EP1358160A1 - Aminal diones as potassium channel openers - Google Patents

Aminal diones as potassium channel openers

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Publication number
EP1358160A1
EP1358160A1 EP02704321A EP02704321A EP1358160A1 EP 1358160 A1 EP1358160 A1 EP 1358160A1 EP 02704321 A EP02704321 A EP 02704321A EP 02704321 A EP02704321 A EP 02704321A EP 1358160 A1 EP1358160 A1 EP 1358160A1
Authority
EP
European Patent Office
Prior art keywords
amino
dioxo
cyclobuten
pyridinylamino
hydrogen
Prior art date
Legal status (The legal status 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 status listed.)
Withdrawn
Application number
EP02704321A
Other languages
German (de)
French (fr)
Inventor
Michael E. Kort
William A. Carroll
Arturo Perez Medrano
Jurgen Dinges
Robert J. Gregg
Fatima Z. Basha
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Abbott Laboratories
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
Publication of EP1358160A1 publication Critical patent/EP1358160A1/en
Withdrawn legal-status Critical Current

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    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/72—Nitrogen atoms
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    • 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
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    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/72—Nitrogen atoms
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    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/72—Nitrogen atoms
    • C07D213/76—Nitrogen atoms to which a second hetero atom is attached
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    • 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
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    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
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    • 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
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    • 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
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    • 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
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    • 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

  • 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 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).
  • R 7 is selected from hydrogen, haloalkyl, and lower alkyl; or
  • Ri is selected from aryl, arylalkyl, heterocycle and heterocyclealkyl
  • 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 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 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 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.
  • 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 (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).
  • 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.
  • 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
  • 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 .
  • 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.
  • 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 )
  • cyano refers to a -CN group.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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 .
  • 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
  • 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.
  • 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.
  • (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.
  • 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.
  • 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.
  • 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 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 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 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 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 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 22 4-chloro-N-(2-c yclohexyl- 1 - ⁇ [3 ,4-dioxo-2-( " 3 -pyridinylamino)- 1 -cyclobuten- 1 -yl] amino 1-2- methylpropyPbenzamide
  • 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 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 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 27B 3-Amino-4-(3-fluoro-phenylamino)-cvclobut-3-ene-l,2-dione
  • 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 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 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 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 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 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 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 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 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 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 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 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 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 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 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 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);
  • 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 85B N-[l-( ⁇ 2- (2-chloropyridin-3-yl)amino1-3,4-dioxo-l-cvclobuten-l-yllamino)-2,2-dimethyl-3- phenylpropyl]benzamide
  • 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 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 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 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 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) + ;

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Abstract

Compounds of formula (I), may be useful in treating diseases prevented by or ameliorated with potassium channel openers. Also disclosed are potassium channel opening compositions and a method of opening potassium channels in a mammal.

Description

AMINAL DIONES AS POTASSIUM CHANNEL OPENERS
TECHNICAL FIELD Novel aminal dione compounds and their derivatives can open potassium channels and are useful for treating a variety of medical conditions.
BACKGROUND OF INVENTION
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. 145-152 (1996)); (Nurse et al., Br. J. Urol, v. 68 pp. 27-31 (1991)); (Howe et al., J. Pharmacol. Exp. Ther., v. 274 pp. 884-890 (1995)); (Spanswick et al., Nature, v. 390 pp. 521-25 (December 4, 1997)); (Dompeling Vasa. Supplementum (1992) 3434); (WO9932495); (Grover, J Mol Cell Cardiol. (2000) 32, 677); and (Buchheit, Pulmonary Pharmacology & Therapeutics (1999) 12, 103). 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.
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. Because 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 irritative symptoms of BPH (urgency, frequency, nocturia and urge incontinence) have been shown to be correlated to bladder instability (Pandita, The J. of Urology (1999) 162, 943). Therefore the ability of potassium channel openers to hyperpolarize bladder cells and relax bladder smooth muscle may provide a method to ameliorate or prevent the symptoms associated with BPH. (Andersson, Prostate (1997) 30: 202-215).
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. By 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.
The sexual response in women is classified into four stages: excitement, plateau, orgasm and resolution. Sexual arousal and excitement increase blood flow to the genital area, and lubrication ofthe vagina as a result of plasma transudation. Topical application of KCOs like minoxidil and nicorandil have been shown to increase clitoral blood flow (Kim, et al., J. Urol. (2000) 163 (4): 240). 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. (1998) 10:S84-S90), as KCOs can increase blood flow to female sexual organs. 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.
(1995) 19, 31-40; Morrison, Am. J. Obstet. Gynecol. (1993) 169(5), 1277-85). 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.,
(1996) 70, 39-63).
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 KAτp 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 KAτp channels at the spinal cord level (Vergoni, Life Sci. (1992) 50(16), PL135-8; Asano, Anesth. Analg. (2000) 90(5), 1146-51). Thus, 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).
Neuronal cell depolarization can lead to excitotoxicity and neuronal cell death. When this occurs as a result of acute ischemic conditions, it can lead to stroke. Long-term neurodegeneration can bring about conditions such as Alzheimer's and Parkinson's diseases. 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 Ν-(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.
SUMMARY OF THE INVENTION
In its principle embodiment, the present invention discloses compounds having formula (I)
(I), or a pharmaceutically acceptable salt thereof, wherein A is selected from the group consisting of
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 , R3 and R4 are independently selected from hydrogen and alkyl;
R5 is selected from aryl, arylalkenyl, arylalkyl, aryloxyalkyl, heterocycle and heterocyclealkyl;
R6 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)alkyl, aryloxyalkyl, aryloxycarbonyl, aryloxycarbonylalkyl, arylalkylthioalkyl, arylsulfonylalkyl, carboxy, carboxyalkyl, carboxy(halo)alkyl, cyanoalkyl, cyano(halo)alkyl, cycloalkenyl, cycloalkenylalkyl, cycloalkyl, cycloalkylalkoxyalkyl, cycloalkylalkyl, cycloalkylcarbonyl, cycloalkyloxyalkyl, cycloalkylalkylthioalkyl, formyl, haloalkenyl, haloalkyl, haloalkylcarbonyl, haloalkynyl, heterocycle, heterocyclealkoxyalkyl, heterocyclealkyl, heterocyclecarbonyl, heterocycleoxyalkyl, heterocyclealkylthioalkyl, hydroxyalkyl, mercaptoalkyl, sulfamylalkyl, sulfamyl(halo)alkyl, (NR9R10)alkyl, (NR9Rι0)carbonyl, and (NR9Rιo)carbonylalkyl;
R7 is selected from hydrogen, haloalkyl, and lower alkyl; or
Rό and R7 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;
R9 and Rio are independently selected from hydrogen, alkoxysulfonyl, alkyl, alkylcarbonyl, alkylsulfonyl, aryl, arylalkyl, arylcarbonyl, arylsulfonyl and formyl.
DETAILED DESCRIPTION OF THE INVENTION It is understood that the foregoing detailed description and accompanying examples are merely illustrative and are not to be taken as limitations upon the scope of the invention, which is defined solely by the appended claims and their equivalents. Various changes and modifications to the disclosed embodiments will be apparent to those skilled in the art. Such changes and modifications, including without limitation those relating to the chemical structures, substituents, derivatives, intermediates, syntheses, formulations and/or methods of use ofthe invention, may be made without departing from the spirit and scope thereof.
All patents, patent applications, and literature references cited in the specification are herein incoφorated by reference in their entirety.
In its principle embodiment, the present invention discloses compounds having formula (I)
R2 R3 R4
R6 R? o
(I), or a pharmaceutically acceptable salt thereof, wherein A is selected from the group consisting of
X is selected from the group consisting of CH2, O and N(Z);
Z is selected from the group consisting of hydrogen and alkyl;
Ri is selected from aryl, arylalkyl, heterocycle and heterocyclealkyl;
R2, R3 and R4 are independently selected from hydrogen and alkyl;
R5 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, aryloxyalkyl, aryloxycarbonyl, aryloxycarbonylalkyl, arylalkylthioalkyl, arylsulfonylalkyl, carboxy, carboxyalkyl, carboxy(halo)alkyl, cyanoalkyl, cyano(halo)alkyl, cycloalkenyl, cycloalkenylalkyl, cycloalkyl, cycloalkylalkoxyalkyl, cycloalkylalkyl, cycloalkylcarbonyl, cycloalkyloxyalkyl, cycloalkylalkylthioalkyl, formyl, haloalkenyl, haloalkyl, haloalkylcarbonyl, haloalkynyl, heterocycle, heterocyclealkoxyalkyl, heterocyclealkyl, heterocyclecarbonyl, heterocycleoxyalkyl, heterocyclealkylthioalkyl, hydroxyalkyl, mercaptoalkyl, sulfamylalkyl, sulfamyl(halo)alkyl, (NR9Rιo)alkyl, (NR9Rι0)carbonyl and (NR9R10)carbonylalkyl;
R7 is selected from hydrogen, haloalkyl, and lower alkyl; or
Re and R7 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;
R9 and Rio are independently selected from hydrogen, alkoxysulfonyl, alkyl, alkylcarbonyl, alkylsulfonyl, aryl, arylalkyl, arylcarbonyl, arylsulfonyl and formyl.
In another embodiment ofthe present invention, compounds have formula (I) wherein A is selected from
Ri , R2, R3, R , R5, Rό and R7 are as defined in formula (I).
In another embodiment ofthe present invention, compounds have formula (II)
(II), or a pharmaceutically acceptable salt thereof, wherein Ri, R2, R3, Rt, R5, Re and R7 are as defined in formula (I).
In another embodiment ofthe present invention, compounds have formula (II) wherein Ri is heterocycle; R5 is aryl; and R2, R3, t, e and R7 are as defined in formula (I).
In another embodiment ofthe present invention, compounds have formula (II) wherein Ri is heterocycle wherein said heterocycle is selected from optionally substituted pyridinyl and optionally substituted pyrazinyl; R5 is aryl wherein said aryl is optionally substituted phenyl; and R2, R3, Rt, Rs and R7 are as defined in formula (I).
In another embodiment ofthe present invention, compounds have formula (II) wherein Ri is heterocycle wherein said heterocycle is selected from optionally substituted pyridinyl and optionally substituted pyrazinyl; R2 is hydrogen; R3 is hydrogen; R4 is hydrogen; R5 is aryl wherein said aryl is optionally substituted phenyl; R6 is selected from hydrogen and alkyl; and R is hydrogen.
In another embodiment ofthe present invention, compounds have formula (II) wherein Ri is heterocycle wherein said heterocycle is optionally substituted pyridinyl; R2 is hydrogen; R3 is hydrogen; } is hydrogen; R5 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 R7 is hydrogen.
In another embodiment of the present invention, compounds have formula (II) wherein Ri is heterocycle wherein said heterocycle is optionally substituted pyridinyl; R2 is hydrogen; R3 is hydrogen; R is hydrogen; R5 is aryl wherein said aryl is optionally substituted phenyl; R6 is haloalkyl; and R7 is hydrogen.
In another embodiment ofthe present invention, compounds have formula (II) wherein Ri is heterocycle wherein said heterocycle is optionally substituted pyridinyl; R is hydrogen; R3 is hydrogen; R is hydrogen; R5 is aryl wherein said aryl is optionally substituted phenyl; R6 is selected from alkenyl, alkenyloxy(alkenyloxy)alkyl, cyanoalkyl and cycloalkylalkyl; and R7 is hydrogen.
In another embodiment ofthe present invention, compounds have formula (II) wherein Ri is heterocycle wherein heterocycle is optionally substituted pyridinyl; R5 is aryl wherein aryl is selected from optionally substituted naphthyl and optionally substituted fluorenyl; and R2, R3, Rt, Re and R7 are as defined in formula (I).
In another embodiment of the present invention, compounds have formula (II) wherein Ri is heterocycle wherein heterocycle is optionally substituted pyridinyl; R2 is hydrogen; R3 is hydrogen; t is hydrogen; R5 is aryl wherein aryl is selected from optionally substituted naphthyl and optionally substituted fluorenyl; R6 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.
In another embodiment ofthe present invention, compounds have formula (II) wherein Ri is heterocycle wherein said heterocycle is optionally substituted pyridinyl; R is hydrogen; R3 is hydrogen; Rt is hydrogen; R5 is aryl wherein aryl is selected from optionally substituted naphthyl and optionally substituted fluorenyl 1; Re is alkyl; and R7 is hydrogen.
In another embodiment ofthe present invention, compounds have formula (II) wherein Ri is aryl; R5 is aryl; and R2, R3, R , Rό and R7 are as defined in formula (I).
In another embodiment ofthe present invention, compounds have formula (II) wherein Ri is aryl wherein said aryl is optionally substituted phenyl; R5 is aryl wherein said aryl is optionally substituted phenyl; and R2, R3, t, R6 and R are as defined in formula (I).
In another embodiment ofthe present invention, compounds have formula (II) wherein Ri is aryl wherein said aryl is optionally substituted phenyl; R is hydrogen; R3 is hydrogen; R is hydrogen; R5 is aryl wherein said aryl is optionally substituted phenyl; R6 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. In another embodiment ofthe present invention, compounds have formula (II) wherein Ri is aryl wherein said aryl is optionally substituted phenyl; R2 is hydrogen; R3 is hydrogen; Rt is hydrogen; R5 is aryl wherein said aryl is optionally substituted phenyl; Re is alkyl; and R7 is hydrogen.
In another embodiment ofthe present invention, compounds have formula (II) wherein Ri is heterocycle; R5 is arylalkyl; and R , R3, R4, R6 and R7 are as defined in formula (I).
In another embodiment ofthe present invention, compounds have formula (II) wherein Ri is heterocycle wherein said heterocycle is optionally substituted pyridinyl; R5 is selected from arylalkyl, arylalkenyl and aryloxyalkyl wherein the aryl portion of said arylalkyl, arylalkenyl, and aryloxyalkyl is optionally substituted phenyl; and R2, R3, t, R and R7 are as defined in formula (I).
In another embodiment ofthe present invention, compounds have formula (II) wherein Ri is heterocycle wherein said heterocycle is optionally substituted pyridinyl; R2 is hydrogen; R3 is hydrogen; Rt is hydrogen; R5 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 R7 is hydrogen.
In another embodiment ofthe present invention, compounds have formula (II) wherein Ri is heterocycle wherein said heterocycle is optionally substituted pyridinyl; R2 is hydrogen; R3 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 R7 is hydrogen.
In another embodiment ofthe present invention, compounds have formula (II) wherein Ri is heterocycle; R5 is heterocyclealkyl; and R2, R3, R4, Re and R7 are as defined in formula
(I)-
In another embodiment ofthe present invention, compounds have formula (II) wherein
Ri is heterocycle wherein said heterocycle is optionally substituted pyridinyl; R5 is heterocyclealkyl wherein the heterocycle portion of said heterocyclealkyl is optionally substituted pyridinyl; and R2, R3, Rt, Re and R7 are as defined in formula (I).
In another embodiment ofthe present invention, compounds have formula (II) wherein Ri is heterocycle wherein said heterocycle is optionally substituted pyridinyl; R2 is hydrogen; R3 is hydrogen; Rt is hydrogen; R5 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 R7 is hydrogen.
In another embodiment ofthe present invention, compounds have formula (II) wherein Ri is heterocycle wherein said heterocycle is optionally substituted pyridinyl; R2 is hydrogen; R3 is hydrogen; R4 is hydrogen; R5 is heterocyclealkyl wherein the heterocycle portion of said heterocyclealkyl is optionally substituted pyridinyl; R6 is alkyl; and R7 is hydrogen.
In another embodiment ofthe present invention, compounds have formula (II) wherein Ri is heterocycle; R5 is heterocycle; and R2, R3, Rt, R and R7 are as defined in formula (I).
In another embodiment ofthe present invention, 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 R2, R3, R4, Re and R7 are as defined in formula (I).
In another embodiment ofthe present invention, compounds have formula (II) wherein Ri is heterocycle wherein said heterocycle is optionally substituted pyridinyl; R2 is hydrogen; R3 is hydrogen; R4 is hydrogen; R5 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 R7 is hydrogen.
In another embodiment ofthe present invention, compounds have formula (II) wherein Ri is heterocycle wherein said heterocycle is optionally substituted pyridinyl; R is hydrogen; R3 is hydrogen; R4 is hydrogen; R5 is heterocycle wherein said heterocycle is selected from optionally substituted pyridinyl, optionally substituted thienyl and optionally substituted furyl; Re is alkyl; and R7 is hydrogen. In another embodiment ofthe present invention, compounds have formula (III)
(HI), or a pharmaceutically acceptable salt therof, wherein Ri, R2, R3, Rt, R5, Re and R7 are as defined in formula (I).
In another embodiment ofthe present invention, compounds have formula (III) wherein R] is heterocycle; R5 is aryl; and R2, R3, Rt, R5 and R7 are as defined in formula (I).
In another embodiment ofthe present invention, compounds have formula (III) wherein Ri is heterocycle wherein said heterocycle is optionally substituted pyridinyl; R5 is aryl wherein said aryl is optionally substituted phenyl; and R , R3, R4, R6 and R7 are as defined in formula (I).
In another embodiment ofthe present invention, compounds have formula (III) wherein Ri is heterocycle wherein said heterocycle is optionally substituted pyridinyl; R2 is hydrogen; R3 is hydrogen; R is hydrogen; R5 is aryl wherein said aryl is optionally substituted phenyl; R6 is selected from alkenyl, alkenyloxy(alkenyloxy)alkyl, arylalkyl wherein the aryl portion of said arylalkyl is optionally substituted phenyl, cyanoalkyl, cycloalkylalkyl and haloalkyl; and R7 is hydrogen.
In another embodiment ofthe present invention, compounds have formula (III) wherein Ri is heterocycle wherein said heterocycle is optionally substituted pyridinyl; R2 is hydrogen; R3 is hydrogen; R is hydrogen; R5 is aryl wherein said aryl is optionally substituted phenyl; Re is alkyl; and R7 is hydrogen.
In another embodiment ofthe present invention, compounds have formula (IN)
R2 R3 R4
R ^Ν N N R5 0 °R6 R7 O (IV), or a pharmaceutically acceptable salt therof, wherein Ri, R2, R3, R , R5, Re and R7 are as defined in formula (I).
In another embodiment ofthe present invention, compounds have formula (IV) wherein Ri is heterocycle; R5 is aryl; and R2, R3, R4, R and R7 are as defined in formula (I).
In another embodiment ofthe present invention, compounds have formula (IN) wherein Ri is heterocycle wherein said heterocycle is optionally substituted pyridinyl; R5 is aryl wherein said aryl is optionally substituted phenyl; and R2, R3, Rt, R6 and R7 are as defined in formula (I).
In another embodiment ofthe present invention, compounds have formula (IV) wherein Ri is heterocycle wherein said heterocycle is optionally substituted pyridinyl; R2 is hydrogen; R3 is hydrogen; t is hydrogen; R5 is aryl wherein said aryl is optionally substituted phenyl; R6 is selected from alkenyl, alkenyloxy(alkenyloxy)alkyl, arylalkyl wherein the aryl portion of said arylalkyl is optionally substituted phenyl, cyanoalkyl, cycloalkylalkyl and haloalkyl; and R7 is hydrogen.
In another embodiment ofthe present invention, compounds have formula (IV) wherein Ri is heterocycle wherein said heterocycle is optionally substituted pyridinyl; R is hydrogen; R3 is hydrogen; Rt is hydrogen; R5 is aryl wherein said aryl is optionally substituted phenyl; Re is alkyl; and R7 is hydrogen.
Another embodiment ofthe present invention relates to pharmaceutical 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 hypeφlasia (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)
R -R2
R1-N R3 R4
o
(V), wherein Ri is selected from aryl, arylalkyl, heterocycle and heterocyclealkyl;
R2, R3 and R4 are independently selected from hydrogen and alkyl;
R5 is selected from aryl, arylalkyl, heterocycle and heterocyclealkyl;
R6 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)alkyl, aryloxyalkyl, aryloxycarbonyl, aryloxycarbonylalkyl, arylalkylthioalkyl, arylsulfonylalkyl, carboxy, carboxyalkyl, carboxy(halo)alkyl, cyanoalkyl, cyano(halo)alkyl, cycloalkenyl, cycloalkenylalkyl, cycloalkyl, cycloalkylalkoxyalkyl, cycloalkylalkyl, cycloalkylcarbonyl, cycloalkyloxyalkyl, cycloalkylalkylthioalkyl, formyl, haloalkenyl, haloalkyl, haloalkylcarbonyl, haloalkynyl, heterocycle, heterocyclealkoxyalkyl, heterocyclealkyl, heterocyclecarbonyl, heterocycleoxyalkyl, heterocyclealkylthioalkyl, hydroxyalkyl, mercaptoalkyl, sulfamylalkyl, sulfamyl(halo)alkyl, (NR9R1o)alkyl, (NR9Rιo)carbonyl and (NR9Rι0)carbonylalkyl; and
R9 and Rio are independently selected from hydrogen, alkoxysulfonyl, alkyl, alkylcarbonyl, alkylsulfonyl, aryl, arylalkyl, arylcarbonyl, arylsulfonyl and formyl; the process comprising:
(a) reacting an aldehyde of formula (VI)
(VI), with three components, an amide of formula (VII)
O
R5^N'R4 H
(VII), lH-benzotriazole-polystyrene resin and an acid in a first solvent at about 50 °C to about 80 °C, wherein Rt, R5 and Re are as defined above;
(b) reacting the product of step (a) with a base and a compound of formula (VIII)
(VIII) in a second solvent wherein Ri, R2 and R3 are as defined above to provide a compound of formula (V).
In another embodiment of the present invention is disclosed a process for preparing a compound of formula (V) using an acid selected from para-toluenesulfonic acid monohydrate and acetic acid.
In another embodiment ofthe present invention is disclosed a process for preparing a compound of formula (V) using a first solvent selected from 1,4-dioxane, 2-methoxyethanol, tetrahydrofuran, trimefhyl orthoformate and mixtures thereof.
In another embodiment ofthe present invention is disclosed a process for preparing a compound of formula (V) using a first solvent selected from tetrahydrofuran:2- methoxyethanol in about a (1:1) ratio, tetrahydrofuran:trimethyl orthoformate in about a (1 :1) ratio and 1,4-dioxane :trimethyl orthoformate in about a (1 :0.3) to (1 :3) ratio.
In another embodiment ofthe present invention is disclosed a process for preparing a compound of formula (V) wherein step (a) is conducted for a period of about 12 hours to about 48 hours. In another embodiment ofthe present invention is disclosed a process for preparing a compound of formula (V) using a base selected from cesium carbonate, potassium carbonate and sodium carbonate.
In another embodiment ofthe present invention is disclosed a process for preparing a compound of formula (V) using a second solvent selected from dimethylacetamide, N,N- dimethylformamide, dimethylsulfoxide and mixtures thereof.
In another embodiment ofthe present invention is disclosed a process for preparing a compound of formula (V) wherein step (b) is conducted at about 15 °C to about 50 °C.
In another embodiment ofthe present invention is disclosed a process for preparing a compound of formula (V) wherein step (b) is conducted for a period of about 24 hours to about 168 hours.
In another embodiment ofthe present invention is disclosed a process for preparing a compound of formula (V) wherein the acid is para-toluenesulfonic acid monohydrate; the first solvent is tetrahydrofuran:2-methoxyethanol in about a (1:1) ratio; 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.
In another embodiment ofthe present invention is disclosed a process for preparing a compound of formula (V) wherein the acid is para-toluenesulfonic acid monohydrate; the first solvent is tetrahydrofuran:2-methoxyethanol in about a (1 :1) ratio; 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.
Definition of Terms
As used throughout this specification and the appended claims, the following terms have the following meanings.
The term "alkenyl," as used herein, 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. The term "alkenyloxy," as used herein, 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 .
The term "alkenyloxyalkyl," as used herein, refers to a alkenyloxy group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein. Representative examples of alkenyloxyalkyl include, but are not limited to, (allyloxy)methyl, (2-butenyloxy)methyl and (3-butenyloxy)methyl.
The term "alkenyloxy(alkenyloxy)alkyl," as used herein, 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.
The term "alkoxy," as used herein, 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.
The term "alkoxyalkyl," as used herein, 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.
The term "alkoxycarbonyl," as used herein, 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.
The term "alkoxycarbonylalkyl," as used herein, 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.
The term "alkoxycarbonyl(halo)alkyl," as used herein, 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.
The term "alkoxy(halo)alkyl," as used herein, 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.
The term "alkoxysulfonyl," as used herein, 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.
The term "alkyl," as used herein, 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.
The term "alkylcarbonyl," as used herein, 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.
The term "alkylcarbonylalkyl," as used herein, 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.
The term "alkylcarbonyl (halo)alkyl," as used herein, 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. The term "alkylcarbonyloxy," as used herein, 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.
The term "alkylcarbonyloxyalkyl," as used herein, 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.
The term "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, -CH2- -CH2CH2-, and -CH2CH2CH2-.
The term "alkylsulfinyl," as used herein, 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.
The term "alkylsulfinylalkyl," as used herein, 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.
The term "alkylsulfonyl," as used herein, 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.
The term "alkylsulfonylalkyl," as used herein, 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.
The term "alkylthio," as used herein, 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. The term "alkylthioalkyl," as used herein, refers to an alkylthio group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein. Representative examples of alkylthioalkyl include, but are not limited to, tert- butylsulfanylmethyl, 2-ethylsulfanylethyl, 2-methylsulfanylethyl and methylsulfanylmethyl.
The term "alkynyl," as used herein, 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.
The term "aryl," as used herein, 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.
The 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, -NRARB, (NRARB)alkyl, (NRARB)carbonyl, (NRARB)carbonylalkyl, furyl, imidazolyl, isothiazolyl, isoxazolyl, naphthyl, oxadiazolyl, oxazolyl, phenyl, pyrazinyl, pyrazolyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrrolyl, tetrazinyl, tetrazolyl, thiadiazolyl, thiazolyl, thienyl, triazinyl, triazolyl, benzimidazolyl, benzothiazolyl, benzothiadiazolyl, benzothienyl, benzoxadiazolyl, benzoxazolyl, benzofuranyl, cinnolinyl, indolyl, naphthyridinyl, isobenzofuranyl, isobenzothienyl, isoindolyl, isoquinolinyl and quinolinyl wherein said furyl, imidazolyl, isothiazolyl, isoxazolyl, naphthyl, oxadiazolyl, oxazolyl, phenyl, pyrazinyl, pyrazolyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrrolyl, tetrazinyl, tetrazolyl, thiadiazolyl, thiazolyl, thienyl, triazinyl, triazolyl benzimidazolyl, benzothiazolyl, benzothiadiazolyl, benzothienyl, benzoxadiazolyl, benzoxazolyl, benzofuranyl, benzopyranyl, benzothiopyranyl, cinnolinyl, indolyl, naphthyridinyl, isobenzofuranyl, isobenzothienyl, isoindolyl, isoquinolinyl, and ' quinolinyl may 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, cyano, halo, haloalkyl, haloalkoxy, nitro, sulfamyl, sulfamylalkyl, -NRARB, (NRARB)alkyl, (NRARB)carbonyl and (NRARB)carbonylalkyl as defined herein.
The term "arylalkoxy," as used herein, 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.
The term "arylalkoxyalkyl," as used herein, 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.
The term "arylalkoxycarbonyl," as used herein, 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.
The term "arylalkoxycarbonylalkyl," as used herein, 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.
The term "arylalkyl," as used herein, 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.
The term "arylalkylthio," as used herein, 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.
The term "arylalkylthioalkyl," as used herein, 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.
The term "arylcarbonyl," as used herein, 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.
The term "arylcarbonylalkyl," as used herein, 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.
The term "arylcarbonyloxy," as used herein, 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.
The term "arylcarbonyloxyalkyl," as used herein, 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.
The term "aryl(halo)alkyl," as used herein, 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.
The term "aryloxy," as used herein, 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.
The term "aryloxyalkyl," as used herein, 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. The term "aryloxycarbonyl," as used herein, 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.
The term "aryloxycarbonylalkyl," as used herein, 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.
The term "arylsulfonyl," as used herein, 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.
The term "arylsulfonylalkyl," as used herein, 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.
The term "arylthio," as used herein, 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.
The term "arylthioalkyl," as used herein, 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.
The term "carbonyl," as used herein, refers to a -C(O)- group.
The term "carboxy," as used herein, refers to a -CO2H group.
The term "carboxyalkyl," as used herein, 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 . The term "carboxy(halo)alkyl," as used herein, 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. Representative examples of 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.
The term "cyano," as used herein, refers to a -CN group.
The term "cyanoalkyl," as used herein, 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 .
The term "cyano(halo)alkyl," as used herein, 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.
The term "cycloalkenyl," as used herein, 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, -NRARB, (NRARB)alkyl, (NRARB)carbonyl and (NRARB)carbonylalkyl.
The term "cycloalkenylalkyl," as used herein, 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.
The term "cycloalkyl," as used herein, 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. Representative examples of 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. Representative examples of tricyclic-ring systems include, but are not limited to, tricyclo[3.3.1.03'7]nonane and tricyclo[3.3.1.13'7]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, sulfamylalkyl, -NRARB, (NRARB)alkyl, (NRARB)carbonyl and (NRARB)carbonylalkyl.
The term "cycloalkylalkoxy," as used herein, 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.
The term "cycloalkylalkoxyalkyl," as used herein, 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.
The term "cycloalkylalkyl," as used herein, 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.
The term "cycloalkylcarbonyl," as used herein, 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.
The term "cycloalkyloxy," as used herein, 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.
The term "cycloalkyloxyalkyl," as used herein, 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.
The term "cycloalkylalkylthio," as used herein, 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.
The term "cycloalkylalkylthioalkyl," as used herein, 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.
The term "cycloalkylthio," as used herein, 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.
The term "cycloalkylthioalkyl," as used herein, 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.
The term "formyl," as used herein, refers to a -C(O)H group.
The term "halo" or "halogen," as used herein, refers to -Cl, -Br, -I or -F. The term "haloalkoxy," as used herein, 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.
The term "haloalkenyl," as used herein, 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.
The term "haloalkyl," as used herein, 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.
The term "haloalkylcarbonyl," as used herein, 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.
The term "haloalkylsulfonyl," as used herein, 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.
The term "haloalkynyl," as used herein, 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 .
The term "heterocycle," as used herein, 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. Representative examples of 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, moφholinyl, oxadiazolyl, oxadiazolinyl, oxadiazolidinyl, oxazolyl, oxazolinyl, oxazolidinyl, piperazinyl, piperidinyl, pyranyl, pyrazinyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrrolyl, pyrrolinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, tetrazinyl, tetrazolyl, thiadiazolyl, thiadiazolinyl, thiadiazolidinyl, thiazolyl, thiazolinyl, thiazolidinyl, thienyl, thiomoφholinyl, thiomoφholine sulfone, thiopyranyl, triazinyl, triazolyl and trithianyl. 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- isoindolinonyl, isoquinolinyl, 1-isoquinolinonyl, phthalazinyl, pyranopyridinyl, quinolinyl, quinolizinyl, quinoxalinyl, quinazolinyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl and thiopyranopyridinyl.
The 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, -NRARB, (NRARβ)alkyl, (NRARB)carbonyl, (NRARB)carbonylalkyl, furyl, imidazolyl, isothiazolyl, isoxazolyl, naphthyl, oxadiazolyl, oxazolyl, phenyl, pyrazinyl, pyrazolyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrrolyl, tetrazinyl, tetrazolyl, thiadiazolyl, thiazolyl, thienyl, triazinyl, triazolyl, benzimidazolyl, benzothiazolyl, benzothiadiazolyl, benzothiophenyl, benzoxadiazolyl, benzoxazolyl, benzofuranyl, cinnolinyl, indolyl, naphthyridinyl, isobenzofuranyl, isobenzothienyl, isoindolyl, isoquinolinyl, and quinolinyl wherein said furyl, imidazolyl, isothiazolyl, isoxazolyl, naphthyl, oxadiazolyl, oxazolyl, phenyl, pyrazinyl, pyrazolyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrrolyl, tetrazinyl, tetrazolyl, thiadiazolyl, thiazolyl, thienyl, triazinyl, triazolyl, benzimidazolyl, benzothiazolyl, benzothiadiazolyl, benzothiophenyl, benzoxadiazolyl, benzoxazolyl, benzofuranyl, cinnolinyl, indolyl, naphthyridinyl, isobenzofuranyl, isobenzothienyl, isoindolyl, isoquinolinyl and quinolinyl may be substituted with 1 or 2 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, sulfamyl, sulfamylalkyl, -NRARB, (NRARβ)alkyl, (NRARB)carbonyl and (NRARB)carbonylalkyl.
The term "heterocyclealkoxy," as used herein, 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.
The term "heterocyclealkoxyalkyl," as used herein, 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.
The term "heterocyclealkyl," as used herein, 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.
The term "heterocyclealkylthio," as used herein, 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.
The term "heterocyclealkylthioalkyl," as used herein, 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.
The term "heterocyclecarbonyl," as used herein, 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.
The term "heterocycleoxy," as used herein, 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.
The term "heterocycleoxyalkyl," as used herein, 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.
The term "heterocyclethio," as used herein, 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.
The term "heterocyclethioalkyl," as used herein, 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.
The term "hydroxy," as used herein, refers to an -OH group.
The term "hydroxyalkyl," as used herein, 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.
The term "lower alkyl," as used herein, 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.
The term "mercapto," as used herein, refers to a -SH group.
The term "mercaptoalkyl," as used herein, 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.
The term "-NR9Rιo," as used herein, refers to two groups, R9 and Rio, which are appended to the parent molecular moiety through a nitrogen atom. R9 and Rio are independently selected from hydrogen, alkoxysulfonyl, alkyl, alkylcarbonyl, alkylsulfonyl, aryl, arylalkyl, arylcarbonyl, arylsulfonyl and formyl, as defined herein. Representative examples of -NR9Rι0 include, but are not limited to, acetylamino, amino, methylamino, (ethylcarbonyl)methylamino, ethylmethylamino, formylamino, mefhylsulfonylamino and phenylsulfonylamino.
The term "(NR9Rι0)alkyl," as used herein, refers to a -NR9Rιo group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein. Representative examples of (NR9Rι0)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.
The term "(NR9Rι0)carbonyl," as used herein, refers to a -NR9Rιo group, as defined herein, appended to the parent molecular moiety through a carbonyl group, as defined herein. Representative examples of (NR9Rιo)carbonyl include, but are not limited to, aminocarbonyl, dimefhylaminocarbonyl, ethylaminocarbonyl and benzylaminocarbonyl.
The term "(NR9Rι0)carbonylalkyl," as used herein, refers to a (NR9Rι0)carbonyl group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein. Representative examples of (NR9Rι0)carbonylalkyl include, but are not limited to, aminocarbonylmethyl, dimethylaminocarbonylmethyl, 2-(ethylaminocarbonyl)ethyl and 3- (benzylaminocarbonyl)propyl.
The term "-NRARB," as used herein, refers to two groups, RA and RB, which are appended to the parent molecular moiety through a nitrogen atom. RA and RB are independently selected from hydrogen, alkyl, alkylcarbonyl and formyl, as defined herein. Representative examples of-NRARβ include, but are not limited to, acetylamino, amino, methylamino, (ethylcarbonyl)methylamino, dimethylamino, ethylmethylamino and formylamino.
The term "(NRARB)alkyl," as used herein, refers to a -NRARB group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein. Representative examples of (NRARβ)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.
