the 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 immediately before (pre-treatment) and 1, 3, and 5 hours following administration of a Pyridylene Compound. Data are expressed as tail flick latency(s) and the percentage of the maximal possible effect (% MPE), i.e., 20 seconds, is calculated as follows:




  
    %
    ⁢
    
      
    
    ⁢
    MPE
  
  =
  
    
      
        [
        
          
            (
            
              post
              ⁢
              
                
              
              ⁢
              administration
              ⁢
              
                
              
              ⁢
              latency
            
            )
          
          -
          
            (
            
              pre
              ⁢
              
                -
              
              ⁢
              administration
              ⁢
              
                
              
              ⁢
              latency
            
            )
          
        
        ]
      
      
        (
        
          20
          ⁢
          s
          ⁢
          
            
          
          ⁢
          pre
          ⁢
          
            -
          
          ⁢
          administration
          ⁢
          
            
          
          ⁢
          latency
        
        )
      
    
    ×
    100
  




The rat tail flick test is described in F. E. D'Amour et al., “A Method for Determining Loss of Pain Sensation,” J. Pharmacol. Exp. Ther. 72:74-79 (1941).
Acute pain can also be assessed by measuring the animal's response to noxious mechanical stimuli by determining the paw withdrawal threshold (“PWT”), as described below.
Inflammatory Pain: To assess the actions of the Pyridylene 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 hyperalgesia and provides reliable prediction of the anti-hyperalgesic 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 Pharmacol. 342:666-670 (1990)). The left hind paw of each animal is administered a 50 μL 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 Pyridylene Compound; 30 mg/kg of a control selected from Celebrex, indomethacin or naproxen; or carrier. Responses to noxious mechanical stimuli are then determined 1, 3, 5 and 24 hours post administration. Percentage reversal of hyperalgesia for each animal is defined as:




  
    %
    ⁢
    
      
    
    ⁢
    Reversal
  
  =
  
    
      
        [
        
          
            (
            
              post
              ⁢
              
                
              
              ⁢
              administration
              ⁢
              
                
              
              ⁢
              PWT
            
            )
          
          -
          
            (
            
              pre
              ⁢
              
                -
              
              ⁢
              administration
              ⁢
              
                
              
              ⁢
              PWT
            
            ⁢
            
              
            
            )
          
        
        ]
      
      
        [
        
          
            (
            
              baseline
              ⁢
              
                
              
              ⁢
              PWT
            
            )
          
          -
          
            (
            
              pre
              ⁢
              
                -
              
              ⁢
              administration
              ⁢
              
                
              
              ⁢
              PWT
            
            )
          
        
        ]
      
    
    ×
    100
  




Neuropathic Pain: To assess the actions of the Pyridylene 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 of the left sciatic nerve is performed under isoflurane/O2 inhalation anaesthesia. Following induction of anesthesia, the left thigh of the rat is shaved and the sciatic nerve exposed at high thigh level through a small incision and is carefully cleared of surrounding connective tissues at a site near the trocanther just distal to the point at which the posterior biceps semitendinosus nerve branches off of the common sciatic nerve. A 7-0 silk suture is inserted into the nerve with a 3⁄8 curved, reversed-cutting mini-needle and tightly ligated so that the dorsal 1⁄3 to 1⁄2 of the nerve thickness is held within the ligature. The wound is closed with a single muscle suture (4-0 nylon (Vicryl)) and vetbond tissue 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 drug administration for rear paw of the animal. Percentage reversal of neuropathic hyperalgesia is defined as:




  
    %
    ⁢
    
      
    
    ⁢
    Reversal
  
  =
  
    
      
        [
        
          
            (
            
              post
              ⁢
              
                
              
              ⁢
              administration
              ⁢
              
                
              
              ⁢
              PWT
            
            )
          
          -
          
            (
            
              pre
              ⁢
              
                -
              
              ⁢
              administration
              ⁢
              
                
              
              ⁢
              PWT
            
            ⁢
            
              
            
