WO2002062761A1 - Aminal diones as potassium channel openers - Google Patents

Aminal diones as potassium channel openers Download PDF

Info

Publication number
WO2002062761A1
WO2002062761A1 PCT/US2002/002949 US0202949W WO02062761A1 WO 2002062761 A1 WO2002062761 A1 WO 2002062761A1 US 0202949 W US0202949 W US 0202949W WO 02062761 A1 WO02062761 A1 WO 02062761A1
Authority
WO
WIPO (PCT)
Prior art keywords
amino
dioxo
cyclobuten
pyridinylamino
hydrogen
Prior art date
Application number
PCT/US2002/002949
Other languages
English (en)
French (fr)
Inventor
Michael E. Kort
William A. Carroll
Arturo Perez Medrano
Jurgen Dinges
Robert J. Gregg
Fatima Z. Basha
Original Assignee
Abbott Laboratories
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from US09/778,684 external-priority patent/US20020147230A1/en
Priority claimed from US10/046,465 external-priority patent/US6495576B2/en
Application filed by Abbott Laboratories filed Critical Abbott Laboratories
Priority to JP2002562717A priority Critical patent/JP2004530650A/ja
Priority to MXPA03007071A priority patent/MXPA03007071A/es
Priority to CA002437400A priority patent/CA2437400A1/en
Priority to EP02704321A priority patent/EP1358160A1/en
Publication of WO2002062761A1 publication Critical patent/WO2002062761A1/en

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—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
    • 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
    • C07D213/72—Nitrogen atoms
    • C07D213/74—Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/02—Drugs for disorders of the urinary system of urine or of the urinary tract, e.g. urine acidifiers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/10—Drugs for disorders of the urinary system of the bladder
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/14—Drugs for dermatological disorders for baldness or alopecia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • 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
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/06—Antimigraine agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/08—Antiepileptics; Anticonvulsants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C233/00—Carboxylic acid amides
    • C07C233/64—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings
    • C07C233/77—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by amino groups
    • C07C233/78—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by amino groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—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
    • 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
    • C07D213/72—Nitrogen atoms
    • C07D213/75—Amino or imino radicals, acylated by carboxylic or carbonic acids, or by sulfur or nitrogen analogues thereof, e.g. carbamates
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—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
    • 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
    • C07D213/72—Nitrogen atoms
    • C07D213/76—Nitrogen atoms to which a second hetero atom is attached
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—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
    • 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
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/81—Amides; Imides
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—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
    • 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
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/81—Amides; Imides
    • C07D213/82—Amides; Imides in position 3
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
    • C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
    • C07D241/10—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
    • C07D241/14—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D241/20—Nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/04—Systems containing only non-condensed rings with a four-membered ring

