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`(3S, 5S)-l-(4-Amino-quinazoiin-7-yimethyl)-4-[2-(5-chloro-thiophen-2-yl)-ethenesuIfonyI]-3, 5-
`dimethyl-piperazin-2-one,
`l-(4-Amino-quinazolin-7-ylmethyI)-4-[2-(5-chloro-thiophen-2-yl)-ethenesulfonyl]-piperazin-2-one,
`(+/-)-1 -(4- Amino-quinazolin-7-ylmethyl)-4-(6-chloro-benzo[b]thiophene-2-sulfonyl)-6-oxo-piperazine-
`2-carboxylic acid,
`l-(4-Amino-quinoIin-7-yimethyl)-4-(5-chIoro-lH-indoI-2-ylmethyI)-3-(S)-methyl-piperazin-2-one,
`4-(5-Chloro-lH-indol-2-ylmethyl)-3-(S)-methyl-l-(4-methylamino-quinolin-7-ylmethyl)-piperazin-2-
`one,
`4-(5-Chloro-1 H-indol-2-ylmethyl)-3-(S)-methoxymethyl-1 -(4-methy lamino-quinolin-7-ylmethyi)-
`piperazin-2-one,
`l-(4-Amino-quinolin-7-ylmethyl)-4-(6-chloro-benzo[b]thiophene-2-sulfonyl)-6-oxo-ptperazine-2-
`carboxylic acid dimethylamide,
`1-(4-Aniino-quinazolin-7-ylmethyl)-4-(6-chloro-benzo[b]thiophene-2-sulfonyl)-6-oxo-piperazine-2-(S)-
`carboxylic acid methyl ester,
`(+/-)-1 -(4-Amino-quinazoiin-7-ylmethyl)-4-(6-chloro-benzo[b]thiophene-2-suifonyl)-6-oxo-piperazine-
`2-carboxylic acid amide,
`l-(4-Amino-quinazolin-7-ylmethyl)-4-(lH-5 3-chloro-l-aza-inden-2-ylmethyl)-6-oxo-piperazine-2-
`carboxylic acid,
`(+/-)-1 -(4-Amino-quinazolin-7-ylmethyl)-4-(5-chloro-1 H-indol-2-ylmethyl)-6-oxo-piperazine-2-
`carboxylic acid methylamide,
`(+/-)- l-(4-Amino-quinazolin-7-ylmethyl)-4-(5-chloro-lH-indol-2-ylmethyl)-6-oxo-piperazine-2-
`carboxylic acid ethylamide,
`1-(4-Amino-quinazolin-7-ylmethyl)-4-(5-chloro-lH-indol-2-ylmethyl)-6-oxo-piperazine-2-carboxylic
`acid (2-hydroxy-ethyl>-amide,
`(+/-)-l-(4-Amino-quinazolin-7-ylmethyl)-4-[(5-chloro-thiophen-2-yloxy)-acetyl]-6-oxo-piperazine-2-
`carboxylic acid methyl ester,
`(+/-)-l-(4-Amino-quinazolin-7-ylmethyl)-4-[3-(5-chloro-thiophen-2-yl)-allyl]-6-oxo-piperazine-2-
`carboxylic acid methyl ester,
`(+/-)-l-(4-Amino-quinazolin-7-ylmethyI)-4-[3-(5-chloro-thiophen-2-yl)-allyl]-6-oxo-piperazine-2-
`carboxylic acid,
`4-(5'-Chloro-[2,2,]bithiophenyl-5-ylmethyl)-6-oxo-l-(lH-pyrrolo[3,2-c]pyridin-2-ylmethyl)-piperazine-
`2-carboxylic acid methyl ester,
`4-[2-(5-Chloro-thiophen-2-yl)-ethenesulfonyl]-5-hydroxymethyl-1 -(1 H-pyrrolo[3,2-c]pyridin-2-
`ylmethyl)-piperazin-2-one.
`
`5
`
`10
`
`15
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`20
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`25
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`30
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`MYLAN - EXHIBIT 1004 Part 5 of 10
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`l-[2-(5-Chloro-thiophen-2-yI)-ethenesulfonyl]-5-oxo-4-(lH-pyrrolo[3,2-c]pyridin-2-ylmethyl)-
`piperazine-2-carboxylic acid methyi ester,
`or a pharmaceutically acceptable salt thereof, pharmaceuticaliy acceptable prodrug thereof, an N-oxide
`thereof, a hydrate thereof or a solvate thereof.
`
`5
`
`Still yet more preferred compounds are selected from
`l-(4-Amino-quinazoiin-7-yImethyl)-4-[(5-chloro-thiophen-2-yioxy)-acetyl]-3-(S)-methoxymethyl-
`piperazin-2-one.
`l-(4-Amino-quinazolin-7-ylmethyl)-4-[(5-chloro-thiophen-2-yloxy)-acetyi]-3-(S)-methoxymethyl-6-
`10 methyl-piperazin-2-one,
`4-(6-Chloro-benzo[b]thiophene-2-sulfonyl)-l-(lH-pyrrolo[3,2-c]pyridin-2-ylmethyl)-piperazin-2-one,
`4-[2-(5-Chloro-thiophen-2-yl)-ethenesulfonyl]-l-(lH-pyrrolo[3,2-c]pyridin-2-ylmethyl)-piperazin-2-one,
`l-(4-Amino-quinazoHn-7-ylmethyl)-4-[3-(5-chloro-thiophen-2-yl)-acryloyl]-3-(S)-methoxymethyl-
`piperazin-2-one.
`l-(4-Amino-quinazolin-7-ylmethyl)-4-[3-(5-chloro-thiophen-2-yl)-allyl]-piperazin-2-one,
`4-[2-(5-Chloro-thiophen-2-yl)-ethenesulfonyl]-6-(R)-hydroxymethyl-1 -(1 H-pyrroio[3,2-c]pyridin-2-