            )
          
        
        ]
      
      
        [
        
          
            (
            
              baseline
              ⁢
              
                
              
              ⁢
              PWT
            
            )
          
          -
          
            (
            
              pre
              ⁢
              
                -
              
              ⁢
              administration
              ⁢
              
                
              
              ⁢
              PWT
            
            )
          
        
        ]
      
    
    ×
    100
  




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 L4-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 nerve(s) is not manipulated. Following surgery animals are weighed, administered a subcutaneous (s.c.) injection of saline or ringers lactate, the wound area is dusted with antibiotic powder and they are kept on a warm pad until they recover from the anesthesia. Animals are then 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 Pyridylene Compound for the left rear paw of the animal. The animal can also be assessed for response to noxious thermal 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).

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 analgesymeter (Model 7200, commercially available from Ugo Basile of Italy) as described in C. Stein, “Unilateral Inflammation of the Hindpaw in Rats as a Model of Prolonged Noxious Stimulation: Alterations in Behavior and Nociceptive Thresholds,” Pharmacol. Biochem. and Behavior 31:451-455 (1988). The maximum weight that can be applied to the hind paw is set at 250 g and the end point is taken as complete withdrawal of the paw. PWT is determined once for each rat at each time point and only the affected (ipsilateral) paw is tested.
Response to Thermal 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 Hyperalgesia,” Pain 32(1):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, plexiglass compartments with a wire mesh floor and allowed to habituate for a period of at least 15 minutes. After habituation, a series of von Frey monofilaments are presented to the plantar surface of the left (operated) foot of each rat. The series of von Frey monofilaments consists of six monofilaments of increasing diameter, with the smallest diameter fiber presented first. Five trials are conducted with each filament with each trial separated by approximately 2 minutes. Each presentation lasts for a period of 4-8 seconds or until a nociceptive withdrawal behavior is observed. Flinching, paw withdrawal or licking of the paw are considered nociceptive behavioral responses.
5.5 Example 5
In Vivo Assays for Prevention or Treatment of Anxiety
The elevated plus maze test or the shock-probe burying test can be used to assess the anxiolytic activity of Pyridylene Compounds in rats or mice.
The Elevated Plus Maze Test: The elevated plus maze consists of a platform with 4 arms, two open and two closed (50×10×50 cm enclosed with an open roof). Rats (or mice) are placed in the center of the platform, at the crossroad of the 4 arms, facing one of the closed arms. Time spent in the open arms vs the closed arms and number of open arm entries during the testing period are recorded. This test is conducted prior to drug administration and again after drug administration. Test results are expressed as the mean time spent in open arms 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 40×30×40 cm, evenly covered with approximately 5 cm of bedding material (odor absorbent kitty litter) with a small hole in one end through which a shock probe (6.5 cm long and 0.5 cm in diameter) is inserted. The plexiglass shock probe is helically wrapped with two copper wires through which an electric current is administered. 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 of the test chamber following drug administration. The probe is not electrified until the rat touches it with its snout or fore paws, at which point the rat receives a brief 2 mA shock. The 15 min testing period begins once the rat receives its first shock and the probe remains electrified for the remainder of the testing period. The shock elicits burying behavior by the rat. Following the first shock, the duration of time the rat spends spraying bedding material toward or over the probe with its snout or fore 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 of the rat's reactivity to each shock is scored on a 4 point scale. The total time spent immobile during the 15 min testing period is used as an index of general activity. The shock-probe burying test is described in D. Treit, 1985, supra.
5.6 Example 6
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 Pyridylene Compounds to attenuate the rewarding properties of known drugs of abuse.
The Conditioned Place Preference Test: The apparatus for the conditioned place preference test consists of two large compartments (45×45×30 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 (36×18×20 cm) made of wood, painted grey, with a ceiling of wire mesh. The two large compartments differ in terms of shading (white vs black), level of illumination (the plexiglass door of the white compartment is covered with aluminum foil except for a window of 7×7 cm), texture (the white compartment has a 3 cm thick floor board (40×40 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-treatment+carrier (control group), Pyridylene Compound pre-treatment+carrier, carrier pre-treatment+morphine, Pyridylene Compound pre-treatment+morphine. 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 other 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 morphine 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 Pyridylene Compound blocks or reduces the acquisition of morphine conditioned place preference (reward), there will be no difference or less of a difference in time spent in each side in rats pre-treated with a Pyridylene 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 Pyridylene 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 morphine. Rats are then presented with two levers, an “active” lever and an “inactive” lever. Pressing of the 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 illumination of a light above the levers). Pressing of the inactive lever results in infusion of excipient. Training continues until the total number of morphine infusions stabilizes to within ±10% per session. Trained rats are then used to evaluate the effect of Pyridylene Compounds pre-treatment on drug self-administration. On test day, rats are pre-treated with a Pyridylene Compound or excipient and then are allowed to self-administer drug as usual. If the Pyridylene Compound blocks or reduces the rewarding effects of morphine, rats pre-treated with the Pyridylene Compound will show a lower rate of responding compared to their previous rate of responding and compared to excipient pre-treated rats. Data are analyzed as the change in number of drug infusions per testing session (number of infusions during test session−number of infusions during training session).