Definitions

  • TECHNICAL FIELD Novel aminal dione compounds and their derivatives can open potassium channels and are useful for treating a variety of medical conditions.
  • Potassium channels play an important role in regulating cell membrane excitability. When the potassium channels open, changes in the electrical potential across the cell membrane occur and result in a more polarized state. A number of diseases or conditions may be treated with therapeutic agents that open potassium channels; see for example (Lawson, Pharmacol. Ther., v. 70, pp. 39-63 (1996)); (Gehlert et al., Prog. Neuro-Psychopharmacol & Biol. Psychiat, v. 18, pp. 1093-1102 (1994)); (Gopalakrishnan et al., Drug Development Research, v. 28, pp. 95-127 (1993)); (Freedman et al., The Neuroscientist, v. 2, pp.
  • Such diseases or conditions include asthma, epilepsy, male sexual dysfunction, female sexual dysfunction, pain, bladder overactivity, stroke, diseases associated with decreased skeletal blood flow such as Raynaud's phenomenon and intermittent claudication, eating disorders, functional bowel disorders, neurodegeneration, benign prostatic hyperplasia (BPH), dysmenorrhea, premature labor, alopecia, cardioprotection, coronary artery disease, angina and ischemia.
  • diseases or conditions include asthma, epilepsy, male sexual dysfunction, female sexual dysfunction, pain, bladder overactivity, stroke, diseases associated with decreased skeletal blood flow such as Raynaud's phenomenon and intermittent claudication, eating disorders, functional bowel disorders, neurodegeneration, benign prostatic hyperplasia (BPH), dysmenorrhea, premature labor, alopecia, cardioprotection, coronary artery disease, angina and ischemia.
  • BPH benign prostatic hyperplasia
  • dysmenorrhea premature labor
  • alopecia cardioprotection
  • coronary artery disease an
  • Bladder overactivity is a condition associated with the spontaneous, uncontrolled contractions ofthe bladder smooth muscle. Bladder overactivity thus is associated with sensations of urgency, urinary incontinence, pollakiuria, bladder instability, nocturia, bladder hyerreflexia, and enuresis (Resnick, The Lancet (1995) 346, 94-99; Hampel, Urology (1997) 50 (Suppl 6A), 4-14; Bosch, BJU International (1999) 83 (Suppl 2), 7-9). Potassium channel openers (KCOs) act as smooth muscle relaxants.
  • KCOs Potassium channel openers
  • bladder overactivity and urinary incontinence can result from the spontaneous, uncontrolled contractions ofthe smooth muscle ofthe bladder
  • the ability of potassium channel openers to hyperpolarize bladder cells and relax bladder smooth muscle may provide a method to ameliorate or prevent bladder overactivity, pollakiuria, bladder instability, nocturia, bladder hyperreflexia, urinary incontinence, and enuresis (Andersson, Urology (1997) 50 (Suppl 6A), 74-84; Lawson, Pharmacol. Ther., (1996) 70, 39-63; Nurse., Br. J. Urol., (1991) 68, 27-31; Howe, J. Pharmacol. Exp. Ther., (1995) 274, 884-890; Gopalakrishnan, Drug Development Research, (1993) 28, 95-127).
  • the excitability of corpus cavernosum smooth muscle cells is important in the male erectile process.
  • the relaxation of corporal smooth muscle cells allows arterial blood to build up under pressure in the erectile tissue ofthe penis leading to erection (Andersson, Pharmacological Reviews (1993) 45, 253).
  • Potassium channels play a significant role in modulating human corporal smooth muscle tone, and thus, erectile capacity.
  • patch clamp technique potassium channels have been characterized in human corporal smooth muscle cells (Lee, Int. J. hnpot. Res. (1999) 11(4), 179-188).
  • Potassium channel openers are smooth muscle relaxants and have been shown to relax corpus cavernosal smooth muscle and induce erections (Andersson, Pharmacological Reviews (1993) 45, 253; Lawson, Pharmacol. Ther., (1996) 70, 39-63, Nick, J. Urol. (2000) 163: 202). Potassium channel openers therefore may have utility in the treatment of male sexual dysfunctions such as male erectile dysfunction, impotence and premature ejaculation.
  • KCOs may be effective for the treatment of female sexual dysfunction including clitoral erectile insufficiency, vaginismus and vaginal engorgement (Goldstein and Berman., Int. J. Impotence Res.
  • Potassium channel openers may have utility as tocolytic agents to inhibit uterine contractions to delay or prevent premature parturition in individuals or to slow or arrest delivery for brief periods to undertake other therapeutic measures (Sanborn, Semin. Perinatol.
  • Potassium channel openers also inhibit contractile responses of human uterus and intrauterine vasculature. This combined effect would suggest the potential use of KCOs for dysmenhorrea (Kostrzewska, Acta Obstet. Gynecol. Scand. (1996) 75(10), 886-91). Potassium channel openers relax uterine smooth muscle and intrauterine vasculature and therefore may have utility in the treatment of premature labor and dysmenorrhoea (Lawson, Pharmacol. Ther.,
  • Potassium channel openers relax gastrointestinal smooth tissues and therefore may be useful in the treatment of functional bowel disorders such as irritable bowel syndrome (Lawson, Pharmacol. Ther., (1996) 70, 39-63).
  • Potassium channel openers relax airway smooth muscle and induce bronchodilation. Therefore potassium channel openers may be useful in the treatment of asthma and airways hyperreactivity (Lawson, Pharmacol. Ther., (1996) 70, 39-63; Buchheit, Pulmonary Pharmacology & Therapeutics (1999) 12, 103; Gopalakrishnan, Drug Development Research, (1993) 28, 95-127).
  • Neuronal hyperpolarization can produce analgesic effects.
  • the opening of potassium channels by potassium channel openers and resultant hyperpolarization in the membrane of target neurons is a key mechanism in the effect of opioids.
  • the peripheral antinociceptive effect of mo hine results from activation of ATP-sensitive potassium channels, which causes hyperpolarization of peripheral terminals of primary afferents, leading to a decrease in action potential generation (Rodrigues, Br. J. Pharmacol. (2000) 129(1), 110-4). Opening of K A ⁇ p channels by potassium channel openers plays an important role in the antinociception mediated by alpha-2 adrenoceptors and mu opioid receptors.
  • KCOs can potentiate the analgesic action of both morphine and dexmedetomidine via an activation of K A ⁇ p channels at the spinal cord level (Vergoni, Life Sci. (1992) 50(16), PL135-8; Asano, Anesth. Analg. (2000) 90(5), 1146-51).
  • potassium channel openers can hyperpolarize neuronal cells and have shown analgesic effects. Potassium channel openers therefore may be useful as analgesics in the treatment of various pain states including but not limited to migraine and dyspareunia (Lawson, Pharmacol. Ther., (1996) 70, 39-63; Gopalakrishnan, Drug Development Research, (1993) 28, 95-127; Gehlert, Prog. Neuro-Psychopharmacol. & Biol. Psychiat., (1994) 18, 1093-1102).
  • Epilepsy results from the propagation of nonphysiologic electrical impulses. Potassium channel openers hyperpolarize neuronal cells and lead to a decrease in cellular excitability and have demonstrated antiepileptic effects. Therefore potassium channel openers may be useful in the treatment of epilepsy (Lawson, Pharmacol. Ther., (1996) 70, 39-63; Gopalakrishnan, Drug Development Research, (1993) 28, 95-127; Gehlert, Prog. Neuro- Psychopharmacol. & Biol. Psychiat., (1994) 18, 1093-1102).
  • Potassium channel openers can hyperpolarize neuronal cells and lead to a decrease in cellular excitability. Activation of potassium channels has been shown to enhance neuronal survival. Therefore potassium channel openers may have utility as neuroprotectants in the treatment of neurodegenerative conditions and diseases such as cerebral ischemia, stroke, Alzheimer's disease and Parkinson's disease (Lawson, Pharmacol. Ther., (1996) 70, 39-63; Gopalakrishnan, Drug Development Research, (1993) 28, 95-127; Gehlert, Prog. Neuro- Psychopharmacol & Biol. Psychiat., (1994) 18, 1093-1102; Freedman, The Neuroscientist (1996) 2, 145).
  • Potassium channel openers may have utility in the treatment of diseases or conditions associated with decreased skeletal muscle blood flow such as Raynaud's syndrome and intermittent claudication (Lawson, Pharmacol. Ther., (1996) 70, 39-63; Gopalakrishnan, Drug Development Research, (1993) 28, 95-127; Dompeling Vasa. Supplementum (1992) 3434; and WO9932495).
  • Potassium channel openers may be useful in the treatment of eating disorders such as obesity (Spanswick, Nature, (1997) 390, 521-25; Freedman, The Neuroscientist (1996) 2, 145).
  • Potassium channel openers have been shown to promote hair growth therefore potassium channel openers have utility in the treatment of hair loss and baldness also known as alopecia (Lawson, Pharmacol. Ther., (1996) 70, 39-63; Gopalakrishnan, Drug Development Research, (1993) 28, 95-127). Potassium channel openers possess cardioprotective effects against myocardial injury during ischemia and reperfusion. (Garlid, Circ. Res. (1997) 81(6), 1072-82). Therefore, potassium channel openers may be useful in the treatment of heart diseases (Lawson, Pharmacol. Ther., (1996) 70, 39-63; Grover, J. Mol. Cell Cardiol. (2000) 32, 677).
  • Potassium channel openers by hyperpolarization of smooth muscle membranes, can exert vasodilation ofthe collateral circulation ofthe coronary vasculature leading to increase blood flow to ischemic areas and could be useful for the coronary artery disease (Lawson, Pharmacol. Ther., (1996) 70, 39-63; Gopalakrishnan, Drug Development Research, (1993) 28, 95-127).
  • US 3,636,105 discloses a group of l-fluoroacetylamino-2,2,2-trichloroethyl urea rodenticide agents.
  • US 4,146,646 discloses a group of bis-amides as fungicide agents.
  • ZA 695324 discloses a group of thioureas useful as insecticide, acaricidal, and rodenticide agents.
  • US 5,397,790 discloses a group of substituted isoquinolinyl-l,2-diaminocyclobutene-3,4- diones as smooth muscle relaxants.
  • US 5,401,753 and US 5,403,854 disclose groups of substituted N-heteroaryl-l,2-diaminocyclobutene-3,4-diones as smooth muscle relaxants.
  • US 5,403,853, US 5,466,712, and WO 98/33763 disclose groups of substituted N-aryl-1,2- diaminocyclobutene-3,4-diones.
  • US 5,464,867 and US 5,512,585 disclose groups of substituted N-heteroaryl-N'-alkyl-l,2-diaminocyclobutene-3,4-diones as smooth muscle relaxants.
  • US 5,506,252 and WO 96/15103 disclose groups of substituted N-aryl- and N- heteroaryl-l,2-diaminocyclobutene-3,4-diones as smooth muscle relaxants.
  • US 5,750,574 discloses a group of substituted fluorinated N-arylmefhylamino derivatives of cyclobutene- 3,4-dione as agents for reducing the adverse effects of smooth muscle contractions.
  • US 5,763,474, US 5,780,505, US 5,846,999, and WO 98/02413 disclose groups of substituted N- arylmethylamino derivatives of cyclobutene-3,4-diones as smooth muscle relaxants.
  • US 5,872,139 and WO 97/48682 disclose groups of N-heterocyclylmethylamino derivatives of cyclobutene-3,4-dione as agents for reducing the adverse effects of smooth muscle contractions.
  • US 6,166,050 discloses a group of amino(heterocyclylanilino)-3-cyclobutene- 1,2-diones as inhibitors of leukocyte adhesion mediated by NLA-4.
  • WO 94/29277 discloses a group of 3, 4-diaminocyclobutene- 1,2-diones as inhibitors of cGMP phosphodiesterase.
  • WO 00/51973 and WO 00/63160 discloses groups of substituted ⁇ -(cyclohexylmethyl)amino-3- cyclobutene- 1,2-diones as inhibitors phosphodiesterase V.
  • WO 00/73260 discloses a group of 3, 4-diamino-3-cyclobutene- 1,2-diones as inhibitors of leukocyte adhesion mediated by VLA- 4.
  • Compounds ofthe present invention are novel, hyperpolarize cell membranes, open potassium channels, relax smooth muscle cells, inhibit bladder contractions and may be useful for treating diseases that can be ameliorated by opening potassium channels.
  • X is selected from the group consisting of CH , O and N(Z);
  • Z is selected from the group consisting of hydrogen and alkyl
  • Ri is selected from aryl, arylalkyl, heterocycle and heterocyclealkyl
  • R , R 3 and R 4 are independently selected from hydrogen and alkyl
  • R 5 is selected from aryl, arylalkenyl, arylalkyl, aryloxyalkyl, heterocycle and heterocyclealkyl;
  • R 6 is selected from hydrogen, alkenyl, alkenyloxyalkyl, alkenyloxy(alkenyloxy)alkyl, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkoxycarbonyl(halo)alkyl, alkoxy(halo)alkyl, alkyl, alkylcarbonyl, alkylcarbonylalkyl, alkylcarbonyl(halo)alkyl, alkylcarbonyloxyalkyl, alkylsulfinylalkyl, alkylsulfonylalkyl, alkylthioalkyl, alkynyl, aryl, arylalkoxyalkyl, arylalkoxycarbonyl, arylalkoxycarbonylalkyl, arylalkyl, arylcarbonyl, arylcarbonylalkyl, arylcarbonyloxyalkyl, aryl(halo)alky
  • R 7 is selected from hydrogen, haloalkyl, and lower alkyl; or
  • R ⁇ and R 7 taken together with the carbon atom to which they are attached, together form a 5 or 6 membered carbocyclic ring wherein the 5 or 6 membered carbocyclic ring is optionally substituted with 1 or 2 substituents independently selected from alkenyl, alkoxy, alkyl, alkynyl, halogen, haloalkoxy, and haloalkyl;
  • R 9 and Rio are independently selected from hydrogen, alkoxysulfonyl, alkyl, alkylcarbonyl, alkylsulfonyl, aryl, arylalkyl, arylcarbonyl, arylsulfonyl and formyl.
  • X is selected from the group consisting of CH 2 , O and N(Z);
  • Z is selected from the group consisting of hydrogen and alkyl
  • Ri is selected from aryl, arylalkyl, heterocycle and heterocyclealkyl
  • R 2 , R 3 and R 4 are independently selected from hydrogen and alkyl
  • R 5 is selected from aryl, arylalkyl, aryloxyalkyl, heterocycle and heterocyclealkyl;
  • R is selected from hydrogen, alkenyl, alkenyloxyalkyl, alkenyloxy(alkenyloxy)alkyl, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkoxycarbonyl(halo)alkyl, alkoxy(halo)alkyl, alkyl, alkylcarbonyl, alkylcarbonylalkyl, alkylcarbonyl(halo)alkyl, alkylcarbonyloxyalkyl, alkylsulfmylalkyl, alkylsulfonylalkyl, alkylthioalkyl, alkynyl, aryl, arylalkoxyalkyl, arylalkoxycarbonyl, arylalkoxycarbonylalkyl, arylalkyl, arylcarbonyl, arylcarbonylalkyl, arylcarbonyloxyalkyl, aryl(halo)alkyl,
  • R 7 is selected from hydrogen, haloalkyl, and lower alkyl; or
  • Re and R 7 taken together with the carbon atom to which they are attached, together form a 5 or 6 membered carbocyclic ring wherein the 5 or 6 membered carbocyclic ring is optionally substituted with 1 or 2 substituents independently selected from alkenyl, alkoxy, alkyl, alkynyl, halogen, haloalkoxy, and haloalkyl;
  • R 9 and Rio are independently selected from hydrogen, alkoxysulfonyl, alkyl, alkylcarbonyl, alkylsulfonyl, aryl, arylalkyl, arylcarbonyl, arylsulfonyl and formyl.
  • compounds have formula (I) wherein A is selected from
  • Ri , R 2 , R 3 , R , R 5 , R ⁇ and R 7 are as defined in formula (I).
  • compounds have formula (II) wherein Ri is heterocycle; R 5 is aryl; and R 2 , R 3 , t , e and R 7 are as defined in formula (I).
  • compounds have formula (II) wherein Ri is heterocycle wherein said heterocycle is selected from optionally substituted pyridinyl and optionally substituted pyrazinyl; R 5 is aryl wherein said aryl is optionally substituted phenyl; and R 2 , R 3 , R t , Rs and R 7 are as defined in formula (I).
  • compounds have formula (II) wherein Ri is heterocycle wherein said heterocycle is selected from optionally substituted pyridinyl and optionally substituted pyrazinyl; R 2 is hydrogen; R 3 is hydrogen; R 4 is hydrogen; R 5 is aryl wherein said aryl is optionally substituted phenyl; R 6 is selected from hydrogen and alkyl; and R is hydrogen.
  • compounds have formula (II) wherein Ri is heterocycle wherein said heterocycle is optionally substituted pyridinyl; R 2 is hydrogen; R 3 is hydrogen; ⁇ is hydrogen; R 5 is aryl wherein said aryl is optionally substituted phenyl; Re is selected from arylalkyl and heterocyclealkyl wherein the aryl portion of said arylalkyl is optionally substituted phenyl and the heterocycle portion of said heterocyclealkyl is optionally substituted pyridinyl; and R 7 is hydrogen.
  • compounds have formula (II) wherein Ri is heterocycle wherein said heterocycle is optionally substituted pyridinyl; R 2 is hydrogen; R 3 is hydrogen; R is hydrogen; R 5 is aryl wherein said aryl is optionally substituted phenyl; R 6 is haloalkyl; and R 7 is hydrogen.
  • compounds have formula (II) wherein Ri is heterocycle wherein said heterocycle is optionally substituted pyridinyl; R is hydrogen; R 3 is hydrogen; R is hydrogen; R 5 is aryl wherein said aryl is optionally substituted phenyl; R 6 is selected from alkenyl, alkenyloxy(alkenyloxy)alkyl, cyanoalkyl and cycloalkylalkyl; and R 7 is hydrogen.
  • compounds have formula (II) wherein Ri is heterocycle wherein heterocycle is optionally substituted pyridinyl; R 5 is aryl wherein aryl is selected from optionally substituted naphthyl and optionally substituted fluorenyl; and R 2 , R 3 , R t , Re and R 7 are as defined in formula (I).
  • compounds have formula (II) wherein Ri is heterocycle wherein heterocycle is optionally substituted pyridinyl; R 2 is hydrogen; R 3 is hydrogen; t is hydrogen; R 5 is aryl wherein aryl is selected from optionally substituted naphthyl and optionally substituted fluorenyl; R 6 is selected from alkenyl, alkenyloxy(alkenyloxy)alkyl, arylalkyl wherein the aryl portion of said arylalkyl is optionally substituted phenyl, cyanoalkyl, cycloalkylalkyl and haloalkyl; and R is hydrogen.
  • compounds have formula (II) wherein Ri is heterocycle wherein said heterocycle is optionally substituted pyridinyl; R is hydrogen; R 3 is hydrogen; R t is hydrogen; R 5 is aryl wherein aryl is selected from optionally substituted naphthyl and optionally substituted fluorenyl 1; Re is alkyl; and R 7 is hydrogen.
  • compounds have formula (II) wherein Ri is aryl; R 5 is aryl; and R 2 , R 3 , R , R ⁇ and R 7 are as defined in formula (I).
  • compounds have formula (II) wherein Ri is aryl wherein said aryl is optionally substituted phenyl; R 5 is aryl wherein said aryl is optionally substituted phenyl; and R 2 , R 3 , t , R 6 and R are as defined in formula (I).
  • compounds have formula (II) wherein Ri is aryl wherein said aryl is optionally substituted phenyl; R is hydrogen; R 3 is hydrogen; R is hydrogen; R 5 is aryl wherein said aryl is optionally substituted phenyl; R 6 is selected from alkenyl, alkenyloxy(alkenyloxy)alkyl, alkyl, arylalkyl wherein the aryl portion of said arylalkyl is optionally substituted phenyl, cyanoalkyl, cycloalkylalkyl and haloalkyl; and R is hydrogen.
  • compounds have formula (II) wherein Ri is aryl wherein said aryl is optionally substituted phenyl; R 2 is hydrogen; R 3 is hydrogen; R t is hydrogen; R 5 is aryl wherein said aryl is optionally substituted phenyl; Re is alkyl; and R 7 is hydrogen.
  • compounds have formula (II) wherein Ri is heterocycle; R 5 is arylalkyl; and R , R 3 , R 4 , R 6 and R 7 are as defined in formula (I).
  • compounds have formula (II) wherein Ri is heterocycle wherein said heterocycle is optionally substituted pyridinyl; R 5 is selected from arylalkyl, arylalkenyl and aryloxyalkyl wherein the aryl portion of said arylalkyl, arylalkenyl, and aryloxyalkyl is optionally substituted phenyl; and R 2 , R 3 , t, R and R 7 are as defined in formula (I).
  • compounds have formula (II) wherein Ri is heterocycle wherein said heterocycle is optionally substituted pyridinyl; R 2 is hydrogen; R 3 is hydrogen; R t is hydrogen; R 5 is selected from arylalkyl, arylalkenyl and aryloxyalkyl wherein the aryl portion of said arylalkyl is optionally substituted phenyl, the aryl portion of said arylalkenyl is optionally substituted phenyl and the aryl portion of said aryloxyalkyl is optionally substituted phenyl; Re is selected from alkenyl, alkenyloxy(alkenyloxy)alkyl, arylalkyl wherein the aryl portion of said arylalkyl is optionally substituted phenyl, cyanoalkyl, cycloalkylalkyl and haloalkyl; and R 7 is hydrogen.
  • compounds have formula (II) wherein Ri is heterocycle wherein said heterocycle is optionally substituted pyridinyl; R 2 is hydrogen; R 3 is hydrogen; t is hydrogen; R is selected from arylalkyl, arylalkenyl and aryloxyalkyl wherein the aryl portion of said arylalkyl is optionally substituted phenyl, the aryl portion of said arylalkenyl is optionally substituted phenyl and the aryl portion of said aryloxyalkyl is optionally substituted phenyl; Re is selected from alkyl and arylalkyl wherein the aryl portion of said arylalkyl is optionally substituted phenyl; and R 7 is hydrogen.
  • compounds have formula (II) wherein Ri is heterocycle; R 5 is heterocyclealkyl; and R 2 , R 3 , R 4 , Re and R 7 are as defined in formula
  • Ri is heterocycle wherein said heterocycle is optionally substituted pyridinyl
  • R 5 is heterocyclealkyl wherein the heterocycle portion of said heterocyclealkyl is optionally substituted pyridinyl
  • R 2 , R3, Rt, Re and R 7 are as defined in formula (I).
  • compounds have formula (II) wherein Ri is heterocycle wherein said heterocycle is optionally substituted pyridinyl; R 2 is hydrogen; R 3 is hydrogen; R t is hydrogen; R 5 is heterocyclealkyl wherein the heterocycle portion of said heterocyclealkyl is optionally substituted pyridinyl; Re is selected from alkenyl, alkenyloxy(alkenyloxy)alkyl, arylalkyl wherein the aryl portion of said arylalkyl is optionally substituted phenyl, cyanoalkyl, cycloalkylalkyl and haloalkyl; and R 7 is hydrogen.
  • compounds have formula (II) wherein Ri is heterocycle wherein said heterocycle is optionally substituted pyridinyl; R 2 is hydrogen; R 3 is hydrogen; R 4 is hydrogen; R 5 is heterocyclealkyl wherein the heterocycle portion of said heterocyclealkyl is optionally substituted pyridinyl; R 6 is alkyl; and R 7 is hydrogen.
  • compounds have formula (II) wherein Ri is heterocycle; R 5 is heterocycle; and R 2 , R 3 , R t , R and R 7 are as defined in formula (I).
