EP0871628A1 - Quinolizinone type compounds - Google Patents

Quinolizinone type compounds

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Publication number
EP0871628A1
EP0871628A1 EP96919103A EP96919103A EP0871628A1 EP 0871628 A1 EP0871628 A1 EP 0871628A1 EP 96919103 A EP96919103 A EP 96919103A EP 96919103 A EP96919103 A EP 96919103A EP 0871628 A1 EP0871628 A1 EP 0871628A1
Authority
EP
European Patent Office
Prior art keywords
fluoro
methyl
oxo
carboxylic acid
cyclopropyl
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Withdrawn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
EP96919103A
Other languages
German (de)
French (fr)
Inventor
Daniel T. Chu
Qun Li
Curt S. Cooper
Anthony K. L. Fung
Cheuk M. Lee
Jacob J. Plattner
Zhenkun Ma
Wei-Bo Wang
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
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Publication date
Application filed by Abbott Laboratories filed Critical Abbott Laboratories
Publication of EP0871628A1 publication Critical patent/EP0871628A1/en
Withdrawn legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/61—Halogen atoms or nitro radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/62—Oxygen or sulfur atoms
    • C07D213/63—One oxygen atom
    • C07D213/68—One oxygen atom attached in position 4
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D455/00—Heterocyclic compounds containing quinolizine ring systems, e.g. emetine alkaloids, protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine
    • C07D455/02—Heterocyclic compounds containing quinolizine ring systems, e.g. emetine alkaloids, protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine containing not further condensed quinolizine ring systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/06—Dipeptides
    • C07K5/06008—Dipeptides with the first amino acid being neutral
    • C07K5/06017—Dipeptides with the first amino acid being neutral and aliphatic
    • C07K5/06026—Dipeptides with the first amino acid being neutral and aliphatic the side chain containing 0 or 1 carbon atom, i.e. Gly or Ala
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

Definitions

  • the present invention relates to compounds having antimicrobial activity, pharmaceutical compositions containing such compounds, methods of treatment utilizing such compounds, and processes for their chemical synthesis. More particularly, this invention relates to novel 4-oxo-4H-quinolizine-3-carboxylic acid compounds which are highly effective in the treatment of microbial and especially bacterial infections, as well as compositions containing the same and the therapeutic use of such compounds.
  • Rl in formula (I) is selected from (a) loweralkyl, (b) loweralkenyl, (c) halo(lower-alkyl), (d) loweralkoxy, (e) cycloalkyl of from three to eight carbon atoms, (f) phenyl,
  • R and R ⁇ are independently selected from hydrogen, loweralkyl and alkanoyl of from one to eight carbon atoms or, taken together with the nitrogen atom to which they are attached, R ⁇ and R may form a 5-, 6- or 7-membered heterocycle, preferably in which the remainder of the ring atoms are carbon atoms.
  • R in formula (I) is selected from (a) halogen, (b) loweralkyl, (c) loweralkenyl, (d) cycloalkyl of from three to eight carbons, (e) cycloalkenyl of from four to eight carbons, (f) loweralkoxy, (g) aryloxy, (h) aryl(loweralkyl)oxy, (i) aryl(loweralkyl), (j) cycloalkyl(loweralkyl), (k) amino, (1) (loweralkyl)amino, (m) aryl(loweralkyl)-amino, (n) hydroxy-substituted (loweralkyl)amino, (o) phenyl, (p) substituted phenyl, (q) bicyclic nitrogen-containing heterocycle, (r) nitrogen-containing aromatic heterocycle, (s) nitrogen- containing heterocycle having the formula
  • x is zero, one, two or three
  • R ⁇ is either (i) -(CH2)m- where m is one, two or three, or (ii) -(CH2)nR ⁇ (CH2)p- where R ⁇ i s selected from -S-, -O- and -NH-, R*0 i s CH2, or when R ⁇ is selected from option (i) may be O, S or N, n is one or two, and p is one or two.
  • the radical(s) Y is/are independently selected at each occurrence from the following: (i) loweralkyl,
  • R*l and R* are independently selected from hydrogen and loweralkyl or, when one of R ⁇ and Rl2 is hydrogen, the other is alkanoyl of from one to eight carbon atoms, an alpha-amino acid, or a polypeptide residue of from two to five amino acids, and
  • R21 and R2 are independently selected from among hydrogen, loweralkyl, hydroxy-substituted loweralkyl, amino(loweralkyl), loweralkoxy-(loweralkyl), thioloweralkoxy(loweralkyl), cycloalkyl of from three to six carbon atoms, and loweralkyl substituted with nitrogen-containing aromatic heterocycle (or, taken together with the carbon atom to which they are attached, R 1 and R22 form a ring structure selected from cycloalkyl of from three to six carbon atoms and nitrogen- containing heterocycle).
  • x is zero, one, two or three
  • R ⁇ l is -(CH2)qR3 - where R32 is selected from -S- and -O-, q is one, two or three, and the radical(s) Y is/are as defined above.
  • R3 in formula (I) is selected from among hydrogen, halogen and loweralkoxy, while R ⁇ is selected from hydrogen, loweralkyl, a pharmaceutically acceptable cation, and a prodrug ester group.
  • R5 in formula (I) is selected from (a) hydrogen, (b) halogen, (c) hydroxy, (d) loweralkyl, (e) halo(loweralkyl), (f) loweralkoxy, and (g) -NR13R14 here R 3 and R 4 are independently selected from among hydrogen, loweralkyl, hydroxy-substituted loweralkyl, loweralkoxy-(loweralkyl), and alkanoyl of from one to eight carbon atoms.
  • R ⁇ and R*> may form a 6-membered saturated ring optionally containing an oxygen or a sulfur atom and optionally substituted with loweralkyl, so as to produce a tricyclic compound.
  • Susceptible organisms whose growth can be inhibited generally include both aerobic and anaerobic pathogens of the genera Staphylococcus, Lactobacillus, Micrococc s, Enterococcus, Streptococcus, Sarcina, Escherichia, Enter obacter, Klebsiella, Pseudomonas, Acinobacter, Proteus, Providencia, Citrobacter, Nisseria, Bacillus, Bacteroides, Camphylobacter, Peptococcus, Clostridium, Salmonella, Shigella, Legionella, Serratia, Haemophilus, Brucella and the like.
  • compositions which are useful in the treatment and prophylaxis of bacterial and/or fungal infection in humans and animals, comprising a compound of the invention in combination with a pharmaceutically acceptable ca ⁇ ier.
  • a is CR6- and R*> is selected from among halogen, loweralkyl, halo(loweralkyl), hydroxy- substituted loweralkyl, loweralkoxy(loweralkyl), loweralkoxy, or amino(loweralkyl).
  • R*> is methyl.
  • R-3 is halogen (especially fluoro);
  • R' is hydrogen, loweralkyl, halo-(loweralkyl), or -NR ⁇ 14 ( ere R ⁇ and R ⁇ are as previously defined);
  • R* is cycloalkyl of from three to eight carbon atoms or substituted phenyl; and/or R" is halogen, loweralkyl, or loweralkoxy.
  • the radical R in the above compounds is preferably bicyclic nitrogen-containing heterocycle or a nitrogen-containing heterocycle of the formula
  • R is selected from among radicals of the formulae
  • R is preferably one or two
  • Y is preferably either -NR.1 1R1 0 r -C(R21)(R22)NH2, where R 1 ] , R 12 , R21 and R 2 2 are as defined above.
  • R is either bicyclic nitrogen-containing heterocycle or a nitrogen-containing heterocycle having the formula
  • 6-oxopyrido[ 1 ,2-a]pyrimidine-7-carboxylic acid 2-((2S,4S)-4-acetamido-2-methylpyrroUdin- 1 -yl)-9-(2,4-difluorophenyl)-3-fluoro-6H-6- oxopyrido[l,2-a]pyrimidine-7-carboxylic acid;
  • Especially preferred among the representative compounds of the present invention are the following: 8-(3(S)-amino- 1 -pyrrolidinyl)- 1 -cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3- carboxylic acid;
  • alkanoyl of from one to eight carbons refers to a radical of the formula -C(0)R15 where Rl5 J S hydrogen or an alkyl radical of from one to eight carbon atoms including, but not limited to, acetyl and pivaloyl.
  • alkyl refers to saturated, straight- or branched-chain hydrocarbon radicals containing between one and ten carbon atoms including, but not limited to, methyl, ethyl, propyl, isopropyl, n-butyl, tert-butyl and neopentyl.
  • alpha-amino acid and “polypeptide residue” refer, respectively, to a single amino acid and two to five amino acids each joined by amide (peptide) bonds.
  • the amino acids may be any of the naturally-occurring amino acids such as valine, phenylalanine and glycine or synthetic alpha-amino acids such as cyclohexylalanine, and further may be in either the L or D configuration or a mixture of the two isomers.
  • amino acid substituents are optically active and have the L configuration.
  • amino(loweralkyl) refers to a loweralkyl radical having appended thereto at least one amino substituent which in turn is optionally substituted with one or two loweralkyl radicals or an alpha-amino acid or polypeptide residue.
  • amino(loweralkyl) groups include aminoethyl, aminomethyl and N,N-dimethylaminoethyl.
  • aminooxy refers to an amino group, optionally substituted once or twice with loweralkyl or halo(loweralkyl), which is appended to the rest of the molecule via an oxygen atom; (e.g. -O-NR'R" wherein R' and R" are hydrogen, loweralkyl or halo(loweralkyl).
  • aminothioloweralkoxy refers to a thioloweralkoxy radical having appended thereto an amino group, as for example aminothiomethoxy and 2-aminothioethoxy.
  • aromatic group refers to a C6-to-C10 cyclic radical which is aromatic according to Huckel's rule.
  • aromatic groups include carbocyclic aromatic radicals such as phenyl and naphthyl as well as nitrogen-containing aromatic heterocyclic radicals, defined below.
  • aryl(loweralkyl) refers to a loweralkyl radical having appended thereto an aromatic hydrocarbon group, as for example benzyl and phenylethyl.
  • aryl(loweralkyl)amino refers to an amino radical having appended thereto an aryl(loweralkyl) group. Examples of aryl(loweralkyl)amino groups include benzylamino and phenylethylamino.
  • aryl(loweralkyl)oxy refers to an aryl(loweralkyl) radical which is joined to the rest of the molecule via an ether linkage (i.e., through an oxygen atom).
  • aryl(loweralkyl)oxy radicals include benzyloxy and phenylethyloxy.
  • aryloxy refers to an aromatic hydrocarbon radical which is joined to the rest of the molecule via an ether linkage (i.e., through an oxygen atom), as for example phenoxy.
  • bicycloalkyl refers to a radical comprising a bridged, saturated or unsaturated hydrocarbon ring system having between five and nine carbon atoms in which two non-adjacent carbon atoms of a first ring are linked by an alkylene bridge of between one and three additional carbon atoms, the bicycloalkyl radical being optionally substituted with between one and three additional radicals selected from among aryl(loweralkyl), alkoxycarbonyl, loweralkyl, halo(loweralkyl), amino(loweralkyl), hydroxy-substituted loweralkyl, hydroxy, loweralkoxy, halogen, and amino, (loweralkyl)amino or alkanoylamino of from one to eight carbon atoms in which the amino group may be further substituted with alkanoyl of from one to eight carbons, an alpha-amino acid or a polypeptide.
  • bicycloalkyl radicals include, but are not limited to
  • bicyclic nitrogen-containing heterocyclic group refers to a radical comprising a bicyclic ring system in which the rings are of the (a) fused, (b) bridged or (c) spiro form.
  • Fused-ring bicyclic nitrogen-containing heterocyclic groups are those in which a first nitrogen-containing heterocycle or aromatic heterocycle has fused to it a second saturated or unsaturated carbocyclic or heterocyclic ring of between three and six atoms of which zero, one or two are heteratoms selected from S, O, and N.
  • Both the first and the second ring may be optionally substituted with between one and three additional radicals A2 independently selected from among loweralkyl, halo(loweralkyl), hydroxy- substituted loweralkyl, hydroxy, halogen, amino(loweralkyl), alkanoylamino of from one to eight carbons, phenyl and -NR17R18 where RC and Rl8 are independently hydrogen or loweralkyl or, when one is hydrogen, the other is an alpha-amino acid or a polypeptide residue.
  • fused-ring bicyclic nitrogen-containing heterocychc radicals are those having 5:3, 5:4, 5:5, 5:6 and 6:5 ring systems and include, but are not limited to, radicals of the formulae
  • Bridged-ring bicyclic nitrogen-containing heterocyclic groups are those selected the formulae
  • Spiro-ring bicyclic nitrogen-containing heterocyclic groups are those in which a first nitrogen-containing heterocycle or aromatic heterocycle to which is joined, by a single shared carbon atom, a second carbocyclic or heterocyclic ring of between three and six atoms of which zero, one or two are heteratoms selected from S, O, and N. Either the first or the second ring may be substituted with between one and three additional radicals A , where A is as previously defined.
  • Examples of spiro-ring bicyclic nitrogen-containing heterocyclic radicals include, but are not limited to, those having the formulae
  • cyclic ether refers to a 4- to 6-membered monocyclic hydrocarbon radical containing an oxygen ring atom and joined to the rest of the molecule via any of the carbon atoms including, but not limited to, oxetane.
  • cycloalkenyl of from four to eight carbons refers to a mono- unsaturated monocyclic hydrocarbon radical having from four to eight carbon atoms in the ring, including, but not limited to, cyclobutenyl, cyclopentenyl, cyclohexenyl and cycloheptenyl, and optionally substituted with between one and three additionals radicals selected from among aryl(loweralkyl), alkoxycarbonyl, loweralkyl, halo(loweralkyl), amino(loweralkyl), hydroxy-substituted loweralkyl, hydroxy, loweralkoxy, halogen, amino, loweralkylamino, and amino, (loweralkyl)amino or alkanoylamino of from one to eight carbon atoms in which the amino group may be further substituted with alkanoyl of from one to eight carbons, an alpha-amino acid or a polypeptide.
  • cycloalkyl of from three to eight carbons refers to a saturated monocychc hydrocarbon radical having from three to eight carbon atoms in the ring and optionally substituted with between one and three additional radicals selected from among aryl(loweralkyl), alkoxycarbonyl, loweralkyl, halo(loweralkyl), amino(loweralkyl), hydroxy-substituted loweralkyl, hydroxy, loweralkoxy, halogen, and amino, (loweralkyl)amino or alkanoylamino of from one to eight carbon atoms in which the amino group may be further substituted with alkanoyl of from one to eight carbons, an alpha- amino acid or a polypeptide.
  • cycloalkyl radicals include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, 1-fluoro-cyclopropyl, 2-fluorocyclopropyl and 2-aminocyclopropyl.
  • cycloalkyl(amino) refers to an amino group substituted with at least one cycloalkyl group, typically having from three to eight carbons.
  • cycloalkyl(loweralkyl) refers to a loweralkyl radical having appended thereto a cycloalkyl radical of from three to eight carbon atoms, which cycloalkyl radical may be optionally substituted as described above.
  • fused refers to two cyclic groups having two adjacent ring atoms in common.
  • halo and “halogen” refer to a monovalent radical selected from among chloro (Cl), bromo (Br), fluoro (F) and iodo (I).
  • halo(loweralkyl) refers to a loweralkyl radical having appended thereto between one and three halogen atoms. Examples of halo(loweralkyl) radicals include fluoromethyl, trifluoromethyl, 1-fluoroethyl, 2-fluoroethyl and 1,2-difluoroethyl.
  • halo(loweralkyl)amino refers to an amino group substituted with at least one halo(loweralkyl) group.
  • halo(loweralkyl)amino(loweralkyl) refers to an amino(loweralkyl) radical having appended thereto a halo(loweralkyl) group, as for example 2-fluoroethylaminomethyl.
  • halo-substituted nitrogen-containing aromatic heterocycle refers to a nitrogen-containing aromatic heterocycle radical having appended thereto between one and three halogen atoms including, but not limited to, 5-fluoro-2-pyrimidyl.
  • hydroxy-substituted loweralkyl refers to a loweralkyl radical having appended thereto between one and three hydroxyl groups, as for example hydroxymethyl and 2-hydroxyethyl.
  • hydroxy-substituted (loweralkyl)amino refers to a (loweralkyl)amino radical having appended thereto between one and three hydroxyl groups, as for example hydroxymethylamino and 2-hydroxyethylamino.
  • loweralkenyl refers to a straight- or branched-chain hydrocarbon radical containing between two and six carbon atoms and possessing at least one carbon- carbon double bond.
  • loweralkenyl radicals include vinyl, allyl, 2- or 3- butenyl, 2-,3- or 4-pentenyl, 2-,3-,4- or 5-hexenyl and isomeric forms thereof.
