US20090176796A1 - Trpv1 antagonists including amide substituent and uses thereof - Google Patents

Trpv1 antagonists including amide substituent and uses thereof Download PDF

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US20090176796A1
US20090176796A1 US12/110,212 US11021208A US2009176796A1 US 20090176796 A1 US20090176796 A1 US 20090176796A1 US 11021208 A US11021208 A US 11021208A US 2009176796 A1 US2009176796 A1 US 2009176796A1
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halo
another embodiment
alkyl
compound
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Laykea Tafesse
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Purdue Pharma LP
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Priority to US13/396,450 priority patent/US8575199B2/en
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    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • A—HUMAN NECESSITIES
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    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • A—HUMAN NECESSITIES
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    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
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    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/72—Nitrogen atoms
    • C07D213/74—Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals
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    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
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    • C07D407/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing three or more hetero rings
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    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings

Definitions

  • the invention relates to compounds of formula I, and pharmaceutically acceptable derivatives thereof, compositions comprising an effective amount of a compound of formula I and methods for treating or preventing a condition such as pain, UI, an ulcer, IBD, and IBS, comprising administering to an animal in need thereof an effective amount of a compound of formula I.
  • 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)).
  • 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 central nervous system and is maintained by aberrant somatosensory processing.
  • vanilloid receptors V. Di Marzo et al., Current Opinion in Neurobiology 12:372-379 (2002)
  • 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.
  • opioid analgesics including morphine, hydromorphone, methadone, levorphanol, fentanyl, oxycodone, and oxymorphone.
  • 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).
  • anti-epileptics e.g., gabapentin, carbamazepine, valproic acid, topiramate, phenyloin
  • NMDA antagonists e.g., ketamine, dextromethorphan
  • topical lidocaine for post-herpetic neuralgia
  • tricyclic antidepressants e.g., fluoxetine, sertraline and amitriptyline
  • UI uncontrollable urination, generally caused by bladder-detrusor-muscle instability.
  • UI affects people of all ages and levels of physical health, both in health care settings and in the community at large.
  • 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.
  • Antacids such as aluminum hydroxide, magnesium hydroxide, sodium bicarbonate, and calcium bicarbonate can be used to neutralize stomach acids. Antacids, however, can cause alkalosis, leading to nausea, headache, and weakness. Antacids can also interfere with the absorption of other drugs into the blood stream and cause diarrhea.
  • H 2 antagonists such as cimetidine, ranitidine, famotidine, and nizatidine are also used to treat ulcers. H 2 antagonists promote ulcer healing by reducing gastric acid and digestive-enzyme secretion elicited by histamine and other H 2 agonists in the stomach and duodenum. H 2 antagonists, however, can cause breast enlargement and impotence in men, mental changes (especially in the elderly), headache, dizziness, nausea, myalgia, diarrhea, rash, and fever.
  • H + , K + -ATPase inhibitors such as omeprazole and lansoprazole are also used to treat ulcers.
  • H + , K + -ATPase inhibitors inhibit the production of enzymes used by the stomach to secrete acid.
  • Side effects associated with H + , K + -ATPase inhibitors include nausea, diarrhea, abdominal colic, headache, dizziness, somnolence, skin rashes, and transient elevations of plasma activities of aminotransferases.
  • IBD Inflammatory-bowel disease
  • Crohn's disease which can include regional enteritis, granulomatous ileitis, and ileocolitis, is a chronic inflammation of the intestinal wall. Crohn's disease occurs equally in both sexes and is more common in Jews of eastern-European ancestry. Most cases of Crohn's disease begin before age 30 and the majority start between the ages of 14 and 24. The disease typically affects the full thickness of the intestinal wall. Generally the disease affects the lowest portion of the small intestine (ileum) and the large intestine, but can occur in any part of the digestive tract.
  • 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.
  • ulcerative colitis Treatment of ulcerative colitis is directed to controlling inflammation, reducing symptoms, and replacing lost fluids and nutrients.
  • Anticholinergic drugs and low doses of diphenoxylate or loperamide are administered for treating mild diarrhea. For more intense diarrhea higher doses of diphenoxylate or loperamide, or deodorized opium tincture or codeine are administered.
  • IBS Irritable-bowel syndrome
  • IBS Irritable-bowel syndrome
  • stimuli such as stress, diet, drugs, hormones, or irritants can cause the gastrointestinal tract to contract abnormally.
  • contractions of the gastrointestinal tract become stronger and more frequent, resulting in the rapid transit of food and feces through the small intestine, often leading to diarrhea.
  • Cramps result from the strong contractions of the large intestine and increased sensitivity of pain receptors in the large intestine.
  • IBS IBS-patient's diet
  • an IBS patient avoid beans, cabbage, sorbitol, and fructose.
  • a low-fat, high-fiber diet can also help some IBS patients.
  • Regular physical activity can also help keep the gastrointestinal tract functioning properly.
  • Drugs such as propantheline that slow the function of the gastrointestinal tract are generally not effective for treating IBS.
  • Antidiarrheal drugs such as diphenoxylate and loperamide, help with diarrhea. The Merck Manual of Medical Information 525-526 (R. Berkow ed., 1997).
  • U.S. Pat. No. 5,891,889 describes a class of substituted piperidine compounds that are useful as inhibitors of farnesyl-protein transferase, and the farnesylation of the oncogene protein Ras.
  • Japanese patent application no. 11-199573 to Kiyoshi et al. describes benzothiazole derivatives that are neuronal 5HT3 receptor agonists in the intestinal canal nervous system and useful for treating digestive disorders and pancreatic insufficiency.
  • German patent application no 199 34 799 to Rainer et al. describes a chiral-smectic liquid crystal mixture containing compounds with 2 linked (hetero)aromatic rings or compounds with 3 linked (hetero)aromatic rings.
  • the invention encompasses compounds of formula I:
  • X is O, S, N—CN, N—OH, or N—OR 10 ;
  • W is N or C
  • R 4 is absent, otherwise R 4 is —H, —OH, —OCF 3 , -halo, —(C 1 -C 6 )alkyl, —CH 2 OH, —CH 2 Cl, —CH 2 Br, —CH 2 I, —CH 2 F, —CH(halo) 2 , —CF 3 , —OR 10 , —SR 10 , —COOH, —COOR 10 , —C(O)R 10 , —C(O)H, —OC(O)R 10 , —OC(O)NHR 10 , —NHC(O)R 13 , —CON(R 13 ) 2 , —S(O) 2 R 10 , or —NO 2 ;
  • R 10 is —(C 1 -C 4 )alkyl
  • each R 13 is independently —H, —(C 1 -C 4 )alkyl, —(C 1 -C 4 )alkenyl, —(C 1 -C 4 )alkynyl, or -phenyl;
  • c is the integer 0, 1, or 2;
  • Y 1 , Y 2 , and Y 3 are independently C, N, or O;
  • Y 1 , Y 2 , or Y 3 can be O, and for each Y 1 , Y 2 , and Y 3 that is N, the N is bonded to one R 21 group, and for each Y 1 , Y 2 , and Y 3 that is C, the C is bonded to two R 20 groups, provided that there are no more than a total of two (C 1 -C 6 )alkyl groups substituted on all of Y 1 , Y 2 , and Y 3 ;
  • R 12a and R 12b are independently —H or —(C 1 -C 6 )alkyl
  • E is ⁇ O, ⁇ S, ⁇ CH(C 1 -C 5 )alkyl, ⁇ CH(C 1 -C 5 )alkenyl, —NH(C 1 -C 6 )alkyl, or ⁇ N—OR 20 ;
  • R 1 is —H, -halo, —(C 1 -C 4 )alkyl, —NO 2 , —CN, —OH, —OCH 3 , —NH 2 , —C(halo) 3 , —CH(halo) 2 , —CH 2 (halo), —OC(halo) 3 , —OCH(halo) 2 , or —OCH 2 (halo);
  • each R 2 is independently:
  • Z 1 is —H, —OR 7 , —SR 7 , —CH 2 —OR 7 , —CH 2 —SR 7 , —CH 2 —N(R 20 ) 2 , or -halo;
  • Z 2 is —H, —(C 1 -C 6 )alkyl, —(C 2 -C 6 )alkenyl, —(C 2 -C 6 )alkynyl, —CH 2 —OR 7 , -phenyl, or -halo;
  • each Z 3 is independently —H, —(C 1 -C 6 )alkyl, —(C 2 -C 6 )alkenyl, —(C 2 -C 6 )alkynyl, or -phenyl;
  • Z 4 is —H, —OH, —OR 20 , —(C 1 -C 6 )alkyl, or —N(R 20 ) 2 ;
  • J is —OR 20 , —SR 20 , —N(R 20 ) 2 , or —CN;
  • R 2 group is a group of formula Q, and provided that when Z 1 is —OR 7 or —SR 7 , then Z 2 is not -halo;
  • each R 3 is independently:
  • R a is —H, —(C 1 -C 6 )alkyl, —(C 3 -C 8 )cycloalkyl, —CH 2 —C(O)—R c , —(CH 2 )—C(O)—OR c , —(CH 2 )—C(O)—N(R) 2 , —(CH 2 ) 2 —O—R c , —(CH 2 ) 2 —S(O) 2 —N(R) 2 , or —(CH 2 ) 2 —N(R c )S(O) 2 —R c ;
  • R b is:
  • each R c is independently —H or —(C 1 -C 4 )alkyl
  • each R 7 is independently —H, —(C 1 -C 6 )alkyl, —(C 2 -C 6 )alkenyl, —(C 2 -C 6 )alkynyl, —(C 3 -C 8 )cycloalkyl, —(C 5 -C 8 )cycloalkenyl, -phenyl, —(C 1 -C 6 )haloalkyl, —(C 1 -C 6 )hydroxyalkyl, —(C 1 -C 6 )alkoxy(C 1 -C 6 )alkyl, —(C 1 -C 6 )alkyl-N(R 20 ) 2 , or —CON(R 20 ) 2 ;
  • each R 8 and R 9 is independently:
  • each R 11 is independently —CN, —OH, —(C 1 -C 6 )alkyl, —(C 2 -C 6 )alkenyl, -halo, —N 3 , —NO 2 , —N(R 7 ) 2 , —CH ⁇ NR 7 , —NR 7 OH, —OR 7 , —C(O)R 7 , —C(O)OR 7 , —OC(O)R 7 , or —OC(O)OR 7 ;
  • each R 14 is independently —H, —(C 1 -C 6 )alkyl, —(C 2 -C 6 )alkenyl, —(C 2 -C 6 )alkynyl, —(C 3 -C 8 )cycloalkyl, —(C 5 -C 8 )cycloalkenyl, —(C 1 -C 6 )alkoxy-(C 1 -C 6 )alkyl, -phenyl, —C(halo) 3 , —CH(halo) 2 , —CH 2 (halo), -(3- to 7-membered)heterocycle, —(C 1 -C 6 )haloalkyl, —(C 2 -C 6 )haloalkenyl, —(C 2 -C 6 )haloalkynyl, —(C 2 -C 6 )hydroxyalkenyl, —(C 2 -C 6 )hydroxy
  • each R 20 is independently —H, —(C 1 -C 6 )alkyl, or —(C 3 -C 8 )cycloalkyl;
  • each R 21 is independently —H, —(C 1 -C 6 )alkyl
  • each halo is independently —F, —Cl, —Br, or —I;
  • n is the integer 1, 2, or 3;
  • p is the integer 1 or 2
  • each b is independently the integer 1 or 2;
  • q is the integer 0, 1, 2, 3, or 4;
  • r is the integer 0, 1, 2, 3, 4, 5, or 6;
  • s is the integer 0, 1, 2, 3, 4, or 5;
  • t is the integer 0, 1, 2, or 3;
  • n is the integer 0, 1, or 2.
  • Compounds of formula I are potent at TRPV1 receptors, and are highly soluble in aqueous solutions at either pH 6.8 or pH 1.2.
  • a compound of formula I, or a pharmaceutically acceptable derivative thereof, is useful for treating or preventing pain, UI, an ulcer, IBD, or IBS (each being a “Condition”) in an animal.
  • the invention also relates to compositions comprising an effective amount of a compound of formula I, or a pharmaceutically acceptable derivative thereof, and a pharmaceutically acceptable carrier or excipient.
  • 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 compound of formula I, or a pharmaceutically acceptable derivative thereof.
  • the invention further relates to use of a compound of formula I in the manufacture of a medicament for treating and/or preventing a Condition.
  • the invention further relates to methods for preventing a Condition comprising administering to an animal in need thereof an effective amount of a compound of formula I, or a pharmaceutically acceptable derivative thereof.
  • the invention still further relates to methods for inhibiting Transient Receptor Potential Vanilloid 1 (“TRPV1,” formerly known as Vanilloid Receptor 1 or VR1) function in a cell, comprising contacting a cell capable of expressing TRPV1 with an effective amount of a compound of formula I, or a pharmaceutically acceptable derivative thereof.
  • TRPV1 Transient Receptor Potential Vanilloid 1
  • the invention still further relates to a method for preparing a composition
  • a method for preparing a composition comprising the step of admixing a compound of formula I, or a pharmaceutically acceptable derivative thereof, and a pharmaceutically acceptable carrier or excipient.
  • the invention still further relates to a kit comprising a container containing an effective amount of a compound of formula I, or a pharmaceutically acceptable derivative thereof.
  • compounds of formula I are compounds of formula IA′′:
  • compounds of formula I are compounds of formula II:
  • Ar 1 is:
  • each Z 3 is independently —H, —(C 1 -C 6 )alkyl, —(C 2 -C 6 )alkenyl, —(C 2 -C 6 )alkynyl, or -phenyl;
  • R 20 is —H, —(C 1 -C 6 )alkyl, or —(C 3 -C 8 )cycloalkyl;
  • R 1 is —Cl, —F, —CF 3 , or —CH 3 ;
  • R 14 is —H, —Cl, —F, —Br, —CF 3 , —OCF 3 , —(C 1 -C 6 )alkyl, —SO 2 CF 3 , —SO 2 (C 1 -C 6 )alkyl, —OCH 3 , —OCH 2 CH 3 , or —OCH(CH 3 ) 2 , and optionally is —H, —CF 3 , —OCF 3 , —Cl, or —F;
  • R 14′ is —H, —Cl, —F, —Br, —CF 3 , —OCF 3 , —(C 1 -C 6 )alkyl, —SO 2 CF 3 , —SO 2 (C 1 -C 6 )alkyl, —OCH 3 , —OCH 2 CH 3 , or —OCH(CH 3 ) 2 , and optionally is —H, —CF 3 , —OCF 3 , —Cl, or —F; and
  • each R 8 and R 9 is independently —H, —Cl, —Br, —F, —CH 3 , —OCH 3 , —OCH 2 CH 3 , —CF 3 , —OCF 3 , iso-propyl, or tert-butyl.
  • FIG. 1 96-well plate with different agonist solutions (Agonist Plate). Seven different sulfuric acid solutions, or agonist solutions, with different sulfuric acid (H 2 SO 4 ) concentrations (of from 15.0 mM to 18 mM as indicated) were used for the pH assay as indicated. For the wells in row A, measuring buffer alone was used. The final concentration of sulfuric acid in the wells for each row, after a 1:4 dilution of the agonist solution, is also indicated in each row in parenthesis.
  • H 2 SO 4 sulfuric acid
  • FIG. 2 pH dependent Ca 2+ responses in TRPV1/CHO cells.
  • Ca 2+ influx into TRPV1/CHO cells as measured by Fura-2 AM fluorescence is indicated by the graph within each rectangular field.
  • the graph presents the fluorescence intensity over time starting from the addition of agonist solution.
  • Each rectangular field presents one experiment performed in one well of a 96-well plate.
  • Each row presents six experiments performed at the same final sulfuric acid concentration; the final sulfuric acid concentration is indicated at the left. Actual pH values were measured after the experiment and are indicated above the graph. No antagonists were added to the cell culture.
  • Final sulfuric acid concentrations of 3.2 and 3.3 mM produced an appropriate Ca 2+ response and were selected for subsequent assays. These final sulfuric acid concentrations can be obtained by 1:4 dilutions of agonist solution with sulfuric acid concentrations of 16.0 mM or 16.5 mM, respectively (see FIG. 1 ).
  • FIG. 3 A 96-well plate with two different sulfuric acid concentrations. Wells in columns 1 to 6 had one final sulfuric acid concentration; wells in columns 7 to 12 had a different final sulfuric acid concentration. The final sulfuric acid concentration was reached by 1:4 dilution of two different agonist solutions with sulfuric acid concentrations of X mM and (X+0.5) mM, respectively. In the experiment described in Section 2 of Protocol 2, X was determined to be 16 mM.