The term "(NRARB)carbonyl," as used herein, refers to a -NRARB group, as defined herein, appended to the parent molecular moiety through a carbonyl group, as defined herein. Representative examples of (NRARB)carbonyl include, but are not limited to, aminocarbonyl, dimethylaminocarbonyl, methylaminocarbonyl, ethylaminocarbonyl and diethylaminocarbonyl.
The term "(NRARβ)carbonylalkyl," as used herein, refers to a (NRARB)carbonyl group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein. Representative examples of (NRARB)carbonylalkyl include, but are not limited to, aminocarbonylmefhyl, dimethylaminocarbonylmethyl, 2-(efhylaminocarbonyl)ethyl and 3- (diethylaminocarbonyl)propyl.
The term "nitro," as used herein, refers to a -NO2 group.
The term "oxo," as used herein, refers to a (=O) moiety.
The term "oxy," as used herein, refers to a (-O-) moiety.
The term "sulfamyl," as used herein, refers to a -SO NR R95 group, wherein R94 and R95 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.
The term "sulfamylalkyl," as used herein, 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.
The term "sulfamyl(halo)alkyl," as used herein, 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. Representative examples of 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.
The term "sulfinyl," as used herein, refers to a -S(O)- group.
The term "sulfonyl," as used herein, refers to a -SO2- group.
The term "thio," as used herein, refers to a (-S-) moiety.
Compounds ofthe present invention 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. The terms "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. The present invention contemplates various stereoisomers and mixtures thereof and are specifically included within the scope of this invention. Stereoisomers include enantiomers and diastereomers, and mixtures of enantiomers or diastereomers. In particular, the carbon atom attached to R6 and R7 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. These methods of resolution are exemplified by (1) attachment of a mixture of enantiomers to a chiral auxiliary, separation of the resulting mixture of diastereomers by recrystalhzation or chromatography and liberation of the optically pure product from the auxiliary or (2) direct separation of the mixture of optical enantiomers on chiral chromatographic columns.
Preferred compounds ofthe present invention include
3 -chloro-N-( 1 - { [3 ,4-dioxo-2-(5 -pyrimidinylamino)- 1 -cyclobuten- 1 -yl] amino } -2,2- dimefhylpropyl)benzamide;
N-( 1 - { [3 ,4-dioxo-2-(5 -pyrimidinylamino)- 1 -cyclobuten- 1 -yl] amino } -2,2- dimethylpropyl)-3 , 5 -difluorobenzamide;
N-(l-{[3,4-dioxo-2-(2-pyrazinylamino)-l-cyclobuten-l-yl]amino}-2,2- dimethylpropyl)-3, 5 -difluorobenzamide;
3 -chloro-N-( 1 - { [3 ,4-dioxo-2-(2-pyrazinylamino)- 1 -cyclobuten- 1 -yl] amino } -2,2- dimethylpropyl)benzamide; 3-chloro-N- { 1 - [(3 ,4-dioxo-2- { [2-(trifluoromethyl)-3 -pyridinyl] amino} - 1 -cyclobuten- l-yl)amino]-2,2-dimethylpropyl}benzamide;
3 -chloro-N- [ 1 -( {2-[(2-methoxy-3 -pyridinyl)amino] -3, 4-dioxo- 1 -cyclobuten- 1 - yl}amino)-2,2-dimethylpropyl]benzamide;
3,5-difluoro-N-[l-({2-[(2-methoxy-3-pyridinyl)amino]-3,4-dioxo-l-cyclobuten-l- yl}amino)-2,2-dimethylpropyl]benzamide;
N- [2,2-dimethyl- 1 -( {2- [(2 -methyl-3 -pyridinyl)amino] -3 ,4-dioxo- 1 -cyclobuten- 1 - yl } amino)propyl] -3 ,5 -difluorobenzamide;
3-chloro-N- { 1 -[(3,4-dioxo-2- { [4-(trifluoromethyl)-3-pyridinyl] amino} - 1 -cyclobuten- l-yl)amino]-2,2-dimethylpropyl}benzamide;
3 -chloro-N- { 1 -[(3 ,4-dioxo-2- { [4-(trifluoromethyl)-3 -pyridinyl] amino } - 1 -cyclobuten- l-yl)amino]-2,2-dimethyl-3-phenylpropyl}benzamide;
3 -chloro-N- [ 1 -( {2-[(2-methoxy-3 -pyridinyl)amino] -3 ,4-dioxo- 1 -cyclobuten- 1 - yl}amino)-2,2-dimethyl-3-phenylpropyl]benzamide;
3-chloro-N- { 1 -[(3 ,4-dioxo-2- { [2-(trifluoromethyl)-3 -pyridinyl] amino } - 1 -cyclobuten- l-yl)amino]-2,2-dimethyl-3-phenylpropyl}benzamide;
N- [2,2-dimethyl- 1 -( {2-[(4-methyl-3 -pyridinyl)amino] -3 ,4-dioxo- 1 -cyclobuten- 1 - yl}amino)propyl] -3, 5 -difluorobenzamide;
3,5-difluoro-N-[l-({2-[(4-methoxy-3-pyridinyl)amino]-3,4-dioxo-l-cyclobuten-l- yl}amino)-2,2-dimethylpropyl]benzamide;
N-( 1 - { [3 ,4-dioxo-2-(3 -pyridinylamino)- 1 -cyclobuten- 1 -yl] amino } -2 ,2- dimethylpropyl)-3-(3-pyridinyl)propanamide;
3-chloro-N-[ 1 - { [3 ,4-dioxo-2-(3 -pyridinylamino)- 1 -cyclobuten- 1 -yl] amino } -2 ,2- dimethyl-3-(4-pyridinyl)propyl]benzamide;
4-(3 - [(3 -chlorobenzoyl)amino]-3 - { [3 ,4-dioxo-2-(3-pyridinylamino)- 1 -cyclobuten- 1 - yljamino} -2,2-dimethylpropyl)benzoic acid;
N-( 1 - { [3 ,4-dioxo-2-(3 -pyridinylamino)- 1 -cyclobuten- 1 -yl] amino } -2,2- dimethylpropyl)nicotinamide;
5-bromo-N-(l-{[3,4-dioxo-2-(3-pyridinylamino)-l-cyclobuten-l-yl]amino}-2,2- dimethylpropyl)nicotinamide;
3 - { [( 1 - { [3 ,4-dioxo-2-(3-pyridinylamino)- 1 -cyclobuten- 1 -yl] amino } -2,2- dimethylpropyl)amino]carbonyl}benzoic acid; N-( 1 - { [3 ,4-dioxo-2-(3 -pyridinylamino)- 1 -cyclobuten- 1 -yl] amino } -2,2- dimethylpropyl)-3-(lH-tetraazol-5-yl)benzamide;
N-(l-{[3,4-dioxo-2-(3-pyridinylamino)-l-cyclobuten-l-yl]amino}-2,2- dimethylpropyl)-3-(3-pyridinyl)benzamide and pharmaceutically acceptable salts thereof.
The foregoing compounds, representative of formula (II), may be prepared by one skilled in the art using known synthetic methodology or by using synthetic methodology described in the Schemes and Examples contained herein.
Most preferred compounds of formula (I) include
N-( 1 - { [3 ,4-dioxo-2-(3 -pyridinylamino)- 1 -cyclobuten- 1 -yl] amino } -2,2- dimethylpropyl)-4-rnethylbenzamide;
4-chloro-N-(l- {[3,4-dioxo-2-(3-pyridinylamino)-l -cyclobuten- 1 -yl]amino} -2,2- dimethylpropyl)benzamide;
N-( 1 - { [3 ,4-dioxo-2-(3 -pyridinylamino)- 1 -cyclobuten- 1 -yl] amino } -2,2- dimethylpropyl)-4-iodobenzamide;
N-( 1 - { [3 ,4-dioxo-2-(3-pyridinylamino)- 1 -cyclobuten- 1 -yl] amino } -2,2- dimethylpropyl)-4-(2-furyl)benzamide;
3-chloro-N-( 1 - { [3 ,4-dioxo-2-(3-pyridinylamino)- 1 -cyclobuten- 1 -yl] amino } -2 ,2- dimethylpropyl)benzamide;
N-( 1 - { [3 ,4-dioxo-2-(3 -pyridinylamino)- 1 -cyclobuten- 1 -yl] amino } -2,2- dimethylpropyl)-3-methylbenz amide;
N-( 1 - { [3 ,4-dioxo-2-(3 -pyridinylamino)- 1 -cyclobuten- 1 -yl] amino } -2,2- dimethylpropyl)-3-fluorobenz amide;
N-( 1 - { [3 ,4-dioxo-2-(3 -pyridinylamino)- 1 -cyclobuten- 1 -yl] amino } -2,2- dimethylpropyl)-3-iodobenzamide;
N-( 1 - { [3 ,4-dioxo-2-(3-pyridinylamino)- 1 -cyclobuten- 1 -yl] amino } -2,2- dimethylpropyl)-3,4-dimethylbenzamide;
N-( 1 - { [3 ,4-dioxo-2-(3-pyridinylamino)- 1 -cyclobuten- 1 -yl] amino } -2,2- dimethylpropyl)-3,4-dimethoxybenzamide;
N-( 1 - { [3 ,4-dioxo-2-(3 -pyridinylamino)- 1 -cyclobuten- 1 -yl] amino } -2,2- dimethylpropyl)- 1 -naphthamide;
3 ,5-dichloro-N-( 1 - { [3 ,4-dioxo-2-(3 -pyridinylamino)- 1 -cyclobuten- 1 -yl] amino} -2,2- dimethylpropyl)benzamide; N-(l-{[3,4-dioxo-2-(3-pyridinylamino)-l-cyclobuten-l-yl]amino}-2,2- dimethylpropyl)-3,5-dimethoxybenzamide;
(-) N-(l - { [3 ,4-dioxo-2-(3-pyridinylamino)- 1 -cyclobuten- 1 -yl] amino} -2,2- dimethylpropyl)-3,5-dimethoxybenzamide;
(+) N-(l-{[3,4-dioxo-2-(3-pyridinylamino)-l-cyclobuten-l-yl]amino}-2,2- dimethylpropyl)-3,5-dimethoxybenzamide;
N-( 1 - { [3 ,4-dioxo-2-(3-pyridinylamino)- 1 -cyclobuten- 1 -yl] amino } -2,2- dimethylpropyl)-3 ,5 -difluorobenzamide;
4-chloro-N-(l- {[3, 4-dioxo-2-(3 -pyridinylamino)- 1 -cyclobuten- 1 -yl] amino} -2,2- dimefhyl-4-pentenyl)benzamide;
4-chloro-N-( 1 - { [3 ,4-dioxo-2-(3 -pyridinylamino)- 1 -cyclobuten- 1 -yl] amino } -2 ,2- dimethyl-3-phenylpropyl)benzamide;
4-chloro-N-(4-cyano- 1 - { [3 ,4-dioxo-2-(3 -pyridinylamino)- 1 -cyclobuten- 1 -yl] amino } - 2,2-diethylbutyl)benzamide;
N-(2,2-bis[(allyloxy)methyl]- 1 - {[3,4-dioxo-2-(3-pyridinylamino)- 1 -cyclobuten- 1 - yl]amino}butyl)-4-chlorobenz amide;
4-chloro-N-( 1 - { [3 ,4-dioxo-2-(3 -pyridinylamino)- 1 -cyclobuten- 1 -yl] amino } -2- ethylbutyl)benzamide;
4-chloro-N-(2-cyclohexyl- 1 - { [3 ,4-dioxo-2-(3 -pyridinylamino)- 1 -cyclobuten- 1 - yl]amino}-2-methylpropyl)benzamide;
N-(2-( 1 -adamantyl)- 1 - { [3 ,4-dioxo-2-(3-pyridinylamino)- 1 -cyclobuten- 1 - yl] amino } ethyl)-4-chlorobenzamide;
4-chloro-N-(2,2-dichloro-l-{[3,4-dioxo-2-(3-pyridinylamino)-l-cyclobuten-l- yl]amino}propyl)benzamide;
3-chloro-N-(2,2-dichloro-l-{[3,4-dioxo-2-(3-pyridinylamino)-l-cyclobuten-l- yl] amino} prop yl)benzamide;
3-chloro-N-(l-{[3,4-dioxo-2-(3-pyridinylamino)-l-cyclobuten-l-yl]amino} -2,2, 3,3,3- pentafluoropropyl)benzamide;
4-chloro-N-( 1 - { [2-(3 -fluoroanilino)-3 ,4-dioxo- 1 -cyclobuten- 1 -yl] amino } -2,2- dimethylpropyl)benzamide;
4-chloro-N-( 1 - { [2-(4-fluoroanilino)-3 ,4-dioxo- 1 -cyclobuten- 1 -yl] amino } -2,2- dimethylpropyl)benzamide; 4-chloro-N-[ 1 -( {2- [(2-chloro-3 -pyridinyl)amino] -3 ,4-dioxo- 1 -cyclobuten- 1 -yl } amino)- 2,2-dimethylpropyl]benzamide;
N-[l-({2-[(5-bromo-6-fluoro-3-pyridinyl)amino]-3,4-dioxo-l -cyclobuten- 1 -yl}amino)- 2,2-dimethylpropyl]-4-chlorobenzamide;
4-chloro-N-[ 1 -( {2- [(2-chloro-3 -pyridinyl)amino] -3 ,4-dioxo- 1 -cyclobuten- 1 -yl} amino)- 2,2-dimethyl-3-phenylpropyl]benzamide;
N-[ 1 -( {2-[(2-chloro-3 -pyridinyl)amino] -3, 4-dioxo- 1 -cyclobuten- 1 -yl} amino)-2,2- dimethylpropyl]-3-methylbenzamide;
4-chloro-N-(2,2-dimethyl-l-{[(3-pyridinylamino)sulfonyl]amino}propyl)benzamide;
N-(2,2-dimethyl-l-{[(3-pyridinylamino)sulfonyl]amino}propyl)-4-iodobenzamide;
N1- { 1 -[(4-chlorobenzoyl)amino]-2,2-dimethylpropyl} -N2-(3-pyridinyl)ethanediamide;
N-(l-{[3,4-dioxo-2-(3-pyridinylamino)-l-cyclobuten-l-yl]amino}-2,2- dimethylpropyl)-3-phenylpropanamide;
N-[l-({2-[(2-chloro-3-pyridinyl)amino]-3,4-dioxo-l-cyclobuten-l-yl}amino)-2,2- dimethylpropyl]-3-(3-pyridinyl)propanamide;
N-(l - {[3,4-dioxo-2-(3-pyridinylamino)-l -cyclobuten- 1-yl] amino} -2,2- dimethylproρyl)-3-vinylbenzamide;
N-( 1 - { [3 ,4-dioxo-2-(3 -pyridinylamino)- 1 -cyclobuten- 1 -yl] amino } -2,2- dimethylproρyl)[ 1 , 1 '-biphenyl]-3-carboxamide;
3 -acetyl-N-( 1 - { [3 ,4-dioxo-2-(3 -pyridinylamino)- 1 -cyclobuten- 1 -yl] amino } -2,2- dimefhylpropyl)benzamide;
N-( 1 - { [3 ,4-dioxo-2-(3 -pyridinylamino)- 1 -cyclobuten- 1 -yl] amino } -2,2- dimethylpropyl)-2-pyridinecarboxamide;
N-( 1 - { [3 ,4-dioxo-2-(3 -pyridinylamino)- 1 -cyclobuten- 1 -yl] amino } -2,2- dimethylpropyl)-4-fluoro-3-(trifluoromethyl)benzamide;
N-( 1 - { [3 ,4-dioxo-2-(3 -pyridinylamino)- 1 -cyclobuten- 1 -yl] amino } -2,2- dimethylpropyl)-2-phenylacetamide;
N-( 1 - { [3 ,4-dioxo-2-(3 -pyridinylamino)- 1 -cyclobuten- 1 -yl] amino } -2,2- dimethylpropyl)-3-phenylprop-2-enamide;
4-chloro-N-(2,2-dichloro- 1 - { [3 ,4-dioxo-2-(3 -pyridinylamino)- 1 -cyclobuten- 1 - yl] amino} pentyl)benzamide; 4-chloro-N-( 1 - { [3 ,4-dioxo-2-(4-pyridinylamino)- 1 -cyclobuten- 1 -yl] amino} -2,2- dimefhylpropyl)benzamide;
4-chloro-N-( 1 - { [3 ,4-dioxo-2-(2-pyridinylamino)- 1 -cyclobuten- 1 -yl] amino } -2 ,2- dimethylpropyl)benzamide;
N-( 1 - { [3 ,4-dioxo-2-(3 -pyridinylamino)- 1 -cyclobuten- 1 -yl] amino } -2,2- dimethylpropyl)benzamide;
(+) N-( 1 - { [3 ,4-dioxo-2-(3 -pyridinylamino)- 1 -cyclobuten- 1 -yl] amino } -2,2- dimethylpropyl)-3,5-difluorobenzamide;
(-) N-( 1 - { [3 ,4-dioxo-2-(3 -pyridinylamino)- 1 -cyclobuten- 1 -yl] amino } -2,2- dimethylpropyl)-3,5-difluorobenzamide;
N-(2,2-dichloro- 1 - { [3 ,4-dioxo-2-(3 -pyridinylamino)- 1 -cyclobuten- 1 - yl] amino }propyl)-3, 5 -difluorobenzamide;
4-chloro-N- { 1 -[(3 ,4-dioxo-2- { [5 -(trifluoromethyl)pyridin-3 -yl] amino } - 1 -cyclobuten- 1 -yl) amino] -2 ,2-dimethylpropyl } benzamide ;
3,5-dichloro-N- { 1 -[(3,4-dioxo-2- {[5-(trifluoromethyl)pyridin-3-yl]amino} - 1 - cyclobuten- l-yl)amino]-2,2-dimethylpropyl} benzamide;
4-chloro-N- { 1 -[(3,4-dioxo-2- {[5-(trifluoromethyl)pyridin-3-yl]amino} - 1 -cyclobuten- l-yl)amino]-2,2-dimethyl-3-phenylpropyl}benzamide;
N-( 1 - { [3 ,4-dioxo-2-(3 -pyridinylamino)- 1 -cyclobuten- 1 -yl] amino } -2,2-dimethyl-3 - phenylpropyl)-3,5-difluorobenzamide;
(+) 3 -chloro-N-( 1 - { [3 ,4-dioxo-2-(3 -pyridinylamino)- 1 -cyclobuten- 1 -yl] amino } -2,2- dimefhylpropyl)benzamide;
(-) 3-chloro-N-(l-{[3,4-dioxo-2-(3-pyridinylamino)-l-cyclobuten-l-yl]amino}-2,2- dimefhylpropyl)benzamide;
3,5-dichloro-N-(l-{[3,4-dioxo-2-(3-pyridinylamino)-l-cyclobuten-l-yl]amino}-2,2- dimethyl-3-phenylpropyl)benzamide;
3-chloro-N-(l-{[3,4-dioxo-2-(3-pyridinylamino)-l-cyclobuten-l-yl]amino}-2,2- dimethyl-3-phenylpropyl)benzamide;
N-( 1 - { [3 ,4-dioxo-2-(3 -pyridinylamino)- 1 -cyclobuten- 1 -yl] amino } -2,2-dimethyl-3 - phenylpropyl)-3-methylbenzamide;
N-[l-({2-[(2-chloropyridin-3-yl)amino]-3,4-dioxo-l-cyclobuten-l-yl}amino)-2,2- dimethyl-3-phenylpropyl]-3-methylbenzamide; 4-chloro-N-[ 1 -( {2-[(6-chloropyridin-3-yl)amino]-3 ,4-dioxo- 1 -cyclobuten- 1 -yl} amino)- 2,2-dimethylpropyl]benzamide;
4-chloro-N- [ 1 -( {2- [(2-fluoropyridin-3-yl)amino] -3 ,4-dioxo- 1 -cyclobuten- 1 -yl} amino)- 2,2-dimethylpropyl]benzamide;
3 -chloro-N-( 1 - { [3 ,4-dioxo-2-(3 -pyridinylamino)- 1 -cyclobuten- 1 -yl] amino } -3 ,3 - dimethylbutyl)benzamide;
N-( 1 - { [3 ,4-dioxo-2-(3 -pyridinylamino)- 1 -cyclobuten- 1 -yl] amino } -2,2- dimethylpropyl)thiophene-2-carboxamide;
3 -bromo-N-( 1 - { [3 ,4-dioxo-2-(3 -pyridinylamino)- 1 -cyclobuten- 1 -yl] amino } -2 ,2- dimefhylpropyl)benzamide;
3-bromo-N- [ 1 -( {2- [(2-chloropyridin-3 -yl)amino] -3 ,4-dioxo- 1 -cyclobuten- 1 - yl}amino)-2,2-dimethylpropyl]benzamide;
N-( 1 - { [3 ,4-dioxo-2-(3 -pyridinylamino)- 1 -cyclobuten- 1 -yl] amino } -2,2- dimethylpropyl)-9-oxo-9H-fluorene-4-carboxamide; methyl 3-{[(l-{[3,4-dioxo-2-(3-pyridinylamino)-l-cyclobuten-l-yl]amino}-2,2- dimethylpropyl)amino]carbonyl}benzoate;
(+) N-( 1 - { [3 ,4-dioxo-2-(3-pyridinylamino)- 1 -cyclobuten- 1 -yl] amino } -2,2- dimethylpropyl)-3-methylbenzamide;
(-) N-( 1 - { [3 ,4-dioxo-2-(3-pyridinylamino)- 1 -cyclobuten- 1 -yl] amino } -2,2- dimethylpropyl)-3-methylbenzamide;
(+) N-( 1 - { [3 ,4-dioxo-2-(3 -pyridinylamino)- 1 -cyclobuten- 1 -yl] amino} -2 ,2-dimefhyl-3 - phenylpropyl)-3-methylbenzamide;
(-) N-( 1 - { [3 ,4-dioxo-2-(3 -pyridinylamino)- 1 -cyclobuten- 1 -yl] amino } -2,2-dimethyl-3 - phenylpropyl)-3-mefhylbenzarnide;
(+) N-[l-({2-[(2-chloropyridin-3-yl)amino]-3,4-dioxo-l-cyclobuten-l-yl}amino)-2,2- dimethylpropyl]-3-methylbenzamide;
(-) N-[l-({2-[(2-chloropyridin-3-yl)amino]-3,4-dioxo-l-cyclobuten-l-yl}amino)-2,2- dimethylpropyl]-3-methylbenzamide;
(+) N-(l-{[3,4-dioxo-2-(3-pyridinylamino)-l-cyclobuten-l-yl]amino}-2,2-dimethyl-3- phenylpropyl)-3,5-difluorobenzamide;
N-( 1 - { [3 ,4-dioxo-2-(3 -pyridinylamino)- 1 -cyclobuten- 1 -yl] amino} -2,2- dimethylpropyl)-3-(2-furyl)benz amide; N-[ 1 -( {2-[(2-chloropyridin-3-yl)amino]-3 ,4-dioxo- 1 -cyclobuten- 1 -yl} amino)-2,2- dimethylpropyl]-3-fluorobenzamide;
3 ,5-dichloro-N- [ 1 -( {2- [(2-chloropyridin-3 -yl)amino] -3 ,4-dioxocyclobut- 1 -en- 1 - yl}amino)-2,2-dimethylpropyl]benzamide;
4-chloro-N-[ 1 -( {2- [(2 -methoxyp yridin-3 -yl)amino]-3 ,4-dioxo- 1 -cyclobuten- 1 - yl}amino)-2,2-dimethylpropyl]benzamide;
N-[l-({2-[(2 -methoxyp yridin-3-yl)amino] -3, 4-dioxo-l -cyclobuten- 1 -yl} amino)-2,2- dimethylpropyl]-3-methylbenzamide;
3 ,5-difluoro-N-[ 1 -( {2-[(2-methoxypyridin-3-yl)amino]-3 ,4-dioxo- 1 -cyclobuten- 1 - yl}amino)-2,2-dimethylpropyl]benzamide;
N-[ 1 -( {2-[(2-methoxypyridin-3-yl)amino]-3,4-dioxo- 1 -cyclobuten- 1 -yl} amino)-2,2- dimethyl-3-phenylpropyl]-3-methylbenzamide;
3 -chloro-N- [ 1 -( {2-[(2-methoxyp yridin-3 -yl)amino] -3 ,4-dioxo- 1 -cyclobuten- 1 - yl}amino)-2,2-dimethylpropyl]benzamide;
N-[l-({2-[(2-chloropyridin-3-yl)amino]-3,4-dioxo-l-cyclobuten-l-yl}amino)-2,2- dimethyl-3-phenylpropyl]benzamide;
N-( 1 - { [3 ,4-dioxo-2-(3 -pyridinylamino)- 1 -cyclobuten- 1 -yl] amino } -2,2-dimethyl-3 - phenylpropyl)benzamide;
N-[ 1 -( {2-[(2-chloropyridin-3-yl)amino]-3,4-dioxo- 1 -cyclobuten- 1 -yl} amino)-2,2- dimethylpropyl]-3-phenylpropanamide;
N-( 1 - { [3 ,4-dioxo-2-(3-pyridinylamino)- 1 -cyclobuten- 1 -yl] amino } -2,2- dimethylpropyl)-2-phenoxyacetamide;
N-[l-({2-[(2-chloropyridin-3-yl)amino]-3,4-dioxo-l-cyclobuten-l-yl}amino)-2,2- dimethylpropyl]-2-phenoxyacetamide;
N-( 1 - { [3 ,4-dioxo-2-(3 -pyridinylamino)- 1 -cyclobuten- 1 -yl] amino } -2,2- dimethylpropyl)-2-methyl-2-phenylpropanamide;
3-chloro-N-(l-{[3,4-dioxo-2-(pyrazin-2-ylamino)-l-cyclobuten-l-yl]amino}-2,2- dimethylpropyl)benzamide;
N-[l-({2-[(2-chloropyridin-3-yl)amino]-3,4-dioxo-l-cyclobuten-l-yl}amino)-3,3- dimethylbutyljbenzamide;
3 -chloro-N-[ 1 -( {2- [(6-chloropyridin-3 -yl)amino] -3 ,4-dioxo- 1 -cyclobuten- 1 -yl } amino)- 2,2-dimethylpropyl]benzamide; 3-chloro-N- {1 -[(3 ,4-dioxo-2-{[6-(trifluoromethyl)pyridin-3-yl]amino}-l-cyclobuten- l-yl)amino]-2,2-dimethylpropyl}benzamide;
3-chloro-N-[l-({2-[(2-chloropyridin-3-yl)amino]-3,4-dioxo-l-cyclobuten-l-yl}amino)- 2,2-dimethylpropyl]benzamide;
N-( 1 - { [3 ,4-dioxo-2-(3 -pyridinylamino) ■ 1 -cyclobuten- 1 -yl] amino -2,2-dimethyl-3- phenylpropyl)isonicotinamide;
N-( 1 - { [3 ,4-dioxo-2-(3 -pyridinylamino) ■ 1 -cyclobuten- 1 -yl] amino -2,2-dimethyl-3- phenylpropyl)-3-phenylpropanamide;
N-( 1 - { [3 ,4-dioxo-2-(3 -pyridinylamino - 1 -cyclobuten- 1 -yl] amino -2,2-dimethyl-3- phenylpropyl)-2-methyl-2-phenylpropanamide;
N-( 1 - { [3 ,4-dioxo-2-(3 -pyridinylamino - 1 -cyclobuten- 1 -yl] amino -2,2-dimethyl-3- phenylpropyl)-2-phenoxyacetamide;
N-( 1 - { [3 ,4-dioxo-2-(3-pyridinylamino -1 -cyclobuten- 1 -yl] amino -2,2-dimethyl-3- phenylpropyl)nicotinamide;
N-( 1 - { [3 ,4-dioxo-2-(3 -pyridinylamino - 1 -cyclobuten- 1 -yl] amino -2,2- dimethylpropyl)nicotinamide;
N-( 1 - { [3 ,4-dioxo-2-(3 -pyridinylamino - 1 -cyclobuten- 1 -yl] amino -2,2- dimethylpropyl)isonicotinamide;
N-(l-{[3,4-dioxo-2-(3-pyridinylamino - 1 -cyclobuten- 1 -yl] amino -2,2- dimethylpropyl)-2-fur amide;
N-( 1 - { [3 ,4-dioxo-2-(3 -pyridinylamino - 1 -cyclobuten- 1 -yl] amino -2,2-dimefhyl-3- pyridin-4-ylpropyl)-3-methylbenzamide;
(-) 3-chloro-N-(l-{[3,4-dioxo-2-(3-pyridinylamino)-l-cyclobuten-l-yl]amino}-2,2- dimethyl-3-phenylpropyl)benzamide;
(+) 3 -chloro-N-( 1 - { [3 ,4-dioxo-2-(3 -pyridinylamino)- 1 -cyclobuten- 1 -yl] amino } -2 ,2- dimethyl-3-phenylpropyl)benz amide;
4-chloro-N-( { [3 ,4-dioxo-2-(3 -pyridinylamino)- 1 -cyclobuten- 1 - yl] amino } methyl)benzamide;
(+) 3,5-dichloro-N-[(lS)-l-({2-[(2-chloropyridin-3-yl)amino]-3,4-dioxocyclobut-l-en- 1 -yl} amino)-2,2-dimethylpropyl]benzamide;
(-) 3,5-dichloro-N-[(lR)-l-({2-[(2-chloropyridin-3-yl)amino]-3,4-dioxocyclobut-l-en- 1 -yl} amino)-2,2-dimethylpropyl]benzamide; (+) N-(l - {[3, 4-dioxo-2-(2-chloro3 -pyridinylamino)- 1 -cyclobuten- 1 -yl] amino } -2,2- dimethylpropyl)-3,5-difluorobenzamide;
(-) N-(l-{[3,4-dioxo-2-(2-chloro3-pyridinylamino)-l-cyclobuten-l-yl]amino}-2,2- dimethylpropyl)-3,5-difluorobenzamide and pharmaceutically acceptable salts thereof.
Abbreviations
Abbreviations which have been used in the descriptions ofthe schemes and the examples that follow are: Ac for acetyl; COD for 1,4-cyclooctadiene; DMA for'N,N- dimethylacetamide; DMAP for 4-dimethylaminopyridine; DME for dimethoxyethane; DMF for N,N-dimethylformamide; DMSO for dimethylsulfoxide; dppf for 1,1'- bis(diphenylphosphino)ferrocene; Et3N for triethylamine; Et2O for diethyl ether; EtOAc for ethyl acetate; EtOH for ethanol; HPLC for high pressure liquid chromatography; MeOH for methanol; NMP for l-methyl-2-pyrrolidinone; pyr for pyridine; t-BuOH for tert-butanol; Tf for triflate or -OS(O)2CF3; TFA for trifluoroacetic acid; THF for tetrahydrofuran; and p-TsOH or TsOH for para-toluenesulfonic acid monohydrate.
Preparation of Compounds of The Invention
The compounds and processes ofthe present invention will be better understood in connection with the following synthetic schemes and methods which illustrate a means by which the compounds ofthe invention can be prepared.
The compounds of this invention may be prepared by a variety of synthetic routes. Representative procedures are described in Schemes 1-16.
Scheme 1
(1 ) (2) (3)
(4) (6) (8)
(8) (3) (9)
A preferred route for preparing aminals of general formula (9), wherein Ri, R , R3, Rt, R5 and Re are as defined in formula (I) is described in Scheme 1. A three-component condensation including benzotriazole, aldehydes of general formula (1), and amides of general formula (2) in the presence of an acid catalyst such as, but not limited to, p-toluenesulfonic acid monohydrate as described in Katritzky, Urogdi, Mayence, J. Org. Chem. (1990), 55, 2206); Katritzky, Chem. Rev. (1998), 98, 409; and Katritzky, J. Heterocyclic Chem. (1996), 33, 1935 provides benzotriazole adducts of general formula (3). Substitution of a bis(ether) precursor of general formula (4), wherein R is alkyl such as, but not limited to, ethyl, with a primary or secondary amine of general formula (5) provides adducts of general formula (6) which can undergo further substitution with ammonia or a primary amine of general formula (7) to provide amines of general formula (8). Benzotriazoles of general formula (3) can be treated with amines of general formula (8) as described in Katritzky, Urogdi, Mayence, J. Org. Chem. (1990), 55, 2206); Katritzky, Chem. Rev. (1998), 98, 409; and Katritzky, J. Heterocyclic Chem. (1996), 33, 1935 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 aminals of general formula (9). Scheme 2
(3) (15)
Squarate aminals of general formula (15), wherein Ri, R2, R4, and R5 are as defined in formula (I), and Re is selected from alkyl such as, but not limited to, t-butyl, arylalkyl such as, but not limited to, phenethyl, or haloalkyl such as, but not limited to, -CCI2CH3 or -CF2CF3, can be prepared as described in Scheme 2. 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. Med. Chem. (2000), 43, 1187; and Gilbert, J. Med. Chem. (2000), 43, 1203 to provide squarates of general formula (13). 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).
Scheme 3
(17) (1 ) (2)
A process for the synthesis of squarate aminals of general formula (15), wherein Ri, R , and R5 are as defined in formula (I), R4 is hydrogen, and R6 is selected from alkyl such as, but not limited to, t-butyl, arylalkyl such as, but not limited to, phenethyl, or haloalkyl such as, but not limited to, -CC12CH3 or -CF2CF3, can be used as described in Scheme 3. Commercially available 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). 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).
In the polymer-bound benzotriazole method as described in Scheme 3, the desired components are bound to the resin allowing for efficient purification. In the final product formation, an excess of a squarate of general formula (14) can be used to cleave only the desired products off the resin. The process described in Scheme 3 also offers the potential to create a combinatorial library (array synthesis) of squarate aminals of general formula (15) by enabling diversity at Ri, R2, R5,and R6 to be explored. Scheme 4
Squarate aminals of general formula (15), wherein Ri, R2, Rt, and R5 are as defined in formula (I) and Re is haloalkyl such as, but not limited to, -CC13 or -CF3, can be prepared as described in Scheme 4. Amides of general formula (2) can be treated with α-haloaldehyde hydrates or α-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). 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).
Scheme 5
(23) (24)
An alternate route for preparing squarate aminals of general formula (15), wherein Ri, R2, R5, and R6 are as defined in formula (I) is described in Scheme 5. 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).
(3) (27)
An alternate route for preparing squarate aminals of general formula (15), wherein Ri, R2, Rt, R5, and R6 are as defined in formula (I) is described in Scheme 6. Compounds of general formula (3) can be treated with ammonia in an alcoholic solvent such as, but not limited to, methanol as described in Katritzky, Urogdi, Mayence, J. Org. Chem. (1990), 55, 2206; Katritzky, Chem. Rev. (1998), 98, 409; and Katritzky; J. Heterocyclic Chem. (1996), 33, 1935 to provide aminoamides of general formula (27). 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).
Scheme 7
(27) (12)
Squarate aminals of general formula (15), wherein Rl s R2, R^ R5, and R6 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).
Scheme 8
(30) (31 )
(27) (12)
Squarate aminals of general formula (15), wherein R1 } R2, R , R5, and R6 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). Acylaminoamides of general formula (31) can undergo a Hofmann rearrangement as described in Wallis and Lane, Org. React. (1946), 3, 267-306, and references contained therein with reagents such as, but not limited to, iodosobenzene diacetate as described in Loudon et al., Org. Chem. (1984), 49, 4272; Loudon and Boutin, J. Org. Chem. (1984), 49, 4277; and Chan et al, Synth. Commun. (1988), 53, 5158 to provide aminoamides of general formula (27), which can be typically isolated as their hydrochloride salts. 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). Scheme 9
(36)
Geminally-substituted squarate aminals of general formula (36), wherein Rl 5 R2, R5,
Re, and R7 are as defined in formula (I) and Re = R or Re and R7 taken together with the carbon atom to which they are attached, together form a 5 or 6 membered carbocyclic ring, can be prepared as described in Scheme 9 or as described in Steglich, Chem. Ber. (1974), 107,
1488; and Burger, J. Fluorine Chem. (1982), 20, 813. 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). 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).