`ylmethyl)-piperazin-2-one and
`4-[3-(6-Amino-pyridin-3-yl)-acryloyl]-l-(4-amino-quinazolin-7-ylmethyl)-3-(S)-propyl-piperazin-2-one,
`or
`a pharmaceutically acceptable salt thereof, pharmaceutically acceptable prodrug thereof, an N-oxide
`thereof, a hydrate thereof or a solvate thereof.
`
`20
`
`15
`
`Preferred intermediates according to this invention have formula II wherein Cy2 contains at least
`one nitrogen atom and when Cyj is optionally substituted aryl, optionally substituted cycloalkyl,
`optionally substituted cycloalkenyl, optionally substituted fused phenylcycloalkyl or optionally
`substituted fused phenylcycloalkenyl, then said nitrogen atom is a basic nitrogen atom.
`
`25
`
`Other preferred intermediates according to this invention have formula II wherein Z is absent.
`
`30
`
`Other preferred intermediates according to this invention have formula II wherein R,, Rla, R2,
`R2a, R4 and R^ are hydrogen.
`
`More preferred intermediates according to this invention are selected from
`(2S, 6RS)-4-(4-chloro-quinolin-7-ylmethyl)-2,6-dimethyl-3-oxo-piperazine-l-carboxylic acid benzyl
`ester.
`
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`(3S,5RS)-l-(4-chloro-quinolin-7-ylmethyl)-3,5-dimethyl-piperazin-2-one,
`(3S, 5R)-l-(4-chioro-quinolin-7-ylmethyl)-3,5-dimethyl-piperazin-2-one,
`(3S, 5S)-l-(4-chloro-quinolin-7-ylmethyl)-3,5-dimethyl-piperazin-2-one,
`(3S, 5R)-l-(4-chloro-quinolin-7-ylrnethyl)-3,5-dimethyl-piperazin-2-one,
`(2S, 6R)-4-(4-chloro-quinolin-7-ylmethyl)-2,6-dimethyl-3-oxo-piperazine-l-carboxylic acid benzyl
`ester.
`(3S, 5S)-l-(4-chloro-quinolin-7-ylmethly)-4-[3-(5-chloro-thiophen-2-yl)-allyl]-3,5-dimethyl-piperazine-
`2-one,
`(3S, 5R)-l-(4-chloro-quinolin-7-ylmethIy)-4-[3-(5-chloro-thiophen-2-yl)-aIlyI]-3,5-dimethyI-piperazine-
`2-one,
`4-(2-Oxopiperazin-1 -ylmethyl)benzamidine,
`1-(2-Aniinoquinolin-6-ylmethyl)piperazin-2-one,
`1 -(l-Aminoisoquinolin-6-ylmethyl)piperazin-2-one,
`2-(2-Oxopiperazin-l-ylmethyl)pyrro]o[3,2-c]pyridin-l-carboxylic acid tert-butyl ester,
`2-(5-(±)-Methoxycarbony]-2-oxo-piperazin-l-y]methyl)-pyrrolo[3,2- c]pyridine-l-carboxyiic acid tert-
`butyl ester,
`2-(2-(±)-Methoxycarbonyl-6-oxo-piperazin-l-ylmethyl)-pyrrolo[3,2-c]pyridine-l-carboxylic acid tert-
`butyl ester,
`l-(4-Aminoquinazoline-7-ylmethyl)piperazine-2-one,
`l-(4-Amino-thieno[2,3-d]pyrimidin-6-ylmethyl)-piperazin-2-one,
`4-[3-(2-Oxo-piperazin-l-yl)-propyl]-piperidine-l-carboxylic acid tert-butyl ester,
`l-(4-Amino-quinazoline-7-ylmethyl)-3-methoxymethyl-piperazine-2-one,
`l-(4-Aminoquinazoiine-7-ylmethyl)-3-butyl-piperazine-2-one,
`l-(4-Aminoquinazoline-7-ylmethyl)-3-ethyl-piperazine-2-one,
`l-(4-Aminoquinazoline-7-ylmethyl)-3-propyl-piperazine-2-one,
`l-(4-Amino-quinazoline-7-ylmethyl)-3-ethoxymethyl-piperazine-2-one,
`l-(4-Amino-quinazoline-7-ylmethyl)-3-methyl-piperazine-2-one,
`l-(4-Amino-quinazoline-7-ylmethyl)-3-benzyl-piperazine-2-one,
`l-(4-Amino-quinazoline-7-ylmethyl)-3-(l-methoxyethyl)-piperazine-2-one,
`l-(4-Amino-quinazoline-7-ylmethyl)-3,3-dimethyl-piperazine-2-one,
`l-(4-Amino-quinazoline-7-ylmethyl)-3-isopropyl-piperazine-2-one,
`l-(4-Amino-quinazoline-7-ylmethyl)-3-isobutyl-piperazine-2-one,
`l-(4-Amino-quinazoline-7-ylmethyl)-3-(2-niethoxyethyl) l-piperazine-2-one,
`1 -(4-Am ino-quinazo line- 7-y lmethyI)-3-niethoxyinethy 1-6-methy l-piperazine-2-one,
`(3S,5RS)-l-(4-amino-quinazolin-7-ylmethyl)-3,5-dimethyl-piperazin-2-one,
`
`5
`
`10
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`15
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`20
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`