  • B A 96-well plate with different test compound, or antagonist, concentrations indicated in nM. Only one kind of test compound was applied per 96-well plate. Since two different sulfuric acid concentrations were used (columns 1-6 vs.
  • test compound concentration and agonist solution e.g., wells A1, B1, C1, E1, F1, G1, and H1 were tested for test compound concentration 0.977 nM and agonist solution with sulfuric acid solution X mM.
  • wells in row D did not include an antagonist in order to measure the maximal Ca 2+ response.
  • the invention encompasses compounds of formula I:
  • a compound of formula I is a pharmaceutically acceptable derivative of a compound of formula I.
  • a compound of formula I is a compound of formula I wherein the derivative is a pharmaceutically acceptable salt.
  • a compound of formula I is a pharmaceutically acceptable salt of a compound of formula I.
  • Ar 1 is a pyridyl group.
  • Ar 1 is a pyrimidinyl group.
  • Ar 1 is a pyrazinyl group.
  • Ar 1 is pyridazinyl group.
  • W is C.
  • W is N.
  • X is O.
  • X is S.
  • X is N—CN.
  • X is N—OH.
  • X is N—OR 10 .
  • Ar 2 is a benzoimidazolyl group.
  • Ar 2 is a benzothiazolyl group.
  • Ar 2 is a benzooxazolyl group.
  • Ar 2 is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
  • Ar 2 is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
  • Ar 2 is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
  • Ar 2 is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
  • Ar 2 is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
  • Ar 2 is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
  • Ar 2 is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
  • Ar 2 is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
  • n or p is 1.
  • n or p is 2.
  • n 3.
  • n 2
  • each R 3 is independently —H, or —(C 1 -C 6 )alkyl.
  • two R 3 groups together form a (C 2 -C 6 ) bridge, which is unsubstituted or substituted with 1, 2 or 3 independently selected R 8 groups, and which bridge optionally contains —HC ⁇ CH— within the (C 2 -C 6 ) bridge.
  • two R 3 groups together form a (C 2 -C 6 ) bridge, which is unsubstituted or substituted with an R 8 group, and which bridge optionally contains —HC ⁇ CH— within the (C 2 -C 6 ) bridge.
  • two R 3 groups together form a (C 2 -C 3 ) bridge, which is unsubstituted or substituted with an R 8 group, and which bridge optionally contains —HC ⁇ CH— within the (C 2 -C 3 ) bridge.
  • two R 3 groups together form a (C 2 -C 3 ) bridge, which is unsubstituted and which bridge optionally contains —HC ⁇ CH— within the (C 2 -C 3 ) bridge.
  • two R 3 groups together form a (C 2 ) bridge, a —HC ⁇ CH— bridge, or a (C 3 ) bridge each of which is unsubstituted.
  • two R 3 groups together form a (C 2 -C 6 ) bridge, which is unsubstituted or substituted with 1, 2 or 3 independently selected R 8 groups, which bridge optionally contains —HC ⁇ CH— within the (C 2 -C 6 ) bridge, and which bridge joins positions 2 and 6 of the piperidine, 1,2,3,6-tetrahydropyridine or piperazine ring.
  • two R 3 groups together form a (C 2 -C 6 ) bridge, which is unsubstituted or substituted with an R 8 group, which bridge optionally contains —HC ⁇ CH— within the (C 2 -C 6 ) bridge, and which bridge joins positions 2 and 6 of the piperidine, 1,2,3,6-tetrahydropyridine or piperazine ring.
  • two R 3 groups together form a (C 2 -C 3 ) bridge, which is unsubstituted or substituted with an R 8 group, which bridge optionally contains —HC ⁇ CH— within the (C 2 -C 3 ) bridge, and which bridge joins positions 2 and 6 of the piperidine, 1,2,3,6-tetrahydropyridine or piperazine ring.
  • two R 3 groups together form a (C 2 -C 3 ) bridge, which is unsubstituted, which bridge optionally contains —HC ⁇ CH— within the (C 2 -C 3 ) bridge, and which bridge joins positions 2 and 6 of the piperidine, 1,2,3,6-tetrahydropyridine or piperazine ring.
  • two R 3 groups together form a (C 2 ) bridge, a —HC ⁇ CH— bridge, or a (C 3 ) bridge each of which is unsubstituted, and which bridge joins positions 2 and 6 of the piperidine, 1,2,3,6-tetrahydropyridine or piperazine ring.
  • two R 3 groups together form a —CH 2 —N(R a )—CH 2 — bridge (B1), a
  • R a is —H, —(C 1 -C 6 )alkyl, —(C 3 -C 8 )cycloalkyl, —CH 2 —C(O)—R c , —(CH 2 )—C(O)—OR c , —(CH 2 )—C(O)—N(R c ) 2 , —(CH 2 ) 2 —O—R c , —(CH 2 ) 2 —S(O) 2 —N(R c ) 2 , or —(CH 2 ) 2 —N(R c )S(O) 2 —R c ;
  • R b is:
  • each R 1 is independently —H or —(C 1 -C 4 )alkyl
  • the B1, B2, or B3 bridge joins positions 2 and 6 of the piperidine, 1,2,3,6-tetrahydropyridine or piperazine ring.
  • two R 3 groups form a bicyclo group to give one of the following structures
  • n 1
  • n 0.
  • s or q is 0.
  • s or q is 1.
  • s or q is 2.
  • R 1 is —H.
  • R 1 is -halo
  • R 1 is —Cl
  • R 1 is —F.
  • R 1 is —CH 3 .
  • R 1 is —NO 2 .
  • R 1 is —CN.
  • R 1 is —OH.
  • R 1 is —OCH 3 .
  • R 1 is —NH 2 .
  • R 1 is —C(halo) 3 .
  • R 1 is —CF 3 .
  • R 1 is —CH(halo) 2 .
  • R 1 is —CH 2 (halo).
  • Ar 1 is a pyridyl group and n is 1.
  • Ar 1 is a pyrazinyl group and p is 1.
  • Ar 1 is a pyrimidinyl group and p is 1.
  • Ar 1 is a pyridazinyl group and p is 1.
  • R 2 when n and p are 1, then R 2 must be Q.
  • Z 1 is —H.
  • Z 1 is —OH.
  • Z 1 is —OCH 3 .
  • Z 1 is —CH 2 OH.
  • Z 2 is —CH 2 —OR 7 .
  • Z 2 is —CH 2 OH.
  • Z 2 is —H, —(C 1 -C 6 )alkyl, —(C 2 -C 6 )alkenyl, —(C 2 -C 6 )alkynyl, -phenyl, or -halo.
  • Z 2 is —H.
  • Z 2 is —CH 3 .
  • Z 3 is —H.
  • Z 3 is —CH 3 .
  • m is 1 and R 3 is —CH 3 or —CH 2 CH 3 .
  • m is 1 and R 3 is —CH 3 .
  • m is 1 and R 3 is —CH 2 OH.
  • n 0.
  • R 4 is —OH.
  • R 4 is —OCF 3 .
  • R 4 is -halo
  • R 4 is —F.
  • R 4 is —Cl
  • R 4 is —(C 1 -C 6 )alkyl.
  • R 4 is —CH 3 .
  • R 4 is —CH 2 OH.
  • R 4 is —CH 2 Cl.
  • R 4 is —CH 2 Br.
  • R 4 is —CH 2 I.
  • R 4 is —CH 2 F.
  • R 4 is —CH(halo) 2 .
  • R 4 is —CF 3 .
  • R 4 is —NO 2 .
  • R 4 is —OR 10 .
  • R 4 is —SR 10 .
  • R 4 is —C(O)R 10 .
  • R 4 is —COOH
  • R 4 is —C(O)H.
  • R 4 is —COOR 10 .
  • R 4 is —OC(O)R 10 .
  • R 4 is —SO 2 R 10 .
  • R 4 is —OC(O)NHR 10 .
  • R 4 is —NHC(O)R 13 .
  • R 4 is —CON(R 13 ) 2 .
  • each R 20 is independently —H or —(C 1 -C 6 )alkyl.
  • each R 20 is —H.
  • each R 20 is —(C 1 -C 6 )alkyl.
  • Ar 2 is a benzothiazolyl, benzoimidazolyl, or benzooxazolyl group; and at least one of R 8 and R 9 is —H.
  • Ar 2 is a benzothiazolyl, benzoimidazolyl, or benzooxazolyl group; and at least one of R 8 and R 9 is not —H.
  • Ar 2 is a benzothiazolyl, benzoimidazolyl, or benzooxazolyl group; and at least one of R 8 and R 9 is -halo.
  • Ar 2 is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
  • R 14 is —(C 1 -C 6 )alkyl, -halo, —C(halo) 3 , —OC(halo) 3 , —OR 7 , —N(R 7 ) 2 , —SO 2 R 7 , or —SO 2 C(halo) 3 .
  • Ar 2 is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
  • each R 14 is independently —(C 1 -C 6 )alkyl, -halo, —C(halo) 3 , —OC(halo) 3 , —OR 7 , —N(R 7 ) 2 , —SO 2 R 7 , or —SO 2 C(halo) 3 .
  • the invention encompasses compounds of formula I.4:
  • X is O, S, N—CN, N—OH, or N—OR 10 ;
  • W is N or C
  • R 4 is absent, otherwise R 4 is —H, —OH, —OCF 3 , -halo, —(C 1 -C 6 )alkyl, —CH 2 OH, —CH 2 Cl, —CH 2 Br, —CH 2 I, —CH 2 F, —CH(halo) 2 , —CF 3 , —OR 10 , —SR 10 , —COOH, —COOR 10 , —C(O)R 10 , —C(O)H, —OC(O)R 10 , —OC(O)NHR 10 , —NHC(O)R 13 , —CON(R 13 ) 2 , —S(O) 2 R 10 , or —NO 2 ;
  • R 10 is —(C 1 -C 4 )alkyl
  • each R 13 is independently: —H, —(C 1 -C 4 )alkyl, —(C 1 -C 4 )alkenyl, —(C 1 -C 4 )alkynyl, or -phenyl;
  • c is the integer 0, 1, or 2;
  • Y 1 , Y 2 , and Y 3 are independently C, N, or O;
  • Y 1 , Y 2 , or Y 3 can be 0, and for each Y 1 , Y 2 , and Y 3 that is N, the N is bonded to one R 21 group, and for each Y 1 , Y 2 , and Y 3 that is C, the C is bonded to two R 20 groups, provided that there are no more than a total of two (C 1 -C 6 )alkyl groups substituted on all of Y 1 , Y 2 , and Y 3 ;
  • R 12a and R 12b are independently —H or —(C 1 -C 6 )alkyl
  • E is ⁇ O, ⁇ S, ⁇ C(C 1 -C 5 )alkyl, ⁇ C(C 1 -C 5 )alkenyl, ⁇ NH(C 1 -C 6 )alkyl, or ⁇ N—OR 20 ;
  • R 1 is —H, -halo, —(C 1 -C 4 )alkyl, —NO 2 , —CN, —OH, —OCH 3 , —NH 2 , —C(halo) 3 , —CH(halo) 2 , —CH 2 (halo), —OC(halo) 3 , —OCH(halo) 2 , or —OCH 2 (halo);
  • each R 2 is independently:
  • Z 1 is —H, —OR 7 , —SR 7 , —CH 2 —OR 7 , —CH 2 —SR 7 , —CH 2 —N(R 20 ) 2 , or -halo;
  • Z 2 is —H, —(C 1 -C 6 )alkyl, —(C 2 -C 6 )alkenyl, —(C 2 -C 6 )alkynyl, -phenyl, or -halo;
  • each Z 3 is independently —H, —(C 1 -C 6 )alkyl, —(C 2 -C 6 )alkenyl, —(C 2 -C 6 )alkynyl, or -phenyl;
  • R 2 group is a group of formula Q, and provided that when Z 1 is —OR 7 or —SR 7 , then Z 2 is not -halo;
  • each R 3 is independently:
  • each R 7 is independently —H, —(C 1 -C 6 )alkyl, —(C 2 -C 6 )alkenyl, —(C 2 -C 6 )alkynyl, —(C 3 -C 8 )cycloalkyl, —(C 5 -C 8 )cycloalkenyl, -phenyl, —(C 1 -C 6 )haloalkyl, —(C 1 -C 6 )hydroxyalkyl, —(C 1 -C 6 )alkoxy(C 1 -C 6 )alkyl, —(C 1 -C 6 )alkyl-N(R 20 ) 2 , or —CON(R 20 ) 2 ;
  • each R 8 and R 9 are independently —H, —(C 1 -C 6 )alkyl, —(C 2 -C 6 )alkenyl, —(C 2 -C 6 )alkynyl, —(C 3 -C 8 )cycloalkyl, —(C 5 -C 8 )cycloalkenyl, -phenyl, —CH 2 C(halo) 3 , —C(halo) 3 , —CH(halo) 2 , —CH 2 (halo), —OC(halo) 3 , —OCH(halo) 2 , —OCH 2 (halo), —O—CN, —OH, -halo, —N 3 , —NO 2 , —CH ⁇ NR 7 , —N(R 7 ) 2 , —NR 7 OH, —OR 7 , —C(O)R 7 , —C(O)OR 7 , —OC(
  • each R 11 is independently —CN, —OH, —(C 1 -C 6 )alkyl, —(C 2 -C 6 )alkenyl, -halo, —N 3 , —NO 2 , —N(R 7 ) 2 , —CH ⁇ NR 7 , —NR 7 OH, —OR 7 , —C(O)R 7 , —C(O)OR 7 , —OC(O)R 7 , or —OC(O)OR 7 ;
  • each R 14 is independently —(C 1 -C 6 )alkyl, —(C 2 -C 6 )alkenyl, —(C 2 -C 6 )alkynyl, —(C 3 -C 8 )cycloalkyl, —(C 5 -C 8 )cycloalkenyl, —(C 1 -C 6 )alkoxy-(C 1 -C 6 )alkyl, -phenyl, —C(halo) 3 , —CH(halo) 2 , —CH 2 (halo), -(3- to 7-membered)heterocycle, —(C 1 -C 6 )haloalkyl, —(C 2 -C 6 )haloalkenyl, —(C 2 -C 6 )haloalkynyl, —(C 2 -C 6 )hydroxyalkenyl, —(C 2 -C 6 )hydroxyalkyny
  • each R 20 is independently —H or —(C 1 -C 6 )alkyl
  • each R 21 is independently —H, —(C 1 -C 6 )alkyl
  • each halo is independently —F, —Cl, —Br, or —I;
  • n is the integer 1, 2, or 3;
  • p is the integer 1 or 2;
  • each b is independently the integer 1 or 2;
  • q is the integer 0, 1, 2, 3, or 4;
  • r is the integer 0, 1, 2, 3, 4, 5, or 6;
  • s is the integer 0, 1, 2, 3, 4, or 5;
  • t is the integer 0, 1, 2, or 3;
  • n is the integer 0, 1, or 2.
  • E is ⁇ O, ⁇ S, ⁇ CH(C 1 -C 5 )alkyl, ⁇ CH(C 1 -C 5 )alkenyl, or ⁇ N—OR 20 .
  • E is ⁇ O, ⁇ S, or ⁇ N—OR 20 .