Scheme 10
Squarate aminals of general formula (38), wherein Ri, R2, R3, t and R6 are as defined in formula (I) and R is selected from alkoxycarbonyl, aryl, carboxy, heterocycle and -NRARB wherein RA and RB are as defined in formula (I), can be prepared as described in Scheme 10. Squarate aminals of general formula (37), wherein R is Br, I or -OS(O)2CF3, 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. (1990), 55, 5833 to provide aminals of general formula (38). Alternatively, cross-coupling reactions and carbonylations can be done on squarate aminals of general formula (37) using Buchwald, Stille, Suzuki or Heck coupling reaction conditions, all of which are well known to those skilled in the art of organic chemistry.
Scheme 11
Scheme 11 describes a preferred method that provides squarate aminals of general formula (38), wherein R1 } R2, R4, and R6 are as defined in formula (I) and R' is selected from alkoxycarbonyl, aryl, carboxy, heterocycle and -NRARβ wherein RA and RB are as defined in formula (I). Benzotriazole compounds of general formula (40), wherein R is Br, I or - OS(O)2CF3, 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. (1990), 55, 5833 to provide elaborated benzotriazoles of general formula (41). Alternatively, cross-coupling reactions and carbonylations can be done on benzotriazoles of general formula (40) using Buchwald, Stille, Suzuki or Heck coupling reaction conditions all of which are well known to those skilled in the art of organic chemistry. Benzotriazoles of general formula (41) 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 (38). Scheme 12
H H
C CIISS0022NNCCOO N ^ / CF3C02H
R NH2 » -N^Nγγ0^
(42) t-BuOH
(43)
(44) (3) (45)
Sulfonylamino aminals of general formula (45), wherein Rl s Rt, R5, 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).
Scheme 13
(47) (48)
(49) (3) (50)
Ethanediamide aminals of general formula (50), wherein Ri, Rt, R5, 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).
Scheme 14
(52) (53)
(54)
Aminals of general formula (54), wherein R1 } R2, R , R5 and R6 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).
Altematively, 3,4-dichloro-2,5-furandione can be processed as described in Schemes 6-8 to provide aminals of general formula (54). Scheme 15
Aminals of general formula (56), wherein Ri, R2, Rt, R5 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, R2, Rt, R5 and R6 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).
Scheme 16
ROH
(59) (60)
(3) (15)
Squarate aminals of general formula (15), wherein Ri, R2, Rt, and R5 are as defined in formula (I) and Re is selected from alkyl such as, but not limited to, t-butyl, arylalkyl such as, but not limited to, phenethyl, or haloalkyl such as, but not limited to, -CC12CH3 or -CF CF3, can be prepared as described in Scheme 16. Squaric acid (59) can be treated with oxalyl chloride as described in Ohno et al., J. Chem. Soc, Perkin Trans. 1 (1993), 263; and Yamamoto et al., Tetrahedron (2000), 50, 7783, to provide 3,4-dichloro-cyclobut-3-ene-l,2- dione (60) which can be treated with alcohols such as, but not limited to, methanol as described in Ohno et al, J. Chem. Soc, Perkin Trans. 1 (1993), 263, to provide compounds of general formula (61) wherein R is alkyl. Compounds of general formula (61) can be treated with amines of general formula (5) in the presence of a base such as, but not limited to, sodium bicarbonate in a polar aprotic solvent such as, but not limited to, DMF, to provide squarates of general formula (13). 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). The compounds and processes ofthe present invention will be better understood by reference to the following examples, which are intended as an illustration of and not a limitation upon the scope ofthe invention.
Example 1 N-(l-{ 3,4-dioxo-2-(3-pyridinylaminoVl-cyclobuten-l-yl1amino|-2.2-dimethylpropyπ-4- methylbenzamide
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. The residue was purified by flash chromatography on silica gel (elution with 5% EtOH/EtOAc) to provide 4.42 g ofthe title compound as a white powder. MS (DCI/NH3) m/z 219 (M+H)+.
Example IB 3-amino-4-(3-pyridinylaminoY3-cyclobutene-L2-dione The product from Example 1 A (4.42 g, 20.2 mmol) in ethanol (80 mL) was treated with 2.0M NH3 in methanol (30 mL) and stirred at ambient temperature for 16 hours. 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. MS (DCI/NH3) m/z 190 (M+H)+.
Example 1C
N-(l-(lH- 2,3-benzotriazol-l-yl -2,2-dimethylpropylV4-methylbenzamide
A suspension of p-toluamide (4.11 g, 30.4 mmol), pivaldehyde (2.62 g, 30.4 mmol), and benzotriazole (3.62 g, 30.4 mmol) in toluene (200 mL) was treated with p-toluenesulfonic acid (286 mg, 1.52 mmol). The solution was heated at reflux under Dean-Stark conditions for
10 hours, cooled gradually to ambient temperature, and further cooled to 5 °C. The white precipitate which formed was collected by filtration and was washed with 50% di ethyl ether/hexanes (100 mL) to provide 6.67 g ofthe title compound as a white solid. MS (DCI/NH3) m/z 323 (M+H)+.
Example ID N-( 1 - ( \ ,4-dioxo-2-(3-p yridinylamino)- 1 -cyclobuten- 1 -yl] amino } -2,2-dimethylprop vD-4- mefhylbenzamide 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 K2CO3 (0.55 g, 3.97 mmol). The reaction mixture was stirred at ambient temperature for 20 hours then diluted with 25 mL H2O and extracted with EtOAc (2 x 50 mL). The combined extracts were dried over Na2SO4, and EtOH (5 mL) was added. The crude reaction mixture was filtered through a 0.5 inch silica gel plug and concentrated under reduced pressure to a volume of 20 mL. The title compound (0.13 g) was collected by filtration and dried under reduced pressure for 1 hour, mp 258-259 °C;
MS (DCI/NH3) m/z 393 (M+H)+;
Η NMR (DMSO-d6) δ 9.89 (s, IH), 8.58 (d, IH, J=3 Hz), 8.25 (d, IH, J=5 Hz), 8.06 (br s, IH) 7.94 (dd, IH, J=8, 1 Hz), 7.77 (d, 2H, J=8 Hz), 7.38 (dd, IH, J=8, 5 Hz), 7.29 (d, 2H, J=8 Hz), 5.86 (t, IH, J=8 Hz), 2.36 (s, 3H), 1.06 (s, 9H); Anal, calcd for C22H24N4O3: C, 67.33; H, 6.16; N, 14.28. Found: C, 66.99; H, 5.94; N, 14.20.
Example 2 4-chloro-N-( 1 - { [3 ,4-dioxo-2-(3 -pyridinylamino)- 1 -cyclobuten- 1 - yl] amino } -2,2- dimefhyrpropyDbenzamide
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. MS (DCI/NH3) m/z 343 (M+H)+. Example 2B
4-chloro-N-( 1 - { \3 ,4-dioxo-2-(3 -pyridinylamino )- 1 -cyclobuten- 1 - yl] amino 1-2,2- dimethylpropyDbenz amide
A suspension ofthe product from Example IB, the product from Example 2 A, and K CU3 was processed as described in Example ID to provide the title compound, mp 257-258 °C;
MS (DCI/NH3) m/z 413 (M+H)+;
Η NMR (DMSO-de) δ 9.90 (br s, IH), 8.74 (d, IH, J=7 Hz), 8.58 (d, IH, J=2 Hz), 8.25 (d, IH, J=4 Hz), 8.06 (br s, IH), 7.93 (d, IH, J=8 Hz), 7.87 (d, 2H, J=8 Hz), 7.56 (d, 2H, J=8 Hz), 7.38 (dd, IH, J=8, 5 Hz), 5.86 (s, IH), 1.06 (s, 9H);
Anal, calcd for C2ιH2,ClN4O3: C, 61.09; H, 5.13; N, 13.57. Found: C, 60.86; H, 5.07; N, 13.44.
Example 3 N-(l-{r3,4-dioxo-2-(3-pyridinylamino)-l-cvclobuten-l-yl]amino|-2,2-dimethylpropyl -4- iodobenzamide
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. MS (DC1/NH3) m z 435 (M+H)+.
Example 3B N-( 1 - ( T3 ,4-dioxo-2-(3 -pyridinylamino)- 1 -cyclobuten- 1 - yl] amino 1 -2,2-dimethylprop yl)-4- iodobenzamide A suspension ofthe product from Example IB , the product from Example 3 A, and K2CO3 was processed as described in Example ID to provide the title compound, mp 256-257 °C; MS (ESI+) m/z 505 (M+H)+; Η NMR (DMSO-d6) δ 9.90 (br s, IH), 8.71 (d, IH, J=8 Hz), 8.57 (d, IH, J=3 Hz), 8.25 (dd, IH, J=5, 1 Hz), 8.05 (br s, IH), 7.93 (dd, IH, J=8, 1 Hz), 7.88 (d, 2H, J=8 Hz), 7.63 (d, 2H, J=8 Hz), 7.38 (dd, IH, J=8, 5 Hz), 5.84 (br s, IH), 1.05 (s, 9H); Anal, calcd for C2,H2,rN4O3: C, 50.01 ; H, 4.20; N, 11.11. Found: C, 50.37; H, 4.50; N, 10.80.
Example 4 N-( 1 - { [3 ,4-dioxo-2-(3 -pyridinylamino)- 1 -cyclobuten- 1 -yllaminol -2,2-dimefhylpropyi)-4-(2- furvDbenzamide
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 μL, 0.13 mmol) followed by triphenylarsine (3.7 mg, 0.012 mmol) and then tris(dibenzylideneacetone)dipalladium(0) (5.4 mg, 0.006 mmol). The reaction mixture was stirred for 3.5 hours then partitioned between EtOAc (15 mL) and water (5 mL). The organic portion was washed with water (5 mL) then brine (5 mL) and dried (Na2SO4). Filtration and concentration afforded a oily residue which was purified by flash chromatography (elution with 5% EtOAc/l :l hexanes:CH2Cl2) to provide 37 mg (84%) ofthe title compound as a white solid. MS (DCI NH3) m/z 375 (M+H)+.
Example 4B N-(fl-{ 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 K2CO3 was processed as described in Example ID to provide the title compound, mp 230-232 °C;
MS (DCI/NH3) m/z 445 (M+H)+;
Η NMR (DMSO-d6) δ 9.88 (br s, IH), 8.67 (br s, IH), 8.55 (d, IH, J=2.7 Hz), 8.23 (dd, IH, J=4.6, 1.0 Hz), 8.04 (br s, IH), 7.96-7.87 (m, 3H), 7.83-7.77 (m, 3H), 7.37 (dd, IH, J=8.5, 4.8 Hz), 7.10 (d, IH, J=3.4 Hz), 6.62 (dd, IH, J=3.4, 2.0 Hz), 5.86 (br t, IH, J=6.8 Hz), 1.04 (s,
9H);
Anal, calcd for C25H24N4O4: C, 67.55; H, 5.44; N, 12.60. Found: C, 66.92; H, 5.46; N, 12.69.
Example 5 3-chloro-N-(l-{r3,4-dioxo-2-('3-pyridinylamino)-l-cvclobuten-l-yl]aminol-2,2- dimethylpropyDbenzamide
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/NH3) m/z 343 (M+H)+.
Example 5B
3 -chloro-N-( 1 - { \3 ,4-dioxo-2-(3 -pyridinylamino)- 1 -cyclobuten- 1 -yl] amino 1-2,2- dimethylpropyDbenz amide
A suspension ofthe product from Example IB, the product from Example 5 A, and K2CO3 was processed as described in Example ID to provide the title compound. MS (ESI) m/z 413 (M+H)+;
Η NMR (DMSO-de) δ 9.73 (br s, IH), 9.40 (br d, IH, J=8.4 Hz), 8.77 (d, IH, J=2.5 Hz), 8.50 (d, IH, J=8.4 Hz), 8.26 (dd, IH, J=5.5, 1.1 Hz), 7.93 (br s, IH), 7.79 (br s, IH), 7.83 (d, IH, J=7.9 Hz), 7.61 (br d, IH, J=8.6 Hz), 7.58 (t, IH, J=8.2 Hz), 7.41 (dd, IH, J=8.7, 4.8 Hz), 5.47 (t, IH, J=8.5 Hz), 0.90 (s, 9H);
Anal, calcd forC2ιH5ιClN4O3: C, 61.09; H, 5.13; N, 13.57. Found: C, 61.56; H, 5.02; N, 13.79.
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. MS (DCI NH3) m/z 323 (M+H)+.
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 CO3 was processed as described in Example ID to provide the title compound, mp 236-237 °C; MS (ESI+) m/z 393 (M+H)+;
Η NMR (DMSO-de) δ 9.93 (br s, IH), 8.64 (br d, IH, J=7.1 Hz), 8.57 (d, IH, J=2.7 Hz), 8.25 (dd, IH, J=4.7, 1.4 Hz), 8.08 (br s, IH), 7.93 (br d, IH, J=7.9 Hz), 7.66-7.60 (m, 2H), 7.41- 7.34 (m, 3H), 5.87 (br t, IH, J=6.8 Hz), 2.37 (s, 3H), 1.05 (s, 9H); Anal, calcd for C22H24N4O3: C, 67.33; H, 6.16; N, 14.28. Found: C, 66.98; H, 6.17; N, 14.10.
Example 7 N-(l - { [3,4-dioxo-2-f 3-pyridinylamino)- 1 -cyclobuten- 1 - yl] amino 1 -2,2-dimethylprop vD-3- fluorobenzamide
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 K2CO3 was processed as described in Example ID to provide the title compound, mp 231-232 °C;
MS (DCI/NH3) m/z 397 (M+H)+;
Η NMR (DMSO-d6) δ 9.88 (s, IH), 8.75 (d, IH, J=8 Hz), 8.59 (d, IH, J=2 Hz), 8.26 (dd, IH, J=5, 1 Hz), 8.04 (br s, IH), 7.94 (ddd, IH, J=8, 3, 1 Hz), 7.71 (dt, IH, J=8, 1 Hz), 7.66 (ddd, IH, J=10, 3, 2 Hz), 7.55 (td, IH, J=10, 6 Hz), 7.44-7.37 (m, 2H), 5.88 (t, IH, J=8 Hz), 1.07 (s, 9H);
Anal, calcd for C21H2ιFN4O3 .5H2O: C, 62.21; H, 5.47; N, 13.82. Found: C, 62.12; H, 5.52; N, 14.07.
Example 8 N-( 1 - { [3 ,4-dioxo-2-(3 -pyridinylamino)- 1 -cyclobuten- 1 - yl] amino 1 -2,2-dimethylprop yl)-3 - iodobenzamide
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. MS (DCI/NH3) m/z 435 (M+H)+.
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 K2CO3 was processed as described in Example ID to provide the title compound, mp 234-236 °C;
MS (DCI NH3) m/z 505 (M+H)+;
1H NMR (DMSO-d6) δ 10.03 (br s, IH), 8.77 (br d, IH, J=7.0 Hz), 8.69 (d, IH, J=2.4 Hz), 8.33 (dd, IH, J=4.8, 1.4 Hz), 8.15 (t, IH, J=1.4 Hz), 8.10 (br s, IH), 8.06 (ddd, IH, J=8.5, 2.7, 1.4 Hz), 7.93 (br d, IH, J=7.4 Hz), 7.83 (br d, IH, J=7.9 Hz), 7.56 (dd, IH, J=8.5, 5.2 Hz),
7.80 (t, IH, J=7.8 Hz), 5.85 (br t, IH, J=6.9 Hz), 1.09 (s, 9H);
Anal, calcd for C21H21IN4O3: C, 50.01; H, 4.20; N, 11.11. Found: C, 49.56; H, 4.03; N,
10.86.
Example 9 N-( 1 - { r3 ,4-dioxo-2-(3 -pyridinylamino)- 1 -cyclobuten- 1 - yl] amino 1 -2,2-dimethylprop yl)-3 ,4- dimethylbenzamide
A mixture of lH-benzotriazole polystyrene (purchased from Novabiochem, 1.33 mmol/g, 500 mg, 0.665 mmol), pivalaldehyde (580 mg, 6.70 mmol), 3,4-dimethylbenzamide (1.00 g, 6.70 mmol) and p-toluenesulfonic acid (50 mg, 0.30 mmol) in anhydrous THF (3 mL) and 2-methoxyethanol (3 mL) was heated at 65 °C for 24 hours. 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), CH2C12 (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)+;
1H NMR (DMSO-d6) δ 13.19 (br s, 1 H), 11.67 (s, 1 H), 8.63 (br d, IH, J=7.0 Hz), 8.55 (d, IH, J=2.0 Hz), 8.13 (dd, IH, J=8.8, 2.0 Hz), 7.98 (d, 1 H, J=9.2 Hz), 7.87 (br d, IH, J=0.8 Hz), 7.49-7.30 (m, 3H), 5.87 (br t, IH, J=6.8 Hz), 2.34 (s, 6H), 1.06 (s, 9H).
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 Cs2CO3 as described in Example 9 to provide the title compound. MS (ESI) m/z 439 (M+H)+; Η NMR (DMSO-de) δ 9.94 (s, IH), 8.26 (d, IH, J=8.5 Hz), 7.33-7.15 (m, 5H), 7.08-7.03 (m, 2H), 6.23 (s, IH), 5.73 (t, IH, J=8.2 Hz), 3.79 (s, 6H), 1.08 (s, 9H).
Example 11 N-( 1 - { [3 ,4-dioxo-2-(3 -pyridinylamino)- 1 -cyclobuten- 1 -yl] amino 1 -2,2-dimethylprop yl)-
1-naphthamide A suspension of resin-bound benzotriazole was treated with 1 -naphthamide, pivaldehyde, and p-toluenesulfonic acid and was then processed with the product from Example IB and Cs2CO3 as described in Example 9 to provide the title compound. MS (ESI) m/z 429 (M+H)+;
!H NMR (DMSO-de) δ 9.88 (s, IH), 8.75 (d, IH, J=8 Hz), 8.59 (d, IH, J=2 Hz), 8.31-8.17 (m, 3H), 8.26 (d, IH, J=5Hz), 8.06 (br s, IH), 7.94 (dd, IH, J=8, 1 Hz), 7.74 (br d, IH, J=8 Hz), 7.71 (dt, IH, J=8, 1 Hz), 7.66 (ddd, IH, J=10, 3, 2 Hz), 7.42-7.34 (m, IH), 7.35 (dd, IH, J=8, 5 Hz), 5.88 (t, IH, J=8 Hz), 1.07 (s, 9H).
Example 12 3,5-dichloro-N-(l-{r3,4-dioxo-2-(3-pyridinylamino)-l-cyclobuten-l-yllaminol-2,2- dimethylpropyDbenzamide
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.
MS (DCI/NH3) m/z 377 (M+H)+.
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 K2CO3 was processed as described in Example ID to provide the title compound, mp 260-262 °C; MS (ESI+) m/z 447 (M+H)+;
]K NMR (DMSO-de) δ 9.88 (br s, IH), 8.86 (d, IH, J=7.8 Hz), 8.57 (d, IH, J=2.7 Hz), 8.25
(dd, IH, J=4.7, 1.3 Hz), 8.02 (br s, IH), 7.86 (br d, IH, J=8.4 Hz), 7.67 (s, 3H), 7.39 (dd, IH,
J=8.1, 4.4 Hz), 5.84 (t, IH, J=8.3 Hz), 1.06 (s, 9H);
Anal, calcd for C2ιH20Cl2N4O3: C, 56.39; H, 4.51; N, 12.53. Found: C, 56.16; H, 4.49; N,
12.34.
Example 13 N-(l-{ 3,4-dioxo-2-(3-pyridinylamino)-l-cyclobuten-l-yllaminol-2,2-dimethylpropyl)-3.5- dimefhoxybenzamide
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.
MS (ESI+) m/z 369 (M+H)+.
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 K2CO3 was processed as described in Example ID to provide the title compound. MS (ESI+) m z 439 (M+H)+;
Η NMR (DMSO-d6) δ 10.82 (br s, IH), 8.80 (d, IH, J=2.4 Hz), 8.62 (d, IH, J-7.8 Hz), 8.56 (d, IH, J=7.9 Hz), 8.35 (d, IH, J=5.1 Hz), 8.28 (br d, IH, J=8.8 Hz), 7.66 (dd, IH, J=8.5, 5.1 Hz), 6.92 (d, 2H, J=2.4 Hz), 6.67 (t, IH, J=2.4 Hz), 5.82 (t, IH, J=8.3 Hz), 3.82 (s, 6H), 1.07 (s, 9H); Anal, calcd for C23H26N4O5: C, 63.00; H, 5.98; N, 12.78. Found: C, 62.76; H, 6.11; N, 12.98.
Example 14 (-) N-( 1 - ( [3 ,4-dioxo-2-('3 -pyridinylamino)- 1 -cyclobuten- 1 -yl] amino 1 -2 ,2-dimethylprop yl)-
3 , 5 -dimefhox ybenzamide The product from Example 13B was chromatographed over a Daicel Chiral Technologies Chiralcel AS chiral column (2.0 cmχ25 cm) eluting with 7% ethanol/hexanes (flow rate=10 mL/minute) to provide ofthe title compound as the levorotatory enantiomer. [α]D 23 = -14° (c 0.10, DMSO); MS (ESI+) m/z 439 (M+H)+;
Η NMR (DMSO-d6) δ 10.82 (br s, IH), 8.80 (d, IH, J=2.4 Hz), 8.62 (d, IH, J=7.8 Hz), 8.56 (d, IH, J=7.9 Hz), 8.35 (d, IH, J=5.1 Hz), 8.28 (br d, IH, J=8.8 Hz), 7.66 (dd, IH, J=8.5, 5.1 Hz), 6.92 (d, 2H, J=2.4 Hz), 6.67 (t, IH, J=2.4 Hz), 5.82 (t, IH, J=8.3 Hz), 3.82 (s, 6H), 1.07 (s, 9H);
Example 15 (+) N-f 1 - { [3 ,4-dioxo-2-(3-pyridinylamino)- 1 -cyclobuten- 1 - yl] amino 1 -2,2-dimethylpropyl)-
3,5-dimefhoxybenzamide The product from Example 13B was chromatographed over a Daicel Chiral Technologies Chiralcel AS chiral column (2.0 cmx25 cm) eluting with 7% ethanol/hexanes (flow rate=10 mL/minute) to provide ofthe title compound as the dextrorotatory enantiomer. [ ]D 23 = +16° (c 0.11, DMSO); MS (ESI+) m/z 439 (M+H)+;
1H NMR (DMSO-d6) δ 10.82 (br s, IH), 8.80 (d, IH, J=2.4 Hz), 8.62 (d, IH, J=7.8 Hz), 8.56 (d, IH, J=7.9 Hz), 8.35 (d, IH, J=5.1 Hz), 8.28 (br d, IH, J=8.8 Hz), 7.66 (dd, IH, J=8.5, 5.1 Hz), 6.92 (d, 2H, J=2.4 Hz), 6.67 (t, IH, J=2.4 Hz), 5.82 (t, IH, J=8.3 Hz), 3.82 (s, 6H), 1.07 (s, 9H);
Example 16 N-(- 1 - { \3 ,4-dioxo-2-(3 -pyridinylamino)- 1 -cyclobuten- 1 -yl] amino 1 -2 ,2-dimethylprop yl)-3 ,5 - difluorobenzamide
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. MS (ESI+) m/z 345 (M+H)+.
Example 16B N-(- 1 - { f3 ,4-dioxo-2-(3 -pyridinylamino)- 1 -cyclobuten- 1 -yl] amino 1 -2,2-dimethylprop yl)-3 ,5 - difluorobenzamide
A suspension of the product from Example IB, the product from Example 16A, and K2CO3 was processed as described in Example ID to provide the title compound. MS (ESI+) m/z 415 (M+H)+;
1H NMR (DMSO-de) δ 9.85 (br s, IH), 8.76 (br d, IH, J=8.2 Hz), 8.55 (d, IH, J=2.7 Hz), 8.23 (d, IH, J=4.5 Hz), 8.05-7.96 (m, IH), 7.91 (dd, IH, J=7.8, 1.0 Hz), 7.59-7.42 (m, 3H), 7.38 (dd, IH, J=8.5, 4.7 Hz), 5.83 (t, IH, J=8.3 Hz), 1.06 (s, 9H);
Example 17 4-chloro-N-(- 1 - { r3,4-dioxo-2-(3-pyridinylamino)- 1 -cyclobuten- 1 -yl] amino 1 -2,2-dimethyl-4- pentenvDbenzamide
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.
MS (ESI+) m/z 369 (M+H)+.
Example 17B 4-chloro-N-(- 1 - { [3 ,4-dioxo-2-(3-pyridinylamino)- 1 -cyclobuten- 1 - yl] aminol -2,2-dimethyl-4- pentenyPbenzamide A suspension ofthe product from Example IB, the product from Example 17A, and K2CO3 was processed as described in Example ID to provide the title compound, mp 242-243 °C; MS (DCI/NH3) m/z 439 (M+H)+; 1H NMR (DMSO-d6) δ 9.87 (s, IH), 8.74 (d, IH, J= 6 Hz), 8.56 (d, IH, J= 3 Hz), 8.25 (dd,
IH, J= 5, 1 Hz), 8.03 (br s, IH), 7.93 (dd, IH, J= 8, 1 Hz), 7.87 (d, 2H, J= 8 Hz), 7.57 (d, 2H,
J= 8 Hz), 7.38 (dd, IH, J= 8, 5 Hz), 5.93-5.83 (m, 2H), 5.11-5.05 (m, 2H), 2.22 (dd, IH, J= 14,
8 Hz), 2.12 (dd, IH, J= 14, 8 Hz), 1.02 (s, 3H), 1.01 (s, 3H);
Anal, calcd for CΛsClN^: C, 62.94; H, 5.28; N, 12.77. Found: C, 62.85; H, 5.20; N,
12.87.
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. After stirring the reaction at -78 °C for 30 minutes, triethylamine (20.1 g, 198 mmol) was added and the reaction mixture was stirred for 10 minutes, then at 0 °C for 5 minutes. The reaction mixture was quenched with saturated aqueous ammonium chloride (20 mL) and the aqueous layer was extracted with diethyl ether (2 x 50 mL). The organic portions were individually washed with brine (15 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was redissolved in diethyl ether and the resulting precipitate was filtered through a pad of Celite. The filtrate was concentrated under reduced pressure to provide the title compound (6.89 g) as an oil.
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. The solvent was removed under vacuum and the residue was purified by flash chromatography (elution with 15% EtOAc/hexanes) to provide the title compound (3.63 g) as a white solid. MS (ESI) m/z 419 (M+H)+.
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 2CO3 was processed as described in Example ID to provide the title compound, mp 223-224 °C; MS (ESI+) m/z 489 (M+H)+;
Η NMR (DMSO-de) δ 9.90 (br s, IH), 8.84 (br s, IH), 8.59 (d, IH, J=3 Hz), 8.26 (dd, IH, J=5, 2 Hz), 8.14 (br s, IH), 7.96-7.92 (m, IH), 7.91 (d, 2H, J=8 Hz), 7.76 (d, 2H, J=8 Hz), 7.39 (dd, IH, J=8, 5 Hz), 7.32-7.20 (m, 5H), 5.95 (br s, IH), 2.74 (ABq, 2H, JAB=13 Hz, ΔvAB=32 Hz), 0.97 (s, 3H), 0.95 (s, 3H);
Anal, calcd for C27H25ClN4O3 .5H2O: C, 65.12; H, 5.26; N, 11.25. Found: C, 65.02; H, 5.39; N, 11.36.
Example 19 4-chloro-N-(4-cyano-l-(r3,4-dioxo-2-(3-pyridinylamino)-l-cvclobuten-l-yl1aminol-2,2- diethylbutyDbenzamide
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 K2CO3 was processed as described in Example ID to provide the title compound, mp 242-243 °C; MS (ESI+) m/z 480 (M+H)+;
Η NMR (DMSO-d6) δ 10.50 (br s, IH), 9.04 (br s, IH), 8.82-8.61 (m, 2H), 8.24 (d, IH, J=4 Hz), 8.00-7.91 (m, IH), 7.89 (d, 2H, J=8 Hz), 7.57 (d, 2H, J=8 Hz), 7.32 (dd, IH, J=8, 5 Hz), 5.47 (br s, IH), 2.90-2.51 (m, 2H), 1.85 (br s, IH), 1.60 (br s, IH), 1.48-1.25 (m, 4H), 0.85 (t, 3H, J=8 Hz), 0.78 (t, 3H, J=8 Hz);
Anal, calcd for C25H2eClN5O3T/3H2O: C, 61.79; H, 5.53; N, 14.41. Found: C, 61.90; H, 5.34; N, 14.16.
Example 20 N-(2,2-bisr(allyloxy)methyl]-l-{ 3,4-dioxo-2-('3-pyridinylamino)-l-cvclobuten-l- yll amino 1 butyl)-4-chlorobenzamide
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. MS (ESI) m/z 469 (M+H)+.
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 K2CO3 was processed as described in Example ID to provide the title compound, mp 176-177 °C; MS (ESI+) m/z 539 (M+H)+;
1H NMR (DMSO-d6) δ 9.79 (br s, IH), 8.69 (br s, IH), 8.56 (d, IH, J=3 Hz), 8.25 (dd, IH, J=5, 1 Hz), 8.03 (br s, IH), 7.90 (ddd, IH, J=8, 2, 1 Hz), 7.78 (d, 2H, J=8 Hz), 7.58 (d, 2H, J=8 Hz), 7.38 (dd, IH, J=8, 5 Hz), 6.12 (br s, IH), 5.95-5.84 (m, 2H), 5.31-5.23 (m, 2H), 5.19-
5.14 (m, 2H), 4.00-3.94 (m, 4H), 3.56 (ABq, 2H, JAB=10 Hz, ΔVAB=43 HZ), 3.49-3.45 (m, 2H),
1.60-1.49 (m, 2H), 0.88 (t, 3H, J=8 Hz);
Anal, calcd for C28H3ιClN4O5: C, 62.39; H, 5.80; N, 10.39. Found: C, 62.33; H, 5.75; N,
10.39.
Example 21 4-chloro-N-( 1 - { f3 ,4-dioxo-2-(3-p yridinylamino)- 1 -cyclobuten- 1 - yl] amino 1-2- ethylbutvDbenzamide
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. MS (ESI+) m/z 357 (M+H)+.
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 K2CO3 was processed as described in Example ID to provide the title compound, mp 232-233 °C;
MS (DCI/NH3) m/z 427 (M+H)+;
Η NMR (DMSO-de) δ 9.92 (br s, IH), 9.11 (br s, IH), 8.57 (d, IH, J=2 Hz), 8.24 (dd, 1H, J=5, 2 Hz), 8.20 (br s, IH), 7.95-7.93 (m, IH) 7.90 (d, 2H, J=8 Hz), 7.58 (d, 2H, J=8 Hz), 7.37 (dd, IH, J=8, 5 Hz), 5.74 (br s, IH), 1.99 (br s, IH), 1.58-1.35 (m, 4H), 0.89 (q, 6H, J=7 Hz); Anal, calcd for C22H23ClN4O3: C, 61.90; H, 5.43; N, 13.12. Found: C, 61.60; H, 5.30; N, 13.30.
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 K2CO3 was processed as described in Example ID to provide the title compound, mp 275-276 °C;
MS (ESI+) m/z 326 (M-C8H5C1N (amide))+;
*H NMR (DMSO-de) δ 9.82 (br s, IH), 8.61 (br s, IH), 8.57 (d, IH, J=3 Hz), 8.24 (dd, IH, J=5, 1 Hz), 7.95 (s, IH), 7.94 (ddd, IH, J=8, 3, 1 Hz), 7.85 (d, 2H, J=8 Hz), 7.57 (d, 2H, J=8 Hz), 7.38 (dd, IH, J=8, 5 Hz), 6.13 (br s, IH), 1.84-1.60 (m, 6H), 1.38 (t, IH, J=12 Hz), 1.19- 1.00 (m, 4H), 0.99 (s, 3H), 0.92 (s, 3H);
Anal, calcd for C26H29ClN4O3: C, 64.92; H, 6.08; N, 11.65. Found: C, 64.56; H, 6.13; N, 11.54.
Example 23 N-(2-( 1 -adamantyl)- 1 - ( \3 ,4-dioxo-2-(3-pyridinylamino)- 1 -cyclobuten- 1 -yl]aminol ethyl)-2- chlorobenz amide
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/NH3) 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. MS (ESI) m/z 435 (M+H)+.
Example 23C N-(2-( 1 -adamantyl)- 1 - ( [3 ,4-dioxo-2-(3 -pyridinylamino)- 1 -cyclobuten- 1 - yl] amino 1 ethvι)-2- chlorobenzamide A suspension ofthe product from Example IB, the product from Example 23B, and K CO3 were processed as described in Example ID to provide the title compound, mp 224-225 °C; MS (ESI+) m/z 505 (M+H)+;
Η NMR (DMSO-de) δ 9.91 (br s, IH), 9.16 (br s, IH), 8.57 (d, IH, J=3 Hz), 8.34 (br s, IH), 8.23 (dd, IH, J=5, 1 Hz), 7.94-7.90 (m, IH), 7.90 (d, 2H, J=8 Hz), 7.58 (d, 2H, J=8 Hz), 7.37 (dd, IH, J=8, 5 Hz), 5.96 (m IH), 1.92 (br s, IH), 1.73-1.57 (m, 14H);
Anal, calcd for C28H29ClN4O3-2/3H2O: C, 65.05; H, 5.91; N, 10.84. Found: C, 64.94; H, 5.84; N, 11.08.
Example 24 4-chloro-N-(2,2-dichloro-l-(r3,4-dioxo-2-('3-pyridinylamino)-l-cvclobuten-l- yl] amino 1 -prop vDbenzamide
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, Cl2 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
A suspension ofthe product from Example IB, the product from Example 24B, and K2CO3 was processed as described in Example ID to provide the title compound, mp 201-202 °C; MS (ESI+) m/z 453 (M+H)+;
1H NMR (DMSO-de) δ 10.24 (br s, IH), 9.44 (br d, IH, J=8.4 Hz); 8.59 (d, IH, J=2.4 Hz), 8.48 (d, IH, J=8.2 Hz), 8.28 (dd, IH, J=5.8, 1.1 Hz), 7.90-7.78 (m, IH), 7.81 (d, 2H, J=8.8 Hz), 7.61 (d, 2H, J=8.7 Hz), 7.41 (dd, IH, J=8.6, 4.8 Hz), 6.66 (t, IH, J=8.5 Hz), 2.22 (s, 3H); Anal, calcd forCι9Hι5Cl3N4O3: C, 50.30; H, 3.33; N, 12.35. Found: C, 50.55; H, 3.52; N, 12.29.