`l-(4-Chloroquinolin-7-ylmethyl)-piperaz!n-2-orie,
`l-(4-Chlorocinnolin-7-ylmethyl)-piperazin-2-one,
`l-(4-Chloroquinolin-7-ylmethyl)-3-(S)-methylpiperazin-2-one,
`l-[2-(Pyridin-4-ylainino)-ethyl]-piperazin-2-one,
`l-[2-{(Methyl)-(pyridin-4-yl)-amino}-ethyl]-piperazin-2-one trifluroacetate,
`l-[2-(3-Methylpyndin-4-yl-amino)-ethyl]-piperazin-2-one,
`l-[2-(Pyridazin-4-ylaniino)-ethyI]-piperazin-2-one,
`4-[3-(4-tert-Butoxycarbonylamino-pyridin-3-yl)-propenyl]-3-oxo-piperazine-l-carboxylic acid tert-butyl
`ester,
`4-[3-(4-tert-butoxycarbonylaminopyridin-3-yl)-allyl]-3-oxo-piperazine-1 -carboxylic acid tert-butyl ester
`4-[3-(4-tert-Butoxycarbonylamino-pyridin-3-yl)-propyl]-3-oxo-piperazine-1 -carboxylic acid tert-butyl
`ester.
`4-(Benzyloxycarbony])-l-(2-pyrrolo[3,2-c]pyridin-l-ylethyl)-piperazin-2-one,
`(±)-l-(3-Amino-4-cyano-benzyl)-4-(6-chIoro-benzo[b]thiophene-2-sulfonyl)-6-oxo-piperazine-2-
`carboxylic acid methyl ester and
`(±)-l-(3-Amino-4-cyano-benzyl)-4-(6-chloro-benzo[b]thiophene-2-sulfonyl)-6-oxo-piperazine-2-
`carboxylic acid.
`
`Preparation of the Compounds of the Invention
`A general route to the compounds of this invention wherein A is N and R,, Rla, R,, R
`2a?
`R4, R4a, L,, L2, Cy,, Cy2, m and n are defined herein is outlined in Scheme 1.
`
`R3, RSBJ
`
`Scheme 1
`
`H
`I
`
`R1
`
`R4
`
`Li
`1
`
`CVi
`R4
`
`R1
`
`R a
`
`I
`
`R3a
`
`R2-T^NA ~R3
`Lk
`11
`
`c y 2
`
`R2-7^n^V R3
`LU
`
`R,a
`
`I
`
`R 3 a
`
`c y 2
`
`5
`
`10
`
`15
`
`20
`
`25
`
`As shown in Scheme 1, coupling of a compound of formula II with a sulfonyl chloride, an alkyl
`halide, an acid or an activated derivative thereof such as an anhydride or acid chloride, an isocyanate,
`chloroformate or activated sulfamyl ester in an appropriate solvent generates the compound of formula I
`
`1935
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`in which the L,-Cy, portion is a sulfonamide, aikyl amine, amide, urea, carbamate or sulfamyl urea
`respectively. Sulfonamide formation is accomplished with a base such as a trialkylamine in an inert
`solvent such as dichloromethane, THF or acetonitrile at about 0 0C to about 100 0C in the presence or
`absence of an activating agent such as dimethylaminopyridine (DMAP). Alkyl amine formation can be
`achieved with a suitable base such as K2CO3 or trialkylamine in an appropriate solvent such as DMF or
`acetonitrile at about 0 0C to about 100 0C. Amide, urea, carbamate and sulfamyl urea formation can be
`conducted with acids and coupling reagents such as EDC or TBTU or with any variant of reactive acid
`derivatives and the use of an appropriate base additive such as triethylamine, N-methylmorpholine or
`diisopropylethylamine.
`
`The preparation of the compound of formula II wherein R,, R!a, R2, R^a, Rj, Rja* R4,
`m and n are defined herein is outlined in Scheme 2.
`
`L,, Cy2,
`
`Scheme 2
`
`R1
`R1a
`
`R2
`R?a
`
`P
`I
`N
`
`R4
`R„a
`
`R3
`R3a
`
`N
`I
`Li
`2 \
`c y 2
`
`1
`
`H
`1
`
`R1
`
`R4
`
`R2~7\N-^rR3
`R,a
`I
`R3 a
`L"
`2 ^
`c y 2
`
`11
`
`As shown in Scheme 2, the compound of formula II is prepared by removing a nitrogen
`protecting group P from the compound of formula 1. In a preferred aspect, P is an alkyl, aralkyl or aryl
`carbamate moiety which is removed using strong acid, strong base or catalytic hydrogenation in an
`appropriate solvent such as methanol or ethanol.
`
`The preparation of the compound of formula 1 wherein R,, RIa, R2, Rja* RJ* Rja» R*. Rtw Li> L2,
`Cy,, Cyj, m and n and P are defined herein is outlined in Scheme 3.
`
`5
`
`10
`
`15
`
`20
`
`25
`
`Scheme 3
`
`1936
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`