  • the invention encompasses compounds of formula I.3:
  • X is O, S, N—CN, N—OH, or N—OR 10 ;
  • W is N or C
  • R 4 is absent, otherwise R 4 is —H, —OH, —OCF 3 , -halo, —(C 1 -C 6 )alkyl, —CH 2 OH, —CH 2 Cl, —CH 2 Br, —CH 2 I, —CH 2 F, —CH(halo) 2 , —CF 3 , —OR 10 , —SR 10 , —COOH, —COOR 10 , —C(O)R 10 , —C(O)H, —OC(O)R 10 , —OC(O)NHR 10 , —NHC(O)R 13 , —CON(R 13 ) 2 , —S(O) 2 R 10 , or —NO 2 ;
  • R 10 is —(C 1 -C 4 )alkyl
  • each R 13 is independently: —H, —(C 1 -C 4 )alkyl, —(C 1 -C 4 )alkenyl, —(C 1 -C 4 )alkynyl, or -phenyl;
  • c is the integer 0, 1, or 2;
  • Y 1 , Y 2 , and Y 3 are independently C or N;
  • R 12a and R 12b are independently —H or —(C 1 -C 6 )alkyl
  • E is ⁇ O, ⁇ S, ⁇ C(C 1 -C 5 )alkyl, ⁇ C(C 1 -C 5 )alkenyl, ⁇ NH(C 1 -C 6 )alkyl, or ⁇ N—OR 20 ;
  • R 1 is —H, -halo, —(C 1 -C 4 )alkyl, —NO 2 , —CN, —OH, —OCH 3 , —NH 2 , —C(halo) 3 , —CH(halo) 2 , —CH 2 (halo), —OC(halo) 3 , —OCH(halo) 2 , or —OCH 2 (halo);
  • each R 2 is independently:
  • Z 1 is —H, —OR 7 , —SR 7 , —CH 2 —OR 7 , —CH 2 —SR 7 , —CH 2 —N(R 20 ) 2 , or -halo;
  • Z 2 is —H, —(C 1 -C 6 )alkyl, —(C 2 -C 6 )alkenyl, —(C 2 -C 6 )alkynyl, -phenyl, or -halo;
  • each Z 3 is independently —H, —(C 1 -C 6 )alkyl, —(C 2 -C 6 )alkenyl, —(C 2 -C 6 )alkynyl, or -phenyl;
  • R 2 group is a group of formula Q, and provided that when Z 1 is —OR 7 or —SR 7 , then Z 2 is not -halo;
  • each R 3 is independently:
  • each R 7 is independently —H, —(C 1 -C 6 )alkyl, —(C 2 -C 6 )alkenyl, —(C 2 -C 6 )alkynyl, —(C 3 -C 8 )cycloalkyl, —(C 5 -C 8 )cycloalkenyl, -phenyl, —(C 1 -C 6 )haloalkyl, —(C 1 -C 6 )hydroxyalkyl, —(C 1 -C 6 )alkoxy(C 1 -C 6 )alkyl, —(C 1 -C 6 )alkyl-N(R 20 ) 2 , or —CON(R 20 ) 2 ;
  • each R 8 and R 9 are independently —H, —(C 1 -C 6 )alkyl, —(C 2 -C 6 )alkenyl, —(C 2 -C 6 )alkynyl, —(C 3 -C 8 )cycloalkyl, —(C 5 -C 8 )cycloalkenyl, -phenyl, —CH 2 C(halo) 3 , —C(halo) 3 , —CH(halo) 2 , —CH 2 (halo), —OC(halo) 3 , —OCH(halo) 2 , —OCH 2 (halo), —O—CN, —OH, -halo, —N 3 , —NO 2 , —CH ⁇ NR 7 , —N(R 7 ) 2 , —NR 7 OH, —OR 7 , —C(O)R 7 , —C(O)OR 7 , —OC(
  • each R 11 is independently —CN, —OH, —(C 1 -C 6 )alkyl, —(C 2 -C 6 )alkenyl, -halo, —N 3 , —NO 2 , —N(R 7 ) 2 , —CH ⁇ NR 7 , —NR 7 OH, —OR 7 , —C(O)R 7 , —C(O)OR 7 , —OC(O)R 7 , or —OC(O)OR 7 ;
  • each R 14 is independently —(C 1 -C 6 )alkyl, —(C 2 -C 6 )alkenyl, —(C 2 -C 6 )alkynyl, —(C 3 -C 8 )cycloalkyl, —(C 5 -C 8 )cycloalkenyl, —(C 1 -C 6 )alkoxy-(C 1 -C 6 )alkyl, -phenyl, —C(halo) 3 , —CH(halo) 2 , —CH 2 (halo), -(3- to 7-membered)heterocycle, —(C 1 -C 6 )haloalkyl, —(C 2 -C 6 )haloalkenyl, —(C 2 -C 6 )haloalkynyl, —(C 2 -C 6 )hydroxyalkenyl, —(C 2 -C 6 )hydroxyalkyny
  • each R 20 is independently —H or —(C 1 -C 6 )alkyl
  • each halo is independently —F, —Cl, —Br, or —I;
  • n is the integer 1, 2, or 3;
  • p is the integer 1 or 2;
  • each b is independently the integer 1 or 2;
  • q is the integer 0, 1, 2, 3, or 4;
  • r is the integer 0, 1, 2, 3, 4, 5, or 6;
  • s is the integer 0, 1, 2, 3, 4, or 5;
  • t is the integer 0, 1, 2, or 3;
  • n is the integer 0, 1, or 2.
  • E is ⁇ O, ⁇ S, ⁇ CH(C 1 -C 5 )alkyl, ⁇ CH(C 1 -C 5 )alkenyl, or ⁇ N—OR 20 .
  • E is ⁇ O, ⁇ S, or ⁇ N—OR 20 .
  • the invention encompasses compounds of formula I.2:
  • X is O, S, N—CN, N—OH, or N—OR 10 ;
  • W is N or C
  • R 4 is absent, otherwise R 4 is —H, —OH, —OCF 3 , -halo, —(C 1 -C 6 )alkyl, —CH 2 OH, —CH 2 Cl, —CH 2 Br, —CH 2 I, —CH 2 F, —CH(halo) 2 , —CF 3 , —OR 10 , —SR 10 , —COOH, —COOR 10 , —C(O)R 10 , —C(O)H, —OC(O)R 10 , —OC(O)NHR 10 , —NHC(O)R 13 , —CON(R 13 ) 2 , —S(O) 2 R 10 , or —NO 2 ;
  • R 10 is —(C 1 -C 4 )alkyl
  • each R 13 is independently: —H, —(C 1 -C 4 )alkyl, —(C 1 -C 4 )alkenyl, —(C 1 -C 4 )alkynyl, or -phenyl;
  • c is the integer 0, 1, or 2;
  • Y 1 , Y 2 , and Y 3 are independently C or N;
  • R 12a and R 12b are independently —H or —(C 1 -C 6 )alkyl
  • E is ⁇ O, ⁇ S, ⁇ C(C 1 -C 5 )alkyl, ⁇ C(C 1 -C 5 )alkenyl, ⁇ NH(C 1 -C 6 )alkyl, or ⁇ N—OR 20 ;
  • R 1 is —H, -halo, —(C 1 -C 4 )alkyl, —NO 2 , —CN, —OH, —OCH 3 , —NH 2 , —C(halo) 3 , —CH(halo) 2 , —CH 2 (halo), —OC(halo) 3 , —OCH(halo) 2 , or —OCH 2 (halo);
  • each R 2 is independently:
  • Z 1 is —H, —OR 7 , —SR 7 , —CH 2 —OR 7 , —CH 2 —SR 7 , —CH 2 —N(R 20 ) 2 , or -halo;
  • Z 2 is —H, —(C 1 -C 6 )alkyl, —(C 2 -C 6 )alkenyl, —(C 2 -C 6 )alkynyl, -phenyl, or -halo;
  • each Z 3 is independently —H, —(C 1 -C 6 )alkyl, —(C 2 -C 6 )alkenyl, —(C 2 -C 6 )alkynyl, or -phenyl;
  • R 2 group is a group of formula Q, and provided that when Z 1 is —OR 7 or —SR 7 , then Z 2 is not -halo;
  • each R 3 is independently:
  • each R 7 is independently —H, —(C 1 -C 6 )alkyl, —(C 2 -C 6 )alkenyl, —(C 2 -C 6 )alkynyl, —(C 3 -C 8 )cycloalkyl, —(C 5 -C 8 )cycloalkenyl, -phenyl, —(C 1 -C 6 )haloalkyl, —(C 1 -C 6 )hydroxyalkyl, —(C 1 -C 6 )alkoxy(C 1 -C 6 )alkyl, —(C 1 -C 6 )alkyl-N(R 20 ) 2 , or —CON(R 20 ) 2 ;
  • each R 8 and R 9 are independently —H, —(C 1 -C 6 )alkyl, —(C 2 -C 6 )alkenyl, —(C 2 -C 6 )alkynyl, —(C 3 -C 8 )cycloalkyl, —(C 5 -C 8 )cycloalkenyl, -phenyl, —CH 2 C(halo) 3 , —C(halo) 3 , —CH(halo) 2 , —CH 2 (halo), —OC(halo) 3 , —OCH(halo) 2 , —OCH 2 (halo), —O—CN, —OH, -halo, —N 3 , —NO 2 , —CH ⁇ NR 7 , —N(R 7 ) 2 , —NR 7 OH, —OR 7 , —C(O)R 7 , —C(O)OR 7 , —OC(
  • each R 11 is independently —CN, —OH, —(C 1 -C 6 )alkyl, —(C 2 -C 6 )alkenyl, -halo, —N 3 , —NO 2 , —N(R 7 ) 2 , —CH ⁇ NR 7 , —NR 7 OH, —OR 7 , —C(O)R 7 , —C(O)OR 7 , —OC(O)R 7 , or —OC(O)OR 7 ;
  • each R 14 is independently —(C 1 -C 6 )alkyl, —(C 2 -C 6 )alkenyl, —(C 2 -C 6 )alkynyl, —(C 3 -C 8 )cycloalkyl, —(C 5 -C 8 )cycloalkenyl, —(C 1 -C 6 )alkoxy-(C 1 -C 6 )alkyl, -phenyl, —C(halo) 3 , —CH(halo) 2 , —CH 2 (halo), -(3- to 7-membered)heterocycle, —(C 1 -C 6 )haloalkyl, —(C 2 -C 6 )haloalkenyl, —(C 2 -C 6 )haloalkynyl, —(C 2 -C 6 )hydroxyalkenyl, —(C 2 -C 6 )hydroxyalkyny
  • each R 20 is independently —H or —(C 1 -C 6 )alkyl
  • each halo is independently —F, —Cl, —Br, or —I;
  • n is the integer 1, 2, or 3;
  • p is the integer 1 or 2;
  • each b is independently the integer 1 or 2;
  • q is the integer 0, 1, 2, 3, or 4;
  • r is the integer 0, 1, 2, 3, 4, 5, or 6;
  • s is the integer 0, 1, 2, 3, 4, or 5;
  • t is the integer 0, 1, 2, or 3;
  • n is the integer 0, 1, or 2.
  • E is ⁇ O, ⁇ S, ⁇ CH(C 1 -C 5 )alkyl, ⁇ CH(C 1 -C 5 )alkenyl, or ⁇ N—OR 20 .
  • E is ⁇ O, ⁇ S, or ⁇ N—OR 20 .
  • the invention encompasses compounds of formula I.1:
  • X is O, S, N—CN, N—OH, or N—OR 10 ;
  • W is N or C
  • R 4 is absent, otherwise R 4 is —H, —OH, —OCF 3 , -halo, —(C 1 -C 6 )alkyl, —CH 2 OH, —CH 2 Cl, —CH 2 Br, —CH 2 I, —CH 2 F, —CH(halo) 2 , —CF 3 , —OR 10 , —SR 10 , —COOH, —COOR 10 , —C(O)R 10 , —C(O)H, —OC(O)R 10 , —OC(O)NHR 10 , —NHC(O)R 13 , —CON(R 13 ) 2 , —S(O) 2 R 10 , or —NO 2 ;
  • R 10 is —(C 1 -C 4 )alkyl
  • each R 13 is independently: —H, —(C 1 -C 4 )alkyl, —(C 1 -C 4 )alkenyl, —(C 1 -C 4 )alkynyl, or -phenyl;
  • c is the integer 0, 1, or 2;
  • Y 1 , Y 2 , and Y 3 are independently C or N;
  • R 12a and R 12b are independently —H or —(C 1 -C 6 )alkyl
  • E is ⁇ O, ⁇ S, ⁇ C(C 1 -C 5 )alkyl, ⁇ C(C 1 -C 5 )alkenyl, ⁇ NH(C 1 -C 6 )alkyl, or ⁇ N—OR 20 ;
  • R 1 is —H, -halo, —(C 1 -C 4 )alkyl, —NO 2 , —CN, —OH, —OCH 3 , —NH 2 , —C(halo) 3 , —CH(halo) 2 , —CH 2 (halo), —OC(halo) 3 , —OCH(halo) 2 , or —OCH 2 (halo);
  • each R 2 is independently:
  • Z 1 is —H, —OR 7 , —SR 7 , —CH 2 —OR 7 , —CH 2 —SR 7 , —CH 2 —N(R 20 ) 2 , or -halo;
  • Z 2 is —H, —(C 1 -C 6 )alkyl, —(C 2 -C 6 )alkenyl, —(C 2 -C 6 )alkynyl, -phenyl, or -halo;
  • each Z 3 is independently —H, —(C 1 -C 6 )alkyl, —(C 2 -C 6 )alkenyl, —(C 2 -C 6 )alkynyl, or -phenyl;
  • R 2 group is a group of formula Q, and provided that when Z 1 is —OR 7 or —SR 7 , Z 2 in not -halo;
  • each R 3 is independently:
  • each R 7 is independently —H, —(C 1 -C 6 )alkyl, —(C 2 -C 6 )alkenyl, —(C 2 -C 6 )alkynyl, —(C 3 -C 8 )cycloalkyl, —(C 5 -C 8 )cycloalkenyl, -phenyl, —(C 1 -C 6 )haloalkyl, —(C 1 -C 6 )hydroxyalkyl, —(C 1 -C 6 )alkoxy(C 1 -C 6 )alkyl, —(C 1 -C 6 )alkyl-N(R 20 ) 2 , or —CON(R 20 ) 2 ;
  • each R 8 and R 9 are independently —H, —(C 1 -C 6 )alkyl, —(C 2 -C 6 )alkenyl, —(C 2 -C 6 )alkynyl, —(C 3 -C 8 )cycloalkyl, —(C 5 -C 8 )cycloalkenyl, -phenyl, —CH 2 C(halo) 3 , —C(halo) 3 , —CH(halo) 2 , —CH 2 (halo), —OC(halo) 3 , —OCH(halo) 2 , —OCH 2 (halo), —O—CN, —OH, -halo, —N 3 , —NO 2 , —CH ⁇ NR 7 , —N(R 7 ) 2 , —NR 7 OH, —OR 7 , —C(O)R 7 , —C(O)OR 7 , —OC(
  • each R 11 is independently —CN, —OH, —(C 1 -C 6 )alkyl, —(C 2 -C 6 )alkenyl, -halo, —N 3 , —NO 2 , —N(R 7 ) 2 , —CH ⁇ NR 7 , —NR 7 OH, —OR 7 , —C(O)R 7 , —C(O)OR 7 , —OC(O)R 7 , or —OC(O)OR 7 ;
  • each R 14 is independently —(C 1 -C 6 )alkyl, —(C 2 -C 6 )alkenyl, —(C 2 -C 6 )alkynyl, —(C 3 -C 8 )cycloalkyl, —(C 5 -C 8 )cycloalkenyl, —(C 1 -C 6 )alkoxy-(C 1 -C 6 )alkyl, -phenyl, —C(halo) 3 , —CH(halo) 2 , —CH 2 (halo), -(3- to 7-membered)heterocycle, —(C 1 -C 6 )haloalkyl, —(C 2 -C 6 )haloalkenyl, —(C 2 -C 6 )haloalkynyl, —(C 2 -C 6 )hydroxyalkenyl, —(C 2 -C 6 )hydroxyalkyny
  • each R 20 is independently —H or —(C 1 -C 6 )alkyl
  • each halo is independently —F, —Cl, —Br, or —I;
  • n is the integer 1, 2, or 3;
  • p is the integer 1 or 2;
  • each b is independently the integer 1 or 2;
  • q is the integer 0, 1, 2, 3, or 4;
  • r is the integer 0, 1, 2, 3, 4, 5, or 6;
  • s is the integer 0, 1, 2, 3, 4, or 5;
  • t is the integer 0, 1, 2, or 3;
  • n is the integer 0, 1, or 2.
  • E is ⁇ O, ⁇ S, ⁇ CH(C 1 -C 5 )alkyl, ⁇ CH(C 1 -C 5 )alkenyl, or ⁇ N—OR 20 .
  • E is ⁇ O, ⁇ S, or ⁇ N—OR 20 .
  • the compound of formula I is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
  • Aqueous solubility of compounds is often a desirable feature.
  • aqueous solubility of a compound permits that compound to be more easily formulated into a variety of dosage forms that may be administered to an animal.
  • Aqueous solubility increases the likelihood that a compound will not precipitate in an animal's blood, and increases the ability to predict exposure at the target sight of the compound.
  • Compounds of formula I are highly soluble in aqueous solution.
  • compound 200 is insoluble in aqueous solution, i.e., has an aqueous solubility ⁇ 0.1 ⁇ M.
  • the aqueous solubility at pH 6.8, in ⁇ M, of compounds of formula I F2, E6, F6, and G2 is 3.0, 9.0, 9.2, and 38.2, respectively.
  • the aqueous solubility at pH 1.2, in ⁇ M, of compounds of formula I F2, E6, F6 and G2 is 1.0, 27.2, >50 and >50, respectively.
  • the aqueous solubility at either pH 6.8 or pH 1.2 of each of compounds of formula I G6, H6, J2, and Z 1 is >50 ⁇ M.
  • the following compounds are aqueous insoluble at pH 6.8: 203, 207, 200, and 208.
  • the following compounds have very low aqueous solubility at pH 6.8: 209, 210, 211, 212, 213, 214, and 215 have aqueous solubility, in ⁇ M, of 1.0, 0.4, 0.4, 1.9, 0.8, 1.8, and 0.6, respectively.