  • loweralkoxy refers to a loweralkyl radical which is appended to the rest of the molecule via an ether linkage (i.e., through an oxygen atom), as for example methoxy, ethoxy, propoxy, tert-butoxy, pentyloxy, hexyloxy, isomeric forms thereof and the like.
  • loweralkoxycarbonyl refers to a radical of the formula -C(O)R25 wherein R25 is a loweralkoxy group, as for example ethoxycarbonyl and methoxycarbonyl.
  • loweralkoxy(loweralkoxy)(loweralkyl) refers to a loweralkoxy(loweralkyl) radical having appended thereto a loweralkoxy group, as for example methoxymethoxymethyl and ethoxymethoxymethyl
  • loweralkoxy(loweralkyl) refers to a loweralkyl radical having appended thereto a loweralkoxy group and optionally substituted with an additional amino radical, as for example methoxyethyl, ethoxymethyl and l-amino-2-methoxyethyl.
  • loweralkyl refers to an alkyl radical containing one to six carbon atoms including, but not limited to, methyl, ethyl, propyl, isopropyl, n-butyl, tert-butyl and neopentyl.
  • (loweralkyl)amino refers to an amino radical substituted with between one and three loweralkyl radicals including, but not limited to, methylamino, ethylamino, dimethylamino, propylamino and ethylmethylamino.
  • loweralkynyl refers to a straight- or branched-chain hydrocarbon radical containing between two and six carbon atoms and possessing at least one carbon- carbon triple bond.
  • loweralkynyl radicals include ethynyl, 2-hexyn-l-yl, 3,3- dimethyl- 1 -butyn- 1 -yl and 3-methylbutyn-3-yl.
  • nitrogen-containing aromatic heterocycle refers to a monocyclic aromatic radical having from five to seven ring atoms of which one ring atom is nitrogen; zero, one or two ring atoms are additional heteroatoms independently selected from S, O and N; and the remaining ring atoms are carbon, the radical being joined to the rest of the molecule via any of the ring atoms.
  • nitrogen-containing aromatic heterocycles include pyridine, pyrazine, pyrimidine, pyrrole, pyrazole, imidazole, thiazole, oxazole, isooxazole, thiadiazole, oxadiazole and substituted derivatives thereof.
  • nitrogen-containing heterocycle refers to a saturated or unsaturated monocyclic ring system radical having from four to seven ring atoms of which one is nitrogen; zero, one or two are additional heteroatoms independently selected from S, O and N; and the remainder are carbon, the radical being joined to the rest of the molecule via any of the ring atoms and being optionally substituted, either on a nitrogen or a carbon atom, by an additional radical selected from among aryl(loweralkyl), alkoxycarbonyl, loweralkyl, halo(loweralkyl), amino(loweralkyl), hydroxy-substituted loweralkyl, hydroxy, loweralkoxy, halogen, amino, loweralkylamino, and amino, (loweralkyl)amino or alkanoylamino of from one to eight carbon atoms in which the amino group may be further substituted with alkanoyl of from one to eight carbons, an alpha-amino acid or a polypeptid
  • nitrogen-containing heterocycles examples include pyrrolidine, dihydropyrrole, isooxazolidine, oxazolidine, tetrhydropyridine, piperidine, piperazine, morpholine, thiomorpholine, aziridine and azetidine.
  • pharmaceutically acceptable cation refers to a positively-charged inorganic or organic ion that is generally considered suitable for human consumption.
  • Examples of pharmaceutically acceptable cations are hydrogen, alkali metal (hthium, sodium and potassium), magnesium, calcium, ferrous, ferric, ammonium, alkylammonium, dialkylammonium, trialkylammonium, tetraalkylammonium, diethanolammmonium, triethanolammonium, and guanidinium ions, and protonated forms of lysine, procaine and choline. Cations may be interchanged by methods known in the art, such as ion exchange. Where compounds of the present invention are prepared in the carboxylic acid form (that is, where R4 is hydrogen) addition of a base form of the cation, (such as a hydroxide or a free amine) will yield the appropriate cationic form.
  • a base form of the cation such as a hydroxide or a free amine
  • esters and amides as of the compounds of formula I, is meant those carboxylate salts, amino acid addition salts, esters and amides which are, within the scope of sound medical judgement, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, commensurate with a reasonable benefit/risk ratio, and effective for their intended use, as well as the zwitterionic forms thereof.
  • salts are well known in the art.
  • S. M Berge, et al. describe pharmaceutically acceptable salts in detail in Pharmaceutical Sciences. 66:1-19 (1977).
  • 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.
  • salts include nitrate, bisulfate, borate, formate, butyrate, valerate, 3-phenylpropionate, 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 or 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.
  • esters of the present invention include Cl-to-C6 alkyl esters and C5-to-C7 cycloalkyl esters, although Cl-to-C4 alkyl esters are preferred.
  • Esters of the compounds of formula I may be prepared according to conventional methods.
  • Examples of pharmaceutically acceptable, non-toxic amides of the present invention include amides derived from ammonia, primary Cl-to-C6 alkyl amines and secondary Cl-to-C6 dialkyl amines. In the case of secondary amines, the amine may also be in the form of a 5- or 6-membered heterocycle containing one nitrogen atom. Amides derived from ammonia, Cl-to-C3 alkyl primary amides and Cl-to-C2 dialkyl secondary amides are preferred. Amides of the compounds of formula I may be prepared according to conventional methods. It is intended that amides of the present invention include amino acid and peptide derivatives of the compounds of formula I as well.
  • the term "pharmaceutically acceptable carrier” means a non-toxic, inert solid, semi-solid or liquid filler, diluent, encapsulating material or formulation auxiliary of any type.
  • materials that can serve as pharmaceutically acceptable carriers are sugars, such as lactose, glucose and sucrose; starches such as corn 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 as propylene glycol; polyols such as glycerin, sorbitol, mannitol and polyethylene glycol; esters such as ethyl oleate and ethyl laur
  • wetting agents such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, releasing agents, coating agents, sweetening, flavoring and perfuming agents, and preservatives can also be present in the composition, according to the judgement of the formulator.
  • prodrug refers to derivative compounds that are rapidly transformed in vivo to yield the parent compound of the formula I, as for example by hydrolysis in blood.
  • T. Higuchi and V. Stella provide a thorough discussion of the prodrug concept in "Pro-drugs as Novel Delivery Systems", Vol 14 of the A.C.S. Symposium Series, American Chemical Society (1975).
  • esters useful as prodrugs for compounds containing carboxyl groups can be found on pages 14-21 of "Bioreversible Carriers in Drug Design: Theory and Application", edited by E.B. Roche, Pergamon Press:New York (1987). It is intended that these references, and any others cited throughout this specification, are incorporated herein by reference.
  • prodrug ester group refers to any of several ester-forming groups that are hydrolyzed under physiological conditions.
  • Examples of prodrug ester groups include pivoyloxymethyl, acetoxymethyl, phthalidyl, indanyl and methoxymethyl, as well as other such groups known in the art, including a (5-R-2-oxo-l,3-dioxolen-4-yl)methyl group.
  • Other examples of prodrug ester groups can be found in the book "Pro-drugs as Novel Delivery Systems", by Higuchi and Stella, cited above.
  • protecting group is well-known in the art and refers to substituents on functional groups of compounds undergoing chemical transformation which prevent undesired reactions and degradations during a synthesis; see, for example, T.H. Greene, "Protective Groups in Organic Synthesis", John Wiley & Sons, New York (1981).
  • substituted phenyl refers to a benzene ring having between one and five non-hydrogen substituents, each independently selected from among halogen, hydroxy, loweralkoxy, loweralkyl, hydroxy-substituted loweralkyl, amino, (loweralkyl)amino, amino(loweralkyl) and nitrogen-containing heterocycle.
  • substituted phenyl radicals include 2-fluorophenyl, 4-fluorophenyl and 2,4-difluorophenyl.
  • thioloweralkoxy refers to a radical of the formula -SR35 where R35 i s a loweralkyl group including, but not limited to, thiomethoxy and thioethoxy.
  • thioloweralkoxy(loweralkyl) refers to a loweralkyl radical having appended thereto a thioloweralkoxy group including, but not limited to, thiomethoxymethyl and thiomethoxyethyl. According to the methods of treatment of the present invention, the compounds of the invention may be administered alone or in combination or in concurrent therapy with other agents.
  • 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 of the disorder; activity of the particular compound used; the specific composition employed; the age, body weight, general health, sex and diet of the patient; the time of administration, route of administration, and rate of excretion of the specific compound employed; the duration of the treatment; drugs used in combination or coincidently with the specific compound employed; and like factors well known in the medical arts.
  • the total daily dose of the compounds of this invention administered to a host in single or in divided doses can be in amounts, as for example from 0.1 to 200 mg/kg body weight or more usually from 0.25 to 100 mg/kg body weight.
  • Single dose compositions may contain such amounts or submultiples thereof as make up the daily dose.
  • the compounds of the invention may be administered orally, parenterally, by inhalation spray, rectally, or topically in unit dosage formulations containing conventional nontoxic pharmaceutically acceptable carriers, adjuvants, diluents and/or vehicles as desired.
  • parenteral as used herein includes subcutaneous injections, intravenous, intramuscular, intrasternal injection or infusion techniques.
  • injectable preparations as 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 or suspension in a nontoxic parenterally acceptable diluent or solvent, as for example as a solution in 1,3-butanediol.
  • a nontoxic parenterally acceptable diluent or solvent as for example as a solution in 1,3-butanediol.
  • acceptable vehicles and solvents that may be employed are water. Ringer's solution, U.S. P. and isotonic sodium chloride solution.
  • sterile, fixed oils are conventionally employed as a solvent or suspending medium.
  • any bland fixed oil can be employed including synthetic mono- or diglycerides.
  • fatty acids such as oleic acid are used in the preparation of injectables.
  • the most common way to accomplish this is to inject a suspension of crystalline or amorphous material with poor water solubility
  • the rate of absorption of the drug becomes dependent on the rate of dissolution of the drug which is, in turn, dependent on the physical state of the drug, for example, the crystal size and the crystalline form.
  • Another approach to delaying abso ⁇ tion of a drug is to administer the drug as a solution or suspension in oil.
  • Injectable depot forms can also be made by forming microcapsule matrices of drugs and biodegradable polymers such as polylactide-polyglycolide.
  • the rate of drug release can be controlled.
  • biodegradable polymers include poly-orthoesters and polyanhydrides. Depot injectables can also be made by entrapping the drug in liposomes or microemulsions which are compatible with body tissues.
  • Suppositories for rectal or vaginal administration of the drug can be prepared by mixing the drug with a suitable nonirritating excipient such as cocoa butter and polyethylene glycol which are solid at ordinary temperature but will melt in the rectum or in the vagina and release the drug.
  • Solid dosage forms for oral administration may include capsules, tablets, pills, powders, prills and granules. In such solid dosage forms the active compound may 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 as magnesium stearate and microcrystalUne cellulose.
  • additional substances other than inert diluents e.g., tableting lubricants and other tableting aids such as magnesium stearate and microcrystalUne cellulose.
  • the dosage forms may also comprise buffering agents. Tablets and piUs can additionaUy be prepared with enteric coatings and other release-controUing coatings.
  • Liquid dosage forms for oral administration may include pharmaceuticaUy acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs containing inert diluents commonly used in the art such as water. Such compositions may also comprise adjuvants, such as wetting agents; emulsifying and suspending agents; and sweetening, flavoring and perfuming agents. If desired, the compounds of the present invention can be inco ⁇ orated into slow release or targeted dehvery systems such as polymer matrices, Uposomes and microspheres.
  • sterile solid compositions which can dissolve in sterile water, or some other sterile injectable medium immediately before use.
  • the active compounds can also be in micro-encapsulated form with one or more excipients as noted above.
  • Dosage forms for topical or transdermal administration of a compound of this invention further 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 formulations, 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, siUcones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.
  • excipients such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, siUcones, 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 or substitutes therefor.
  • Transdermal patches have the added advantage of providing controUed deUvery of a compound to the body.
  • dosage forms can be made by dissolving or dispersing the compound in the proper medium.
  • Abso ⁇ tion enhancers can also be used to increase the flux of the compound across the skin.
  • the rate can be controUed by either providing a rate controlUng membrane or by dispersing the compound in a polymer matrix or gel.
  • a further possibility for delivery and/or utiUzation of the compounds of the present invention is by chemical conjugation of the compounds with other antibacterials such as beta-lactams.
  • Sirrular dual-action conjugates are proposed in the published European patent appUcation No. 597 303 of Dax, etal. (published on May 18, 1994) and the pubUshed international patent appUcation No. PCT/US92/08246 of White, et al. (Publication No. WO 93/07154, published on April 15, 1993).
  • a carbon-nitrogen bond or other covalent Unk may be formed between, for example, either an amino substituent at the C-8 position or a carboxylic acid group at the C-3 position of a compound of the present invention, and an alkyl or other group of a beta-lactam.
  • the compounds of the present invention are synthesized according to reaction Schemes I through XVIII presented below, in which Rl through Rl , A, X, Y and Z correspond to the groups defined in connection with formula (I), R is a loweralkyl group, X is a halogen atom, P is a protecting group and L is a suitable leaving group, as for example a halogen atom.
  • BOC for t-butoxycarbonyl
  • (BOC)2 for di-t-butyl dicarbonate
  • CBZ for benzyloxy-carbonyl
  • DMF for dimethyl formamide
  • DMSO for dimethyl sulfoxide
  • HRMS for high resolution mass spectroscopy
  • LAH for Uthium aluminum hydride
  • LDA for Uthium diethyl amide
  • RaNi for Raney Nickel
  • THF for tetrahydrofuran.
  • the condensation of the amino group with amino acids and peptides may be effected in accordance with conventional condensation methods such as the azide method, the mixed acid anhydride method, the DCC (dicyclohexylcarbodumide) method, the active ester method ( p-nitrophenyl ester method, N-hydroxysuccinic acid imide ester method, cyanomethyl ester method and the like), the Woodward reagent K method, the DCC-HOBT (1-hydroxy-benzotriazole) method and the like.
  • Classical methods for amino acid condensation reactions are described in "Peptide Synthesis", Second Edition, M.
  • amino acid coupling reaction could be carried out before or after the amino-containing group is inco ⁇ orated into the compound by displacement of the 7- fluorine atom of the appropriate intermediate.
  • branched chain amino and carboxyl groups at alpha and omega positions in amino acids may be protected and deprotected if necessary.
  • the protecting groups for amino groups which can be used involve, for example, benzyloxycarbonyl (Z), o-chloro-benzyloxycarbonyl((2-Cl)Z), p-nitrobenzyloxycarbonyl (Z(NO2)), p-methoxybenzyloxycarbonyl (Z(OMe)), t-butoxycarbonyl (Boc), t-amyloxycarbonyl (Aoc), isobornealoxycarbonyl, adamantyloxycarbonyl (Adoc), 2-(4-biphenyl)-2-propyloxy carbonyl (Bpoc), 9-fluorenyl-methoxycarbonyl (Fmoc), methylsulfonylethoxy carbonyl (Msc), trifluoroacetyl, phthalyl, formyl,
  • protecting groups for carboxyl groups involve, for example, benzyl ester (OBzl), cyclohexyl ester, 4-nitrobenzyl ester (OBzlNO2), t-butyl ester (OtBu), 4-pyridylmethyl ester (OPic) and the like.
  • the guanidino group (NG) in arginine be protected with nitro, p-toluenesulfonyl (Tos), benzyloxycarbonyl (Z), adamantyloxycarbonyl (Adoc), p-methoxybenzenesulfonyl, 4- methoxy-2,6-dimethyl-benzenesulfonyl (Mts) or the like; that the thiol group in cysteine be protected with benzyl, p-methoxybenzyl, triphenylmethyl, acetamidomethyl, ethylcarbamyl, 4-methylbenzyl (4-MeBzl), 2,4,6,-trimethylbenzyl (Tmb) or the like; and that the hydroxy group in serine may be protected with benzyl (Bzl), t-butyl, acetyl, tetrahydropyranyl (THP) or the like.
  • Tos nitro,
  • R 1 is not cyclopropyl
  • an alpha-halo acetate derivative of formula 1, such as ethyl 2-fluoroacetate, is condensed with a formate ester of formula 2 in the presence of a suitable base, as for example sodium ethoxide, in an inert solvent such as diethyl ether to give an enolate compound of formula 3.
  • a suitable base as for example sodium ethoxide
  • diethyl ether inert solvent
  • Compounds of formula 3 are, in turn, converted to compounds of formula 5 by condensation with an amidine derivative of formula 4, in which R is an electron withdrawing group such as phenyl, trifluoromethyl, cyano, perfluoroalkyl, vinyl, substituted vinyl, fluorine, nitro, acetylene, substituted acetylene, alkoxycarbonyl, or a nitrogen-containing aromatic heterocycle.