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`
`P
`R4
`R l
`R1a-4«-N^isrR1a
`R2-^^n'^VR3
`
`R3a
`
`R7a
`2
`
`I
`H
`2
`
`67
`
`R1
`
`P
`
`R4
`
`R 2 W ^N" V ^ R 3
`R2a
`R3a
`cy 2
`L 2 \
`
`1
`
`As shown in Scheme 3, the compound of formula 1 is obtained by coupling a compound of
`formula 2 with an appropriate Cy2-L2-LG group wherein LG is a leaving group such as chloro, bromo,
`iodo, or optionally substituted lower alkylsulfonyloxy or arylsulfonyioxy in an inert organic solvent such
`as THF, Et20 or DMF in the presence of a strong base such as NaH, lithium hexamethyldisilylazide or
`lithium diisopropylamine. In a preferred aspect, P is an aikyl, aralkyl or aryl carbamate group.
`
`The preparation of intermediate compounds of formula 7 and 10 are outlined in Scheme 4.
`
`5
`
`10
`
`Scheme 4
`
`Ar
`
`3
`
`CHO
`
`Ar
`
`4
`
`CO2R
`
`Ar = monocyclic aryl or heteroaryl
`
`Br
`
`Ar
`
`|
`
`NH
`
`5
`
`a>
`R4
`boc
`
`R2
`R l R^a
`
`ci
`
`6
`
`c i
`
`7
`
`Ar
`
`j
`
`CI
`
`Ar
`
`|
`
`8
`
`Br
`
`CI
`
`Ar
`
`|
`
`9
`
`R4a,
`
`R4
`boc
`
`R2
`Rl Rja
`
`10
`
`15
`
`As shown in Scheme 4, reacting a compound of formula 3 with an appropriate malonic acid in a
`polar solvent such as pyridine or ethanol and a base such as piperidine or pyridine at reflux provides a
`compound of formula 4 wherein R is H. Alternatively, a compound of formula 3 may be reacted with a
`suitable Wittig or Homer-Emmons reagent in an inert solvent such as THF to give a compound of
`formula 4 wherein R is lower alkyl. When R is lower alkyl, the ester is hydrolyzed to the corresponding
`carboxylic acid (R is H) by an appropriate strong acid or alkali base. The corresponding acid is
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`converted to the acid chloride using standard methods such as thionyl chloride or is converted to the
`mixed anhydride in a polar solvent such as acetone or THF to form an activated acyl compound. The
`activated acyl compound is then treated with a solution of NaNj in water at about -10 0C to about 25 0C
`to yield the corresponding acyl azide. The acyl azide compound is then heated slowly in an inert solvent
`such as benzene or toluene at about 60 0C to about 110 0C then concentrated in vacuo and heated in a
`higher boiling inert solvent such as 1,2-dichlorobenzene or phenyl ether at about 180 0C to about 240 0C
`with a catalyst such as iodine or tributylamine to obtain a compound of formula 5. Alternatively the acyl
`azide compound can be added directly to a high boiling inert solvent such as phenyl ether at about 190
`0C to about 240 0C with a catalyst such as iodine or tributylamine to obtain the compound of formula 5.
`A compound of formula 8, prepared as described in Syn., 739 (1975), which is incorporated
`herein by reference, or formula 5 above may be chlorinated using standard methods such as POClj or
`POClj/PClj and halogenated using standard conditions such as N-halosuccinimide and benzoyl peroxide
`in an inert solvent such as carbon tetrachloride to give the corresponding chloro-halomethyl compounds
`6 and 9, respectively.
`
`The preparation of aminoquinazoline, quinazolinone or amino-thienopyrimidine intermediates is
`outlined in Scheme 5.
`
`Scheme 5
`
`NH2
`
`Ar
`
`Ar = monocyclic aryl or heteroaryl
`
`R4
`R4a
`
`P'
`
`R2
`Rja
`R1 R^
`
`14
`
`R4
`R4a
`
`R2
`R/ R^3 16
`
`ci
`
`NH2
`
`Br
`
`ci
`
`Ti
`
`N
`
`OH
`
`R4
`R4a
`
`R2
`R1 R^2®
`
`Ar
`
`15
`
`5
`
`10
`
`15
`
`20
`
`As shown in Scheme 5, an aminoheteroaryl carboxylic acid or an aminoarylcarboxylic acid 11 in
`which the amino and carboxylic acid are adjacent is treated with formamidine under heat to form the
`corresponding quinazolinone or thienopyrimidinone 12. The quinazolinone or thienopyrimidinone 12 is
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`then converted to the chloroquinazoline or chlorothienopyrimidine using a chlorinating reagent such as
`P(0)Cl3 and heat. The chloroquinazoline or chlorothienopyrimidine is brominated at the benzylic carbon
`using radical bromination conditions. Alternatively, a chloroquinazoline or chlorothienopyrimidine,
`containing a hydroxy-methylene group is converted to the corresponding bromide using CB^/PPhj; or
`PBrj conditions. The bromide 13 is then reacted with the anion of the ring nitrogen of compounds of
`formula 2, formed using NaH, LiNCSiMej^, NaN(SiMe3)3, LDA, lithium alkoxides, sodium alkoxides or
`an appropriate base, in an inert solvent such as THF, DMF, ether, or DME. This yields compounds of
`formula 14 in which Cy2 is a chloro-quinazoline or a chloro-thienopyrimidine. The chloro group is
`converted to an amino group using NHj in ethanol in the presence of a catalytic acid source.
`Alternatively, the chloro group is converted to a substituted amino using a primary or secondary amine in
`a solvent. Alternatively, the chloro group is converted to a hydroxy group using acetic acid in water with
`heating or using a hydroxide source. Alternatively, the chloro is converted to an alkoxy group using an
`alcoholic solvent with heated in the presence of a base.
`
`5
`
`10
`
`15
`
`An alternative synthesis of quinazolines and thienoquinazolines is outlined in Scheme 6.
`
`Scheme 6.
`
`Ar
`
`Ph
`N=<
`Ph
`
`C N 18
`
`Br
`
`R4
`R4a
`
`R2
`R1 R^2®
`
`NH2
`
`CN
`
`NH2
`
`Ph
`N=<
`Ph
`CN 19
`
`O
`
`N
`
`Ar
`
`Ar
`
`21
`
`NH2
`Ar
`TT™
`Ar = monocyclic aryl or heteroaryl
`o
`
`R4
`R4a
`
`Ar
`
`R2
`R1 R^3 20
`
`R4
`R4a
`
`R1 R.a
`
`20
`
`25
`
`As shown in Scheme 6, an amino-aryl nitrile or an amino heteroaryl nitrile 17 is treated with an
`aldehyde or ketone under imine forming conditions. The corresponding aryl or heteroaryl imine is
`brominated using radical bomination with NBS. The bromide is then reacted with the anion of the ring
`nitrogen of compounds of formula 2, formed using NaH, LiN(SiMe3)3, NaN(SiMe3)3, LDA, lithium
`alkoxides, sodium alkoxides or an appropriate base, in an inert solvent such as THF, DMF, ether, or
`DME. This yields compounds of formula 20 in which Cy2 is an imino-aryl nitrile or an imino heteroaryl
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`nitrile. The imine is deprotected using an acid such as HCI to give the corresponding aniline. The
`aniline-aryl-nitrile or the aniline-heteroaryl nitrile is converted to the amino-quinazoline or
`thienopyrimidine using triazine or formamidine. The quinazolinone or thienopyrimidinone 21 is formed
`using formamide.
`
`The preparation of cinnoline (X = N) and quinoline (X = CH) intermediates is outlined in
`Scheme 7.
`
`Scheme 7
`
`F3C.
`
`H
`X
`
`23 CI
`
`Br'
`
`Me02C
`
`N
`
`HO'
`
`N^.
`
`24 ci
`
`O
`
`boc
`
`26
`
`CI
`
`25 ci
`
`^X
`
`HN.
`
`27
`
`ci
`
`28
`
`CI
`
`As shown in Scheme 7, halogenated azaarenes exemplified by 4-chloro-7-
`trifluoromethylquinoline or cinnoline are treated with H2SO4 (70 -95 %) at 180-220 0C for about 16 to 48
`hours in a sealed reaction vessel. The solution is cooled, poured into water and neutralized with base to
`pH ~ 3-4. The product is dissolved in aqueous base and precipitated by acidification to yield 7-carboxy-
`4-chloroquinoline or cinnoline. This material is converted to the alkyl ester (such as methyl or ethyl) by
`standard methods. 7-Alkyloxycarbonyl-4-chloroquinoline or cinnoline is dissolved in an anhydrous,
`aprotic solvent (THF or ether). The solution is cooled (-60 to -95 0C) and treated with a reducing agent
`such as lithium aluminum hydride. The solution is warmed (approximately -40 to -50 0C) for about 15 to
`30 minutes and quenched with a solvent such as ethyl acetate. Standard workup gives the product 7-
`hydroxymethyl-4-chloroquinoline or cinnoline. This material is treated with 45-50 % HBr and heated to
`about 100-140 0C for about 45 to 90 minutes. After cooling and standard workup 7-bromomethyl-4-
`chloroquinoline or cinnoline is obtained.
`
`5
`
`10
`
`15
`
`20
`
`25
`
`The preparation of pyrrolopyridine derivatives is outlined in Scheme 8.
`
`Scheme 8
`
`1940
`
`