  • compounds have formula (II) wherein Ri is heterocycle wherein said heterocycle is optionally substituted pyridinyl; R is heterocycle wherein said heterocycle is selected from optionally substituted pyridinyl, optionally substituted thienyl and optionally substituted furyl; and R 2 , R 3 , R 4 , Re and R 7 are as defined in formula (I).
  • compounds have formula (II) wherein Ri is heterocycle wherein said heterocycle is optionally substituted pyridinyl; R 2 is hydrogen; R 3 is hydrogen; R 4 is hydrogen; R 5 is heterocycle wherein said heterocycle is selected from optionally substituted pyridinyl, optionally substituted thienyl and optionally substituted furyl; Re is selected from alkenyl, alkenyloxy(alkenyloxy)alkyl, arylalkyl wherein the aryl portion of said arylalkyl is optionally substituted phenyl, cyanoalkyl, cycloalkylalkyl and haloalkyl; and R 7 is hydrogen.
  • compounds have formula (II) wherein Ri is heterocycle wherein said heterocycle is optionally substituted pyridinyl; R is hydrogen; R 3 is hydrogen; R 4 is hydrogen; R 5 is heterocycle wherein said heterocycle is selected from optionally substituted pyridinyl, optionally substituted thienyl and optionally substituted furyl; Re is alkyl; and R 7 is hydrogen.
  • compounds have formula (III) wherein
  • compounds have formula (III) wherein R] is heterocycle; R 5 is aryl; and R 2 , R 3 , Rt, R 5 and R 7 are as defined in formula (I).
  • compounds have formula (III) wherein Ri is heterocycle wherein said heterocycle is optionally substituted pyridinyl; R 5 is aryl wherein said aryl is optionally substituted phenyl; and R , R3, R 4 , R 6 and R 7 are as defined in formula (I).
  • compounds have formula (III) wherein Ri is heterocycle wherein said heterocycle is optionally substituted pyridinyl; R 2 is hydrogen; R 3 is hydrogen; R is hydrogen; R 5 is aryl wherein said aryl is optionally substituted phenyl; R 6 is selected from alkenyl, alkenyloxy(alkenyloxy)alkyl, arylalkyl wherein the aryl portion of said arylalkyl is optionally substituted phenyl, cyanoalkyl, cycloalkylalkyl and haloalkyl; and R 7 is hydrogen.
  • compounds have formula (III) wherein Ri is heterocycle wherein said heterocycle is optionally substituted pyridinyl; R 2 is hydrogen; R 3 is hydrogen; R is hydrogen; R 5 is aryl wherein said aryl is optionally substituted phenyl; Re is alkyl; and R 7 is hydrogen.
  • compounds have formula (IV) wherein Ri is heterocycle; R 5 is aryl; and R 2 , R 3 , R 4 , R and R 7 are as defined in formula (I).
  • compounds have formula (IN) wherein Ri is heterocycle wherein said heterocycle is optionally substituted pyridinyl; R 5 is aryl wherein said aryl is optionally substituted phenyl; and R 2 , R 3 , Rt, R 6 and R 7 are as defined in formula (I).
  • compounds have formula (IV) wherein Ri is heterocycle wherein said heterocycle is optionally substituted pyridinyl; R 2 is hydrogen; R3 is hydrogen; t is hydrogen; R 5 is aryl wherein said aryl is optionally substituted phenyl; R 6 is selected from alkenyl, alkenyloxy(alkenyloxy)alkyl, arylalkyl wherein the aryl portion of said arylalkyl is optionally substituted phenyl, cyanoalkyl, cycloalkylalkyl and haloalkyl; and R 7 is hydrogen.
  • compounds have formula (IV) wherein Ri is heterocycle wherein said heterocycle is optionally substituted pyridinyl; R is hydrogen; R 3 is hydrogen; Rt is hydrogen; R 5 is aryl wherein said aryl is optionally substituted phenyl; Re is alkyl; and R 7 is hydrogen.
  • compositions comprising a therapeutically effective amount of a compound of formula I-PV or a pharmaceutically acceptable salt, ester, amide, or prodrug thereof in combination with a • pharmaceutically acceptable carrier.
  • Another embodiment ofthe present invention relates to a method of treating male sexual dysfunction including, but not limited to, male erectile dysfunction and premature ejaculation, comprising administering a therapeutically effective amount of a compound of formula I-IV or a pharmaceutically acceptable salt, ester, amide, or prodrug thereof.
  • Another embodiment ofthe present invention relates to a method of treating female sexual dysfunction including, but not limited to, female anorgasmia, clitoral erectile insufficiency, vaginal engorgement, dyspareunia, and vaginismus comprising administering a therapeutically effective amount of a compound of formula I-IV or a pharmaceutically acceptable salt, ester, amide, or prodrug thereof.
  • Another embodiment ofthe present invention relates to a method of treating asthma, epilepsy, Raynaud's syndrome, intermittent claudication, migraine, pain, bladder overactivity, pollakiuria, bladder instability, nocturia, bladder hyperreflexia, eating disorders, urinary incontinence, enuresis, functional bowel disorders, neurodegeneration, benign prostatic hype ⁇ lasia (BPH), dysmenorrhea, premature labor, alopecia, cardioprotection, and ischemia comprising administering a therapeutically effective amount of a compound of formula I-IV or a pharmaceutically acceptable salt, ester, amide, or prodrug thereof.
  • Another embodiment ofthe present invention relates to a process of preparing a compound of formula (V)
  • Ri is selected from aryl, arylalkyl, heterocycle and heterocyclealkyl
  • R 2 , R 3 and R 4 are independently selected from hydrogen and alkyl
  • R 5 is selected from aryl, arylalkyl, heterocycle and heterocyclealkyl
  • R 6 is selected from hydrogen, alkenyl, alkenyloxyalkyl, alkenyloxy(alkenyloxy)alkyl, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkoxycarbonyl(halo)alkyl, alkoxy(halo)alkyl, alkyl, alkylcarbonyl, alkylcarbonylalkyl, alkylcarbonyl(halo)alkyl, alkylcarbonyloxyalkyl, alkylsulfinylalkyl, alkylsulfonylalkyl, alkylthioalkyl, alkynyl, aryl, arylalkoxyalkyl, arylalkoxycarbonyl, arylalkoxycarbonylalkyl, arylalkyl, arylcarbonyl, arylcarbonylalkyl, arylcarbonyloxyalkyl, aryl(halo)alky
  • R 9 and Rio are independently selected from hydrogen, alkoxysulfonyl, alkyl, alkylcarbonyl, alkylsulfonyl, aryl, arylalkyl, arylcarbonyl, arylsulfonyl and formyl; the process comprising:
  • step (b) reacting the product of step (a) with a base and a compound of formula (VIII)
  • step (a) is conducted for a period of about 12 hours to about 48 hours.
  • step (b) is conducted at about 15 °C to about 50 °C.
  • step (b) is conducted for a period of about 24 hours to about 168 hours.
  • step (a) is conducted at about 50 °C to about 80 °C and step (a) is conducted for a period of about 12 hours to about 48 hours.
  • step (a) is conducted at about 50 °C to about 80 °C; step (a) is conducted for a period of about 12 hours to about 48 hours; the base is cesium carbonate; the second solvent is dimethylacetamide; step (b) is conducted at about 18 °C to about 23 °C; and step (b) is conducted for a period of about 48 hours to about 168 hours.
  • alkenyl refers to a straight or branched chain hydrocarbon containing from 2 to 10 carbons and containing at least one carbon-carbon double bond formed by the removal of two hydrogens.
  • Representative examples of alkenyl include, but are not limited to, ethenyl, 2-propenyl, 2-methyl-2-propenyl, 3-butenyl, l,l-dimethyl-3-butenyl, 4-pentenyl, 5-hexenyl, 2-heptenyl, 2-methyl-l-heptenyl and 3-decenyl.
  • alkenyloxy refers to an alkenyl group, as defined herein, appended to the parent molecular moiety through an oxy moiety, as defined herein.
  • Representative examples of alkenyloxy include, but are not limited to, allyloxy, 2-butenyloxy and 3-butenyloxy .
  • alkenyloxyalkyl refers to a alkenyloxy group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein.
  • alkenyloxyalkyl include, but are not limited to, (allyloxy)methyl, (2-butenyloxy)methyl and (3-butenyloxy)methyl.
  • alkenyloxy(alkenyloxy)alkyl refers to 2 independent alkenyloxy groups, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein.
  • Representative examples of alkenyloxy(alkenyloxy)alkyl include, but are not limited to, l,2-bis(allyloxy)ethyl and l,l-bis[(allyloxy)methyl]propyl.
  • alkoxy refers to an alkyl group, as defined herein, appended to the parent molecular moiety through an oxy moiety, as defined herein.
  • Representative examples of alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, 2-propoxy, butoxy and tert-butoxy.
  • alkoxyalkyl refers to an alkoxy group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein.
  • Representative examples of alkoxyalkyl include, but are not limited to, tert-butoxymethyl, 2- ethoxyethyl, 2-methoxyethyl, methoxyrnethyl and l,l-dirnethyl-3-(methoxy)propyl.
  • alkoxycarbonyl refers to an alkoxy group, as defined herein, appended to the parent molecular moiety through a carbonyl group, as defined herein.
  • Representative examples of alkoxycarbonyl include, but are not limited to, methoxycarbonyl, ethoxycarbonyl and tert-butoxycarbonyl.
  • alkoxycarbonylalkyl refers to an alkoxycarbonyl group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein.
  • Representative examples of alkoxycarbonylalkyl include, but are not limited to, methoxycarbonylmethyl, ethoxycarbonylmethyl, tert-butoxycarbonylmethyl and 1,1 -dimethyl - 2-(mefhoxycarbonyl)ethyl.
  • alkoxycarbonyl(halo)alkyl refers to an alkoxycarbonyl group and at least one halogen, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein.
  • Representative examples of alkoxycarbonyl(halo)alkyl include, but are not limited to, l,l-dichloro-2-methoxy-2-oxoethyl, l,l-difluoro-2-methoxy-2-oxoethyl, l,l-dichloro-3-methoxy-3-oxopropyl and l,l-difluoro-3- methoxy-3-oxopropyl.
  • alkoxy(halo)alkyl refers to an alkoxy group and at least one halogen, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein.
  • Representative examples of alkoxy(halo)alkyl include, but are not limited to, dichloro(methoxy)methyl, dichloro(efhoxy)methyl, dichloro(tert-butoxy)methyl, 1,1- dichloro-2-ethoxyethyl, l,l-dichloro-2-methoxyethyl, l,l-dichloro-3-methoxypropyl and 1,2- dichloro-3-methoxypropyl.
  • alkoxysulfonyl refers to an alkoxy group, as defined herein, appended to the parent molecular moiety through a sulfonyl group, as defined herein.
  • Representative examples of alkoxysulfonyl include, but are not limited to, methoxysulfonyl and ethoxysulfonyl.
  • alkyl refers to a straight or branched chain hydrocarbon containing from 1 to 10 carbon atoms.
  • Representative examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, n- pentyl, isopentyl, neopentyl, n-hexyl, 3-methylhexyl, 1-ethylpropyl, 2,2-dimethylpentyl, 2,3- dimethylpentyl, n-heptyl, n-octyl, n-nonyl and n-decyl.
  • alkylcarbonyl refers to an alkyl group, as defined herein, appended to the parent molecular moiety through a carbonyl group, as defined herein.
  • Representative examples of alkylcarbonyl include, but are not limited to, acetyl, 1-oxopropyl, 2,2-dimethyl- 1-oxopropyl, 1-oxobutyl and 1-oxopentyl.
  • alkylcarbonylalkyl refers to an alkylcarbonyl group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein.
  • Representative examples of alkylcarbonylalkyl include, but are not limited to, 2- oxopropyl, l,l-dimethyl-3-oxobutyl, 3-oxobutyl and 3-oxopentyl.
  • alkylcarbonyl (halo)alkyl refers to an alkylcarbonyl group and at least one halogen, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein.
  • Representative examples of alkylcarbonyl(halo)alkyl include, but are not limited to, l,l-dichloro-2-oxopropyl, l,l-dichloro-3-oxobutyl, 1,1- difluoro-3-oxobutyl and l,l-dichloro-3-oxopentyl.
  • alkylcarbonyloxy refers to an alkylcarbonyl group, as defined herein, appended to the parent molecular moiety through an oxy moiety, as defined herein.
  • Representative examples of alkylcarbonyloxy include, but are not limited to, acetyloxy and ethylcarbonyloxy.
  • alkylcarbonyloxyalkyl refers to an alkylcarbonyloxy group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein.
  • Representative examples of alkylcarbonyloxyalkyl include, but are not limited to, acetyloxymethyl and 2-(ethylcarbonyloxy)ethyl.
  • alkylene or "alkylene bridge” refers to a divalent group derived from a straight chain hydrocarbon of from 1 to 3 carbon atoms.
  • Representative examples of alkylene or alkylene bridge include, -CH 2 - -CH 2 CH 2 -, and -CH 2 CH 2 CH 2 -.
  • alkylsulfinyl refers to an alkyl group, as defined herein, appended to the parent molecular moiety through a sulfinyl group, as defined herein.
  • Representative examples of alkylsulfinyl include, but are not limited to, methylsulfinyl and ethylsulfmyl.
  • alkylsulfinylalkyl refers to an alkylsulfinyl group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein.
  • Representative examples of alkylsulfinylalkyl include, but are not limited to, methylsulfinylmefhyl and ethylsulfinylmethyl.
  • alkylsulfonyl refers to an alkyl group, as defined herein, appended to the parent molecular moiety through a sulfonyl group, as defined herein.
  • Representative examples of alkylsulfonyl include, but are not limited to, methylsulfonyl and ethylsulfonyl.
  • alkylsulfonylalkyl refers to an alkylsulfonyl group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein.
  • Representative examples of alkylsulfonylalkyl include, but are not limited to, methylsulfonylmethyl and ethylsulfonylmethyl.
  • alkylthio refers to an alkyl group, as defined herein, appended to the parent molecular moiety through a thio moiety, as defined herein.
  • Representative examples of alkylthio include, but are not limited to, methylsulfanyl, ethylsulfanyl, propylsulfanyl, 2-propylsulfanyl and tert-butylsulfanyl.
  • alkylthioalkyl refers to an alkylthio group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein.
  • alkylthioalkyl include, but are not limited to, tert- butylsulfanylmethyl, 2-ethylsulfanylethyl, 2-methylsulfanylethyl and methylsulfanylmethyl.
  • alkynyl refers to a straight or branched chain hydrocarbon group containing from 2 to 10 carbon atoms and containing at least one carbon-carbon triple bond.
  • Representative examples of alkynyl include, but are not limited to, acetylenyl, 1- propynyl, 2-propynyl, 3-butynyl, 2-pentynyl and 1-butynyl.
  • aryl refers to a monocyclic carbocyclic ring system or a bicyclic carbocyclic fused ring system having one or more aromatic rings.
  • Representative examples of aryl include, azulenyl, indanyl, indenyl, naphthyl, phenyl, tetrahydronaphthyl and fluorenyl.
  • aryl groups of this invention may be substituted with 1, 2, 3, 4, or 5 substituents independently selected from alkenyl, alkoxy, alkoxycarbonyl, alkoxycarbonylalkyl, alkyl, alkylcarbonyl, alkylcarbonyloxy, alkylcarbonyloxyalkyl, alkylsulfinyl, alkoxysulfonyl, alkylsulfonyl, alkynyl, arylalkoxycarbonyl, arylalkoxycarbonylalkyl, arylcarbonyloxy, arylcarbonyloxyalkyl, aryloxycarbonyl, aryloxycarbonylalkyl, arylsulfonyl, carboxy, cyano, halo, haloalkyl, haloalkoxy, nitro, oxo, sulfamyl, sulfamylalkyl, -NR A R B , (NR A R B )
  • arylalkoxy refers to an aryl group, as defined herein, appended to the parent molecular moiety through an alkoxy group, as defined herein.
  • Representative examples of arylalkoxy include, but are not limited to, 2-phenylethoxy, 3- naphth-2-ylpropoxy and 5-phenylpentyloxy.
  • arylalkoxyalkyl refers to an arylalkoxy group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein.
  • Representative examples of arylalkoxyalkyl include, but are not limited to, 2- phenylefhoxymethyl, 2-(3-naphth-2-ylpropoxy)ethyl and 5-phenylpentyloxymethyl.
  • arylalkoxycarbonyl refers to an arylalkoxy group, as defined herein, appended to the parent molecular moiety through a carbonyl group, as defined herein.
  • Representative examples of arylalkoxycarbonyl include, but are not limited to, benzyloxycarbonyl and naphth-2-ylmethyloxycarbonyl.
  • arylalkoxycarbonylalkyl refers to an arylalkoxycarbonyl group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein.
  • Representative examples of arylalkoxycarbonylalkyl include, but are not limited to, benzyloxycarbonylmethyl, 2-(benzyloxycarbonyl)ethyl and 2-(naphth-2- ylmethyloxycarbonyl)ethyl.
  • arylalkyl refers to an aryl group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein.
  • Representative examples of arylalkyl include, but are not limited to, benzyl, 2-phenylethyl, l,l-dimethyl-2-phenylethyl, 3-phenylpropyl and 2-naphth-2-ylethyl.
  • arylalkylthio refers to an arylalkyl group, as defined herein, appended to the parent molecular moiety through a thio moiety, as defined herein.
  • Representative examples of arylalkylthio include, but are not limited to, 2-phenylethylthio, 3-naphth-2-ylpropylthio and 5-phenylpentylthio.
  • arylalkylthioalkyl refers to an arylalkylthio group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein.
  • Representative examples of arylalkylthioalkyl include, but are not limited to, 2- phenylethylsulfanylmethyl, 3-naphth-2-ylpropylsulfanylmethyl and 2-(5- phenylpentylsulfanyl)ethyl.
  • arylcarbonyl refers to an aryl group, as defined herein, appended to the parent molecular moiety through a carbonyl group, as defined herein.
  • Representative examples of arylcarbonyl include, but are not limited to, benzoyl and naphthoyl.
  • arylcarbonylalkyl refers to an arylcarbonyl group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein.
  • Representative examples of arylcarbonylalkyl include, but are not limited to, 2-oxo-3- phenylpropyl and l,l-dimethyl-3-oxo-4-phenylbutyl.
  • arylcarbonyloxy refers to an arylcarbonyl group, as defined herein, appended to the parent molecular moiety through an oxy moiety, as defined herein.
  • Representative examples of arylcarbonyloxy include, but are not limited to, benzoyloxy and naphthoyloxy.
  • arylcarbonyloxyalkyl refers to an arylcarbonyloxy group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein.
  • Representative examples of arylcarbonyloxyalkyl include, but are not limited to, benzoyloxymethyl, 2-(benzoyloxy)ethyl and 2-(naphthoyloxy)ethyl.
  • aryl(halo)alkyl refers to an aryl group and at least one halogen, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein.
  • Representative examples of aryl(halo)alkyl include, but are not limited to, dichloro(phenyl)methyl, l,l-dichloro-2-phenylethyl, l,l-difluoro-2-phenylethyl, 1,1-dichloro- 3-phenylpropyl and l,l-difluoro-3-phenylpropyl.
  • aryloxy refers to an aryl group, as defined herein, appended to the parent molecular moiety through an oxy moiety, as defined herein.
  • Representative examples of aryloxy include, but are not limited to, phenoxy, naphthyloxy, 3-bromophenoxy, 4-chlorophenoxy, 4-methylphenoxy and 3,5-dimethoxyphenoxy.
  • aryloxyalkyl refers to an aryloxy group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein.
  • Representative examples of aryloxyalkyl include, but are not limited to, phenoxymethyl, 2- phenoxyethyl, 3-naphth-2-yloxypropyl and 3-bromophenoxymethyl.
  • aryloxycarbonyl refers to an aryloxy group, as defined herein, appended to the parent molecular moiety through an oxy moiety, as defined herein.
  • Representative examples of aryloxycarbonyl include, but are not limited to, phenoxycarbonyl and naphthyloxycarbonyl.
  • aryloxycarbonylalkyl refers to an aryloxycarbonyl group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein.
  • Representative examples of aryloxycarbonylalkyl include, but are not limited to, phenoxycarbonylmefhyl, 2-(phenoxycarbonyl)ethyl and naphthyloxycarbonyl.
  • arylsulfonyl refers to an aryl group, as defined herein, appended to the parent molecular moiety through a sulfonyl group, as defined herein.
  • Representative examples of arylsulfonyl include, but are not limited to, naphthylsulfonyl, phenylsulfonyl and 4-fluorophenylsulfonyl.
  • arylsulfonylalkyl refers to an arylsulfonyl group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein.
  • Representative examples of arylsulfonylalkyl include, but are not limited to, l,l-dimethyl-3- (phenylsulfonyl)propyl, naphthylsulfonylmethyl, 2-(phenylsulfonyl)ethyl, phenylsulfonylmethyl and 4-fluorophenylsulfonylmethyl.
  • arylthio refers to an aryl group, as defined herein, appended to the parent molecular moiety through a thio moiety, as defined herein.
  • Representative examples of arylthio include, but are not limited to, phenylsulfanyl, naphth-2- ylsulfanyl and 5-phenylhexylsulfanyl.
  • arylthioalkyl refers to an arylthio group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein.
  • Representative examples of arylthioalkyl include, but are not limited to, phenylsulfanylmethyl, 2-naphth-2-ylsulfanylethyl and 5-phenylhexylsulfanylmethyl.
  • carbonyl refers to a -C(O)- group.
  • carboxyalkyl refers to a carboxy group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein.
  • Representative examples of carboxyalkyl include, but are not limited to, carboxymethyl, 2- carboxyethyl, 3-carboxypropyl and 3 -carboxy- 1,1-dimethylpropyl .
  • carboxy(halo)alkyl refers to a carboxy group and at least one halogen, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein.
  • carboxy(halo)alkyl include, but are not limited to, carboxy(dichloro)methyl, carboxy(difluoro)methyl, 2-carboxy-l,l-dichloroethyl and 2-carboxy-l,l-difluoroethyl.
  • cyano refers to a -CN group.
  • cyanoalkyl refers to a cyano group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein.
  • Representative examples of cyanoalkyl include, but are not limited to, cyanomethyl, 2- cyanoethyl, 3-cyanopropyl, 3-cyano-l,l-dimethylpropyl and 3-cyano-l,l-diethylpropyl .
  • cyano(halo)alkyl refers to a cyano group and at least one halogen, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein.
  • Representative examples of cyano(halo)alkyl include, but are not limited to, 3-cyano-l,l-difluoropropyl, l,l-dichloro-3-cyanopropyl and 3-cyano-l,l- bis(trifluoromethyl)propyl.
  • cycloalkenyl refers to a cyclic hydrocarbon containing from 3 to 8 carbons and containing at least one carbon-carbon double bond formed by the removal of two hydrogens.
  • Representative examples of cycloalkenyl include, but are not limited to, cyclohexene, l-cyclohexen-2-yl, 3,3-dimethyl-l-cyclohexene, cyclopentene and cycloheptene.