  • the aqueous solubility, in ⁇ M, at pH 1.2 of compounds 209, 210, 211, 212, 213, 214 and 215 is 9.3, 2.0, 1.3, 10.3, 39.6, >50 and 9.6, respectively.
  • the aqueous solubility at pH 6.8, in ⁇ M, of compounds of formula I N1, F1, C1, Y3, and U3 is 28.0, 22.6, 15.7, 17.4, and 26.4, respectively.
  • compounds of formula I N1, F1, C1, Y3 and U3 all have an aqueous solubility of >50 ⁇ M.
  • the aqueous solubility, at either pH 6.8 or pH 1.2 is >50 ⁇ M for each of the following compounds of formula I: H1, N6, Z1, S1, E2, and U1.
  • compounds of formula I are compounds of formula IA′′:
  • a compound of formula IA′′ is a pharmaceutically acceptable derivative of a compound of formula IA′′.
  • a compound of formula IA′′ is a compound of formula I wherein the derivative is a pharmaceutically acceptable salt.
  • a compound of formula IA′′ is a pharmaceutically acceptable salt of a compound of formula IA′′.
  • Ar 1 is a pyridyl group.
  • Ar 1 is a pyrimidinyl group.
  • Ar 1 is a pyrazinyl group.
  • Ar 1 is pyridazinyl group.
  • W is C.
  • W is N.
  • X is O.
  • X is S.
  • X is N—CN.
  • X is N—OH.
  • X is N—OR 10 .
  • Ar 2 is a benzoimidazolyl group.
  • Ar 2 is a benzothiazolyl group.
  • Ar 2 is a benzooxazolyl group.
  • Ar 2 is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
  • Ar 2 is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
  • Ar 2 is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
  • Ar 2 is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
  • Ar 2 is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
  • Ar 2 is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
  • Ar 2 is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
  • Ar 2 is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
  • n or p is 1.
  • n or p is 2.
  • n 3.
  • n 2
  • each R 3 is independently —H, or —(C 1 -C 6 )alkyl.
  • two R 3 groups together form a (C 2 -C 6 ) bridge, which is unsubstituted or substituted with 1, 2 or 3 independently selected R 8 groups, and which bridge optionally contains —HC ⁇ CH— within the (C 2 -C 6 ) bridge.
  • two R 3 groups together form a (C 2 -C 6 ) bridge, which is unsubstituted or substituted with an R 8 group, and which bridge optionally contains —HC ⁇ CH— within the (C 2 -C 6 ) bridge.
  • two R 3 groups together form a (C 2 -C 3 ) bridge, which is unsubstituted or substituted with an R 8 group, and which bridge optionally contains —HC ⁇ CH— within the (C 2 -C 3 ) bridge.
  • two R 3 groups together form a (C 2 -C 3 ) bridge, which is unsubstituted and which bridge optionally contains —HC ⁇ CH— within the (C 2 -C 3 ) bridge.
  • two R 3 groups together form a (C 2 ) bridge, a —HC ⁇ CH— bridge, or a (C 3 ) bridge each of which is unsubstituted.
  • two R 3 groups together form a (C 2 -C 6 ) bridge, which is unsubstituted or substituted with 1, 2 or 3 independently selected R 8 groups, which bridge optionally contains —HC ⁇ CH— within the (C 2 -C 6 ) bridge, and which bridge joins positions 2 and 6 of the piperidine, 1,2,3,6-tetrahydropyridine or piperazine ring.
  • two R 3 groups together form a (C 2 -C 6 ) bridge, which is unsubstituted or substituted with an R 8 group, which bridge optionally contains —HC ⁇ CH— within the (C 2 -C 6 ) bridge, and which bridge joins positions 2 and 6 of the piperidine, 1,2,3,6-tetrahydropyridine or piperazine ring.
  • two R 3 groups together form a (C 2 -C 3 ) bridge, which is unsubstituted or substituted with an R 8 group, which bridge optionally contains —HC ⁇ CH— within the (C 2 -C 3 ) bridge, and which bridge joins positions 2 and 6 of the piperidine, 1,2,3,6-tetrahydropyridine or piperazine ring.
  • two R 3 groups together form a (C 2 -C 3 ) bridge, which is unsubstituted, which bridge optionally contains —HC ⁇ CH— within the (C 2 -C 3 ) bridge, and which bridge joins positions 2 and 6 of the piperidine, 1,2,3,6-tetrahydropyridine or piperazine ring.
  • two R 3 groups together form a (C 2 ) bridge, a —HC ⁇ CH— bridge, or a (C 3 ) bridge each of which is unsubstituted, and which bridge joins positions 2 and 6 of the piperidine, 1,2,3,6-tetrahydropyridine or piperazine ring.
  • two R 3 groups together form a —CH 2 —N(R a )—CH 2 — bridge (B1), a
  • R a is —H, —(C 1 -C 6 )alkyl, —(C 3 -C 8 )cycloalkyl, —CH 2 —C(O)—R c , —(CH 2 )—C(O)—OR c , —(CH 2 )—C(O)—N(R c ) 2 , —(CH 2 ) 2 —O—R c , —(CH 2 ) 2 —S(O) 2 —N(R c ) 2 , or —(CH 2 ) 2 —N(R c )S(O) 2 —R c ;
  • R b is:
  • each R c is independently —H or —(C 1 -C 4 )alkyl
  • the B1, B2, or B3 bridge joins positions 2 and 6 of the piperidine, 1,2,3,6-tetrahydropyridine or piperazine ring.
  • two R 3 groups form a bicyclo group to give one of the following structures
  • n 1
  • n 0.
  • s or q is 0.
  • s or q is 1.
  • s or q is 2.
  • R 1 is —H.
  • R 1 is -halo
  • R 1 is —Cl
  • R 1 is —F.
  • R 1 is —CH 3 .
  • R 1 is —NO 2 .
  • R 1 is —CN.
  • R 1 is —OH.
  • R 1 is —OCH 3 .
  • R 1 is —NH 2 .
  • R 1 is —C(halo) 3 .
  • R 1 is —CF 3 .
  • R 1 is —CH(halo) 2 .
  • R 1 is —CH 2 (halo).
  • Ar 1 is a pyridyl group and n is 1.
  • Ar 1 is a pyrazinyl group and p is 1.
  • Ar 1 is a pyrimidinyl group and p is 1.
  • Ar 1 is a pyridazinyl group and p is 1.
  • R 2 when n and p are 1, then R 2 must be Q.
  • Z 1 is —H.
  • Z 1 is —OH.
  • Z 1 is —OCH 3 .
  • Z 1 is —CH 2 OH.
  • Z 2 is —CH 2 —OR 7 .
  • Z 2 is —CH 2 OH.
  • Z 2 is —H, —(C 1 -C 6 )alkyl, —(C 2 -C 6 )alkenyl, —(C 2 -C 6 )alkynyl, -phenyl, or -halo.
  • Z 2 is —H.
  • Z 2 is —CH 3 .
  • Z 3 is —H.
  • Z 3 is —CH 3 .
  • m is 1 and R 3 is —(C 1 -C 6 )alkyl.
  • m is 1 and R 3 is —CH 3 or —CH 2 CH 3 .
  • m is 1 and R 3 is —CH 3 .
  • m is 1 and R 3 is —CH 2 OH.
  • n 0.
  • R 4 is —OH.
  • R 4 is —OCF 3 .
  • R 4 is -halo
  • R 4 is —F.
  • R 4 is —Cl
  • R 4 is —(C 1 -C 6 )alkyl.
  • R 4 is —CH 3 .
  • R 4 is —CH 2 OH.
  • R 4 is —CH 2 Cl.
  • R 4 is —CH 2 Br.
  • R 4 is —CH 2 I.
  • R 4 is —CH 2 F.
  • R 4 is —CH(halo) 2 .
  • R 4 is —CF 3 .
  • R 4 is —NO 2 .
  • R 4 is —OR 10 .
  • R 4 is —SR 10 .
  • R 4 is —C(O)R 10 .
  • R 4 is —COOH
  • R 4 is —C(O)H.
  • R 4 is —COOR 10 .
  • R 4 is —OC(O)R 10 .
  • R 4 is —SO 2 R 10 .
  • R 4 is —OC(O)NHR 10 .
  • R 4 is —NHC(O)R 13 .
  • R 4 is —CON(R 13 ) 2 .
  • each R 20 is independently —H or —(C 1 -C 6 )alkyl.
  • each R 20 is —H.
  • each R 20 is —(C 1 -C 6 )alkyl.
  • Ar 2 is a benzothiazolyl, benzoimidazolyl, or benzooxazolyl group; and at least one of R 8 and R 9 is —H.
  • Ar 2 is a benzothiazolyl, benzoimidazolyl, or benzooxazolyl group; and at least one of R 8 and R 9 is not —H.
  • Ar 2 is a benzothiazolyl, benzoimidazolyl, or benzooxazolyl group; and at least one of R 8 and R 9 is -halo.
  • Ar 2 is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
  • R 14 is —(C 1 -C 6 )alkyl, -halo, —C(halo) 3 , —OC(halo) 3 , —OR 7 , —N(R 7 ) 2 , —SO 2 R 7 , or —SO 2 C(halo) 3 .
  • Ar 2 is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
  • each R 14 is independently —(C 1 -C 6 )alkyl, -halo, —C(halo) 3 , —OC(halo) 3 , —OR 7 , —N(R 7 ) 2 , —SO 2 R 7 , or —SO 2 C(halo) 3 .
  • R 4 is -halo, n or p is 1, R 2 is Q, wherein Q is
  • R 20 is —(C 1 -C 6 )alkyl.
  • R 4 is -halo, n or p is 1, R 2 is Q, wherein Q is
  • R 20 is —(C 3 -C 8 )cycloalkyl.
  • R 4 is -halo, n or p is 1, R 2 is Q, wherein Q is
  • R 20 is —(C 1 -C 6 )alkyl and Z 1 is —OR 7 .
  • R 4 is -halo, n or p is 1, R 2 is Q, wherein Q is
  • R 20 is —(C 1 -C 6 )alkyl and Z 1 is —CH 2 OR 7 .
  • R 4 is -halo, n or p is 1, R 2 is Q, wherein Q is
  • R 20 is —(C 1 -C 6 )alkyl and Z 1 is —OH.
  • R 4 is -halo, n or p is 1, R 2 is Q, wherein Q is
  • R 20 is —(C 1 -C 6 )alkyl and Z 1 is —CH 2 OH.
  • R 4 is -halo, n or p is 1, R 2 is Q, wherein Q is
  • R 20 is —(C 3 -C 8 )cycloalkyl and Z 1 is —OR 7 .
  • R 4 is -halo, n or p is 1, R 2 is Q, wherein Q is
  • R 20 is —(C 3 -C 8 )cycloalkyl and Z 1 is —CH 2 OR 7 .
  • R 4 is -halo, n or p is 1, R 2 is Q, wherein Q is
  • R 20 is —(C 3 -C 8 )cycloalkyl and Z 1 is —OH.
  • R 4 is -halo, n or p is 1, R 2 is Q, wherein Q is
  • R 20 is —(C 3 -C 8 )cycloalkyl and Z 1 is —CH 2 OH.
  • R 4 is —F, n or p is 1, R 2 is Q, wherein Q is
  • R 20 is —(C 1 -C 6 )alkyl.
  • R 4 is —F, n or p is 1, R 2 is Q, wherein Q is
  • R 20 is —(C 3 -C 8 )cycloalkyl.
  • R 4 is —F, n or p is 1, R 2 is Q, wherein Q is
  • R 20 is —(C 1 -C 6 )alkyl and Z 1 is —OR 7 .
  • R 4 is —F, n or p is 1, R 2 is Q, wherein Q is
  • R 20 is —(C 1 -C 6 )alkyl and Z 1 is —CH 2 OR 7 .
  • R 4 is —F, n or p is 1, R 2 is Q, wherein Q is
  • R 20 is —(C 1 -C 6 )alkyl and Z 1 is —OH.
  • R 4 is —F, n or p is 1, R 2 is Q, wherein Q is
  • R 20 is —(C 1 -C 6 )alkyl and Z 1 is —CH 2 OH.
  • R 4 is —F, n or p is 1, R 2 is Q, wherein Q is
  • R 20 is —(C 3 -C 8 )cycloalkyl and Z 1 is —OR 7 .
  • R 4 is —F, n or p is 1, R 2 is Q, wherein Q is
  • R 20 is —(C 3 -C 8 )cycloalkyl and Z 1 is —CH 2 OR 7 .
  • R 4 is —F, n or p is 1, R 2 is Q, wherein Q is
  • R 20 is —(C 3 -C 8 )cycloalkyl and Z 1 is —OH.
  • R 4 is —F, n or p is 1, R 2 is Q, wherein Q is
  • R 20 is —(C 3 -C 8 )cycloalkyl and Z 1 is —CH 2 OH.
  • R 1 is -halo
  • R 4 is -halo
  • n or p is 1
  • R 2 is Q, wherein Q is
  • R 20 is —(C 1 -C 6 )alkyl.
  • R 1 is -halo
  • R 4 is -halo
  • n or p is 1
  • R 2 is Q, wherein Q is
  • R 20 is —(C 3 -C 8 )cycloalkyl.
  • R 1 is -halo
  • R 4 is -halo
  • n or p is 1
  • R 2 is Q, wherein Q is
  • R 20 is —(C 1 -C 6 )alkyl and Z 1 is —OR 7 .
  • R 1 is -halo
  • R 4 is -halo
  • n or p is 1
  • R 2 is Q, wherein Q is
  • R 20 is —(C 1 -C 6 )alkyl and Z 1 is —CH 2 OR 7 .
  • R 1 is -halo
  • R 4 is -halo
  • n or p is 1
  • R 2 is Q, wherein Q is
  • R 20 is —(C 1 -C 6 )alkyl and Z 1 is —OH.
  • R 1 is -halo
  • R 4 is -halo
  • n or p is 1
  • R 2 is Q, wherein Q is
  • R 20 is —(C 1 -C 6 )alkyl and Z 1 is —CH 2 OH.
  • R 1 is -halo
  • R 4 is -halo
  • n or p is 1
  • R 2 is Q, wherein Q is
  • R 20 is —(C 3 -C 8 )cycloalkyl and Z 1 is —OR 7 .
  • R 1 is -halo
  • R 4 is -halo
  • n or p is 1
  • R 2 is Q, wherein Q is
  • R 20 is —(C 3 -C 8 )cycloalkyl and Z 1 is —CH 2 OR 7 .
  • R 1 is -halo
  • R 4 is -halo
  • n or p is 1
  • R 2 is Q, wherein Q is
  • R 20 is —(C 3 -C 8 )cycloalkyl and Z 1 is —OH.
  • R 1 is -halo
  • R 4 is -halo
  • n or p is 1
  • R 2 is Q, wherein Q is
  • R 20 is —(C 3 -C 8 )cycloalkyl and Z 1 is —CH 2 OH.
  • R 1 is —Cl
  • R 4 is —F
  • n or p is 1
  • R 2 is Q
  • Q is
  • R 20 is —(C 1 -C 6 )alkyl.
  • R 1 is —Cl
  • R 4 is —F
  • n or p is 1
  • R 2 is Q
  • Q is
  • R 20 is —(C 3 -C 8 )cycloalkyl.
  • R 1 is —Cl
  • R 4 is —F
  • n or p is 1
  • R 2 is Q
  • Q is
  • R 20 is —(C 1 -C 6 )alkyl and Z 1 is —OR 7 .
  • R 1 is —Cl
  • R 4 is —F
  • n or p is 1
  • R 2 is Q
  • Q is
  • R 20 is —(C 1 -C 6 )alkyl and Z 1 is —CH 2 OR 7 .
  • R 1 is —Cl
  • R 4 is —F
  • n or p is 1
  • R 2 is Q
  • Q is
  • R 20 is —(C 1 -C 6 )alkyl and Z 1 is —OH.
  • R 1 is —Cl
  • R 4 is —F
  • n or p is 1
  • R 2 is Q
  • Q is
  • R 20 is —(C 1 -C 6 )alkyl and Z 1 is —CH 2 OH.
  • R 1 is —Cl
  • R 4 is —F
  • n or p is 1
  • R 2 is Q
  • Q is
  • R 20 is —(C 3 -C 8 )cycloalkyl and Z 1 is —OR 7 .
  • R 1 is —Cl
  • R 4 is —F
  • n or p is 1
  • R 2 is Q
  • Q is
  • R 20 is —(C 3 -C 8 )cycloalkyl and Z 1 is —CH 2 OR 7 .