`

`WO 99/37304
`
`PCT/US99/01682
`
`71
`
`H,N
`
`29
`
`H,N
`
`30
`
`BocNH
`
`31
`
`CbzN.
`
`32
`
`NH
`
`CbzN.
`33
`
`N-/ \
`
`CbzN.
`
`HN.
`
`boc
`34
`
`•N—/ XN
`boc
`35
`
`As shown in Scheme 8 pyrrolopyridine derivatives are prepared by alkylation of a suitably
`protected oxopiperazine with propargyl bromide in the presence of a base such as sodium hydride. The
`resulting alkyne is heated (100-120 0C) with a halopyridine optionally substituted with hydroxy,
`alkoxycarbonylamino, or sulfhydryl, a catalyst such as Pd^Pl^CU, copper iodide and triethylamine in a
`suitable solvent such as acetonitrile in a sealed vessel or in DMF for 2-20 hours. When the pyridine is
`substituted with a hydroxy! moiety furopyridines are isolated directly. If the pyridine is substituted with
`an alkoxycarbonylamino moiety, additional treatment with DBU at about 60 0C in DMF yields
`pyrrolopyridines. Subsequent carbamate deprotection using transfer hydrogenation conditions such as Pd
`black in formic acid yields the desired oxopiperazine furopyridines or pyrrolopyridine-1-carboxylic acid
`alkyl ester derivatives. After further reaction with the LpCyj group, an additional deprotection step such
`as Boc removal using, for example, TFA, HC1 is required for generating the oxopiperazine
`pyrrolopyridines.
`
`5
`
`10
`
`15
`
`The preparation of the compound of formula 40 are shown in Scheme 9.
`
`Scheme 9
`
`1941
`
`

`

`WO 99/37304
`
`PCT/US99/01682
`
`O
`
`H2N
`
`NHP
`
`H
`
`O
`
`R4a R4
`36
`
`R4
`F^a
`
`N
`
`P
`
`72
`
`R2
`
`OP
`
`37 op NHP
`
`O
`
`R2
`
`9
`
`38
`
`OP
`
`OP
`
`R4
`F^a
`
`N
`
`P
`
`o
`
`NH
`
`R2
`
`39
`
`R4a R4
`
`o
`
`NH
`
`R2
`
`40
`
`5
`
`10
`
`15
`
`As shown in Scheme 9, compounds of formula 40 are prepared from an appropriateiy protected
`mono- or di- substituted amino-acid. To this is added an amino-acetaidehyde, protected as an acetal
`derivative, under standard peptide coupling procedures, employing activating reagents such as EDC,
`TBTU, or BOP. The resulting dipeptidyl moiety is subjected to conditions which remove the acetal, such
`as acidic conditions (TsOH). The resulting cyclic material is reduced using hydrogenating conditions to
`yield compounds of formula 40. This reduction, alternatively can be carried out using a reagent which
`acts as a hydride source.
`
`The preparation of compounds of formula 46a and b is shown scheme 10.
`
`Scheme 10.
`
`R4 O
`
`i
`
`O.
`
`H-0
`
`I
`H
`
`41
`
`o.
`
`H
`
`R4 O A>-
`
`R1
`
`45
`
`O.
`
`N
`
`H
`
`R1
`
`I
`H
`
`O
`
`42
`
`H
`
`O.
`
`H
`
`R4
`
`R4
`
`O.
`
`H
`
`R1
`
`I
`H
`
`O
`
`43
`
`O
`
`H
`
`R4
`
`H
`
`N
`
`R1
`
`44
`
`R4 O A,
`
`R1
`
`46a
`
`+
`
`o.
`
`N
`
`H
`
`R4 O -A
`
`R1
`
`46b
`
`As shown in Scheme 10, a protected amino acid is coupled to a beta-aminoalcohol using
`standard peptide coupling procedures as describe above. The alcohol is then oxidized to a ketone using,
`for example, Swem oxidation conditions. The protecting group is removed and the resulting compound
`
`1942
`
`