  • R is an electron withdrawing group such as phenyl, trifluoromethyl, cyano, perfluoroalkyl, vinyl, substituted vinyl, fluorine, nitro, acetylene, substituted acetylene, alkoxycarbonyl, or a nitrogen-containing aromatic heterocycle.
  • the compounds of formula 9A are cyclized in the presence of a base, as for example DBU or piperidine, or in the presence of an acid, such as sulfuric acid, in a solvent such as toluene, THF, ethanol or chlorobenzene, or by heating the compound in a solvent, as for example xylene, diglyme, triglyme, sulfolane or Dowtherm A® (a eutectic mixture of biphenyl and diphenyl ether) at a temperature greater than 120°C, to give the compounds of formula IOC.
  • a base as for example DBU or piperidine
  • an acid such as sulfuric acid
  • a solvent such as toluene, THF, ethanol or chlorobenzene
  • a solvent such as toluene, THF, ethanol or chlorobenzene
  • esters IOC are converted into the esters 11 A via tr ⁇ westerif ⁇ cation with an alcohol suitable for selective hydrolysis, such as benzyl alcohol or 2-(trimethylsilyl)ethanol (TMSE), in the presence of a catalyst, as for example titanium tetraethoxide.
  • an alcohol suitable for selective hydrolysis such as benzyl alcohol or 2-(trimethylsilyl)ethanol (TMSE)
  • TMSE 2-(trimethylsilyl)ethanol
  • the 2-hydroxy compounds of formula 11 A are converted to the corresponding halo-derivatives of formula 12A by treatment with a halogenating agent, for example phosphorous oxychloride to afford the chloro derivative, optionally in an inert solvent at a temperature between about 20°C and 145°C, depending on the halogenating agent and the boiling point of the solvent if one is used, and conveniently at room temperature.
  • a halogenating agent for example phosphorous oxychloride
  • the leaving group L in the compounds of formula 12A is then displaced by a nucleophile such as a nucleophilic amine, for example N-methylpiperazine or 2-methylpiperazine, to give the compounds of formula 13 A.
  • the reaction may be conducted at a temperature from about 20°C to about 130°C in a suitable organic solvent such as pyridine, methylene chloride, chloroform or l-methyl-2-pyrrolidinone. It is desirable to carry out the reaction in the presence of an acid-acceptor such as triethylamine, potassium carbonate and the like, at a molar ratio of 1.0 to 2.0 moles of the acid acceptor per mole of compound of the formula 6.
  • the amine can also be used as an acid acceptor in which case two or more equivalents of this reagent are used.
  • the benzyl ester group of compounds of formula 13 A is then removed by hydrogenolysis when R is benzyl, or with tetrabutylammonium fluoride when R is TMSE, to afford a compound of formula I.
  • the cyano group of the compounds of formula 5B is then reacted with an inorganic acid, such as hydrochloric acid, in the presence of one equivalent of anhydrous alcohol, such as ethanol, followed by reaction with ammonia to give the substituted amidine ester of formula 6B, which is then condensed with an enolate compound of formula 7B, prepared in a manner similar to compounds of formula 3 in Scheme I, in the presence of a suitable base, for example triethylamine, in a polar solvent such as methanol to give the substituted hydroxy- pyrimidine ester compounds of formula 8B.
  • an inorganic acid such as hydrochloric acid
  • anhydrous alcohol such as ethanol
  • the ester function of the compounds of formula 8B is converted into an aldehyde function by reduction, for example with a hindered aluminum hydride, such as diisobutylaluminum hydride or LiAlH(O-t-butyl)3, or with N,N-dimethyl-chloromethyleneiminium chloride in pyridine or diarninoaluminum hydride to produce a compound of formula 9B.
  • This reaction may be conducted at a temperature below -20°C, and conveniently at -78°C in the presence of a aprotic solvent such as hexane, toluene, methylene chloride or THF.
  • the aldehyde compounds of formula 9B are reacted with a malonic acid diester, such as diethyl malonate, dibenzyl malonate, t-butyl malonate or di-t-butyl malonate, in the presence of a suitable base such as piperidine and a catalytic amount of an acid, such as acetic acid or sulfuric acid, in a polar solvent, such as ethanol, to afford the pyridopyrimidine compounds of formula 10B.
  • the compounds of formula 10B are reacted with a suitable halogenating agent such as phosphoryl chloride at room temperature to afford the compounds of formula 1 IB.
  • the halo group is displaced as discussed in reaction Scheme I to afford the compounds of formula 12B, which are in turn converted into the compounds of formula I as described in Scheme I for the conversion of compounds of formula 10 into compounds of formula I.
  • reaction Scheme HI illustrated above 2-picoline-N-oxide is converted to a mixture of compounds of formulae 22 and 23 by treatment with a halogenating agent, for example phosphorus oxychloride, optionally in an inert solvent.
  • a halogenating agent for example phosphorus oxychloride
  • the reaction may be run at a temperature between about 25°C and 125°C, depending on the halogenating agent selected.
  • the reaction temperature is preferably between 60°C and 120°C.
  • a compound of formula 23 is, in turn, reacted with an alkoxymethylene malonate derivative of formula 8 in the presence of a suitably strong and hindered base, for example lithium dusopropylamide (LDA), preferably at a temperature below 0°C, and conveniently at -78°C to afford the compounds of formula 24.
  • a suitably strong and hindered base for example lithium dusopropylamide (LDA)
  • LDA lithium dusopropylamide
  • Compounds of formula 24 are cyclized by heating the compound in a solvent with a boiling point greater than 120°C, for example xylene, diglyme, triglyme, sulfolane or Dowtherm A® (a eutectic mixture of biphenyl and diphenyl ether), to afford compounds of formula 25.
  • the leaving group in the 8-position of the quinolizinone compound of formula 25 is then displaced using 3-aminopyrrolidine with the primary amino group protected, for example with t-butoxycarbonyl.
  • the protecting group is then removed to give the compounds of formula 26.
  • esters of formula 26 are than converted to the carboxylic acids of formula UI as described in Scheme 1 for the conversion of compounds of formula 10 to compounds of formula I.
  • compounds of formula 23 are converted to compounds of formula 27, wherein Rl is alkyl, cycloalkyl or carbocyclic aryl(loweralkyl), by treatment with an alkyl, cycloalkyl or carbocyclic aryl(loweralkyl) halide in the presence of a suitable base such as LDA.
  • Compounds of formula 23 are converted to compounds of formula 27, wherein Rl is a phenyl group as defined herein or an alkylamino group by conversion to the corresponding halomethyl compound and treatment of the halomethyl compound with an aryl metal compound such as phenyllithium as described above, or with an alkylamine such as methylamine as shown in reaction Scheme VA.
  • the compounds of formula 27 are converted to the compounds of formula 29 by the sequence of reactions described above for the conversion of compounds of formula 25.
  • the leaving group in the 8-position of the quinolizinone compound of formula 29 is then displaced, for example by a nucleophilic amine such as N-methylpiperazine or 2-methylpiperazine, to give the the compounds of formula 30.
  • the reaction may be conducted at a temperature from about 20 °C to about 130°C in a suitable organic solvent such as pyridine, methylene chloride, chloroform or 1- methyl-2-pyrrolidinone. It is desirable to carry out the reaction in the presence of an acid- acceptor such as triethylamine, potassium carbonate and the like, at a molar ratio of 1.0 to 2.0 moles of the acid acceptor per mole of compound of the formula29.
  • the amine can also be used as an acid acceptor in which case two or more equivalents of this reagent are used.
  • R2 is a phenyl group as defined herein, compounds of formula
  • reaction-inert solvent i.e., a solvent which does not interfere with the coupling reaction of the aryl metal compound with a compound of formula29.
  • Suitable reaction-inert solvents include ethers, for example diethyl ether, dimethoxyethane and tetrahydrofuran (THF). Co-solvents may be used with ethers if desired.
  • aryl metal compounds may be prepared by known methods. For example, they may be prepared by direct lithium-halogen exchange of the corresponding aryl halide using n-butyl-, sec-butyl- or t-butyl-lithium followed by tr ⁇ /wmetallation by a wide variety of salts by known methods such as described by E. Negishi in "Organometallics in Organic Sysnthesis", Vol. 1, page 104.
  • a compound of formula 31 is treated with a malononic acid ester, for example diethyl malonate, in the presence of a suitable base such as sodium hydride in a polar nonprotic solvent such as an ether, for example diethyl ether or THF, to afford a compound of formula 32.
  • a suitable base such as sodium hydride
  • a polar nonprotic solvent such as an ether, for example diethyl ether or THF
  • Compounds of formula 32 are, in turn, decarboxylated, for example by heating them in strong mineral acid such as aqueous sulfuric acid, to afford the compounds of formula 33.
  • the nitro-compound of formula 33 is reduced to the corresponding amino-compound of formula 34.
  • the nitro group may be reduced by catalytic hydrogenation using standard techniques or by any of a variety of known reducing agents such as using a metal, for example zinc, tin or iron, in the presence if a mineral acid, usually hydrochloric acid.
  • the amino-compound of formula 34 is converted to the corresponding fluoro-compound of formula 35 by treatment with ethyl nitrite and tetrafluoroboric acid, followed by treatment with potassium fluoride.
  • the compound of formula 35 is then converted into the corresponding N-oxide of formula 36 by oxidation, for example using peracetic acid.
  • the reaction is carried out in the range from about 20°C up to the reflux temperature of the solvent employed, preferably at about 50°C.
  • the compound of formula 36 is nitrated to afford compounds of formula 37.
  • the nitration reaction can be carried out using a variety of known nitrating agents, for example a mixture of nitric acid and sulfuric acid or a mixture of sulfuric acid and potassium nitrate, or by using nitronium salts such as nitronium trifluoromethanesulfonate.
  • the nitro compound of formula 37 is, in turn, converted to the corresponding halo compound of formula 38 by treatment with mineral acid at ambient or elevated temperature as desired.
  • the compound of formula 37 is treated with aqueous hydrochloric acid at a temperature of about 100-120°C to afford the compound of formula 38 wherein L is Cl.
  • the compound of formula 38 is, in turn converted to the compound of formula IV A 1 by reduction, for example using a metal such as iron or zinc in the presence of an acid such as acetic acid.
  • the compound of formula IV A 1 is, in turn, converted to the compound of formula IV A2 by treatment with a suitable base, such as LDA, followed by treatment with a halogenating agent, for example N-chloro or N-bromo succinimide.
  • the compounds of formula IV A 1 are converted to compounds of formula IV A3, wherein R is alkyl, cycloalkyl or carbocyclic aryl(loweralkyl), by treatment with an alkyl, cycloalkyl or carbocyclic aryl(loweralkyl) halide in the presence of a suitable base such as LDA.
  • a suitable base such as LDA
  • a halogenating agent for example N-chloro or N-bromo succinimide to afford the compounds of formula IV A4.
  • Compounds of formulae IV Al - IV A4 are key intermediates used in the synthesis of quinolizinone compounds.
  • the compounds of formulae IV A3 and IV A4 are converted to the quinolizinone compounds of formula IV B and IV C, respectively, by the following series of reactions: (1) reaction with an alkoxymethylene malonate derivative of formula 8 in the presence of a suitably strong and hindered base, for example lithium dusopropylamide (LDA), preferably at a temperature below 0°C, and conveniently at -78°C, to afford the compounds of formulae 39 and 42, respectively (2) cyclization as discussed in reaction Scheme HI, to afford the compounds of formulae 40 and 43, respectively (3) displacement of the leaving group in the 8-position as discussed in reaction Scheme HI to afford the compounds of formulae 41 and 44, respectively and (4) hydrolysis or hydrogenolysis as discussed in reaction Scheme HI of the carboxylic acid ester to the corresponding carboxylic acids of formulae IV B and IV C, respectively.
  • a suitably strong and hindered base for example lithium dusopropylamide (LDA), preferably at a temperature below 0°C, and conveniently
  • the compounds of formula 51 are converted to the compounds of formula V A2 by the following series of reactions: (1) reaction with an alkoxymethylene malonate derivative of formula 8 in the presence of a suitably strong and hindered base, for example Uthium dusopropylamide (LDA), preferably at a temperature below 0°C, and conveniently at -78 °C, to afford the compounds of formula 52 (2) cyclization as discussed in reaction Scheme IH, to afford the compounds of formula 53 (3) displacement of the leaving group in the 8-position as discussed in reaction Scheme HI to afford the compounds of formula 54 and (4) conversion of the carboxyUc acid ester to the corresponding carboxylic acids of formula V A2.
  • a suitably strong and hindered base for example Uthium dusopropylamide (LDA), preferably at a temperature below 0°C, and conveniently at -78 °C
  • LDA Uthium dusopropylamide
  • reaction Scheme V B Ulustrated above compounds of formula IV A2 are converted to compounds of formulae V B 1 and V B2 by the same procedures discussed in reaction Scheme V A for the conversion of compounds of formula IV A 1 to compounds of formulae V Al and V A2.
  • reaction Scheme VI illustrated above perfluoroinated pyridine is converted to the compound of formula 66 by the procedures described in reaction Scheme IV A for the preparation of compounds of formula 33.
  • Compounds of formula 66 are, in turn, converted to the compounds of formula VI A and VI B by the series of reactions discussed in reaction Scheme HI for the conversion of compounds of formula 23 to compounds of formula IH.
  • compounds of formula IV A2 are reacted with a protected alcohol of formula 71 , in the presence of a suitable base such as LDA, to afford compounds of formula 72.
  • the hydroxy protecting group is preferably a THP (tetrahydopyranyl) ether group.
  • the compounds of formula 72 are, in turn, deprotected by standard methods to afford the compounds of formula 73.
  • the compounds of formula 73 are cyclized, in the presence of a suitable non-nucleophUic base such as sodium hydride, to afford the compounds of formula 74.
  • the compounds of formula 74 are then comverted to the compounds of formula 77 by the series of reactions described in reaction Scheme IV B for the conversion of the compounds of formula IV A3 to the compounds of formula IV B.
  • the hydroxy-substituted compounds of formula 5 are converted to the corresponding halo- derivatives of formula 6 by treatment with a halogenating agent, for example phosphorus oxychloride to afford the chloro derivative, optionaUy in an inert solvent at a temperature between about 20°C and 145°C, depending on the halogenating agent and the boiting point of the solvent if one is used.
  • a halogenating agent for example phosphorus oxychloride
  • the reaction temperature is preferably between about 80°C and 100°C.
  • the leaving group in the 5-position of the pyrimidine ring of compounds of formula 6 is then displaced by a nucleophile such as a nucleophiUc amine, for example N-methylpiperazine or 2- methylpiperazine, to give the the compounds of formula 7.
  • a nucleophile such as a nucleophiUc amine, for example N-methylpiperazine or 2- methylpiperazine
  • the reaction may be conducted at a temperature from about 20°C to about 130°C in a suitable organic solvent such as pyridine, methylene chloride, chloroform or l-methyl-2-pyrrolidinone. It is desirable to carry out the reaction in the presence of an acid-acceptor such as triethylamine, potassium carbonate and the like, at a molar ratio of 1.0 to 2.0 moles of the acid acceptor per mole of compound of the formula 6.
  • the amine can also be used as an acid acceptor in which case two or more equivalents of this reagent are used.
  • the compounds of formula 7 are reacted with an alkoxymethylene malonate derivative of formula 8 in the presence of a suitably strong hindered base, for example Uthium dUsopropylamide (LDA), preferably at a temperature below 0°C, and conveniently at -78 °C to afford the compounds of formula 9.
  • a suitably strong hindered base for example Uthium dUsopropylamide (LDA)
  • LDA Uthium dUsopropylamide
  • the compounds of formula 9 are cycUzed in the presence of a suitable hindered base, for example DBU, in an aprotic solvent, such as toluene, THF or chlorobenzene to give the compounds of formulalO.
  • the cyclization is carried out at a temperature in the range of about 30°C to about 130°C, preferably at the reflux temperture of the reaction mixture.
  • the compounds of formula 10 are hydrolyzed in the presence of a suitable base such as sodium or potasium hydroxide to afford the compounds of formula 78.
  • the compounds of formula 78 are, in turn, chlorinated to afford the compounds of formula 10a using an appropriate chlorinating agent such as phosphorus oxychloride.
  • the leaving group in the 8-position of the quinoUzinone compound of formula 10a is then displaced using a nucleophiUc amine such as 3- aminopyrToUdine (with the primary amino group protected, for example with t- butoxycarbonyl).
  • the protecting group is then removed to give the compounds of formula 10b.
  • the esters of formula 10b are then converted to the carboxylic acids of formula I.