Example 25 3-chloro-N-(2,2-dichloro- 1 - { [3 ,4-dioxo-2-(3 -pyridinylamino)- 1 -cyclobuten- 1 - yl] amino 1 -prop vDbenzamide
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)+;
Η NMR (DMSO-d6) δ 10.23 (br s, IH), 9.49 (br d, IH, J=8.5 Hz); 8.59 (d, IH, J=2.7 Hz), 8.47 (d, IH, J=8.6 Hz), 8.29 (dd, IH, J=5.7, 0.9 Hz), 7.94 (br s, IH), 7.91 (br s, IH), 7.83 (d, IH, J=7.8 Hz), 7.69 (br d, IH, J=8.5 Hz), 7.57 (t, IH, J=8.1 Hz), 7.41 (dd, IH, J=8.6, 4.8 Hz), 6.66 (t, IH, J=8.5 Hz), 2.19 (s, 3H);
Anal, calcd forCι9Hι5Cl3N4O3: C, 50.30; H, 3.33; N, 12.35;. Found: C, 50.48; H, 3.40; N, 12.51.
Example 26 3-chloro-N-(l-{ 3,4-dioxo-2-(3-pyridinylamino)-l-cyclobuten-l- yl1aminol-2,2,3,3,3-pentafluoropropyl)benzamide
Example 26A pentafluoropropanal Pentafluoropropanol, oxalyl chloride and dimethylsulfoxide were processed as described in Example 18 A to provide the title compound. MS (DCI/NH3) 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 Cs2CO3 was processed as described in Example ID to provide the title compound, mp 212-213 °C; MS (ESI+) m/z 475 (M+H)+;
1H NMR (DMSO-de) δ 10.18 (br s, IH), 9.93 (br d, IH, J=8.4 Hz); 8.62 (d, IH, J=8.7 Hz), 8.57 (d, IH, J=2.7 Hz), 8.28 (dd, IH, J=5.8, 0.9 Hz), 7.91 (br s, IH), 7.87 (br s, IH), 7.83 (br d, IH, J=7.9 Hz), 7.70 (br d, IH, J=8.6 Hz), 7.58 (t, IH, J=8.1 Hz), 7.39 (dd, IH, J=8.6, 4.8 Hz), 7.01-6.87 (m, IH);
Anal, calcd forCι9Hι2ClF5N4O3: C, 48.07; H, 2.55; N, 11.80. Found: C, 48.13; H, 2.61; N, 11.94.
Example 27 4-chloro-N-( 1 - { [3 ,4-dioxo-2-(3 -fluoroanilino)- 1 -cyclobuten- 1 - yl1aminol-2,2-dimethylpropyl)benzamide
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. MS (DCI/NH3) m/z 236 (M+H)+.
Example 27B 3-Amino-4-(3-fluoro-phenylamino)-cvclobut-3-ene-l,2-dione A solution ofthe product from Example 27A and ammonia in methanol was processed as described in Example IB to provide the title compound. MS (DCI/NH3) m/z 207 (M+H)+.
Example 27B
4-chloro-N-(' 1 - ( [3 ,4-dioxo-2-(3 -fluoroanilino)- 1 -cyclobuten- 1 - yl]aminol-2,2-dimethylpropyl)benzamide A suspension ofthe product from Example 2 A, the product from Example 27B, and K2CO3 was processed as described in Example ID to provide the title compound, mp 271-272 °C; MS (ESI+) m/z 430 (M+H)+;
Η NMR (DMSO-de) δ 9.88 (s, IH), 8.71 (d, IH, J=7.2 Hz), 8.01-7.99 (m, IH), 7.87 (d, 2H, J=8.6 Hz), 7.56 (d, 2H, J=8.2 Hz), 7.48 (dt, IH, J=10.7, 2.2 Hz), 7.37 (dt, IH, J=8.4, 6.7 Hz), 7.13 (dd, IH, J=8.3, 2.7 Hz), 6.85 (td, IH, J=8.3, 2.2 Hz), 5.85 (t, IH, J=8.1 Hz), 1.05 (s, 9H); Anal, calcd for C22H2,ClFN3O3: C, 61.47; H, 4.92; N, 9.78. Found: C, 61.31; H, 4.57; N, 9.99.
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 A solution ofthe product from Example 28 A and ammonia in methanol was processed as described in Example IB to provide the title compound. MS (DCI/NH3) m z 207 (M+H)+.
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 K2CO3 was processed as described in Example ID to provide the title compound, mp 247-249 °C; MS (ESI+) m/z 430 (M+H)+;
Η NMR (DMSO-de) δ 9.78 (br s, IH), 8.72 (br d, IH, J=6.8 Hz), 8.01-7.92 (m, IH), 7.86 (d,
2H, J=8.6 Hz), 7.55 (d, 2H, J=8.4 Hz), 7.47-7.39 (m, IH), 7.42 (dd, IH, J=8.1, 4.8 Hz), 7.18
(t, 2H, J=8.8 Hz), 5.82 (t, IH, J=8.0 Hz), 1.04 (s, 9H);
Anal, calcd for C22H2ιClFN3O3: C, 61.47; H, 4.92; N, 9.78. Found: C, 61.35; H, 4.99; N, 9.42.
Example 29 4-chloro-N- 1 -( |2-[(2-chloro-3 -pyridinyDamino] -3 ,4-dioxo- 1 -cyclobuten- 1 - yl 1 amino)-2,2- dimethylpropyl]benz amide
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. MS (DCI/NH3) m/z 253 (M+H)+.
Example 29B 3-Amino-4-(2-chloro-pyridin-3-ylamino)-cvclobut-3-ene-l,2-dione A solution ofthe product from Example 29A and ammonia in methanol was processed as described in Example IB to provide the title compound. MS (DCI/NH3) m/z 224 (M+H)+.
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 K2CO3 was processed as described in Example ID to provide the title compound, mp 259-261 °C; MS (DCI/NH3) m/z 464 (M+H)+;
Η NMR (DMSO-de) δ 9.46 (br s, IH), 8.70 (d, IH, J=8.1 Hz), 8.48 (d, IH, J=9.1 Hz), 8.10
(dd, IH, J=4.6, 1.7 Hz), 8.00 (d, IH, J=7.8 Hz), 7.85 (d, 2H, J=8.5 Hz), 7.55 (d, 2H, J=8.5
Hz), 7.42 (dd, IH, J=8.1, 4.8 Hz), 5.88 (br t, IH, J=8.3 Hz), 1.04 (s, 9H);
Anal, calcd for C2,H20C12N4O3: C, 56.39; H, 4.51; N, 12.53. Found: C, 56.13; H, 4.49; N,
12.38.
Example 30 N-[l-((2- ('5-bromo-6-fluoro-3-pyridinvDamino1-3,4-dioxo-l-cvclobuten-l-yllamino)-2,2- dimethylpropyl]-4-chlorobenzamide
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. MS (DCI NH3) m/z 315 (M+H)+.
Example 30B 3-Amino-4-(5-bromo-6-fluoro-pyridin-3-ylamino)-cyclobut-3-ene-l,2-dione A solution ofthe product from Example 30A and ammonia in methanol was processed as described in Example IB to provide the title compound. MS (DCI/NH3) m/z 286 (M+H)+.
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 A suspension of the product from Example 2A, the product from Example 30B, and K2CO3 was processed as described in Example ID to provide the title compound, mp 249-252 °C; MS (ESI+) m/z 509 (M+H)+; Η NMR (DMSO-de) δ 10.00 (br s, IH), 8.72 (br d, IH, J=7.0 Hz), 8.47 (br d, IH, J=7.2 Hz),
8.10 (t, IH, J=15 Hz), 8.04 (br s, IH), 7.87 (d, 2H, J=8.5 Hz), 7.58 (d, 2H, J=8.5 Hz), 5.85 (br t, lH, J=6.6 Hz), 1.05 (s, 9H);
Anal, calcd for C2ιH19BrClFN4O3: C, 49.48; H, 3.76; N, 10.99. Found: C, 49.14; H, 3.83; N,
10.71.
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 K2CO3 was processed as described in Example ID to provide the title compound, mp 236-237 °C;
MS (DCI NH3) m/z 523 (M+H)+;
1H NMR (DMSO-d6) δ 9.47 (br s, IH), 8.71 (d, IH, J=8.0 Hz), 8.48 (d, IH, J=8.9 Hz), 8.10 (dd, IH, J=4.7, 1.6 Hz), 8.02 (br d, IH, J=8.3 Hz), 7.91-7.85 (m, 3H), 7.59-7.48 (m, 2H), 7.42 (dd, IH, J=7.8, 4.7 Hz), 7.32-7.16 (m, 4H), 5.88 (br t, IH, J=8.3 Hz), 2.72 (ABq, 2H, JAB=12.2 Hz, ΔvAB=28.5 Hz), 0.96 (s, 3H), 0.92 (s, 3H);
Anal, calcd for C27H24Cl2N4O3: C, 61.96; H, 4.62; N, 10.70. Found: C, 61.55; H, 4.66; N, 10.39.
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 K2CO3 was processed as described in Example ID to provide the title compound, mp 238-239 °C; MS (ESI+) m/z 427 (M+H)+;
Η NMR (DMSO-d6) δ 9.47 (s, IH), 8.61 (d, IH, J=8 Hz), 8.52 (d, IH, J=9 Hz), 8.11 (dd, IH, J= 4, 2 Hz), 8.03 (d, IH, J=8 Hz), 7.67-7.61 (m, 2H), 7.44 (dd, IH, J=8, 5 Hz), 7.39- 7.35 (m, 2H), 5.92 (t, IH, J=8 Hz), 2.37 (s, 3H), 1.07 (s, 9H); Anal, calcd for C22H23C1N4O3 0.5H2O: C, 61.04; H, 5.51; N, 12.94. Found: C, 60.87; H, 5.51 ; N, 12.90.
Example 33 4-chloro-N-(2,2-dimethyl-l-{[(3-pyridinylamino)sulfonyl1aminolpropylbenzamide
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 CH2C12 (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 CH2C12 (20 mL) via canula. The reaction mixture was stirred at ambient temperature for an additional 1.5 hours and then filtered through a 0.25 inch silica gel plug. The solvent was removed under reduced pressure and the residue was purified by flash chromatography on silica gel (elution with EtOAc) to provide 1.17 g of the title compound as a white solid. MS (ESI+) m/z 274 (M+H)+.
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 CH2C12 (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 NaHCO3 (50 mL). The aqueous layer was extracted with EtOAc (25 mL) and the organic phases were combined, dried over Na2SO4 and filtered. The filtrate was concentrated under reduced pressure and the residue was triturated from Et2O/hexanes to provide 0.40 g of the title compound as a white powder. MS (DCJVNH3) 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 K2CO3 was processed as described in Example ID to provide the title compound, mp 166-167 °C; MS (ESI+) m/z 397 (M+H)+;
Η NMR (DMSO-de) δ 10.07 (s, IH), 8.32 (d, IH, J=2 Hz), 8.12, (d, IH, J=9 Hz), 8.03 (dd, IH, J=5, 1 Hz), 7.62 (d, IH, J=9 Hz), 7.53 (d, 2H, J=9 Hz), 7.45 (ddd, IH, J=8, 3, 2 Hz), 7.42 (d, 2H, J=8 Hz), 7.12 (dd, IH, J=9, 5 Hz), 5.19 (t, IH, J=9 Hz), 0.87 (s, 9H); Anal, calcd for Cι7H2ιClN4O3S: C, 51.45; H, 5.33; N, 14.12. Found: C, 51.44; H, 5.56; N, 14.05.
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 K2CO3 was processed as described in Example ID to provide the title compound, mp 177-178 °C;
MS (DCI/NH3) m/z 489 (M+H)+;
Η NMR (DMSO-d6) δ 10.06 (s, IH), 8.31 (d, IH, J=2 Hz), 8.10 (d, IH J=9 Hz), 8.03 (dd, IH, J=5, 2 Hz), 7.74 (d, 2H, J=8 Hz), 7.60 (d, IH, J=9 Hz), 7.46 (ddd, IH, J=8, 3, 2 Hz), 7.30 (d, 2H, J= 8 Hz), 7.13 (dd, IH, J=9, 5 Hz), 5.18 (t, IH, J=9 Hz), 0.86 (s, 9H); Anal, calcd for Cι7H2ιrN4O3S: C, 41.81; H, 4.33; N, 11.47. Found: C, 42.00; H, 4.37; N, 11.26.
Example 35 N1 - { 1 -[(4-chlorobenzoyl)aminol-2,2-dimethylpropyll -N2-(3-pyridinyl)ethanediamide
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. The organic portion was washed with 10% sodium bicarbonate solution (30 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure to provide 4.30 g ofthe title compound. MS (ESI+) m/z 195 (M+H)+.
Example 35B N1 -(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-chlorόbenzoyl)amino]-2,2-dimethylpropyll-N2-('3-pyridinvDethanediamide A suspension ofthe product from Example 2A, the product from Example 35B, and K2CO3 was processed as described in Example ID to provide the title compound, mp 168-170 °C; MS (ESI+) m/z 389 (M+H)+;
1H NMR (DMSO-de) δ 11.01 (s, IH), 8.99 (d, IH, J=2.3 Hz), 8.75 (d, IH, J=9.2 Hz), 8.49 (d, IH, J=8.8 Hz), 8.35 (dd, IH, J=4.8, 1.4 Hz), 8.19 (br d, IH, J=8.4 Hz), 7.88 (d, 2H, J=8.5 Hz), 7.60 (d, 2H, J=8.5 Hz), 7.41 (dd, IH, J=8.5, 4.8 Hz), 5.82 (t, IH, J=9.1 Hz), 0.94 (s, 9H); Anal, calcd for C,9H2,ClN4O3: C, 58.69; H, 5.44; N, 14.41. Found: C, 58.43; H, 5.41 ; N, 14.26.
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. MS (DCI/NH3) m/z 337 (M+H)+.
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 K2CO3 was processed as described in Example ID to provide the title compound, mp 219-220 °C; MS (ESI+) m/z 407 (M+H)+;
1H NMR (DMSO-de) δ 9.71 (s, IH), 8.57 (d, IH, J=3 Hz), 8.24 (dd, IH, J=5, 1 Hz), 8.17 (s, IH), 7.95 (d, IH, J=7 Hz), 7.89 (br s, IH), 7.38 (dd, IH, J=8, 5 Hz), 7.26-7.13 (m, 5H), 5.63 (br s, IH), 2.83 (t, 2H, J=8 Hz), 2.61-2.43 (m, 2H), 0.94 (s, 9H),
Anal, calcd for C23H26N4O3 .2H2O: C, 67.36; H, 6.49; N, 13.66. Found: C, 67.22; H, 6.44; N, 13.95.
Example 37 N-|T -( (2- (2-chloro-3 -pyridinyl)amino]-3,4-dioxo- 1 -cyclobuten- 1 - yll amino)-2,2- dimethylpropyl]-3-(3-pyridinyl)propanamide
Example 37A methyl 3-(3-pyridinvPpropanoate To a solution of 3-(3-pyridinyl)propanoic acid (2.50 g, 16.5 mmol) in CH C12 (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 NaHCO3 (100 mL) was added. The mixture was extracted with CH2C12 (100 mL) and the combined extracts were dried over Na2SO4, filtered, and evaporated in vacuo. The residue was purified by flash chromatography on silica gel (elution with 60% EtOAc/hexanes) to provide 2.70 g (99%) ofthe desired product. MS (DCI/NH3) m/z 166 (M+H)+.
Example 37B 3-(3-pyridinyl)propanamide A solution ofthe product from Example 37A (2.70 g, 16.3 mmol) in NH3 (2.0 M in MeOH, 40 mL) was heated at 80 °C in a sealed vessel for 24 hours. 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 K2CO3 (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)+;
Η NMR (DMSO-d6) δ 9.31 (s, IH), 8.44-8.38 (m, 3H), 8.18 (d, IH, J=7 Hz), 8.10 (dd, IH, J=5, 1 Hz), 8.06 (d, IH, J=8 Hz), 7.61 (d, IH, J=8 Hz), 7.44 (dd, IH, J=8, 5 Hz), 7.27 (dd, IH, J=8, 5 Hz), 5.67 (t, IH, J=8 Hz), 2.85 (t, 2H, J=7 Hz), 2.65-2.46 (m, 2H), 0.93 (s, 9H); Anal, calcd for C22H24C1N5O3 0.8H2O: C, 57.91; H, 5.65; N, 15.35. Found: C, 57.86; H, 5.51 ; N, 15.18.
Example 38 N-( 1 - ( \ ,4-dioxo-2-(3 -pyridinylamino)- 1 -cyclobuten- 1 -yl] amino 1 -2,2-dimethylprop yl)-3 - vinylbenzamide
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 Na2SO4, filtered, and absorbed onto silica gel. The crude material was purified by flash chromatography on silica gel (elution with EtOAc/CH Cl2/hexanes, 5:47.5:47.5) to provide 223 mg (58%) the title compound. MS (DCI/NH3) 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 K2CO3 was processed as described in Example ID to provide the title compound, mp 209-210 °C; MS (ESI+) m/z 405 (M+H)+;
1H NMR (DMSO-de) δ 9.89 (s, IH), 8.73 (d, IH, J=6 Hz), 8.59 (d, IH, J=2 Hz), 8.25 (dd, IH, J=5, 1 Hz), 8.08 (br s, IH), 7.94 (dd, IH, J=l Hz), 7.89 (s, IH), 7.74 (d, IH, J=8 Hz), 7.67 (d, IH, J=8 Hz), 7.47 (t, IH, J=8 Hz), 7.39 (dd, IH, J=8, 5 Hz), 6.81 (dd, IH, JAB=18 Hz, JAC=11 Hz), 5.92 (d, IH, JAB=18 Hz), 5.87 (s, IH), 5.36 (d, IH, J=l l Hz), 1.07 (s, 9H); Anal, calcd for C23H24N4O3 .lH2O: C, 68.00; H, 6.00; N, 13.79. Found: C, 67.62; H, 5.67; N, 13.88.
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 -( 1 H- 1 ,2,3-benzotriazol- 1 -yl)-2,2-dimethylpropyl] ["1,1 '-biphenyl]-3-carboxamide The product from Example 8A, trimethyl(phenyl)tin, triphenylarsine, and tris(dibenzylidineacetone)dipalladium(0) were processed as described in Example 38B to provide the the title compound. MS (DCI/NH3) m/z 385 (M+H)+.
Example 39B N-( 1 - { [3 ,4-dioxo-2-(3-p yridinylamino)- 1 -cyclobuten- 1 - yllaminol -2,2-dimethylprop yl)[ 1,1'- biphenyll-3-carboxamide A suspension of the product from Example IB, the product from Example 39 A, and K2CO3 was processed as described in Example ID to provide the title compound, mp 240-241 °C; MS (ESI+) m/z 455 (M+H)+; lK NMR (DMSO-de) δ 9.89 (s, IH), 8.82 (d, IH, J=7 Hz), 8.59 (d, IH, J=3 Hz), 8.25 (dd, IH, J=5, 2 Hz), 8.10 (br s, IH), 7.95 (ddd, IH, J=8, 3, 1 Hz), 7.87-7.83 (m, 2H), 7.73 (dd, 2H, J=8, 1 Hz), 7.59 (t, IH, J=8 Hz), 7.51 (t, 2H, J=7 Hz), 7.43-7.37 (m, 2H), 5.91 (br s, IH), 1.08 (s, 9H);
Anal, calcd for C27H26N4O3 .15H2O: C, 70.93; H, 5.80; N, 12.25. Found: C, 70.90; H, 5.66; N, 12.25.
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. To this solution was added 2 N HCI (10 mL) and the reaction mixture was stirred for 30 minutes at 23 °C. The mixture was extracted EtOAc (2 x 25 mL) and the combined organic phases were dried (Na2SO4), filtered, and absorbed onto silica gel. The crude material was purified by flash chromatography on silica gel (elution with 50% EtOAc/hexanes) to provide 207 mg (51%) ofthe title compound. MS (ESI+) m/z 351 (M+H)+.
Example 40B
3 -acetyl-N-( 1 - { [3 ,4-dioxo-2-(3-pyridinylamino)- 1 -cyclobuten- 1 -yl] amino 1-2,2- dimethylpropyDbenzamide
A suspension ofthe product from Example IB, Example 40 A, and K2CO3 was processed as described in Example ID to provide the title compound, mp 218-219 °C; MS (ESI+) m/z 421 (M+H)+;
Η NMR (DMSO-de) δ 10.28 (s, IH), 8.89 (d, IH, J=7 Hz), 8.62 (d, IH, J=3 Hz), 8.35 (t, IH, J=2 Hz), 8.34 (br s, IH), 8.24 (dd, IH, J=5, 1 Hz), 8.11 (ddt, 2H, J=16, 8, 2 Hz), 7.96 (dd, IH, J=8, 2 Hz), 7.65 (t, IH, J=8 Hz), 7.38 (dd, IH, J=8, 5 Hz), 5.90 (d, IH, J=6 Hz), 2.64 (s, 3H), 1.08 (s, 9H); Anal, calcd for C23H24N4O4: C, 63.26; H, 5.95; N, 12.83. Found: C, 63.04; H, 5.62; N, 12.80.
Example 41 N-d-{r3,4-dioxo-2-(3-pyridinylamino)-l-cyclobuten-l-yl]aminol-2,2-dimethylpropyl)-2- pyridinecarboxamide
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.
MS (DCI/NH3) m/z 310 (M+H)+.
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 K2CO3 was processed as described in Example ID to provide the title compound. MS (ESI+) m/z 380 (M+H)+;
Η NMR (DMSO-d6) δ 10.26 (s, IH), 8.89 (d, IH, J=8 Hz), 8.71 (d, IH, J=3 Hz), 8.65 (d, IH, J=5 Hz), 8.37 (br s, IH), 8.33 (d, IH, J=5 Hz), 8.08 (dd, IH, 3=7, 1 Hz), 8.03-7.97 (m, 2H), 7.64-7.58 (m, 2H), 5.88 (t, IH, J=7 Hz), 1.06 (s, 9H).
Example 42 N-d-( 3,4-dioxo-2-(3-pyridinylamino)-l-cyclobuten-l-yllaminol-2,2-dimethylpropyl)-4- fluoro-3-(trifluoromethyl)benzamide
Example 42A N-ri-dH-l^ -benzotriazol-l-yD-Σ^-dimethylpropyll^-fluoro-S-CtrifluoromethvDbenzamide
A suspension of 4-fluoro-3-(trifluoromethyl)benzamide, pivaldehyde, benzotriazole, and p-toluenesulfonic acid was processed as in Example IC to provide the title compound. MS (ESI+) m/z 395 (M+H)+.
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 K2CO3 was processed as described in Example ID to provide the title compound. MS (DCI/NH3) m/z 465 (M+H)+;
]H NMR (DMSO-d6) δ 9.86 (s, IH), 8.90 (d, IH, J=7.8 Hz), 8.59 (d, IH, J=2.7 Hz), 8.30-8.16 (m, 3H), 8.12-8.00 (m, IH), 7.95 (ddd, IH, J=8.4, 2.7, 1.4 Hz), 7.66 (t, IH, J=8.4 Hz), 7.39 (dd, IH, J=8.3, 4.6 Hz), 5.89 (t, IH, J=7.9 Hz), 1.67 (s, 9H).
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 Cs2CO3 were processed as described in Example 9 to provide the title compound. MS (ESI+) m/z 393 (M+H)+;
]H NMR (DMSO-de) δ 9.79 (s, IH), 8.64 (s, IH), 8.39 (br s, IH), 8.29 (dd, IH, J=4.8, 1.5 Hz), 8.02 (br d, IH, J=7.7 Hz), 7.98 (br s, IH), 7.50 (dd, IH, J=8.4, 4.8 Hz), 7.32-7.24 (m, 4H), 7.23-7.19 (m, IH), 5.61 (br s, IH), 3.63-3.49 (m, 2H, Ph-CH2, obscured), 0.98 (s, 9H).
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 CS2CO3 were processed as described in Example 9 to provide the title compound. MS (ESI+) m/z 405 (M+H)+;
Η NMR (DMSO-de) δ 9.82 (s, IH), 8.67 (d, IH, J=2.6 Hz), 8.41 (br s, IH), 8.30 (dd, IH, J=5.1, 1.1 Hz), 8.04 (ddd, IH, J=8.4, 2.6, 1.1 Hz), 8.01 (br s, IH), 7.60-7.55 (m, 2H), 7.55- 7.45 (m, 2H), 7.45-7.37 (m, 3H), 6.87 (d, IH, J=15.7 Hz), 5.76 (br s, IH), 1.04 (s, 9H).
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 K2CO3 was processed as described in Example ID to provide the title compound, mp 258-259 °C;
MS (DCI/NH3) m/z 481 (M+H)+;
Η NMR (DMSO-d6) δ 10.21 (s, IH), 9.37 (br d, IH, J=8.0 Hz), 8.59-8.53 (m, IH), 8.52-8.45 (m, IH), 8.28 (br d, IH, J=3.8 Hz), 7.93-7.88 (m, 3H), 7.63-7.58 (m, 2H), 7.41 (dd, IH, J=8.2, 4.4 Hz), 6.69 (t, IH, J=8.4 Hz), 2.32-2.23 (m, 2H), 1.77-1.68 (m, 2H), 0.97 (t, 3H, J=7.8 Hz); Anal, calcd for C2,Hι9Cl3N4O3: C, 52.35; H, 3.98; N, 11.63. Found: C, 52.45; H, 3.84; N, 11.53.
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. MS (DCI/NH3) m/z 219 (M+H)+. 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. MS (DCI NH3) m/z 190 (M+H)+.
Example 46C
4-chloro-N-( 1 - { [3 ,4-dioxo-2-(4-pyridinylamino)- 1 -cyclobuten- 1 -yl] amino 1-2,2- dimethylpropypbenzamide
A suspension ofthe product from Example 46B, the product from Example 2 A, and K2CO3 was processed as described in Example ID to provide the title compound, mp 244-246 °C; MS (ESI+) m/z 413 (M+H)+;
Η NMR (DMSO-de) δ 11.62 (br s, IH), 8.79 (d, IH, J=9.1 Hz), 8.72 (d, IH, J=7.8 Hz), 8.60 (br d, IH, J=6.4 Hz), 7.97-7.79 (m, 4H), 7.55 (d, IH, J=8.4 Hz), 5.87 (t, IH, J=8.1 Hz), 1.07 (s, 9H);
Anal, calcd for C2ιH2ιClN4O3: C, 61.09; H, 5.13; N, 13.57. Found: C, 60.95; H, 5.08; N, 13.51.
Example 47 4-chloro-N-d- {ff3,4-dioxo-2-("2 -pyridinylamino)-! -cyclobuten-1 -yl]aminol -2,2- dimethylpropyDbenzamide
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. MS (DCI/NH3) m/z 219 (M+H)+.
Example 47B 3-amino-4-(2-pyridinylamino)-3-cyclobutene-l,2-dione A solution ofthe product from Example 47 A and ammonia in methanol was processed as described in Example IB to provide the title compound. MS (DCI/NH3) m/z 190 (M+H)+.
Example 47C
4-chloro-N-( 1 - { [3 ,4-dioxo-2-(2 -pyridinylamino)- 1 -cyclobuten- 1 -yl] amino 1-2,2- dimethylpropyDbenzamide
A suspension ofthe product from Example 47B, the product from Example 2A, and K2CO3 was processed as described in Example ID to provide the title compound, mp 246-248 °C; MS (ESI+) m/z 413 (M+H)+;
Η NMR (DMSO-de) δ 10.95 (br s, IH), 9.82 (d, IH, J=9.8 Hz), 8.88 (d, IH, J=8.5 Hz), 8.31 (dd, IH, J=5.1, 1.7 Hz), 7.86 (d, 2H, J=8.4 Hz), 7.85-7.77 (m, 2H), 7.57 (d, IH, J=8.4 Hz), 7.23 (d, IH, J=8.1 Hz), 7.08 (dd, IH, J=6.8, 5.1 Hz), 6.06 (t, IH, J=8.1 Hz), 1.03 (s, 9H); Anal, calcd for C2ιH2ιClN4O3: C, 61.09; H, 5.13; N, 13.57. Found: C, 61.12; H, 5.24; N, 13.53.
Example 48 N-d - { [3 ,4-dioxo-2-(3-p yridinylamino)- 1 -cyclobuten- 1 - yl] amino 1-2,2- dimethylpropyDbenzamide
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. MS (ESI+) m/z 309 (M+H)+.
Example 48B
N-( 1 - (r3,4-dioxo-2-(3-pyridinylamino)-l -cyclobuten- 1 -yl]aminol -2,2- dimethylpropyl)benzamide A suspension ofthe product from Example IB, the product from Example 48 A, and K2CO3 was processed as described in Example ID to provide the title compound, mp 246-247 °C;
MS (DCI/NH3) m/z 379 (M+H)+;
Η NMR (DMSO-d6) δ 9.88 (s, IH), 8.67 (br d, IH, J=7.1 Hz), 8.57 (d, IH, J=2.5 Hz), 8.23 (d, IH, J=4.6 Hz), 8.04 (br s, IH), 7.92 (br d, IH, J=8.3 Hz), 7.83 (d, 2H, J=7.4 Hz), 7.53 (t, IH, J=7.2 Hz), 7.47 (t, 2H, J=7.2 Hz), 7.36 (dd, IH, J=8.3, 4.6 Hz), 5.87 (br s, IH), 1.04 (s, 9H);
Anal, calcd for C2ιH22N4O3-0.55 H2O: C, 64.95; H, 6.00; N, 14.43. Found: C, 64.78; H, 5.69; N, 14.14.
Example 49 (+) N-( 1 - { [3 ,4-dioxo-2-(3 -pyridinylamino)- 1 -cyclobuten- 1 - yl]aminol -2,2-dimethylpropyl)-
3.5-difluorobenzamide The product from Example 16B was chromatographed over a Daicel Chiral Technologies Chiralpak AS chiral column (2.0 cm x 25 cm) eluting with 10% ethanol/hexanes (flow rate=10 mL/minute) to provide the title compound as the dextrorotatory enantiomer. [α]D 23 = +30 ° (c 0.013, DMSO); MS (ESI+) m/z 415 (M+H)+;
1H NMR (DMSO-d6) δ 9.87 (s, IH), 8.78 (d, IH, J=8.1 Hz), 8.57 (d, IH, J=2.7 Hz), 8.25 (dd, IH, J=4.4, 1.4 Hz), 8.02 (br s, IH), 7.93 (ddd, IH, J=8.1, 2.7, 1.4 Hz), 7.62-7.45 (m, 3H), 7.40 (dd, IH, J=8.1, 4.4 Hz), 5.85 (t, IH, J=8.1 Hz), 1.06 (s, 9H).
Example 50 (-) N-d - { f3.4-dioxo-2-(3 -pyridinylamino)- 1 -cyclobuten- 1 -yl] amino 1 -2,2-dimethylprop yl)-
3,5-difluorobenzamide The product from Example 16B was chromatographed over a Daicel Chiral Technologies Chiralpak AS chiral column (2.0 cm x 25 cm) eluting with 10% ethanol/hexanes (flow rate=10 mL/minute) to provide the title compound as the levorotatory enantiomer. [α]D 23 = -26 ° (c 0.013, DMSO); MS (ESI+) m/z 415 (M+H)+; 1H NMR (DMSO-de) δ 9.87 (s, IH), 8.78 (d, IH, J=8.1 Hz), 8.57 (d, IH, J=2.7 Hz), 8.25 (dd, IH, J=4.4, 1.4 Hz), 8.02 (br s, IH), 7.93 (ddd, IH, J=8.1, 2.7, 1.4 Hz), 7.62-7.45 (m, 3H), 7.40 (dd, IH, J=8.1, 4.4 Hz), 5.85 (t, IH, J=8.1 Hz), 1.06 (s, 9H).
Example 51 N-(2,2-dichloro- 1 - ( [3 ,4-dioxo-2-(3 -pyridinylamino)- 1 -cyclobuten- 1 - yl] amino 1 propyl)-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 IB 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 K2CO3 was processed as described in Example ID to provide the title compound, mp 231-232 °C; MS (ESI+) m/z 455 (M+H)+;
Η NMR (DMSO-de) δ 10.22 (s, IH), 9.50 (d, IH, J=7.8 Hz), 8.58 (d, IH, J=2.0 Hz), 8.46 (d, IH, J=7.8 Hz), 8.28 (d, IH, J=4.8 Hz), 7.91 (br d, IH, J=7.8 Hz), 7.63-7.50 (, 3H), 7.41 (dd, IH, J=8.5, 4.7 Hz), 6.64 (t, IH, J=7.8 Hz), 2.24 (s, 3H);
Anal, calcd for Cι9Hι4Ci2F2N4O3: C, 50.13; H, 3.10; N, 12.31. Found: C, 50.35; H, 3.14; N, 12.31.
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 A suspension of 4-chloro-5-trifluoromethyl pyridine (4.86 g, 26.8 mmol), Ni(COD)2 (0.368 g, 1.34 mmol), Pd(dppf)2 CH2Cl2 (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), and sodium tert-butoxide (3.60 g, 37.5 mmol) in toluene was heated at reflux for 16 hours. The reaction mixture was cooled and evaporated in vacuo. The crude material was purified by chromatography, eluting with EtOAc/hexanes (1 :1). The chromatographed product was dissolved in THF (200 mL) and 2 N HCI (10 mL) was added and the mixture was stirred for 0.5 hours. The reaction mixture was partitioned between 0.5 M HCI and (2:1) hexanes/EtOAc The aqueous layer was separated and made alkaline with 10% NaOH. The product aniline was extracted with CH2CI2, dried over anhydrous Na SO4 and concentrated in vacuo to provide 2.98 g (67 % yield) of white crystalline solid. MS (DCI/NH3) m/z 163 (M+H)+.
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/NH3) 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 NH3 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 K2CO3 was processed as described in Example ID to provide the title compound, mp 231-232 °C; MS (ESI+) m/z 481 (M+H)+;
Η NMR (DMSO-d6) δ 10.13 (s, IH), 8.75 (d, IH, J=2.4 Hz), 8.72 (br s, IH), 8.59 (d, IH, J=0.7 Hz), 8.34 (br s, IH), 8.11 (br s, IH), 7.87 (d, 2H, J=8.5 Hz), 7.57 (d, 2H, J=8.5 Hz), 5.86 (m, IH), 1.06 (s, 9H);
Anal, calcd for C22H20CιF3N4O3: C, 54.95; H, 4.19; N, 11.65. Found: C, 54.58; H, 4.19; N, 11.99.
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 K2CO3 was processed as described in Example ID to provide the title compound, mp 233-234 °C; MS (ESI+) m/z 515 (M+H)+;
1H NMR (DMSO-de) δ 10.13 (s, IH), 8.86 (d, IH, J=6.9 Hz), 8.76 (d, IH, J=2.4 Hz), 8.59 (s, IH), 8.39 (s, IH), 8.09 (br s, IH), 7.85 (d, 2H, J=1.9 Hz), 7.82 (d, IH, J=1.9 Hz), 5.86 (s, IH), 1.07 (s, lH);
Anal, calcd for C22Hι9Cl2F3N4O3: C, 51.28; H, 3.72; N, 10.87. Found: C, 50.92; H, 3.62; N, 11.05.
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 K2CO3 was processed as described in Example ID to provide the title compound. mp 194-195 °C;
MS (ESI+) m/z 551 (M+H)+;
Η NMR (DMSO-de) δ 10.14 (s, IH), 8.84 (s, IH), 8.77 (d, IH, J=2.3 Hz), 8.60 (s, IH), 8.41
(s, IH), 8.21 (br s, IH), 7.91 (d, 2H, J=8.5 Hz), 7.59 (d, 2H, J=8.7 Hz), 7.32-7.20 (m, 5H),
5.95 (br s, IH), 2.75 (ABq, 2H, JAB=12.8 Hz, ΔvAB=35.7 Hz), 0.98 (s, 3H), 0.95 (s, 3H);
Anal, calcd for C28H24ClF3N4O3: C, 60.38; H, 4.34; N, 10.06. Found: C, 60.36; H, 4.46; N,
10.03.