`

`WO 99/37304
`
`PCT7US99/01682
`
`73
`is reduced under hydrogenation conditions to give the 2-piperidinone. The free amine can be reprotected
`and diastereomers are separated by chromatographic methods, or in some cases by recrystallization.
`
`A chirai synthesis of compounds of formula 46 is shown in Scheme 11.
`
`5
`
`Scheme 11
`R4
`
`O.
`
`H-0
`
`H
`
`N
`I
`H
`47
`
`O
`
`o
`49
`
`H
`
`o
`
`O
`
`R4 O
`
`O.
`
`H"0
`
`F
`
`N
`
`A FF
`
`48
`
`O
`
`I
`
`O
`
`H
`I
`
`N1 A.
`
`Rr
`
`50
`
`R4 O
`
`F
`
`N
`
`F F
`R1
`
`I
`
`O
`
`O.
`
`N
`
`52
`
`o
`
`o.
`
`N
`
`R4 O
`
`R1
`
`54
`
`O
`
`I
`
`R4 O
`
`F
`
`O.
`
`O
`
`I
`
`O
`
`F t 1 R1
`
`N
`
`O
`
`51
`
`R1
`
`R4
`
`O
`
`O
`
`53
`
`R4 O
`
`0':^^N
`N
`
`H
`
`O
`
`R1
`
`46
`
`As shown in Scheme 11, an amino acid is protected as its trifluoroacetate derivative using
`trifluoroacetic anhydride and a base. An amino-alcohol is derivatized via reductive amination conditions
`using a benzaldehyde derivative, such as 2,4-dimethoxybenzaldehyde. The resulting secondary amine is
`then coupled to an amino-acid protected as a trifluoroacetate using standard peptide coupling procedures.
`Ring closure is then accomplished by utilizing Mitsinobu conditions. The trifluoroacetate group is
`removed under basic conditions, and the amide of the ring is deproteced using an aqueous solution of
`potassium persulfate and sodium phosphate and heat. All possible enantiomers of piperazin-2-one can
`be made from the corresponding amino-alcohol and amino acid as shown in scheme 2c.
`
`10
`
`15
`
`R4 and R4a are hydrogen and
`The preparation of the compound of formula 58 wherein R,, R2, R
`2a 9
`Rla is carbomethoxy, methoxymethyl, or a protected hydroxymethyl group is shown in Scheme 12.
`
`1943
`
`

`

`WO 99/37304
`
`Scheme 12
`
`Rla .NHCBZ
`R i
`NH2HCI
`R2'
`R2a
`
`55
`
`PCT/US99/01682
`
`74
`
`Rla .NHCBZ
`R l
`R2-
`
`NH
`R2a
`
`56
`
`CBZ
`Rla . N H
`O
`Rf
`
`Br
`R4a
`
`R4
`
`57
`
`CBZ
`R l a / N .
`Rl
`R4
`m N o
`R2
`
`58
`
`5
`
`As shown in Scheme 12, alkylating a compound of formula 55 with propargyl bromide in the
`presence of an amine base such as triethylamine provides the compound of formula 56. Coupling with
`bromoacetic acid using a standard reagent such as DCC gives the compound of formula 57 which can be
`cyclized using a non-nucleophilic strong base such as NaH in a solvent such as THF to yield the desired
`compound of formula 58.
`
`10
`
`The preparation of a compound of formula 59 is outlined in Scheme 13.
`
`Scheme 13
`
`H
`N
`
`Me02C
`
`N "O
`H
`
`MeQzC
`
`P
`N
`
`N "O
`H
`59
`
`15
`
`20
`
`As shown in Scheme 13, protection of methyl 6-oxopiperazine-2-carboxylate (Aebischer, B.,
`Helv. Chim. Acta 1989, 72, 1043-1051) using, for example, benzyl chloroformate or allyl chloroformate
`under standard conditions provides compound 59. Alkylation of 59 with propargyl bromide using a
`strong base such as NaH in polar solvents as THF or DMF provides the compound of formula 58.
`
`The preparation of a compound of formula 61 wherein R,, R2, R4, R,,,, L, and Cy, are defined
`as above and Rla or R2a are independently carboxy, acetamido or hydroxymethyl is outlined in Scheme
`14.
`
`Scheme 14
`
`1944
`
`

