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  • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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  • 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
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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
  • C07D213/81—Amides; Imides
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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
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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
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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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  • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
  • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
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  • 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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