5.7 Example 7
Functional Assay for Characterizing mGluR1 Antagonistic Properties
Functional assays for the characterization of mGluR 1 antagonistic properties are known in the art. For example, the following procedure can be used.
A CHO-rat mGluR1 cell line is generated using cDNA encoding rat mGluR1 receptor (M. Masu and S. Nakanishi, Nature 349: 760-765 (1991)). The cDNA encoding rat mGluR1 receptor can be obtained from, e.g., Prof. S. Nakanishi (Kyoto, Japan).
40,000 CHO-rat mGluR1 cells/well are plated into a Costar 3409, black, clear bottom, 96 well, tissue culture treated plate (commercially available from Fisher Scientific of Chicago, Ill.) and are incubated in Dulbecco's Modified Eagle's Medium (DMEM, pH 7.4) supplemented with glutamine, 10% FBS, 1% Pen/Strep, and 500 μg/mL Geneticin for about 12 h. The CHO-rat mGluR1 cells are then washed and treated with Optimem medium (commercially available from Invitrogen, Carlsbad, Calif.) and incubated for a time period ranging from 1 to 4 hours prior to loading the cells with the dye Fluo-4. After incubation, the cell plates are washed with loading buffer (127 mM NaCl, 5 mM KCl, 2 mM MgCl2, 700 μM, NaH2PO4, 2 mM CaCl2, 5 mMNaHCO3, 8 mM HEPES, and 10 mM glucose, pH 7.4) and incubated with 3 μM Fluo-4 in 0.1 mL loading buffer for 90 min. The cells are then washed twice with 0.2 mL loading buffer, resuspended in 0.1 mL of loading buffer, and transferred to a FLIPR for measurement of calcium mobilization flux in the presence of glutamate and in the presence or absence of a Pyridylene Compound.
To measure calcium mobilization flux, fluorescence is monitored for about 15 s to establish a baseline and DMSO solutions containing various concentrations of a Pyridylene Compound ranging from about 50 μM to about 0.8 nM diluted in loading buffer (0.05 mL of a 4× dilution) are added to the cell plate and fluorescence is monitored for about 2 min. 0.05 mL of a 4× Glutamate solution (agonist) is then added to each well to provide a final glutamate concentration in each well of 10 μM and fluorescence is monitored for about 1 additional min. The final DMSO concentration in the assay is 1%. In each experiment fluorescence is monitored as a function of time and the data is analyzed using a non-linear regression to determine the IC50 value. In each experiment each data point is determined twice.
5.8 Example 8
Binding of Pyridylene Compounds to VR1
Methods for assaying compounds capable of inhibiting VR1 are known to those skilled in the art, for example, those methods disclosed in U.S. Pat. No. 6,239,267 to Duckworth et al.; U.S. Pat. No. 6,406,908 to McIntyre et al.; or U.S. Pat. No. 6,335,180 to Julius et al.
Binding of Compound E35(a) to VR1
Assay Protocol
Human VR1 Cloning: Human spinal cord RNA (commercially available from Clontech, Palo Alto, Calif.) was used. Reverse transcription was conducted on 1.0 μg total RNA using Thermoscript Reverse Transcriptase (commercially available from Invitrogen) 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 VR1 cDNA sequence was obtained by comparison of the 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 VR1 were designed as follows: forward primer, GAAGATCTTCGCTGGTTGCACACTGGGCCACA; and reverse primer, GAAGATCTTCGGGGACAGTGACGGTTGGATGT.
PCR of VR1 was performed on one tenth of the 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, Ind.). 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 VR1 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 the identity of the human VR1.
Generation of Inducible Cell Lines: Unless noted otherwise, cell culture reagents were purchased from Life Technologies of Rockville, Md. HEK 293-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, Utah), 1× penicillin/streptomycin, 1× glutamine, 1 mM sodium pyruvate and 400 μg/mL Zeocin (commercially available from Invitrogen)). The VR1-pIND constructs 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) and CAP-mediated calcium influx was measured using a FLIPR 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 to induce expression. On the day of the assay, the plates were washed with 0.2 mL 1× 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 mL 1× Hank's Balanced Salt Solution containing 3.5 mM CaCl2 and 10 mM Citrate, pH 7.4 (“assay buffer”). Plates were then transferred to a FLIPR for assay. Compound E35(a) was diluted in assay buffer, and 50 mL of the resultant solution were added to the cell plates and the solution monitored for two minutes. The final concentration of Compound E35(a) ranged from about 50 μM to about 3 μM. Agonist buffer (wash buffer titrated with 1N HCl to provide a solution 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 E35(a) when assayed according to this protocol had an IC50 of 825.5±247.8 nM (n=4).
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 to induce expression. On the day of the assay, the plates were washed with 0.2 mL 1× Hank's Balanced Salt Solution 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 for assay. 50 μL of Compound E35(a) diluted with assay buffer were added to the cell plates and incubated for 2 min. The final concentration of Compound E35(a) ranged from about 50 μM to about 3 μM. Human VR1 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 E35(a) when assayed according to this protocol had an IC50 of 65.5±17.3 nM (n=3).
The results of the pH-based assay and the capsaicin-based assay demonstrate that Compound E35(a), an illustrative Pyridylene Compound, binds to and modulates the activity of human VR1 and accordingly is useful for treating or preventing pain, UI, an ulcer, IBD, or IBS in an animal.
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 of the 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 of the appended claims.
A number of references have been cited, the entire disclosures of which are incorporated herein by reference.