Example 55 N-d - ( f3 ,4-dioxo-2-("3 -pyridinylamino)- 1 -cyclobuten- 1 -yl] amino 1 -2,2-dimethyl-3 - phenylpropyl)-3,5-difluorobenzamide
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/NH3) m/z 421 (M+H)+.
Example 55B N-d-{r3,4-dioxo-2-(3-pyridinylamino)-l-cyclobuten-l-yllaminol-2,2-dimethyl-3- phenylpropyl)-3,5-difluorobenzamide
A suspension ofthe product from Example IB, the product from Example 55A, and
K2CO3 was processed as described in Example ID to provide the title compound. mp 223-224 °C;
MS (ESI+) m/z 491 (M+H)+;
Η NMR (DMSO-de) δ 9.88 (s, IH), 8.89 (d, IH, J=7.4 Hz), 8.59 (d, IH, J=2.6 Hz), 8.26 (dd,
IH, J=4.5, 1.2 Hz), 8.12 (br s, IH), 7.95 (ddd, IH, J=8.5, 2.3, 1.2), 7.63-7.57 (m, 2H), 7.50 (tt,
IH, J=9.2, 2.4), 7.26 (ddd, IH, J=8.5, 4.7, 0.7), 7.33-7.21 (m, 5H), 5.94 (s, IH), 2.74 (ABq,
2H, JAB=12.7 Hz, ΔvAB=31.4 Hz), 0.97 (s, 3H), 0.95 (s, 3H);
Anal, calcd for C27H24F2N4O3: C, 66.11; H, 4.93; N, 11.42. Found: C, 65.87; H, 4.79; N,
11.40. Example 56 (+) 3 -chloro-N-( 1 - ( [3 ,4-dioxo-2-(3-p yridinylamino)- 1 -cyclobuten- 1 -yl] amino 1-2,2- dimethylpropyPbenzamide The product from Example 5B was chromatographed over a Daicel Chiral Technologies Chiralpak AS chiral column (2.0 cm x 25 cm) eluting with 10% ethanol/hexanes (flow rate=10 mL/minute) to provide the title compound as the dextrorotatory enantiomer. [α]D 20 = +40° (c 0.11, DMSO); MS (ESI+) m z 413 (M+H)+;
Η NMR (DMSO-de) δ 9.73 (br s, IH), 9.40 (br d, IH, J=8.4 Hz), 8.77 (d, IH, J=2.5 Hz), 8.50 (d, IH, J=8.4 Hz), 8.26 (dd, IH, J=5.5, 1.1 Hz), 7.93 (br s, IH), 7.79 (br s, IH), 7.83 (d, IH, J=7.9 Hz), 7.61 (br d, IH, J=8.6 Hz), 7.58 (t, IH, J=8.2 Hz), 7.41 (dd, IH, J=8.7, 4.8 Hz), 5.47 (t, IH, J=8.5 Hz), 0.90 (s, 9H);
Anal, calcd for C2ιH51ClN4O3: C, 61.09; H, 5.13; N, 13.57. Found: C, 61.26; H, 4.99; N, 13.49.
Example 57 (-) 3 -chloro-N-C 1 - { [3 ^-dioxo^-H -pyridinylamino)- 1 -cyclobuten- 1 -yl] amino 1-2,2- dimethylpropyPbenzamide The product from Example 5B was chromatographed over a Daicel Chiral Technologies Chiralpak AS chiral column (2.0 cm x 25 cm) eluting with 10% ethanol/hexanes (flow rate=10 mL/minute) to provide the title compound as the levorotatory enantiomer. [α]D 20 = -43° (c 0.09, DMSO); MS (ESI+) m/z 413 (M+H)+;
Η NMR (DMSO-de) δ 9.73 (br s, IH), 9.40 (br d, IH, J=8.4 Hz), 8.77 (d, IH, J=2.5 Hz), 8.50 (d, IH, J=8.4 Hz), 8.26 (dd, IH, J=5.5, 1.1 Hz), 7.93 (br s, IH), 7.79 (br s, IH), 7.83 (d, IH, J=7.9 Hz), 7.61 (br d, IH, J=8.6 Hz), 7.58 (t, IH, J=8.2 Hz), 7.41 (dd, IH, J=8.7, 4.8 Hz), 5.47 (t, IH, J=8.5 Hz), 0.90 (s, 9H);
Anal, calcd for C2ιH5,ClN4O3: C, 61.09; H, 5.13; N, 13.57. Found: C, 61.17; H, 5.00; N, 13.44. Example 58 3,5-dichloro-N-d-{[3,4-dioxo-2-('3-pyridinylamino)-l-cvclobuten-l-yllaminol-2,2-dimethyl-
3-phenylpropyl)benzamide
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/NH3) m/z 453 (M+H)+.
Example 58B 3 ,5-dichloro-N-( 1 - {[3 ,4-dioxo-2-(3-pyridinylamino)- 1 -cyclobuten- 1 - yl] aminol -2,2-dimethyl-
3-phenylpropyl)benzamide
A suspension of the product from Example IB, the product from Example 58A, and
K2CO3 was processed as described in Example ID to provide the title compound. mp 197-198 °C;
MS (ESI+) m/z 523 (M+H)+;
1H NMR (DMSO-de) δ 9.86 (s, IH), 8.96 (d, IH, J=7.6 Hz), 8.59 (d, IH, J=2.8 Hz), 8.26 (dd,
IH, J=4.7, 1.4 Hz), 8.10 (br s, IH), 7.94 (dd, IH, J=8.3, 1.2 Hz), 7.87 (d, 2H, J=1.9 Hz), 7.85
(d, IH, J=1.9 Hz), 7.39 (ddd, IH, J=8.3, 4.8, 0.5 Hz), 7.32-7.20 (m, 5H), 5.93 (t, IH, J=7.3
Hz), 5.48 (ABq, JAB=13.0, ΔVΛB=29.7 HZ), 0.97 (s, 3H), 0.96 (s, 3H);
Anal, calcd for C27H24Cl2N4O3O.95 H2O: C, 60.00; H, 4.83; N, 10.37. Found: C, 59.76; H,
4.59; N, 10.22.
Example 59 3 -chloro-N-d - { [3 ,4-dioxo-2-(3 -pyridinylamino)- 1 -cyclobuten- 1 - yl] amino 1 -2,2-dimethyl-3 - phenylpropyPbenzamide
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 59B 3 -chloro-N-( 1 - ( \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 59 A, and
K2CO3 was processed as described in Example ID to provide the title compound. mp 178-179 °C;
MS (ESI+) m/z 489 (M+H)+;
Η NMR (DMSO-de) δ 9.87 (s, IH), 8.90 (d, IH, J=3.7 Hz), 8.60 (d, IH, J=1.6 Hz), 8.26 (d,
IH, J=4.2 Hz), 8.13 (br s, IH), 7.95 (dd, IH, J=8.3, 1.2 Hz), 7.90 (t, IH, J=1.7 Hz), 7.83 dt,
IH, J=7.8, 1.2 Hz), 7.65 (ddd, IH, J=8.0, 2.1, 1.2 Hz), 7.55 (t, IH, J=8.1 Hz), 7.39 (dd, IH,
J=8.2, 4.7 Hz), 7.32-7.20 (m, 5H), 5.95 (s, IH), 2.74 (ABq, JAB=12.8, ΔvAB=32.1 Hz), 0.97 (s,
3H), 0.95 (s, 3H);
Anal, calcd for C27H25C1N4O3-0.5 H2O: C, 65.12; H, 5.26; N, 11.25. Found: C, 65.19; H,
5.42; N, 11.26.
Example 60 N-d-{r3,4-dioxo-2-(3-pyridinylamino)-l-cvclobuten-l-yl]aminol-2,2-dimethyl-3- phenylprop yl)-3 -methylbenzamide
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/NH3) 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 K2CO3 was processed as described in Example ID to provide the title compound, mp 234-235 °C; MS (ESI+) m/z 469 (M+H)+;
!H NMR (DMSO-de) δ 9.88 (s, IH), 8.74 (br s, IH), 8.60 (d, IH, J=2.6 Hz), 8.26 (dd, IH, J=4.7, 1.1 Hz), 8.14 (br s, IH), 7.95 (dd, IH, J=8.3, 1.0 Hz), 7.67 (m, 2H), 7.41-7.37 (m, 3H), 7.32-7.20 (m, 5H), 5.96 (br s, IH), 5.48 (ABq, JAB=12.8, ΔvAB=33.8 Hz), 2.38 (s, 3H), 0.97 (s, 3H), 0.95 (s, 3H);
Anal, calcd for C28H28N4O3-0.1 H2O: C, 69.12; H, 6.21; N, 11.51. Found: C, 69.21; H, 6.37; N, 11.48.
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 K2CO3 was processed as described in Example ID to provide the title compound, mp 234-235 °C; MS (ESI+) m/z 503 (M+H)+;
1H NMR (DMSO-d6) δ 9.47 (s, IH), 8.73 (d, IH, J=7.8 Hz), 8.62 (d, IH, J=7.5 Hz), 8.12 (dd, IH, J=4.8, 1.7 Hz), 8.05 (d, IH, J=7.5 Hz), 7.70-7.65 (m, 2H), 7.45 (dd, IH, J=8.3, 4.8 Hz), 7.40-7.38 (m, 2H), 7.32-7.28 (m, 2H), 7.25-7.21 (m, 3H), 6.01 (br s, IH), 2.75 (ABq, JAB=12.8, ΔvAB=38.7 Hz), 2.39 (s, 3H), 0.99 (s, 3H), 0.95 (s, 3H); Anal, calcd for C28H27C1N4O3-0.2 H2O: C, 66.39; H, 5.45; N, 11.06. Found: C, 66.57; H, 5.67; N, 10.82.
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. The mixture was then heated at 80 °C for an additional 18 hours, filtered, and the solvents removed in vacuo. The crude product was suspended in 10% EtOH/EtOAc (30 mL) and adsorbed onto silica gel (15 g). Purification by flash chromatography on silica gel (eluted with 5% EtOH/EtOAc) provided 1.98 g ofthe desired product as a pale yellow powder. MS (DCI/NH3) m/z 253 (M+H)+.
Example 62B 3-amino-4-(6-chloro-3-pyridinylamino)-cyclobut-3-ene-l,2-dione A solution ofthe product from Example 62 A and ammonia in methanol was processed as described in Example IB to provide the title compound. MS (DCI/NH3) m/z 224 (M+H)+.
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 K2CO3 was processed as described in Example ID to provide the title compound, mp 258-259 °C; MS (ESI+) m/z 447 (M+H)+;
Η NMR (DMSO-de) δ 9.96 (br s, IH), 8.74 (br d, IH, J=9.1 Hz), 8.08-7.97(m, IH), 7.92-7.84 (m, 3H), 7.77 (d, IH, J=7.8 Hz), 7.61-7.48 (m, 3H), 5.85 (dd, IH, J=9.2, 7.8 Hz), 1.04 (s, 9H); Anal, calcd for C2iH2oCl2N4O3: C, 56.39; H, 4.51; N, 12.53. Found: C, 56.43; H, 4.40; N, 12.46.
Example 63 4-chloro-N-r 1 -( {2-["(2-fluoropyridin-3-yPamino]-3 ,4-dioxo- 1 -cyclobuten- 1 -yll amino)-2.2- dimethylpropyl]benz amide
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/NH3) m/z 113 (M+H)+.
Example 63B 4-(2-fluoropyridin-3-ylamino)-3-ethoxy-cyclobut-3-ene-l,2-dione A solution of Example 63A and 3,4-diethoxy-3-cyclobutene-l,2-dione in ethanol was processed as described in Example 62A to provide the title compound. MS (DCI/NH3) m/z 237 (M+H)+.
Example 63C 3-amino-4-(6-fluoro-3-pyridinylamino)-cyclobut-3-ene-l,2-dione A solution ofthe product from Example 63B and ammonia in methanol was processed as described in Example IB to provide the title compound. MS (DCI/NH3) m/z 208 (M+H)+.
Example 63D 4-chloro-N-ri-({2-r(2-fluoropyridin-3-yl)amino1-3,4-dioxo-l-cvclobuten-l-yllamino)-2,2- dimethylpropyl]benzamide A suspension ofthe product from Example 63C, the product from Example 2A, and K2CO3 was processed as described in Example ID to provide the title compound, mp 231-234 °C; MS (ESI+) m/z 431 (M+H)+; !H NMR (DMSO-d6) δ 9.47 (br s, IH), 8.72 (d, IH, J=7.8 Hz), 8.50 (d, IH, J=8.8 Hz), 8.11
(dd, IH, J=4.4, 1.4 Hz), 8.02 (d, IH, J=7.8 Hz), 7.87 (d, 2H, J=8.5 Hz), 7.57 (d, 2H, J=8.5
Hz), 7.44 (dd, IH, J=8.1, 4.4 Hz), 5.89 (t, IH, J=8.5 Hz), 1.06 (s, 9H);
Anal, calcd for C2ιH20ClFN4O3: C, 58.54; H, 4.68; N, 13.00. Found: C, 58.58; H, 4.70; N,
13.18.
Example 64 3 -chloro-N-C 1 - { [3 ,4-dioxo-2-(3 -pyridinylamino)- 1 -cyclobuten- 1 - yl] amino 1-3,3- dimethylbutvPbenzamide
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/NH3) m/z 357 (M+H)+.
Example 64B
3 -chloro-N-( 1 - { [3 ,4-dioxo-2-(3-p yridinylamino)- 1 -cyclobuten- 1 -yl] amino 1-3,3- dimethylbutv benzamide
A suspension ofthe product from Example IB, the product from Example 64A, and K2CO3 was processed as described in Example ID to provide the title compound, mp 238-239 °C; MS (ESI+) m/z 427 (M+H)+;
1H NMR (DMSO-de) δ 9.89 (s, IH), 9.25 (s, IH), 8.57 (d, IH, J=2.6 Hz), 8.34 (br s, IH), 8.27 (dd, IH, J=4.5, 1.2 Hz), 7.95-7.91 (m, 2H), 7.85 (d, IH, J=7.8 Hz), 7.64 (ddd, IH, J=8.0, 2.1, 0.9 Hz), 7.54 (t, IH, J=7.8 Hz), 7.37 (ddd, IH, J=8.3, 4.7, 0.5 Hz), 5.99-5.87 (m, IH), 2.04 (dd, IH, J=14.2, 6.4 Hz), 1.86 (dd, IH, J=14.4, 6.3 Hz), 0.98 (s, 9H); Anal, calcd for C22H23ClN4O3: C, 61.90; H, 5.43; N, 13.12. Found: C, 62.00; H, 5.39; N, 12.89.
Example 65 N-d -{[3, 4-dioxo-2-(3 -pyridinylamino)-! -cyclobuten- 1-yl] amino 1-2,2- dimethylpropyl)thiophene-2-carboxamide
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.
MS (ESI+) m/z 315 (M+H)+.
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 K2CO3 was processed as described in Example ID to provide the title compound. MS (ESI+) m/z 385 (M+H)+;
Η NMR (DMSO-de) δ 10.19 (s, IH), 8.75 (br s, IH), 8.57 (br d, IH, J=5.2 Hz), 8.36 (d, IH, J=4.7 Hz), 8.24 (br s, IH), 8.11 (br d, IH, J=8.1 Hz), 7.94 (d, IH, J=3.4 Hz), 7.81 (d, IH, J=5.0 Hz), 7.62 (dd, IH, J=8.4, 5.0 Hz), 7.18 (dd, IH, J=5.0, 3.7 Hz), 5.81 (t, IH, J=7.5 Hz), 1.05 (s, 9H).
Example 66 3-bromo-N-d-{ 3,4-dioxo-2-(3-pyridinylamino)-l-cyclobuten-l-yllaminol-2,2- dimethylpropyPbenzamide
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. MS (DCI/NH3) m/z 387 (M+H)+.
Example 66B 3 -bromo-NY 1 - { \ ,4-dioxo-2-(3 -pyridinylamino)- 1 -cyclobuten- 1 - yll amino 1-2,2- dimethylpropypbenzamide
A suspension ofthe product from Example IB, the product from Example 66A, and K2CO3 was processed as described in Example ID to provide the title compound, mp 244-245 °C; MS (ESI+) m/z 459 (M+H)+;
Η NMR (DMSO-de) δ 9.86 (br s, IH), 8.79 (d, IH, J=7.8 Hz), 8.57 (d, IH, J=3.1 Hz), 8.11 (dd, IH, J=4.4, 1.4 Hz), 8.09-8.00 (m, IH), 7.99 (t, IH, J=1.7 Hz), 7.93 (ddd, IH, J=8.2, 2.6, 1.0 Hz), 7.83 (dt, 2H, J=7.8, 1.4 Hz), 7.76 (ddd, IH, J=8.2, 2.2, 1.0 Hz), 7.46 (t, IH, J=7.8 Hz), 7.38 (dd, IH, J=8.5, 4.8 Hz), 5.86 (t, IH, J=8.5 Hz), 1.06 (s, 9H); Anal, calcd for C21H2ιBrN4O3: C, 55.15; H, 4.63; N, 12.25. Found: C, 54.94; H, 4.45; N, 12.31.
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 K2CO3 was processed as described in Example ID to provide the title compound, mp 257-259 °C; MS (ESI+) m/z 493 (M+H)+;
Η NMR (DMSO-de) δ 9.46 (br s, IH), 8.78 (d, IH, J=7.8 Hz), 8.48 (d, IH, J=8.5 Hz), 8.11 (dd, IH, J=4.4, 1.4 Hz), 8.05-8.02 (m, IH), 8.00 (t, IH, J=1.7 Hz), 7.84 (dt, IH, J=7.8, 1.4 Hz), 7.76 (ddd, IH, J=8.1, 2.0, 1.0 Hz), 7.46 (t, IH, J=8.1 Hz), 7.44 (dd, IH, J=8.1, 3.4 Hz), 5.89 (t, IH, J=8.1 Hz), 1.07 (s, 9H);
Anal, calcd for C2ιH20BrClN4O3-0.1 H2O: C, 51.10; H, 4.12; N, 11.35. Found: C, 50.78; H, 3.78; N, 11.11.
Example 68 N-d - ( \3 ,4-dioxo-2-(3 -pyridinylamino)- 1 -cyclobuten- 1 -yl] amino 1 -2,2-dimethylprop yl)-9-oxo-
9H-fluorene-4-carboxamide Example 68A 9-oxo-9H-fluorene-4-carboxamide 9-Oxo-9H-fluorene-4-carbonyl chloride (5.00 g, 20.6 mmoL) in 200 mL of THF was cooled to 0 °C and 100 mL of a solution of H2O/NH4OH (2:1) was added dropwise over 10 minutes. The reaction mixture was warmed to 23 °C and stirred for 45 minutes then concentrated in vacuo to a volume of approximately 100 mL. The mixture was filtered and the filter cake was washed with 100 mL of H2O and 25 mL EtOAc/Et2O (1 :1). The product was dried in vacuo and used without further purification. MS (DCI/NH3) m/z 224 (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. MS (ESI+) m/z 411 (M+H)+.
Example 68C N-( 1 - { \3 ,4-dioxo-2-(3 -pyridinylamino)- 1 -cyclobuten- 1 -yl] amino 1 -2,2-dimethylprop yl)-9-oxo-
9H-fluorene-4-carboxamide A suspension ofthe product from Example IB, the product from Example 68B, and K2CO3 was processed as described in Example ID to provide the title compound, mp 201-202 °C; MS (ESI+) m/z 481 (M+H)+;
Η NMR (DMSO-d6) δ 9.89 (s, IH), 9.23 (d, IH, J=8.0 Hz), 8.61 (d, IH, J=2.6 Hz), 8.27 (dd, IH, J=4.7, 1.2 Hz), 8.09 (br s, IH), 7.99 (ddd, IH, J=8.2, 2.6, 1.1 Hz), 7.72 (dd, IH, J=7.3, 1.2 Hz), 7.66-7.63 (m, IH), 7.62 (d, IH, J=7.1 Hz), 7.56 (dd, IH, 7.5, 1.2 Hz), 7.49 (d, IH, J=7.3 Hz), 7.46-7.36 (m, 3H), 6.02 (t, IH, J=8.7 Hz), 1.09 (s, 9H); Anal, calcd for C28H24N4O4-1.05 H2O: C, 67.34; H, 5.27; N, 11.22. Found: C, 67.68; H, 5.41; N, 10.85.
Example 69 methyl 3- {["d- ([3, 4-dioxo-2-(3 -pyridinylamino)- 1 -cyclobuten- 1-yll amino 1-2,2- dimethylpropyl)amino]carbonyllbenzoate
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. The aqueous layer was extracted with 25 mL of EtOAc and the combined extracts were washed with NaHCO3, dried over Na2SO4, and filtered through a 1/4" silica gel frit. The filtrate was concentrated in vacuo and the crude material was recrystallized from EtOAc/hexanes to provide the desired product (0.817 g, 82 % yield). MS (DCI/NH3) m/z 180 (M+H)+.
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. MS (ESI+) m/z 367 (M+H)+.
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 K2CO3 was processed as described in Example ID to provide the title compound, mp 228-229 °C; MS (ESI+) m/z 437 (M+H)+;
1H NMR (DMSO-de) δ 9.89 (s, IH), 8.90 (d, IH, J=7.6 Hz), 8.58 (d, IH, J=2.4 Hz), 8.39 (t, IH, J=1.8 Hz), 8.25 (dd, IH, J=4.7, 1.4 Hz), 8.14-8.09 (m, 2H), 8.05 (br s, IH), 7.94 (ddd, IH, J=8.5, 2.8, 1.4 Hz), 7.66 (t, IH, J=8.0 Hz), 7.39 (dd, IH, J=8.5, 4.7 Hz), 5.90 (br s, IH),
3.90 (s, 3H), 1.07 (s, 9H);
Anal, calcd for C23H24N4O5: C, 63.29; H, 5.54; N, 12.84. Found: C, 62.92; H, 5.61; N, 13.04.
Example 70 ("+) N-d - { [3 ,4-dioxo-2-(3 -pyridinylamino)- 1 -cyclobuten- 1 - yl] amino 1 -2,2-dimethylprop yl)-3 - methylbenzamide The product from Example 6B was chromatographed over a Daicel Chiral Technologies Chiralpak AS chiral column (2.0 cm x 25 cm) eluting with 15% ethanol/hexanes (flow rate=15 mL/minute) to provide the title compound as the dextrorotatory enantiomer. [α]D 23 = +98° (c 0.25, EtOH);
HRMS (FAB) calcd for C22H25N4O3 (M+H)+ 393.1927, found 393.1917; Η NMR (DMSO-de) δ 9.93 (br s, IH), 8.64 (br d, IH, J=7.1 Hz), 8.57 (d, IH, J=2.7 Hz), 8.25 (dd, IH, J=4.7, 1.4 Hz), 8.08 (br s, IH), 7.93 (br d, IH, J=7.9 Hz), 7.66-7.60 (m, 2H), 7.41- 7.34 (m, 3H), 5.87 (br t, IH, J=6.8 Hz), 2.37 (s, 3H), 1.05 (s, 9H).
Example 71 (-) N-d-{[3,4-dioxo-2-("3-pyridinylamino)-l-cvclobuten-l-yl]aminol-2,2-dimethylpropyP-3- methylbenzamide The product from Example 6B was chromatographed over a Daicel Chiral Technologies Chiralpak AS chiral column (2.0 cm x 25 cm) eluting with 15% ethanol/hexanes (flow rate=15 mL/minute) to provide the title compound as the levorotatory enantiomer. [ ]D 23 = -96° (c 0.30, EtOH);
HRMS (FAB) calcd for C22H25N4O3 (M+H)+ 393.1927, found 393.1933; Η NMR (DMSO-d6) δ 9.93 (br s, IH), 8.64 (br d, IH, J=7.1 Hz), 8.57 (d, IH, J=2.7 Hz), 8.25 (dd, IH, J=4.7, 1.4 Hz), 8.08 (br s, IH), 7.93 (br d, IH, J=7.9 Hz), 7.66-7.60 (m, 2H), 7.41- 7.34 (m, 3H), 5.87 (br t, IH, J=6.8 Hz), 2.37 (s, 3H), 1.05 (s, 9H).
Example 72 ("+) N-( 1 - ( [3 ,4-dioxo-2-(3 -pyridinylamino)- 1 -cyclobuten- 1 - yl] amino 1 -2,2-dimethyl-3 - phenylprop yl)-3 -methylbenzamide The product from Example 60B was chromatographed over a Daicel Chiral Technologies Chiralpak AS chiral column (2.0 cm x 25 cm) eluting with 15%) ethanol/hexanes (flow rate=15 mL/minute) to provide the title compound as the dextrorotatory enantiomer. [α]D 23 = +105° (c 0.36, EtOH);
HRMS (FAB) calcd for C28H29N4O3 (M+H)+ 469.2240, found 469.2243; Η NMR (DMSO-de) δ 9.88 (s, IH), 8.74 (br s, IH), 8.60 (d, IH, J=2.6 Hz), 8.26 (dd, IH, J=4.7, 1.1 Hz), 8.14 (br s, IH), 7.95 (dd, IH, J=8.3, 1.0 Hz), 7.67 (m, 2H), 7.41-7.37 (m, 3H), 7.32-7.20 (m, 5H), 5.96 (br s, IH), 5.48 (ABq, JAB=12.8, ΔvAB=33.8 Hz), 2.38 (s, 3H), 0.97 (s, 3H), 0.95 (s, 3H).
Example 73 (-) N-d - {[3,4-dioxo-2-(3-pyridinylamino)-l -cyclobuten- 1 -yllaminol -2,2-dimethyl-3- phenylprop yl)-3 -methylbenzamide The product from Example 60B was chromatographed over a Daicel Chiral Technologies Chiralpak AS chiral column (2.0 cm x 25 cm) eluting with 15% ethanol/hexanes (flow rate=15 mL/minute) to provide the title compound as the levorotatory enantiomer. [α]D 23 = -96° (c 0.34, EtOH);
HRMS (FAB) calcd for C28H29N4O3 (M+H)+ 469.2240, found 469.2252; 1H NMR (DMSO-de) δ 9.88 (s, IH), 8.74 (br s, IH), 8.60 (d, IH, J=2.6 Hz), 8.26 (dd, IH, J=4.7, 1.1 Hz), 8.14 (br s, IH), 7.95 (dd, IH, J=8.3, 1.0 Hz), 7.67 (m, 2H), 7.41-7.37 (m, 3H), 7.32-7.20 (m, 5H), 5.96 (br s, IH), 5.48 (ABq, JAB=12.8, ΔvAB=33.8 Hz), 2.38 (s, 3H), 0.97 (s, 3H), 0.95 (s, 3H).
Example 74 (+) N-[ 1 -( {2- |Y2-chlorop yridin-3 - vPamino] -3 ,4-dioxo- 1 -cyclobuten- 1 - yll amino)-2 ,2- dimethylprop yl] -3 -methylbenzamide The product from Example 32 was chromatographed over a Daicel Chiral Technologies Chiralpak AS chiral column (2.0 cm x 25 cm) eluting with 15% ethanol/hexanes (flow rate=15 mL/minute) to provide the title compound as the dextrorotatory enantiomer. [α]D 23 = +77° (c 0.22, EtOH); HRMS (FAB) calcd for C27H25F2N4O3 (M+H)+ 491.1895, found 491.1893; Η NMR (DMSO-d6) δ 9.88 (s, IH), 8.89 (d, IH, J=7.6 Hz), 8.59 (d, IH, J=2.4 Hz), 8.26 (dd, IH, J=4.7, 1.0 Hz), 8.12 (br s, IH), 7.95 (ddd, IH, J=8.0, 2.5, 1.0 Hz), 7.63-7.57 (m, 2H), 7.50 (dt, IH, J=9.0, 2.4 Hz), 7.39 (dd, IH, J=9.0, 4.7 Hz),7.33-7.27 (m, 2H), 7.26-7.19 (m, 3H), 5.94 (br s, IH), 2.74 (ABq, JAB=12.8, ΔvAB=31.2 Hz), 0.97 (s, 3H), 0.95 (s, 3H).
Example 75 (-) N- l-((2-r('2-chloropyridin-3-vPamino1-3,4-dioxo-l-cvclobuten-l-yllamino)-2.2- dimethylpropyl]-3-methylbenzamide The product from Example 32 was chromatographed over a Daicel Chiral Technologies Chiralpak AS chiral column (2.0 cm x 25 cm) eluting with 15% ethanol/hexanes (flow rate=15 mL/minute) to provide the title compound as the levorotatory enantiomer. [α]D 23 = -136° (c 0.27, EtOH);
HRMS (FAB) calcd for C22H24ClN4O3 (M+H)+ 427.1537, found 427.1529; 1H NMR (DMSO-de) δ 9.47 (s, IH), 8.61 (d, IH, J=8.0 Hz), 8.52 (d, IH, J=8.8 Hz), 8.11 (dd, IH, J=4.5, 1.6 Hz), 8.03 (d, IH, J=7.8 Hz), 7.67-7.61 (m, 2H), 7.44 (dd, IH, J=8.3, 4.7 Hz), 7.39-7.35 (m, 2H), 5.92 (t, IH, J=8.0 Hz), 2.37 (s, 3H), 1.07 (s, 9H).
Example 76 (+) N-d - 3 ,4-dioxo-2-(3-pyridinylamino)- 1 -cyclobuten- 1 -yl] amino 1 -2,2-dimethyl-3- phenylpropyl)-3,5-difluorobenzamide The product from Example 55B was chromatographed over a Daicel Chiral Technologies Chiralpak AS chiral column (2.0 cm x 25 cm) eluting with 15% ethanol/hexanes (flow rate=15 mL/minute) to provide the title compound as the dextrorotatory enantiomer. [α]D 23 = +77° (c 0.22, EtOH);
HRMS (FAB) calcd for C27H25F2N4O3 (M+H)+ 491.1895, found 491.1893; 1H NMR (DMSO-de) δ 9.88 (s, IH), 8.89 (d, IH, J=7.6 Hz), 8.59 (d, IH, J=2.4 Hz), 8.26 (dd, IH, J=4.7, 1.0 Hz), 8.12 (br s, IH), 7.95 (ddd, IH, J=8.0, 2.5, 1.0 Hz), 7.63-7.57 (m, 2H), 7.50 (dt, IH, J=9.0, 2.4 Hz), 7.39 (dd, IH, J=9.0, 4.7 Hz),7.33-7.27 (m, 2H), 7.26-7.19 (m, 3H), 5.94 (br s, IH), 2.74 (ABq, JAB=12.8, ΔvAB=31.2 HZ), 0.97 (s, 3H), 0.95 (s, 3H).
Example 77 N-( 1 - { [3 ,4-dioxo-2-("3 -pyridinylamino)- 1 -cyclobuten- 1 -yl] amino 1 -2,2-dimethylprop yl)-3 -(2- furvPbenzamide
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 H2O and extracted twice with 50 mL of EtOAc. The combined extracts were dried over Na2SO4, and absorbed onto silica gel. The crude product was purified by flash chromatography (eluting with EtOAc/hexanes (1 :4)) to provide 0.34 g ofthe desired compound. MS (DCI/NH3) m/z 375 (M+H)+.
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 CO3 was processed as described in Example ID to provide the title compound, mp 251-252 °C; MS (ESI+) m/z 445 (M+H)+;
1H NMR (DMSO-d6) δ 9.89 (s, IH), 8.80 (d, IH, J=7.4 Hz), 8.59 (d, IH, J=2.8 Hz), 8.25 (dd, IH, J=4.6, 1.2 Hz), 8.11 (s, IH), 8.09 (br s, IH), 7.95 (ddd, IH, J=8.3, 2.5, 1.2 Hz), 7.88(dt, IH, J=8.0, 1.2 Hz), 7.80 (d, IH, J=1.5 Hz), 7.75 (d, IH, J=8.0 Hz), 7.55 (t,lH, J=8.0 Hz), 7.39 (dd, IH, J=8.3, 4.6 Hz), 7.04 (d, IH, J=3.4 Hz), 6.63 (dd, IH, J=3.4, 1.8 Hz), 5.90 (t, IH, J=8.0 Hz), 1.08 (s, 9H);
Anal, calcd for C25H24N4O4 .25 H2O: C, 66.88; H, 5.50; N, 12.48. Found: C, 66.74; H, 5.55; N, 12.69.
Example 78 N-ri-(, |2-f('2-chloropyridin-3-vPaminol-3.4-dioxo-l-cvclobuten-l-yllamino)-2.2- dimethylpropyl]-3-fluorobenzamide A suspension ofthe product from Example 29B, the product from Example 7 A, and K2CO3 was processed as described in Example ID to provide the title compound, mp 228-229 °C; MS (ESI+) m/z 431 (M+H)+;
Η NMR (DMSO-de) δ 9.47 (s, IH), 8.72 (d, IH, J=7.7 Hz), 8.51 (d, IH, J=8.3 Hz), 8.12 (dd, IH, J=4.6, 1.5 Hz), 8.03 (d, IH, J=7.4 Hz), 7.71 (dt, IH, J=8.0, 1.2 Hz), 7.66 (ddd, IH, J=9.8, 2.5, 1.5 Hz), 7.55 (td, IH, J=8.0, 5.8 Hz), 7.45 (dd, IH, J=8.0, 4.6 Hz), 7.44-7.39 (m, IH), 5.91 (t, IH, J=8.0 Hz), 1.07 (s, 9H);
Anal, calcd for C2ιH20ClFN4O4: C, 58.54; H, 4.68; N, 13.00. Found: C, 58.35; H, 4.90; N, 12.98.
Example 79 3,5-dichloro-N-fl-({2-[('2-chloropyridin-3-yl)amino]-3,4-dioxocyclobut-l-en-l-yllamino)-
2,2-dimethylpropyllbenzamide A suspension ofthe product from Example 29B, the product from Example 12 A, and K2CO3 was processed as described in Example ID to provide the title compound, mp 233-234 °C; MS (ESI+) m/z 482 (M+H)+;
Η NMR (DMSO-de) δ 9.45 (s, IH), 8.86 (d, IH, J=7.7 Hz), 8.47 (d, IH, J=8.9 Hz), 8.12 (dd, IH, J=4.6, 1.8 Hz), 8.03 (d, IH, J=8.0 Hz), 7.86 (d, 2H, J=2.2 Hz), 7.82 (t, IH, J=1.8 Hz), 7.45 (dd, IH, J=8.3, 4.6 Hz), 5.90 (t, IH, J=8.0 Hz), 1.08 (s, 9H);
Anal, calcd for C2ιHι9Cl3N4O4: C, 52.35; H, 3.98; N, 11.63. Found: C, 52.32; H, 4.04; N, 12.00.
Example 80 4-chloro-N-ri-({2-r(2-methoxypyridin-3-yl)amino]-3,4-dioxo-l-cvclobuten-l-yllamino)-2,2- dimethylpropyl]benzamide
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. MS (DCI/NH3) m/z 249 (M+H)+.
Example 80B 3-amino-4-r(2 -methoxyp yridin-3-yl)amino]cvclobut-3-ene-l,2-dione A solution ofthe product from Example 80 A and ammonia in methanol was processed as described in Example IB to provide the title compound. MS (DCI/NH3) m/z 220 (M+H)+.