  • the conversion may be achieved by conventional hydrolysis or by converting a compound of formula 10b to the corresponding ester, via tr ⁇ westerification with an alcohol suitable for selective hydrolysis, such as benzyl alcohol or 2-(rrimethylsilyl)ethanol (TMSE), in the presence of a catalyst, for example titanium tetraethoxide, and then, in turn, removing the alcohol group by hydrogenolysis when R is benzyl or tetrabutylammonium fluoride when R is TMSE to afford a compound of formula I.
  • an alcohol suitable for selective hydrolysis such as benzyl alcohol or 2-(rrimethylsilyl)ethanol (TMSE)
  • TMSE 2-(rrimethylsilyl)ethanol
  • R* is an alkyl, halo(loweralkyl) or cycloalkyl group, or may be an electron withdrawing group such as phenyl, trifluoromethyl, cyano, perfluoroalkyl, vinyl, substituted vinyl, fluorine, nitro, acetylene, substituted acetylene, alkoxycarbonyl, or a nitrogen-containing aromatic heterocycle, in the presence of a suitable base, such as sodium methoxide or sodium ethoxide, in the presence of a suitable solvent, such as methanol or ethanol, to give compounds of formulae 81 or 80, respectively.
  • a suitable base such as sodium methoxide or sodium ethoxide
  • a suitable solvent such as methanol or ethanol
  • Compounds of formula 80 may be substituted for compounds of formula 8B in Scheme H and converted via the reactions in that Scheme, described above, into compounds of formula I.
  • Compounds of formula 81 may be substituted for compounds of formula 5 in Scheme I and converted into compounds of formula I via the reactions of Scheme I described above.
  • the compounds of formula 81 may be substituted for compounds of formula 5 in Scheme VIH and converted via the reactions in that scheme, described above, into compounds of formula I.
  • an organo-metalUc derivative of formula 82 such as phenyl magnesium bromide, cyclopentyl magnesium bromide, or N- methylpiperidin-4-yl magnesium bromide is condensed with an alpha-haloacetate derivative of formula 83, where X may be a halogen or alkoxy group, such as ethyl 2-fluoroacetate or 2-fluoroacetyl chloride, in an anhydrous solvent, for example ether or THF, to produce the alpha-fluoro compounds of formula 84.
  • organo-metalUc derivative of formula 82 such as phenyl magnesium bromide, cyclopentyl magnesium bromide, or N- methylpiperidin-4-yl magnesium bromide is condensed with an alpha-haloacetate derivative of formula 83, where X may be a halogen or alkoxy group, such as ethyl 2-fluoroacetate or 2-fluoroacetyl chloride, in
  • the compounds of formula 85 are in turn converted to compounds of formula 86 or 87 by condensation with an amidine derivative of formula 4 or 6, in which R* is loweralkyl, halo(loweralkyl) or cycloalkyl, or is an electron withdrawing group such as phenyl, trifluoromethyl, cyano, perfluoroalkyl, vinyl, substituted vinyl, fluorine, nitro, acetylene, substituted acetylene, alkoxycarbonyl, or a nitrogen-containing aromatic heterocycle, in the presence of a suitable base, for example triethylamine, in a polar solvent such as methanol.
  • R* is loweralkyl, halo(loweralkyl) or cycloalkyl, or is an electron withdrawing group such as phenyl, trifluoromethyl, cyano, perfluoroalkyl, vinyl, substituted vinyl, fluorine, nitro, acetylene, substituted acetylene, alkoxy
  • Compounds of formula 87 may be substituted for compounds of formula 7 in Scheme VIH, and converted via the reactions in that scheme, described above, into compounds of formula I.
  • Compounds of formula 86 may be substituted for compounds of formula 9B in Scheme H and, by reaction with a malonic acid diester as described for Scheme II above, converted directly into compounds of formula 12B and, thence, into compounds of formula I.
  • An alpha-haloacetate derivative of formula 1 is condensed with an acid haUde or ester derivative of formula 88, for example acetyl chloride, benzoyl chloride, isonicotinoyl chloride, or 2,6-dimethylisonicotinoyl chloride, in an anhydrous solvent, for example ether, THF, anhydrous methanol or an hydrous ethanol, in the presence of a suitable base, such as sodium methoxide or NaN(TMS)2, to produce the beta-ketoester derivative of formula 91, which is converted into compounds of formula 92 in the presence of a suitable base, such as sodium methoxide or sodium ethoxide, in the presence of a suitable solvent, such as methanol, ethanol or ether, to give the hydroxy-substituted compounds of formulae 92 or 93.
  • an acid haUde or ester derivative of formula 88 for example acetyl chloride, benzoyl chloride, isonico
  • non-fluorinated derivatives of formula 90 may be converted to the beta-ketoester derivatives of formula 91 using a reagent such as N-fluoropyridinium triflate, N-fluorosulfonyl amide, cesium fluorooxysulfate, or acetyl hypofluoride.
  • a reagent such as N-fluoropyridinium triflate, N-fluorosulfonyl amide, cesium fluorooxysulfate, or acetyl hypofluoride.
  • the compound of formula 89 is then reacted with hydrogen over a noble catalyst, such as Pd/C in a sodium acetate buffer, to remove the chlorine and give the compound of formula 90 (also isolated from a mixture of products by chromatography).
  • a noble catalyst such as Pd/C in a sodium acetate buffer
  • the compound of formula 90 is then reacted with a suitable alkyl halide, for example methyl halide or the like, hi the presence of a suitably strong and hindered base, for example Uthium dUsopropylamide (LDA), preferably at a temperature below 0°C, and conveniently at -78°C to afford the compounds of formula 91.
  • LDA Uthium dUsopropylamide
  • R ⁇ is haloalkyl, for example fluoroalkyl
  • the compound of formula 90 is first reacted with a suitably strong and hindered base, for example lithium dusopropylamide (LDA), preferably at a temperature below 0°C, and conveniently at -78°C foUowed by reaction with formaldehyde to give the compound where R ⁇ is hydroxymethyl which is then reacted with diaminosulfur trifluoride (DAST) in a non-polar solvent such as methylene chloride to give the compound of formula 91.
  • a suitably strong and hindered base for example lithium dusopropylamide (LDA), preferably at a temperature below 0°C, and conveniently at -78°C foUowed by reaction with formaldehyde to give the compound where R ⁇ is hydroxymethyl which is then reacted with diaminosulfur trifluoride (DAST) in a non-polar solvent such as methylene chloride to give the compound of formula 91.
  • the compound of formula 90 is first reacted with a suitably strong and hindered base, for example lithium dusopropylamide (LDA), preferably at a temperature below 0°C, and conveniently at -78°C foUowed by reaction with DMF to form the intermediate compound wherein R" is CHO, and this intermediate is then reacted with DAST to prepare the compound of formula 91, wherein R6 is difluoromethyl.
  • a suitably strong and hindered base for example lithium dusopropylamide (LDA)
  • LDA lithium dusopropylamide
  • the compounds of formula 91 are then reacted with hydrazine under nitrogen at reflux temperature for 2-8 hours, and after removal of excess hydrazine the residue is dissolved in an organic solvent, such as methanol or benzene, for example, and air is then passed through the solution of the hydrazino product for 8-16 hours to give the compounds of formula 92.
  • an organic solvent such as methanol or benzene, for example
  • he compounds of formula 92 are then condensed with cyclopropyl acetonitrile in a polar organic solvent, such as THF, for example, in the presence of strong base, such as Uthium diethylamide (LDA) or lithium dusopropylamide, at -78°C for 1-4 hours and then at 0°C for 1-4 hours or NaNH2 at -5°C to -10°C for 1 to 8 hours in order to prepare compounds of formula 93.
  • a polar organic solvent such as THF
  • strong base such as Uthium diethylamide (LDA) or lithium dusopropylamide
  • the compounds of formula 93 are then reacted with trifluoroacetic acid under nitrogen for 1-4 hours at ambient temperature to removed the protecting t-butoxide group, and the unprotected material is then reacted with POC13 in a suitable organic solvent, such as DMF or methylene chloride, for example, at ambient temperature for 8-24 hours in order to prepare the compounds of formula 94.
  • a suitable organic solvent such as DMF or methylene chloride
  • the compounds of formula 89 may be converted directly to the compounds of formula 91 by treatment with a strong base, such as t-butyllithium or s-butyllithium, for example, in a polar solvent such as THF or the like for a period of from 0.5 to 3 hours, followed by reaction with methyl iodide at a temperature firstly below -50°C then at ambient temperature for a period of from 4 to 20 hours.
  • a strong base such as t-butyllithium or s-butyllithium
  • a polar solvent such as THF or the like
  • the compounds of formula 91 may then be converted to the compounds of formula 92 by treatment with a hydride reducing agent, such as LAH or sodium bis-(2-methoxyethoxy)aluminum hydride (Red-AlTM), for example, at from 0°C to ambient temperature for a period of from 8-24 hours.
  • a hydride reducing agent such as LAH or sodium bis-(2-methoxyethoxy)aluminum hydride (Red-AlTM)
  • the resulting compounds of formula 93 are then reacted with POCI3 in an organic solvent such as DMF or methylene chloride, for example, at ambient temperature for a period of from 6-20 hours in order to prepare directly the compounds of formula 94.
  • the cyano compounds of formula 94 are converted to esters of formula 95 by treatment with anhydrous ethanolic HCI foUowed by treatment with H2O.
  • the ester compounds of formula 95 are then reduced to the aldehyde compounds of formula 96 by reaction with Uthium aluminum hydride in THF at reduced temperatures for 0.5 -2 hours, followed by reaction with oxalyl chloride and DMSO in the presence of triethyl amine at -78°C for 0.25- 1.0 hours.
  • the compounds of formula 96 are reacted with with a malonic acid diester, such as diethyl malonate, dibenzyl malonate, t-butyl malonate or di-t-butyl malonate, in the presence of a suitable base such as piperidine and a catalytic amount of an acid, such as acetic acid or sulfuric acid, in a polar solvent, such as ethanol, followed by isolation of the intemediate compounds of formula 97 with subsequent treatment thereof by heating in a polar, high-boUing solvent such as DMF or DMSO at reflux temperature or in Dowtherm ATM for a period of from 0.5 to 4 hours to form the pyridopyrimidine compounds of formula 98.
  • a malonic acid diester such as diethyl malonate, dibenzyl malonate, t-butyl malonate or di-t-butyl malonate
  • a suitable base such as piperidine
  • a catalytic amount of an acid such as
  • trifluoropyridine ether of formula 90 is reacted with a suitable strong base, for example, LDA, preferrably at a temperature below 0°C and convenientyly at -78°C, in an inert solvent such as THF, for example.
  • a suitable strong base for example, LDA
  • THF inert solvent
  • the anion thus generated is then reacted with an alkyl borate, such as, for example, trimethylborate or triethylborate, foUowed by oxidation with hydrogen peroxide in the presence of base such as sodium hydroxide in situ to give the compound of formula 100, wherein R' is lower alkyl.
  • Compound 100 is then alkylated with a suitable alkylating agent, such as an alkyl iodide or alkyl sulfate, for example methyl sulfate or ethyl iodide or the like, in the presence of a base such as sodium hydroxide, barium hydroxide, potassium carbonate, lithium carbonate, or the like, in a polar solvent, such as acetone, ethanol, DMF, THF, or the like, within a temperature range of room temperature to reflux temperature of the solvent, to give the compound of formula 101.
  • a suitable alkylating agent such as an alkyl iodide or alkyl sulfate, for example methyl sulfate or ethyl iodide or the like
  • a base such as sodium hydroxide, barium hydroxide, potassium carbonate, lithium carbonate, or the like
  • a polar solvent such as acetone, ethanol, DMF, THF, or the like
  • compound 101 can be obtained by treating compound 100 with an alcohol of the formula R ⁇ OH, wherein R ⁇ is as described above, triphenylphosphine and diethyldiazocarboxylate in a solvent such as THF at a temperature in the range of 0°C to room temperture.
  • Compound 103 is then reacted with hydrazine at a temperature in the range of room temperature to reflux temperature, and in a solvent such as methanol, iso-propanol, ether, or the like, foUowed by bubbling air through the solution of the intermediate in a solvent such as benzene of toluene, in the presence of a base such as sodium hydroxide to give to compound of formula 104.
  • a solvent such as methanol, iso-propanol, ether, or the like
  • the pentafluoropyridine of formula 102 is dissolved in a solvent, such as for example, THF or methylene chloride, and reacted with a cyclic amine of the formula R ⁇ H, wherein R ⁇ is as defined above, or, when R ⁇ is substituted with a reactive group such as an amino group, a cycUc amine with suitably protected reactive substituents, in the presence iof a suitable base, such as a tertiary amine, such as for example triethylamine, at a temperature in the range of 0°C to room temperature.
  • a solvent such as for example, THF or methylene chloride
  • the reactant of formula 106 wherein R ⁇ 6 i s as defined above and TBS represents a tributylsUyl group, is generated from the corresponding iodide starting material by reaction with t-butyl lithium in ether at -78°C, and is reacted with compound 105 in a solvent such as THF or ether at -78°C to give the compound of formula 107.
  • the protecting TBS group is removed from compound 107 by reaction with tetrabutylammonium fluoride in THF at room temperature to give the compound of formula 108.
  • the trifluoro compound 108 is converted into the difluoro compound 109 by reacting compound 108 with hydrazine at reflux temperature in a solvent such as ether, propanol, or methoxymethyl ether, followed by treatment of an intermediate hydrazino product with CuSO4 in a solvent such as methanol, ethanol, or toluene, or alternately by reaction with air in the presence of a base such as NaOH.
  • the monocycUc compound 109 is then converted into the bicycUc compound of formula 110 by reaction with NaH at reflux temperature in a solvent such as dioxane or THF.
  • Compound 110 is then treated with a strong base, such as LDA at -78°C, for example, and condensed with diethyl ethoxymethylenemalonate to give an intermediate product which is cycUzed in the presence of a base such as DBU or piperidine/acetic acid, in a solvent such a ethanol or aqueous THF, at a temperature from room temperature to 60°C, to give the tricyclic ester of formula 111.
  • the ester 111 is hydrolyzed to the acid of formula 112 with an alkaU metal hydroxide in aqueous THF, for example. Any protecting groups remaining onthe R2 or R16 groups may conveniently be removed at this point to give the desired compound of Formula I.
  • the trifluoro compound 113 is converted into the difluoro compound 114 by reaction with hydrazine at reflux temperature in a solvent such as ether, propanol, or methoxymethyl ether, foUowed by treatment of an intermediate hydrazino product with CuSO4 in a solvent such as methanol, ethanol, or toluene, or alternately by reaction with air in the presence of a base such as NaOH.
  • the monocyclic compound 114 is then converted into the bicyclic compound of formula 115 by reaction with NaH at reflux temperature in a solvent such as dioxane or THF.
  • Compound 115 is then treated with a strong base, such as LDA at -78°C, for example, and condensed with diethyl ethoxymethylenemalonate to give an intermediate product which is cycUzed in the presence of a base such as DBU or piperidine/acetic acid, in a solvent such a ethanol or aqueous THF, at a temperature from room temperature to 60°C, to give the tricycUc ester of formula 116.
  • the protecting t-butoxy group is removed from compounds 1 16 by reaction with an acid, such as HCI or trifluoroacetic acid at room temperature, and optionally in a suitable solvent, such as methylene chloride or dioxane to give compound s 117.
  • Compounds of formula 125 are then cycUzed to compounds of formula 126 by reaction with Br(CH2) n B(CH2) m Br or I(CH2 ) n B(CH2) m I or R substituted iodide or bromide, for example, wherein B is CH2, N, O or S, in the presence of a base such as NaH and in a solvent such as DMF, DMSO, or the like, at room temperature or elevated temperature.
  • Sodium hydride (4.36 g of 60% NaH in mineral oil, 107.6 mmol) was suspended, under a nitrogen atmosphere, in 125 mL of anhydrous diethyl ether in a 500 mL round-bottom flask fitted with a mechanical stirrer, a thermometer and a condenser. To this mixture, with vigorous stirring, was slowly added 6.28 mL (107.6 mmol) of anhydrous ethyl alcohol. After the evolution of gas ceased, a mixture of ethyl 2- fluoroacetate (10 mL, 102.5 mmol) and ethyl formate (12.5 mL, 153.7 mmol) was added, dropwise, to the ethoxide solution.
  • the reaction mixture was cooled when necessary in order to maintain the reaction temperature between 18°C and 20°C.
  • the reaction mixture was stirred, under a nitrogen atmosphere, at 18-20°C for 4.75 hours.
  • the solvent was removed under aspirator pressure, fresh anhydrous diethyl ether was added to the residue and the ether solution was concentrated under reduced pressure to afford, as a solid residue, the sodium enolate of ethyl 2-fluoro-3-oxo-2-propanecarboxylate, as described by E.EUdk and M. Imbeaux-Oudotte in ⁇ ull S ⁇ c Chim. 1165-1169, 1975.