  • R 1 is —Cl
  • R 4 is —F
  • n or p is 1
  • R 2 is Q
  • Q is
  • R 20 is —(C 3 -C 8 )cycloalkyl and Z 1 is —OH.
  • R 1 is —Cl
  • R 4 is —F
  • n or p is 1
  • R 2 is Q
  • Q is
  • R 20 is —(C 3 -C 8 )cycloalkyl and Z 1 is —CH 2 OH.
  • Ar 1 is a pyridyl group, wherein n is 1, and R 2 is Q.
  • Ar 1 is a pyridyl group, wherein n is 1, R 2 is Q, and Q is
  • R 20 is —(C 1 -C 6 )alkyl.
  • Ar 1 is a pyridyl group, wherein n is 1, R 2 is Q, and Q is
  • R 20 is —(C 3 -C 8 )cycloalkyl.
  • Ar 1 is a pyridyl group, wherein n is 1, R 2 is Q, and Q is
  • R 20 is —(C 1 -C 6 )alkyl and Z 1 is —OR 7 .
  • Ar 1 is a pyridyl group, wherein n is 1, R 2 is Q, and Q is
  • R 20 is —(C 1 -C 6 )alkyl and Z 1 is —CH 2 OR 7 .
  • Ar 1 is a pyridyl group, wherein n is 1, R 2 is Q, and Q is
  • R 20 is —(C 1 -C 6 )alkyl and Z 1 is —OH.
  • Ar 1 is a pyridyl group, wherein n is 1, R 2 is Q, and Q is
  • R 20 is —(C 1 -C 6 )alkyl and Z 1 is —CH 2 OH.
  • Ar 1 is a pyridyl group, wherein n is 1, R 2 is Q, and Q is
  • R 20 is —(C 3 -C 8 )cycloalkyl and Z 1 is —OR 7 .
  • Ar 1 is a pyridyl group, wherein n is 1, R 2 is Q, and Q is
  • R 20 is —(C 3 -C 8 )cycloalkyl and Z 1 is —CH 2 OR 7 .
  • Ar 1 is a pyridyl group, wherein n is 1, R 2 is Q, and Q is
  • R 20 is —(C 3 -C 8 )cycloalkyl and Z 1 is —OH.
  • Ar 1 is a pyridyl group, wherein n is 1, R 2 is Q, and Q is
  • R 20 is —(C 3 -C 8 )cycloalkyl and Z 1 is —CH 2 OH.
  • R 1 is -halo
  • R 4 is -halo
  • Ar 1 is a pyridyl group, wherein n is 1, R 2 is Q, and Q is
  • R 20 is —(C 1 -C 6 )alkyl.
  • R 1 is -halo
  • R 4 is -halo
  • Ar 1 is a pyridyl group, wherein n is 1, R 2 is Q, and Q is
  • R 20 is —(C 3 -C 8 )cycloalkyl.
  • R 1 is -halo
  • R 4 is -halo
  • Ar 1 is a pyridyl group, wherein n is 1, R 2 is Q, and Q is
  • R 20 is —(C 1 -C 6 )alkyl and Z 1 is —OR 7 .
  • R 1 is -halo
  • R 4 is -halo
  • Ar 1 is a pyridyl group, wherein n is 1, R 2 is Q, and Q is
  • R 20 is —(C 1 -C 6 )alkyl and Z 1 is —CH 2 OR 7 .
  • R 1 is -halo
  • R 4 is -halo
  • Ar 1 is a pyridyl group, wherein n is 1, R 2 is Q, and Q is
  • R 20 is —(C 1 -C 6 )alkyl and Z 1 is —OH.
  • R 1 is -halo
  • R 4 is -halo
  • Ar 1 is a pyridyl group, wherein n is 1, R 2 is Q, and Q is
  • R 20 is —(C 1 -C 6 )alkyl and Z 1 is —CH 2 OH.
  • R 1 is -halo
  • R 4 is -halo
  • Ar 1 is a pyridyl group, wherein n is 1, R 2 is Q, and Q is
  • R 20 is —(C 3 -C 8 )cycloalkyl and Z 1 is —OR 7 .
  • R 1 is -halo
  • R 4 is -halo
  • Ar 1 is a pyridyl group, wherein n is 1, R 2 is Q, and Q is
  • R 20 is —(C 3 -C 8 )cycloalkyl and Z 1 is —CH 2 OR 7 .
  • R 1 is -halo
  • R 4 is -halo
  • Ar 1 is a pyridyl group, wherein n is 1, R 2 is Q, and Q is
  • R 20 is —(C 3 -C 8 )cycloalkyl and Z 1 is —OH.
  • R 1 is -halo
  • R 4 is -halo
  • Ar 1 is a pyridyl group, wherein n is 1, R 2 is Q, and Q is
  • R 20 is —(C 3 -C 8 )cycloalkyl and Z 1 is —CH 2 OH.
  • R 1 is -halo
  • R 4 is -halo
  • Ar 1 is a pyridyl group, wherein n is 1, R 2 is Q, and Q is
  • R 20 is —(C 1 -C 6 )alkyl and Ar 2 is benzothiazolyl, wherein at least one of R 8 or R 9 is not —H.
  • R 1 is -halo
  • R 4 is -halo
  • Ar 1 is a pyridyl group, wherein n is 1, R 2 is Q, and Q is
  • R 20 is —(C 3 -C 8 )cycloalkyl and Ar 2 is benzothiazolyl, wherein at least one of R 8 or R 9 is not —H.
  • R 1 is -halo
  • R 4 is -halo
  • Ar 1 is a pyridyl group, wherein n is 1, R 2 is Q, and Q is
  • R 20 is —(C 1 -C 6 )alkyl
  • Z 1 is —OR 7
  • Ar 2 is benzothiazolyl, wherein at least one of R 8 or R 9 is not —H.
  • R 1 is -halo
  • R 4 is -halo
  • Ar 1 is a pyridyl group, wherein n is 1, R 2 is Q, and Q is
  • R 20 is —(C 1 -C 6 )alkyl
  • Z 1 is —CH 2 OR 7
  • Ar 2 is benzothiazolyl, wherein at least one of R 8 or R 9 is not —H.
  • R 1 is -halo
  • R 4 is -halo
  • Ar 1 is a pyridyl group, wherein n is 1, R 2 is Q, and Q is
  • R 20 is —(C 1 -C 6 )alkyl, Z 1 is —OH and Ar 2 is benzothiazolyl, wherein at least one of R 8 or R 9 is not —H.
  • R 1 is -halo
  • R 4 is -halo
  • Ar 1 is a pyridyl group, wherein n is 1, R 2 is Q, and Q is
  • R 20 is —(C 1 -C 6 )alkyl
  • Z 1 is —CH 2 OH
  • Ar 2 is benzothiazolyl, wherein at least one of R 8 or R 9 is not —H.
  • R 1 is -halo
  • R 4 is -halo
  • Ar 1 is a pyridyl group, wherein n is 1, R 2 is Q, and Q is
  • R 20 is —(C 3 -C 8 )cycloalkyl
  • Z 1 is —OR 7
  • Ar 2 is benzothiazolyl, wherein at least one of R 8 or R 9 is not —H.
  • R 1 is -halo
  • R 4 is -halo
  • Ar 1 is a pyridyl group, wherein n is 1, R 2 is Q, and Q is
  • R 20 is —(C 3 -C 8 )cycloalkyl
  • Z 1 is —CH 2 OR 7
  • Ar 2 is benzothiazolyl, wherein at least one of R 8 or R 9 is not —H.
  • R 1 is -halo
  • R 4 is -halo
  • Ar 1 is a pyridyl group, wherein n is 1, R 2 is Q, and Q is
  • R 20 is —(C 3 -C 8 )cycloalkyl, Z 1 is —OH and Ar 2 is benzothiazolyl, wherein at least one of R 8 or R 9 is not —H.
  • R 1 is -halo
  • R 4 is -halo
  • Ar 1 is a pyridyl group, wherein n is 1, R 2 is Q, and Q is
  • R 20 is —(C 3 -C 8 )cycloalkyl
  • Z 1 is —CH 2 OH
  • Ar 2 is benzothiazolyl, wherein at least one of R 8 or R 9 is not —H.
  • R 1 is -halo
  • R 4 is -halo
  • Ar 1 is a pyridyl group, wherein n is 1, R 2 is Q, and Q is
  • R 20 is —(C 1 -C 6 )alkyl and Ar 2 is benzooxazolyl, wherein at least one of R 8 or R 9 is not —H.
  • R 1 is -halo
  • R 4 is -halo
  • Ar 1 is a pyridyl group, wherein n is 1, R 2 is Q, and Q is
  • R 20 is —(C 3 -C 8 )cycloalkyl and Ar 2 is benzooxazolyl, wherein at least one of R 8 or R 9 is not —H.
  • R 1 is -halo
  • R 4 is -halo
  • Ar 1 is a pyridyl group, wherein n is 1, R 2 is Q, and Q is
  • R 20 is —(C 1 -C 6 )alkyl
  • Z 1 is —OR 7
  • Ar 2 is benzooxazolyl, wherein at least one of R 8 or R 9 is not —H.
  • R 1 is -halo
  • R 4 is -halo
  • Ar 1 is a pyridyl group, wherein n is 1, R 2 is Q, and Q is
  • R 20 is —(C 1 -C 6 )alkyl
  • Z 1 is —CH 2 OR 7
  • Ar 2 is benzooxazolyl, wherein at least one of R 8 or R 9 is not —H.
  • R 1 is -halo
  • R 4 is -halo
  • Ar 1 is a pyridyl group, wherein n is 1, R 2 is Q, and Q is
  • R 20 is —(C 1 -C 6 )alkyl, Z 1 is —OH and Ar 2 is benzooxazolyl, wherein at least one of R 8 or R 9 is not —H.
  • R 1 is -halo
  • R 4 is -halo
  • Ar 1 is a pyridyl group, wherein n is 1, R 2 is Q, and Q is
  • R 20 is —(C 1 -C 6 )alkyl
  • Z 1 is —CH 2 OH
  • Ar 2 is benzooxazolyl, wherein at least one of R 8 or R 9 is not —H.
  • R 1 is -halo
  • R 4 is -halo
  • Ar 1 is a pyridyl group, wherein n is 1, R 2 is Q, and Q is
  • R 20 is —(C 3 -C 8 )cycloalkyl
  • Z 1 is —OR 7
  • Ar 2 is benzooxazolyl, wherein at least one of R 8 or R 9 is not —H.
  • R 1 is -halo
  • R 4 is -halo
  • Ar 1 is a pyridyl group, wherein n is 1, R 2 is Q, and Q is
  • R 20 is —(C 3 -C 8 )cycloalkyl
  • Z 1 is —CH 2 OR 7
  • Ar 2 is benzooxazolyl, wherein at least one of R 8 or R 9 is not —H.
  • R 1 is -halo
  • R 4 is -halo
  • Ar 1 is a pyridyl group, wherein n is 1, R 2 is Q, and Q is
  • R 20 is —(C 3 -C 8 )cycloalkyl, Z 1 is —OH and Ar 2 is benzooxazolyl, wherein at least one of R 8 or R 9 is not —H.
  • R 1 is -halo
  • R 4 is -halo
  • Ar 1 is a pyridyl group, wherein n is 1, R 2 is Q, and Q is
  • R 20 is —(C 3 -C 8 )cycloalkyl
  • Z 1 is —CH 2 OH
  • Ar 2 is benzooxazolyl, wherein at least one of R 8 or R 9 is not —H.
  • R 1 is -halo
  • R 4 is -halo
  • Ar 1 is a pyridyl group, wherein n is 1, R 2 is Q, and Q is
  • R 20 is —(C 1 -C 6 )alkyl and Ar 2 is benzoimidazolyl, wherein at least one of R 8 or R 9 is not —H.
  • R 1 is -halo
  • R 4 is -halo
  • Ar 1 is a pyridyl group, wherein n is 1, R 2 is Q, and Q is
  • R 20 is —(C 3 -C 8 )cycloalkyl and Ar 2 is benzoimidazolyl, wherein at least one of R 8 or R 9 is not —H.
  • R 1 is -halo
  • R 4 is -halo
  • Ar 1 is a pyridyl group, wherein n is 1, R 2 is Q, and Q is
  • R 20 is —(C 1 -C 6 )alkyl
  • Z 1 is —OR 7
  • Ar 2 is benzoimidazolyl, wherein at least one of R 8 or R 9 is not —H.
  • R 1 is -halo
  • R 4 is -halo
  • Ar 1 is a pyridyl group, wherein n is 1, R 2 is Q, and Q is
  • R 20 is —(C 1 -C 6 )alkyl
  • Z 1 is —CH 2 OR 7
  • Ar 2 is benzoimidazolyl, wherein at least one of R 8 or R 9 is not —H.
  • R 1 is -halo
  • R 4 is -halo
  • Ar 1 is a pyridyl group, wherein n is 1, R 2 is Q, and Q is
  • R 20 is —(C 1 -C 6 )alkyl, Z 1 is —OH and Ar 2 is benzoimidazolyl, wherein at least one of R 8 or R 9 is not —H.
  • R 1 is -halo
  • R 4 is -halo
  • Ar 1 is a pyridyl group, wherein n is 1, R 2 is Q, and Q is
  • R 20 is —(C 1 -C 6 )alkyl
  • Z 1 is —CH 2 OH
  • Ar 2 is benzoimidazolyl, wherein at least one of R 8 or R 9 is not —H.
  • R 1 is -halo
  • R 4 is -halo
  • Ar 1 is a pyridyl group, wherein n is 1, R 2 is Q, and Q is
  • R 20 is —(C 3 -C 8 )cycloalkyl
  • Z 1 is —OR 7
  • Ar 2 is benzoimidazolyl, wherein at least one of R 8 or R 9 is not —H.
  • R 1 is -halo
  • R 4 is -halo
  • Ar 1 is a pyridyl group, wherein n is 1, R 2 is Q, and Q is
  • R 20 is —(C 3 -C 8 )cycloalkyl
  • Z 1 is —CH 2 OR 7
  • Ar 2 is benzoimidazolyl, wherein at least one of R 8 or R 9 is not —H.
  • R 1 is -halo
  • R 4 is -halo
  • Ar 1 is a pyridyl group, wherein n is 1, R 2 is Q, and Q is
  • R 20 is —(C 3 -C 8 )cycloalkyl, Z 1 is —OH and Ar 2 is benzoimidazolyl, wherein at least one of R 8 or R 9 is not —H.
  • R 1 is -halo
  • R 4 is -halo
  • Ar 1 is a pyridyl group, wherein n is 1, R 2 is Q, and Q is
  • R 20 is —(C 3 -C 8 )cycloalkyl
  • Z 1 is —CH 2 OH
  • Ar 2 is benzoimidazolyl, wherein at least one of R 8 or R 9 is not —H.
  • R 1 is -halo
  • R 4 is -halo
  • Ar 1 is a pyridyl group, wherein n is 1, R 2 is Q, and Q is
  • R 20 is —(C 1 -C 6 )alkyl and Ar 2 is phenyl, wherein s is 0 or 1.
  • R 1 is -halo
  • R 4 is -halo
  • Ar 1 is a pyridyl group, wherein n is 1, R 2 is Q, and Q is
  • R 20 is —(C 3 -C 8 )cycloalkyl and Ar 2 is phenyl, wherein s is 0 or 1.
  • R 1 is -halo
  • R 4 is -halo
  • Ar 1 is a pyridyl group, wherein n is 1, R 2 is Q, and Q is
  • R 20 is —(C 1 -C 6 )alkyl
  • Z 1 is —OR 7
  • Ar 2 is phenyl, wherein s is 0 or 1.
  • R 1 is -halo
  • R 4 is -halo
  • Ar 1 is a pyridyl group, wherein n is 1, R 2 is Q, and Q is
  • R 20 is —(C 1 -C 6 )alkyl
  • Z 1 is —CH 2 OR 7
  • Ar 2 is phenyl, wherein s is 0 or 1.
  • R 1 is -halo
  • R 4 is -halo
  • Ar 1 is a pyridyl group, wherein n is 1, R 2 is Q, and Q is
  • R 20 is —(C 1 -C 6 )alkyl, Z 1 is —OH and Ar 2 is phenyl, wherein s is 0 or 1.
  • R 1 is -halo
  • R 4 is -halo
  • Ar 1 is a pyridyl group, wherein n is 1, R 2 is Q, and Q is
  • R 20 is —(C 1 -C 6 )alkyl
  • Z 1 is —CH 2 OH
  • Ar 2 is phenyl, wherein s is 0 or 1.
  • R 1 is -halo
  • R 4 is -halo
  • Ar 1 is a pyridyl group, wherein n is 1, R 2 is Q, and Q is
  • R 20 is —(C 3 -C 8 )cycloalkyl
  • Z 1 is —OR 7
  • Ar 2 is phenyl, wherein s is 0 or 1.