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 K2CO3 was processed as described in Example ID to provide the title compound, mp 239-241 °C; MS (ESI+) m/z 443 (M+H)+;
Η NMR (DMSO-d6) δ 9.47 (br s, IH), 8.70 (d, IH, J=8.1 Hz), 8.49 (d, IH, J=8.8 Hz), 8.07 (d, IH, J=7.8 Hz), 7.90-7.82 (m, 3H), 7.56 (d, 2H, J=8.5 Hz), 7.01 (dd, IH, J=7.8, 5.1 Hz), 5.87 (t, IH, J=8.1 Hz), 3.99 (s, 3H), 1.05 (s, 9H);
Anal, calcd for C22H23ClN4O4: C, 59.66; H, 5.23; N, 12.65. Found: C, 59.51; H, 5.13; N, 12.49.
Example 81 N- l-d2-[(2-methoxypyridin-3-yl)amino]-3,4-dioxo-l-cyclobuten-l-yllamino)-2,2- dimethylpropyl]-3-methylbenzamide A suspension ofthe product from Example 80B, the product from Example 6 A, and K2CO3 was processed as described in Example ID to provide the title compound, mp 224-226 °C; MS (ESI+) m/z 423 (M+H)+; Η NMR (DMSO-d6) δ 9.50 (br s, IH), 8.61 (d, IH, J=8.1 Hz), 8.52 (d, IH, J=8.8 Hz), 8.07 (d, IH, J=7.8 Hz), 7.83 (dd, IH, J=4.8, 1.4 Hz), 7.66-7.59 (m, 2H), 7.39-7.33 (m, 2H), 7.00 (dd, IH, J=7.8, 4.8 Hz), 5.89 (t, IH, J=8.1 Hz), 3.99 (s, 3H), 2.37 (s, 3H), 1.05 (s, 9H); Anal, calcd for C22H26N4O4: C, 65.39; H, 6.20; N, 13.28. Found: C, 65.45; H, 6.11; N, 13.28.
Example 82 3,5-difluoro-N-ri-({2-[(2-methoxypyridin-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 16A, and K2CO3 was processed as described in Example ID to provide the title compound, mp 221-223 °C; MS (ESI+) m/z 445 (M+H)+;
1H NMR (DMSO-de) δ 9.48 (br s, IH), 8.76 (d, IH, J=7.8 Hz), 8.47 (d, IH, J=8.8 Hz), 8.06 (dd, IH, J=7.8, 1.4 Hz), 7.84 (dd, IH, J=4.8, 1.4 Hz), 7.61-7.53 (m, 2H), 7.49 (tt, IH, J=9.2, 2.4 Hz), 7.01 (dd, IH, J=7.8, 5.1 Hz), 5.87 (t, IH, J=8.1 Hz), 3.99 (s, 3H), 1.06 (s, 9H); Anal, calcd for C22H22F2N4O4: C, 59.45; H, 4.99; N, 12.61. Found: C, 59.33; H, 4.86; N, 12.66.
Example 83 N-[l-({2- (2-methoxypyridin-3-yl)aminol-3,4-dioxo-l-cyclobuten-l-yllamino)-2,2-dimethyl-
3-phenylpropyl1-3-methylbenzamide A suspension ofthe product from Example 80B, the product from Example 60 A, and K2CO3 was processed as described in Example ID to provide the title compound, mp 233-235 °C; MS (ESI+) m/z 499 (M+H)+;
Η NMR (DMSO-d6) δ 9.49 (br s, IH), 8.73 (d, IH, J=8.1 Hz), 8.61 (d, IH, J=8.8 Hz), 8.08 (d, IH, J=7.5 Hz), 7.84 (dd, IH, J=5.1, 1.7 Hz), 7.69-7.63 (m, 2H), 7.41-7.36 (m, 2H), 7.34- 7.18 (m, 5H), 7.01 (dd, IH, J=7.8, 5.1 Hz), 5.97 (t, IH, J=8.1 Hz), 4.00 (s, 3H), 2.73 (Abq, 2H, Hz, ΔvAB=26.8 Hz), 2.38 (s, 3H), 0.96 (s, 3H), 0.93 (s, 3H); Anal, calcd for C29H30N4O4: C, 69.86; H, 6.06; N, 11.24. Found: C, 69.73; H, 5.95; N, 11.18. 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 K2CO3 was processed as described in Example ID to provide the title compound, mp 208-210 °C; MS (ESI+) m/z 443 (M+H)+;
Η NMR (DMSO-de) δ 9.50 (br s, IH), 8.77 (d, IH, J=7.8 Hz), 8.53 (d, IH, J=8.1 Hz), 8.06 (d, IH, J=7.4 Hz), 7.87 (t, IH, J=1.8 Hz), 7.84 (dd, IH, J=5.1, 1.7 Hz), 7.80 (br d, IH, J=7.8 Hz), 7.63 (br d, IH, J=8.2 Hz), 7.52 (t, IH, J=7.8 Hz), 7.00 (dd, IH, J=7.8, 5.1 Hz), 5.88 (t, IH, J=8.1 Hz), 3.99 (s, 3H), 1.05 (s, 9H);
Anal, calcd for C22H23ClN4O4: C, 59.66; H, 5.23; N, 12.65. Found: C, 59.49; H, 5.04; N, 12.62.
Example 85 N-[ !-(" {2-[(2-chlorop yridin-3- vPamino] -3, 4-dioxo- 1 -cyclobuten- 1 -yl) amino)-2,2-dimethyl-3- phenylpropyl]benzamide
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/NH3) 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 A suspension ofthe product from Example 29B, the product from Example 85 A, and K2CO3 was processed as described in Example ID to provide the title compound, mp 225-226 °C; MS (ESI+) m/z 489 (M+H)+; 1H NMR (DMSO-d6) δ 9.18 (s, IH), 8.49 (d, IH, J=6.8 Hz), 8.33 (d, IH, J=6.8 Hz), 7.82 (dd,
IH, J=4.6, 1.5 Hz), 7.75 (d, IH, J=7.7 Hz), 7.62-7.57 (m, 2H), 7.32-7.26 (m, IH), 7.24-7.19
(m, 2H), 7.15 (dd, IH, J=8.3, 4.6 Hz), 7.03-6.97 (m, 2H), 6.96-6.90 (m, 3H), 5.72 (br s, IH),
2.46 (ABq, JAB= 12.9, ΔvAB= 37.8 Hz), 0.70 (s, 3H), 0.65 (s, 3H);
Anal, calcd for C27H25ClN4O4: C, 66.32; H, 5.15; N, 11.46. Found: C, 66.14; H, 5.03; N,
11.33.
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 K2CO3 was processed as described in Example ID to provide the title compound, mp 237-238 °C; MS (ESI+) m/z 455 (M+H)+;
Η NMR (DMSO-d6) δ 9.91 (s, IH), 8.80 (s, IH), 8.60 (d, IH, J=2.8 Hz), 8.26 (dd, IH, J=4.6, 1.2 Hz), 8.16 (br s, IH), 7.98-7.92 (m, IH), 7.90-7.86 (m, 2H), 7.61-7.55 (m, IH), 7.54-7.48 (m, 2H), 7.39 (dd, IH, J=8.3, 4.9 Hz), 7.33-7.27 (m, 2H), 7.25-7.19 (m, 3H), 5.96 (br s, IH), 2.75 (ABq, JAB= 12.9, ΔVAB= 32.8 Hz), 0.97 (s, 3H), 0.95 (s, 3H);
Anal, calcd for C27H26N4O4.0.85 H2O: C, 69.02; H, 5.94; N, 11.92. Found: C, 68.73; H, 5.91; N, 12.30.
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 K2CO3 was processed as described in Example ID to provide the title compound, mp 160-161 °C; MS (ESI+) m/z 441 (M+H)+;
1H NMR (DMSO-d6) δ 9.32 (s, IH), 8.42 (d, IH, J=9.2 Hz), 8.17 (d, IH, J=7.4 Hz), 8.10(dd, IH, J=4.6, 1.5 Hz), 8.07 (d, IH, J=7.7 Hz), 7.45 (dd, IH, J=8.0, 4.6 Hz), 7.28-7.13 (m, 5H), 5.69 (t, IH, J=8.0 Hz), 2.83 (t, 2H, J=7.7 Hz), 2.63-2.43 (m, 2H), 0.95 (s, 9H); Anal, calcd for C23H25ClN4O3: C, 62.65; H, 5.71; N, 12.71. Found: C, 62.37; H, 5.63; N, 12.66.
Example 88 N-d - ( [3.4-dioxo-2-(3 -pyridinylamino)- 1 -cyclobuten- 1 -yl] amino 1 -2 ,2-dimethylprop yl)-2- phenoxyacetamide
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 NH4OH 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 NaHCO3, and 100 mL of brine. The organic phase was dried over Na2SO4 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/NH3) 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. MS (DCI/NH3) m/z 339 (M+H)+.
Example 88C N-d - (r3,4-dioxo-2-(3 -pyridinylamino)- 1 -cyclobuten- 1 -yl]aminol -2,2-dimethylpropyl)-2- phenoxyacetamide A suspension ofthe product from Example IB, the product from Example 88B, and K2CO3 was processed as described in Example ID to provide the title compound, mp 227-228 °C; MS (ESI+) m/z 409 (M+H)+; Η NMR (DMSO-d6) δ 9.79 (s, IH), 8.57 (d, IH, J=2.8 Hz), 8.45 (d, IH, J=8.0 Hz), 8.25 (dd, IH, J=4.6, 1.2 Hz), 8.02 (br s, IH), 7.93 (d, IH, J=8.0 Hz), 7.38 (dd, IH, J=8.3, 4.6 Hz), 7.29 (t, 2H, J=8.0 Hz), 6.98-6.91 (m, 3H), 5.68 (br s, IH), 4.61 (ABq, JAB= 14.7, ΔvAB= 21.8 Hz), 0.97 (s, 9H);
Anal, calcd for C22H24N4O4'0.2 H2O: C, 64.13; H, 5.97; N, 13.60. Found: C, 63.91; H, 5.89; N, 13.89.
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 K2CO3 was processed as described in Example ID to provide the title compound, mp 220-221 °C; MS (ESI+) m/z 443 (M+H)+;
Η NMR (DMSO-de) δ 9.37 (s, IH), 8.50 (d, IH, J=8.6 Hz), 8.44 (d, IH, J=8.3 Hz), 8.11 (dd, IH, J=4.6, 1.5 Hz), 8.03 (d, IH, J=7.4 Hz), 7.44 (dd, IH, J=8.3, 4.6 Hz), 7.29 (t, 2H, J=8.0 Hz), 6.98-6.91 (m, 3H), 5.72 (t, IH, J=8.0 Hz), 4.62 (ABq, JAB= 14.7, ΔvAB= 22.1 Hz), 0.98 (s, 9H);
Anal, calcd for C22H23ClN4O4: C, 59.66; H, 5.23; N, 12.65. Found: C, 59.55; H, 5.18; N, 12.68.
Example 90 N-d - { [3 ,4-dioxo-2-("3 -pyridinylamino)- 1 -cyclobuten- 1 -yl] amino 1 -2,2-dimethylprop yl)-2- methyl-2-phenylpropanamide
Example 90A 2-methyl-2-phenylpropanamide To a solution of 2-methyl-2-phenylpropionic acid in 100 mL of CH2C12 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 NH4OH was added. The mixture was stirred at 23 °C for 1 hour then and the mixture was concentrated under reduced pressure. The crude product was dissolved in 150 mL of EtOAc and washed with 100 mL of 2 N HCI, 100 mL NaHCO3, and 100 mL of brine. The organic phase was dried over Na2SO4 and concentrated. The product was purified by recrystalhzation from EtOAc/hexanes to provide 3.50 g (88 % yield) ofthe desired product as a white powder. MS (DCI NH3) m/z 164 (M+H)+.
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. MS (DCI/NH3) m/z 351 (M+H)+.
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 K2CO3 was processed as described in Example ID to provide the title compound, mp 247-248 °C; MS (ESI+) m/z 421 (M+H)+;
1H NMR (DMSO-d6) δ 9.86 (s, IH), 8.57 (d, IH, J=2.6 Hz), 8.26 (d, IH, J=4.6, 1.2 Hz), 7.97 (br s, IH), 7.93 (d, IH, J=8.0 Hz), 7.39 (d, IH, J=8.3, 4.6 Hz), 7.39-7.28 (m, 5H), 7.26-7.19 (m, IH), 5.58 (t, IH, J=8.0 Hz), 1.49 (s, 3H), 1.48 (s, 3H), 0.85 (s, 9H); Anal, calcd for C2 H28N4O3: C, 68.55; H, 6.71; N, 13.32. Found: C, 68.34; H, 6.75; N, 13.35.
Example 91 3 -chloro-N-C 1 - ( [3 ,4-dioxo-2-(pyrazin-2- ylamino)- 1 -cyclobuten- 1 -yl] amino 1-2,2- dimethylpropyPbenzamide
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/NH3) m/z 220 (M+H)+.
Example 9 IB 3-amino-4-(2-pyrazinylamino)-3-cyclobutene-l,2-dione A solution ofthe product from Example 91 A and ammonia in methanol was processed as described in Example IB to provide the title compound. MS (DCI/NH3) m/z 191 (M+H)+.
Example 91 C
3 -chloro-N-( 1 - ( \3 ,4-dioxo-2-(p yrazin-2- ylamino)- 1 -cyclobuten- 1 -yl] amino 1-2,2- dimethylpropyPbenzamide
A suspension ofthe product from Example 9 IB, the product from Example 5 A, and K2CO3 was processed as described in Example ID to provide the title compound, mp 245-247 °C; MS (ESI+) m/z 414 (M+H)+;
1H NMR (DMSO-de) δ 11.28 (br s, IH), 8.88 (d, IH, J=8.5 Hz), 8.83 (d, IH, J=10.2 Hz), 8.61 (d, IH, J=1.4 Hz), 8.31-8.27 (m, 2H), 7.85 (t, IH, J=1.7 Hz), 7.79 (dt, IH, J=7.5, 1.4 Hz), 7.63 (ddd, IH, J=8.1, 2.2, 1.4 Hz), 7.53 (t, IH, J=7.8 Hz), 6.05 (dd, IH, J=9.0, 8.1 Hz), 1.03 (s, 9H);
Anal, calcd for C20H20C1N5O4: C, 58.04; H, 4.87; N, 16.92. Found: C, 57.67; H, 4.85; N, 16.89.
Example 92 N-[l-({2-r(2-chloropyridin-3-yl)amino1-3,4-dioxo-l-cvclobuten-l-yllamino)-3,3- dimethylbutyl]benzamide
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, K2CO3, 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)+;
Η NMR (DMSO-de) δ 9.47 (s, IH), 9.07 (br s, IH), 8.87 (br s, IH), 8.08 (dd, IH, J=4.6, 1.5 Hz), 8.03 (d, IH, J=8.0 Hz), 7.87 (d, IH, J=7.1 Hz), 7.58-7.52 (m, IH), 7.51-7.45 (m, 2H), 7.41 (dd, IH, J=8.0, 4.6 Hz), 5.97 (br s, IH), 2.07 (dd, IH, J=14.1, 6.8 Hz), 1.83 (dd, IH, J=14.1, 5.8 Hz), 0.97 (s, 9H);
Anal, calcd for C22H23C1N4O3-0.75 C4H8O2: C, 60.91; H, 5.93; N, 11.36. Found: C, 60.82; H, 5.76; N, 11.77.
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 K2CO3 was processed as described in Example ID to provide the title compound, mp 241-242 °C; MS (ESI+) m/z 481 (M+H)+;
Η NMR (DMSO-d6) δ 9.95 (s, IH), 8.77 (d, IH, J=7.7 Hz), 8.38 (d, IH, J=2.9 Hz), 8.04 (br s, IH), 7.99 (dd, IH, J=8.8, 2.9 Hz), 7.87 (t, IH, J=1.8 Hz), 7.80 (dt, IH, J=7.7, 1.5 Hz), 7.63 (ddd, IH, J=8.1, 2.2, 1.1 Hz), 7.56-7.47 (m, 2H), 5.86 (t, IH, J=8.4 Hz), 1.06 (s, 9H); Anal, calcd for C22H2oCl2N4O3: C, 56.39; H, 4.51; N, 12.53. Found: C, 56.11; H, 4.53; N, 12.33. Example 94 3-chloro-N- ( 1 -IT 3.4-dioxo-2- {[6-(trifluoromethyl)pyridin-3-yl] amino 1 - 1 -cyclobuten- 1 - yl)amino1-2,2-dimethylpropyllbenzamide
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 CH2C12 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 To a solution ofthe product from Example 94A (5.92 g, 39.2 mmol) in 100 mL of THF was added MeOH (1.26 g, 39.2 mmol). 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 NaHCO3 (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 CH2CI2 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. The filtrate was washed with 50 mL of H2O and the aqueous layer was extracted twice with 50 mL of EtOAc. The combined organic extracts were washed with 50 mL of brine, dried over Na2SO4 and concentrated under reduced pressure. The crude material was purified by flash chromatography eluting with EtOAC/hexanes (3:2) to provide the desired product (0.281 g, 10 % yield) as a pale yellow powder. MS (DCI/NH3) m/z 273 (M+H)+.
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 NH3 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 Et2O 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- (|"6-(trifluoromethyl)pyridin-3-yl]aminol-l -cyclobuten- 1- yl)amino]-2,2-dimethylpropyllbenzamide A suspension ofthe product from Example 94D, the product from Example 5 A, and K2CO3 was processed as described in Example ID to provide the title compound, mp 226-227 °C; MS (ESI+) m/z 481 (M+H)+;
Η NMR (DMSO-de) δ 10.16 (s, IH), 8.78 (d, IH, J=7.0 Hz), 8.68 (d, IH, J=2.2 Hz), 8.21- 8.06 (m, 2H), 7.92-7.85 (m, 2H), 7.80 (d, IH, J=7.7 Hz), 7.64 (ddd, IH, J=8.1, 1.8, 1.1 Hz), 7.53 (t, IH, J=7.8 Hz), 5.88 (br s, IH), 1.07 (s, 9H);
Anal, calcd for C22H2oF3N4O3: C, 54.95; H, 4.19; N, 11.65. Found: C, 54.80; H, 4.17; N, 11.52.
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 K2CO3 was processed as described in Example ID to provide the title compound, mp 213-214 °C; MS (ESI+) m/z 448 (M+H)+;
1H NMR (DMSO-d6) δ 9.46 (s, IH), 8.77 (d, IH, J=8.1 Hz), 8.50 (d, IH, J=8.8 Hz), 8.12 (dd, IH, J=4.4, 1.5 Hz), 8.03 (dd, IH, J=8.1, 1.5 Hz), 7.88 (t, IH, J=1.7 Hz), 7.81 (dt, IH, J=7.7, 1.5 Hz), 7.63 (ddd, IH, J=8.1, 1.8, 1.8 Hz), 7.57-7.48 (m, IH), 7.44 (dd, IH, J=8.1, 4.8 Hz), 5.91 (t, IH, J=8.1 Hz), 1.07 (s, 9H);
Anal, calcd for C2ιH20Cl2N4O3-0.65 H2O: C, 54.95; H, 4.68; N, 12.21. Found: C, 54.80; H, 4.40; N, 11.92.
Example 96 N-d - ( [3 ,4-dioxo-2-(3 -pyridinylamino)- 1 -cyclobuten- 1 -yl] amino 1 -2,2-dimefhyl-3 - phenylpropypisonicotinamide
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.
MS (ESI+) m/z 386 (M+H)+.
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 K2CO3 was processed as described in Example ID to provide the title compound, mp 251-254 °C; MS (ESI+) m/z 456 (M+H)+;
Η NMR (DMSO-d6) δ 9.92 (br s, IH), 9.07 (br d, IH, J=8.1 Hz), 8.79-8.75 (m, 2H), 8.58 (d, IH, J=2.7 Hz), 8.27 (dd, IH, J=4.7, 1.2 Hz), 8.19-8.11 (m, IH), 7.95 (br d, IH, J=7.1 Hz), 7.78-7.75 (m, 2H), 7.40 (dd, IH, J=8.5, 4.8 Hz), 7.34-7.19 (m, 5H), 5.95 (t, IH, J=7.8 Hz),
2.73 (ABq, 2H, JAB=12.9 Hz, ΔvAB=25.1 Hz), 0.96 (s, 3H), 0.94 (s, 3H);
Anal, calcd for C26H25N5O3: C, 68.56; H, 5.53; N, 15.37. Found: C, 68.37; H, 5.31; N, 15.20.
Example 97 N-d - { r3 ,4-dioxo-2-("3 -pyridinylamino)- 1 -cyclobuten- 1 -yl] amino 1 -2,2-dimethyl-3- phenylpropyl)-3-phenylpropanamide
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. MS (DCI/NH3) m/z 413 (M+H)+.
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 K2CO3 was processed as described in Example ID to provide the title compound, mp 221-223 °C; MS (ESI+) m/z 483 (M+H)+;
1H NMR (DMSO-de) δ 9.73 (s, IH), 8.57 (d, IH, J=2.4 Hz), 8.34 (br s, IH), 8.24 (dd, IH, J=4.8, 1.4 Hz), 8.06-7.90 (m, 2H), 7.39 (dd, IH, J=8.1, 4.8 Hz), 7.33-7.09 (m, 10H), 5.70 (br s, IH), 2.91-2.81 (m, 2H), 2.69-2.54 (m, 4H), 0.85 (s, 3H), 0.81 (s, 3H); Anal, calcd for C29H3oN4O3: C, 72.18; H, 6.27; N, 11.61. Found: C, 71.86; H, 6.02; N, 11.41.
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 K2CO3 was processed as described in Example 92B to provide the title compound, mp 228-231 °C; MS (ESI+) m/z 497 (M+H)+;
Η NMR (DMSO-de) δ 9.90 (s, IH), 8.58 (d, IH, J=2.7 Hz), 8.26 (dd, IH, J=4.7, 1.4 Hz), 8.05 (br s, IH), 7.94 (d, IH, J=7.7 Hz), 7.51 (br s, IH), 7.40 (dd, IH, J=8.5, 4.8 z), 7.37-7.16 (m, 7H), 7.10-7.03 (m, 3H), 5.67 (br s, IH), 2.51-2.44 (m, 2H, PhCH2 obscured), 1.50 (s, 6H), 0.74 (s, 3H), 0.72 (s, 3H); Anal, calcd for C30H32N4O3: C, 72.56; H, 6.49; N, 11.28. Found: C, 72.72; H, 6.40; N, 11.26.
Example 99 N-( 1 - ( [3 ,4-dioxo-2-(3-p yridinylamino)- 1 -cyclobuten- 1 - yl] aminol -2,2-dimethyl-3- phenylpropyp-2-phenoxyacetamide
Example 99A N-ri-dH-l,2,3-benzotriazol-l-yl)-2,2-dimethyl-3-phenylpropyl]-2-ρhenoxyacetamide 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. MS (DCI/NH3) m/z 415 (M+H)+.
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 K2CO3 was processed as described in Example ID to provide the title compound, mp 249-250 °C; MS (ESI+) m/z 485 (M+H)+;
Η NMR (DMSO-de) δ 9.80 (s, IH), 8.62 (d, IH, J=7.5 Hz), 8.57 (d, IH, J=2.4 Hz), 8.25 (dd, IH, J=4.7, 1.4 Hz), 8.10 (br s, IH), 7.93 (d, IH, J=8.2 Hz), 7.39 (dd, IH, J=8.5, 4.7 Hz), 7.34- 7.18 (m, 5H), 7.17-7.11 (m, 2H), 6.99-6.91 (m, 3H), 5.74 (br s, IH), 4.66 (ABq, 2H, JAB= 14.6 Hz, ΔvAB= 20.7 Hz), 2.61 (d, 2H, J=4.4 Hz), 0.87 (s, 3H), 0.84 (s, 3H); Anal, calcd for C28H28N4O4: C, 69.41; H, 5.82; N, 11.56. Found: C, 69.51; H, 5.76; N, 11.44.
Example 100 N-d-( 3.4-dioxo-2-(3-pyridinylamino)-l-cvclobuten-l-yl]aminol-2,2-dimethyl-3- phenylpropyPnicotinamide
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. MS (ESI+) m/z 386 (M+H)+.
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 K2CO3 was processed as described in Example ID to provide the title compound, mp 253-254 °C; MS (ESI+) m/z 456 (M+H)+;
Η NMR (DMSO-de) δ 9.87 (s, IH), 9.03 (d, IH, J=2.1 Hz), 8.98 (br d, IH, J=7.5 Hz), 8.75
(dd, IH, J=4.8, 1.7 Hz), 8.59 (d, IH, J=2.8 Hz), 8.25 (dd, IH, J=4.7, 1.4 Hz), 8.21 (dt, IH,
J=7.8, 1.7 Hz), 8.20-8.13 (m, IH), 7.95 (br d, IH, J=8.4 Hz), 7.55 (ddd, IH, J=8.1, 4.7, 0.7
Hz), 7.39 (dd, IH, J=8.4, 4.7 Hz), 7.34-7.26 (m, 2H), 7.26-7.18 (m, 3H), 5.96 (t, IH, J=7.5
Hz), 2.75 (ABq, 2H, JAB=12.9 HZ, ΔvAB=25.8 Hz), 0.97 (s, 3H), 0.92 (s, 3H);
Anal, calcd for C2eH25N5O3: C, 68.56; H, 5.53; N, 15.37. Found: C, 68.42; H, 5.52; N, 15.40.
Example 101
N-d-([3,4-dioxo-2-(3-pyridinylamino)-l -cyclobuten- l-yl]aminol -2,2- dimethylpropyPnicotinamide
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 K2CO3 was processed as described in Example ID to provide the title compound, mp 233-234 °C; MS (ESI+) m/z 380 (M+H)+;
Η NMR (DMSO-d6) δ 9.86 (br s, IH), 8.98 (d, IH, J=2.4 Hz), 8.87 (br d, IH, J=7.8 Hz), 8.73 (dd, IH, J=4.7, 1.4 Hz), 8.57 (d, IH, J=2.4 Hz), 8.25 (dd, IH, J=4.7, 1.4 Hz), 8.17 (dt, IH, J=8.1, 2.0 Hz), 8.11-8.04 (m, IH), 7.94 (ddd, IH, J=9.2, 2.7, 1.0 Hz), 7.53 (dd, IH, J=8.1, 4.7 Hz), 7.39 (dd, IH, J=8.1, 4.7 Hz), 5.88 (t, IH, J=7.8 Hz), 1.07 (s, 9H); Anal, calcd for C2oH2ιN5O3: C, 63.61; H, 5.58; N, 18.43. Found: C, 63.61; H, 5.67; N, 18.43. Example 102 N-d-l 3.4-dioxo-2-(3-pyridinylamino)-l-cvclobuten-l-yl]aminol-2,2- dimethylpropyPisonicotinamide
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. MS (ESI+) m/z 310 (M+H)+.
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 K2CO3 was processed as described in Example ID to provide the title compound, mp 220-222 °C; MS (ESI+) m/z 380 (M+H)+;
Η NMR (DMSO-d6) δ 9.88 (br s, IH), 8.95 (d, IH, J=7.5 Hz), 8.76-.71 (m, 2H), 8.57 (d, IH, J=2.7 Hz), 8.25 (dd, IH, J=4.7, 1.4 Hz), 8.05 (br s, IH), 7.93 (ddd, IH, J=8.1, 2.7, 1.4 Hz), 7.74-7.71 (m, 2H), 7.39 (dd, IH, J=8.5, 4.7 Hz), 5.86 (t, IH, J=7.5 Hz), 1.06 (s, 9H); Anal, calcd for C20H21N5O3: C, 63.61; H, 5.58; N, 18.46. Found: C, 63.31; H, 5.67; N, 18.47.
Example 103 N-( 1 - { [3 ,4-dioxo-2-('3-p yridinylamino)- 1 -cyclobuten- 1 - yl] amino 1 -2,2-dimethylprop yl)-2- furamide
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 K2CO3 was processed as described in Example ID to provide the title compound, mp 204-205 °C; MS (ESI+) m/z 369 (M+H)+;
Η NMR (DMSO-d6) δ 9.95 (br s, IH), 8.61 (br d, IH, J=8.1 Hz), 8.57 (d, IH, J=2.7 Hz), 8.25 (dd, IH, J=4.7, 1.4 Hz), 8.18-8.08 (m, IH), 7.98-7.91 (m, 2H), 7.82 (dd, IH, J=5.1, 1.4 Hz), 7.38 (dd, IH, J=8.1, 4.7 Hz), 7.18 (dd, IH, J=5.1, 3.7 Hz), 5.80 (t, IH, J=8.5 Hz), 1.05 (s, 9H); Anal, calcd for Cι9H20N4O4: C, 61.95; H, 5.47; N, 15.21. Found: C, 61.72; H, 5.33; N, 15.24.
Example 104 N-d - { [3 ,4-dioxo-2-(3 -pyridinylamino)- 1 -cyclobuten- 1 - yl] amino 1 -2,2-dimethyl-3 -p yridin-4- ylpropyP-3 -methylbenzamide
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. NaHCO3 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). The solution of aledyde and bromide was then added via addition funnel in dropwise fashion over a period of 30 minutes to a stirred suspension of powdered NaOH (608 mg, 15.2 mmol) in benzene (90 mL) at 60 °C. The reaction was stirred at 60 °C for 5 hours then cooled to ambient temperature. EtOAc (40 mL) was added and the reaction mixture was washed with water (40 mL), satd. aq. sodium bisulfite solution (2 x 25 mL), then brine (30 mL). The organic portion was dried (Na2SO4) and concentrated. Purification ofthe resulting oily residue by flash chromatography (gradient elution: hexanes then 7% EtOH/hexanes) provided the title compound (608 mg, 3.73 mmol) as a off-yellow waxy solid. MS (DCI/NH3) m/z 164 (M+H)+.
Example 104B N-ri-dH-1.2,3-benzotriazol-l-yl)-2,2-dimethyl-3-('pyridin-4-vPpropyl1-3-methylbenzamide
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/NH3) 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 K2CO3 was processed as described in Example ID to provide the title compound, mp 219-221 °C; MS (ESI+) m/z 470 (M+H)+;
1H NMR (DMSO-de) δ 8.81 (br s, IH), 8.59 (br d, IH, J=2.4 Hz), 8.50-8.43 (m, 2H), 8.24 (dd, IH, J=4.7, 1.4 Hz), 7.98-7.86 (m, 2H), 7.71-7.62 (m, 3H), 7.44 (dd, IH, J=6.4, 3.1 Hz), 7.41- 7.23 (m, 4H), 5.99-5.92 (m, IH), 2.84 (ABq, 2H, JAB=11.2, ΔvAB=22.0 Hz), 2.41 (s, 3H), 0.99 (s, 3H), 0.91 (s, 3H); Anal, calcd for C27H27N5O3: C, 69.07; H, 5.80; N, 14.92. Found: C, 68.90; H, 5.88; N, 14.77.
Example 105 (-) 3 -chloro-N-C 1 - { [3 ,4-dioxo-2-(3 -pyridinylamino)- 1 -cyclobuten- 1 - yl] amino 1 -2,2-dimethyl-
3-phenylpropyl)benzamide The product from Example 59B was chromatographed over a Daicel Chiral Technologies Chiralpak AS chiral column (2.0 cm x 25 cm) eluting with 10% ethanol/hexanes (flow rate=10 mL/minute) to provide the title compound as the levorotatory enantiomer. [α]D 20 = -80° (c 0.20, DMSO); mp l78-179 °C; MS (ESI+) m/z 489 (M+H)+; 1H NMR (DMSO-de) δ 9.87 (s, IH), 8.90 (d, IH, J=3.7 Hz), 8.60 (d, IH, J=1.6 Hz), 8.26 (d, IH, J=4.2 Hz), 8.13 (br s, IH), 7.95 (dd, IH, J=8.3, 1.2 Hz), 7.90 (t, IH, J=1.7 Hz), 7.83 dt, IH, J=7.8, 1.2 Hz), 7.65 (ddd, IH, J=8.0, 2.1, 1.2 Hz), 7.55 (t, IH, J=8.1 Hz), 7.39 (dd, IH, J=8.2, 4.7 Hz), 7.32-7.20 (m, 5H), 5.95 (s, IH), 2.74 (ABq, JAB=12.8, ΔvAB=32.1 Hz), 0.97 (s, 3H), 0.95 (s, 3H).
Example 106 (+) 3-chloro-N-( 1 - { \3 ,4-dioxo-2-(3 -pyridinylamino)- 1 -cyclobuten- 1 - yl] amino 1 -2,2-dimethyl -
3-phenylpropyl)benz amide The product from Example 59B was chromatographed over a Daicel Chiral Technologies Chiralpak AS chiral column (2.0 cm x 25 cm) eluting with 10% ethanol/hexanes (flow rate=10 mL/minute) to provide the title compound as the dextrorotatory enantiomer. [α]D 20 = +78° (c 0.24, DMSO); mp l78-179 °C; MS (ESI+) m/z 489 (M+H)+;
1H NMR (DMSO-de) δ 9.87 (s, IH), 8.90 (d, IH, J=3.7 Hz), 8.60 (d, IH, J=1.6 Hz), 8.26 (d, IH, J=4.2 Hz), 8.13 (br s, IH), 7.95 (dd, IH, J=8.3, 1.2 Hz), 7.90 (t, IH, J=1.7 Hz), 7.83 dt, IH, J=7.8, 1.2 Hz), 7.65 (ddd, IH, J=8.0, 2.1, 1.2 Hz), 7.55 (t, IH, J=8.1 Hz), 7.39 (dd, IH, J=8.2, 4.7 Hz), 7.32-7.20 (m, 5H), 5.95 (s, IH), 2.74 (ABq, JAB=12.8, ΔvAB=32.1 Hz), 0.97 (s, 3H), 0.95 (s, 3H);
Anal, calcd for C27H25C1N4O3-0.5 H2O: C, 65.12; H, 5.26; N, 11.25. Found: C, 65.19; H, 5.42; N, 11.26.
Example 107 4-chloro-N-(' { r3,4-dioxo-2-(3-p yridinylamino)- 1 -cyclobuten- 1 -yllaminol methyPbenzamide
Example 107 A N-( 1 H- 1 ,2,3 -benzotriazol- 1 - ylmethvP-4-chlorobenzamide 4-Chlorobenzamide, paraformaldehyede, benzotriazole, and p-toluenesulfonic acid were processed as described in Example 18B to provide the title compound. MS (DCI/NH3) m/z 287 (M+H)+. Example 107B 4-chloro-N-( { [3 ,4-dioxo-2-(3-p yridinylamino)- 1 -cyclobuten- 1 -yl] amino 1 meth vDbenzamide A suspension ofthe product from Example IB, the product from Example 107A, and K2CO3 was processed as described in Example IB to provide the title compound, mp 174-176 °C; MS (ESI+) m/z 357 (M+H)+;
1H NMR (DMSO-de) δ 9.99 (br t, IH, J=6.1 Hz), 8.04 (br d, 2H, J=8.4 Hz), 7.91 (d, 2H, J=8.8 Hz), 7.63-7.52 (m, 4H), 7.43 (d, IH, J=8.1 Hz), 7.40 (d, IH, J=8.1 Hz), 6.21 (app d, 2H, J=6.4 Hz); Anal, calcd for Cι7Hι3N4O3: C, 57.23; H, 3.67; N, 15.70. Found: C, 56.85; H, 3.65; N, 16.10.