  • the cycloalkenyl groups of this invention can be substituted with 1, 2, 3, 4, or 5 substituents independently selected from alkenyl, alkoxy, alkoxycarbonyl, alkoxycarbonylalkyl, alkyl, alkylcarbonyloxy, alkylcarbonyloxyalkyl, alkynyl, arylalkoxycarbonyl, arylalkoxycarbonylalkyl, arylcarbonyloxy, arylcarbonyloxyalkyl, aryloxycarbonyl, aryloxycarbonylalkyl, halo, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, sulfamylalkyl, -NR A R B , (NR A R B )alkyl, (NR A R B )carbonyl and (NR A R B )carbonylalkyl.
  • cycloalkenylalkyl refers to a cycloalkenyl group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein.
  • Representative examples of cycloalkenylalkyl include, but are not limited to, (2,6,6-trimethyl- l-cyclohexen-l-yl)methyl, 1-cyclohexen-l-ylmethyl and 2-(2-cyclohepten-l-yl)ethyl.
  • cycloalkyl refers to a monocyclic, bicyclic, or tricyclic ring system.
  • Monocyclic ring systems are exemplified by a saturated cyclic hydrocarbon group containing from 3 to 8 carbon atoms. Examples of monocyclic ring systems include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.
  • Bicyclic ring systems are exemplified by a bridged monocyclic ring system in which two non-adjacent carbon atoms ofthe monocyclic ring are linked by an alkylene bridge of between one and three carbon atoms.
  • bicyclic ring systems include, but are not limited to, bicyclo[3.1.1]heptane, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, bicyclo[3.2.2]nonane, bicyclo[3.3.1]nonane and bicyclo[4.2.1]nonane.
  • Tricyclic ring systems are exemplified by a bicyclic ring system in which two non-adjacent carbon atoms of the bicyclic ring are linked by a bond or an alkylene bridge of between one and three carbon atoms.
  • tricyclic-ring systems include, but are not limited to, tricyclo[3.3.1.0 3 ' 7 ]nonane and tricyclo[3.3.1.1 3 ' 7 ]decane (adamantane).
  • the cycloalkyl groups of this invention can be substituted with 1, 2, 3, 4, or 5 substituents independently selected from alkenyl, alkoxy, alkoxycarbonyl, alkoxycarbonylalkyl, alkyl, alkylcarbonylalkyl, alkylcarbonyloxy, alkylcarbonyloxyalkyl, alkylsulfonylalkyl, alkynyl, alkylcarbonyloxy, arylalkoxycarbonyl, arylalkoxycarbonylalkyl, arylalkyl, arylcarbonyloxy, arylcarbonyloxyalkyl, aryloxycarbonyl, aryloxycarbonylalkyl, arylsulfonylalkyl, cyanoalkyl, cycloalkylalkyl, halo, haloalkoxy, haloalkyl, heterocyclealkyl, hydroxy, hydroxyalkyl, sulfamylalky
  • cycloalkylalkoxy refers to a cycloalkyl group, as defined herein, appended to the parent molecular moiety through an alkoxy group, as defined herein.
  • Representative examples of cycloalkylalkoxy include, but are not limited to, cyclopropylmefhoxy, 2-cyclobutylethoxy, cyclopentylmethoxy, cyclohexylmethoxy and 4- cycloheptylbutoxy.
  • cycloalkylalkoxyalkyl refers to a cycloalkylalkoxy group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein.
  • Representative examples of cycloalkylalkoxyalkyl include, but are not limited to, cyclopropylmethoxymethyl, 2-cyclobutylethoxymethyl, cyclopentylmefhoxymefhyl, 2- cyclohexylethoxymethyl and 2-(4-cycloheptylbutoxy)ethyl.
  • cycloalkylalkyl refers to a cycloalkyl group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein.
  • Representative examples of cycloalkylalkyl include, but are not limited to, cyclopropylmethyl, 2-cyclobutylethyl, cyclopentylmethyl, cyclohexylmethyl and 4-cycloheptylbutyl.
  • cycloalkylcarbonyl refers to a cycloalkyl group, as defined herein, appended to the parent molecular moiety through a carbonyl group, as defined herein.
  • Representative examples of cycloalkylcarbonyl include, but are not limited to, cyclopropylcarbonyl, 2-cyclobutylcarbonyl and cyclohexylcarbonyl.
  • cycloalkyloxy refers to a cycloalkyl group, as defined herein, appended to the parent molecular moiety through an oxy moiety, as defined herein.
  • Representative examples of cycloalkyloxy include, but are not limited to, cyclohexyloxy and cyclopentyloxy.
  • cycloalkyloxyalkyl refers to a cycloalkyloxy group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein.
  • Representative examples of cycloalkyloxyalkyl include, but are not limited to, 4- (cyclohexyloxy)butyl and cyclohexyloxymethyl.
  • cycloalkylalkylthio refers to a cycloalkylalkyl group, as defined herein, appended to the parent molecular moiety through a thio moiety, as defined herein.
  • Representative examples of cycloalkylalkylthio include, but are not limited to, (2- cyclohexylethyl)sulfanyl and cyclohexylmethylsulfanyl.
  • cycloalkylalkylthioalkyl refers to a cycloalkylalkylthio group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein.
  • Representative examples of cycloalkylalkylthioalkyl include, but are not limited to, 2-[(2-cyclohexylethyl)sulfanyl]ethyl and (2-cyclohexylethyl)sulfanylmethyl.
  • cycloalkylthio refers to a cycloalkyl group, as defined herein, appended to the parent molecular moiety through a thio moiety, as defined herein.
  • Representative examples of cycloalkylthio include, but are not limited to, cyclohexylsulfanyl and cyclopentylsulfanyl.
  • cycloalkylthioalkyl refers to a cycloalkylthio group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein.
  • Representative examples of cycloalkylthioalkyl include, but are not limited to, 4- (cyclohexylsulfanyl)butyl and cyclohexylsulfanylmethyl.
  • halo refers to -Cl, -Br, -I or -F.
  • haloalkoxy refers to at least one halogen, as defined herein, appended to the parent molecular moiety through an alkoxy group, as defined herein. Representative examples of haloalkoxy include, but are not limited to, chloromethoxy, 2- fluoroethoxy, 1,2-difluoroethoxy, trifluoromethoxy and pentafluoroethoxy.
  • haloalkenyl refers to at least one halogen, as defined herein, appended to the parent molecular moiety through an alkenyl group, as defined herein.
  • Representative examples of haloalkenyl include, but are not limited to, 2,2-dichloroethenyl, 2,2-difluoroethenyl and 5-chloropenten-2-yl.
  • haloalkyl refers to at least one halogen, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein.
  • Representative examples of haloalkyl include, but are not limited to, chloromethyl, trichloromethyl, 1,1-dichloroethyl, 2-fluoroethyl, trifluoromethyl, 2,2,2-trifluoroethyl, 2,2,2- trifluoro-1 -(trifluoromethyl)- l-(methyl)ethyl, pentafluoroethyl and 2-chloro-3-fluoropentyl.
  • haloalkylcarbonyl refers to a haloalkyl group, as defined herein, appended to the parent molecular moiety through a carbonyl group, as defined herein.
  • Representative examples of haloalkylcarbonyl include, but are not limited to, chloromethylcarbonyl, trichloromethylcarbonyl and trifluoromethylcarbonyl.
  • haloalkylsulfonyl refers to a haloalkyl group, as defined herein, appended to the parent molecular moiety through a sulfonyl group, as defined herein.
  • Representative examples of haloalkylsulfonyl include, but are not limited to, chloromethylsulfonyl, trichloromethylsulfonyl and trifluoromethylsulfonyl.
  • haloalkynyl refers to at least one halogen, as defined herein, appended to the parent molecular moiety through an alkynyl group, as defined herein.
  • Representative examples of haloalkynyl include, but are not limited to and 4,4,4- trichlorobutyn-2 -yl .
  • heterocycle refers to a monocyclic or a bicyclic ring system.
  • Monocyclic ring systems are exemplified by any 5 or 6 membered ring containing 1, 2, 3, or 4 heteroatoms independently selected from oxygen, nitrogen and sulfur.
  • the 5- membered ring has from 0-2 double bonds and the 6-membered ring has from 0-3 double bonds.
  • monocyclic ring systems include, but are not limited to, azetidinyl, azepinyl, aziridinyl, diazepinyl, 1,3-dioxolanyl, dioxanyl, 1,3-dioxanyl, dithianyl, furyl, imidazolyl, imidazolinyl, imidazolidinyl, isothiazolyl, isothiazolinyl, isothiazolidinyl, isoxazolyl, isoxazolinyl, isoxazolidinyl, mo ⁇ holinyl, oxadiazolyl, oxadiazolinyl, oxadiazolidinyl, oxazolyl, oxazolinyl, oxazolidinyl, piperazinyl, piperidinyl, pyranyl, pyrazinyl, pyrazolyl, pyrazolinyl, pyrazolidiny
  • Bicyclic ring systems are exemplified by any ofthe above monocyclic ring systems fused to an aryl group as defined herein, a cycloalkyl group as defined herein, or another monocyclic ring system as defined herein.
  • Representative examples of bicyclic ring systems include but are not limited to, for example, benzimidazolyl, benzothiazolyl, benzothiadiazolyl, benzothienyl, benzoxadiazolyl, benzoxazolyl, benzofuranyl, benzopyranyl, benzothiopyranyl, benzotriazolyl, benzodioxinyl, 1,3-benzodioxolyl, cinnolinyl, indazolyl, indolyl, indolinyl, indolizinyl, naphthyl, isobenzofuranyl, isobenzothienyl, isoindolyl, isoindolinyl, 1- isoin
  • heterocycle groups of this invention can be substituted with 1, 2,or 3 substituents independently selected from alkenyl, alkoxy, alkoxycarbonyl, alkoxycarbonylalkyl, alkyl, alkylcarbonyl, alkylcarbonyloxy, alkylcarbonyloxyalkyl, alkylsulfinyl, alkoxysulfonyl, alkylsulfonyl, alkynyl, arylalkoxycarbonyl, arylalkoxycarbonylalkyl, arylcarbonyloxy, arylcarbonyloxyalkyl, aryloxycarbonyl, aryloxycarbonylalkyl, arylsulfonyl, carboxy, cyano, halo, haloalkyl, haloalkoxy, nitro, oxo, sulfamyl, sulfamylalkyl, -NR A R B , (NR A R ⁇ )alkyl,
  • heterocyclealkoxy refers to a heterocycle group, as defined herein, appended to the parent molecular moiety through an alkoxy group, as defined herein.
  • Representative examples of heterocyclealkoxy include, but are not limited to, 2-pyrid-3- ylethoxy, 3-quinolin-3-ylpropoxy and 5-pyrid-4-ylpentyloxy.
  • heterocyclealkoxyalkyl refers to a heterocyclealkoxy group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein.
  • Representative examples of heterocyclealkoxyalkyl include, but are not limited to, 2-pyrid-3-ylethoxymethyl, 2-(3-quinolin-3-ylpropoxy)ethyl and 5-pyrid-4- ylpentyloxymethyl.
  • heterocyclealkyl refers to a heterocycle, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein.
  • Representative examples of heterocyclealkyl include, but are not limited to, pyrid-3-ylmethyl and pyrirnidin-5-ylmefhyl.
  • heterocyclealkylthio refers to a heterocyclealkyl group, as defined herein, appended to the parent molecular moiety through a thio moiety, as defined herein.
  • Representative examples of heterocyclealkylthio include, but are not limited to, 2- pyrid-3-ylethysulfanyl, 3-quinolin-3-ylpropysulfanyl and 5-pyrid-4-ylpentylsulfanyl.
  • heterocyclealkylthioalkyl refers to a heterocyclealkylthio group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein.
  • Representative examples of heterocyclealkylthioalkyl include, but are not limited to, 2-pyrid-3-ylethysulfanylmethyl, 2-(3-quinolin-3-ylpropysulfanyl)ethyl and 5-pyrid- 4-ylpentylsulfanylmefhyl.
  • heterocyclecarbonyl refers to a heterocycle, as defined herein, appended to the parent molecular moiety through a carbonyl group, as defined herein.
  • Representative examples of heterocyclecarbonyl include, but are not limited to, pyrid-3- ylcarbonyl, quinolin-3-ylcarbonyl and thiophen-2-ylcarbonyl.
  • heterocycleoxy refers to a heterocycle group, as defined herein, appended to the parent molecular moiety through an oxy moiety, as defined herein.
  • Representative examples of heterocycleoxy include, but are not limited to, pyrid-3-yloxy and quinolin-3 -yloxy.
  • heterocycleoxyalkyl refers to a heterocycleoxy group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein.
  • Representative examples of heterocycleoxyalkyl include, but are not limited to, pyrid- 3-yloxymefhyl and 2-quinolin-3-yloxyethyl.
  • heterocyclethio refers to a heterocycle group, as defined herein, appended to the parent molecular moiety through a thio moiety, as defined herein.
  • Representative examples of heterocyclethio include, but are not limited to, pyrid-3-ylsulfanyl and quinolin-3-ylsulfanyl.
  • heterocyclethioalkyl refers to a heterocyclethio group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein.
  • Representative examples of heterocyclethioalkyl include, but are not limited to, pyrid- 3-ylsulfanylmethyl and 2-quinolin-3-ylsulfanylethyl.
  • hydroxy refers to an -OH group.
  • hydroxyalkyl refers to 1 or 2 hydroxy groups, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein.
  • Representative examples of hydroxyalkyl include, but are not limited to, hydroxymethyl, 2- hydroxyethyl, 3-hydroxypropyl, 2,3-dihydroxypropyl, 2-ethyl-4-hydroxyheptyl, 2-hydroxy- 1, 1-dimethylethyl and 3-hydroxy-l,l-dimethylpropyl.
  • lower alkyl is a subset of alkyl as defined herein and refers to a straight or branched chain hydrocarbon group containing from 1 to 6 carbon atoms.
  • Representative examples of lower alkyl include, but are not limited to, methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl and tert-butyl.
  • mercapto refers to a -SH group.
  • mercaptoalkyl refers to a mercapto group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein.
  • Representative examples of mercaptoalkyl include, but are not limited to, 2-sulfanylethyl and 3-sulfanylpropyl.
  • R 9 R ⁇ o refers to two groups, R 9 and Rio, which are appended to the parent molecular moiety through a nitrogen atom.
  • R 9 and Rio are independently selected from hydrogen, alkoxysulfonyl, alkyl, alkylcarbonyl, alkylsulfonyl, aryl, arylalkyl, arylcarbonyl, arylsulfonyl and formyl, as defined herein.
  • Representative examples of -NR 9 R ⁇ 0 include, but are not limited to, acetylamino, amino, methylamino, (ethylcarbonyl)methylamino, ethylmethylamino, formylamino, mefhylsulfonylamino and phenylsulfonylamino.
  • (NR 9 R ⁇ 0 )alkyl refers to a -NR 9 R ⁇ o group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein.
  • Representative examples of (NR 9 R ⁇ 0 )alkyl include, but are not limited to, acetylaminomethyl, aminomethyl, 2-aminoethyl, 2-(methylamino)ethyl, (ethylcarbonyl)methylaminomethyl, 3- (ethylmethylamino)propyl, 1 , 1 -dimethyl-3 -(dimethylamino)propyl, 2-(formylamino)efhyl, methylsulfonylaminomethyl, 2-(phenylsulfonylamino)ethyl and benzylsulfonylaminomefhyl.
  • (NR 9 R ⁇ 0 )carbonyl refers to a -NR 9 R ⁇ o group, as defined herein, appended to the parent molecular moiety through a carbonyl group, as defined herein.
  • Representative examples of (NR 9 R ⁇ o)carbonyl include, but are not limited to, aminocarbonyl, dimefhylaminocarbonyl, ethylaminocarbonyl and benzylaminocarbonyl.
  • (NR 9 R ⁇ 0 )carbonylalkyl refers to a (NR 9 R ⁇ 0 )carbonyl group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein.
  • Representative examples of (NR 9 R ⁇ 0 )carbonylalkyl include, but are not limited to, aminocarbonylmethyl, dimethylaminocarbonylmethyl, 2-(ethylaminocarbonyl)ethyl and 3- (benzylaminocarbonyl)propyl.
  • -NR A R B refers to two groups, R A and R B , which are appended to the parent molecular moiety through a nitrogen atom.
  • R A and R B are independently selected from hydrogen, alkyl, alkylcarbonyl and formyl, as defined herein.
  • Representative examples of-NR A R ⁇ include, but are not limited to, acetylamino, amino, methylamino, (ethylcarbonyl)methylamino, dimethylamino, ethylmethylamino and formylamino.
  • (NR A R B )alkyl refers to a -NR A R B group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein.
  • Representative examples of (NR A R ⁇ )alkyl include, but are not limited to, acetylaminomethyl, aminomethyl, 2-aminoethyl, 2-(mefhylamino)ethyl, (ethylcarbonyl)methylaminomethyl, 3- (ethylmethylamino)propyl, l,l-dimethyl-3-(dimethylamino)propyl and 2-(formylamino)ethyl.
  • (NR A R B )carbonyl refers to a -NR A R B group, as defined herein, appended to the parent molecular moiety through a carbonyl group, as defined herein.
  • Representative examples of (NR A RB)carbonyl include, but are not limited to, aminocarbonyl, dimethylaminocarbonyl, methylaminocarbonyl, ethylaminocarbonyl and diethylaminocarbonyl.
  • (NR A R ⁇ )carbonylalkyl refers to a (NR A R B )carbonyl group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein.
  • Representative examples of (NR A R B )carbonylalkyl include, but are not limited to, aminocarbonylmefhyl, dimethylaminocarbonylmethyl, 2-(efhylaminocarbonyl)ethyl and 3- (diethylaminocarbonyl)propyl.
  • nitro refers to a -NO 2 group.
  • oxy refers to a (-O-) moiety.
  • sulfamyl refers to a -SO NR R 95 group, wherein R 94 and R 95 are independently selected from hydrogen, alkyl, aryl, and arylalkyl, as defined herein.
  • Representative examples of sulfamyl include, but are not limited to, aminosulfonyl, mefhylaminosulfonyl, dimethylaminosulfonyl, phenylaminosulfonyl and benzylaminosulfonyl.
  • sulfamylalkyl refers to a sulfamyl group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein.
  • Representative examples of sulfamylalkyl include, but are not limited to, (aminosulfonyl)methyl, (dimethylaminosulfonyl)methyl, 2-(aminosulfonyl)ethyl, 3- (aminosulfonyl)propyl and 3-aminosulfonyl-l,l-dimethylpropyl.
  • sulfamyl(halo)alkyl refers to a sulfamyl group and at least one halogen, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein.
  • sulfamyl(halo)alkyl include, but are not limited to, (aminosulfonyl)dichloromethyl, (aminosulfonyl)difluoromefhyl, (dimethylaminosulfonyl)difluoromethyl, 2-(aminosulfonyl)- 1 , 1 -dichloroethyl, 3- (aminosulfonyl)-l,l-difluoropropyl, 3-aminosulfonyl-l,l-dichloropropyl and 3- (aminosulfonyl)- 1 ,2-difluoropropyl.
  • sulfinyl refers to a -S(O)- group.
  • sulfonyl refers to a -SO 2 - group.
  • Stereoisomers may exist as stereoisomers wherein, asymmetric or chiral centers are present. These stereoisomers are “R” or “S” depending on the configuration of substituents around the chiral carbon atom.
  • R and “S” used herein are configurations as defined in IUPAC 1974 Recommendations for Section E, Fundamental Stereochemistry, Pure Appl. Chem., 1976, 45: 13-30.
  • Stereoisomers include enantiomers and diastereomers, and mixtures of enantiomers or diastereomers.
  • the carbon atom attached to R 6 and R 7 of formula (I-IV), may be individually the (R) enantiomer or individually the (S) enantiomer or a mixture thereof.
  • Individual stereoisomers of compounds ofthe present invention may be prepared synthetically from commercially available starting materials which contain asymmetric or chiral centers or by preparation of racemic mixtures followed by resolution well-known to those of ordinary skill in the art.
  • Preferred compounds ofthe present invention include
  • the compounds of this invention may be prepared by a variety of synthetic routes. Representative procedures are described in Schemes 1-16.
  • a preferred route for preparing aminals of general formula (9), wherein Ri, R , R 3 , R t , R 5 and Re are as defined in formula (I) is described in Scheme 1.
  • Dialkyl squarate esters of general formula (12), wherein R is alkyl, such as, but not limited to, diethyl squarate can be treated with amines of general formula (5) in an alcoholic solvent such as, but not limited to, ethanol as described in Butera, J.
  • Squarates of general formula (13) can be treated with ammonia in an alcoholic solvent such as, but not limited to, methanol to provide squarates of general formula (14).
  • Benzotriazoles of general formula (3) can be treated with squarates of general formula (14) in a polar, aprotic solvent such as, but not limited to, DMF in the presence of a base such as, but not limited to, cesium carbonate to provide squarate aminals of general formula (15).
  • lH-benzotriazole-polystyrene resin (Novabiochem) can be loaded in a three-component condensation including aldehydes of general formula (1), and amides of general formula (2) in the presence of an acid catalyst, but not limited to, p-toluenesulfonic acid monohydrate as described in Katritzky, Belyakov, Tymoshenko, J. Comb. Chem. (1999), 1, 173; and Paio, Zaramella, J. Comb. Chem. (1999), 1, 317 to provide benzotriazole adducts of general formula (18).
  • an acid catalyst but not limited to, p-toluenesulfonic acid monohydrate as described in Katritzky, Belyakov, Tymoshenko, J. Comb. Chem. (1999), 1, 173; and Paio, Zaramella, J. Comb. Chem. (1999), 1, 317 to provide benzotriazole adducts of general formula (18).
  • Benzotriazole adducts of general formula (18) can undergo nucleophilic displacement ofthe resin bound benzotriazole moiety with squarate amides of general formula (14) in a solvent such as, but not limited to, dimethylacetamide or a cosolvent such as, but not limited to, THF and dimethylacetamide in the presence of a base such as, but not limited to, cesium carbonate to provide aminals of general formula (15).
  • a solvent such as, but not limited to, dimethylacetamide or a cosolvent such as, but not limited to, THF and dimethylacetamide
  • a base such as, but not limited to, cesium carbonate
  • Amides of general formula (2) can be treated with ⁇ -haloaldehyde hydrates or ⁇ -halohemiacetals of general formula (20), wherein R is hydrogen and R' is selected from hydrogen or alkyl, such as, but not limited to, 2,2,2-trichloro-l,l-ethanediol or l-ethoxy-2,2,2-trifluoro-l -ethanol, followed by addition of a chlorinating agent such as, but not limited to, thionyl chloride and a base such as, but not limited to, pyridine to provide chloroamides of general formula (21).
  • a chlorinating agent such as, but not limited to, thionyl chloride and a base such as, but not limited to, pyridine
  • Chloroamides of general formula (21) can be treated with squarates of general formula (14) in a polar, aprotic solvent such as, but not limited to, DMF in the presence of a base such as, but not limited to, cesium carbonate to provide squarate aminals of general formula (15).
  • a polar, aprotic solvent such as, but not limited to, DMF
  • a base such as, but not limited to, cesium carbonate
  • Squarate aminals of general formula (23), wherein R" is alkoxy can be prepared following the strategy described in Scheme 2.
  • Squarate aminals of general formula (23) can be treated with an acid such as, but not limited to, hydrobromic acid or trifluoroacetic acid to provide primary amines of general formula (24).