`

`WO 99/37304
`
`PCT/US99/01682
`
`N
`
`MeC^C
`
`R2a
`
`RJ /Ll^
`—N R4 Cy,
`R4;
`
`R2 N
`
`N
`BOC
`
`o
`
`60
`
`75
`
`N
`I
`
`N
`H
`
`Rla Ri /Li
`Cyi
`R2a
`^
`R4a
`
`R2 N
`
`o
`
`61
`
`As shown in Scheme 14, the compound of formula 61 is prepared by hydrolysis of the ester
`using a base such as NaOH or LiOH to yield the acid, coupling the corresponding acid with a primary or
`secondary amine or ammonia using standard coupling reagents such as TBTU or EDC and reduction of
`the ester using a reducing agent such as NaBH4 to yield hydroxymethyl.
`
`The preparation of diketopiperazine compounds formula 66 in which R, and Ria together and Rj
`and Rja together are oxygen are prepared as outlined in Scheme 15.
`
`5
`
`10
`
`Scheme 15
`
`CY2
`
`H
`
`T
`
`O
`62
`
`R1
`
`O
`
`N
`CY^
`
`P
`
`N
`H
`R4
`
`HO
`
`O
`65
`
`NHP
`
`O
`
`OH
`R4 64
`
`H
`I
`N
`CY^
`V-0
`63
`
`R1
`
`O
`
`R1
`
`O
`
`N
`CY^
`
`NH
`
`O
`
`R4
`66
`As shown in Scheme 15, an aldehyde containing the Cy2 group is condensed with an amino acid
`ester under reductive amination conditions. The resulting secondary amine is then coupled to an N-
`protected amino acid. The resulting dipeptide is deprotected which in general results in cyclization to the
`Cyj diketopiperazine. Alternatively for cases which do not cyclize, diketopiperazine formation can be
`achieved using a peptide coupling reagent such as EDC, TBTU, or BOP.
`
`15
`
`The preparation of sulfonyl chloride intermediates is outlined in Scheme 16.
`
`1945
`
`

`

`WO 99/37304
`
`PCT/US99/01682
`
`Scheme 17
`
`C y ' - H
`67
`
`CVi
`
`r0
`
`H
`70
`
`76
`
`cy^
`SOjLi
`68
`
`S02Me
`
`71
`
`cy^
`so2ci
`69
`
`so2ci
`
`72
`
`As shown in Scheme 16, Cy, substituted sulfonyl chlorides are prepared by treatment of the
`appropriate aryl and heteroaryl compounds with a strong base such as n-BuLi at -78 C followed by the
`addition of SCX gas and treatment of the lithium heteroaryl sulfonate with a chlorinating agent such as
`NCS or S02CI2 or, alternately, by homologation of the appropriate aryl and heteroaryl aldehydes using,
`for example, ethylmethanesulfonate and ethylchlorophosphonate.
`
`The preparation of intermediate compounds of formula Cy^CCXH is outlined in Scheme 17.
`
`Scheme 17
`
`Cy^
`H
`
`73
`
`cy:
`
`Y0
`
`H
`
`76
`
`Cy
`
`.0
`
`74 H
`
`CVi
`
`.o
`
`OR
`
`77
`
`Cy
`
`Y0
`
`OH
`
`75
`
`cy!
`
`.0
`
`78 0H
`
`As shown in Scheme 17, the requisite Cy, acids as defined above can be obtained by oxidation of
`the corresponding alcohols or the aldehydes using, for example, Mn02, PDC or AgNOj in an appropriate
`solvent such as CHjCU or H20/EtOH. The Cy! substituted aiyl and heteroaryl groups can be
`functionaiized by deprotonation methods using an appropriate non-nucleophilic base such as n-BuLi in
`an appropriate solvent such as Et20 or THF and quenching with an appropriate carbonyl electrophile
`such as DMF, C02 or alkyl chloroformate. Alternatively, the acids can also be generated by hydrolysis
`of the corresponding esters using, for example, NaOH or LiOH. For example, in the acrylic esters, the
`Cyr(alkenylene)- groups as defined above are generated by homologation of the Cy! aldehydes using the
`usual Wittig type or Homer-Emmons type reagents in an appropriate solvent such as CH2C12 or THF.
`
`5
`
`10
`
`15
`
`20
`
`1946
`
`

`

`WO 99/37304
`
`PCT/US99/01682
`
`The preparation of Cy, alkyl and alkenyl halides is outlined in Scheme 18.
`
`77
`
`Scheme 18 r cy
`
`H 79
`
`Cy
`
`,0
`
`82
`
`OR
`
`Cy
`
`OH
`80
`
`Cy
`
`Br
`
`81
`
`83
`
`84
`
`As shown in Scheme 18, Cy! alkyl and alkenyl halides as defined above can be prepared by
`halogenation of the corresponding alcohols using either NBS, CBr4 or PBrj under standard solvent
`conditions. The alcohols are generated by reduction of the corresponding aldehydes or esters using
`NaBH4 or DIBAL in an appropriate solvent.
`
`10
`
`The preparation of Cy, isocyanate intermediates is outlined in Scheme 19.
`
`Scheme 19
`
`CyiXNH2
`85
`or
`
`Cy 'X NHR
`
`
`
`87
`
`Cy
`CO2H
`1X
`89
`
`Cy
`NCO
`'X
`86
`
`c y i
`
`R
`I
`
`88 O
`
`CI
`
`Cy
`CON3
`1X
`90
`
`NCO
`Cy
`X
`91
`
`As shown in Scheme 19, Cy! isocyanates are obtained by chlorocarbonylation methods using
`phosgene or triphosgene in an appropriate solvent such as CHXlz with an appropriate base additive such
`as triethylamine or pyridine on the corresponding primary or secondary amines. Alternatively, the
`isocyanates can also be generated by Curtius rearrangement in an appropriate solvent such as toluene, p-
`dioxane or DMF of the corresponding Cy, carbonyl azides. The carbonyl azides, in turn, are derived
`
`15
`
`20
`
`1947
`
`