## Claims

1. A compound of formula:




or a pharmaceutically acceptable salt thereof, wherein:
Ar1 is




Ar2 is




X is O or S;
R1 is -halo, —CH3, —C(halo)3, —CH(halo)2, or —CH2(halo);
each R2 is independently:
(a) -halo, —OH, —NH2, —CN, or —NO2;
(b) —(C1-C10)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, -(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 R3 is independently:
(a) -halo, —CN, —OH, —NO2, or —NH2;
(b) —(C2-C10)alkenyl, —(C2-C10)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
(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 R5 is independently —CN, —OH, —(C1-C6)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 R6 is independently —(C1-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, —N(R7)2, —CH═NR7, —NR7OH, —COR7, —C(O)OR7, —OC(O)R7, —OC(O)OR7, —SR7, —S(O)R7, or —S(O)2R7;
each R7 is independently —H, —(C1-C6)alkyl, —(C2-C6)alkenyl, —(C2-C6)alkynyl, —(C3-C8)cycloalkyl, —(C5-Cs)cycloalkenyl, -phenyl, -(3- to 5-membered)heterocycle, —C(halo)3, —CH(halo)2, or —CH2(halo);
each Rg is independently —(C1-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, —N(R7)2, —CH═NR7, —NR7OH, —COR7, —C(O)OR7, —OC(O)R7, —OC(O)OR7, —S(O)R7, or —S(O)2R7;
each halo is independently —F, —Cl, —Br, or —I;
m is an integer ranging from 0 to 3;
n is an integer ranging from 1 to 3; and
r is an integer ranging from 0 to 5.