  • Amines of general formula (24) can be treated with acid chlorides of general formula (25) in the presence of a base such as, but not limited to, diisopropylefhylamine to provide squarate aminals of general formula (15).
  • Aminoamides of general formula (27) can be treated with squarates of general formula (13) in alcoholic solvent such as, but not limited to, ethanol or a polar, aprotic solvent such as, but not limited to, acetonitrile to provide squarate aminals of general formula (15).
  • alcoholic solvent such as, but not limited to, ethanol or a polar, aprotic solvent such as, but not limited to, acetonitrile
  • Squarate aminals of general formula (15), wherein R l s R 2 , R ⁇ R 5 , and R 6 are as defined in formula (I), can be prepared as described in Scheme 7.
  • Aminoamides of general formula (27) can be treated with dialkyl squarates of general formula (12), wherein R is alkyl, such as, but not limited to, diethyl squarate in an alcoholic solvent such as, but not limited to, ethanol or a polar, aprotic solvent such as, but not limited to, acetonitrile to provide squarates of general formula (29).
  • Squarates of general formula (29) can be treated with amines of general formula (5) in an alcoholic solvent such as, but not limited to, ethanol to provide squarate aminals of general formula (15).
  • Squarate aminals of general formula (15), wherein R 1 ⁇ R 2 , R , R 5 , and R 6 are as defined in formula (I), can be prepared as described in Scheme 8.
  • Aminoacetamides of general formula (30) can be treated with acid chlorides of general formula (25) in the presence of a base such as, but not limited to, pyridine or triethylamine to provide the corresponding acylaminoamides of general formula (31).
  • a base such as, but not limited to, pyridine or triethylamine
  • Acylaminoamides of general formula (31) can undergo a Hofmann rearrangement as described in Wallis and Lane, Org. React.
  • Aminoamides of general formula (27) can be treated with squarates of general formula (12), wherein R is alkyl, such as, but not limited to, diethyl squarate in an alcoholic solvent such as, but not limited to, ethanol or a polar, aprotic solvent such as, but not limited to, acetonitrile to provide squarates of general formula (29).
  • Squarates of general formula (29) can then be treated with amines of general formula (5) in an alcoholic solvent such as, but not limited to, ethanol to provide squarate aminals of general formula (15).
  • Primary amides of general fonnula (2) can be treated with symmetrical ketones of general formula (34) in the presence of a dehydrating agent such as, but not limited to, trifluoroacetic anhydride and a base such as, but not limited to, pyridine to provide symmetrical imines of general formula (35).
  • a dehydrating agent such as, but not limited to, trifluoroacetic anhydride
  • a base such as, but not limited to, pyridine
  • Symmetrical imines of general formula (35) can be treated with squarates of general formula (14) in the presence of a base such as, but not limited to, triethylamine to provide geminally-substituted squarate aminals of general formula (36).
  • Squarate aminals of general formula (37), wherein R is Br, I or -OS(O) 2 CF 3 can be treated with a palladium catalyst, a trialkyltin reagent and triphenylarsine in a solvent such as, but not limited to, N-methylpyrrolidin-2-one as described in Farina and Baker, J. Org. Chem.
  • Scheme 11 describes a preferred method that provides squarate aminals of general formula (38), wherein R 1 ⁇ R 2 , R 4 , and R 6 are as defined in formula (I) and R' is selected from alkoxycarbonyl, aryl, carboxy, heterocycle and -NR A R ⁇ wherein R A and R B are as defined in formula (I).
  • Benzotriazole compounds of general formula (40), wherein R is Br, I or - OS(O) 2 CF 3 can be treated with a palladium catalyst, a trialkyltin reagent and triphenylarsine in a solvent such as, but not limited to, N-methylpyrrolidin-2-one as described in Farina and Baker, J. Org. Chem.
  • Sulfonylamino aminals of general formula (45), wherein R l s R t , R 5 , and Re are as defined in formula (I), can be prepared as described in Scheme 12.
  • Primary amines of general formula (42) can be treated with chlorosulfonyl isocyante in the presence of an alcoholic nucleophile such as, but not limited to, t-butanol as described in Abdaoui, Bioorg. Med. Chem. Lett. (1996), 4, 1227 to provide sulfonylamino carbamates of general formula (43).
  • Sulfonylamino carbamates of general formula (43) can be treated with a protic acid such as, but not limited to, trifluoroacetic acid to provide amino sulfonamides of general formula (44).
  • Amino sulfonamides of general formula (44) can be treated with benzotriazoles of general formula (3) in a polar, aprotic solvent such as, but not limited to, DMF in the presence of a base such as, but not limited to, potassium carbonate or cesium carbonate to provide sulfonylamino aminals of general formula (45).
  • Ethanediamide aminals of general formula (50), wherein Ri, Rt, R 5 , and R are as defined in formula (I) can be prepared as described in Scheme 13.
  • Chloroalkyloxalates of general formula (47), wherein R is alkyl, such as, but not limited to, chloroethyloxalate can be treated with primary amines of general formula (42) in the presence of a base such as, but not limited to, triethylamine to provide amidoesters of general formula (48).
  • Amidoesters of general formula (48) can be treated with ammonia in an alcoholic solvent such as, but not limited to, methanol to provide oxalamides of general formula (49).
  • Oxalamides of general formula (49) can be treated with benzotriazoles of general formula (3) in a polar, aprotic solvent such as, but not limited to, DMF in the presence of a base such as, but not limited to, potassium carbonate or cesium carbonate to provide ethanediamide aminals of general formula (50).
  • a polar, aprotic solvent such as, but not limited to, DMF
  • a base such as, but not limited to, potassium carbonate or cesium carbonate to provide ethanediamide aminals of general formula (50).
  • Aminals of general formula (54), wherein R 1 ⁇ R 2 , R , R 5 and R 6 are as defined in formula (I), can be prepared as described in Scheme 14.
  • 3,4-Dichloro-2,5-furandione purchased from Aldrich Chemical Company, can be treated with amines of general formula (5) as described in previous Schemes to provide furandiones of general formula (52).
  • Furandiones of general formula (52) can be treated with ammonia as described in previous Schemes to provide compounds of general formula (53).
  • Compounds of general formula (53) can be processed as described in Schemes 1-5 and Scheme 9 to provide aminals of general formula (54).
  • Aminals of general formula (56), wherein Ri, R 2 , R t , R 5 and Re are as defined in formula (I), can be prepared as described in Scheme 15.
  • Pyrrole diones of general formula (55) can be prepared as described in Augustin, Tetrahedron (1980) 36, 1801; and Hanaineh- Abdelnour, Tetrahedron (1999) 55, 11859 and then processed as described in previous Schemes to provide aminals of general formula (56).
  • Aminals of general formula (58), wherein Ri, R 2 , Rt, R 5 and R 6 are as defined in formula (I), can be prepared as described in Scheme 15.
  • Cyclopentene diones of general formula (57) can be prepared as described in Lee et al., JOC (1995) 60, 735; and Yamamoto et al., JACS (1995) 117, 9653 and then processed as described in previous Schemes to provide aminals of general formula (58).
  • Squaric acid (59) can be treated with oxalyl chloride as described in Ohno et al., J. Chem. Soc, Perkin Trans.
  • Squarates of general formula (13) can be treated with ammonia in an alcoholic solvent such as, but not limited to, methanol to provide squarates of general formula (14).
  • Benzotriazoles of general formula (3) can be treated with squarates of general formula (14) in a polar, aprotic solvent such as, but not limited to, DMF in the presence of a base such as, but not limited to, cesium carbonate to provide squarate aminals of general formula (15).
  • a polar, aprotic solvent such as, but not limited to, DMF
  • a base such as, but not limited to, cesium carbonate
  • Example 1A 3 -ethox y-4-(3 -p yridinylamino Y3 -cyclobutene- 1 ,2-dione 3-Aminopyridine (2.77 g, 29.4 mmol) in ethanol (30 mL) was added to a refluxing solution of 3,4-diethoxy-3-cyclobutene-l,2-dione (5.00 g, 29.4 mmol) in ethanol (100 mL) over a period of 1 hour. The mixture was heated at reflux for 24 hours, filtered, and the filtrate removed under reduced pressure.
  • Example IB 3-amino-4-(3-pyridinylaminoY3-cyclobutene-L2-dione
  • ethanol 80 mL
  • 2.0M NH 3 in methanol 30 mL
  • the solvent was removed under reduced pressure and the residue was triturated with diethyl ether to provide 3.80 g ofthe title compound as a pale yellow powder.
  • the product from Example IB (0.15 g, 0.79 mmol), and the product from Example 1C (0.26 g, 0.79 mmol) in DMF (3 mL) were treated with K 2 CO 3 (0.55 g, 3.97 mmol).
  • the reaction mixture was stirred at ambient temperature for 20 hours then diluted with 25 mL H 2 O and extracted with EtOAc (2 x 50 mL).
  • Example 2A N-Cl-CIH- 1,2, 3-benzotriazol-l-yl)-2.2-dimethylpropyl)-4-chlorobenz amide
  • a suspension of 4-chlorobenzamide, pivaldehyde, benzotriazole, and p-toluenesulfonic acid was processed as described in Example 1C to provide the title compound.
  • Example 2B N-Cl-CIH- 1,2, 3-benzotriazol-l-yl)-2.2-dimethylpropyl)-4-chlorobenz amide
  • Example IB A suspension ofthe product from Example IB, the product from Example 2 A, and K CU 3 was processed as described in Example ID to provide the title compound, mp 257-258 °C;
  • Example 3A N-(l-dH-l,2,3-benzotriazol-l-yl ' )-2,2-dimethylpropyl ' )-4-iodobenzamide
  • a suspension of 4-iodobenzamide, pivaldehyde, benzotriazole, and p-toluenesulfonic acid was processed as described in Example 1C to provide the title compound.
  • Example 3B N-( 1 - ( T3 ,4-dioxo-2-(3 -pyridinylamino)- 1 -cyclobuten- 1 - yl] amino 1 -2,2-dimethylprop yl)-4- iodobenzamide
  • Example 4A N-Cl -( 1 H- 1 ,2,3-benzotriazol- 1 -yl)-2,2-dimethylpropyl)-4-(2-furyl)benzamide
  • a solution of Example 3 A (51 mg, 0.12 mmol) in N-methylpyrrolidinone (2 mL) at 23 °C was treated with 2-(tributylstannyl)furan (41 ⁇ L, 0.13 mmol) followed by triphenylarsine (3.7 mg, 0.012 mmol) and then tris(dibenzylideneacetone)dipalladium(0) (5.4 mg, 0.006 mmol).
  • Example 4B N-( f l- ⁇ 3,4-dioxo-2-(3-pyridinylamino)-l-cvclobuten-l-yl]aminol-2,2-dimethylpropyl)-4-(2- furvDbenzamide
  • a suspension ofthe product from Example IB, the product from Example 4A, and K 2 CO 3 was processed as described in Example ID to provide the title compound, mp 230-232 °C;
  • Example 5A N-( 1 -( 1 H- 1 ,2,3 -benzotriazol- 1 - yl)-2,2-dimethylprop yl)-3 -chlorobenzamide A suspension of 3-chlorobenzamide, pivaldehyde, benzotriazole, and p-toluenesulfonic acid was processed as described in Example 1C to provide the title compound. MS (DCI/NH 3 ) m/z 343 (M+H) + .
  • Example 6 N-( 1 - ( [3 ,4-dioxo-2-(3 -pyridinylamino)- 1 -cyclobuten- 1 -yl] amino 1 -2,2-dimethylprop yl)-3 - mefhylbenzamide
  • Example 6A N-d-(lH-l,2,3-benzotriazol-l-yl)-2,2-dimethylpropyl)-3-methylbenzamide
  • a suspension of m-toluamide, pivaldehyde, benzotriazole, and p-toluenesulfonic acid was processed as described in Example 1C to provide the title compound.
  • Example 6B N-( 1 - ( [3 ,4-dioxo-2-( " 3 -pyridinylamino)- 1 -cyclobuten- 1 -yl] amino 1 -2,2-dimethylprop yl)-3 - mefhylbenzamide
  • a suspension ofthe product from Example IB, the product from Example 6 A, and K CO 3 was processed as described in Example ID to provide the title compound, mp 236-237 °C; MS (ESI+) m/z 393 (M+H) + ;
  • Example 7A N-d-(lH-l,2,3-benzotriazol-l-yl)-2,2-dimethylpropyl)-3-fluorobenzamide
  • a suspension of 3-fluorobenzamide, pivaldehyde, benzotriazole, and p-toluenesulfonic acid was processed as described in Example 1C to provide the title compound.
  • MS (DCI/NH3) m/z 327 (M+H) + .
  • Example 7B N-( 1-1 [3 ,4-dioxo-2-(3 -pyridinylamino)- 1 -cyclobuten- 1 - yl] amino 1 -2,2-dimethylprop yl)-3 - fluorobenz amide
  • a suspension ofthe product from Example IB, the product from Example 7 A, and K 2 CO3 was processed as described in Example ID to provide the title compound, mp 231-232 °C;
  • Example 8A N-(l-(lH-l,2,3-benzotriazol-l-yl)-2,2-dimethylpropyl)-3-iodobenzamide
  • a suspension of 3 -iodobenzamide, pivaldehyde, benzotriazole, and p-toluenesulfonic acid was processed as described in Example 1C to provide the title compound.
  • Example 8B N-( 1 - ⁇ [ “ 3 ,4-dioxo-2-(3-p yridinylamino)- 1 -cyclobuten- 1 -yl] amino 1 -2,2-dimethylprop yl)-3 - iodobenzamide
  • a suspension ofthe product from Example IB, the product from Example 8 A, and K 2 CO 3 was processed as described in Example ID to provide the title compound, mp 234-236 °C;
  • the resin was filtered to remove solvent and washed sequentially with DMF (3 x 0.5 mL), methanol (0.5 mL), DMF (3 x 0.5 mL), CH 2 C1 2 (3 x 0.5 mL), diethyl ether (2 x 0.5 mL) and dried.
  • the resin (126 mg, 0.133 mmol) was stirred with the product from Example IB (30 mg, 0.66 mmol) and cesium carbonate (100 mg, 0.310 mmol) in anhydrous dimethylacetamide (2 mL) for 7 days at 23 °C. The solution was filtered and the filtrate concentrated under reduced pressure. The residue was purified by preparative reverse-phase HPLC (elution with aqueous acetonitrile + 0.5% TFA) to provide 7 mg (13%) ofthe title compound. MS (DCI/NH3) m/z 407 (M+H) + ;
  • Example 10 N-( 1 - ⁇ [3 ,4-dioxo-2-(3 -pyridinylamino)- 1 -cyclobuten- 1 - yl] amino 1 -2,2-dimethylpropyl)-2,3 - dimefhoxybenzamide
  • a suspension of resin-bound benzotriazole was treated with 2,3-dimethoxybenzamide, pivaldehyde, and p-toluenesulfonic acid and was then processed with the product from Example IB and Cs 2 CO 3 as described in Example 9 to provide the title compound.
  • Example 12A N-( 1 -( 1 H- 1 ,2,3 -benzotriazol- 1 - yl)-2,2-dimethylpropyl)-3 ,5 -dichlorobenzamide A suspension of 3,5-dichlorobenzamide, pivaldehyde, benzotriazole, and p- toluenesulfonic acid was processed as described in Example 1C to provide the title compound.
  • Example 12B 3,5-dichloro-N-( ' l- ⁇ r3,4-dioxo-2-( ' 3-pyridinylamino)-l-cvclobuten-l-yllaminol-2,2- dimethylpropyDbenzamide
  • a suspension ofthe product from Example IB, the product from Example 12A, and K 2 CO 3 was processed as described in Example ID to provide the title compound, mp 260-262 °C; MS (ESI+) m/z 447 (M+H) + ;
  • Example 13 A N-(l-( ' lH-l,2,3-benzotriazol-l-yl)-2,2-dimethylpropyl)-3,5-dimethoxybenzamide A suspension of 3,5-dimethoxybenzamide, pivaldehyde, benzotriazole, and p- toluenesulfonic acid was processed as described in Example IC to provide the title compound.
  • Example 13B N-( 1 - 1 [3 ,4-dioxo-2-(3-pyridinylamino)- 1 -cyclobuten- 1 -yl]aminol -2,2-dimethylpropyl)-3 ,5- dimethoxybenz amide
  • a suspension ofthe product from Example IB, the product from Example 13A, and K 2 CO 3 was processed as described in Example ID to provide the title compound.
  • Example 16A N-( 1 -( 1 H- 1 ,2,3-benzotriazol- 1 -yl)-2,2-dimethylpropyl)-3 , 5 -difluorobenzamide
  • a suspension of 3,5-difluorobenzamide, pivaldehyde, benzotriazole, and p- toluenesulfonic acid was processed as described in Example IC to provide the title compound.
  • Example 17A N- l-(lH-l,2,3-benzotriazol-l-yl)-2,2-dimethyl-4-pentenyl]-4-chlorobenzamide
  • a suspension of 4-chlorobenzamide, 2,2-dimethyl -4-pentenal, benzotriazole, and p- toluenesulfonic acid was processed as in Example IC to provide the desired compound.
  • Example 17B 4-chloro-N-(- 1 - ⁇ [3 ,4-dioxo-2-(3-pyridinylamino)- 1 -cyclobuten- 1 - yl] aminol -2,2-dimethyl-4- pentenyPbenzamide
  • Example 18 4-chloro-N-( " - 1 - ⁇ [3 ,4-dioxo-2-(3 -pyridinylamino)- 1 -cyclobuten- 1 - yl] amino 1 -2,2-dimethyl-3 - phenylpropyDbenzamide
  • Example 18A 2,2-dimethyl-3-phenylpropanal To a solution of oxalyl chloride (10.1 g, 79.4 mmol) in methylene chloride (70 mL) at -78 °C was added dimethylsufoxide (10.0 mL, 139 mmol). The solution was stirred at -78 °C for 10 minutes then a solution of 2,2-dimethyl-3-phenylpropanol (6.52 g, 39.7 mmol) in methylene chloride (15 mL) was added.
  • Example 18B N-[l-(lH-l,2,3-benzotriazol-l-yl)-2,2-dimethyl-3-phenylpropyl]-4-chlorobenzamide
  • a suspension of p-chlorobenzamide (3.02 g, 20.0 mmol), the product from Example 18A (3.24 g, 20.0 mmol), and benzotriazole (2.38 g, 20.0 mmol) in benzene (75 mL) was treated with p-toluenesulfonic acid (190 mg, 1.00 mmol). The solution was heated at reflux under Dean-Stark conditions for 10 hours, then cooled gradually to ambient temperature.
  • Example 18C 4-chloro-N-(- 1 - ( ⁇ 3 ,4-dioxo-2-(3 - yridinylamino)- 1 -cyclobuten- 1 -yl] amino 1 -2,2-dimethyl-3 - phenylpropyDbenzamide
  • a suspension ofthe product from Example IB, the product from Example 18B, and 2 CO 3 was processed as described in Example ID to provide the title compound, mp 223-224 °C; MS (ESI+) m/z 489 (M+H) + ;
  • Example 19A 4-ethyl-4-formylhexanenitrile 2,2-Diethyl-4-cyanobutanol, oxalyl chloride and dimethylsulfoxide were processed as described in Example 18A to provide the title compound.
  • Example 19B N-ri-(lH-l,2,3-benzotriazol-l-yl)-2,2-diethyl-4-cyanobutyl]-4-chlorobenzamide
  • the product from Example 19A, 4-chlorobenzamide, benzotriazole, and p- toluenesulfonic acid were processed as described in Example IC to provide the title compound.
  • MS (ESI) m/z 410(M+H) + .
  • Example 19C 4-chloro-N-(4-c yano- 1 - ⁇ f 3 ,4-dioxo-2-( " 3 -pyridinylamino)- 1 -cyclobuten- 1 - yl] amino 1-2.2- diethylbutyl)benzamide
  • a suspension ofthe product from Example IB, the product from Example 19B, and K 2 CO 3 was processed as described in Example ID to provide the title compound, mp 242-243 °C; MS (ESI+) m/z 480 (M+H) + ;
  • Example 20A 2,2-bisr(allyloxy)methyl]butanal 2,2-Bis(allyloxymethyl)-l-butanol, oxalyl chloride and dimethylsulfoxide were processed as described in Example 18A to provide the title compound.
  • Example 20B N-r2,2-bisf( " allyloxy)methvn-l-(lH-l,2,3-benzotriazol-l-yl)butvn-4-chlorobenzamide
  • the product from Example 20A, 4-chlorobenzamide, benzotriazole, and p- toluenesulfonic acid were processed as described in Example 1 C to provide the title compound.
  • Example 20C N-(2,2-bisr(allyloxy)methyl]-l- ⁇ 3,4-dioxo-2-( ' 3-pyridinylamino)-l-cvclobuten-l- yl] amino lbutyl)-4-chlorobenzamide
  • a suspension ofthe product from Example IB, the product from Example 20B, and K 2 CO 3 was processed as described in Example ID to provide the title compound, mp 176-177 °C; MS (ESI+) m/z 539 (M+H) + ;
  • Example 21 A N-[lYlH-l,2,3-benzotriazol-l-yl)-2-ethylbutyl]-4-chlorobenzamide
  • a suspension of 4-chlorobenzamide, 2-ethylbutanal, benzotriazole, and p- toluenesulfonic acid was processed as in Example IC to provide the title compound.
  • Example 2 IB 4-chloro-N-( 1 - ⁇ T3 ,4-dioxo-2-( ' 3 -pyridinylamino)- 1 -cyclobuten- 1 -yl] amino ) -2- ethylbutvDbenzamide
  • a suspension ofthe product from Example IB, the product from Example 21 A, and K 2 CO 3 was processed as described in Example ID to provide the title compound, mp 232-233 °C;
  • Example 22 4-chloro-N-(2-c yclohexyl- 1 - ⁇ [3 ,4-dioxo-2-( " 3 -pyridinylamino)- 1 -cyclobuten- 1 -yl] amino 1-2- methylpropyPbenzamide
  • Example 22A 2-cyclohexyl-2-methylpropanal 2-Cyclohexyl-2-methyl-l -propanol, oxalyl chloride and dimethylsulfoxide were processed as described in Example 18A to provide the title compound.
  • Example 22B N-ri-(lH-l,2,3-benzotriazol-l-yl)-2-cyclohexyl-2-methylpropyl]-4-chlorobenzamide
  • the product from Example 22A, 4-chlorobenzamide, benzotriazole, and p- toluenesulfonic acid were processed as described in Example IC to provide the title compound.
  • MS (ESI) m/z 383 (M+H) + .
  • Example 22C 4-chloro-N-(2-cyclohexyl- 1 - ⁇ [3 ,4-dioxo-2-( " 3 -pyridinylamino)- 1 -cyclobuten- 1 - yl] amino 1 -2- methylpropyDbenzamide
  • a suspension of the product from Example IB, the product from Example 22B, and K 2 CO3 was processed as described in Example ID to provide the title compound, mp 275-276 °C;
  • Example 23A 1 -adamantylacetaldehvde 2-(l-Adamantyl)ethanol, oxalyl chloride and dimefhylsulfoxide were processed as described in Example 18 A to provide the title compound. MS (DCI/NH 3 ) m/z 179 (M+H) + .
  • Example 23B N-[2-( 1 -adamantyl)- 1 -( 1 H- 1 ,2,3-benzotriazol- 1 -vDethyl] -4-chlorobenzamide
  • the product from Example 23A, 4-chlorobenzamide, benzotriazole, and p- toluenesulfonic acid were processed as described in Example IC to provide the title compound.
  • Example 23C N-(2-( 1 -adamantyl)- 1 - ( [3 ,4-dioxo-2-(3 -pyridinylamino)- 1 -cyclobuten- 1 - yl] amino 1 ethv ⁇ )-2- chlorobenzamide
  • a suspension ofthe product from Example IB, the product from Example 23B, and K CO 3 were processed as described in Example ID to provide the title compound, mp 224-225 °C; MS (ESI+) m/z 505 (M+H) + ;
  • Example 24A 2,2-dichloropropionaldehyde Chlorine gas was bubbled through dimethylformamide (14.7 g, 0.202 mmol) for 5 minutes. The solution was heated to 45-55 °C and a solution of propionaldehyde (11.7, 0.202 mmol) in dimethylformamide (29.5 g, 0.404 mmol) was added slowly, maintaining the reaction temperature at 45-55 °C (a cooling bath was necessary to control the temperature). During the addition, Cl 2 was bubbled through the reaction to maintain a yellow color. After the addition, the reaction mixture was heated at 45-55 °C for 30 minutes. The solution was cooled to 0 °C and diethyl ether (100 mL) was added followed by cold water (100 mL). The organic portion was separated and washed with aqueous sodium bicarbonate (20 mL), brine (20 mL), dried (sodium sulfate), and concentrated under reduced pressure to provide 21.1 g of the title compound as an oil.