  • Step 2 4-Chloro-5-fluoro-2-( -fluorobenzylVpyrimidine
  • Step 4 Diethyl 2-ethoxy-3-(4-fluorophenyl)-3-[5-fluoro-4- (4-methvpiperazin- 1 -vDpyrimidin-2-yll-propane- 1.1 -dicarboxylate
  • a solution of 0.35 mL (2.5 mmol) of diisopropylamine in 5 mL of anhydrous tetrahydrofuran (THF) was prepared under a nitrogen atmosphere and cooled in an ice/water bath.
  • THF anhydrous tetrahydrofuran
  • To this solution was added via syringe, 1.0 mL of a 2.5 M solution of n- butylUthium (2.5 mmol) in hexane. The solution was stirred for 15 minutes at 0°C and then cooled to -78 °C.
  • reaction mixture was poured into 30 mL of water, with 6 g of soUd ammonium chloride.
  • the aqueous mixture was extracted with 4 X 50 mL of methylene chloride.
  • the combined organic extract was dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was dissolved in 300 mL of methylene chloride.
  • Step 5 Ethyl 3-fluoro-9-(4-fluorophenyl)-2-(4-methylpiperazin- 1 -yl) -6H-6-oxo-pyridor 1 ,2-alpyrimidine-7-carboxylate
  • the layers were separated and the organic layer was dUuted with 75 mL of methylene chloride and washed with 20 mL of water. The aqueous layer was extracted with 25 mL of methylene chloride and the methylene chloride layer from this extraction was combined with the organic layer. The combined organic layers were dried over anhydrous magnesium sulfate, filtered and concentrated.
  • Step 7 3-Fluoro-9-(4-fluorophenyl)-2-(4-methylpiperazin-l-yl)- 6H-6-oxo-pyridor 1 ,2-alpyrimidine-7 -carboxylic acid
  • the solid was purified by chromatography on a 70-230 mesh sUica gel column (1.8 X 18.5 cm) eluted with chloroform:methanol:acetic acid:water (100:25:5:2.5 v/v/v/v). The fractions containing the desired product were combined and concentrated. Toluene was added to the residue and evaporated in vacuo. Chloroform was then added to the residue and evaporated in vacuo to afford the title compound as a yeUow solid, m.p.
  • Step 1 Ethyl 3-fluoro-9-(4-fluorophenyl)-2-hydroxy- 6H-6-oxo-pyridor 1.2-alpyrimidine-7 -carboxylate
  • Step 2 Ethyl 2-chloro-3-fluoro-9-(4-fluorophenyl)- 6H-6-oxo-pyridor 1.2-alpyrimidine-7-carboxylate
  • Step 3 Ethyl 3-fluoro-9-(4-fluorophenyl)-2-(4-methylpiperazin- 1 -yl)- 6H-6-oxo-pyridoI 1.2-alpyrimidine-7-carbox ylate
  • Step 4 Benzyl 3-fluoro-9-(4-fluorophenyl)-2-(4-methylpiperazin- 1 -yl)- 6H-6-oxo-pyridor 1.2-alpyrimidine-7 -carboxylate
  • the layers were separated and the organic layer was dUuted with 75 mL of methylene chloride and washed with 20 mL of water.
  • the aqueous layer was extracted with 25 mL of methylene chloride and the methylene chloride layer from this extraction was combined with the organic layer.
  • the combined organic layers were dried over anhydrous magnesium sulfate, fUtered and concentrated.
  • Step 5 3-Fluoro-9-(4-fluorophenyl)-2-(4-methylpiperazin-l-yl)- 6H-6-oxo-pyrido ⁇ ,2-alpyrimidine-7 -carboxylic acid
  • the solid was purified by chromatography on a 70-230 mesh sUica gel column (1.8 X 18.5 cm) eluted with chloroform:methanol:acetic acid:water (100:25:5:2.5 v/v/v/v). The fractions containing the desired product were combined and concentrated. Toluene was added to the residue and evaporated in vacuo. Chloroform was then added to the residue and evaporated in vacuo to afford the title compound as a yeUow solid, m.p.
  • Examples 3-20 as disclosed in Table 1 , may be prepared which have the general formula
  • Examples 21-38 as also disclosed in Table 1, may be prepared by using the appropriate amine and 2,4-difluorobenzylamidine instead of 4-fluoro- benzylamidine to produce the general formula
  • the cyclopropylacetic acid (15 g, 150 mmol) in a flask protected from moisture is cooled in an ice bath and 13.2 mL (180 mmol) of thionyl chloride is added dropwise with stirring. After the addition is complete, the reaction mixture is warmed to ambient temperature and then to 50°C. The reaction mixture is heated at 50°C for 1 hour and then cooled in an ice bath. Absolute ethanol (26 mL, 450 mmol) is added dropwise with stirring to the reaction mixture. After the addition is complete, the reaction mixture is stirred at ambient temperature overnight. The reaction mixture is diluted with 500 mL of methylene chloride and then washed with 200 mL of 5% aqueous sodium bicarbonate solution. The organic layer is dried over anhydrous sodium sulfate, filtered and the ethyl ester of cyclopropylacetic acid is obtained by distillation.
  • 2-Cyclopropyl-3-hydroxyacrylic acid (12.8 g, 100 mmol), from Step 1, is dissolved in 150 mL of dry dimethoxyethane in an oven-dried system under positive nitrogen atmosphere.
  • the resultant solution is cooled in an ice bath and 4.4 g of 60% sodium hydride in mineral oU is added.
  • the mixture is stirred for several hours at approximately 0°C and then for several hours at ambient temperature.
  • the reaction mixture is cooled in an ice bath and 8.9 mL (110 mmol) of ethyl formate in 90 mL of dry dimethoxyethane is added dropwise with stirring. After the addition is complete, the reaction mixture is sti ⁇ ed overnight at ambient temperature.
  • a solution of 11.5 (88 mmol) of monoethyl malonate monoamide in 25 mL of dry THF is cooled in an ice bath and is treated with 10.7 g (95 mmol) of potassium t-butoxide.
  • the reaction mixture is stirred at 0-5 °C for 1 hour.
  • a solution of 12.5 g (80 mmol) of 2- cyclopropyl-3-hydroxyacryUic acid, from Step 1, in 20 mL of dry THF is added dropwise with stirring.
  • the reaction mixture is then warmed to ambient temperature and then heated at reflux overnight.
  • the reaction mixture is poured into brine and is extracted with ethyl acetate.
  • the organic layer is dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to afford the title compound.
  • Ethyl 5-Cyclopropyl-2,6-dichloro-nicotinic acid (11.2 g, 50 mmol) from Step 3 is dissolved in 15 mL of anhydrous DMF. To this solution is added 25 mL of concentrated ammonium hydroxide and the reaction mixture is heated at reflux overnight. The reaction mixture is cooled to ambient temperature, dUuted with water and extracted with 1 ,2- dichloroethane. The organic layer is dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue is dissolved in 250 mL of 1,2-dichloroethane and 200 mL of 10% aqueous sodium carbonate solution.
  • reaction mixture is slowly warmed to ambient temperature and stirred overnight at ambient temperature.
  • the reaction mixture is then poured into brine and extracted with ethyl acetate.
  • the ethyl acetate solution is dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. to afford the title compound.
  • Step 6 2-Chloro-5-cyclopropyl-6- N-((4,5dimethoxy-2-nitro-phenyl)methoxy- carbonylVN-(2-fluoro-3-hvdrox v- 1 -oxo- 1 -prop-2-enyl amino-nicotinic acid
  • Step 7 Ethyl 9-cyclopropyl- 1 -((4,5dimethoxy-2-nitro-phenyl)methoxycarbonyl)3- fluoro-2-hvdroxy-6H-6-oxo-pyridor 1.2-alpyrimidine-7-carboxylate
  • Step 8 Ethyl 9-cyclopropyl-3-fluoro-2-chloro-6H- 6-oxo-pyridori.2-alpyrimidine-7 -carboxylate
  • Step 7 The residue is purified by siUca gel chromatography to afford the product of Step 7 with the nitrogen protecting group removed.
  • This product is dissolved in 1,2-dichloroethane and tretaed with phosphorous oxychloride at ambient temperature for 18 hours.
  • the reaction mixture is dUuted with 1,2-dichloroethane and is washed with saturated aqueous sodium bicarbonate solution and brine.
  • the organic layer is dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to afford crude title compound which is purified by recrystallization from ethyl alcohol.
  • Step 9 Ethyl 9-cyclopropyl-3-fluoro-2-(4-methylpiperazin-l-yl)- 6H-6-oxo-pyridor 1.2-alpyrimidine-7 -carboxylic acid
  • Step 10 9-Cyclopropyl-3-fluoro-2-(4-methylpiperazin-l-yl)- 6H-6-oxo-pyrido ⁇ .2-a1pyrimidine-7 -carboxylic acid
  • Examples 40 - 57 may be prepared as disclosed in Table 2 wherein the compounds have the general formula
  • Example 58 8-(3- Amino- 1 -pyrrolidinyl 4H-quinolizin-4-one-3-carboxyUc acid hydrochloride
  • the ether extract was discarded.
  • the aqueous layer was adjusted to pH 8.0 with potassium carbonate and then extracted with ethyl acetate.
  • the organic extract was dried over anhydrous sodium sulfate, fUtered and concentrated under reduced pressure.
  • the Uquid concentrate was distilled to afford 8.737 g of a mixture of the title compound and the isomeric 6-chloro-2-picoline as a clear colorless liquid, b.p. 70°C (25 mm Hg).
  • This product was combined with another sample of the same mixture prepared separately by the same procedure.
  • the isomeric products were inseparable by distillation.
  • the combined products (12.905 g) were dissolved in 750 mL of ethyl alcohol.
  • Lithium dUsopropylamide (LDA: 16 mL of a 1.5 M solution in hexane) was added to 8 mL of dry THF, under a nitrogen atmosphere, and the resultant solution was cooled to -70°C in a isopropyl alcohol/dry ice bath.
  • LDA Lithium dUsopropylamide
  • the solution turned a very dark red color.
  • the black-green-colored solution was then poured into 500 mL of hexane and a precipitate formed.
  • the precipitate was collected by filtration, washed with 5 X 100 mL of hexane and dried to afford 1.487 g (48% yield) of the title compound.
  • Ethyl 8-chloro-4H-quinolizin-4-one-3-carboxylate (1.0 g, 3.97 mmol), from Step 3, was dissolved in 20 mL of dry pyridine under a nitrogen atmosphere. To the resultant solution was added a solution of 1.85 g (9.92 mmol) of 3-(N-t- butoxycarbonylamino)pyrrolidine in 5 mL of dry pyridine and the reaction mixture was heated at 70°C for 4.5 hours. The reaction mixture was then concentrated in vacuo in order to remove all of the pyridine.
  • 3-Amino-l-benzylpy ⁇ olidine (I. Sumio and T. Matsuo, Japanese Kokai JP 5328161, published March 16, 1978) is coupled to N-t-butoxycarbonyl norvaline (Boc- nVal) using conventional N-hydroxysuccinimide coupling procedures.
  • the 1 -benzyl group is removed by hydrogenolysis in methanol using paUadium on carbon catalyst.
  • the 3-(N- Boc-norvalyl)aminopyrrolidine is then reacted with ethyl 8-chloro-4H-quinolizin-4-one-3- carboxylate, the product of Step 3 of Example 58, as described in Step 4 of Example 58, replacing 3-(N-t-butoxycarbonylamino)pyrrolidine with 3-(N-Boc- norvalyl)aminopyrroUdine, to give 8-(3-(N-norvalyl)amino-pyrrolidinyl)-4H-quinoUzin-4- one-3-carboxyUc acid with the nitrogen of the amino acid protected with a Boc group.
  • the Boc protecting group is removed by standard hydrolysis using trifluoroacetic acid and dUute aqueous hydrochloric acid.
  • amino acids which can be coupled include naturaUy occurring amino acids such as glycine, alanine, leucine, isoleucine, methionine, phenylalanine, valine, and the like, as weU as synthetic amino acids such as cyclohexylala.nine, cyclohexylglycine, aminopentanoic acid, and the like.
  • Ethyl 8-chloro-4H-quinolizin-4-one-3-carboxylate (125 mg, 0.5 mmol) was suspended in 5 mL of 0.5 N aqueous sodium hydroxide solution. The reaction mixture was heated to 65 °C and 2 mL of THF was added. After the reaction mixture was stirred at 65°C for 1 hour, the THF was distilled from the mixture. Stirring was continued for 2 hours at 65°C and then the reaction mixture was allowed to cool to ambient temperature. The aqueous mixture was adjusted to pH 2 with 3 mL of 1.0 N aqueous hydrochloric acid solution and diluted with 10 mL of water.
  • the precipitate was coUected by filtration, washed with 2 X 15 mL of water and dried in vacuo to afford 100 mg (89% yield) of the title compound, m.p. 229-230°C.
  • the product was recrystaUized from ethyl alcohol and dried in vacuo to afford 50 mg (44.5% yield) of the title compound, m.p.
  • Step 1 Ethyl 8-f 4-methylpiperazin- 1 -ylV4H-quinolizin-4-one-3-carboxylate
  • Ethyl 8-chloro-4H-quinolizin-4-one-3-carboxylate (755 mg, 3.0 mmol), the product of Step 3 of Example 58, was suspended in 12 mL of dry pyridine under a nitrogen atmosphere. To the resultant solution was added 6.0 mL (6.0 mmol) of N- methylpiperazine and the reaction mixture was heated at 70°C for 8 hours. The reaction mixture was then concentrated in vacuo in order to remove aU of the pyridine. The dry residue (3.124 g) was dissolved in 125 mL of methylene chloride and the methylene chloride solution was washed with 125 mL of saturated sodium chloride solution (brine).
  • Ethyl 8-chloro-l-ethyl-4H-quinolizin-4-one-3-carboxylate (1.20 g, 4.3 mmol), from Step 3, was dissolved, under a nitrogen atmosphere, in 15 mL of dry pyridine.
  • To the resultant solution was added 1.04 g (5.59 mmol) of 3-(N-t-butoxycarbonylamino- pyrrolidine) and 1.8 mL (12.9 mmol) of dry triethylamine and the reaction mixture was heated at 60°C for 12 hours. The reaction mixture was then concentrated in vacuo in order to remove all of the pyridine.
  • Ethyl alcohol (4 mL) was added to the dry residue.
  • amino acids which can be coupled include naturally occurring amino acids such as glycine, alanine, leucine, isoleucine, methionine, phenylalanine, valine, and the like, as weU as synthetic amino acids such as cyclohexylalanine, cyclohexylglycine, aminopentanoic acid, and the like.
  • Ethyl 8-chloro-l-ethyl-4H-quinoUzin-4-one-3-carboxylate (558 mg, 2.0 mmol), the product of Step 3 of Example 62, was dissolved in 10 mL of dry pyridine under a nitrogen atmosphere. To the resultant solution was added 600 mg (6.0 mmol) of 2- methylpiperazine and the stirred reaction mixture was heated at 65°C for 3 hours. The reaction mixture was aUowed to cool to ambient temperature and then concentrated in vacuo in order to remove aU of the pyridine. The residue was dissolved in 60 mL of methylene chloride and the methylene chloride solution was washed with 60 mL of water.
  • the aqueous layer was extracted with 2 X 60 mL of methylene chloride and the combined methylene chloride solutions were dried over anhydrous sodium sulfate, fUtered and concentrated and dried in vacuo to afford 690 mg of the title compound.
  • the product was carried on to the next step without purification.
  • Ethyl 8-chloro-l-ethyl-4H-quinoUzin-4-one-3-carboxylate (279 mg, 1.0 mmol), the product of Step 3 of Example 62, was dissolved in 5 mL of dry pyridine under a nitrogen atmosphere. To the resultant solution was added 2 mL (2.0 mmol) of N- methylpiperazine and the stirred reaction mixture was heated at 85°C for 2.5 hours. The reaction mixture was aUowed to cool to ambient temperature and then concentrated in vacuo in order to remove aU of the pyridine. The residue was dissolved in 50 mL of methylene chloride and the methylene chloride solution was washed with 50 mL of 5% aqueous sodium bicarbonate solution.
  • the reaction was carried out in a flask vented to a gas scrubber containing aqueous sodium hydroxide solution.
  • the product of Step 5 5-fluoro-2-picoline-N-oxide (1.0 g, 7.86 mmol) was cooled to 0°C and concentrated sulfuric acid (4.2 mL) was slowly added, with stirring. Solid potassium nitrate (1.27 g, 12.5 mmol) was then added to this mixture at 0°C, in smaU portions over a 45 minute period. The reaction mixture was aUowed to warm to ambient temperature and was stirred at ambient temperature for 1 hour.