  • R 1 is -halo
  • R 4 is -halo
  • Ar 1 is a pyridyl group, wherein n is 1, R 2 is Q, and Q is
  • R 20 is —(C 3 -C 8 )cycloalkyl
  • Z 1 is —CH 2 OR 7
  • Ar 2 is phenyl, wherein s is 0 or 1.
  • R 1 is -halo
  • R 4 is -halo
  • Ar 1 is a pyridyl group, wherein n is 1, R 2 is Q, and Q is
  • R 20 is —(C 3 -C 8 )cycloalkyl
  • Z 1 is —OH
  • Ar 2 is phenyl, wherein s is 0 or 1.
  • R 1 is -halo
  • R 4 is -halo
  • Ar 1 is a pyridyl group, wherein n is 1, R 2 is Q, and Q is
  • R 20 is —(C 3 -C 8 )cycloalkyl
  • Z 1 is —CH 2 OH
  • Ar 2 is phenyl, wherein s is 0 or 1.
  • R 1 is -halo
  • R 4 is -halo
  • Ar 1 is a pyridyl group, wherein n is 1, R 2 is Q, and Q is
  • R 20 is —(C 1 -C 6 )alkyl and Ar 2 is phenyl, wherein s is 2.
  • R 1 is -halo
  • R 4 is -halo
  • Ar 1 is a pyridyl group, wherein n is 1, R 2 is Q, and Q is
  • R 20 is —(C 3 -C 8 )cycloalkyl and Ar 2 is phenyl, wherein s is 2.
  • R 1 is -halo
  • R 4 is -halo
  • Ar 1 is a pyridyl group, wherein n is 1, R 2 is Q, and Q is
  • R 20 is —(C 1 -C 6 )alkyl
  • Z 1 is —OR 7
  • Ar 2 is phenyl, wherein s is 2.
  • R 1 is -halo
  • R 4 is -halo
  • Ar 1 is a pyridyl group, wherein n is 1, R 2 is Q, and Q is
  • R 20 is —(C 1 -C 6 )alkyl
  • Z 1 is —CH 2 OR 7
  • Ar 2 is phenyl, wherein s is 2.
  • R 1 is -halo
  • R 4 is -halo
  • Ar 1 is a pyridyl group, wherein n is 1, R 2 is Q, and Q is
  • R 20 is —(C 1 -C 6 )alkyl, Z 1 is —OH and Ar 2 is phenyl, wherein s is 2.
  • R 1 is -halo
  • R 4 is -halo
  • Ar 1 is a pyridyl group, wherein n is 1, R 2 is Q, and Q is

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US12/110,155 Active 2029-05-26 US8476277B2 (en) 2007-04-27 2008-04-25 TRPV1 antagonists including dihydroxy substituent and uses thereof
US13/396,450 Active US8575199B2 (en) 2007-04-27 2012-02-14 Formula (IA″) compounds comprising (piperidin-4-yl)pyridine or (1,2,3,6-tetrahydropyridin-4-4yl) as TRPV1 antagonists
US13/852,913 Active US8889690B2 (en) 2007-04-27 2013-03-28 TRPV1 antagonists including dihydroxy substituent and uses thereof
US14/498,724 Active US9365563B2 (en) 2007-04-27 2014-09-26 TRPV1 antagonists including dihydroxy substituent and uses thereof
US15/179,612 Active US9878991B2 (en) 2007-04-27 2016-06-10 TRPV1 antagonists including dihydroxy substituent and uses thereof
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US13/396,450 Active US8575199B2 (en) 2007-04-27 2012-02-14 Formula (IA″) compounds comprising (piperidin-4-yl)pyridine or (1,2,3,6-tetrahydropyridin-4-4yl) as TRPV1 antagonists
US13/852,913 Active US8889690B2 (en) 2007-04-27 2013-03-28 TRPV1 antagonists including dihydroxy substituent and uses thereof
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Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20090170868A1 (en) * 2007-04-27 2009-07-02 Purdue Pharma L. P. Trpv1 antagonists including dihydroxy substituent and uses thereof
US20100120862A1 (en) * 2008-10-24 2010-05-13 Laykea Tafesse Monocyclic compounds and their use as trpv1 ligands
US20100130499A1 (en) * 2008-10-24 2010-05-27 Laykea Tafesse Bicycloheteroaryl compounds and their use as trpv1 ligands
US20100137306A1 (en) * 2008-10-24 2010-06-03 Laykea Tafesse Heterocyclic trpv1 receptor ligands
WO2012158844A1 (fr) 2011-05-17 2012-11-22 Shionogi & Co., Ltd. Composés hétérocycliques
WO2012176061A1 (fr) 2011-06-22 2012-12-27 Purdue Pharma L.P. Antagonistes de trpv1 comprenant un substituant dihydroxy et leurs utilisations
WO2013021276A1 (fr) 2011-08-10 2013-02-14 Purdue Pharma L.P. Antagonistes du trpv1 comprenant un substituant dihydroxy et leurs utilisations
US9017722B2 (en) 2001-01-29 2015-04-28 Intermune, Inc. Pharmaceutical composition containing as an active ingredient 5-methyl-1-phenyl-2-(1H)-pyridone
US10188637B2 (en) 2016-03-29 2019-01-29 Hoffmann-La Roche Inc. Granulate formulation of 5-methyl-1-phenyl-2-(1H)-pyridone and method of making the same

Families Citing this family (16)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP3309151A1 (fr) 2009-06-25 2018-04-18 Alkermes Pharma Ireland Limited Composés hétérocycliques pour le traitement de troubles neurologiques et psychologiques
WO2011140183A1 (fr) 2010-05-04 2011-11-10 Alkermes, Inc. Procédé de synthèse de lactames oxydés
EA201890869A3 (ru) 2010-06-03 2019-03-29 Фармасайкликс, Инк. Применение ингибиторов тирозинкиназы брутона (btk)
EP2585446A4 (fr) * 2010-06-22 2013-12-25 Shionogi & Co Composés présentant une activité antagoniste des trpv1 et leurs utilisations
JP5848761B2 (ja) 2010-06-24 2016-01-27 アルカーメス ファーマ アイルランド リミテッド Ｎｈ酸性化合物のプロドラッグ：エステル、カルボネート、カルバメートおよびホスホネートの誘導体
EP2654751B1 (fr) 2010-12-22 2016-11-23 Purdue Pharma L.P. Composés de pipéridine de type quinoxaline substitués par du phosphore et leurs utilisations
KR20130032846A (ko) * 2011-09-23 2013-04-02 주식회사유한양행 페닐이미드를 포함하는 벤조싸이아졸 유도체 또는 그의 염 및 이를 포함하는 약학 조성물
CA3015208C (fr) 2012-06-04 2024-01-02 Pharmacyclics Llc Formes cristallines d'un inhibiteur de tyrosine kinase de bruton
CN104704129A (zh) 2012-07-24 2015-06-10 药品循环公司 与对布鲁顿酪氨酸激酶(btk)抑制剂的抗性相关的突变
JP6249517B2 (ja) * 2012-11-08 2017-12-20 花王株式会社 体感温度低減用外用剤
EP2774919A1 (fr) * 2013-03-06 2014-09-10 Pharmeste S.R.L. In Liquidazione Nouveaux antagonistes des récepteurs TRPA1 de sulfonamide
EP3049082B1 (fr) 2013-09-24 2019-05-22 Purdue Pharma L.P. Traitement de la douleur occasionnée par des brûlures par des modulateurs de trpv1
JP6308881B2 (ja) * 2014-06-11 2018-04-11 保土谷化学工業株式会社 電荷制御剤およびそれを用いたトナー
KR20170122220A (ko) 2015-03-03 2017-11-03 파마싸이클릭스 엘엘씨 브루톤 타이로신 키나제 저해제의 약제학적 제제
CN113292485B (zh) * 2021-06-08 2023-10-27 河南大学 苄基哌嗪脲类trpv1拮抗和mor激动双靶点药物及制备方法和应用
WO2024095962A1 (fr) * 2022-10-31 2024-05-10 塩野義製薬株式会社 Utilisation d'un dérivé de pyridine qui est un antagoniste de trpv1

Citations (92)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3536809A (en) * 1969-02-17 1970-10-27 Alza Corp Medication method
US3598123A (en) * 1969-04-01 1971-08-10 Alza Corp Bandage for administering drugs
US3845770A (en) * 1972-06-05 1974-11-05 Alza Corp Osmatic dispensing device for releasing beneficial agent
US3916899A (en) * 1973-04-25 1975-11-04 Alza Corp Osmotic dispensing device with maximum and minimum sizes for the passageway
US4008719A (en) * 1976-02-02 1977-02-22 Alza Corporation Osmotic system having laminar arrangement for programming delivery of active agent
US4409229A (en) * 1977-12-02 1983-10-11 Hoechst-Roussel Pharmaceuticals, Inc. Antidepressive and tranquilizing substituted 1,3-dihydrospiro[benzo(c)thiophene]s
US4797419A (en) * 1986-11-03 1989-01-10 Warner-Lambert Company Method of treating the symptoms of senile cognitive decline employing di- or trisubstituted urea cholinergic agents
US5059595A (en) * 1989-03-22 1991-10-22 Bioresearch, S.P.A. Pharmaceutical compositions containing 5-methyltetrahydrofolic acid, 5-formyltetrahydrofolic acid and their pharmaceutically acceptable salts in controlled-release form active in the therapy of organic mental disturbances
US5073543A (en) * 1988-07-21 1991-12-17 G. D. Searle & Co. Controlled release formulations of trophic factors in ganglioside-lipsome vehicle
US5120548A (en) * 1989-11-07 1992-06-09 Merck & Co., Inc. Swelling modulated polymeric drug delivery device
US5138058A (en) * 1989-02-22 1992-08-11 Hoechst Aktiengesellschaft Piperazine substituted pyrimidine derivatives and physiologically tolerated salts thereof
US5354556A (en) * 1984-10-30 1994-10-11 Elan Corporation, Plc Controlled release powder and process for its preparation
US5442064A (en) * 1992-10-12 1995-08-15 Dr. Karl Thomae Gmbh Carboxylic acid derivatives, pharmaceutical compositions containing these compounds and processes for preparing them
US5529998A (en) * 1994-08-03 1996-06-25 Bayer Aktiengesellschaft Benzoxazolyl- and benzothiazolyloxazolidinones
US5591767A (en) * 1993-01-25 1997-01-07 Pharmetrix Corporation Liquid reservoir transdermal patch for the administration of ketorolac
US5639476A (en) * 1992-01-27 1997-06-17 Euro-Celtique, S.A. Controlled release formulations coated with aqueous dispersions of acrylic polymers
US5674533A (en) * 1994-07-07 1997-10-07 Recordati, S.A., Chemical And Pharmaceutical Company Pharmaceutical composition for the controlled release of moguisteine in a liquid suspension
US5698155A (en) * 1991-05-31 1997-12-16 Gs Technologies, Inc. Method for the manufacture of pharmaceutical cellulose capsules
US5728704A (en) * 1992-09-28 1998-03-17 Pfizer Inc. Substituted pyridmidines for control of diabetic complications
US5733566A (en) * 1990-05-15 1998-03-31 Alkermes Controlled Therapeutics Inc. Ii Controlled release of antiparasitic agents in animals
US5837716A (en) * 1995-11-13 1998-11-17 Albany Medical College Analgesic heterocyclic compounds
US5854245A (en) * 1996-06-28 1998-12-29 Merck & Co., Inc. Fibrinogen receptor antagonists
US5891889A (en) * 1996-04-03 1999-04-06 Merck & Co., Inc. Inhibitors of farnesyl-protein transferase
US5948786A (en) * 1996-04-12 1999-09-07 Sumitomo Pharmaceuticals Company, Limited Piperidinylpyrimidine derivatives
US5990107A (en) * 1996-06-28 1999-11-23 Merck & Co., Inc. Fibrinogen receptor antagonist prodrugs
US6051712A (en) * 1995-09-07 2000-04-18 Hoffmann-La Roche Inc. Piperidine derivatives having renin inhibiting activity
US6136839A (en) * 1995-06-12 2000-10-24 G. D. Searle & Co. Treatment of inflammation and inflammation-related disorders with a combination of a cyclooxygenase-2 inhibitor and a 5-lipoxygenase inhibitor
US6150129A (en) * 1996-08-01 2000-11-21 Isis Pharmaceuticals, Inc. Antimicrobial determination of N-(aminoalkyl) and/or N-(Amidoalkyl) dinitrogen heterocyclic compositions
US6239267B1 (en) * 1998-03-10 2001-05-29 Smithkline Beecham Plc VANILREP1 polynucleotides and VANILREP1 polypeptides
US6335180B1 (en) * 1997-08-20 2002-01-01 The Regents Of The University Of California Nucleic acid sequences encoding capsaicin receptor and uses thereof
US6406908B1 (en) * 1999-03-26 2002-06-18 Novartis Ag Vanilloid receptor
US6414149B1 (en) * 1999-04-01 2002-07-02 Pfizer Inc. Sorbitol dehydrogenase inhibitors
US6482479B1 (en) * 1999-07-28 2002-11-19 Clariant International Ltd. Active matrix displays having high contrast values
US6544998B2 (en) * 2000-11-30 2003-04-08 Pfizer Inc Combination of gaba agonists and sorbitol dehydrogenase inhibitors
US20030153568A1 (en) * 2000-02-07 2003-08-14 Basf Aktiengesellschaft Ludwigshafen, Germany Benzothiazole derivatives
US20030186994A1 (en) * 2000-10-18 2003-10-02 Mylari Banavara L. Combination of statins and sorbitol dehydrogenase inhibitors
US20030232996A1 (en) * 2001-04-20 2003-12-18 Brown David L Regioselective synthesis of 3,4-di{(carboclyl or heterocyclyl)thiophenes
US20040038982A1 (en) * 2001-07-13 2004-02-26 Bondinell William E. Compounds and methods
US6723730B2 (en) * 2000-07-20 2004-04-20 Neurogen Corporation Capsaicin receptor ligands
US20040102450A1 (en) * 1998-01-27 2004-05-27 Aventis Pharmaceuticals Inc. Substituted oxoazaheterocyclyl compounds
US20040152690A1 (en) * 2002-10-17 2004-08-05 Amgen Inc. Vanilloid receptor ligands and their use in treatments
US20040186111A1 (en) * 2002-12-24 2004-09-23 Qun Sun Therapeutic agents useful for treating pain
US20040259912A1 (en) * 2001-09-28 2004-12-23 Takahiro Matsumoto Benzine derivatives, process for preparing the same and use thereof
US20050009841A1 (en) * 2003-07-11 2005-01-13 Zheng Guo Zhu Novel amides useful for treating pain
US6887870B1 (en) * 1999-10-12 2005-05-03 Bristol-Myers Squibb Company Heterocyclic sodium/proton exchange inhibitors and method
US20050107384A1 (en) * 2002-03-13 2005-05-19 Angibaud Patrick R. New inhibitors of histone deacetylase
US20050119251A1 (en) * 2001-12-21 2005-06-02 Jian-Min Fu Nicotinamide derivatives and their use as therapeutic agents
US20050222410A1 (en) * 2002-04-27 2005-10-06 Stokes Elaine Sophie E Inhibitors of histone deacetylase
US6963000B2 (en) * 2000-06-21 2005-11-08 Hoffman-La Roche Inc. Benzothiazole derivatives with activity as adenosine receptor ligands
US6974818B2 (en) * 2002-03-01 2005-12-13 Euro-Celtique S.A. 1,2,5-thiadiazol-3-YL-piperazine therapeutic agents useful for treating pain
US20060009459A1 (en) * 2003-07-30 2006-01-12 Nagasree Chakka Pyridazine derivatives and their use as therapeutic agents
US20060116368A1 (en) * 2004-11-29 2006-06-01 Calvo Raul R 4-Piperidinecarboxamide modulators of vanilloid VR1 receptor
US7060331B2 (en) * 2000-07-13 2006-06-13 Merck Patent Gmbh Chiral compounds 1
US20060128717A1 (en) * 2003-07-24 2006-06-15 Qun Sun Therapeutic agents useful for treating pain
US7071335B2 (en) * 2002-02-01 2006-07-04 Euro-Celtique S.A. 2-pyridinyl-1-piperazine therapeutic agents useful for treating pain
US20060199824A1 (en) * 2003-07-24 2006-09-07 Qun Sun Therapeutic agents useful for treating pain
US20060199802A1 (en) * 2003-07-30 2006-09-07 Melwyn Abreo Pyridyl derivatives and their use as therapeutic agents
US20060223849A1 (en) * 2005-03-14 2006-10-05 Mjalli Adnan M Benzazole derivatives, compositions, and methods of use as beta-secretase inhibitors
US20060235004A1 (en) * 2003-03-13 2006-10-19 Abbot Gmbh & Co. Kg Pyrimidin-2-one compounds and their use as dopamine d3 receptor ligands