  • Example 24B N-[ 1 -( 1 H- 1 ,2,3-benzotriazol- 1 -yl)-2,2-dichloropropyl1-4-chlorobenzamide 4-Chlorobenzamide, the product from Example 24A, benzotriazole, and p- toluenesulfonic acid were processed as described in Example IC to provide the title compound. MS (ESI) m/z 381 (M-HV.
  • Example 24C 4-chloro-N-(2,2-di chloro- 1 - ( [3 ,4-dioxo-2-(3-p yridinylamino)- 1 -cyclobuten- 1 - yl] amino 1 -prop vDbenzamide
  • Example IB A suspension ofthe product from Example IB, the product from Example 24B, and K 2 CO 3 was processed as described in Example ID to provide the title compound, mp 201-202 °C; MS (ESI+) m/z 453 (M+H) + ;
  • Example 25A N-[l-(lH-l,2,3-benzotriazol-l-yl)-2,2-dichloropropyl]-3-chlorobenzamide 3-Chlorobenzamide, the product from Example 24A, benzotriazole, and p- toluenesulfonic acid were processed as described in Example IC to provide the title compound.
  • MS (ESI) m/z 381 (M-H) ⁇
  • Example 25B 3-chloro-N-(2,2-dichloro-l- ⁇ 3,4-dioxo-2-(3-pyridinylamino)-l-cyclobuten-l- yl] amino 1 -prop vDbenzamide
  • a suspension ofthe product from Example IB, the product from Example 25 A, and K2CO3 was processed as described in Example ID to provide the title compound, mp 202-204 °C; MS (ESI+) m/z 453 (M+H) + ;
  • Example 26A pentafluoropropanal Pentafluoropropanol, oxalyl chloride and dimethylsulfoxide were processed as described in Example 18 A to provide the title compound. MS (DCI/NH 3 ) m/z 149 (M+H) + .
  • Example 26B N- l-(lH-l,2,3-benzotriazol-l-yl)-2,2,3,3,3-pentafluoropropyll-4-chlorobenzamide 3-Chlorobenzamide, the product from Example 26A, benzotriazole, and p- toluenesulfonic acid were processed as described in Example IC to provide the title compound. MS (ESI-) m/z 403 (M-H) " .
  • Example 26C 3 -chloro-N-( 1 - ⁇ ⁇ 3 ,4-dioxo-2-(3 -pyridinylamino)- 1 -cyclobuten- 1 - yl]aminol-2,2,3,3,3-pentafluoropropyl)benzamide
  • a suspension ofthe product from Example IC, the product from Example 26B, and Cs 2 CO 3 was processed as described in Example ID to provide the title compound, mp 212-213 °C; MS (ESI+) m/z 475 (M+H) + ;
  • Example 27A 3-Ethoxy-4-(3-fluoro-phenylamino)-cvclobut-3-ene-l,2-dione
  • a solution of 3-fluoroaniline and 3,4-diethoxy-3-cyclobutene-l,2-dione in ethanol was processed as described in Example 1 A to provide the title compound.
  • Example 27B 3-Amino-4-(3-fluoro-phenylamino)-cvclobut-3-ene-l,2-dione
  • Example 28 4-chloro-N-( 1 - ⁇ [3 ,4-dioxo-2-(4-fluoroanilino)- 1 -cyclobuten- 1 - yllaminol-2,2-dimethylpropyl)benzamide
  • Example 28A 3-Ethoxy-4-(4-fluoro-phenylamino)-cyclobut-3-ene- 1 ,2-dione
  • a solution of 4-fluoroaniline and 3,4-diethoxy-3-cyclobutene-l,2-dione in ethanol was processed as described in Example 1 A to provide the title compound.
  • MS (DCI/NH3) m/z 236 (M+H) + .
  • Example 28B 3-A ino-4-(3-fluoro-phenylamino)-cyclobut-3-ene-l,2-dione
  • Example 28C 4-chloro-N-( 1 - ⁇ ⁇ 3 ,4-dioxo-2-(4-fluoroanilino)- 1 -cyclobuten- 1 - yl]aminol-2,2-dimethylpropyl)benzamide
  • a suspension ofthe product from Example 2A, the product from Example 28B, and K 2 CO 3 was processed as described in Example ID to provide the title compound, mp 247-249 °C; MS (ESI+) m/z 430 (M+H) + ;
  • Example 29A 3-(2-Chloro-pyridin-3-ylamino)-4-ethoxy-cyclobut-3-ene-l,2-dione
  • a solution of 2-chloro-3-aminopyridine and 3,4-diethoxy-3-cyclobutene-l,2-dione in ethanol was processed as described in Example 1 A to provide the title compound.
  • Example 29B 3-Amino-4-(2-chloro-pyridin-3-ylamino)-cvclobut-3-ene-l,2-dione
  • Example 29C 4-chloro-N-r 1 -( (2-[( " 2-chloro-3-p yridinyl)amino]-3 ,4-dioxo- 1 -cyclobuten- 1 -yll amino)-2,2- dimethylpropyl]benzamide
  • a suspension ofthe product from Example 2A, the product from Example 29B, and K 2 CO 3 was processed as described in Example ID to provide the title compound, mp 259-261 °C; MS (DCI/NH3) m/z 464 (M+H) + ;
  • Example 30A 3-(5-Bromo-6-fluoro-pyridin-3-ylamino)-4-ethoxy-cyclobut-3-ene-l,2-dione
  • a solution of 2-fluoro-3-bromo-5-aminopyridine and 3,4-diethoxy-3-cyclobutene-l,2- dione in ethanol was processed as described in Example 1 A to provide the title compound.
  • Example 30B 3-Amino-4-(5-bromo-6-fluoro-pyridin-3-ylamino)-cyclobut-3-ene-l,2-dione
  • Example 30C N- l-((2-f(5-bromo-6-fluoro-3-pyridinyl)amino1-3,4-dioxo-l-cvclobuten-l-yllamino)-2,2- dimethylpropyl]-4-chlorobenzamide
  • Example 31 4-chloro-N-ri-( ⁇ 2-[( " 2-chloro-3-pyridinyl)amino]-3,4-dioxo-l-cvclobuten-l-yllamino)-2,2- dimethyl-3-phenylpropyl]benzamide
  • a suspension ofthe product from Example 18B, the product from Example 29B, and K 2 CO 3 was processed as described in Example ID to provide the title compound, mp 236-237 °C;
  • Example 32 N- l-( , ⁇ 2-[(2-chloro-3-pyridinyl)amino1-3,4-dioxo-l-cvclobuten-l-yllamino)-2,2- dimethylpropyll-3-methylbenzamide
  • a suspension ofthe product from Example 6 A, the product from Example 29B, and K 2 CO 3 was processed as described in Example ID to provide the title compound, mp 238-239 °C; MS (ESI+) m/z 427 (M+H) + ;
  • Example 33 A tert-butyl 3-(3-pyridinyl)diazathiane-l-carboxylate 2,2-dioxide tert-Butanol (2.0 mL, 21.1 mmol) was added to a solution of chlorosulfonyl-isocyanate (1.8 mL, 21.1 mmol) in CH 2 C1 2 (40 mL). The reaction mixture was stirred at ambient temperature for 0.5 hours and then treated with a solution of 3-aminopyridine (2.00 g, 21.1 mmol) and triethylamine (4.4 mL, 31.6 mmol) in CH 2 C1 2 (20 mL) via canula.
  • Example 33B N-(3-pyridinyl)sulfamide Trifluoroacetic acid (10 mL) was added to a solution ofthe product from Example 33 A (1.17 g, 4.28 mmol) in CH 2 C1 2 (40 mL). The reaction mixture was stirred at ambient temperature for 2 hours and then the solvent was removed under reduced pressure. The crude reaction mixture was diluted with EtOAc (25 mL) and washed with saturated aqueous NaHCO 3 (50 mL). The aqueous layer was extracted with EtOAc (25 mL) and the organic phases were combined, dried over Na 2 SO 4 and filtered. The filtrate was concentrated under reduced pressure and the residue was triturated from Et 2 O/hexanes to provide 0.40 g of the title compound as a white powder. MS (DCJVNH 3 ) m/z 174 (M+H) + .
  • Example 33C 4-chloro-N-( ' 2,2-dimethyl-l-(r(3-pyridinylamino)sulfonyl1aminolpropyl)benzamide
  • a suspension ofthe product from Example 33B , the product from Example 2 A, and K 2 CO 3 was processed as described in Example ID to provide the title compound, mp 166-167 °C; MS (ESI+) m/z 397 (M+H) + ;
  • Example 34 N-(2.2-dimethyl-l-(r(3-pyridinylamino)sulfonvnaminolpropyl)-4-iodobenzamide A suspension ofthe product from Example 33B, the product from Example 3 A, and K 2 CO 3 was processed as described in Example ID to provide the title compound, mp 177-178 °C;
  • Example 35 A ethyl oxo(3-pyridinylamino)acetate To a solution 3-aminopyridine (3.00 g, 27.0 mmol) in methylene chloride (110 mL) at 23 °C was added triethylamine (7.53 mL mL, 54.0 mmol) and N,N-dimethylaminopyridine (330 mg, 2.70 mmol). The solution was cooled to 0 °C and chloroethyloxalate 4.42 g, 32.4 mmol) was added in a dropwise fashion. The reaction mixture was stirred at 0 °C for 2 hours and then quenched with water (30 mL) and partitioned.
  • Example 35B N 1 -(3 -pyridinvDethanediamide A solution ofthe product from Example 35 A and ammonia in methanol was processed as described in Example IB to provide the title compound. MS (ESI-) m/z 164 (M-H) " .
  • Example 35C N'- ⁇ l-r(4-chlor ⁇ benzoyl)amino]-2,2-dimethylpropyll-N 2 -( ' 3-pyridinvDethanediamide
  • a suspension ofthe product from Example 2A, the product from Example 35B, and K 2 CO 3 was processed as described in Example ID to provide the title compound, mp 168-170 °C; MS (ESI+) m/z 389 (M+H) + ;
  • Example 36 N-('l- ⁇ r3,4-dioxo-2-(3-pyridinylamino)-l-cvclobuten-l-yl1aminol-2,2-dimethylpropyl)-3- phenylpropanamide
  • Example 36 A N- 1 -( 1 H- 1 ,2,3 -benzotriazol- 1 -yl)-2,2-dimethylprop yl]-3 -phenylpropanamide
  • a suspension of 3-phenyl-propionamide, pivaldehyde, benzotriazole, and p- toluenesulfonic acid was processed as described in Example IC to provide the title compound.
  • Example 36B N-( 1 - ⁇ ⁇ 3 ,4-dioxo-2-(3 -pyridinylamino)- 1 -cyclobuten- 1 - yl] amino 1 -2,2-dimethylprop yl)-3 - phenylpropionamide
  • a suspension ofthe product from Example IB, the product from Example 36 A, and K 2 CO 3 was processed as described in Example ID to provide the title compound, mp 219-220 °C; MS (ESI+) m/z 407 (M+H) + ;
  • Example 37A methyl 3-(3-pyridinvPpropanoate To a solution of 3-(3-pyridinyl)propanoic acid (2.50 g, 16.5 mmol) in CH C1 2 (110 mL) and MeOH (1 mL) was added DMAP (0.010 g, 0.082 mmol) and diisopropylcarbodiimide (4.17 g, 33.1 mmol). The reaction was stirred for 2 hours at 23 °C then saturated aqueous NaHCO 3 (100 mL) was added. The mixture was extracted with CH 2 C1 2 (100 mL) and the combined extracts were dried over Na 2 SO 4 , filtered, and evaporated in vacuo.
  • Example 37B 3-(3-pyridinyl)propanamide
  • NH 3 2.0 M in MeOH, 40 mL
  • the mixture was allowed to cool to 23 °C and the solvent was evaporated under reduced pressure.
  • the crude product was recrystallized from EtOAc/hexanes to provide 1.71 g (69%) ofthe title compound.
  • MS (DCI/NH3) m/z 151 (M+H) + .
  • Example 37C N-[l-(lH-l,2,3-benzotriazol-l-yl)-2,2-dimethylpropyl]-3-(3-pyridinyl)propanamide
  • a suspension ofthe product from Example 37B, pivaldehyde, benzotriazole, and p- toluenesulfonic acid was processed as described in Example 1 C to provide the desired product.
  • MS (DCI/NH3) m/z 385 (M+H) + .
  • Example 37D N-ri-( ⁇ 2-r( ' 2-chloro-3-pyridinyl)aminol-3,4-dioxo-l-cyclobuten-l-yllamino)-2,2- dimethylpropyll-3-(3-p idinyl)propanamide
  • a suspension ofthe product from Example 29B (0.199 g, 0.889 mmol), the product from Example 37C (0.300 g, 0.889 mmol), and K 2 CO 3 (0.614 g, 4.45 mmol) in DMF (3 mL) was heated at 50 °C for 24 hours. The reaction mixture was allowed to cool to 23 °C and then applied to a silica gel column. Elution with 10% EtOH/EtOAc provided 14 mg (4%) ofthe title compound, mp 179-180 °C; MS (ESI+) m/z 442 (M+H) + ;
  • Example 38A N-[l-(lH-l,2,3-benzotriazol-l-vD-2,2-dimethylpropyl1-3-vinylbenzamide
  • the product from Example 8 A (0.500 g, 1.15 mmol), tributyl(vinyl)tin 0.410 g, 1.27 mmol), triphenylarsine 0.035 g, 0.115 mmol), and tris(dibenzylidineacetone)dipalladium(0) (0.053 g, 0.058 mmol) were combined in anhydrous NMP (4 mL) and stirred at 23 °C for 18 hours.
  • the reaction mixture was diluted with EtOAc (50 mL) and filtered through a 0.25 inch frit of Celite and the frit was washed with additional EtOAc (25 mL). The filtrate was washed with 100 mL brine and the brine back extracted with EtOAc (50 mL). The organic phases were combined, dried over Na 2 SO 4 , filtered, and absorbed onto silica gel. The crude material was purified by flash chromatography on silica gel (elution with EtOAc/CH Cl 2 /hexanes, 5:47.5:47.5) to provide 223 mg (58%) the title compound. MS (DCI/NH 3 ) m/z 335 (M+H) + .
  • Example 38B N-( 1 - ⁇ [3 ,4-dioxo-2-(3 -pyridinylamino)- 1 -cyclobuten- 1 - yl] amino 1 -2,2-dimethylprop yl)-3 - vinylbenzamide
  • a suspension ofthe product from Example IB, the product from Example 38 A, and K 2 CO 3 was processed as described in Example ID to provide the title compound, mp 209-210 °C; MS (ESI+) m/z 405 (M+H) + ;
  • Example 39 N-( 1 - ⁇ [3 ,4-dioxo-2-( " 3 -pyridinylamino)- 1 -cyclobuten- 1 -yl] amino 1 -2,2-dimethylprop vDf 1,1'- biphenyl]-3-carboxamide
  • Example 39A N-( 1 - ⁇ [3 ,4-dioxo-2-( " 3 -pyridinylamino)- 1 -cyclobuten- 1 -yl] amino 1 -2,2-dimethylprop vDf 1,1'- biphenyl]-3-carboxamide
  • Example 39A N-( 1 - ⁇ [3 ,4-dioxo-2-( " 3 -pyridinylamino)- 1 -cyclobuten- 1 -yl] amino 1 -2,2-dimethylprop vDf 1,1'- biphenyl]-3-carboxamide
  • Example 39B N-( 1 - ⁇ [3 ,4-dioxo-2-(3-p yridinylamino)- 1 -cyclobuten- 1 - yllaminol -2,2-dimethylprop yl)[ 1,1'- biphenyll-3-carboxamide
  • Example 40 3-acetyl-N-( ' l-(r3,4-dioxo-2-( ' 3-pyridinylamino)-l-cyclobuten-l-yl1aminol-2,2- dimethylpropyDbenzamide
  • Example 40A 3-acetyl-NT 1 -d H- 1.2.3-benzotriazol- 1 -yl)-2,2-dimethylpropynbenzamide
  • the product from Example 8A (0.500 g, 1.15 mmol), tributyl(l-ethoxyvinyl)tin (0.459 g, 1.27 mmol), triphenylarsine (0.035 g, 0.115 mmol), and tiis(dibenzylidineacetone)dipalladium(0) (0.053 g, 0.058 mmol) were combined in anhydrous NMP (4 mL) and stirred at 23 °C for 18 hours.
  • Example 40 A A suspension ofthe product from Example IB, Example 40 A, and K 2 CO 3 was processed as described in Example ID to provide the title compound, mp 218-219 °C; MS (ESI+) m/z 421 (M+H) + ;
  • Example 41 A N-ri-dH-l,2,3-benzotriazol-l-yl)-2,2-dimethylpropyn-2-pyridinecarboxamide
  • a suspension of 2-pyridinecarboxamide, pivaldehyde, benzotriazole, and p- toluenesulfonic acid was processed as described in Example IC to provide the desired product.
  • Example 41B N-( 1 - ( [3 ,4-dioxo-2-(3-p yridinylamino)- 1 -cyclobuten- 1 - yl]amino 1 -2,2-dimethylprop yl)-2- pyridinecarboxamide
  • a suspension ofthe product from Example IB, the product from Example 41 A, and K 2 CO 3 was processed as described in Example ID to provide the title compound.
  • Example 42B N-( 1 - ⁇ T3 ,4-dioxo-2-(3-p yridinylamino)- 1 -cyclobuten- 1 -yl] amino 1 -2,2-dimethylprop yl)-4- fluoro-3-(trifluoromethyl)benzamide
  • a suspension ofthe product from Example IB, the product from Example 42 A, and K 2 CO 3 was processed as described in Example ID to provide the title compound.
  • Example 43 N-( 1 - ([3,4-dioxo-2-(3-pyridinylamino)- 1 -cyclobuten-1 -yl]aminol -2,2-dimethylpropyl)-2- phenylacetamide Resin-bound benzotriazole, 2-phenylacetamide, pivaldehyde, p-toluenesulfonic acid, the product from Example IB and Cs 2 CO 3 were processed as described in Example 9 to provide the title compound. MS (ESI+) m/z 393 (M+H) + ;
  • Example 44 N-( 1 - ⁇ T3 ,4-dioxo-2-(3 -pyridinylamino)- 1 -cyclobuten- 1 - yl] amino 1 -2,2-dimethylprop yl)-3 - phenylprop-2-enamide Resin-bound benzotriazole, 3-phenylacrylamide, pivaldehyde, p-toluenesulfonic acid, the product from Example IB and CS2CO 3 were processed as described in Example 9 to provide the title compound. MS (ESI+) m/z 405 (M+H) + ;
  • Example 45 4-chloro-N-(2,2-dichloro- 1 - ⁇ [3 ,4-dioxo-2-(3-p yridinylamino)- 1 -cyclobuten- 1 - yl] amino 1 pentyDbenzamide
  • Example 45A N-ri-dH-1.2,3-benzotriazol-l-yl)-2,2-dichloropentyl1-4-chlorobenzamide
  • a suspension of 4-chlorobenzamide, 2,2-dichloropentanal, benzotriazole, and p- toluenesulfonic acid was processed as in Example IC to provide the title compound.
  • MS (ESI+) m/z 411 (M+H) + .
  • Example 45B 4-chloro-N-(2,2-dichloro-l- ⁇ 3,4-dioxo-2-(3-pyridinylamino)-l-cvclobuten-l- yll amino 1 pentvDbenzamide
  • a suspension of the product from Example IB, the product from Example 45 A, and K 2 CO 3 was processed as described in Example ID to provide the title compound, mp 258-259 °C;
  • Example 46 4-chloro-N-( 1 - ⁇ [3 ,4-dioxo-2-(4-pyridinylamino)- 1 -cyclobuten- 1 - yllaminol -2,2- dimethylpropyPbenzamide
  • Example 46A 3-ethoxy-4-(4-pyridinylamino)-3-cyclobutene-l,2-dione
  • a solution of 4-aminopyridine and 3,4-diethoxy-3-cyclobutene-l,2-dione in ethanol was processed as described in Example 1 A to provide the title compound.
  • Example 46B 3-amino-4-(4-pyridinylamino)-3-cyclobutene- 1 ,2-dione
  • a solution ofthe product from Example 46 A and ammonia in methanol was processed as described in Example IB to provide the title compound.
  • Example 46B A suspension ofthe product from Example 46B, the product from Example 2 A, and K 2 CO 3 was processed as described in Example ID to provide the title compound, mp 244-246 °C; MS (ESI+) m/z 413 (M+H) + ;
  • Example 47A 3-ethoxy-4-(2-pyridinylamino)-3-cyclobutene-l,2-dione
  • a solution of 2-aminopyridine and 3,4-diethoxy-3-cyclobutene-l,2-dione in ethanol was processed as described in Example 1 A to provide the title compound.
  • Example 47B 3-amino-4-(2-pyridinylamino)-3-cyclobutene-l,2-dione
  • MS DCI/NH3 m/z 190 (M+H) + .
  • Example 47B A suspension ofthe product from Example 47B, the product from Example 2A, and K2CO 3 was processed as described in Example ID to provide the title compound, mp 246-248 °C; MS (ESI+) m/z 413 (M+H) + ;
  • Example 48A N-[l-dH-l,2,3-benzotriazol-l-yl)-2,2-dimethylpropyl1benzamide
  • a suspension of benzamide, pivaldehyde, benzotriazole, and p-toluenesulfonic acid was processed as in Example IC to provide the title compound.
  • Example 16B 3.5-difluorobenzamide
  • [ ⁇ ] D 23 +30 ° (c 0.013, DMSO); MS (ESI+) m/z 415 (M+H) + ;
  • Example 16B 3,5-difluorobenzamide
  • Example 51 A N-ri-dH-1.2.3-benzotriazol-l-yl)-2,2-dichloropropyll-3,5-difluorobenzamide 3,5-Difluorobenzamide, the product from Example 24A, benzotriazole, and p- toluenesulfonic acid were processed as described in Example IC to provide the title compound. MS (ESI+) m/z 385 (M+H) + .
  • Example 5 N-(2,2-dichloro- 1 - ⁇ [3.4-dioxo-2-(3 -pyridinylamino)- 1 -cyclobuten- 1 - yl]amino 1 propyl)-3 ,5 - difluorobenzamide
  • a suspension ofthe product from Example IB, the product from Example 51 A, and K 2 CO 3 was processed as described in Example ID to provide the title compound, mp 231-232 °C; MS (ESI+) m/z 455 (M+H) + ;
  • Example 52 4-chloro-N- ⁇ l- ( " 3,4-dioxo-2- ⁇ [5-(trifluoromethyPpyridin-3-yllaminol-l-cyclobuten-l- yl)amino]-2,2-dimethylpropyllbenzamide
  • Example 52A 5-(trifluoromethyl)pyridin-3-ylamine
  • 4-chloro-5-trifluoromethyl pyridine (4.86 g, 26.8 mmol)
  • Ni(COD) 2 0.368 g, 1.34 mmol
  • Pd(dppf) 2 CH 2 Cl 2 (2.19 g, 2.68 mmol)
  • 1,1 '- bis(diphenylphosphino)ferrocene (1.00 g, 1.80 mmol
  • benzophenone imine (5.82 g, 32.1 mmol)
  • sodium tert-butoxide (3.60 g, 37.5 mmol) in toluene was heated
  • Example 52B 3-ethoxy-4-(5-trifluoromethyl-3-pyridinylamino)-cyclobut-3-ene-l,2-dione
  • a solution ofthe product from Example 52A (2.98 g, 18.4 mmol) and 3,4,-diethoxy-3- cyclobutene-l,2-dione (3.13 g, 18.4 mmol) in EtOH (50 mL) was heated at reflux for 48 hours. The reaction mixture was filtered while still hot and the filtrate was absorbed onto silica gel. The crude material was purified by chromatography, eluting with EtOAc/hexanes (3:1) to provide 2.00 g (38 % yield) ofthe desired compound as colorless crystals. MS (DCI/NH 3 ) m/z 287 (M+H) + .
  • Example 52C 3-amino-4-(5-trifluoromethyl-3-pyridinylamino)-cvclobut-3-ene-l,2-dione
  • the product from Example 52B (2.00 g, 6.99 mmol) was dissolved in 2.0 M NH 3 in MeOH and stirred in a sealed vessel for 5 hours.
  • the reaction mixture was concentrated in vacuo to a volume of 15 mL and triturated with EtOAc.
  • the product (1.59 g, 89 % yield) was collected by filtration and used without further purification.
  • MS (DCI/NH3) m/z 258 (M+H) + .
  • Example 52D 4-chloro-N- ( 1 - IY3 ,4-dioxo-2- ( ⁇ 5 -( " trifluoromethvPp yridin-3 - yl] amino 1 - 1 -cyclobuten- 1 - yl)amino]-2,2-dimethylpropyllbenzamide
  • a suspension ofthe product from Example 52C, the product from Example 2A, and K 2 CO 3 was processed as described in Example ID to provide the title compound, mp 231-232 °C; MS (ESI+) m/z 481 (M+H) + ;
  • Example 53 3 ,5-dichloro-N- ⁇ 1 - ⁇ (3 ,4-dioxo-2- ⁇ ⁇ 5 -(trifluoromethyl)p yridin-3 - yl] amino 1 - 1 -cyclobuten- 1 - yl)amino]-2,2-dimethylpropyll benzamide
  • a suspension ofthe product from Example 52C, the product from Example 12 A, and K 2 CO 3 was processed as described in Example ID to provide the title compound, mp 233-234 °C; MS (ESI+) m/z 515 (M+H) + ;
  • Example 54 4-chloro-N- ⁇ 1 -(Y3,4-dioxo-2- (r5-(trifluoromethyl)pyridin-3-yl] amino 1- 1 -cyclobuten- 1 - yl)amino1-2,2-dimethyl-3-phenylpropyllbenzamide
  • a suspension ofthe product from Example 52C, the product from Example 18B, and K 2 CO 3 was processed as described in Example ID to provide the title compound. mp 194-195 °C;
  • Example 55A N-[l-dH-l,2,3-benzotriazol-l-yl)-2,2-dimethyl-3-phenylpropyl1-3,5-difluorobenzamide 3,5-DifIuorobenzamide, the product from Example 18A, benzotriazole, and p- toluenesulfonic acid were processed as described in Example 18B to provide the title compound. MS (DCI/NH 3 ) m/z 421 (M+H) + .
  • Example 56 (+) 3 -chloro-N-( 1 - ( [3 ,4-dioxo-2-(3-p yridinylamino)- 1 -cyclobuten- 1 -yl] amino 1-2,2- dimethylpropyPbenzamide
  • [ ⁇ ] D 20 +40° (c 0.11, DMSO); MS (ESI+) m z 413 (M+H) + ;
  • Example 57 (-) 3 -chloro-N-C 1 - ⁇ [3 ⁇ -dioxo ⁇ -H -pyridinylamino)- 1 -cyclobuten- 1 -yl] amino 1-2,2- dimethylpropyPbenzamide
  • [ ⁇ ] D 20 -43° (c 0.09, DMSO); MS (ESI+) m/z 413 (M+H) + ;
  • Example 58A N-ri-(lH-l,2,3-benzotriazol-l-yl)-2,2-dimethyl-3-phenylpropyl1-3,5-dichlorobenzamide 3,5-Dichlorobenzamide, the product from Example 18A, benzotriazole, and p- toluenesulfonic acid were processed as described in Example 18B to provide the title compound. MS (DCI/NH 3 ) m/z 453 (M+H) + .
  • Example 59A N-( " l-dH-l,2,3-benzotriazol-l-yl)-2,2-dimethyl-3-phenylpropyl1-3-chlorobenzamide 3-Chlorobenzamide, the product from Example 18A, benzotriazole, and p- toluenesulfonic acid were processed as described in Example 18B to provide the title compound. MS (DCI/NH3) m/z 419 (M+H) + .
  • Example 60A N-[l-(lH-l,2,3-benzotriazol-l-yl)-2,2-dimethyl-3-phenylpropyl]-3-chlorobenzamide m-Toluamide, the product from Example 18 A, benzotriazole, and p-toluenesulfonic acid were processed as described in Example 18B to provide the title compound. MS (DCI/NH 3 ) m/z 399 (M+H) + .
  • Example 60B N-( 1 - ⁇ [3 ,4-dioxo-2-(3-p yridinylamino)- 1 -cyclobuten- 1 - yl] amino 1 -2,2-dimethyl-3 - phenylprop yl)-3 -methylbenzamide
  • a suspension ofthe product from Example IB, the product from Example 60A, and K 2 CO3 was processed as described in Example ID to provide the title compound, mp 234-235 °C; MS (ESI+) m/z 469 (M+H) + ;
  • Example 61 N- [ 1 -( ⁇ 2- ( " 2-chlorop yridin-3 -vPamino] -3 ,4-dioxo- 1 -cyclobuten- 1 - yll amino)-2,2-dimethyl-3 - phenylprop yl] -3 -methylbenzamide
  • a suspension ofthe product from Example 29B, the product from Example 60 A, and K 2 CO 3 was processed as described in Example ID to provide the title compound, mp 234-235 °C; MS (ESI+) m/z 503 (M+H) + ;
