US20090170867A1 - Trpv1 antagonists including sulfonamide substituent and uses thereof - Google Patents

Trpv1 antagonists including sulfonamide substituent and uses thereof Download PDF

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US20090170867A1
US20090170867A1 US12/110,089 US11008908A US2009170867A1 US 20090170867 A1 US20090170867 A1 US 20090170867A1 US 11008908 A US11008908 A US 11008908A US 2009170867 A1 US2009170867 A1 US 2009170867A1
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Noriyuki Kurose
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Shionogi and Co Ltd
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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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    • 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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    • C07D213/60—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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    • C07D401/02—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
    • C07D401/12—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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    • C07—ORGANIC CHEMISTRY
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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 , 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:
  • R 20 is —H, —(C 1 -C 6 )alkyl, or —(C 3 -C 8 )cycloalkyl;
  • each Z 3 is independently —H or —CH 3 ;
  • 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 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 .
  • 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 , 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 , 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 , 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 , 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;
  • 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 Z1 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 IA′ 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 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 —(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
  • R 20 is —(C 1 -C 6 )alkyl
  • Z 1 is —CH 2 OH
  • 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
  • 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 3 -C 8 )cycloalkyl
  • 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 3 -C 8 )cycloalkyl, 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
  • R 20 is —(C 3 -C 8 )cycloalkyl
  • Z 1 is —CH 2 OH
  • Ar 2 is phenyl, wherein s is 2.
  • the dashed line is a double bond, n or p is 1, R 2 is Q, wherein Q is
  • R 20 is —(C 1 -C 6 )alkyl.
  • the dashed line is a double bond, n or p is 1, R 2 is Q, wherein Q is
  • R 20 is —(C 3 -C 8 )cycloalkyl.
  • the dashed line is a double bond, 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 .
  • the dashed line is a double bond, 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 .
  • the dashed line is a double bond, 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.
  • the dashed line is a double bond, 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.
  • the dashed line is a double bond, 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 .
  • the dashed line is a double bond, 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 .
  • the dashed line is a double bond, 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.
  • the dashed line is a double bond, 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.
  • the dashed line is a double bond
  • R 1 is -halo
  • n or p is 1
  • R 2 is Q
  • Q is
  • R 20 is —(C 1 -C 6 )alkyl.
  • the dashed line is a double bond
  • R 1 is -halo
  • n or p is 1
  • R 2 is Q
  • Q is
  • R 20 is —(C 3 -C 8 )cycloalkyl.
  • the dashed line is a double bond
  • R 1 is -halo
  • 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 .
  • the dashed line is a double bond
  • R 1 is -halo
  • 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 .
  • the dashed line is a double bond
  • R 1 is -halo
  • n or p is 1
  • R 2 is Q
  • Q is
  • R 20 is —(C 1 -C 6 )alkyl and Z 1 is —OH.
  • the dashed line is a double bond
  • R 1 is -halo
  • 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.
  • the dashed line is a double bond
  • R 1 is -halo
  • 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 .
  • the dashed line is a double bond
  • R 1 is -halo
  • 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 .
  • the dashed line is a double bond
  • R 1 is -halo
  • n or p is 1
  • R 2 is Q
  • Q is
  • R 20 is —(C 3 -C 8 )cycloalkyl and Z 1 is —OH.
  • the dashed line is a double bond
  • R 1 is -halo
  • 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.
  • the dashed line is a double bond
  • R 1 is -halo
  • Ar 1 is a pyridyl group
  • n is 1
  • R 2 is Q, wherein Q is
  • R 20 is —(C 1 -C 6 )alkyl.
  • the dashed line is a double bond
  • R 1 is -halo
  • Ar 1 is a pyridyl group
  • n is 1
  • R 2 is Q, wherein Q is
  • R 20 is —(C 3 -C 8 )cycloalkyl.
  • the dashed line is a double bond
  • R 1 is -halo
  • Ar 1 is a pyridyl group
  • n is 1
  • R 2 is Q, wherein Q is
  • R 20 is —(C 1 -C 6 )alkyl and Z 1 is —OR 7 .
  • the dashed line is a double bond
  • R 1 is -halo
  • Ar 1 is a pyridyl group
  • n 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 .
  • the dashed line is a double bond
  • R 1 is -halo
  • Ar 1 is a pyridyl group
  • n is 1
  • R 2 is Q, wherein Q is
  • R 20 is —(C 1 -C 6 )alkyl and Z 1 is —OH.
  • the dashed line is a double bond
  • R 1 is -halo
  • Ar 1 is a pyridyl group
  • n is 1
  • R 2 is Q, wherein Q is
  • R 20 is —(C 1 -C 6 )alkyl and Z 1 is —CH 2 OH.
  • the dashed line is a double bond
  • R 1 is -halo
  • Ar 1 is a pyridyl group
  • n is 1
  • R 2 is Q, wherein Q is
  • R 20 is —(C 3 -C 8 )cycloalkyl and Z 1 is —OR 7 .
  • the dashed line is a double bond
  • R 1 is -halo
  • Ar 1 is a pyridyl group
  • n 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 .
  • the dashed line is a double bond
  • R 1 is -halo
  • Ar 1 is a pyridyl group
  • n is 1
  • R 2 is Q, wherein Q is
  • R 20 is —(C 3 -C 8 )cycloalkyl and Z 1 is —OH.
  • the dashed line is a double bond
  • R 1 is -halo
  • Ar 1 is a pyridyl group
  • n is 1
  • R 2 is Q, wherein Q is
  • R 20 is —(C 3 -C 8 )cycloalkyl and Z 1 is —CH 2 OH.
  • the dashed line is a double bond
  • R 1 is -halo
  • Ar 1 is a pyridyl group
  • n is 1
  • R 2 is Q, wherein 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 a —H.
  • the dashed line is a double bond
  • R 1 is -halo
  • Ar 1 is a pyridyl group
  • n is 1
  • R 2 is Q, wherein 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 a —H.
  • the dashed line is a double bond
  • R 1 is -halo
  • Ar 1 is a pyridyl group
  • n is 1
  • R 2 is Q, wherein 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 a —H.
  • the dashed line is a double bond
  • R 1 is -halo
  • Ar 1 is a pyridyl group
  • n is 1
  • R 2 is Q, wherein 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 a —H.
  • the dashed line is a double bond
  • R 1 is -halo
  • Ar 1 is a pyridyl group
  • n is 1
  • R 2 is Q, wherein 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 a —H.
  • the dashed line is a double bond
  • R 1 is -halo
  • Ar 1 is a pyridyl group
  • n is 1
  • R 2 is Q, wherein 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 a —H.
  • the dashed line is a double bond
  • R 1 is -halo
  • Ar 1 is a pyridyl group
  • n is 1
  • R 2 is Q, wherein 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 a —H.
  • the dashed line is a double bond
  • R 1 is -halo
  • Ar 1 is a pyridyl group
  • n is 1
  • R 2 is Q, wherein Q is

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US12/110,212 Abandoned US20090176796A1 (en) 2007-04-27 2008-04-25 Trpv1 antagonists including amide 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
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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
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JP6249517B2 (ja) * 2012-11-08 2017-12-20 花王株式会社 体感温度低減用外用剤
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
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