US7129235B2 (en) * 2003-07-11 2006-10-31 Abbott Laboratories Amides useful for treating pain
US20060293308A1 (en) * 2003-07-29 2006-12-28 Xenon Pharmaceuticals Inc. Pyridyl derivatives and their use as therapeutic agents
US7157462B2 (en) * 2002-09-24 2007-01-02 Euro-Celtique S.A. Therapeutic agents useful for treating pain
US7193113B2 (en) * 2000-12-15 2007-03-20 Japan Science And Technology Corporation Arylbis(perfluoroalkylsulfonyl) methane and metallic salt thereof, and methods for producing the same
US20070155707A1 (en) * 2005-12-29 2007-07-05 Kadmus Pharmaceuticals, Inc. Ionizable inhibitors of fatty acid amide hydrolase
US7262194B2 (en) * 2002-07-26 2007-08-28 Euro-Celtique S.A. Therapeutic agents useful for treating pain
US20070244088A1 (en) * 2004-06-28 2007-10-18 Astrazeneca Ab New Pyridine Analogues II
US7312246B2 (en) * 2001-05-08 2007-12-25 Yale University Proteomimetic compounds and methods
US20080015230A1 (en) * 2004-09-20 2008-01-17 Xenon Pharmaceuticals Inc. Heterocyclic derivatives and their use as therapeutic agents
US20080039629A1 (en) * 2003-10-17 2008-02-14 Rigel Pharmaceuticals, Inc. Benzothniazole compositions and their use as ubiquition ligation inhibitors
US7332495B2 (en) * 2002-05-22 2008-02-19 Nhwa Pharma. Corporation Aralkyl-ketone piperazine derivatives and their uses as new antalgic or ataractic agent
US7335658B2 (en) * 2003-07-30 2008-02-26 Xenon Pharmaceuticals Inc. Pyridazine derivatives and their use as therapeutic agents
US7343017B2 (en) * 1999-08-26 2008-03-11 American Technology Corporation System for playback of pre-encoded signals through a parametric loudspeaker system
US20080076924A1 (en) * 2006-06-30 2008-03-27 Patrick Betschmann Piperazines as P2X7 antagonists
US20080096895A1 (en) * 2004-09-20 2008-04-24 Xenon Pharmaceuticals Inc. Heterocyclic Derivatives and Their Use as Stearoyl-Coa Desaturase Inhibitors
US7390813B1 (en) * 2001-12-21 2008-06-24 Xenon Pharmaceuticals Inc. Pyridylpiperazines and aminonicotinamides and their use as therapeutic agents
US20080167321A1 (en) * 2004-09-20 2008-07-10 Xenon Pharmaceuticals Inc. Pyridine Derivatives For Inhibiting Human Stearoyl-Coa-Desaturase
US20080182851A1 (en) * 2006-11-20 2008-07-31 Glenmark Pharmaceuticals S.A. Acetylene derivatives as stearoyl coa desaturase inhibitors
US20080280916A1 (en) * 2003-07-30 2008-11-13 Xenon Pharmaceuticals Inc. Pyridazine derivatives and their use as therapeutic agents
US7456180B2 (en) * 2003-07-30 2008-11-25 Xenon Pharmaceuticals Inc. Piperazine derivatives and their use as therapeutic agents
US20080293733A1 (en) * 2007-04-13 2008-11-27 Supergen, Inc. Axl kinase inhibitors
US20090062345A1 (en) * 2007-08-09 2009-03-05 Abbott Laboratories Amide derivatives as trpv1 antagonists
US7514436B2 (en) * 2003-07-30 2009-04-07 Xenon Pharmaceuticals Inc. Pyridazine derivatives and their use as therapeutic agents
US20090093497A1 (en) * 2007-05-22 2009-04-09 David Robert Bolin Diacylglycerol Acyltransferase Inhibitors
US20090105271A1 (en) * 2007-09-19 2009-04-23 Esther Martinborough Pyridyl sulfonamides as modulators of ion channels
US7528134B2 (en) * 2002-05-23 2009-05-05 Abbott Laboratories Inc. Acetamides and benzamides that are useful in treating sexual dysfunction
US20090131447A1 (en) * 2005-02-09 2009-05-21 Xenon Pharmaceuticals Inc. Combination therapy
US7538121B2 (en) * 2002-02-15 2009-05-26 Glaxo Group Limited Vanilloid receptor modulators
US20090143302A1 (en) * 2005-06-14 2009-06-04 Taigen Biotechnology Co., Ltd. Pyrimidine compounds
US20090170867A1 (en) * 2007-04-27 2009-07-02 Shionogi & Co., Ltd. Trpv1 antagonists including sulfonamide substituent and uses thereof
US7592343B2 (en) * 2004-09-20 2009-09-22 Xenon Pharmaceuticals Inc. Pyridazine-piperazine compounds and their use as stearoyl-CoA desaturase inhibitors
US7632950B2 (en) * 2003-08-18 2009-12-15 Fujifilm Finechemicals Co., Ltd Pyridyltetrahydropyridines and pyridylpiperidines and method of manufacturing them
US20100022530A1 (en) * 2006-12-21 2010-01-28 Merck Patent Gmbh Tetrahydrobenzoisoxazole and tetrahydroindazole derivatives as modulators of the mitotic motor protein

Family Cites Families (57)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE3440141A1 (de) 1984-11-02 1986-05-07 Heiner Dipl.-Chem. Dr. 8000 München Eckert Verwendung von kohlensaeure-bis-trichlormethylester als proreagens fuer phosgen
JPH0680054B2 (ja) 1985-06-19 1994-10-12 吉富製薬株式会社 ピペリジン誘導体
JPS6289679U (fr) 1985-11-22 1987-06-08
US4866197A (en) 1987-12-23 1989-09-12 American Home Products Corporation Production of N-((2-alkoxy-6-methoxy-5-(trifluoromethyl)-1-naphthalenyl)carbonyl)-N-methylglycine esters
HU219974B (hu) 1990-06-07 2001-10-28 Astrazeneca Ab, Heterociklusos csoporttal helyettesített indolszármazék, előállítása és a vegyületet hatóanyagként tartalmazó gyógyszerkészítmények
JP3191429B2 (ja) 1992-09-02 2001-07-23 富士通テン株式会社 電子機器の挿排装置
DE4302051A1 (de) 1993-01-26 1994-07-28 Thomae Gmbh Dr K 5-gliedrige Heterocyclen, Verfahren zu ihrer Herstellung und diese Verbindungen enthaltende Arzneimittel
FR2744448B1 (fr) 1996-02-02 1998-04-24 Pf Medicament Nouvelles piperidines derivees d'aryl piperazine, ainsi que leur procede de preparation, les compositions pharmaceutiques et leur utilisation comme medicaments
WO1997038665A2 (fr) 1996-04-03 1997-10-23 Merck & Co., Inc. Inhibiteurs de la farnesyl-proteine transferase
FR2758327B1 (fr) 1997-01-15 1999-04-02 Pf Medicament Nouvelles arylpiperazines derivees de piperidine
FR2758328B1 (fr) 1997-01-15 1999-04-02 Pf Medicament Nouvelles amines aromatiques derivees d'amines cycliques utiles comme medicaments
JPH11199573A (ja) 1998-01-07 1999-07-27 Yamanouchi Pharmaceut Co Ltd ５ｈｔ３受容体作動薬及び新規ベンゾチアゾール誘導体
JP2002518386A (ja) 1998-06-19 2002-06-25 イーライ・リリー・アンド・カンパニー ヘテロアリール化合物の製造
AU4395399A (en) 1998-07-02 2000-01-24 Sankyo Company Limited Five-membered heteroaryl compounds
ATE384048T1 (de) 1998-09-22 2008-02-15 Astellas Pharma Inc Cyanophenyl-derivate
JP2002535256A (ja) 1999-01-25 2002-10-22 スミスクライン・ビーチャム・コーポレイション 化合物および方法
AU4797400A (en) 1999-05-17 2000-12-05 Eli Lilly And Company Metabotropic glutamate receptor antagonists
GB9912411D0 (en) 1999-05-28 1999-07-28 Pfizer Ltd Compounds useful in therapy
WO2001017965A2 (fr) 1999-09-07 2001-03-15 Syngenta Participations Ag Cyanopiperidines
WO2001081333A2 (fr) 2000-04-25 2001-11-01 Pharmacia Corporation Synthese stereoselective de 3,4-di(carbocyclyle ou heterocyclyle) thiophenes
AR028782A1 (es) * 2000-07-05 2003-05-21 Taisho Pharmaceutical Co Ltd Derivados heterociclicos tetrahidropiridino o piperidino
AU2002222644A1 (en) 2000-12-15 2002-06-24 Japan Science And Technology Corporation Arylbis (perfluoroalkylsulfonyl) methane, metal salt of the same, and processes for producing these
JP2003095951A (ja) 2001-09-25 2003-04-03 Sumitomo Pharmaceut Co Ltd 慢性関節リウマチ治療剤
JP2005516950A (ja) 2001-12-19 2005-06-09 メルク　エンド　カムパニー　インコーポレーテッド 代謝型グルタミン酸受容体−５のヘテロアリール置換イミダゾールモジュレータ
JP2003192673A (ja) 2001-12-27 2003-07-09 Bayer Ag ピペラジンカルボキシアミド誘導体
EP1522314B1 (fr) 2002-06-26 2014-03-05 Ono Pharmaceutical Co., Ltd. Remèdes pour les maladies provoquées par la contraction ou la dilatation vasculaire
JP4621502B2 (ja) * 2002-06-28 2011-01-26 ユーロ−セルティーク エス．エイ． 疼痛の治療に有用な治療剤
EP1388538B1 (fr) 2002-07-09 2010-09-01 Merck Patent GmbH Initiateur de polymérisation
AU2003256922A1 (en) 2002-07-31 2004-02-16 Smithkline Beecham Corporation Substituted heterocyclic compounds as modulators of the ccr5 receptor
BR0314761A (pt) 2002-09-27 2005-07-26 Sumitomo Pharma Composto de adenina e seu uso
US7223788B2 (en) * 2003-02-14 2007-05-29 Sanofi-Aventis Deutschland Gmbh Substituted N-aryl heterocycles, process for their preparation and their use as medicaments
WO2004103954A1 (fr) 2003-05-20 2004-12-02 Ajinomoto Co., Inc. Derive d'amide
MY142655A (en) * 2003-06-12 2010-12-15 Euro Celtique Sa Therapeutic agents useful for treating pain
EP1867644B1 (fr) 2003-07-24 2009-05-20 Euro-Celtique S.A. Composés de hétéroaryl-tétrahydropipéridyle utiles pour traiter ou prévenir la douleur
WO2005037284A1 (fr) 2003-10-15 2005-04-28 Pfizer Products Inc. Inhibiteur de la sorbitol-deshydrogenase et associations d'agents antihypertenseurs
GB0325287D0 (en) 2003-10-29 2003-12-03 Merck Sharp & Dohme Therapeutic agents
MY145822A (en) * 2004-08-13 2012-04-30 Neurogen Corp Substituted biaryl piperazinyl-pyridine analogues
DE102004039789A1 (de) 2004-08-16 2006-03-02 Sanofi-Aventis Deutschland Gmbh Arylsubstituierte polycyclische Amine, Verfahren zu ihrer Herstellung und ihre Verwendung als Arzneimittel
DE102005014904A1 (de) 2005-03-26 2007-02-01 Abbott Gmbh & Co. Kg Substituierte Oxindol-Derivate, diese enthaltende Arzneimittel und deren Verwendung
FR2884516B1 (fr) 2005-04-15 2007-06-22 Cerep Sa Antagonistes npy, preparation et utilisations
CA2621164A1 (fr) 2005-08-26 2007-03-01 Shionogi & Co., Ltd. Derive ayant une activite agoniste vis-a-vis du ppar
EP2407459A1 (fr) 2005-09-27 2012-01-18 Shionogi & Co., Ltd. Intermédiaire synthétique dans la production d'un dérivé sulfonamide ayant une activité antagoniste de récepteur PGD2
CA2637411A1 (fr) 2006-01-18 2007-07-26 Siena Biotech S.P.A. Modulateurs des recepteurs nicotiniques alpha7 de l'acetylcholine et leurs utilisations therapeutiques
SG171634A1 (en) 2006-02-28 2011-06-29 Helicon Therapeutics Inc Therapeutic piperazines as pde4 inhibitors
WO2007103719A2 (fr) 2006-03-03 2007-09-13 Incyte Corporation MODULATEURS DE LA 11-β-HYDROXYSTÉROÏDE DÉSHYDROGÉNASE DE TYPE 1, LEURS COMPOSITIONS PHARMACEUTIQUES ET LEURS PROCÉDÉS D'UTILISATION
WO2008013622A2 (fr) 2006-07-27 2008-01-31 E. I. Du Pont De Nemours And Company Amides azocycliques fongicides
AU2008246202B2 (en) * 2007-04-27 2011-12-01 Purdue Pharma L.P. Therapeutic agents useful for treating pain
WO2008147864A2 (fr) 2007-05-22 2008-12-04 Xenon Pharmaceuticals Inc. Procédés d'utilisaton de composés pipérazine dans le traitement de maladies ou états médiés par le canal sodium
EP2581081A3 (fr) 2007-06-01 2013-07-31 The Trustees Of Princeton University Traitement d'infections virales par modulation de voies métaboliques de cellules hôtes
US20110046142A1 (en) 2007-06-13 2011-02-24 Northeastern University Antibiotic compounds
US20100249144A1 (en) 2007-06-28 2010-09-30 Demong Duane Eugene Substituted piperazines as cb1 antagonists
AU2008272964A1 (en) 2007-06-29 2009-01-08 Emory University NMDA receptor antagonists for neuroprotection
US8138168B1 (en) 2007-09-26 2012-03-20 Takeda Pharmaceutical Company Limited Renin inhibitors
AU2008307572A1 (en) 2007-10-04 2009-04-09 Merck Sharp & Dohme Corp. Substituted aryl sulfone derivatives as calcium channel blockers
RU2010128543A (ru) 2007-12-11 2012-01-20 Сайтопатфайндер, Инк. (Jp) Карбоксамидные соединения и их применение в качестве агонистов хемокиновых рецепторов
JP2009249346A (ja) 2008-04-08 2009-10-29 Fujifilm Corp ピリジン骨格を有する血液脳関門透過性化合物
WO2010010458A1 (fr) 2008-07-21 2010-01-28 Purdue Pharma L.P. Composés pipéridine à liaison et substitués par une quinoxaline, et leurs utilisations

Patent Citations (97)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3536809A (en) * 1969-02-17 1970-10-27 Alza Corp Medication method
US3598123A (en) * 1969-04-01 1971-08-10 Alza Corp Bandage for administering drugs
US3845770A (en) * 1972-06-05 1974-11-05 Alza Corp Osmatic dispensing device for releasing beneficial agent
US3916899A (en) * 1973-04-25 1975-11-04 Alza Corp Osmotic dispensing device with maximum and minimum sizes for the passageway
US4008719A (en) * 1976-02-02 1977-02-22 Alza Corporation Osmotic system having laminar arrangement for programming delivery of active agent
US4409229A (en) * 1977-12-02 1983-10-11 Hoechst-Roussel Pharmaceuticals, Inc. Antidepressive and tranquilizing substituted 1,3-dihydrospiro[benzo(c)thiophene]s
US5354556A (en) * 1984-10-30 1994-10-11 Elan Corporation, Plc Controlled release powder and process for its preparation
US4797419A (en) * 1986-11-03 1989-01-10 Warner-Lambert Company Method of treating the symptoms of senile cognitive decline employing di- or trisubstituted urea cholinergic agents
US5073543A (en) * 1988-07-21 1991-12-17 G. D. Searle & Co. Controlled release formulations of trophic factors in ganglioside-lipsome vehicle
US5138058A (en) * 1989-02-22 1992-08-11 Hoechst Aktiengesellschaft Piperazine substituted pyrimidine derivatives and physiologically tolerated salts thereof
US5059595A (en) * 1989-03-22 1991-10-22 Bioresearch, S.P.A. Pharmaceutical compositions containing 5-methyltetrahydrofolic acid, 5-formyltetrahydrofolic acid and their pharmaceutically acceptable salts in controlled-release form active in the therapy of organic mental disturbances
US5120548A (en) * 1989-11-07 1992-06-09 Merck & Co., Inc. Swelling modulated polymeric drug delivery device
US5733566A (en) * 1990-05-15 1998-03-31 Alkermes Controlled Therapeutics Inc. Ii Controlled release of antiparasitic agents in animals
US5698155A (en) * 1991-05-31 1997-12-16 Gs Technologies, Inc. Method for the manufacture of pharmaceutical cellulose capsules
US5639476A (en) * 1992-01-27 1997-06-17 Euro-Celtique, S.A. Controlled release formulations coated with aqueous dispersions of acrylic polymers