  • the flask was tr ⁇ /wferred to a cold water bath and the temperature of the solution brought down to ambient.
  • the reaction mixture was then poured over ice.
  • the resultant aqueous mixture was adjusted to pH 9 with potassium carbonate and steam distiUed.
  • the aqueous distillate collected at 92-96°C was extracted with three portions of methylene chloride.
  • the combined organic extract was dried over anhydrous sodium sulfate, filtered and distilled to afford 15.91 g (71% yield) of the title compound, b.p.
  • Diisopropylamine (924 ⁇ L, 6.59 mmol) was dissolved in 9 mL of dry THF and the resultant solution was cooled to 0°C in an ice bath.
  • n-ButyUithium (3.07 mL of a 2.05 M solution in THF, 6.29 mmol) was added via syringe to the amine solution and the resultant solution was stirred for 30 minutes at 0°C.
  • the Uthium diisopropylamide (LDA) solution was then cooled to -50°C in an isopropyl alcohol/dry ice bath.
  • reaction was then quenched by pouring the reaction solution into 60 mL of 10% aqueous ammonium chloride solution.
  • aqueous mixture was extracted with 2 X 50 mL of methylene chloride.
  • the combined organic extract was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo and the residue was distiUedto afford the title compound, b.p.
  • Example 67 By foUowing the procedures described in Example 67 and replacing 4-chloro-5- fluoro-2-picoUne (the product of Example 66) with 4-chloro-5-fluoro-2-propyl-pyridine (the product of Example 70), the title compound can be prepared.
  • Example 68 By foUowing the procedures described in Example 68 and replacing 4-chloro-5- fluoro-2-picoUne (the product of Example 66) with 4-chloro-5-fluoro-2-propyl-pyridine (the product of Example 70), the title compound can be prepared.
  • the titie compound can be prepared.
  • Example 76 By foUowing the procedures described in Step 2 of Example 62 and in Example 65 and replacing 4-chloropicoline with 4-chloro-5-fluoro-picoline (the product of Example 66), and replacing N-methylpiperazine with 2-methylpiperazine, the title compound can be prepared.
  • Example 76
  • Example 66 Following the procedures described in Example 62, replacing 4-chloropicoUne with 4-chloro-5-fluoro-picoline (the product of Example 66), the title compound is prepared.
  • Example 80 Following the procedures described in Example 62, replacing 4-chloropicoUne with 3,4-dichloro-5-fluoropicoline (the product of Example 67), the title compound is prepared.
  • Example 80 Following the procedures described in Example 62, replacing 4-chloropicoUne with 3,4-dichloro-5-fluoropicoline (the product of Example 67), the title compound is prepared.
  • Example 80
  • Example 84 FoUowing the procedures described in Step 2 of Example 62 and in Example 65, replacing 4-chloropicoUne with 4-chloro-3,5-difluoropicoline (the product of Example 69), the titie compound is prepared.
  • Example 84
  • Example 85 8- (3- Amino- 1 -pyrroUdinyl)-7,9-difluoro- 1 -ethyl-
  • Example 66 and replacing ethyl iodide with cyclopropyl iodide, the title compound is prepared.
  • Example 88 FoUowing the procedures described in Steps 1 and 2 of Example 62, replacing 4- chloropicoUne with 4-chloro-5-fluoropicoUne (the product of Example 66) and replacing ethyl iodide with cyclopropyl iodide, and the procedures described in Example 65, replacing N-methylpiperazine with 2-methylpiperazine, the title compound is prepared.
  • Example 88
  • Example 62 Following the procedures described in Example 62, replacing 4-chloropicoUne with 4-chloro-5-fluoropicoline (the product of Example 66), and replacing ethyl iodide with cyclopropyl iodide, the title compound is prepared.
  • Example 92 Following the procedures described in Example 62, replacing 4-chloropicoUne with 3,4-dichloro-5-fluoropicoUne (the product of Example 67) and replacing ethyl iodide with cyclopropyl iodide, the title compound is prepared.
  • Example 92 Following the procedures described in Example 62, replacing 4-chloropicoUne with 3,4-dichloro-5-fluoropicoUne (the product of Example 67) and replacing ethyl iodide with cyclopropyl iodide, the title compound is prepared.
  • Example 92 Following the procedures described in Example 62, replacing 4-chloropicoUne with 3,4-dichloro-5-fluoropicoUne (the product of Example 67) and replacing ethyl iodide with cyclopropyl iodide, the title compound is prepared.
  • Example 92 Following the procedures described in Example 62, replacing 4-chloropicoUne with 3,4
  • Example 62 FoUowing the procedures described in Example 62, replacing 4-chloropicoUne with 3-bromo-4-chloro-5-fluoropicotine (the product of Example 68) and replacing ethyl iodide with cyclopropyl iodide, the title compound is prepared.
  • Example 96 FoUowing the procedures described in Steps 1 and 2 of Example 62, replacing 4- chloropicoUne with 4-chloro-3,5-difluoropicoUne (the product of Example 69) and replacing ethyl iodide with cyclopropyl iodide, and the procedures described in Example 65, the title compound is prepared.
  • Example 96
  • Example 62 Following the procedures described in Example 62, replacing 4-chloropicoUne with 4-chloro-3,5-difluoropicoUne (the product of Example 69) and replacing ethyl iodide with cyclopropyl iodide, the title compound is prepared.
  • Lithium dUsopropylamide (LDA: 16 mL of a 1.5 M solution in hexane) is added to 8 mL of dry THF, under a nitrogen atmosphere, and the resultant solution is cooled to -70°C in a isopropyl alcohol/dry ice bath.
  • LDA Lithium dUsopropylamide
  • Ethyl 8-chloro-7-fluoro- 1 -methylamino-4H-quinoUzin-4-one-3-carboxylate (899 mg, 3.0 mmol), the product of Step 6, is suspended in 12 mL of dry pyridine under a nitrogen atmosphere. To the resultant solution is added 6.0 mL (6.0 mmol) of N- methylpiperazine and the reaction mixture is heated at 70°C for 8 hours. The reaction mixture is then concentrated in vacuo in order to remove aU of the pyridine. The dry residue is dissolved in 125 mL of methylene chloride and the methylene chloride solution is washed with 125 mL of brine.
  • the THF is removed from the reaction mixture by distiUation during the reaction.
  • the concentrated reaction mixture is cooled to ambient temperature and adjusted to pH 2.0 with 10.5 mL of 1 N aqueous hydrochloric acid solution.
  • the aqueous solution is concentrated in vacuo to remove -80% of the water and the concentrate is diluted with 50 mL of 95% ethyl alcohol.
  • the solid is coUected by filtration, washed with 2 X 5 mL of ethyl alcohol and dried in vacuo to afford the desired product.
  • Examples 99-116 are prepared as disclosed in Table 3 wherein the compounds have the general formula
  • Example No. F Example No. ⁇ '
  • Example 98 By foUowing the procedures described in Example 98 and replacing 4-chloro-5- fluoro-2-picoUne (the product of Example 66) with 4-chloro-3,5-difluoro-2-picoline (the product of Example 69), the titie compound is prepared.
  • Examples 118-135 are prepared as disclosed in Table 4 wherein the compounds have the general formula
  • 2,3,4,5,6-Pentafluoropyridine (commerciaUy avaUable from Aldich Chemical Co.) is oxidized to the corresponding N-oxide foUowing the procedures described in Step 6 of Example 66.
  • the 2,3,4,5,6-pentafluoropyridine N-oxide is treated at ambient temperature with one equivalent of methylmagnesium iodide in diethyl ether as described by F. Binns and H. Suschitsky in Chemical Communications. 750-751 (1970) and J Chem Soc (C). 1223-1231 (1771).
  • the reaction mixture is treated with aqueous ammonium chloride and extracted with diethyl ether.
  • reaction mixture is stirred at -60°C for 0.5 hours, the cooling bath is allowed to slowly (1.5 hours) warm to -30°C.
  • the reaction mixture is poured into cold brine and the aqueous mixture is extracted with methylene chloride. The organic extract is dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue is distilled to afford the titie compound.
  • a solution of 12.6 mL (89.9 mmol) of diisopropylamine in 20 mL of anhydrous tetrahydrofuran (THF) is prepared under a nitrogen atmosphere and cooled in an ice/water bath.
  • THF anhydrous tetrahydrofuran
  • To this solution is added, dropwise over a 30 minute period, 36 mL of a 2.5 M solution of n-butyUithium (90 mmol) in hexane. The solution is stirred for 30 minutes at 0°C and then cooled to -60°C.
  • Step 5 Ethyl l-ethyl-8-(4-methylpiperazin-l-yl)-6,7,9- trifluoro-4H-quinolizin-4-one-3-carboxylate
  • Ethyl 8-chloro- 1 -ethyl-6,7,8,9-tetrafluoro-4H-quinolizin-4-one-3-carboxylate (317 mg, 1.0 mmol), from Step 4, is dissolved in 5 mL of dry pyridine under a nitrogen atmosphere. To the resultant solution is added 2 mL (2.0 mmol) of N-methylpiperazine and the stirred reaction mixture is heated at 85°C for 2.5 hours. The reaction mixture is aUowed to cool to ambient temperature and then concentrated in vacuo in order to remove aU of the pyridine.
  • Step 1 Ethyl 8-(3-(N-t-butoxycarbonyl)amino-l-pyrroUdinyl)- ; l-ethyl-6.7.9-trifluoro-4H-quinolizin-4-one-3-carboxylate
  • Ethyl 6,7,8,9-tetrafluoro-l-ethyl-4H-quinolizin-4-one-3-carboxylate (1.26 g, 3.97 mmol), from Step 3 of Example 136, is dissolved in 20 mL of dry pyridine under a nitrogen atmosphere. To the resultant solution is added a solution of 1.85 g (9.92 mmol) of 3-(N-t-butoxycarbonylamino)pyrroUdine in 5 mL of dry pyridine and the reaction mixture is heated at 70°C for 4.5 hours. The reaction mixture is then concentrated in vacuo in order to remove all of the pyridine. The dry residue (3.124 g) is purified by chromatography on siUca gel to afford the title compound.
  • Step 2 8-(3- Amino- 1 -pyrroUdinyl)- l-ethyl-6,7,9-trifluoro- 4H-quinoUzin-4-one-3-carboxylic acid hydrochloride
  • the mixture is fUtered and the filtrate is concentrated under reduced pressure to afford crude ethyl 8-(3-amino-l-py ⁇ olidinyl)-l-ethyl-6,7,9- trifluoro-4H-quinolizin-4-one-3-carboxylate as a residue.
  • the residue is dissolved in 5 mL of THF and 11 mL of a 1 M aqueous solution of sodium hydroxide is added.
  • the reaction mixture is heated at 60°C for 1 hour and then the reaction temperature is increased to 85°C in order to evaporate the THF.
  • the concentrated reaction solution is diluted with 20 mL of water and the pH of the resultant solution is adjusted to 0 with concentrated hydrochloric acid.
  • the aqueous solution is concentrated in vacuo.
  • the residue is crystalUzed from ethyl alcoholasopropyl alcohobwater (4:4: 1 v/v/v) and recrystallized from ethyl alcohol/water to afford the title compound.
  • the 3-(N- Boc-norvalyl)aminopyrroUdine is then reacted with ethyl 6,7,8,9-tetrafluoro-l-ethyl-4H- quinolizin-4-one-3-carboxylate, as described in Step 1 of Example 137, replacing 3-(N-t- butoxycarbonylamino)pyrroUdine with 3-(N-Boc-norvalyl)aminopyrroUdine, to give 1- ethyl-8-(3-(N-norvalyl)amino-pyrrolidinyl)-4H-quinoUzin-4-one-3-carboxylic acid with the nitrogen of the amino acid protected with a Boc group.
  • the Boc protecting group is removed by standard hydrolysis using trifluoroacetic acid and dilute aqueous hydrochloric acid.
  • amino acids which can be coupled include naturaUy occurring amino acids such as glycine, alanine, leucine, isoleucine, methionine, phenylalanine, valine, and the like, as weU as synthetic amino acids such as cyclohexylalanine, cyclohexylglycine, aminopentanoic acid, and the like.
  • Examples 139-155 are prepared as disclosed in Table 5 in which the compounds have the general formula
  • Step 1 4-Chloro-3.5-difluoro-2-( " l-f2-tetrahydropyranvI)oxy-2-propyl)pyridine
  • a solution of 12.8 g (150 mmol) of 2-chloro-l -propanol is dissolved in 200 mL of acetone.
  • To the resultant solution are added 40 g of anhydrous ferric chloride and 30 g (200 mmol) of sodium iodide.
  • the reaction mixture is stirred at room temperature for 24 hours and then filtered to remove sodium chloride.
  • the solvent is evaporated to afford the corresponding 2-iodo-l -propanol.
  • the iodo alcohol is dissolved in 200 mL of methylene chloride and is treated with 20.5 mL (225 mmol) of 3,4-dihydro-2H-pyran and 50 mg of p- toluenesulfonic acid.
  • reaction mixture is stirtred at room temperature for several hours and then poured into 200 mL of 5% aqueous sodium bicarbonate solution.
  • aqueous mixture is extracted with methylene chloride.
  • the methylene chloride solution is dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford the THP-protected 2-iodo-l -propanol.
  • reaction is quenched by pouring the reaction mixture into 400 mL of saturated aqueous ammonium chloride solution.
  • the aqueous layer is separated and extracted with methylene chloride.
  • the combined organic layers are dried over anhydrous sodium sulfate, fUtered and concentrated under in vacuo to afford the title compound.
  • Step 1 The product of Step 1 is dissolved in 200 mL of 2: 1 THF:water and to this solution is added 6 mL of acetic acid. The reaction mixture is heated at 45 °C for approximately 5 hours. The THF is removed under reduced pressure and the aqueous reaction mixture is adjusted to a pH in the range of 8 to 9 with 10% sodium carbonate and is then extracted with methylene chloride. The organic layer is dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to afford the title compound. Step 3. 8-Chloro-3.4-dihvdro-7-fluoro-3-methyl-2H-pyranor3.2-blpyridine
  • Step 2 The product of Step 2 (15.5 g, 75 mmol) is dissolved in 100 mL of dry THF in an oven-dried system under positive nitrogen atmosphere. The reaction mixture is cooled in ice and 3.2 g (80 mmol) of 60% sodium hydride is added. The reaction mixture is warmed to room temperature and then heated at reflux temperature overnight with stirring. The reaction mixturte is cooled to room temperature and poured into brine. The aqueous mixture is extracted with ethyl acetate. The organic layer is dried over anhydrous magnesium sulfate, fUtered and concentrated in vacuo to afford the titie compound.
  • Step 3 FoUowing the procedure described in Step 2 of Example 62, the product of Step 3 is treated with ethyl 2-carboethoxy-3-ethoxy-2-propenecarboxylate and LDA to afford the title compound.
  • Step 4 the product of Step 4 is heated in refluxing Dowtherm A® to afford the desired cyclized product.
  • Step 7 1 l,12-Dihydro-7-fluoro- 12-methyl-8- (4-methyl- l-piperaziny ⁇ -4H-pyranori.jlquin-olizin-4-one-3-carboxylic acid
  • Example 157 FoUowing the procedures described in Step 2 of Example 65, the tUe compound is prepared.
  • reaction was diluted with 100 mL of anhydrous ethanol, 70 mL of ammonia in ethanol (4.17 M) was added slowly at room temperature and the reaction was stirred for 3 hours.
  • the reaction mixture was filtered to remove the ammonium chloride, and the solvent was removed to afford the title compound as a viscous off-white oil, which was taken directly to the next step.
  • the extract was washed with water, dried over anhydrous magnesium sulfate, and the solvent was removed by evaporation under vacuum to give a dark brown oil.
  • the product was purified by column chromatography on sUica gel eluting with 1 : 1 ethyl acetate: hexane to afford 22.8 g of the methyl ester title compound as a pale yeUow viscous oU and 6.45 g of the ethyl ester title compound as a pale yeUow viscous oil.
  • Step 4 9-Cyclopropyl-3-fluoro-2-hydroxy-6H-6-oxo- pyrido ⁇ .2-alpyrimidine-7-carboxylic acid benzyl ester
  • Step 1 9-Cyclopropyl-3-fluoro-2-hydroxy-6H-6- oxo-pyridori.2-alpyrimidine-7-carboxyUc acid t-butyl ester
  • the boc-protected t-butyl ester from Step 4 was hydrolyzed by reacting the 0.132 g sample with 1 mL of 4N HCI in dioxane under a dry N2 atmosphere .
  • the solvent was removed, the yellow solid was dissolved in water and the solution adjusted to pH 7-8, and extracted with methylene chloride.
  • the reaction was incomplete at this point, so the soUd was redissolved in 5 mL of trifluoroacetic acid and the reaction stirred at room temperature overnight.