2. The compound of claim 1, wherein
X is O; and
R1 is —CH3, -halo or —C(halo)3.

3. The compound of claim 2, wherein:
m is 0;
r is 1; and
R8 is —(C1-C6)alkyl, -halo, —OCF3 or —CF3.

4. The compound of claim 3, wherein the —(C1-C6)alkyl is a tert-butyl group, optionally substituted at the para-position of Ar2.

5. A compound of formula:




or a pharmaceutically acceptable salt thereof, wherein:
Ar1 is




Ar2 is




X is O or S;
R1 is -halo, —CH3, —C(halo)3, —CH(halo)2, or —CH2(halo);
each R2 is independently:
(a) -halo, —OH, —NH2, —CN, or —NO2;
(b) —(C1-C10)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, -(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 R3 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, —(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
(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 R5 is independently —CN, —OH, —(C1-C6)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 R6 is independently —(C1-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, —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 R7 is independently —H, —(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 —(C1-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, —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 R11 is independently —(C1-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, —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, —Cl, —Br, or —I;
m is an integer ranging from 0 to 3;
n is an integer ranging from 0 to 3;
o is an integer ranging from 0 to 4;
q is an integer ranging from 0 to 6; and
s is an integer ranging from 0 to 4.

6. The compound of claim 5, wherein:
Ar2 is




X is O;
R1 is —CH3, —CF3, —Cl, —Br, —I, or —F;
m is 0;
(R8)a is —H; and
(R8)b is —H, —CH3, —CF3, —OCH2CH3, tert-butyl, —Cl, —Br, —I, or —F.

7. The compound of claim 6, wherein R1 is —CH3, —CF3 or —Cl and (R8)b is —Cl, —F, —CF3 or tert-butyl.

8. A compound of formula:




or a pharmaceutically acceptable salt thereof, wherein:
Ar1 is




Ar2 is




X is O or S;
R1 is -halo, —CH3, —C(halo)3, —CH(halo)2, or —CH2(halo);
each R2 is independently:
(a) -halo, —OH, —NH2, —CN, or —NO2;
(b) —(C1-C10)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, -(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 R3 is independently:
(a) -halo, —CN, —OH, —NO2, or —NH2;
(b) —(C2-C10)alkenyl, —(C2-C10)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
(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 R5 is independently —CN, —OH, —(C1-C6)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 R6 is independently —(C1-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, —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 R7 is independently —H, —(C1-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 —(C1-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, —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 R11 is independently —(C1-C6)alkyl, —(C2-C6)alkenyl, —(C2-C6)alkynyl, —(C3-C8)cycloalkyl, —(C5-C8)cycloalkenyl, -phenyl, —C(halo)3, —CH2(halo), —CN, —OH, -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, —Cl, —Br, or —I;
m is an integer ranging from 0 to 3;
n is an integer ranging from 0 to 3;
o is an integer ranging from 0 to 4;
q is an integer ranging from 0 to 6;
r is an integer ranging from 0 to 5; and
s is an integer ranging from 0 to 4.

9. The compound of claim 8, wherein:
Ar2 is




X is O; and
R1 is —CH3, -halo or —C(halo)3.

10. The compound of claim 9, wherein:
m is 0;
r is 1; and
R8 is —(C1-C6)alkyl, -halo, —OCF3 or —CF3.

11. The compound of claim 10, wherein the —(C1-C6)alkyl is a tert-butyl group, optionally substituted at the para-position of Ar2.