US5728704A (en) * 1992-09-28 1998-03-17 Pfizer Inc. Substituted pyridmidines for control of diabetic complications
US5442064A (en) * 1992-10-12 1995-08-15 Dr. Karl Thomae Gmbh Carboxylic acid derivatives, pharmaceutical compositions containing these compounds and processes for preparing them
US5591767A (en) * 1993-01-25 1997-01-07 Pharmetrix Corporation Liquid reservoir transdermal patch for the administration of ketorolac
US5674533A (en) * 1994-07-07 1997-10-07 Recordati, S.A., Chemical And Pharmaceutical Company Pharmaceutical composition for the controlled release of moguisteine in a liquid suspension
US5529998A (en) * 1994-08-03 1996-06-25 Bayer Aktiengesellschaft Benzoxazolyl- and benzothiazolyloxazolidinones
US6136839A (en) * 1995-06-12 2000-10-24 G. D. Searle & Co. Treatment of inflammation and inflammation-related disorders with a combination of a cyclooxygenase-2 inhibitor and a 5-lipoxygenase inhibitor
US6051712A (en) * 1995-09-07 2000-04-18 Hoffmann-La Roche Inc. Piperidine derivatives having renin inhibiting activity
US5837716A (en) * 1995-11-13 1998-11-17 Albany Medical College Analgesic heterocyclic compounds
US5891889A (en) * 1996-04-03 1999-04-06 Merck & Co., Inc. Inhibitors of farnesyl-protein transferase
US6248756B1 (en) * 1996-04-03 2001-06-19 Merck & Co., Inc. Inhibitors of farnesyl-protein transferase
US5948786A (en) * 1996-04-12 1999-09-07 Sumitomo Pharmaceuticals Company, Limited Piperidinylpyrimidine derivatives
US5990107A (en) * 1996-06-28 1999-11-23 Merck & Co., Inc. Fibrinogen receptor antagonist prodrugs
US5854245A (en) * 1996-06-28 1998-12-29 Merck & Co., Inc. Fibrinogen receptor antagonists
US6150129A (en) * 1996-08-01 2000-11-21 Isis Pharmaceuticals, Inc. Antimicrobial determination of N-(aminoalkyl) and/or N-(Amidoalkyl) dinitrogen heterocyclic compositions
US6335180B1 (en) * 1997-08-20 2002-01-01 The Regents Of The University Of California Nucleic acid sequences encoding capsaicin receptor and uses thereof
US20040102450A1 (en) * 1998-01-27 2004-05-27 Aventis Pharmaceuticals Inc. Substituted oxoazaheterocyclyl compounds
US6239267B1 (en) * 1998-03-10 2001-05-29 Smithkline Beecham Plc VANILREP1 polynucleotides and VANILREP1 polypeptides
US6406908B1 (en) * 1999-03-26 2002-06-18 Novartis Ag Vanilloid receptor
US6414149B1 (en) * 1999-04-01 2002-07-02 Pfizer Inc. Sorbitol dehydrogenase inhibitors
US6602875B2 (en) * 1999-04-01 2003-08-05 Pfizer Inc Sorbitol dehydrogenase inhibitors
US6482479B1 (en) * 1999-07-28 2002-11-19 Clariant International Ltd. Active matrix displays having high contrast values
US7343017B2 (en) * 1999-08-26 2008-03-11 American Technology Corporation System for playback of pre-encoded signals through a parametric loudspeaker system
US6887870B1 (en) * 1999-10-12 2005-05-03 Bristol-Myers Squibb Company Heterocyclic sodium/proton exchange inhibitors and method
US20030153568A1 (en) * 2000-02-07 2003-08-14 Basf Aktiengesellschaft Ludwigshafen, Germany Benzothiazole derivatives
US6963000B2 (en) * 2000-06-21 2005-11-08 Hoffman-La Roche Inc. Benzothiazole derivatives with activity as adenosine receptor ligands
US7060331B2 (en) * 2000-07-13 2006-06-13 Merck Patent Gmbh Chiral compounds 1
US6723730B2 (en) * 2000-07-20 2004-04-20 Neurogen Corporation Capsaicin receptor ligands
US20030186994A1 (en) * 2000-10-18 2003-10-02 Mylari Banavara L. Combination of statins and sorbitol dehydrogenase inhibitors
US6544998B2 (en) * 2000-11-30 2003-04-08 Pfizer Inc Combination of gaba agonists and sorbitol dehydrogenase inhibitors
US7193113B2 (en) * 2000-12-15 2007-03-20 Japan Science And Technology Corporation Arylbis(perfluoroalkylsulfonyl) methane and metallic salt thereof, and methods for producing the same
US20030232996A1 (en) * 2001-04-20 2003-12-18 Brown David L Regioselective synthesis of 3,4-di{(carboclyl or heterocyclyl)thiophenes
US7312246B2 (en) * 2001-05-08 2007-12-25 Yale University Proteomimetic compounds and methods
US20040038982A1 (en) * 2001-07-13 2004-02-26 Bondinell William E. Compounds and methods
US20040259912A1 (en) * 2001-09-28 2004-12-23 Takahiro Matsumoto Benzine derivatives, process for preparing the same and use thereof
US7390813B1 (en) * 2001-12-21 2008-06-24 Xenon Pharmaceuticals Inc. Pyridylpiperazines and aminonicotinamides and their use as therapeutic agents
US20050119251A1 (en) * 2001-12-21 2005-06-02 Jian-Min Fu Nicotinamide derivatives and their use as therapeutic agents
US7071335B2 (en) * 2002-02-01 2006-07-04 Euro-Celtique S.A. 2-pyridinyl-1-piperazine therapeutic agents useful for treating pain
US7256193B2 (en) * 2002-02-01 2007-08-14 Euro-Celtique S.A. Therapeutic agents useful for treating pain
US7538121B2 (en) * 2002-02-15 2009-05-26 Glaxo Group Limited Vanilloid receptor modulators
US6974818B2 (en) * 2002-03-01 2005-12-13 Euro-Celtique S.A. 1,2,5-thiadiazol-3-YL-piperazine therapeutic agents useful for treating pain
US20050107384A1 (en) * 2002-03-13 2005-05-19 Angibaud Patrick R. New inhibitors of histone deacetylase
US20050222410A1 (en) * 2002-04-27 2005-10-06 Stokes Elaine Sophie E Inhibitors of histone deacetylase
US7332495B2 (en) * 2002-05-22 2008-02-19 Nhwa Pharma. Corporation Aralkyl-ketone piperazine derivatives and their uses as new antalgic or ataractic agent
US7528134B2 (en) * 2002-05-23 2009-05-05 Abbott Laboratories Inc. Acetamides and benzamides that are useful in treating sexual dysfunction
US7262194B2 (en) * 2002-07-26 2007-08-28 Euro-Celtique S.A. Therapeutic agents useful for treating pain
US20080200472A1 (en) * 2002-07-26 2008-08-21 Euro-Celtique S.A. Therapeutic agents useful for treating pain
US7157462B2 (en) * 2002-09-24 2007-01-02 Euro-Celtique S.A. Therapeutic agents useful for treating pain
US20040152690A1 (en) * 2002-10-17 2004-08-05 Amgen Inc. Vanilloid receptor ligands and their use in treatments
US20040186111A1 (en) * 2002-12-24 2004-09-23 Qun Sun Therapeutic agents useful for treating pain
US20060235004A1 (en) * 2003-03-13 2006-10-19 Abbot Gmbh & Co. Kg Pyrimidin-2-one compounds and their use as dopamine d3 receptor ligands
US7129235B2 (en) * 2003-07-11 2006-10-31 Abbott Laboratories Amides useful for treating pain
US20050009841A1 (en) * 2003-07-11 2005-01-13 Zheng Guo Zhu Novel amides useful for treating pain
US20060128717A1 (en) * 2003-07-24 2006-06-15 Qun Sun Therapeutic agents useful for treating pain
US20060199824A1 (en) * 2003-07-24 2006-09-07 Qun Sun Therapeutic agents useful for treating pain
US20060293308A1 (en) * 2003-07-29 2006-12-28 Xenon Pharmaceuticals Inc. Pyridyl derivatives and their use as therapeutic agents
US20060009459A1 (en) * 2003-07-30 2006-01-12 Nagasree Chakka Pyridazine derivatives and their use as therapeutic agents
US7514436B2 (en) * 2003-07-30 2009-04-07 Xenon Pharmaceuticals Inc. Pyridazine derivatives and their use as therapeutic agents
US7335658B2 (en) * 2003-07-30 2008-02-26 Xenon Pharmaceuticals Inc. Pyridazine derivatives and their use as therapeutic agents
US7456180B2 (en) * 2003-07-30 2008-11-25 Xenon Pharmaceuticals Inc. Piperazine derivatives and their use as therapeutic agents
US20060199802A1 (en) * 2003-07-30 2006-09-07 Melwyn Abreo Pyridyl derivatives and their use as therapeutic agents
US20080280916A1 (en) * 2003-07-30 2008-11-13 Xenon Pharmaceuticals Inc. Pyridazine derivatives and their use as therapeutic agents
US7632950B2 (en) * 2003-08-18 2009-12-15 Fujifilm Finechemicals Co., Ltd Pyridyltetrahydropyridines and pyridylpiperidines and method of manufacturing them
US20080039629A1 (en) * 2003-10-17 2008-02-14 Rigel Pharmaceuticals, Inc. Benzothniazole compositions and their use as ubiquition ligation inhibitors
US20070244088A1 (en) * 2004-06-28 2007-10-18 Astrazeneca Ab New Pyridine Analogues II
US20080096895A1 (en) * 2004-09-20 2008-04-24 Xenon Pharmaceuticals Inc. Heterocyclic Derivatives and Their Use as Stearoyl-Coa Desaturase Inhibitors
US20080167321A1 (en) * 2004-09-20 2008-07-10 Xenon Pharmaceuticals Inc. Pyridine Derivatives For Inhibiting Human Stearoyl-Coa-Desaturase
US20080015230A1 (en) * 2004-09-20 2008-01-17 Xenon Pharmaceuticals Inc. Heterocyclic derivatives and their use as therapeutic agents
US7592343B2 (en) * 2004-09-20 2009-09-22 Xenon Pharmaceuticals Inc. Pyridazine-piperazine compounds and their use as stearoyl-CoA desaturase inhibitors
US20060116368A1 (en) * 2004-11-29 2006-06-01 Calvo Raul R 4-Piperidinecarboxamide modulators of vanilloid VR1 receptor
US20090131447A1 (en) * 2005-02-09 2009-05-21 Xenon Pharmaceuticals Inc. Combination therapy
US20060223849A1 (en) * 2005-03-14 2006-10-05 Mjalli Adnan M Benzazole derivatives, compositions, and methods of use as beta-secretase inhibitors
US20090143302A1 (en) * 2005-06-14 2009-06-04 Taigen Biotechnology Co., Ltd. Pyrimidine compounds
US20070155707A1 (en) * 2005-12-29 2007-07-05 Kadmus Pharmaceuticals, Inc. Ionizable inhibitors of fatty acid amide hydrolase
US20080076924A1 (en) * 2006-06-30 2008-03-27 Patrick Betschmann Piperazines as P2X7 antagonists
US20080182851A1 (en) * 2006-11-20 2008-07-31 Glenmark Pharmaceuticals S.A. Acetylene derivatives as stearoyl coa desaturase inhibitors
US20100022530A1 (en) * 2006-12-21 2010-01-28 Merck Patent Gmbh Tetrahydrobenzoisoxazole and tetrahydroindazole derivatives as modulators of the mitotic motor protein
US20080293733A1 (en) * 2007-04-13 2008-11-27 Supergen, Inc. Axl kinase inhibitors
US20090170867A1 (en) * 2007-04-27 2009-07-02 Shionogi & Co., Ltd. Trpv1 antagonists including sulfonamide substituent and uses thereof
US20090170868A1 (en) * 2007-04-27 2009-07-02 Purdue Pharma L. P. Trpv1 antagonists including dihydroxy substituent and uses thereof
US20090093497A1 (en) * 2007-05-22 2009-04-09 David Robert Bolin Diacylglycerol Acyltransferase Inhibitors
US20090062345A1 (en) * 2007-08-09 2009-03-05 Abbott Laboratories Amide derivatives as trpv1 antagonists
US20090105271A1 (en) * 2007-09-19 2009-04-23 Esther Martinborough Pyridyl sulfonamides as modulators of ion channels

Cited By (25)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9561217B2 (en) 2001-01-29 2017-02-07 Intermune, Inc. Pharmaceutical composition containing as an active ingredient 5-methyl-1-phenyl-2-(1H)-pyridone
US9017722B2 (en) 2001-01-29 2015-04-28 Intermune, Inc. Pharmaceutical composition containing as an active ingredient 5-methyl-1-phenyl-2-(1H)-pyridone
US9365563B2 (en) 2007-04-27 2016-06-14 Purdue Pharma L.P. TRPV1 antagonists including dihydroxy substituent and uses thereof
US20090170868A1 (en) * 2007-04-27 2009-07-02 Purdue Pharma L. P. Trpv1 antagonists including dihydroxy substituent and uses thereof
US8889690B2 (en) 2007-04-27 2014-11-18 Purdue Pharma L.P. TRPV1 antagonists including dihydroxy substituent and uses thereof
US10584110B2 (en) 2007-04-27 2020-03-10 Purdue Pharma L.P. TRPV1 antagonists including dihydroxy substituent and uses thereof
US9878991B2 (en) 2007-04-27 2018-01-30 Purdue Pharma L.P. TRPV1 antagonists including dihydroxy substituent and uses thereof
US8476277B2 (en) 2007-04-27 2013-07-02 Purdue Pharma L.P. TRPV1 antagonists including dihydroxy substituent and uses thereof
US8546388B2 (en) 2008-10-24 2013-10-01 Purdue Pharma L.P. Heterocyclic TRPV1 receptor ligands
US8703962B2 (en) 2008-10-24 2014-04-22 Purdue Pharma L.P. Monocyclic compounds and their use as TRPV1 ligands
US8759362B2 (en) 2008-10-24 2014-06-24 Purdue Pharma L.P. Bicycloheteroaryl compounds and their use as TRPV1 ligands
US20100137306A1 (en) * 2008-10-24 2010-06-03 Laykea Tafesse Heterocyclic trpv1 receptor ligands
US20100130499A1 (en) * 2008-10-24 2010-05-27 Laykea Tafesse Bicycloheteroaryl compounds and their use as trpv1 ligands
US20100120862A1 (en) * 2008-10-24 2010-05-13 Laykea Tafesse Monocyclic compounds and their use as trpv1 ligands
WO2012158844A1 (fr) 2011-05-17 2012-11-22 Shionogi & Co., Ltd. Composés hétérocycliques
US9156830B2 (en) 2011-05-17 2015-10-13 Shionogi & Co., Ltd. Heterocyclic compounds
US9630959B2 (en) 2011-06-22 2017-04-25 Purdue Pharma L.P. TRPV1 antagonists including dihydroxy substituent and uses thereof
US9273043B2 (en) 2011-06-22 2016-03-01 Purdue Pharma L.P. TRPV1 antagonists including dihydroxy substituent and uses thereof
EP3173411A1 (fr) 2011-06-22 2017-05-31 Purdue Pharma L.P. Antagonistes de trpv1 comprenant un substituant dihydroxy et leurs utilisations
US10450308B2 (en) 2011-06-22 2019-10-22 Purdue Pharma L.P. TRPV1 antagonists including dihydroxy substituent and uses thereof
WO2012176061A1 (fr) 2011-06-22 2012-12-27 Purdue Pharma L.P. Antagonistes de trpv1 comprenant un substituant dihydroxy et leurs utilisations
US9394293B2 (en) 2011-08-10 2016-07-19 Purdue Pharma L.P. TRPV1 antagonists including dihydroxy substituent and uses thereof
US9873691B2 (en) 2011-08-10 2018-01-23 Purdue Pharma L.P. TRPV1 antagonists including dihydroxy substituent and uses thereof
WO2013021276A1 (fr) 2011-08-10 2013-02-14 Purdue Pharma L.P. Antagonistes du trpv1 comprenant un substituant dihydroxy et leurs utilisations
US10188637B2 (en) 2016-03-29 2019-01-29 Hoffmann-La Roche Inc. Granulate formulation of 5-methyl-1-phenyl-2-(1H)-pyridone and method of making the same

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