  • the solvent was removed by evaporation.
  • Step 7 9-(2,4-Difluorophenyl)-3-fluoro-2-(4-methylpiperazin-l-yl)- 6H-6-oxopyrido ⁇ .2-alpyrimidine-7-carboxylic acid benzyl ester
  • Step 8. 9-(2,4-Difluorophenyl)-3-fluoro-2-(4-methylpiperazin-l-yl)- 6H-6-oxopyridori.2-alpyrimidine-7-carboxyUc acid
  • Step 1 3-(2,4-Difluorophenyl)-2-ethoxy-3-(5-fluoro-4- hvdroxypyrimidin-2-y0propane-l,l-dicarboxylic acid diethyl ester
  • reaction mixture was quenched with 10% HCI until the mixture was at pH 3, whereupon it was then extracted with ethyl acetate. This was dried over anhydrous magnesium sulfate and the solvent was removed by evaporation under vacuum to afford the title compound as a yeUow oil. This material was taken directly to the next step.
  • the compound from Step 1 was dissolved in 80 ml of ethanol, 2 mL of piperidine and 0.2 mL of acetic acid was added and the mixture heated at reflux (bath temperature at 90°C) for 16 hours under a dry N2 atmosphere. The solvent was removed by evaporation, and the residue was washed with methanol and methylene chloride to give 4.794 g of a pale yeUow solid. The washings were concentrated and the residue was purified by column chromatography on sUica gel, eluting with 2:10:100 acetic acid:methanol:methylene chloride to afford an additional 2.220 g of the title compound as a pale yeUow soUd, mp 239-240°C.
  • Step 1 9-Cyclopropyl-3-fluoro-2-(morpholin-l-yl)-6H-6- oxo-pyridori.2-alpyrimidine-7-carboxyUc acid benzyl ester
  • the benzyl ester product from the previous step was dissolved in 20 mL of anhydrous methanol and stirred with 0.020 g of 10% Pd/C catalyst under 1 atm. Hydrogen at room temperature for 5 hours. The catalyst was removed by filtration, and the solvent was removed under vacuum to afford 0.100 g of the title compound as a yeUow soUd, mp >260°C. MS M/Z 334 (M+H).
  • the sample from the previous step was suspended in 50 mL of THF and dnsopropylethylamine was added with stirring at room temperature until a homogeneous solution resulted. Then 0.885 g (2.66 mmol) of the N-benzyloxycarbonyl protected (s)- norvatine succinamide was added and stirred at room temperature for 1 hour under a dry N2 atmosphere. Another 0.050 g of the protected norvaUne was added, and the solution was stirred for another 0.5 hours. The reaction was diluted with methylene chloride, washed with water (4x), and the organic solvent dried over anhydrous magnesium sulfate and removed by evaporation under vacuum.
  • a 1.515 g sample (2.0822 mmol) sample of the compound from the previous step was dissolved in 80 mL of methanol, and 4.0 mL of 98% formic acid and 0.2 g of 10% Pd/C was added. The mixture was stirred at room temperature for 1.7 hours under a dry N2 atmosphere, filtered and concentrated to leave a yellow soUd residue. This soUd was dissolved in methanol and filtered through sintered glass, then the solvent was removed to leave a yellow solid. This soUd was dissolved in 50 mL of methanol, 3 mL of cone HCI was added and the solvent evaporated off.

Abstract

Antibacterial compounds having formula (I) and the pharmaceutically acceptable salts, esters and amides thereof, selected preferred examples of which include those compounds wherein A is =CR6-; R1 is cycloalkyl of from three to eight carbon atoms or substituted phenyl; R2 is selected from the group consisting of (a), (b), (c) and (d); R3 is halogen; R4 is hydrogen, loweralkyl, a pharmaceutically acceptable cation, or a prodrug ester group; R5 is hydrogen, loweralkyl, halo(loweralkyl), or -NR?13R14; and R6¿ is halogen, loeralkyl, halo(loweralkyl), hydroxy-substituted loweralkyl, loweralkoxy(loweralkyl), loweralkoxy, or amino(loweralkyl), as well as pharmaceutical compositions containing such compounds and the use of the same in the treatment of bacterial infections.

Description

OUINOLLZINONE TYPE COMPOUNDS
This application is a continuation-in-part of co-pending United States patent application Serial No. 08/469,159, filed June 6, 1995, which is a continuation-in-part of copending United States patent application Serial No. 08/316,319, filed September 30, 1994, which is a continuation-in-part of copending United States patent application Serial No. 08/137,236, filed October 14, 1993, which is a continuation-in-part of United States patent application Serial No. 07/940,870, filed October 27, 1992, abandoned, which is a continuation-in-part of United States patent application Serial No. 07/517,780, filed May 2, 1990, abandoned.
TECHNICAL FIELD
The present invention relates to compounds having antimicrobial activity, pharmaceutical compositions containing such compounds, methods of treatment utilizing such compounds, and processes for their chemical synthesis. More particularly, this invention relates to novel 4-oxo-4H-quinolizine-3-carboxylic acid compounds which are highly effective in the treatment of microbial and especially bacterial infections, as well as compositions containing the same and the therapeutic use of such compounds.
BACKGROUND OF THE INVENTION
There is a continuing need for new antibacterial agents. Although many compounds are known which are useful in the treatment of Gram-positive and Gram- negative bacterial infections as well as other microbial infections, the widespread use of such compounds continues to give rise to resistant strains of microorganisms, i.e., strains of microorganisms against which a particular antibiotic or group of antibiotics, which was previously effective, is no longer useful. Also, known antibiotics may be effective against only certain strains of microorganisms or have limited activity against either Gram-positive or Gram-negative, aerobic or anaerobic organisms. The therapeutic use of certain quinolizinone derivatives has been described previously. For example, Y. Kitaura et ai, in U.S. Patent No. 4,650,804, issued March 17, 1987, have disclosed quinolizinone compounds having a tetrazolylcarbamoyl substituent which are useful for the treatment of allergic and ulcer diseases. J.V. Heck and E.D. Thorsett, in European Patent Application No. 0308019, published March 22, 1989, have disclosed the use of certain 4-oxo-4H-quinolizine-3-carboxylic acids and derivatives thereof for treating bacterial infections. However, there remains an ongoing need for novel compounds which have improved antimicrobial potency and/or different spectra of activity. SUMMARY OF THE INVENTION
In one aspect of the present invention are disclosed compounds represented by the following structural formula (I):
as well as the pharmaceutically acceptable salts, esters and amides thereof.
Rl in formula (I) is selected from (a) loweralkyl, (b) loweralkenyl, (c) halo(lower-alkyl), (d) loweralkoxy, (e) cycloalkyl of from three to eight carbon atoms, (f) phenyl,
(g) substituted phenyl, (h) halo, (i) cyano, (j) nitro, (k) bicycloalkyl, (1) loweralkynyl, (m) loweralkoxycarbonyl, (n) nitrogen-containing aromatic heterocycle, (o) halo- substituted nitrogen-containing aromatic heterocycle, (p) a 4-, 5- or 6-membered cyclic ether, and (q) -NR7R8. The radicals R and R^ are independently selected from hydrogen, loweralkyl and alkanoyl of from one to eight carbon atoms or, taken together with the nitrogen atom to which they are attached, R^ and R may form a 5-, 6- or 7-membered heterocycle, preferably in which the remainder of the ring atoms are carbon atoms.
R in formula (I) is selected from (a) halogen, (b) loweralkyl, (c) loweralkenyl, (d) cycloalkyl of from three to eight carbons, (e) cycloalkenyl of from four to eight carbons, (f) loweralkoxy, (g) aryloxy, (h) aryl(loweralkyl)oxy, (i) aryl(loweralkyl), (j) cycloalkyl(loweralkyl), (k) amino, (1) (loweralkyl)amino, (m) aryl(loweralkyl)-amino, (n) hydroxy-substituted (loweralkyl)amino, (o) phenyl, (p) substituted phenyl, (q) bicyclic nitrogen-containing heterocycle, (r) nitrogen-containing aromatic heterocycle, (s) nitrogen- containing heterocycle having the formula
N H
|10
R pB, X
(Y)x (la), and (t) non-nitrogen-containing heterocycle having the formula
In subformula (la) above, x is zero, one, two or three, and R^ is either (i) -(CH2)m- where m is one, two or three, or (ii) -(CH2)nR^(CH2)p- where R^ is selected from -S-, -O- and -NH-, R*0 is CH2, or when R^ is selected from option (i) may be O, S or N, n is one or two, and p is one or two. When present, the radical(s) Y is/are independently selected at each occurrence from the following: (i) loweralkyl,
(ii) hydroxy, (iii) halogen, (iv) halo(loweralkyl), (v) hydroxy- substituted loweralkyl, (vi) loweralkeny lamino,
(vii) loweralkylamino, (viii) loweralkoxy, (ix) (loweralkoxy)loweralkylamino, (x) loweralkoxy (loweralkyl), (xi) loweralkoxy(loweralkoxy)(loweralkyl),
(xii) hydroxy- substituted loweralkyl, (xiϋ) imino, (xiv) alkoxycarbonyl, (xv) carbamoyi, (xvi) aryl(loweralkyl),
(xvii) aminoxy (xviii) amino(loweralkyl), (xix) halo(loweralkyl)amino, (xx) halo(lowera]J yl)amino(loweralkyl), (xxi) thioloweralkoxy(loweralkyl),
(xxϋ) aminothioloweralkoxy, (xxiii) cycloalkyl of from three to six carbon atoms, (xxiv) cycloalkyl(loweralkyl), (xxv) cycloalkylamino, (xxvi) phenyl, (xxvii) substituted phenyl, (xxviϋ) substituted phenyl(loweralkyl) (xxix) nitrogen-containing aromatic heterocycle, (xxx) -NR! 1R12 where R*l and R* are independently selected from hydrogen and loweralkyl or, when one of R^ and Rl2 is hydrogen, the other is alkanoyl of from one to eight carbon atoms, an alpha-amino acid, or a polypeptide residue of from two to five amino acids, and
(xxxi) -C(R21)(R2 )NH2 where R21 and R2 are independently selected from among hydrogen, loweralkyl, hydroxy-substituted loweralkyl, amino(loweralkyl), loweralkoxy-(loweralkyl), thioloweralkoxy(loweralkyl), cycloalkyl of from three to six carbon atoms, and loweralkyl substituted with nitrogen-containing aromatic heterocycle (or, taken together with the carbon atom to which they are attached, R 1 and R22 form a ring structure selected from cycloalkyl of from three to six carbon atoms and nitrogen- containing heterocycle).
In subformula (lb) above, x is zero, one, two or three, and R^l is -(CH2)qR3 - where R32 is selected from -S- and -O-, q is one, two or three, and the radical(s) Y is/are as defined above.
R3 in formula (I) is selected from among hydrogen, halogen and loweralkoxy, while R^ is selected from hydrogen, loweralkyl, a pharmaceutically acceptable cation, and a prodrug ester group.
R5 in formula (I) is selected from (a) hydrogen, (b) halogen, (c) hydroxy, (d) loweralkyl, (e) halo(loweralkyl), (f) loweralkoxy, and (g) -NR13R14 here R 3 and R 4 are independently selected from among hydrogen, loweralkyl, hydroxy-substituted loweralkyl, loweralkoxy-(loweralkyl), and alkanoyl of from one to eight carbon atoms.
A in formula (I) is =N- or =CR^-, where R^ is selected from (a) hydrogen, (b) halogen, (c) loweralkyl, (d) halo(loweralkyl), (e) hydroxy-substituted loweralkyl, (f) loweralkoxy- (loweralkyl), (h) loweralkoxy, and (i) amino(loweralkyl).
Alternatively, taken together with the atoms to which they are attached, RΪ and R*> may form a 6-membered saturated ring optionally containing an oxygen or a sulfur atom and optionally substituted with loweralkyl, so as to produce a tricyclic compound. The compounds of the present invention are subject to the proviso that, if R^ in formula (I) is hydrogen, A is =CR6-, and R^ is hydrogen, then R may not be unsubstituted phenyl.
The above compounds of the invention are found to have a surprising degree of antimicrobial activity against a wide spectrum of Gram-positive and Gram-negative bacteria as well as enterobacteria. Susceptible organisms whose growth can be inhibited generally include both aerobic and anaerobic pathogens of the genera Staphylococcus, Lactobacillus, Micrococc s, Enterococcus, Streptococcus, Sarcina, Escherichia, Enter obacter, Klebsiella, Pseudomonas, Acinobacter, Proteus, Providencia, Citrobacter, Nisseria, Bacillus, Bacteroides, Camphylobacter, Peptococcus, Clostridium, Salmonella, Shigella, Legionella, Serratia, Haemophilus, Brucella and the like. It is therefore expected that the compounds of the present invention will be useful in the treatment and prevention of susceptible bacterial infections in both humans and lower animals. In addition, the compounds, by reason of their in vitro activity, may be used in scrub solutions for surface inhibition of bacterial growth. Accordingly, in a further aspect of the present invention are disclosed pharmaceutical compositions which are useful in the treatment and prophylaxis of bacterial and/or fungal infection in humans and animals, comprising a compound of the invention in combination with a pharmaceutically acceptable caπier.
In yet another aspect of the present invention is disclosed a method of treating and/or preventing microbial infections in human or animal patients in need of such treatment, comprising the administration to such patients of a therapeutically effective amount of a compound of the invention in amounts and for such a period of time as are sufficient to produce the desired result
In still another aspect of the present invention are disclosed synthetic schemes and processes which are useful in the preparation of the compounds of the invention, as well as synthetic (chemical) intermediates which can be utilized therein.
DETAILED DESCRIPTION OF THE INVENTION
Included among the compounds of the present invention are those in which A is =CR6- and R*> is selected from among halogen, loweralkyl, halo(loweralkyl), hydroxy- substituted loweralkyl, loweralkoxy(loweralkyl), loweralkoxy, or amino(loweralkyl). A sub-class of such compounds, particularly preferred and found to be surprisingly effective antibacterial agents, comprises those in which R*> is methyl. In each case, more preferred compounds are those in which R-3 is halogen (especially fluoro); R' is hydrogen, loweralkyl, halo-(loweralkyl), or -NR^ 14 ( ere R^ and R ^ are as previously defined); R* is cycloalkyl of from three to eight carbon atoms or substituted phenyl; and/or R" is halogen, loweralkyl, or loweralkoxy.
The radical R in the above compounds is preferably bicyclic nitrogen-containing heterocycle or a nitrogen-containing heterocycle of the formula
or, even more preferably, R is selected from among radicals of the formulae
In these radicals R , X is preferably one or two, and Y is preferably either -NR.1 1R1 0r -C(R21)(R22)NH2, where R1 ], R12, R21 and R22 are as defined above.