Example 108 (+) 3.5-dichloro-N-rdS)-l-('{2-r(2-chloropyridin-3-yl)aminol-3,4-dioxocvclobut-l-en-l- yllamino)-2,2-dimethylpropyl]benzamide The product from Example 79 was chromatographed over a Regis Technologies Whelk-Ol chiral column (2.0 cm x 25 cm) using gradient elution (10%> methanol-CH2Cl2 (2:l)/hexanes to 30%> methanol-CH2Cl2 (2:l)/hexanes, flow rate=10 mL/minute) to provide the title compound. [α]D 20 = +45° (c 0.15, DMSO); mp 233-234 °C; MS (ESI+) m/z 482 (M+H)+;
HRMS (FAB) calcd for C2iH2oCl3N4O3 (M+H)+ 481.0601; found 481.0581; Η NMR (DMSO-de) δ 9.45 (s, IH), 8.86 (d, IH, J=7.7 Hz), 8.47 (d, IH, J=8.9 Hz), 8.12 (dd, IH, J=4.6, 1.8 Hz), 8.03 (d, IH, J=8.0 Hz), 7.86 (d, 2H, J=2.2 Hz), 7.82 (t, IH, J=1.8 Hz), 7.45 (dd, IH, J=8.3, 4.6 Hz), 5.90 (t, IH, J=8.0 Hz), 1.08 (s, 9H);
Anal, calcd for C2ιHι9Cl3N4O3: C, 52.35; H, 3.98; N, 11.63. Found: C, 52.38; H, 3.84; N, 11.82.
Example 109 (-) 3 ,5-dichloro-N-IY 1 R)- 1 -( {2- (2-chloropyridin-3-vDamino]-3 ,4-dioxocvclobut- 1 -en- 1 - yllamino)-2,2-dimethylpropyl]benzamide The product from Example 79 was chromatographed over a Regis Technologies Whelk-Ol chiral column (2.0 cm x 25 cm) using gradient elution (10%> methanol-CH2Cl2 (2:l)/hexanes to 30%> methanol-CH2Cl (2:l)/hexanes, flow rate=10 mL/minute) to provide the title compound. The absolute stereochemistry was determined by x-ray diffraction. [α]D 2° = -46° (c 0.15, DMSO); mp 233-234 °C;
Crystal data: Single crystals suitable for x-ray diffraction were grown by slow evaporation from hexanes:CH2Cl2:methanol, crystal dimensions 0.40X0.40X0.10 mm, orthorhombic, •P2,2,2ι (#19), a=8.344(l) A, b=l 1.832(2) A, c=24.993(3) A, V=2467.3(5) A3, Z=4, Dcaic=1.383 g/cm3. Crystallographic data were collected using Mo K α radiation (λ=0.71069 A); Refinement ofthe structure using full matrix least squares refinement was based on 4011 observed reflections (I>3.00σ(I)) and 298 variable parameters, R=0.069, Rw=0.088; MS (ESI+) m/z 482 (M+H)+;
1H NMR (DMSO-de) δ 9.45 (s, IH), 8.86 (d, IH, J=7.7 Hz), 8.47 (d, IH, J=8.9 Hz), 8.12 (dd, IH, J=4.6, 1.8 Hz), 8.03 (d, IH, J=8.0 Hz), 7.86 (d, 2H, J=2.2 Hz), 7.82 (t, IH, J=1.8 Hz), 7.45 (dd, IH, J=8.3, 4.6 Hz), 5.90 (t, IH, J=8.0 Hz), 1.08 (s, 9H).
Example 110 ("+) N-d - ( [3 ,4-dioxo-2-(2-chloro3-p yridinylamino)- 1 -cyclobuten- 1 - yl] amino 1-2,2- dimethylpropyD-3,5-difluorobenzamide
Example 110A N-d-{[3,4-dioxo-2-(2-chloro3-pyridinylamino)-l-cvclobuten-l-yl]aminol-2,2- dimethylpropyl)-3,5-difluorobenzamide A suspension ofthe product from Example 29B, the product from Example 16 A, and K2CO3 was processed as described in Example ID to provide the title compound, mp 215-217 °C; MS (ESI+) m/z 449 (M+H)+; Η NMR (DMSO-d6) δ 9.47 (s, IH), 8.77 (d, IH, J=8.1 Hz), 8.48 (d, IH, J=8.8 Hz), 8.11 (dd, IH, J=4.8, 1.7 Hz), 8.02 (dd, IH, J=8.1, 1.4 Hz), 7.62-7.42 (m, 4H), 5.89 (t, IH, J=8.1 Hz), 1.08 (s, 9H).
Example HOB (+) N-d - {[3,4-dioxo-2-(2-chloro3-pyridinylarnino)- 1 -cyclobuten- 1 -yl] amino 1 -2.2- dimethylpropyl)-3.5-difluorobenzamide The product from Example 110A was chromatographed over a Regis Technologies Whelk-Ol chiral column (2.0 cm x 25 cm) using gradient elution (10% methanol-CH2Cl2 (2:l)/hexanes to 30% methanol-CH2Cl2 (2:l)/hexanes, flow rate=10 mL/minute) to provide the title compound as the dextrororotatory enantiomer. [α]D 20 = +73° (c 0.13, DMSO); mp 215-216 °C; MS (ESI+) m/z 449 (M+H)+;
1H NMR (DMSO-de) δ 9.47 (s, IH), 8.77 (d, IH, J=8.1 Hz), 8.48 (d, IH, J=8.8 Hz), 8.11 (dd, IH, J=4.8, 1.7 Hz), 8.02 (dd, IH, J=8.1, 1.4 Hz), 7.62-7.42 (m, 4H), 5.89 (t, IH, J=8.1 Hz), 1.08 (s, 9H);
Anal, calcd for C2ιHι9FCl2N4O3: C, 56.19; H, 4.27; N, 12.48. Found: C, 56.00; H, 4.23; N, 12.29.
Example 111 (-) N-d - { [3 ,4-dioxo-2-(2-chloro3 -pyridinylamino)- 1 -cyclobuten- 1 - yl] amino 1-2,2- dimethylpropyl)-3,5-difluorobenzamide The product from Example 110A was chromatographed over a Regis Technologies Whelk-Ol chiral column (2.0 cm x 25 cm) using gradient elution (10% methanol-CH2Cl2 (2:l)/hexanes to 30% methanol-CH Cl2 (2:l)/hexanes, flow rate=10 mL/minute) to provide the title compound as the levororotatory enantiomer. [α]D 20 = -69° (c 0.20, DMSO); mp 215-217 °C; MS (ESI+) m/z 449 (M+H)+; 1H NMR (DMSO-d6) δ 9.47 (s, IH), 8.77 (d, IH, J=8.1 Hz), 8.48 (d, IH, J=8.8 Hz), 8.11 (dd,
IH, J=4.8, 1.7 Hz), 8.02 (dd, IH, J=8.1, 1.4 Hz), 7.62-7.42 (m, 4H), 5.89 (t, IH, J=8.1 Hz),
1.08 (s, 9H);
Anal, calcd for C2ιH,9FCl2N4O3: C, 56.19; H, 4.27; N, 12.48. Found: C, 55.93; H, 4.48; N,
12.20.
Determination of Potassium Channel Opening Activity Membrane Hyperpolarization Assays
Compounds were evaluated for potassium channel opening activity using primary cultured guinea-pig urinary bladder (GPB) cells.
For the preparation of urinary bladder smooth muscle cells, urinary bladders were removed from male guinea-pigs (Hartley, Charles River, Wilmington, MA) weighing 300-400 g and placed in ice-cold Ca2+-free Krebs solution (composition, mM: KC1, 2.7; KH PO4, 1.5;
NaCl, 75; Na2HPO4, 9.6; Na2HPO4-7H2O, 8; MgSO4, 2; glucose, 5; HEPES, 10; pH 7.4). Cells were isolated by enzymatic dissociation as previously described with minor modifications (Klockner and Isenberg, Pflugers Arch. (1985), 405, 329-339), hereby incorporated by reference. The bladder was cut into small sections and incubated in 5 mL of the Kreb's solution containing 1 mg/niL collagenase (Sigma, St. Louis, MO) and 0.2 mg/mL pronase (Calbiochem, La Jolla, CA) with continuous stirring in a cell incubator for 30 minutes. The mixture was then centrifuged at 1300 x g for 5 minutes, and the pellet resuspended in Dulbecco's PBS (GIBCO, Gaithersburg, MD) and recentrifuged to remove residual enzyme. The cell pellet was resuspended in 5 mL growth media (composition: Dulbecco's modified Eagle's medium supplemented with 10% fetal bovine serum, 100 units/mL penicillin, 100 units/mL streptomycin and 0.25 mg/mL amphotericin B) and further dissociated by pipetting the suspension through a flame-polished Pasteur pipette and passing it through a polypropylene mesh membrane (Spectrum, Houston, TX). The cell density was adjusted to 100,000 cells/mL by resuspension in growth media. Cells were plated in clear- bottomed black 96-well plates (Packard) for membrane potential studies at a density of 20,000 cells/well and maintained in a cell incubator with 90% air: 10% CO2 until confluent. Cells were confirmed to be of smooth muscle type by cytoskeletal staining using a monoclonal mouse anti human-α-smooth muscle actin (Biomeda, Foster City, CA). Functional activity at potassium channels was measured by evaluating changes in membrane potential using the bis-oxonol dye DiBAC(4)3 (Molecular Probes) in a 96-well cell- based kinetic assay system, Fluorescent Imaging Plate Reader (FLIPR) (K.S. Schroeder et al., J. Biomed. Screen., v. 1 pp. 75-81 (1996)), hereby incoφorated by reference. DiBAC(4)3 is an anionic potentiometric probe which partitions between cells and extracellular solution in a membrane potential-dependent manner. With increasing membrane potential (for example, K+ depolarization), the probe further partitions into the cell; this is measured as an increase in fluorescence due to dye interaction with intracellular lipids and proteins. Conversely, decreasing membrane potential (hyperpolarization by potassium channel openers) evokes a decrease in fluorescence.
Confluent guinea-pig urinary bladder cells cultured in black clear-bottomed 96-well plates were rinsed twice with 200 mL assay buffer (composition, mM: HEPES, 20; NaCl, 120; KC1, 2; CaCl2, 2; MgCl2, 1; glucose, 5; pH 7.4 at 25 °C) containing 5 μM DiBAC(4)3 and incubated with 180 mL ofthe buffer in a cell incubator for 30 minutes at 37 °C to ensure dye distribution across the membrane. After recording the baseline fluorescence for 5 minutes, the reference or test compounds, prepared at 10 times the concentration in the assay buffer, were added directly to the wells. Changes in fluorescence were monitored for an additional 25 minutes. Hyperpolarization responses were corrected for any background noise and were normalized to the response observed with 10 μM ofthe reference compound PI 075 (assigned as 100%), a potent opener of smooth muscle KATp channels (Quast et al., Mol. Pharmacol, v. 43 pp. 474-481 (1993)).
Routinely, five concentrations of P1075 or test compounds (log or half-log dilutions) were evaluated and the maximal steady-state hyperpolarization values (expressed as % relative to PI 075) plotted as a function of concentration. The EC50 (concentration that elicites 50%> of the maximal response for the test sample) values were calculated by non-linear regression analysis using a four parameter sigmoidal equation. The maximal response of each compound (expressed as % relative to PI 075) is reported. Stock solutions of compounds were prepared in 100%) DMSO and further dilutions were carried out in the assay buffer and added to a 96- well plate. Table 1 Membrane Hyperpolarization (MHP) in Guinea-Pig Bladder (GPB) Cells
In Nitro Functional Models Compounds were evaluated for functional potassium channel opening activity using tissue strips obtained from Landrace pig bladders.
Landrace pig bladders were obtained from female Landrace pigs of 9-30 kg. Landrace pigs were euthanized with an intraperitoneal injection of pentobarbital solution, Somlethal® , J.A. Webster Inc., Sterling MA. The entire bladder was removed and immediately placed into Krebs Ringer bicarbonate solution (composition, mM: ΝaCl, 120; ΝaHCθ3, 20; dextrose, 11; KCl, 4.7; CaCl2, 2.5; MgSO4, 1.5; KH2PO4, 1.2; K2EDTA, 0.01, equilibrated with 5% CO2/95% O2 pH 7.4 at 37 °C). Propranolol (0.004 mM) was included in all ofthe assays to block β-adrenoceptors. The trigonal and dome portions were discarded. Strips 3-5 mm wide and 20 mm long were prepared from the remaining tissue cut in a circular fashion. The mucosal layer was removed. One end was fixed to a stationary glass rod and the other to a Grass FT03 transducer at a basal preload of 1.0 gram. Two parallel platinum electrodes were included in the stationary glass rod to provide field stimulation of 0.05 Hz, 0.5 milli-seconds at 20 volts. This low frequency stimulation produced a stable twitch response of 100-500 centigrams. Tissues were allowed to equilibrate for at least 60 minutes and primed with 80 mM KCl. A control concentration response curve (cumulative) was generated for each tissue using the potassium channel opener PI 075 as the control agonist. PI 075 completely eliminated the stimulated twitch in a dose dependent fashion over a concentration range of 10"9 to 10"5 M dissolved in DMSO using 1/2 log increments. After a 60 minute rinsing period, a concentration response curve (cumulative) was generated for the test agonist in the same fashion as that used for the control agonist PI 075. The maximal efficacy of each compound (expressed as % relative to PI 075) is reported. The amount of agent necessary to cause 50% ofthe agent's maximal response (ED50) was calculated using "ALLFIT" (DeLean et al., Am. J. Physiol., 235, E97 (1980)), hereby incoφorated by reference. Agonist potencies were also expressed as an index relative to PI 075. The index was calculated by dividing the ED50 for PI 075 by the ED 0 for the test agonist in a given tissue. Each tissue was used for only one test agonist, and the indices obtained from each tissue were averaged to provide an average index of potency. These data are shown in Table 2.
Table 2 Functional Potassium Channel Opening Activity in Isolated Bladder Strips
As shown by the data in Tables 1 and 2, the compounds of this invention reduce stimulated contractions ofthe bladder by opening potassium channels and therefore can have utility in the treatment of diseases prevented by or ameliorated with potassium channel openers.
The term "pharmaceutically acceptable carrier," as used herein, means a non-toxic, inert solid, semi-solid or liquid filler, diluent, encapsulating material or formulation auxiliary of any type. Some examples of materials which can serve as pharmaceutically acceptable carriers are sugars such as lactose, glucose and sucrose; starches such as com starch and potato starch; cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; glycols; such a propylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffering agents such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethyl alcohol, and phosphate buffer solutions, as well as other non-toxic compatible lubricants such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, releasing agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants can also be present in the composition, according to the judgment ofthe formulator.
The present invention provides pharmaceutical compositions which comprise compounds ofthe present invention formulated together with one or more non-toxic pharmaceutically acceptable carriers. The pharmaceutical compositions can be formulated for oral administration in solid or liquid form, for parenteral injection or for rectal administration.
Further included within the scope ofthe present invention are pharmaceutical compositions comprising one or more ofthe compounds of formula I-IV prepared and formulated in combination with one or more non-toxic pharmaceutically acceptable compositions. The pharmaceutical compositions can be formulated for oral administration in solid or liquid form, for parenteral injection or for rectal administration.
The pharmaceutical compositions of this invention can be administered to humans and other mammals orally, rectally, parenterally, intracisternally, intravaginally, intraperitoneally, topically (as by powders, ointments or drops), bucally or as an oral or nasal spray. The term "parenterally," as used herein, refers to modes of administration which include intravenous, intramuscular, intraperitoneal, intrasternal, subcutaneous, intraarticular injection and infusion.
Pharmaceutical compositions of this invention for parenteral injection comprise pharmaceutically acceptable sterile aqueous or nonaqueous solutions, dispersions, suspensions or emulsions and sterile powders for reconstitution into sterile injectable solutions or dispersions. Examples of suitable aqueous and nonaqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols (propylene glycol, polyethylene glycol, glycerol, and the like), suitable mixtures thereof, vegetable oils (such as olive oil) and injectable organic esters such as ethyl oleate. Proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance ofthe required particle size in the case of dispersions, and by the use of surfactants. These compositions can also contain adjuvants such as preservative agents, wetting agents, emulsifying agents, and dispersing agents. Prevention ofthe action of microorganisms can be ensured by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, and the like. It can also be desirable to include isotonic agents, for example, sugars, sodium chloride and the like. Prolonged absoφtion ofthe injectable pharmaceutical form can be brought about by the use of agents delaying absoφtion, for example, aluminum monostearate and gelatin.
In some cases, in order to prolong the effect of a drug, it is often desirable to slow the absoφtion ofthe drug from subcutaneous or intramuscular injection. This can be accomplished by the use of a liquid suspension of crystalline or amoφhous material with poor water solubility. The rate of absoφtion ofthe drug then depends upon its rate of dissolution which, in turn, may depend upon crystal size and crystalline form. Alternatively, delayed absoφtion of a parenterally administered drug form is accomplished by dissolving or suspending the drug in an oil vehicle.
Suspensions, in addition to the active compounds, may contain suspending agents, as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar, tragacanth, and mixtures thereof.
If desired, and for more effective distribution, the compounds of the present invention can be incoφorated into slow-release or targeted-delivery systems such as polymer matrices, liposomes, and microspheres. They may be sterilized, for example, by filtration through a bacteria-retaining filter or by incoφoration of sterilizing agents in the form of sterile solid compositions, which may be dissolved in sterile water or some other sterile injectable medium immediately before use.
The active compounds can also be in micro-encapsulated form, if appropriate, with one or more excipients as noted above. The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings, release controlling coatings and other coatings well known in the pharmaceutical formulating art. In such solid dosage forms the active compound can be admixed with at least one inert diluent such as sucrose, lactose, or starch. Such dosage forms may also comprise, as is normal practice, additional substances other than inert diluents, e.g., tableting lubricants and other tableting aids such a magnesium stearate and microcrystalline cellulose. In the case of capsules, tablets and pills, the dosage forms may also comprise buffering agents. They may optionally contain opacifying agents and can also be of such composition that they release the active ingredient(s) only, or preferentially, in a certain part ofthe intestinal tract in a delayed manner. Examples of embedding compositions which can be used include polymeric substances and waxes.
Injectable depot forms are made by forming microencapsulated matrices of the drug in biodegradable polymers such as polylactide-polyglycolide. Depending upon the ratio of drug to polymer and the nature ofthe particular polymer employed, the rate of drug release can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides) Depot injectable formulations are also prepared by entrapping the drug in liposomes or microemulsions which are compatible with body tissues.
The injectable formulations can be sterilized, for example, by filtration through a bacterial-retaining filter or by incoφorating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium just prior to use.
Injectable preparations, for example, sterile injectable aqueous or oleaginous suspensions may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution, suspension or emulsion in a nontoxic, parenterally acceptable diluent or solvent such as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution, U.S. P. and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this puφose any bland fixed oil can be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid are used in the preparation of injectables.
Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound is mixed with at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and/or a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid; b) binders such as carboxymefhylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia; c) humectants such as glycerol; d) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; e) solution retarding agents such as paraffin); f) absoφtion accelerators such as quaternary ammonium compounds; g) wetting agents such as cetyl alcohol and glycerol monostearate;) absorbents such as kaolin and bentonite clay; and i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets and pills, the dosage form may also comprise buffering agents.
Solid compositions of a similar type may also be employed as fillers in soft and hard- filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like.
The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical formulating art. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part ofthe intestinal tract in a delayed manner. Examples of embedding compositions which can be used include polymeric substances and waxes.
Compositions for rectal or vaginal administration are preferably suppositories which can be prepared by mixing the compounds of this invention with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound.
Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active compounds, the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof. Besides inert diluents, the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
Dosage forms for topical or transdermal administration of a compound of this invention include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants or patches. The active component is admixed under sterile conditions with a pharmaceutically acceptable carrier and any needed preservatives or buffers as may be required. Ophthalmic formulation, ear drops, eye ointments, powders and solutions are also contemplated as being within the scope of this invention.
The ointments, pastes, creams and gels may contain, in addition to an active compound of this invention, excipients such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.
Powders and sprays can contain, in addition to the compounds of this invention, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder, or mixtures of these substances. Sprays can additionally contain customary propellants such as chlorofluorohydrocarbons.
Transdermal patches have the added advantage of providing controlled delivery of a compound to the body. Such dosage forms can be made by dissolving or dispensing the compound in the proper medium. Absoφtion enhancers can also be used to increase the flux ofthe compound across the skin. The rate can be controlled by either providing a rate controlling membrane or by dispersing the compound in a polymer matrix or gel.
Compounds ofthe present invention may also be administered in the form of liposomes. As is known in the art, liposomes are generally derived from phospholipids or other lipid substances. Liposomes are formed by mono- or multi-lamellar hydrated liquid crystals that are dispersed in an aqueous medium. Any non-toxic, physiologically acceptable and metabolizable lipid capable of forming liposomes may be used. The present compositions in liposome form may contain, in addition to the compounds ofthe present invention, stabilizers, preservatives, excipients, and the like. The preferred lipids are the natural and synthetic phospholipids and phosphatidylcholines (lecithins) used separately or together.
Methods to form liposomes are known in the art. See, for example, Prescott, Ed., Methods in Cell Biology, Volume XIN, Academic Press, New York, N. Y., (1976), p 33 et seq.
The term "pharmaceutically acceptable salt," as used herein, refers to salts that are well known in the art. Examples of pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid or by using other methods used in the art such as ion exchange. Other pharmaceutically acceptable salts include nitrate, bisulfate, borate, formate, butyrate, valerate, 3-phenylρropionate, camphorate, adipate, benzoate, oleate, palmitate, stearate, laurate, lactate, fumarate, ascorbate, aspartate, nicotinate, p-toluenesulfonate, camphorsulfonate, methanesulfonate, 2- hydroxyethanesulfonate, gluconate, glucoheptonate, lactobionate, glycerophosphate, pectinate, lauryl sulfate, and the like, metal salts such as sodium, potassium, magnesium or calcium salts or amino salts such as ammonium, triethylamine salts, and the like, all of which may be prepared according to conventional methods.
Dosage forms for topical administration of a compound of this invention include powders, sprays, ointments and inhalants. The active compound is mixed under sterile conditions with a pharmaceutically acceptable carrier and any needed preservatives, buffers or propellants which can be required. Opthalmic formulations, eye ointments, powders and solutions are also contemplated as being within the scope of this invention.
Actual dosage levels of active ingredients in the pharmaceutical compositions of this invention can be varied so as to obtain an amount ofthe active compound(s) which is effective to achieve the desired therapeutic response for a particular patient, compositions and mode of administration. The selected dosage level will depend upon the activity of the particular compound, the route of administration, the severity ofthe condition being treated and the condition and prior medical history ofthe patient being treated. However, it is within the skill ofthe art to start doses of the compound at levels lower than required for to achieve the desired therapeutic effect and to gradually increase the dosage until the desired effect is achieved.
The present invention contemplates compounds of formula I-IV formed by synthetic means or formed by in vivo biotransformation.
The compounds ofthe invention, including but not limited to those specified in the examples, possess potassium channel opening activity in mammals (especially humans). As potassium channel openers, the compounds ofthe present invention may be useful for the treatment and prevention of diseases such as 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 hypeφlasia (BPH), dysmenorrhea, premature labor, alopecia, cardioprotection, coronary artery disease, angina and ischemia.
The ability ofthe compounds ofthe present invention, including but not limited to those specified in the examples, to treat bladder overactivity, sensations of incontinence urgency, urinary incontinence, pollakiuria, bladder instability, nocturia, bladder hyeneflexia, and enuresis may be demonstrated by (Resnick, The Lancet (1995) 346, 94-99; Hampel, Urology (1997) 50 (Suppl 6A), 4-14; Bosch, BJU International (1999) 83 (Suppl 2), 7-9; 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 ability ofthe compounds ofthe present invention, including but not limited to those specified in the examples, to treat male sexual dysfunction such as male erectile dysfunction, impotence and premature ejaculation may be demonstrated by (Andersson, Pharmacological Reviews (1993) 45, 253; Lee, Int. J. Impot. Res. (1999) 11(4),179-188; Andersson, Pharmacological Reviews (1993) 45, 253; Lawson, Pharmacol. Ther., (1996) 70, 39-63, Vick, J. Urol. (2000) 163: 202).
The ability ofthe compounds ofthe present invention, including but not limited to those specified in the examples, to treat female sexual dysfunction such as clitoral erectile insufficiency, vaginismus and vaginal engorgement may be demonstrated by (Kim et al., J. Urol. (2000) 163 (4): 240; Goldstein and Berman., Int. J. Impotence Res. (1998) 10:S84-S90).
The ability ofthe compounds ofthe present invention, including but not limited to those specified in the examples, to treat benign prostatic hypeφlasia (BPH) may be demonstrated by (Pandita, The J. of Urology (1999) 162, 943; Andersson, Prostate (1997) 30: 202-215).
The ability ofthe compounds ofthe present invention, including but not limited to those specified in the examples, to treat premature labor and dysmenorrhoea may be demonstrated by (Sanborn, Semin. Perinatol. (1995) 19, 31-40; Morrison, Am. J. Obstet. Gynecol. (1993) 169(5), 1277-85; Kostrzewska, Acta Obstet. Gynecol. Scand. (1996) 75(10), 886-91; Lawson, Pharmacol. Ther., (1996) 70, 39-63).
The ability ofthe compounds ofthe present invention, including but not limited to those specified in the examples, to treat functional bowel disorders such as irritable bowel syndrome may be demonstrated by (Lawson, Pharmacol. Ther., (1996) 70, 39-63). The ability ofthe compounds ofthe present invention, including but not limited to those specified in the examples, to treat asthma and airways hyperreactivity may be demonstrated by (Lawson, Pharmacol. Ther., (1996) 70, 39-63; Buchheit, Pulmonary Pharmacology & Therapeutics (1999) 12, 103; Gopalakrishnan, Drug Development Research, (1993) 28, 95-127).
The ability ofthe compounds ofthe present invention, including but not limited to those specified in the examples, to treat various pain states including but not limited to migraine and dyspareunia may be demonstrated by (Rodrigues, Br. J. Pharmacol. (2000) 129(1), 110-4; Vergoni, Life Sci. (1992) 50(16), PL135-8; Asano, Anesth. Analg. (2000) 90(5), 1146-51; 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).
The ability ofthe compounds ofthe present invention, including but not limited to those specified in the examples, to treat epilepsy may be demonstrated by (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).
The ability ofthe compounds ofthe present invention, including but not limited to those specified in the examples, to treat neurodegenerative conditions and diseases such as cerebral ischemia, stroke, Alzheimer's disease and Parkinson's disease may be demonstrated by (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).
The ability ofthe compounds ofthe present invention, including but not limited to those specified in the examples, to treat diseases or conditions associated with decreased skeletal muscle blood flow such as Raynaud's syndrome and intermittent claudication may be demonstrated by (Lawson, Pharmacol. Ther., (1996) 70, 39-63; Gopalakrishnan, Drug Development Research, (1993) 28, 95-127; Dompeling Vasa. Supplementum (1992) 3434; WO9932495).
The ability ofthe compounds ofthe present invention, including but not limited to those specified in the examples, to treat eating disorders such as obesity may be demonstrated by (Spanswick, Nature, (1997) 390, 521-25; Freedman, The Neuroscientist (1996) 2, 145). The ability ofthe compounds ofthe present invention, including but not limited to those specified in the examples, to treat alopecia may be demonstrated by (Lawson, Pharmacol. Ther., (1996) 70, 39-63; Gopalakrishnan, Drug Development Research, (1993) 28, 95-127).
The ability of the compounds ofthe present invention, including but not limited to those specified in the examples, to treat myocardial injury during ischemia and reperfusion may be demonstrated by (Garlid, Circ Res (1997) 81(6), 1072-82; Lawson, Phaπnacol. Ther., (1996) 70, 39-63; Grover, J. Mol. Cell Cardiol. (2000) 32, 677).
The ability ofthe compounds ofthe present invention, including but not limited to those specified in the examples, to treat coronary artery disease may be demonstrated by (Lawson, Pharmacol. Ther., (1996) 70, 39-63, Gopalakrishnan, Drug Development Research, (1993) 28, 95-127).
Aqueous liquid compositions ofthe present invention are particularly useful for the treatment and prevention of asthma, epilepsy, hypertension, Raynaud's syndrome, male sexual dysfunction, female sexual dysfunction, migraine, pain, eating disorders, urinary incontinence, functional bowel disorders, neurodegeneration and stroke.
When used in the above or other treatments, a therapeutically effective amount of one ofthe compounds ofthe present invention can be employed in pure form or, where such forms exist, in pharmaceutically acceptable salt, ester, amide or prodrug form. Alternatively, the compound can be administered as a pharmaceutical composition containing the compound of interest in combination with one or more pharmaceutically acceptable excipients. The phrase "therapeutically effective amount" ofthe compound ofthe invention means a sufficient amount ofthe compound to treat disorders, at a reasonable benefit/risk ratio applicable to any medical treatment. It will be understood, however, that the total daily usage ofthe compounds and compositions ofthe present invention will be decided by the attending physician within the scope of sound medical judgement. The specific therapeutically effective dose level for any particular patient will depend upon a variety of factors including the disorder being treated and the severity ofthe disorder; activity ofthe specific compound employed; the specific composition employed; the age, body weight, general health, sex and diet ofthe patient; the time of administration, route of administration, and rate of excretion ofthe specific compound employed; the duration ofthe treatment; drugs used in combination or coincidental with the specific compound employed; and like factors well known in the medical arts. For example, it is well within the skill ofthe art to start doses ofthe compound at levels lower than required to achieve the desired therapeutic effect and to gradually increase the dosage until the desired effect is achieved.
The total daily dose of the compounds of this invention administered to a human or lower animal may range from about 0.003 to about 50 mg/kg/day. For puφoses of oral administration, more preferable doses can be in the range of from about 0.01 to about 25 mg/kg/day. If desired, the effective daily dose can be divided into multiple doses for puφoses of administration; consequently, single dose compositions may contain such amounts or submultiples thereof to make up the daily dose.

Claims

What is claimed is:
1. A compound of formula (I)
R2 R3 4
RΓNYVYR5
R6 R7 o
(I), or a pharmaceutically acceptable salt thereof wherein A is selected from the group consisting of
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 the group consisting of aryl, arylalkyl, heterocycle and heterocyclealkyl;
R2, R and R4 are independently selected from the group consisting of hydrogen and alkyl;
R5 is selected from the group consisting of aryl, arylalkenyl, arylalkyl, aryloxyalkyl, heterocycle and heterocyclealkyl;
R6 is selected from the group consisting of 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)alkyl, aryloxyalkyl, aryloxycarbonyl, aryloxycarbonylalkyl, arylalkylthioalkyl, arylsulfonylalkyl, carboxy, carboxyalkyl, carboxy(halo)alkyl, cyanoalkyl, cyano(halo)alkyl, cycloalkenyl, cycloalkenylalkyl, cycloalkyl, cycloalkylalkoxyalkyl, cycloalkylalkyl, cycloalkylcarbonyl, cycloalkyloxyalkyl, cycloalkylalkylthioalkyl, formyl, haloalkenyl, haloalkyl, haloalkylcarbonyl, haloalkynyl, heterocycle, heterocyclealkoxyalkyl, heterocyclealkyl, heterocyclecarbonyl, heterocycleoxyalkyl, heterocyclealkylthioalkyl, hydroxyalkyl, mercaptoalkyl, sulfamylalkyl, sulfamyl(halo)alkyl, (NR9Rι0)alkyl, (NR9Rι0)carbonyl and (NR9R i o)carbonylalkyl ;
R7 is selected from the group consisting of hydrogen, haloalkyl, and lower alkyl; or ό and R7 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 the group consisting of alkenyl, alkoxy, alkyl, alkynyl, halogen, haloalkoxy, and haloalkyl;
R9 and Rio are independently selected from the group consisting of hydrogen, alkoxysulfonyl, alkyl, alkylcarbonyl, alkylsulfonyl, aryl, arylalkyl, arylcarbonyl, arylsulfonyl and formyl.
2. A compound according to claim 1 wherein A is selected from the group consisting of
3. A compound according to claim 1 of formula (II)
Rι-N' 2 R3 R4
O (II), or a pharmaceutically acceptable salt thereof.
4. A compound according to claim 3 wherein Ri is heterocycle; and
R5 is aryl.
5. A compound according to claim 3 wherein
Ri is heterocycle wherein said heterocycle is selected from the group consisting of optionally substituted pyridinyl and optionally substituted pyrazinyl; and R5 is aryl wherein said aryl is optionally substituted phenyl.
6. A compound according to claim 3 wherein
Ri is heterocycle wherein said heterocycle is selected from the group consisting of optionally substituted pyridinyl and optionally substituted pyrazinyl; R2 is hydrogen; R3 is hydrogen; R4 is hydrogen;
R5 is aryl wherein said aryl is optionally substituted phenyl; Re is selected from the group consisting of hydrogen and alkyl; and R7 is hydrogen.