12. The compound of claim 8, wherein:
Ar2 is




X is O;
R1 is —CH3, —CF3, —Cl, —Br, —I, or —F;
m is 0;
(R8)a is —H; and
(R8)b is —H, —CH3, —CF3, —OCH2CH3, tert-butyl, —Cl, —Br, —I, or —F.

13. The compound of claim 12, wherein R1 is —CH3, —CF3 or —Cl and (R8)b is —Cl, —F, —CF3 or tert-butyl.

14. A pharmaceutical composition comprising the compound or a pharmaceutically acceptable salt of the compound of claim 1 and a pharmaceutically acceptable carrier or excipient.

15. A pharmaceutical composition comprising the compound or a pharmaceutically acceptable salt of the compound of claim 8 and a pharmaceutically acceptable carrier or excipient.

16. A method for treating pain in an animal, comprising administering to an animal in need thereof an effective amount of the compound of formula:




or a pharmaceutically acceptable salt thereof, wherein:
Ar1 is




Ar2 is




X is O or S;
R1 is -halo, —CH3, —C(halo)3, —CH(halo)2, or —CH2(halo);
each R2 is independently:
(a) -halo, —OH, —NH2, —CN, or —NO2;
(b) —(C2-C10)alkenyl, —(C2-C10)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
(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 R3 is independently:
(a) -halo, —CN, —OH, —NO2, or —NH2;
(b) —(C2-C10)alkenyl, —(C2-C10)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
(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 R5 is independently —CN, —OH, —(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)R, or —S(O)2R7;
each R6 is independently —(C1-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, —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 R7 is independently —H, —(C1-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 —(C1-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, —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 R11 is independently —(C1-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, —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, —Cl, —Br, or —I;
m is an integer ranging from 0 to 3;
n is an integer ranging from 0 to 3;
o is an integer ranging from 0 to 4;
q is an integer ranging from 0 to 6;
r is an integer ranging from 0 to 5; and
s is an integer ranging from 0 to 4.

17. 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 of the compound of claim 8.

18. An in vitro method for inhibiting VR1 function in a cell comprising:
contacting a cell expressing VR1 in vitro with a compound of claim 1, or a pharmaceutically acceptable salt thereof, in an amount sufficient to reduce calcium ion mobilization into said cell treated with an activator of VR1 as compared to said cell expressing VR1 in vitro treated with an activator of VR1 and not contacted with said compound.

19. The method of claim 18, wherein said calcium ion mobilization is reduced by 50% or more.

20. An in vitro method for inhibiting VR1 function in a cell comprising:
contacting a cell expressing VR1 in vitro with a compound of claim 8, or a pharmaceutically acceptable salt thereof, in an amount sufficient to reduce calcium ion mobilization into said cell treated with an activator of VR1 as compared to said cell expressing VR1 in vitro treated with an activator of VR1 and not contacted with said compound.

21. The method of claim 20, wherein said calcium ion mobilization is reduced by 50% or more.

22. A pharmaceutical composition comprising the compound or a pharmaceutically acceptable salt of the compound of claim 5 and a pharmaceutically acceptable carrier or excipient.

23. An in vitro method for inhibiting VR1 function in a cell comprising:
contacting a cell expressing VR1 in vitro with a compound of claim 5, or a pharmaceutically acceptable salt thereof, in an amount sufficient to reduce calcium ion mobilization into said cell treated with an activator of VR1 as compared to said cell expressing VR1 in vitro treated with an activator of VR1 and not contacted with said compound.

24. The method of claim 23, wherein said calcium ion mobilization is reduced by 50% or more.

25. A compound of formula:




or a pharmaceutically acceptable salt thereof, wherein:
Ar1 is




Ar2 is




X is O or S;
R1 is -halo, —CH3, —C(halo)3, —CH(halo)2, or —CH2(halo);
each R3 is independently:
(a) -halo, —CN, —OH, —NO2, or —NH2;
(b) —(C2-C10)alkenyl, —(C2-C10)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
(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 R5 is independently —CN, —(C1-C6)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 R6 is independently —(C1-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, —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 R7 is independently —H, —(C1-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 —(C1-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, —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 —Cl, —Br, or —I;
m is an integer ranging from 0 to 3;
n is 0; and
r is an integer ranging from 0 to 5.