  • Example 62 4-chloro-N-ri-((2-r(6-chloropyridin-3-yl)amino]-3,4-dioxo-l-cvclobuten-l-yllamino)-2,2- dimethylpropyllbenzamide
  • Example 62A 4-(6-chloro3-pyridinylamino)-3-ethoxy-cyclobut-3-ene-l,2-dione 5-Amino-2-chloropyridine (2.32 g, 18.0 mmol) in ethanol (50 mL) was added to a solution of 3,4-diethoxy-3-cyclobutene-l,2-dione 3.07 g, 18.0 mmol) in ethanol (200 mL) at 70 °C over a period of 6 hours.
  • Example 62B 3-amino-4-(6-chloro-3-pyridinylamino)-cyclobut-3-ene-l,2-dione
  • Example 62C 4-chloro-N- ⁇ 1 -( (2- [(6-chloropyridin-3-yl)amino] -3, 4-dioxo-l -cyclobuten- 1 -yll amino)-2,2- dimethylpropyl benzamide
  • a suspension ofthe product from Example 62B, the product from Example 2A, and K 2 CO 3 was processed as described in Example ID to provide the title compound, mp 258-259 °C; MS (ESI+) m/z 447 (M+H) + ;
  • Example 63A 3 -amino-2-fluorop yridine To a solution of 2-chloro-6-fluoro-5-nitropyridine (2.30 g, 13.0 mmol) in EtOH (50 mL) and sodium acetate dihydrate (1.69 g, 14.3 mmol) was added 10% Pd/C (230 mg). The suspension was hydrogenated (4 atm) at 23 °C for 5 hours then filtered through Celite. The filter cake was rinsed with EtOH and the filtrate concentrated to provide 1.34 g ofthe crude product as an off-yellow solid which was used without further purification. MS (DCI/NH 3 ) m/z 113 (M+H) + .
  • Example 63B 4-(2-fluoropyridin-3-ylamino)-3-ethoxy-cyclobut-3-ene-l,2-dione
  • Example 63C 3-amino-4-(6-fluoro-3-pyridinylamino)-cyclobut-3-ene-l,2-dione
  • Example 63D 4-chloro-N-ri-( ⁇ 2-r(2-fluoropyridin-3-yl)amino1-3,4-dioxo-l-cvclobuten-l-yllamino)-2,2- dimethylpropyl]benzamide
  • Example 64A N-d -benzotriazol- 1 -yl-3 ,3 -dimethyl-butvP-3 -chloro-benzamide A suspension of 3-chlorobenzamide, 3,3-dimethyl-butyraldehyde, and benzotriazole were processed as described in Example IC to provide the desired product. MS (DCI/NH 3 ) m/z 357 (M+H) + .
  • Example IB A suspension ofthe product from Example IB, the product from Example 64A, and K 2 CO 3 was processed as described in Example ID to provide the title compound, mp 238-239 °C; MS (ESI+) m/z 427 (M+H) + ;
  • Example 65A N-d-(lH-l,2,3-benzotriazol-l-yl)-2,2-dimethylpropyl)thiophene-2-carboxamide
  • a suspension of thiophene-2-carboxamide, pivaldehyde, benzotriazole, and p- toluenesulfonic acid was processed as in Example IC to provide the title compound.
  • Example 65B N-( 1-1 [3 ,4-dioxo-2-(3-p yridinylamino)- 1 -cyclobuten- 1 - yl] amino 1-2,2- dimethylpropyl)thiophene-2-carboxamide
  • a suspension ofthe product from Example IB, the product from Example 65A, and K 2 CO 3 was processed as described in Example ID to provide the title compound.
  • Example 66A N-d-(lH-l,2,3-benzotriazol-l-yl)-2,2-dimethylpropyl)-3-bromobenzamide
  • a suspension of 3-bromobenzamide, pivaldehyde, benzotriazole, and p-toluenesulfonic acid was processed as described in Example IC to provide the title compound.
  • Example IB A suspension ofthe product from Example IB, the product from Example 66A, and K 2 CO 3 was processed as described in Example ID to provide the title compound, mp 244-245 °C; MS (ESI+) m/z 459 (M+H) + ;
  • Example 67 3-bromo-N-ri-( ' ⁇ 2-r( ' 2-chloropyridin-3-yl)amino1-3,4-dioxo-l -cyclobuten- l-yllamino)-2,2- dimethylpropyllbenzamide
  • a suspension ofthe product from Example 29B, the product from Example 66 A, and K 2 CO 3 was processed as described in Example ID to provide the title compound, mp 257-259 °C; MS (ESI+) m/z 493 (M+H) + ;
  • Example 68B N- l-dH-l,2,3-benzotriazol-l-yl)-2,2-dimethylpropyl1-9-oxo-9H-fluorene-4-carboxamide
  • a suspension ofthe product from Example 68 A, pivaldehyde, benzotriazole, and p- toluenesulfonic acid was processed as in Example IC to provide the title compound.
  • Example 69A methyl 3-(aminocarbonyl)benzoate 3-(Methoxycarbonyl)benzoic acid (1.0 g, 5.55 mmol) and SOCl (0.81 g, 11.1 mmol) were dissolved in 20 mL of toluene. A catalytic amount of DMF (3 drops) was added and the reaction mixture was heated at 92 °C for 2.5 hours. The mixture was cooled to 23 °C and the solvent removed in vacuo. The crude material was dissolved in 25 mL THF and 3 mL NH OH was added. The reaction was stirred for 10 minutes then diluted with 50 mL of EtOAc and washed with 10 mL of 2 N HCI.
  • Example 69B methyl 3-( ⁇ [ 1 -(1 H- 1 ,2,3-benzotriazol- 1 -yl)-2,2-dimethylpropyl]amino 1 carbonvPbenzoate
  • a suspension ofthe product from Example 69A, pivaldehyde, benzotriazole, and p- toluenesulfonic acid was processed as in Example IC to provide the title compound.
  • Example 69C methyl 3- ⁇ ( 1 - ⁇ [3 ,4-dioxo-2-(3 -pyridinylamino)- 1 -cyclobuten- 1 - yl] amino 1-2,2- dimethylpropyl)amino]carbonyllbenzoate
  • a suspension ofthe product from Example IB, the product from Example 69B, and K 2 CO 3 was processed as described in Example ID to provide the title compound, mp 228-229 °C; MS (ESI+) m/z 437 (M+H) + ;
  • Example 70 ( " +) N-d - ⁇ [3 ,4-dioxo-2-(3 -pyridinylamino)- 1 -cyclobuten- 1 - yl] amino 1 -2,2-dimethylprop yl)-3 - methylbenzamide
  • [ ⁇ ] D 23 +98° (c 0.25, EtOH);
  • Example 71 N-d- ⁇ [3,4-dioxo-2-( " 3-pyridinylamino)-l-cvclobuten-l-yl]aminol-2,2-dimethylpropyP-3- methylbenzamide
  • D 23 -96° (c 0.30, EtOH);
  • Example 72 ( " +) N-( 1 - ( [3 ,4-dioxo-2-(3 -pyridinylamino)- 1 -cyclobuten- 1 - yl] amino 1 -2,2-dimethyl-3 - phenylprop yl)-3 -methylbenzamide
  • [ ⁇ ] D 23 +105° (c 0.36, EtOH);
  • Example 73 (-) N-d - ⁇ [3,4-dioxo-2-(3-pyridinylamino)-l -cyclobuten- 1 -yllaminol -2,2-dimethyl-3- phenylprop yl)-3 -methylbenzamide
  • [ ⁇ ] D 23 -96° (c 0.34, EtOH);
  • Example 74 (+) N-[ 1 -( ⁇ 2-
  • Example 75 N- l-((2-r( ' 2-chloropyridin-3-vPamino1-3,4-dioxo-l-cvclobuten-l-yllamino)-2.2- dimethylpropyl]-3-methylbenzamide
  • [ ⁇ ] D 23 -136° (c 0.27, EtOH);
  • Example 76 (+) N-d - 3 ,4-dioxo-2-(3-pyridinylamino)- 1 -cyclobuten- 1 -yl] amino 1 -2,2-dimethyl-3- phenylpropyl)-3,5-difluorobenzamide
  • [ ⁇ ] D 23 +77° (c 0.22, EtOH);
  • Example77A N-[l-(lH-1.2.3-benzotriazol-l-yl)-2,2-dimethylpropyl1-3-(2-furyl)benzamide
  • a solution ofthe product from Example 8A (0.50 g, 1.15 mmol), 2- (tributylstannyl)furan (0.45 g, 1.27 mmol), triphenylarsinine (0.035 g, 0.115 mmol), and tris(dibenzylideneacetone)dipalladium(0) (0.053 g, 0.058 mmol) in 6.0 mL NMP was stirred at 23 °C for 16 hours. The mixture was diluted with 50 mL H 2 O and extracted twice with 50 mL of EtOAc.
  • Example 77B N-( 1 - ⁇ ⁇ ,4-dioxo-2-(3-p yridinylamino)- 1 -cyclobuten- 1 -yl] aminol -2,2-dimethylprop yl)-3 -(2- furyPbenzamide
  • a suspension ofthe product from Example IB, the product from Example 77A, and K CO 3 was processed as described in Example ID to provide the title compound, mp 251-252 °C; MS (ESI+) m/z 445 (M+H) + ;
  • Example 78 N-ri-( ,
  • a suspension ofthe product from Example 29B, the product from Example 7 A, and K 2 CO 3 was processed as described in Example ID to provide the title compound, mp 228-229 °C; MS (ESI+) m/z 431 (M+H) + ;
  • Example 80A 3-ethoxy-4- (2-methoxypyridin-3-yl)amino]cyclobut-3-ene-l,2-dione
  • a solution of 3-amino-2-methoxypyridine and 3,4-diethoxy-3-cyclobutene-l,2-dione in ethanol was processed as described in Example 62A to provide the title compound.
  • Example 80B 3-amino-4-r(2 -methoxyp yridin-3-yl)amino]cvclobut-3-ene-l,2-dione
  • Example 80C 4-chloro-N-[l-((2-[(2 -methoxyp yridin-3-yl)amino1-3.4-dioxo-l-cyclobuten-l-yllamino)-2,2- dimethylpropyl]benzamide
  • a suspension ofthe product from Example 80B, the product from Example 2 A, and K 2 CO 3 was processed as described in Example ID to provide the title compound, mp 239-241 °C; MS (ESI+) m/z 443 (M+H) + ;
  • Example 81 N- l-d2-[(2-methoxypyridin-3-yl)amino]-3,4-dioxo-l-cyclobuten-l-yllamino)-2,2- dimethylpropyl]-3-methylbenzamide
  • Example 84 3-chloro-N- 1 -( ⁇ 2- (2-methoxypyridin-3-yl)amino]-3 ,4-dioxo- 1 -cyclobuten- 1 -yl) amino)-2,2- dimethylpropyl]benzamide
  • a suspension ofthe product from Example 80B, the product from Example 5 A, and K 2 CO 3 was processed as described in Example ID to provide the title compound, mp 208-210 °C; MS (ESI+) m/z 443 (M+H) + ;
  • Example 85A N-( 1 -benzotriazol- 1 -yl-2,2-dimethyl-3-phenyl-propyl)-benzamide A suspension of benzamide, the product from Example 18A, and benzotriazole were processed as described in Example 18B to provide the desired product. MS (DC1/NH 3 ) m/z 385 (M+H) + .
  • Example 85B N-[l-( ⁇ 2- (2-chloropyridin-3-yl)amino1-3,4-dioxo-l-cvclobuten-l-yllamino)-2,2-dimethyl-3- phenylpropyl]benzamide
  • Example 86 N-d - ( ⁇ 3 ,4-dioxo-2-(3 -pyridinylamino)- 1 -cyclobuten- 1 - yl] amino 1 -2,2-dimethyl-3- phenylpropyPbenzamide
  • a suspension ofthe product from Example IB, the product from Example 85 A, and K 2 CO 3 was processed as described in Example ID to provide the title compound, mp 237-238 °C; MS (ESI+) m/z 455 (M+H) + ;
  • Example 87 N-f 1 -( ⁇ 2-r(2-chloropyridin-3-yl)amino]-3 ,4-dioxo- 1 -cyclobuten- 1 -vU amino)-2,2- dimethylpropyl]-3-phenylpropanamide
  • a suspension ofthe product from Example 29B, the product from Example 36A, and K 2 CO 3 was processed as described in Example ID to provide the title compound, mp 160-161 °C; MS (ESI+) m/z 441 (M+H) + ;
  • Example 88A 2-(phenoxy)acetamide To a solution of phenoxyacetyl chloride (6.18 g, 36.2 mmol) in 175 mL of THF was added 75 mL of NH 4 OH over 15 minutes. The reaction was stirred for 16 hours at 23 °C then concentrated under reduced pressure. The crude product was dissolved in 200 mL of EtOAc and washed with 100 mL of 2 N HCI, 100 mL NaHCO 3 , and 100 mL of brine. The organic phase was dried over Na 2 SO 4 and concentrated. The product was purified by recrystalhzation from EtOAc/hexanes to provide 4.05 g (74 %> yield) ofthe desired product as a white powder. MS (DCI/NH 3 ) m/z 152 (M+H) + .
  • Example 88B N-[l-dH-l,2,3-benzotriazol-l-yl)-2,2-dimethylpropyl]-2-phenoxyacetamide
  • a suspension ofthe product from Example 88A, pivaldehyde, and benzotriazole were processed as described in Example 18B to provide the desired product.
  • Example 88C N-d - (r3,4-dioxo-2-(3 -pyridinylamino)- 1 -cyclobuten- 1 -yl]aminol -2,2-dimethylpropyl)-2- phenoxyacetamide
  • Example 89 N-[ 1 -( ⁇ 2-r(2-chloropyridin-3-yl)amino] -3 ,4-dioxo- 1 -cyclobuten- 1 -vU amino)-2,2- dimethylpropyll-2-phenoxyacetamide
  • a suspension ofthe product from Example 29B, the product from Example 88B, and K 2 CO 3 was processed as described in Example ID to provide the title compound, mp 220-221 °C; MS (ESI+) m/z 443 (M+H) + ;
  • Example 90A 2-methyl-2-phenylpropanamide To a solution of 2-methyl-2-phenylpropionic acid in 100 mL of CH 2 C1 2 was added 0.50 mL of DMF and oxalyl chloride (3.40 g, 26.8 mmol). The mixture was stirred at 23 °C for 4 hours then the solvent was removed under reduced pressure. The crude material was dissolved in 50 mL of THF and 30 mL of NH 4 OH was added. The mixture was stirred at 23 °C for 1 hour then and the mixture was concentrated under reduced pressure.
  • Example 90B N-f 1 -dH-1 ,2,3-benzotriazol- 1 -yl)-2,2-dimethylpropyl]-2-methyl-2-phenylpropanamide
  • a suspension ofthe product from Example 90A, pivaldehyde, and benzotriazole were processed as described in Example 18B to provide the desired product.
  • Example 90C N-d - ⁇ [3 ,4-dioxo-2-(3 -pyridinylamino)- 1 -cyclobuten- 1 - yl] amino 1 -2,2-dimethylpropyl)-2- methyl-2-phenylpropanamide
  • a suspension ofthe product from Example IB, the product from Example 90B, and K 2 CO 3 was processed as described in Example ID to provide the title compound, mp 247-248 °C; MS (ESI+) m/z 421 (M+H) + ;
  • Example 91 A 3-ethoxy-4-(2-pyrazinylamino)-3-cyclobutene- 1 ,2-dione A solution of aminopyrazine and 3,4-diethoxy-3-cyclobutene-l,2-dione in ethanol was processed as described in Example 1 A to provide the title compound. MS (DCI/NH 3 ) m/z 220 (M+H) + .
  • Example 9 IB 3-amino-4-(2-pyrazinylamino)-3-cyclobutene-l,2-dione
  • Example 9 IB A suspension ofthe product from Example 9 IB, the product from Example 5 A, and K 2 CO 3 was processed as described in Example ID to provide the title compound, mp 245-247 °C; MS (ESI+) m/z 414 (M+H) + ;
  • Example 92A N-[l-(lH-l,2.3-benzotriazol-l-yl)-3,3-dimethylbutyl1benzamide A suspension of benzamide, 3,3-dimethyl-butyraldehyde, and benzotriazole were processed as described in Example 18B to provide the desired product. MS (DC1/NH3) m/z 323 (M+H) + .
  • Example 92B N-r 1 -( (2- r(2-chlorop yridin-3 - vPamino] -3 ,4-dioxo- 1 -cyclobuten- 1 - vU amino)-3 ,3 - dimethylbutyl]benzamide
  • a suspension ofthe product from Example 29B, the product from Example 92 A, K 2 CO 3 , and DMSO as the solvent was processed as described in Example ID to provide the title compound, mp 259-260 °C; MS (ESI+) m/z 427 (M+H) + ;
  • Example 93 3 -chloro-N- f 1 -( " ⁇ 2-[( ' 6-chlorop yridin-3 - vPamino] -3 ,4-dioxo- 1 -cyclobuten- 1 - yl) amino)-2 ,2- dimethylpropyl]benzamide
  • a suspension ofthe product from Example 62B, the product from Example 5 A, and K 2 CO 3 was processed as described in Example ID to provide the title compound, mp 241-242 °C; MS (ESI+) m/z 481 (M+H) + ;
  • Example 94A 3 ,4-dichloroc vclobut-3 -ene- 1 ,2-dione To a solution of squaric acid (5.00 g, 43.8 mmol) in 60 mL of CH 2 C1 2 and 5 drops of DMF was added oxalyl chloride (12.2 g, 96.4 mmol), dropwise. The reaction was stirred at 23 °C for 10 minutes then heated at reflux for 16 hours. The mixture was cooled to 23 °C and the solvent removed under reduced pressure. The crude product was distilled at 80 °C (1 mm Hg) to provide the product (5.92 g, 89 % yield) as a bright yellow solid upon cooling which was used immediately to avoid decomposition.
  • Example 94B 3-chloro-4-methoxycyclobut-3-ene- 1 ,2-dione
  • MeOH MeOH
  • THF THF
  • MeOH MeOH
  • the mixture was heated at reflux for 2 hours then allowed to cool to ambient temperature.
  • the solvent was removed under reduced pressure and the crude product was dissolved in 100 mL of EtOAc/hexanes (1 :1).
  • the mixture was filtered through a 1/2" silica gel frit and the frit was washed with an additional 50 mL of EtOAc/hexanes (1 :1).
  • the solvent was removed in vacuo to provide a pale yellow oil which solidified on standing.
  • the product (4.56 g, 80 % crude yield) was used without further purification.
  • Example 94C 3-methoxy-4-( 6-(trifluoromethyl)pyridin-3-yl1aminol-3-cvclobutene-l,2-dione
  • Example 94B (1.51 g, 10.3 mmol) was dissolved in 3 mL of DMF and NaHCO 3 (0.865 g, 10.3 mmol) was added.
  • a solution of 6-(trifluoromethyl)pyridin-3-ylamine (1.67 g, 10.3 mmol) in 12 mL of CH 2 CI 2 was added dropwise and the mixture was stirred at ambient temperature for 16 hours. The mixture was diluted with 75 mL of EtOAc and filtered through a pad of Celite.
  • Example 94D 3 -amino-4- ⁇ r6-(trifluorornethyl)p yridin-3 - yl] amino 1 -3 -cyclobutene- 1 ,2-dione
  • Example 94C (0.281 g, 1.03 mmol) was dissolved in 20 mL 2.0 M NH 3 in MeOH and the mixture was stirred in a sealed vessel for 16 hours. The solvent was removed under reduced pressure and the crude material was triturated with Et 2 O to provide the desired product (0.230 g, 87 % yield) as a pale yellow powder.
  • MS (ESI+) m/z 258 (M+H) + .
  • Example 94E 3-chloro-N- (1 -[(3, 4-di oxo-2- (
  • a suspension ofthe product from Example 94D, the product from Example 5 A, and K 2 CO 3 was processed as described in Example ID to provide the title compound, mp 226-227 °C; MS (ESI+) m/z 481 (M+H) + ;
  • Example 95 3-chloro-N-r 1 -( ⁇ 2-r(2-chloropyridin-3-yl)aminol-3,4-dioxo- 1 -cyclobuten- 1 -yl amino)-2,2- dimethylpropyllbenzamide
  • a suspension ofthe product from Example 29B, the product from Example 5 A, and K 2 CO 3 was processed as described in Example ID to provide the title compound, mp 213-214 °C; MS (ESI+) m/z 448 (M+H) + ;
  • Example 96 A N- l-dH-l,2,3-benzotriazol-l-yl)-2,2-dimethyl-3-phenylpropyllisonicotinamide
  • the product from Example 18 A, isonicotinamide, benzotriazole, and p-toluenesulfonic acid in toluene were processed as described in Example 18B to provide the title compound.
  • Example 96B N-( 1 - ( T3 ,4-dioxo-2-(3-p yridinylamino)- 1 -cyclobuten- 1 - yl] amino 1 -2,2-dimefhyl-3 - phenylpropypisonicotinamide
  • a suspension ofthe product from Example IB, the product from Example 96 A, and K 2 CO 3 was processed as described in Example ID to provide the title compound, mp 251-254 °C; MS (ESI+) m/z 456 (M+H) + ;
  • Example 97A N-ri-dH-l,2.3-benzotriazol-l-yl)-2.2-dimethyl-3-phenylpropyll-3- phenylpropionamide
  • a suspension of 3-(phenyl)propionamide, the product from Example 18 A, benzotriazole, and p-toluenesulfonic acid was processed as described in Example IC to provide the title compound.
  • Example 97B N-( 1 - ⁇ [3 ,4-dioxo-2-(3-p yridinylamino)- 1 -cyclobuten- 1 - yl] amino 1 -2,2-dimethyl-3 - phenylpropyl)-3-phenylpropanamide
  • a suspension ofthe product from Example IB, the product from Example 97A, and K 2 CO 3 was processed as described in Example ID to provide the title compound, mp 221-223 °C; MS (ESI+) m/z 483 (M+H) + ;
  • Example 98 N-( 1 - ( [3 ,4-dioxo-2-(3-p yridinylamino)- 1 -cyclobuten- 1 -yllaminol -2,2-dimethyl-3- phenylpropyl)-2-methyl-2-phenylpropan amide
  • Example 98A N-ri-dH-1.2.3-benzotriazol-l-yl)-2.2-dimethyl-3-phenylpropyl1-2-methv1-2- phenylpropanamide
  • a suspension ofthe product from Example 90 A, the product from Example 18 A, benzotriazole, and p-toluenesulfonic acid was processed as described in Example IC to provide the title compound.
  • MS (DCI/NH3) m/z 427 (M+H) + .
  • Example 98B N-d - ir3,4-dioxo-2-(3-pyridinylamino)-l -cyclobuten- 1 -yllaminol -2,2-dimethyl-3- phenylpropyl)-2-methyl-2-phenylpropan amide
  • a suspension of the product from Example IB, the product from Example 98 A, and K 2 CO 3 was processed as described in Example 92B to provide the title compound, mp 228-231 °C; MS (ESI+) m/z 497 (M+H) + ;
  • Example 99A N-ri-dH-l,2,3-benzotriazol-l-yl)-2,2-dimethyl-3-phenylpropyl]-2- ⁇ henoxyacetamide
  • a suspension ofthe product from Example 88A, the product from Example 18A, benzotriazole, and p-toluenesulfonic acid was processed as described in Example 1 C to provide the title compound.
  • Example 99B N-d - ( [3 ,4-dioxo-2-(3-p yridinylamino)- 1 -cyclobuten- 1 - yl] amino 1 -2,2-dimethyl-3 - phenylpropyP-2-phenoxyacetamide
  • a suspension ofthe product from Example IB, the product from Example 99A, and K 2 CO 3 was processed as described in Example ID to provide the title compound, mp 249-250 °C; MS (ESI+) m/z 485 (M+H) + ;
  • Example 100A N- l-dH-l,2,3-benzotriazol-l-yl)-2,2-dimethyl-3-phenylpropyl1nicotinamide
  • the product from Example 18 A, nicotinamide, benzotriazole, and p-toluenesulfonic acid in xylene were processed as described in Example 18B to provide the title compound.
  • Example 100B N-d- ⁇ 3,4-dioxo-2-(3-pyridinylamino)-l-cvclobuten-l-yl1aminol-2,2-dimethyl-3- phenylpropyPnicotinamide
  • a suspension ofthe product from Example IB, the product from Example 100A, and K 2 CO 3 was processed as described in Example ID to provide the title compound, mp 253-254 °C; MS (ESI+) m/z 456 (M+H) + ;
  • Example 101 A N- 1 -(IH- 1 ,2,3-benzotriazol-l -yl)-2.2-dimethylpropyl1nicotinamide Nicotinamide, benzotriazole, pivaldehyde and p-toluenesulfonic acid in xylene were processed as described in Example 18B to provide the title compound. MS (ESI+) m/z 310 (M+H) + .
  • Example 10 IB N-( 1 - ⁇ [3 ,4-dioxo-2-( ' 3 -pyridinylamino)- 1 -cyclobuten- 1 - yl] amino 1 -2,2-dimethyl-3 - phenylpropyPnicotinamide
  • a suspension ofthe product from Example IB, the product from Example 101 A, and K 2 CO 3 was processed as described in Example ID to provide the title compound, mp 233-234 °C; MS (ESI+) m/z 380 (M+H) + ;
  • Example 102A N-ri-dH-1.2,3-benzotriazol-l-yl)-2,2-dimethylpropyl]isonicotinamide
  • Isonicotinamide, pivaldehyde, benzotriazole, and p-toluenesulfonic acid in xylene were processed as described in Example 18B to provide the title compound.
  • Example 102B N-( 1 - ⁇ [3 ,4-dioxo-2-(3-p yridinylamino)- 1 -cyclobuten- 1 - yll amino 1 -2 ,2-dimethyl-3 - phenylpropyPnicotinamide
  • a suspension ofthe product from Example IB, the product from Example 102A, and K 2 CO 3 was processed as described in Example ID to provide the title compound, mp 220-222 °C; MS (ESI+) m/z 380 (M+H) + ;
  • Example 103 A N-ri-dH-1.2.3-benzotriazol-l-yl)-2.2-dimethylpropyl1-2-furamide Furan-2-carboxamide, pivaldehyde, benzotriazole, and p-toluenesulfonic acid in xylene were processed as described in Example 18B to provide the title compound. MS (ESI+) m/z 299 (M+H) + .
  • Example 103B N-d- ⁇ 3,4-dioxo-2-(3-pyridinylamino)-l-cvclobuten-l-yl]aminol-2.2-dimethyl-3- phenylpropyPnicotinamide
  • a suspension ofthe product from Example IB, the product from Example 103 A, and K 2 CO 3 was processed as described in Example ID to provide the title compound, mp 204-205 °C; MS (ESI+) m/z 369 (M+H) + ;
  • Example 104A 2,2-dimethyl-3-pyridin-4-ylpropanal 4-(Bromomethyl)pyridine hydrobromide (5.00 g, 19.8 mmol) was suspended in ethyl acetate (40 mL) and water (20 mL) and washed with 10% aq. NaHCO 3 solution (35 mL) to generated the free base. The layers were partitioned and the organic portion was concentrated and redissolved in benzene (30 mL). To this solution was added tetrabutylammonium iodide (112 mg, 0.303 mmol) and isobutyraldehyde (1.10 g, 15.2 mmol).
  • Example 104 A The product from Example 104 A, m-toluamide, benzotriazole, and p-toluenesulfonic acid were processed as described in Example IC to provide the title compound. MS (DCI/NH 3 ) m/z 400 (M+H) + .
  • Example 104C N-( 1 - ⁇ [3 ,4-dioxo-2-(3 -pyridinylamino)- 1 -cyclobuten- 1 - yl] amino 1 -2,2-dimethyl-3 -p yridin-4- ylpropyl)-3 -methylbenzamide
  • a suspension ofthe product from Example IB, the product from Example 104B, and K 2 CO 3 was processed as described in Example ID to provide the title compound, mp 219-221 °C; MS (ESI+) m/z 470 (M+H) + ;