7. A compound according to claim 6 selected from the group consisting of N-(l-{[3,4-dioxo-2-(3-pyridinylamino)-l-cyclobuten-l-yl]amino}-2,2- dimethylpropyl)-4-methylbenzamide;
4-chloro-N-( 1 - { [3 ,4-dioxo-2-(3 -pyridinylamino)- 1 -cyclobuten- 1 -yl] amino } -2 ,2- dimethylpropyl)benzamide;
N-( 1 - { [3 ,4-dioxo-2-(3 -pyridinylamino)- 1 -cyclobuten- 1 -yl] amino } -2,2- dimethylpropyl)-4-iodobenzamide;
N-( 1 - { [3 ,4-dioxo-2-(3-pyridinylamino)- 1 -cyclobuten- 1 -yl] amino } -2,2- dimethylpropyl)-4-(2-ftiryl)benzamide;
3-chloro-N-(l-{[3,4-dioxo-2-(3-pyridinylamino)-l -cyclobuten- l-yl]amino} -2,2- dimethylpropyl)benzamide;
N-( 1 - { [3 ,4-dioxo-2-(3 -pyridinylamino)- 1 -cyclobuten- 1 -yl] amino } -2,2- dimethylpropyl)-3-methylbenzamide;
N-( 1 - { [3 ,4-dioxo-2-(3-pyridinylamino)- 1 -cyclobuten- 1 -yl] amino } -2,2- dimethylprop yl)-3-fluorobenzamide;
N-( 1 - { [3 ,4-dioxo-2-(3 -pyridinylamino)- 1 -cyclobuten- 1 -yl] amino } -2,2- dimethylpropyl)-3-iodobenzamide;
N-( 1 - { [3 ,4-dioxo-2-(3 -pyridinylamino)- 1 -cyclobuten- 1 -yl] amino } -2,2- dimethylpropyl)-3,4-dimethylbenzamide; N-( 1 - { [3 ,4-dioxo-2-(3-pyridinylamino)- 1 -cyclobuten- 1 -yl] amino} -2,2- dimethylpropyl)-3,4-dimethoxybenzamide;
3,5-dichloro-N-(l-{[3,4-dioxo-2-(3-pyridinylamino)-l-cyclobuten-l-yl]amino}-2,2- dimethylpropyl)benzamide;
N-( 1 - { [3 ,4-dioxo-2-(3-pyridinylamino)- 1 -cyclobuten- 1 -yl] amino } -2,2- dimethylpropyl)-3,5-dimethoxybenzamide;
(-) N-( 1 - { [3 ,4-dioxo-2-(3-pyridinylamino)- 1 -cyclobuten- 1 -yl] amino } -2,2- dimethylpropyl)-3,5-dimethoxybenzamide;
(+) N-( 1 - { [3 ,4-dioxo-2-(3 -pyridinylamino)- 1 -cyclobuten- 1 -yl] amino } -2,2- dimethylpropyl)-3,5-dimethoxybenzamide;
N-( 1 - { [3 ,4-dioxo-2-(3 -pyridinylamino)- 1 -cyclobuten- 1 -yl] amino } -2,2- dimethylpropyl)-3,5-difluorobenzamide;
4-chloro-N-( 1 - { [3 ,4-dioxo-2-(3 -pyridinylamino)- 1 -cyclobuten- 1 -yl] amino } -2 - ethylbutyl)benz amide;
4-chloro-N-[ 1 -( {2-[(2-chloro-3-pyridinyl)amino]-3,4-dioxo-l -cyclobuten- 1 -yl} amino)- 2,2-dimethylpropyl]benzamide;
N- [ 1 -( {2-[(5-bromo-6-fluoro-3 -pyridinyl)amino] -3 ,4-dioxo- 1 -cyclobuten- 1 -yl } amino)- 2,2-dimethylpropyl]-4-chlorobenzamide;
N-[l-({2-[(2-chloro-3-pyridinyl)amino]-3,4-dioxo-l-cyclobuten-l-yl}amino)-2,2- dimethylpropyl]-3-methylbenzamide;
N-( 1 - { [3 ,4-dioxo-2-(3 -pyridinylamino)- 1 -cyclobuten- 1 -yl] amino } -2,2- dimethylpropyl)-3-vinylbenzamide;
N-( 1 - { [3 ,4-dioxo-2-(3 -pyridinylamino)- 1 -cyclobuten- 1 -yl] amino } -2,2- dimethylpropyl)[ 1 , 1 '-biphenyl]-3-carboxamide;
3 -acetyl-N-( 1 - { [3 ,4-dioxo-2-(3 -pyridinylamino)- 1 -cyclobuten- 1 -yl] amino } -2,2- dimethylpropyl)benzamide;
N-( 1 - { [3 ,4-dioxo-2-(3-p yridinylamino)- 1 -cyclobuten- 1 -yl] amino } -2,2- dimethylpropyl)-4-fluoro-3-(trifluoromethyl)benz amide;
4-chloro-N-( 1 - { [3 ,4-dioxo-2-(4-pyridinylamino)- 1 -cyclobuten- 1 -yl] amino } -2 ,2- dimethylpropyl)benz amide;
4-chloro-N-( 1 - { [3 ,4-dioxo-2-(2 -pyridinylamino)- 1 -cyclobuten- 1 -yl] amino } -2 ,2- dimethylpropyl)benzamide; N-( 1 - { [3 ,4-dioxo-2-(3 -pyridinylamino)- 1 -cyclobuten- 1 -yl] amino } -2,2- dimefhylpropyl)benzamide;
(+) N-( 1 - { [3 ,4-dioxo-2-(3 -pyridinylamino)- 1 -cyclobuten- 1 -yl] amino} -2,2- dimethylpropyl)-3,5-difluorobenzamide;
(-) N-(l-{[3,4-dioxo-2-(3-pyridinylamino)-l-cyclobuten-l-yl]amino}-2,2- dimethylpropyl)-3,5-difluorobenzamide;
4-chloro-N-{l-[(3,4-dioxo-2-{[5-(trifluoromethyl)pyridin-3-yl]amino}-l-cyclobuten- l-yl)amino]-2,2-dimethylpropyl}benzamide;
3 ,5 -dichloro-N- { 1 -[(3 ,4-dioxo-2- { [5 -(trifluoromethyDpyridin-3 -yl] amino } - 1 - cyclobuten- 1 -yl)amino]-2,2-dimethylpropyl}benzamide;
(+) 3 -chloro-N-( 1 - { [3 ,4-dioxo-2-(3 -pyridinylamino)- 1 -cyclobuten- 1 -yl] amino } -2,2- dimethylpropyl)benzamide;
(-) 3 -chloro-N-( 1 - { [3 ,4-dioxo-2-(3-pyridinylamino)- 1 -cyclobuten- 1 -yl] amino } -2 ,2- dimethylpropyl)benzamide;
4-chloro-N-[ 1 -( {2-[(6-chloropyridin-3 -yl)amino]-3 ,4-dioxo- 1 -cyclobuten- 1 -yl} amino)- 2,2-dimefhylpropyl]benzamide;
4-chloro-N-[l-({2-[(2-fluoropyridin-3-yl)amino]-3,4-dioxo-l-cyclobuten-l-yl}amino)- 2,2-dimethylpropyl]benzamide;
3 -chloro-N-( 1 - { [3 ,4-dioxo-2-(3-pyridinylamino)- 1 -cyclobuten- 1 -yl] amino } -3 ,3- dimethylbutypbenzamide;
3-bromo-N-(l-{[3,4-dioxo-2-(3-pyridinylamino)-l-cyclobuten-l-yl]amino}-2,2- dimethylpropyl)benzamide;
3-bromo-N-[ 1 -( {2-[(2-chloropyridin-3 -yl)amino]-3,4-dioxo- 1 -cyclobuten- 1 - yl } amino)-2 ,2 -dimethylpropyl] benzamide ; methyl 3- { [( 1 - { [3 ,4-dioxo-2-(3 -pyridinylamino)- 1 -cyclobuten- 1 -yl] amino } -2,2- dimethylpropyl)amino]carbonyl}benzoate;
(+) N-( 1 - { [3 ,4-dioxo-2-(3 -pyridinylamino)- 1 -cyclobuten- 1 -yl] amino } -2,2- dimethylpropyl)-3-methylbenzamide;
(-) N-( 1 - { [3 ,4-dioxo-2-(3 -pyridinylamino)- 1 -cyclobuten- 1 -yl] amino} -2,2- dimethylpropyl)-3-mefhylbenzarnide;
(+) N- [ 1 -( {2-[(2-chloropyridin-3 -yl)amino] -3 ,4-dioxo- 1 -cyclobuten- 1 -yl} amino)-2 ,2- dimethylpropyl] -3 -methylbenzamide ; (-) N-[l-({2-[(2-chloropyridin-3-yl)amino]-3,4-dioxo-l-cyclobuten-l-yl}amino)-2,2- dimethylpropyl]-3-methylbenzamide;
N-( 1 - { [3 ,4-dioxo-2-(3-pyridinylamino)- 1 -cyclobuten- 1 -yl] amino } -2,2- dimethylpropyl)-3-(2-furyl)benzamide;
N-[l-({2-[(2-chloropyridin-3-yl)amino]-3,4-dioxo-l-cyclobuten-l-yl}amino)-2,2- dimethylpropyl]-3-fluorobenzamide;
3,5-dichloro-N-[l-({2-[(2-chloropyridin-3-yl)amino]-3,4-dioxocyclobut-l-en-l- yl}amino)-2,2-dimethylpropyl]benzamide;
4-chloro-N- [ 1 -( {2-[(2 -methoxyp yridin-3 -yl)amino] -3, 4-dioxo-l -cyclobuten- 1 - yl}amino)-2,2-dimethylpropyl]benzamide;
N-[ 1 -( {2-[(2 -methoxyp yridin-3-yl)amino]-3 ,4-dioxo- 1 -cyclobuten- 1 -yl} amino)-2,2- dimethylpropyl]-3-methylbenzamide;
3 ,5 -difluoro-N-[ 1 -( {2- [(2 -methoxyp yridin-3 -yl)amino] -3 ,4-dioxo- 1 -cyclobuten- 1 - yl}amino)-2,2-dimethylpropyl]benzamide;
3 -chloro-N-[ 1 -( {2- [(2-methoxyp yridin-3 -yl)amino] -3 ,4-dioxo- 1 -cyclobuten- 1 - yl}amino)-2,2-dimethylpropyl]benzamide;
3 -chloro-N-( 1 - { [3 ,4-dioxo-2-(pyrazin-2-ylamino)- 1 -cyclobuten- 1 -yl] amino } -2,2- dimethylpropyl)benzamide;
N- [ 1 -( {2-[(2-chlorop yridin-3 -yl)amino] -3 ,4-dioxo- 1 -cyclobuten- 1 -yl} amino)-3 ,3 - dimethylbutyl]benzamide;
3-chloro-N- [ 1 -( {2-[(6-chloropyridin-3 -yl)amino] -3 ,4-dioxo- 1 -cyclobuten- 1 -yl } amino)- 2,2-dimethylpropyl]benzamide;
3 -chloro-N- { 1 - [(3 ,4-dioxo-2- { [6-(trifluoromethyl)pyridin-3 -yl] amino } - 1 -cyclobuten- l-yl)amino]-2,2-dimethylpropyl}benzamide;
3-chloro-N- [ 1 -( {2-[(2-chloropyridin-3 -yl)amino] -3 ,4-dioxo- 1 -cyclobuten- 1 -yl } amino)- 2,2-dimethylpropyl]benzamide;
4-chloro-N-( { [3 ,4-dioxo-2-(3-p yridinylamino)- 1 -cyclobuten- 1 - yl] amino } methyl)benzamide ;
(-) 3,5-dichloro-N-[(lR)-l-({2-[(2-chloropyridin-3-yl)amino]-3,4-dioxocyclobut-l-en- 1 -yl} amino)-2,2-dimethylpropyl]benzamide;
(+) N-( 1 - { [3 ,4-dioxo-2-(2-chloro3 -pyridinylamino)- 1 -cyclobuten- 1 -yl] amino } -2,2- dimethylprop yl)-3, 5 -difluorobenzamide; and (-) N-( 1 - { [3 ,4-dioxo-2-(2-chloro3-pyridinylamino)- 1 -cyclobuten- 1 -yl] amino } -2,2- dimethylpropyl)-3,5-difluorobenzamide.
8. A compound according to claim 6 that is (+) 3,5-dichloro-N-[(lS)-l-({2-[(2- chloropyridin-3-yl)amino]-3,4-dioxocyclobut-l-en-l-yl}amino)-2,2- dimethylpropyl]benzamide.
9. A compound according to claim 3 wherein
Ri is heterocycle wherein said heterocycle is optionally substituted pyridinyl;
R2 is hydrogen;
R3 is hydrogen;
Rt is hydrogen;
R is aryl wherein said aryl is optionally substituted phenyl;
Re is selected from the group consisting of 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 is hydrogen.
10. A compound according to claim 9 selected from the group consisting of 4-chloro-N-( 1 - { [3 ,4-dioxo-2-(3 -pyridinylamino)- 1 -cyclobuten- 1 -yl] amino } -2 ,2- dimethyl-3-phenylpropyl)benzamide;
4-chloro-N-[ 1 -( {2-[(2-chloro-3-pyridinyl)amino]-3 ,4-dioxo- 1 -cyclobuten- 1 -yl} amino)- 2,2-dimethyl-3-phenylpropyl]benzamide;
4-chloro-N- { 1 - [(3 ,4-dioxo-2- { [5 -(trifluoromethyl)pyridin-3 -yl] amino } - 1 -cyclobuten- l-yl)amino]-2,2-dimethyl-3-phenylpropyl}benzamide;
N-( 1 - { [3 ,4-dioxo-2-(3-pyridinylamino)- 1 -cyclobuten- 1 -yl] amino } -2,2-dimethyl-3 - phenylpropyl)-3,5-difluorobenzamide;
3 ,5 -dichloro-N-( 1 - { [3 ,4-dioxo-2-(3 -pyridinylamino)- 1 -cyclobuten- 1 -yl] amino } -2,2- dimethyl-3-phenylpropyl)benzamide;
3 -chloro-N-( 1 - { [3 ,4-dioxo-2-(3-pyridinylamino)- 1 -cyclobuten- 1 -yl] amino } -2 ,2- dimethyl-3-phenylpropyl)benz amide; N-( 1 - { [3 ,4-dioxo-2-(3-p yridinylamino)- 1 -cyclobuten- 1 -yl] amino } -2,2-dimethyl-3 - phenylpropyl)-3 -methylbenzamide;
N-[ 1 -( {2-[(2-chloropyridin-3-yl)amino]-3,4-dioxo- 1 -cyclobuten- 1 -yl} amino)-2,2- dimethyl-3 -phenylpropyl] -3 -methylbenzamide;
(+) N-( 1 - { [3 ,4-dioxo-2-(3-pyridinylamino)- 1 -cyclobuten- 1 -yl] amino } -2,2-dimefhyl-3 - phenylpropyl)-3 -methylbenzamide;
(-) N-(l-{[3,4-dioxo-2-(3-pyridinylamino)-l-cyclobuten-l-yl]amino}-2,2-dimethyl-3- phenylpropyl)-3-methylbenzamide;
(+) N-( 1 - { [3 ,4-dioxo-2-(3 -pyridinylamino)- 1 -cyclobuten- 1 -yl] amino } -2,2-dimethyl-3 - phenylpropyl)-3,5-difluorobenzamide;
N-[ 1 -( {2-[(2-methoxypyridin-3-yl)amino]-3 ,4-dioxo- 1 -cyclobuten- 1 -yl} amino)-2,2- dimethyl-3-phenylpropyl]-3-methylbenzamide;
N-[l-({2-[(2-chloropyridin-3-yl)amino]-3,4-dioxo-l-cyclobuten-l-yl}amino)-2,2- dimethyl-3-phenylpropyl]benzamide;
N-( 1 - { [3 ,4-dioxo-2-(3-pyridinylamino)- 1 -cyclobuten- 1 -yl] amino } -2,2-dimethyl-3 - phenylpropyl)benzamide;
N-( 1 - { [3 ,4-dioxo-2-(3-p yridinylamino)- 1 -cyclobuten- 1 -yl] amino } -2,2-dimefhyl-3 - pyridin-4-ylpropyl)-3-methylbenzamide;
(-) 3 -chloro-N-( 1 - { [3 ,4-dioxo-2-(3-pyridinylamino)- 1 -cyclobuten- 1 -yl] amino } -2,2- dimethyl-3-phenylpropyl)benzamide; and
(+) 3-chloro-N-( 1 - { [3 ,4-dioxo-2-(3-pyridinylamino)- 1 -cyclobuten- 1 -yl]amino} -2,2- dimethyl-3-phenylpropyl)benzamide.
11. A compound according to claim 3 wherein
Ri is heterocycle wherein said heterocycle is optionally substituted pyridinyl;
R2 is hydrogen;
R3 is hydrogen;
Rt is hydrogen;
R5 is aryl wherein said aryl is optionally substituted phenyl;
Re is haloalkyl; and
R7 is hydrogen.
12. A compound according to claim 11 selected from the group consisting of 4-chloro-N-(2,2-dichloro- 1 - {[3 ,4-dioxo-2-(3-pyridinylamino)- 1 -cyclobuten- 1 - yl] amino } propyl)benzamide ;
3 -chloro-N-(2,2-dichloro- 1 - { [3 ,4-dioxo-2-(3 -pyridinylamino)- 1 -cyclobuten- 1 - yl] amino } propyl)benzamide;
3-chloro-N-(l-{[3,4-dioxo-2-(3-pyridinylamino)-l-cyclobuten-l-yl]amino}-2,2,3,3,3- pentafluoropropypbenzamide;
4-chloro-N-(2,2-dichloro- 1 - { [3,4-dioxo-2-(3-pyridinylamino)- 1 -cyclobuten- 1 - yl] amino }pentyl)benzamide; and
N-(2,2-dichloro- 1 - { [3,4-dioxo-2-(3-pyridinylamino)- 1 -cyclobuten- 1 - yl]amino}propyl)-3,5-difluorobenzamide.
13. A compound according to claim 3 wherein
Ri is heterocycle wherein said heterocycle is optionally substituted pyridinyl; R2 is hydrogen; R3 is hydrogen; Rt is hydrogen;
R5 is aryl wherein said aryl is optionally substituted phenyl; Re is selected from the group consisting of alkenyl, alkenyloxy(alkenyloxy)alkyl, cyanoalkyl and cycloalkylalkyl; and R7 is hydrogen.
14. A compound according to claim 13 selected from the group consisting of 4-chloro-N-( 1 - { [3 ,4-dioxo-2-(3 -pyridinylamino)- 1 -cyclobuten- 1 -yl] amino } -2 ,2- dimethyl-4-pentenyl)benzamide;
4-chloro-N-(4-cyano- 1 - { [3 ,4-dioxo-2-(3-p yridinylamino)- 1 -cyclobuten- 1 -yl] amino } - 2,2-diethylbutyl)benzamide;
N-(2,2-bis[(allyloxy)methyl]- 1 - {[3, 4-dioxo-2-(3 -pyridinylamino)- 1 -cyclobuten- 1 - yl]amino}butyl)-4-chlorobenzamide;
4-chloro-N-(2-cyclohexyl- 1 - { [3 ,4-dioxo-2-(3 -pyridinylamino)- 1 -cyclobuten- 1 - yl]amino}-2-methylpropyl)benzamide; and N-(2-( 1 -adamantyl)- 1 - { [3 ,4-dioxo-2-(3 -pyridinylamino)- 1 -cyclobuten- 1 - yl]amino}ethyl)-4-chlorobenzamide.
15. A compound according to claim 3 wherein
Ri is heterocycle wherein heterocycle is optionally substituted pyridinyl; and R5 is aryl wherein aryl is selected from the group consisting of optionally substituted naphthyl and optionally substituted fluorenyl.
16. A compound according to claim 3 wherein
Ri is heterocycle wherein heterocycle is optionally substituted pyridinyl;
R2 is hydrogen;
R3 is hydrogen;
R4 is hydrogen;
R5 is aryl wherein aryl is selected from the group consisting of optionally substituted naphthyl and optionally substituted fluorenyl;
Re is selected from the group consisting of alkenyl, alkenyloxy(alkenyloxy)alkyl, arylalkyl wherein the aryl portion of said arylalkyl is optionally substituted phenyl, cyanoalkyl, cycloalkylalkyl and haloalkyl; and
R7 is hydrogen.
17. A compound according to claim 3 wherein
Ri is heterocycle wherein heterocycle is optionally substituted pyridinyl; R2 is hydrogen; R3 is hydrogen; R is hydrogen;
R5 is aryl wherein aryl is selected from the group consisting of optionally substituted naphthyl and optionally substituted fluorenyl; R6 is alkyl; and R7 is hydrogen.
18. A compound according to claim 17 selected from the group consisting of N-( 1 - { [3 ,4-dioxo-2-(3 -pyridinylamino)- 1 -cyclobuten- 1 -yl] amino } -2,2- dimethylpropyl)-l-naphthamide; and
N-( 1 - { [3 ,4-dioxo-2-(3 -pyridinylamino)- 1 -cyclobuten- 1 -yl] amino } -2,2- dimethylpropyl)-9-oxo-9H-fluorene-4-carboxamide.
19. A compound according to claim 3 wherein Ri is aryl; and
R5 is aryl.
20. A compound according to claim 3 wherein
Ri is aryl wherein said aryl is optionally substituted phenyl; and R is aryl wherein said aryl is optionally substituted phenyl.
21. A compound according to claim 3 wherein
Ri is aryl wherein said aryl is optionally substituted phenyl;
R2 is hydrogen;
R3 is hydrogen;
R4 is hydrogen;
R5 is aryl wherein said aryl is optionally substituted phenyl;
R6 is selected from the group consisting of alkenyl, alkenyloxy(alkenyloxy)alkyl, alkyl, arylalkyl wherein the aryl portion of said arylalkyl is optionally substituted phenyl, cyanoalkyl, cycloalkylalkyl and haloalkyl; and
R7 is hydrogen.
22. A compound according to claim 3 wherein
Ri is aryl wherein said aryl is optionally substituted phenyl;
R2 is hydrogen;
R is hydrogen;
Rt is hydrogen;
R5 is aryl wherein said aryl is optionally substituted phenyl;
R6 is alkyl; and
R7 is hydrogen.
23. A compound according to claim 22 selected from the group consisting of 4-chloro-N-(l-{[2-(3-fluoroanilino)-3,4-dioxo-l-cyclobuten-l-yl]amino}-2,2- dimethylpropyl)benzamide; and
4-chloro-N-( 1 - { [2-(4-fluoroanilino)-3 ,4-dioxo- 1 -cyclobuten- 1 -yl] amino } -2,2- dimethylpropyl)benzamide.
24. A compound according to claim 3 wherein Ri is heterocycle; and
R5 is arylalkyl.
25. A compound according to claim 3 wherein
Ri is heterocycle wherein said heterocycle is optionally substituted pyridinyl;
R5 is selected from the group consisting of 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.
26. A compound according to claim 3 wherein
Ri is heterocycle wherein said heterocycle is optionally substituted pyridinyl;
R2 is hydrogen;
R3 is hydrogen;
R is hydrogen;
R5 is selected from the group consisting of 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 the group consisting of alkenyl, alkenyloxy(alkenyloxy)alkyl, arylalkyl wherein the aryl portion of said arylalkyl is optionally substituted phenyl, cyanoalkyl, cycloalkylalkyl and haloalkyl; and
R is hydrogen.
27. A compound according to claim 3 wherein
Ri is heterocycle wherein said heterocycle is optionally substituted pyridinyl;
R2 is hydrogen;
R3 is hydrogen;
R4 is hydrogen;
R5 is selected from the group consisting of 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;
R6 is selected from the group consisting of alkyl and arylalkyl wherein the aryl portion of said arylalkyl is optionally substituted phenyl; and
R7 is hydrogen.
28. A compound according to claim 27 selected from the group consisting of (l-{[3,4-dioxo-2-(3-pyridinylamino)-l-cyclobuten-l-yl]amino}-2,2-dimethylpropyl)-
3 -phenylpropanamide;
N-(l-{[3,4-dioxo-2-(3-pyridinylamino)-l-cyclobuten-l-yl]amino}-2,2- dimefhylpropyl)-2-phenylacetamide;
N-( 1 - { [3 ,4-dioxo-2-(3-pyridinylamino)- 1 -cyclobuten- 1 -yl] amino } -2,2- dimethylpropyl)-3-phenylprop-2-enamide;
N-[ 1 -( {2-[(2-chloropyridin-3-yl)amino]-3,4-dioxo- 1 -cyclobuten- 1 -yl } amino)-2,2- dimethylpropyl] -3 -phenylpropanamide;
N-( 1 - { [3 ,4-dioxo-2-(3 -pyridinylamino)- 1 -cyclobuten- 1 -yl] amino } -2,2- dimethylpropyl)-2-phenoxyacetamide;
N-[ 1 -( {2-[(2-chloropyridin-3-yl)amino]-3,4-dioxo- 1 -cyclobuten- 1 -yl} amino)-2,2- dimethylpropyl]-2-phenoxyacetamide;
N-( 1 - { [3 ,4-dioxo-2-(3 -pyridinylamino)- 1 -cyclobuten- 1 -yl] amino } -2 ,2- dimethylpropyl)-2-methyl-2-phenylpropanamide;
N-(l - { [3 ,4-dioxo-2-(3-p yridinylamino)- 1 -cyclobuten- 1 -yl]amino} -2,2-dimethyl-3- phenylpropyl)-3-phenylpropanamide;
N-( 1 - { [3 ,4-dioxo-2-(3-pyridinylamino)- 1 -cyclobuten- 1 -yljamino} -2,2-dimethyl-3- phenylpropyl)-2-methyl-2-phenylpropanamide; and N-( 1 - { [3 ,4-dioxo-2-(3-pyridinylamino)- 1 -cyclobuten- 1 -yl] amino } -2,2-dimethyl-3 - phenylpropyl)-2-phenoxyacetamide.
29. A compound according to claim 3 wherein Ri is heterocycle; and
R5 is heterocyclealkyl.
30. A compound according to claim 3 wherein
Ri is heterocycle wherein said heterocycle is optionally substituted pyridinyl; R5 is heterocyclealkyl wherein the heterocycle portion of said heterocyclealkyl is optionally substituted pyridinyl.
31. A compound according to claim 3 wherein
Ri is heterocycle wherein said heterocycle is optionally substituted pyridinyl;
R2 is hydrogen;
R3 is hydrogen;
R4 is hydrogen;
R5 is heterocyclealkyl wherein the heterocycle portion of said heterocyclealkyl is optionally substituted pyridinyl;
R6 is selected from the group consisting of alkenyl, alkenyloxy(alkenyloxy)alkyl, arylalkyl wherein the aryl portion of said arylalkyl is optionally substituted phenyl, cyanoalkyl, cycloalkylalkyl and haloalkyl; and
R7 is hydrogen.
32. A compound according to claim 3 wherein
Ri is heterocycle wherein said heterocycle is optionally substituted pyridinyl; R2 is hydrogen; R3 is hydrogen; R4 is hydrogen;
R5 is heterocyclealkyl wherein the heterocycle portion of said heterocyclealkyl is optionally substituted pyridinyl; Re is alkyl; and R7 is hydrogen.
33. A compound according to claim 32 that is N-[l-({2-[(2-chloro-3-pyridinyl)amino]-3,4- dioxo- 1 -cyclobuten- 1 -yl } amino)-2,2-dimethylpropyl] -3 -(3 -pyridinyl)propanamide.
34. A compound according to claim 3 wherein Ri is heterocycle; and
R5 is heterocycle.
35. A compound according to claim 3 wherein
Ri is heterocycle wherein said heterocycle is optionally substituted pyridinyl; R5 is heterocycle wherein said heterocycle is selected from the group consisting of optionally substituted pyridinyl, optionally substituted thienyl and optionally substituted furyl.
36. A compound according to claim 3 wherein
Ri is heterocycle wherein said heterocycle is optionally substituted pyridinyl;
R2 is hydrogen;
R3 is hydrogen;
Rt is hydrogen;
R5 is heterocycle wherein said heterocycle is selected from the group consisting of optionally substituted pyridinyl, optionally substituted thienyl and optionally substituted furyl;
Re is selected from the group consisting of alkenyl, alkenyloxy(alkenyloxy)alkyl, arylalkyl wherein the aryl portion of said arylalkyl is optionally substituted phenyl, cyanoalkyl, cycloalkylalkyl and haloalkyl; and
R7 is hydrogen.
37. A compound according to claim 3 wherein
Ri is heterocycle wherein said heterocycle is optionally substituted pyridinyl; R2 is hydrogen; R3 is hydrogen; Rt is hydrogen; R5 is heterocycle wherein said heterocycle is selected from the group consisting of optionally substituted pyridinyl, optionally substituted thienyl and optionally substituted furyl; s is selected from the group consisting of alkyl and arylalkyl wherein the aryl portion of said arylalkyl is optionally substituted phenyl; and
R7 is hydrogen.
38. A compound according to claim 37selected from the group consisting of
N-( 1 - { [3 ,4-dioxo-2-(3 -pyridinylamino - 1 -cyclobuten- 1 -yl] amino } -2,2- dimethylpropyl)-2-pyridinecarboxamide;
N-( 1 - { [3 ,4-dioxo-2-(3 -pyridinylamino - 1 -cyclobuten- 1 -yl] amino } -2,2- dimethylpropyl)thiophene-2-carboxamide;
N-( 1 - { [3 ,4-dioxo-2-(3 -pyridinylamino - 1 -cyclobuten-1 -yl]amino} -2,2-dimethyl-3- phenylpropypisonicotinamide;
N-(l-{[3,4-dioxo-2-(3-pyridinylamino -l-cyclobuten-l-yl]amino}-2,2-dimethyl-3- phenylpropyl)nicotinamide;
N-(l-{[3,4-dioxo-2-(3-pyridinylamino - 1 -cyclobuten- 1 -yl] amino } -2,2- dimethylpropyl)nicotinamide;
N-(l-{[3,4-dioxo-2-(3-pyridinylamino - 1 -cyclobuten- 1 -yl] amino } -2,2- dimethylpropyl)isonicotinamide; and
N-( 1 - { [3 ,4-dioxo-2-(3 -pyridinylamino -1 -cyclobuten- 1-yl] amino} -2,2- dimethylpropyl)-2-furamide.
39. A compound according to claim 1 of formula (III)
(III), or a pharmaceutically acceptable salt therof.
40. A compound according to claim 39 wherein Ri is heterocycle; and R5 is aryl.
41. A compound according to claim 39 wherein
Ri is heterocycle wherein said heterocycle is optionally substituted pyridinyl; and R5 is aryl wherein said aryl is optionally substituted phenyl.
42. A compound according to claim 39 wherein
Ri is heterocycle wherein said heterocycle is optionally substituted pyridinyl;
R2 is hydrogen;
R3 is hydrogen;
Rt is hydrogen;
R5 is aryl wherein said aryl is optionally substituted phenyl;
Re is selected from the group consisting of alkenyl, alkenyloxy(alkenyloxy)alkyl, arylalkyl wherein the aryl portion of said arylalkyl is optionally substituted phenyl, cyanoalkyl, cycloalkylalkyl and haloalkyl; and
R7 is hydrogen.
43. A compound according to claim 39 wherein
Ri is heterocycle wherein said heterocycle is optionally substituted pyridinyl;
R2 is hydrogen;
R3 is hydrogen;
R is hydrogen;
R5 is aryl wherein said aryl is optionally substituted phenyl;
R6 is alkyl; and
R7 is hydrogen.
44. A compound according to claim 43 that is N -{l-[(4-chlorobenzoyl)amino]-2,2- dimethylpropyl}-N2-(3-pyridinyl)ethanediamide.
45. A compound according to claim 1 of formula (IV)
R2 R3 R4 R /N N N R5
O OR6 R7 0 (IV), or a pharmaceutically acceptable salt therof.
46. A compound according to claim 45 wherein Ri is heterocycle; and R5 is aryl.
47. A compound according to claim 45 wherein
Ri is heterocycle wherein said heterocycle is optionally substituted pyridinyl; and R5 is aryl wherein said aryl is optionally substituted phenyl.
48. A compound according to claim 45 wherein
Ri is heterocycle wherein said heterocycle is optionally substituted pyridinyl;
R2 is hydrogen;
R3 is hydrogen;
Rt is hydrogen;
R5 is aryl wherein said aryl is optionally substituted phenyl;
R6 is selected from the group consisting of alkenyl, alkenyloxy(alkenyloxy)alkyl, arylalkyl wherein the aryl portion of said arylalkyl is optionally substituted phenyl, cyanoalkyl, cycloalkylalkyl and haloalkyl; and
R7 is hydrogen.
49. A compound according to claim 45 wherein
Ri is heterocycle wherein said heterocycle is optionally substituted pyridinyl;
R2 is hydrogen;
R3 is hydrogen;
R4 is hydrogen;
R5 is aryl wherein said aryl is optionally substituted phenyl;
Re is alkyl; and
R7 is hydrogen.
50. A compound according to claim 49 selected from the group consisting of 4-chloro-N-(2,2-dimethyl- 1 - {[(3-pyridinylamino)sulfonyl]amino}propyl)benzamide; and
N-(2,2-dimefhyl- 1 - { [(3 -pyridinylamino)sulfonyl] amino } ρropyl)-4-iodobenzamide.
51. A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 1 in combination with a pharmaceutically acceptable carrier.
52. A method of treating a disorder in a host mammal in need of such treatment comprising administering to the mammal a therapeutically effective amount of a compound of formula (I).
53. The method of claim 52 wherein the disorder is selected from the group consisting of asthma, epilepsy, Raynaud's syndrome, intermittent claudication, migraine, pain, pollakiuria, bladder instability, nocturia, bladder hyperreflexia, enuresis, alopecia, cardioprotection, ischemia, eating disorders, functional bowel disorders, and neurodegeneration.
54. The method of claim 52 wherein the disorder is bladder overactivity.
55. The method of claim 52 wherein the disorder is benign prostatic hypeφlasia.
56. The method of claim 52 wherein the disorder is dysmenorrhea.
57. The method of claim 52 wherein the disorder is premature labor.
58. The method of claim 52 wherein the disorder is urinary incontinence.
59. The method of claim 52 wherein the disorder is selected from the group consisting of male erectile dysfunction and premature ejaculation.
60. The method of claim 52 wherein the disorder is female sexual dysfunction.
61. A process for the preparation of a compound of formula (V)
(V), wherein
Ri is selected from the group consisting of aryl, arylalkyl, heterocycle and heterocyclealkyl;
R2, R3 and R are independently selected from the group consisting of hydrogen and alkyl;
R5 is selected from the group consisting of aryl, arylalkyl, heterocycle and heterocyclealkyl;
R6 is selected from the group consisting of 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, amido, amidoalkyl, aryl, arylalkoxyalkyl, arylalkoxycarbonyl, arylalkoxycarbonylalkyl, arylalkyl, arylcarbonyl, arylcarbonylalkyl, arylcarbonyloxyalkyl, aryl(halo)alkyl, aryloxyalkyl, aryloxycarbonyl, aryloxycarbonylalkyl, arylalkylthioalkyl, arylsulfonylalkyl, carboxy, carboxyalkyl, carboxy(halo)alkyl, cyanoalkyl, cyano(halo)alkyl, cycloalkenyl, cycloalkenylalkyl, cycloalkyl, cycloalkylalkoxyalkyl, cycloalkylalkyl, cycloalkylcarbonyl, cycloalkyloxyalkyl, cycloalkylalkylthioalkyl, formyl, haloalkenyl, haloalkyl, haloalkylcarbonyl, haloalkynyl, heterocycle, heterocyclealkoxyalkyl, heterocyclealkyl, heterocyclecarbonyl, heterocycleoxyalkyl, heterocyclealkylthioalkyl, hydroxyalkyl, mercaptoalkyl, sulfamylalkyl, sulfamyl(halo)alkyl and (NR9Rι0)alkyl; and
R9 and Rι0 are independently selected from the group consisting of hydrogen, alkyl, alkylcarbonyl, aryl, arylalkyl, arylcarbonyl, formyl, and S(O)2Rι 1 wherein Ri 1 is selected from the group consisting of alkoxy, alkyl, aryl and arylalkyl; the process comprising:
(a) reacting an aldehyde of formula (VI)
(VI), an amide of formula (VII)
(VII), lH-benzotriazole-polystyrene resin and an acid in a first solvent at about 50 °C to about 80 °C, wherein R4, R and Re are as defined above;
(b) reacting the product of step (a), a base and a compound of formula (VIII)
(VIII) in a second solvent wherein Rl s R2 and R3 are as defined above to provide a compound of formula (V).
62. The process according to claim 61 wherein the acid is selected from the group consisting of para-toluenesulfonic acid monohydrate and acetic acid.
63. The process according to claim 61 wherein the first solvent is selected from the group consisting of 1 ,4-dioxane, 2-methoxyethanol, tetrahydrofuran, trimethyl orthoformate, and mixtures thereof.
64. The process according to claim 61 wherein the first solvent is selected from the group consisting of tetrahydrofuran: 2-methoxyethanol in about a (1 :1) ratio, tetrahydrofuramtrimefhyl orthoformate in about a (1 :1) ratio and l,4-dioxane:trimethyl orthoformate in about a (1 :0.3) to (1:3) ratio.
65. The process according to claim 61 wherein step (a) is conducted for a period of about 12 hours to about 48 hours.
66. The process according to claim 61 wherein the base is selected from the group consisting of cesium carbonate, potassium carbonate and sodium carbonate.
67. The process according to claim 61 wherein the second solvent is selected from the group consisting of dimethylacetamide, N,N-dimethylformamide, dimethyl sulfoxide and mixtures thereof.
68. The process according to claim 61 wherein step (b) is conducted at about 15 °C to about 50 °C.
69. The process according to claim 61 wherein step (b) is conducted for a period of about 24 hours to about 168 hours.
70. The process according to claim 61 wherein the acid is para-toluenesulfonic acid monohydrate; the first solvent is tetrahydrofuran:2-methoxyethanol in about a (1 :1) ratio; and step (a) is conducted for a period of about 12 hours to about 48 hours.
71. The process according to claim 70 wherein 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.
EP02704321A 2001-02-07 2002-01-31 Aminal diones as potassium channel openers Withdrawn EP1358160A1 (en)

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US10/046,465 US6495576B2 (en) 2001-02-07 2002-01-14 Aminal diones as potassium channel openers
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