26. The compound of claim 25, wherein each R8 is independently —(C1-C6)alkyl, —(C2-C6)alkenyl, —(C2-C6)alkynyl, —(C3-C8)cycloalkyl, —(C5-C8)cycloalkenyl, -phenyl, —C(halo)3, —CH(halo)2, —CH2(halo), —CN, -halo, —N3, —NO2, —N(R7)2, —CH═NR7, —NR7OH, —COR7, —C(O)OR7, —OC(O)R7, —OC(O)OR7, —SR7, —S(O)R7, or —S(O)2R7.

27. A pharmaceutical composition comprising the compound or a pharmaceutically acceptable salt of the compound of claim 25 and a pharmaceutically acceptable carrier or excipient.

28. An in vitro method for inhibiting VR1 function in a cell comprising:
contacting a cell expressing VR1 in vitro with a compound of claim 25, or a pharmaceutically acceptable salt thereof, in an amount sufficient to reduce calcium ion mobilization into said cell treated with an activator of VR1 as compared to said cell expressing VR1 in vitro treated with an activator of VR1 and not contacted with said compound.

29. The method of claim 28, wherein said calcium ion mobilization is reduced by 50% or more.

30. The compound of claim 1, wherein n is 1 and R2 is —(C1-C10)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, -(3- to 7-membered)heterocycle, or -(7- to 10-membered)bicycloheterocycle, each of which is unsubstituted or substituted with one or more R5 groups.

31. The compound of claim 30, wherein R2 is —(C1-C10)alkyl which is substituted with two R5 groups.

32. The compound of claim 8, wherein n is 1 and R2 is —(C1-C10)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, -(3- to 7-membered)heterocycle, or -(7- to 10-membered)bicycloheterocycle, each of which is unsubstituted or substituted with one or more R5 groups.

33. The compound of claim 32, wherein R2 is —(C1-C10)alkyl which is substituted with two R5 groups.

34. The method of claim 16, wherein n is 1 and R2 is —(C1-C10)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, -(3- to 7-membered)heterocycle, or -(7- to 10-membered)bicycloheterocycle, each of which is unsubstituted or substituted with one or more R5 groups.

35. The method of claim 34, wherein R2 is —(C1-C10)alkyl which is substituted with two R5 groups.

36. The compound of claim 5, wherein n is 1 and R2 is —(C1-C10)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, -(3- to 7-membered)heterocycle, or -(7- to 10-membered)bicycloheterocycle, each of which is unsubstituted or substituted with one or more R5 groups.

37. The compound of claim 36, wherein R2 is —(C1-C10)alkyl which is substituted with two R5 groups.

38. The method of claim 16, wherein:
Ar2 is




X is O; and
R1 is —CH3, -halo or —C(halo)3.

39. The method of claim 38, wherein:
m is 0;
r is 1; and
R8 is —(C1-C6)alkyl, -halo, —OCF3 or —CF3.

40. The method of claim 16, wherein:
Ar2 is




X is O;
R1 is —CH3, —CF3, —Cl, —Br, —I, or —F;
m is 0;
(R8)a is —H; and
(R8)b is —H, —CH3, —CF3, —OCH2CH3, tert-butyl, —Cl, —Br, —I, or —F.

41. The method of claim 40, wherein R1 is —CH3, —CF3 or —Cl and (R8)b is —Cl, —F, —CF3 or tert-butyl.

42. The compound of claim 5, wherein X is O; and R1 is —CH3, -halo or —C(halo)3.

43. The compound of claim 25, wherein X is O; and R1 is —CH3, -halo or —C(halo)3.

44. The compound of claim 43, wherein:
m is 0;
r is 1; and
R8 is —(C1-C6)alkyl, -halo, —OCF3 or —CF3.