`

`WO 99/37304
`
`PCT/US99/01682
`
`78
`from the corresponding carboxylic acids using either DPPA reagent or by proceeding through the mixed
`anhydride via an alkyl chloroformate reagent in an appropriate solvent such as DMF or acetone and
`using an appropriate base additive such as treithylamine.
`
`5
`
`The preparation of Cy, chloroformate intermediates is outlined in Scheme 20.
`
`Scheme 20
`
`Cy
`OH
`1X
`92
`
`Cy
`NH,
`1X
`94
`
`ci
`CYi vnV
`
`93 O
`
`H
`
`CYivrN-s-
`
`OR
`
`//W
`n
`95° 0
`
`10
`
`As shown in Scheme 20, Cy, chloroformates are obtained by chlorocarbonylation methods using
`reagents such as phosgene, triphosgene or l,l'-carbonyldiimidazole in an appropriate solvent such as
`CH2C12 on the corresponding alcohols. Activated sulfatnyl esters are prepared from the corresponding
`amines using catechol sulfate in an appropriate solvent.
`
`15
`
`The preparation of acetamido compounds of this invention is outlined in Scheme 21.
`
`Scheme 21
`
`1948
`
`

`

`WO 99/37304
`
`PCT /U S99/01682
`
`R1
`R1 a
`
`R2
`
`CBZ
`I
`N
`
`R4
`R^a
`
`N
`
`O
`
`96
`
`/ G Y i
`Li-
`R4
`•A.
`
`R1
`R-, a
`
`N
`
`R2
`R2a
`Rib
`R9b
`~
`
`R3
`R3a
`O
`
`II
`O
`
`99
`
`79
`
`CBZ
`
`R1
`I
`Rja-^V/^1
`
`R4
`R4a
`
`o
`O
`
`N
`
`R2
`/
`R^a
`R, b
`"R,b
`97°
`
`C Y I
`
`W
`R4
`R1
`R:aA^AH4rnR4a
`R3
`R2
`/ ^ N
`R3a
`R^a
`OH
`Rib
`11
`R ^ b
`O
`"
`100
`
`H
`I
`•N
`
`R1
`Rj^a
`
`R4
`R4a
`
`O
`0
`
`N
`
`R2
`R2a
`R b
`R,b
`98
`
`0
`
`/ C Y i
`Li-
`R4
`•A.
`t=-R.a
`7n
`4
`
`R1
`R, a
`
`N
`
`R2
`R2a
`R1b
`R,b
`"
`
`R3
`R^a
`NCy,
`
`II
`O
`101
`
`5
`
`As shown in Scheme 21, alkylation of piperazin-2-one 96 is achieved with a strong base such as
`NaH and a t-butyl ester of haloacetic acid to give the acetate 97. Pd-catalyzed hydrogenation effectes
`removal of the CBZ group from the acetate 97 to give amine 98 which is converted to the compound 99
`as described in Scheme 1 above. Hydrolysis of t-butyl ester 99 is accomplished using, for example,
`TFA/CHjCU. The resulting acid 100 is coupled with the optionally protected amine HNCy, under typical
`amide bond formation conditions to give the acetamide 101.
`
`10
`
`The preparation of compounds of this invention wherein Cy, is benzimidazot-2-yl is outlined in
`Scheme 22.
`
`Scheme 22
`
`1949
`
`

`

`WO 99/37304
`
`PCT/US99/01682
`
`o.
`
`H
`
`102
`
`o
`
`O
`
`O.
`
`80
`
`o
`
`Cyj
`
`N
`
`O
`
`103
`
`I
`
`H
`
`O
`105
`
`O.
`
`Cy2
`
`N
`
`o.
`
`Cy2-
`
`N
`
`L2
`
`OH
`
`O
`
`104
`
`O.
`
`Cy2-
`
`N
`
`I
`r0it
`
`N—
`
`H
`
`106
`
`CI
`
`O,
`
`Cy 2-
`
`N
`
`I-2
`
`S—
`
`CI
`
`107
`
`O.
`
`cy2
`
`N
`
`N
`
`N—// \
`CI
`108
`
`5
`
`10
`
`15
`
`20
`
`Piperidin-2-one 102 is alkylated as described above to give the ester 103 which is hydrolyzed to
`give the acid 104 or reduced to give aldehyde 105. Coupling of the acid 104 and amines affords amide
`106 which is cyciized with acetic anhydride to give the compound 108. Wittig-coupling of aldehyde 105
`produces compound 107.
`
`This invention is further exemplified but not limited by the following examples which further
`illustrate the preparation of the compounds of this invention. The starting materials and intermediates
`are prepared by the application or adaptation of known methods, for example methods described herein
`or their obvious equivalents.
`
`EXAMPLE 1. 6-Chlorobenzorb1thiophene-2-sulfonvl chloride.
`
`A. 1 -Chloro-3-f2.2-dimethoxvethvlsulfanvDbenzene.
`To a solution of 3-chlorothiophenol (2.4 g, 16.6 mmol) in THF (200 mL) at 0oC is added
`bromoacetaldehyde dimethyl acetal (2.8 g, 16.6 mmol). To the solution is added sodium hydride (60%
`mineral oil dispersion, 0.70 g, 17.4 mmol). The reaction is stirred for 16 hours, and then is quenched by
`the addition of saturated NH4CI (aq.). The solution is diluted with EtOAc. The organic layer is washed
`with a saturated NaCl (aq.). The organic layer is dried over MgSO,,, filtered and concentrated. The
`crude product is purified by column chromatography eluting with hexanes. The title compound (3.7 g,
`15.9 mmol) is obtained as an oil. LH NMR (CDCI3, 300MHz) 5 7.32 (m, 1H), 7.25 (m, 1H), 7.12 (m.
`1H), 4.47 (m, 1H), 3.07 (s, 3H), 3.02 (s, 3H).
`
`25
`
`B. 4-Chlorobenzorblthiophene and 6-ChlorobenzorblthioDhene.
`
`1950
`
`

`

`WO 99/37304
`
`PCT/US99/01682
`
`81
`A solution containing polyphosphoric acid (8 g) and chlorobenzene (50 mL) is heated at reflux.
`A sol