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Biomedical Technology (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Pain & Pain Management (AREA)
  • Psychiatry (AREA)
  • Pulmonology (AREA)
  • Urology & Nephrology (AREA)
  • Dermatology (AREA)
  • Hospice & Palliative Care (AREA)
  • Cardiology (AREA)
  • Psychology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Pyridine Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
PCT/US2002/002949 2001-02-07 2002-01-31 Aminal diones as potassium channel openers WO2002062761A1 (en)

Priority Applications (4)

Application Number Priority Date Filing Date Title
JP2002562717A JP2004530650A (ja) 2001-02-07 2002-01-31 カリウムチャンネル開口薬としてのアミナールジオン
MXPA03007071A MXPA03007071A (es) 2001-02-07 2002-01-31 Aminaldionas como abridores del canal de potasio.
CA002437400A CA2437400A1 (en) 2001-02-07 2002-01-31 Aminal diones as potassium channel openers
EP02704321A EP1358160A1 (en) 2001-02-07 2002-01-31 Aminal diones as potassium channel openers

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
US09/778,684 US20020147230A1 (en) 2001-02-07 2001-02-07 Aminal Diones as potassium channel openers
US09/778,684 2001-02-07
US10/046,465 US6495576B2 (en) 2001-02-07 2002-01-14 Aminal diones as potassium channel openers
US10/046,465 2002-01-14

Publications (1)

Publication Number Publication Date
WO2002062761A1 true WO2002062761A1 (en) 2002-08-15

Family

ID=26723951

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2002/002949 WO2002062761A1 (en) 2001-02-07 2002-01-31 Aminal diones as potassium channel openers

Country Status (5)

Country Link
EP (1) EP1358160A1 (hr)
JP (1) JP2004530650A (hr)
CA (1) CA2437400A1 (hr)
MX (1) MXPA03007071A (hr)
WO (1) WO2002062761A1 (hr)

Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005085197A1 (en) * 2004-02-27 2005-09-15 Schering Corporation Cyclobutenedione groups-containing compounds as inhibitors of hepatitis c virus ns3 serine protease
WO2007140233A1 (en) * 2006-05-26 2007-12-06 Abbott Laboratories Inhibitors of polo-like kinases
FR2918665A1 (fr) * 2007-07-13 2009-01-16 Sod Conseils Rech Applic Derives de tri-amino-pyrimidine cyclobutenedione comme inhibiteurs de phosphatase cdc25
EP2096107A1 (en) 2004-12-23 2009-09-02 GPC Biotech AG Derivatives of squaric acid with anti-proliferative activity
US7635694B2 (en) 2004-02-27 2009-12-22 Schering Corporation Cyclobutenedione-containing compounds as inhibitors of hepatitis C virus NS3 serine protease
WO2011019681A1 (en) * 2009-08-11 2011-02-17 Allergan, Inc. Selective sphingosine-1-phosphate receptor antagonists
US8450348B2 (en) 2007-02-21 2013-05-28 Forma Tm, Llc Derivatives of squaric acid with anti-proliferative activity
US9006426B2 (en) 2008-06-24 2015-04-14 Topotarget A/S Squaric acid derivatives as inhibitors of the nicotinamide
US9018261B2 (en) 2011-09-02 2015-04-28 Novartis Ag Choline salt of an anti-inflammatory substituted cyclobutenedione compound
CN114835639A (zh) * 2022-05-30 2022-08-02 南京红太阳生物化学有限责任公司 一种奈韦拉平中间体的制备方法

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5668157A (en) * 1994-01-28 1997-09-16 Pharmacia & Upjohn Company Cyanoguanidines as K-channel blockers
WO2001009096A2 (en) * 1999-08-03 2001-02-08 Abbott Laboratories Potassium channel openers

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5668157A (en) * 1994-01-28 1997-09-16 Pharmacia & Upjohn Company Cyanoguanidines as K-channel blockers
WO2001009096A2 (en) * 1999-08-03 2001-02-08 Abbott Laboratories Potassium channel openers

Cited By (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005085197A1 (en) * 2004-02-27 2005-09-15 Schering Corporation Cyclobutenedione groups-containing compounds as inhibitors of hepatitis c virus ns3 serine protease
US7635694B2 (en) 2004-02-27 2009-12-22 Schering Corporation Cyclobutenedione-containing compounds as inhibitors of hepatitis C virus NS3 serine protease
EP2096107A1 (en) 2004-12-23 2009-09-02 GPC Biotech AG Derivatives of squaric acid with anti-proliferative activity
US7956185B2 (en) 2006-05-26 2011-06-07 Abbott Laboratories Cyclobut-3-ene-1,2,-dione inhibitors of polo-like kinases
WO2007140233A1 (en) * 2006-05-26 2007-12-06 Abbott Laboratories Inhibitors of polo-like kinases
US8450348B2 (en) 2007-02-21 2013-05-28 Forma Tm, Llc Derivatives of squaric acid with anti-proliferative activity
WO2009034258A1 (fr) * 2007-07-13 2009-03-19 Ipsen Pharma S.A.S. Derives de tri-amino-pyrimidine cyclobutenedione comme inhibiteurs de phosphatase cdc25
FR2918665A1 (fr) * 2007-07-13 2009-01-16 Sod Conseils Rech Applic Derives de tri-amino-pyrimidine cyclobutenedione comme inhibiteurs de phosphatase cdc25
US9006426B2 (en) 2008-06-24 2015-04-14 Topotarget A/S Squaric acid derivatives as inhibitors of the nicotinamide
WO2011019681A1 (en) * 2009-08-11 2011-02-17 Allergan, Inc. Selective sphingosine-1-phosphate receptor antagonists
US8168795B2 (en) 2009-08-11 2012-05-01 Allergan, Inc. Selective sphingosine-1-phosphate receptor antagonists
US9018261B2 (en) 2011-09-02 2015-04-28 Novartis Ag Choline salt of an anti-inflammatory substituted cyclobutenedione compound
CN114835639A (zh) * 2022-05-30 2022-08-02 南京红太阳生物化学有限责任公司 一种奈韦拉平中间体的制备方法
CN114835639B (zh) * 2022-05-30 2023-12-15 南京红太阳生物化学有限责任公司 一种奈韦拉平中间体的制备方法

Also Published As

Publication number Publication date
CA2437400A1 (en) 2002-08-15
EP1358160A1 (en) 2003-11-05
JP2004530650A (ja) 2004-10-07
MXPA03007071A (es) 2004-05-24

Similar Documents

Publication Publication Date Title
AU2009247262B2 (en) Amide compound
KR102083693B1 (ko) Ccr9 길항제로써 피라졸-1-일 벤젠 술폰아미드
TW520362B (en) Substituted pyrimidine compounds and pharmaceutical composition comprising same
JP5582634B2 (ja) ４−置換フェノキシフェニル酢酸誘導体
JP2002509537A (ja) 新規なシクロアルキル置換イミダゾール化合物
US20060069110A1 (en) Substituted heterocyclic compounds and methods of use
JPH07300478A (ja) 複素環化合物
JP2000503304A (ja) 新規シクロアルキル置換イミダゾール
KR20130141500A (ko) 단백질 키나제 억제 활성을 갖는 신규한 아미노퀴나졸린 화합물
US5750699A (en) Method of preparing certain 3-halo-imidazopyridines
KR102195348B1 (ko) 단백질 키나제 억제제로서의 신규 화합물 및 이를 포함하는 약제학적 조성물
WO2002062761A1 (en) Aminal diones as potassium channel openers
DE60036476T2 (de) Kalium kanalaktivatoren
CA2335779A1 (en) Novel benzimidazoles as corticotropin release factor antagonists
US6645968B2 (en) Potassium channel openers
US6495576B2 (en) Aminal diones as potassium channel openers
US20020147230A1 (en) Aminal Diones as potassium channel openers
TW201315731A (zh) 菸鹼乙醯膽鹼受體之新穎正向異位調節劑
WO2021110574A1 (en) Alkynyl-(heteroaryl)-carboxamide hcn1 inhibitors
WO2022237781A1 (zh) 酰胺衍生物及其应用
KR19990077166A (ko) 신규한 시클로알킬 치환 이미다졸

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): CA JP MX

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): AT BE CH CY DE DK ES FI FR GB GR IE IT LU MC NL PT SE TR

121 Ep: the epo has been informed by wipo that ep was designated in this application
WWE Wipo information: entry into national phase

Ref document number: 2002562717

Country of ref document: JP

WWE Wipo information: entry into national phase

Ref document number: 2437400

Country of ref document: CA

WWE Wipo information: entry into national phase

Ref document number: PA/a/2003/007071

Country of ref document: MX

WWE Wipo information: entry into national phase

Ref document number: 2002704321

Country of ref document: EP

WWP Wipo information: published in national office

Ref document number: 2002704321

Country of ref document: EP

WWW Wipo information: withdrawn in national office

Ref document number: 2002704321

Country of ref document: EP