Especially preferred among the compounds of the present invention are those having the general formula
as well as the pharmaceutically acceptable salts, esters and amides thereof, in which R is either bicyclic nitrogen-containing heterocycle or a nitrogen-containing heterocycle having the formula
Of these, particularly preferred compounds are those in which R is selected from among radicals having the formulae
and especially those in which x is one or two and Y is -NR! 1R12 0r -C(R 1)(R )NH2. Also included among the compounds of the present invention are those which have the general formula
as well as the pharmaceutically acceptable salts, esters and amides thereof, in which Z is -CH2-, -O- or -S-; R16 is loweralkyl; and R2, R3, R4 anc ; R5 ^e as defined above. Preferred among such compounds are those in which Z is -O- and R is a nitrogen- containing heterocycle of the formula
Particular compounds which are representative of the compounds of the present invention include the following:
3-fluoro-9-(4-fluorophenyl)-2-(4-methylpiperazin-l-yl)-6(H)-6-oxo-pyrido[l,2- a]pyrimidine-7-carboxylic acid; 9-(2,4-difluorophenyl)-3-fluoro-2-(4-methylpiperazin- 1 -yl)-6(H)-6-oxo-pyrido[ 1 ,2- a]pyrimidine-7 -carboxylic acid;
3-fluoro-9-cyclopropyl-2-(4-methylpiperazin- 1 -yl)-6(H)-6-oxo-pyrido[ 1 ,2-a]pyrimidine-7- carboxyhc acid;
8-(3-aminopyrrolidin- 1 -yl)- 1 -ethyl-4H-quinolizin-4-one-3-carboxylic acid; 2-(3-aιτdnopyιτoUdin-l-yl)-9-cyclopropyl-3-fluoro-6H-6-oxo-pyrido[l,2-a]pyrimidine-7- carboxylic acid;
2-(3-aminopyrrolidin- 1 -yl)-9-cyclopropyl-3-fluoro-6H-6-oxo-pyrido[ 1 ,2-a]pyrimidine-7- carboxylic acid;
9-(2,4-difluorophenyl)-3-fluoro-2-(4-methylpiperazin- 1 -yl)-6H-6-oxopyrido[ 1 ,2- a]pyrimidine-7-carboxyUc acid;
2-(3-aminopyrrolidin- 1 -yl)-9-(2,4-difluorophenyl)-3-fluoro-6H-6-oxopyrido[ 1 ,2- a]pyrimidine-7-carboxylic acid;
2-(3-(N-t-butoxycarbonyl)aminopyrrolidin-l-yl)-9-(2,4-difluorophenyl)-3-fluoro-6H-6- oxopyridof 1 ,2-a]pyrimidine-7-carboxylic acid; 2-(3-aminopyrrolidin- 1 -yl)-9-(2,4-difluorophenyl)-3-fluoro-6H-6-oxopyrido[ 1 ,2- a]pyrimidine-7-carboxyUc acid;
9-cyclopropyl-3-fluoro-2-(4-methylpiperazin- 1 -yl)-6H-6-oxo-pyrido[ 1 ,2-a]pyrimidine-7- carboxyhc acid;
9-cyclopropyl-3-fluoro-2-(piperazin- 1 -yl)-6H-6-oxo-pyrido[ 1 ,2-a]pyrimidine-7 -carboxylic acid;
9-cyclopropyl-3-fluoro-2-(morpholin- 1 -yl)-6H-6-oxo-pyrido[ 1 ,2-a]pyrimidine-7- carboxylic acid;
9-(2,4-difluorophenyl)-3-fluoro-2-(3-(N-(S)-noiΥalyl)aminopyrrolidin-l-yl)-6H-6- oxopyrido[ 1 ,2-a]pyrimidine-7-carboxylic acid; 2-(3-(N-(S)-alanyl)aminopyrrolidin-l-yl)-9-(2,4-difluorophenyl)-3-fluoro-6H-6- oxopyrido[l ,2-a]pyrimidine-7-carboxylic acid;
2-(3-(N-(S)-alanyl-(S)-alanyl)aminopyrrolidin-l-yl)-9-(2,4-difluorophenyl)-3-fluoro-6H-
6-oxopyrido[ 1 ,2-a]pyrimidine-7-carboxylic acid; 2-((2S,4S)-4-acetamido-2-methylpyrroUdin- 1 -yl)-9-(2,4-difluorophenyl)-3-fluoro-6H-6- oxopyrido[l,2-a]pyrimidine-7-carboxylic acid;
9-(2,4-difluorophenyl)-3-fluoro-2-(3-hydroxypyrrolin- 1 -yl)-6H-6-oxopyrido[ 1 ,2- a]pyrimidine-7-carboxylic acid;
2-((2S ,4S)-4-amino-2-methylpyrrolidin- 1 -yl)-9-(2,4-difluorophenyl)-3-fluoro-6H-6- oxopyrido[l,2-a]pyrimidine-7 -carboxylic acid;
8-(3-amino- 1-pyιτolidinyl)- 1 -cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3- carboxylic acid;
8-(3-(aminomethyl)pyrrolidinyl)-l-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-
3-carboxylic acid; 8-(2S,4S-4-amino-2-methylpyrrolidinyl)-l-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H- quinolizine-3-carboxylic acid;
8-(3-aminoazetidinyl)-l-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid;
8-(3(S)-aminopyrrolidinyl)-l-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3- carboxylic acid;
1 -cyclopropyl-7-fluoro-9-methyl-4-oxo-8-(3-methyl- 1 -piperazinyl)-4H-quinolizine-3- carboxylic acid; l-cyclopropyl-7-fluoro-9-methyl-4-oxo-8-piperazinyl-4H-quinoUzine-3-carboxylic acid; l-cyclopropyl-7-fluoro-9-methyl-8-(2-((N-methyl)aminomethyl)-4-morpholinyl)-4-oxo- 4H-quinolizine-3-carboxylic acid;
1 -cyclopropyl-7-fluoro-9-methyl-4-oxo-8-( 1 ,2,3,4- tetrahydro-2-isoquinolinyl)-4H- quinolizine-3-carboxylic acid ;
1 -cyclopropyl -7-fluoro-9-methyl-4-oxo-8-(4-amino- 1 -piperdinyl)-4H-quinolizine-3- carboxylic acid; 1 -cyclopropyl -7 -fluoro-9-methyl-4-oxo-8-(3-amino- 1 -piperdinyl)-4H-quinolizine-3- carboxylic acid;
1 -cyclopropyl-7-fluoro-9-methyl-4-oxo-8-(4-(aminomethyl)- 1 -piperdinyl)-4H-quinolizine-
3-carboxylic acid; l-cyclopropyl-7-fluoro-9-methyl-4-oxo-8-(5-amino-l,2,3,4-tetrahydro-2-isoquinolinyl)- 4H-quinolizine-3-carboxyUc acid;
1 -cyclopropyl-7-fluoro-9-methyl-4-oxo-8-(4-( 1 -pyrrolyl)- 1 -piperidinyl)-4H-quinolizine-3- carboxylic acid; 1 -cyclopropyl-8-(cw-3.5-dimethyl- 1 -piperazinyl)-7-fluoro-9-methyl-4-oxo-4H-quinolizine-
3-carboxylic acid; l-cyclopropyl-8-(2,7-diaza-7-bicyclo[3.3.0]oct-2-yl)-7-fluoro-9-methyl-4-oxo-4H- quinolizine-3-carboxylic acid; l-cyclopropyl-8-(2,8-diaza-8-bicyclo[4.3.0]nonyl)-7-fluoro-9-methyl-4-oxo-4H- quinolizine-3-carboxylic acid;
1 -cyclopropyl-7-fluoro-9-methyl-4-oxo-8-(3(S)-( 1 -pyrrolyl)- 1 -pyrrolidinyl)-4H- quinolizine-3-carboxylic acid ;
1 -cyclopropyl-7-fluoro-8-(3-hydroxy- 1 -pyrrolidinyl)-9-methyl-4-oxo-4H-quinolizine-3- carboxy lie acid;
1 -cyclopropyl-7-fluoro-8-(4-methyl- 1 -piperazinyl)-9-methyl-4-oxo-4H-quinolizine-3- . carboxylic acid;
1 -cyclopropyl- 9-chloro-7-fluoro-8-(3-amino- 1 -pyrrolidinyl )-4-oxo-4H-quinolizine-3- carboxylic acid; 8-(3-amino-l-pyrrohdinyl)-l-cyclopropyl-7,9-difluoro-4-oxo-4H-quinolizine-3-carboxylic acid;
8-(3-amino- 1 -pyrrolidinyl)- 1 -cyclopropyl-7-fluoro-9-methoxy-4-oxo-4H-quinolizine-3- carboxylic acid. l-cyclopropyl-8-(2,7-diaza-7-bicyclo[3.3.0]oct-2-yl)-7-fluoro-9-methyl-4-oxo-4H- quinolizine-3-carboxylic acid; l-cyclopropyl-8-(2,8-diaza-8-bicyclo[4.3.0]nonyl)-7-fluoro-9-methyl-4-oxo-4H- quinolizine-3-carboxylic acid;
1 -cyclopropyl-7-fluoro-9-methyl-4-oxo-8-(3(S)-( 1 -pyrrolyl)- 1 -pyrrolidinyl)-4H- quinolizine-3-carboxylic acid; 1 -cyclopropyl-7-fluoro-8-(3-hydroxy- 1 -pyrrolidinyl)-9-methyl-4-oxo-4H-quinolizine-3- carboxylic acid;
1 -cyclopropyl-7-fluoro-8-(4-methyl- 1 -piperazinyl)-9-methyl-4-oxo-4H-quinolizine-3- carboxylic acid;
1 -cyclopropyl- 9-chloro-7-fluoro-8-(3-amino-l-pyπOlidinyl)-4-oxo-4H-quinoUzine-3- carboxylic acid;
8-(3-amino- 1 -pyrrolidinyl)- 1 -cyclopropyl-7,9-difluoro-4-oxo-4H-quinolizine-3-carboxylic acid;
8-(3-amino- 1 -pyrrolidinyl)- 1 -cyclopropyl-7-fluoro-9-methoxy-4-oxo-4H-quinolizine-3- carboxyhc acid; l-cyclopropyl-7-fluoro-9-methyl-8-(3(S)-methylarnino-l-pyrrolidinyl)-4-oxo-4H- quinolizine-3-carboxylic acid; l-cyclopropyl-7-fluoro-9-methyl-8-(3(S)-methylamino-l-pyrrolidinyl)-4-oxo-4H- quinolizine-3-carboxylic acid;
1 -cyclopropyl-7 -fluoro- 9-methyl-8-(3 (R)-amino- 1 -pyrrolidinyl)-4-oxo-4H-quinolizine-3- carboxylic acid; (3S)-9-fluoro-3-methyl-10-(4-methyl-l-piperazinyl)-2H,3H,6H-6-oxo-pyrano[2.3.4- ij]quinolizine-5-carboxylic acid;
3(R)-9-fluoro-3-methyl-10-(4-methyl-l-piperazinyl)-2H,3H,6H-6-oxo-pyrano[2.3.4- ij]quinolizine-5-carboxylic acid;
9-fluoro- 10-( 1 -morpholinyl)-2H,3H,6H-6-oxo-pyrano[2.3.4-ij]quinolizine-5-carboxylic acid;
(3S)-10-(3-amino-l-pyrrolidinyl)-9-fluoro-3-methyl-2H,3H,6H-6-oxo-pyrano[2.3.4- ij]quinolizine-5-carboxylic acid;
3(S)-10-(3-aminomethyl-l-pyrrolidinyl)-9-fluoro-3-methyl-2H,3H,6H-6-oxo- pyrano[2.3.4-ij]quinolizine-5-carboxylic acid; 3(S)-10-((2S,4S)-4-amino-2-methyl-l-pyrrolidinyl)-9-fluoro-3-methyl-2H,3H,6H-6-oxo- pyrano[2.3.4-ij]quinolizine-5-carboxylic acid;
3(S)-9-fluoro-10-(3-hydroxy-l-ρyrrolidinyl)-3-methyl-2H,3H,6H-6-oxo-pyrano[2.3.4- ij]quinolizine-5-carboxylic acid;
9-fluoro-10-(4-methyl-l-piperazinyl)-2H,3H,6H-6-oxo-pyrano[2.3.4-ij]quinolizine-5- carboxylic acid;
8-(2,4-dimethyl- 1 -piperazinyl)- 1 -cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3- carboxylic acid;
8-(3-(methylamino)- 1 -piperazinyl)- l-cyclopropyl-7 -fluoro-9-methyl-4-oxo-4H- quinolizine-3-carboxylic acid; 8-(3-(methylamino)- 1 -morpholinyl)- 1 -cyclopropyl-7-fluoro-9-methyl-4-oxo-4H- quinolizine-3-carboxylic acid;
8-(3-(S)-(methylamino)- 1 -pyrrolidinyl)- 1 -cyclopropyl-7-fluoro-9-methyl-4-oxo-4H- quinolizine-3-carboxylic acid;
8-(3-(S)-( 1 -(methylamino)methyl)- 1 -pyrrolidinyl)- 1 -cyclopropyl-7-fluoro-9-methyl-4-oxo- 4H-quinoUzine-3-carboxylic acid;
8-(3-(S )-( 1 -(ethylamino)methyl)- 1 -pyrroUdinyl)- 1 -cyclopropyl-7-fluoro-9-methyl-4-oxo-
4H-quinolizine-3-carboxylic acid;
8-(octahydropyιτolo[3,4-c]pyrrol- 1 -yl)- 1 -cyclopropyl-7 -fluoro- 9-methyl-4-oxo-4H- quinolizine-3-carboxylic acid; 8-(octahydropyrrolo[3,4-c]pyridin-5-yl)- 1 -cyclopropyl-7-fluoro-9-methyl-4-oxo-4H- quinolizine-3-carboxylic acid; 8-(cw-4-amino-3-methylpyrrolidinyl)-l-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H- quinolizine-3-carboxylic acid;
8-(trflrø-4-amino-3-methylpyrrolidinyl)-l-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H- quinolizine-3-carboxylic acid; 8-(3-methyl-4-spirocyclopropylpyrrolidinyl)- 1 -cyclopropyl-7-fluoro-9-methyl-4-oxo-4H- quinolizine-3-carboxylic acid;
8-(2S ,4S-4-amino-2-methylpyπOlidinyl)- 1 -cyclopropyl-7-fluoro-9-(fluoro)methyl-4-oxo-
4H-quinolizine-3-carboxylic acid;
8-(3-dimethylaminopyrrolidinyl)-l-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine- 3-carboxylic acid;
(3R)-8-(3-dimethylaminopyrrolidinyl)-l-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H- quinolizine-3-carboxylic acid;
(3R,lS)-8-(3-(l-arninoethyl)pyrrolidinyl)-l-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H- quinolizine-3-carboxylic acid; (3S,lR)-8-(3-(l-aminoethyl)pyrrolidinyl)-l-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H- quinolizine-3-carboxylic acid;
(3R, lR)-8-(3-( 1 -aminoethyl)pyrrolidinyl)- 1 -cyclopropyl-7-fluoro-9-methyl-4-oxo-4H- quinolizine-3-carboxylic acid;
1 -cyclopropyl-8-((R,S )-3-fluoropyrrolidine)-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3 - carboxylic acid;
8-(4-( 1 -piperidyl)- 1 -piperidyl)- 1 -cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3- carboxylic acid;
8-(4-( 1 -piperidyl)- 1 -piperidyl)- 1 -cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3- carboxylic acid; 8-(4-(2-pyridyl)- 1 -piperazinyl)- 1 -cyclopropyl -7 -fluoro-9-methyl-4-oxo-4H-quinolizine-3- carboxylic acid;
8-((2-amino)thioethoxy)-l-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3- carboxylic acid;
(3R, 1 S)-8-(3-( 1 -amino)propyl)pyrrolidinyl)- 1 -cyclopropyl-7-fluoro-9-methyl-4-oxo-4H- quinolizine-3-carboxylic acid;
(3R, 1 S)-8-(3-( l-(N-methyl)amino)propyl)pyrrolidinyl)- 1 -cyclopropyl-7-fluoro-9-methyl-
4-oxo-4H-quinolizine-3-carboxylic acid;
(3R, 1 S)-8-(3-( 1 -amino-3-methylpropyl)pyrrolidinyl)- 1 -cyclopropyl-7- fluoro- 9-methyl-4- oxo-4H-quinoUzine-3-carboxyhc acid; 8-(3-( 1 -aminocyclopropyl)pyrrolidinyl)- 1 -cyclopropyl-7-fluoro-9-methyl-4-oxo-4H- quinolizine-3-carboxylic acid; (3R, 1 S)-8-(3-( 1 -amino-2-hydroxyethyl)pyrrolidinyl)- 1 -cyclopropyl-7-fluoro-9-methyl-4- oxo-4H-quinolizine-3-carboxylic acid;
(8-(3-( 1 -amino- 1 -methylethyl)pyrrolidinyl)- 1 -cyclopropyl-7 -fluoro- 9-methyl-4-oxo-4H- quinolizine-3-carboxylic acid; 8-(3-( 1 -aminobutyl)pyrrolidinyl)- 1 -cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-
3-carboxylic acid; l-cyclopropyl-7-fluoro-9-methyl-4-oxo-8-(trα w-4-trifluoromethyl-3-aminopyrrolidinyl)-
4H-quinolizine-3-carboxylic acid;
1 -cyclopropyl-7 -fluoro- 9-methyl-4-oxo-8-(trα/w-4-trifluoromethyl-3- aminomethylpyrrolidinyl)-4H-quinolizine-3-carboxyhc acid;
3 (S )- 1 -cyclopropyl-7-fluoro-9-methyl-4-oxo- 8-(3-(N-(S )-norvalylamino)pyrrolidinyl)-4H- quinolizine-3-carboxylic acid;
3(S)-l-cyclopropyl-7-fluoro-9-methyl-4-oxo-8-(3-(N-(S)-alanylamino)pyrrolidinyl)-4H- quinolizine-3-carboxylic acid; 3(S)-l-cyclopropyl-7-fluoro-9-methyl-4-oxo-8-(3-(N-(S)-alanyl-(S)- alanylamino)pyrrolidinyl)-4H-quinolizine-3-carboxylic acid; l-cyclopropyl-7-fluoro-6-methyl-4-oxo-8-(3-aminopyrrolidinyl)-4H-quinolizine-3- carboxylic acid;
1 -cyclopropyl-7-fluoro-4H-8-( 1 -imidazolyl)-9-methyl-4-oxo-quinolizine-3-carboxylic acid; 8-(3-amino- 1 -pyrrolidinyl)- 1 -ethyl-7-fluoro-4H-4-oxo-9-methyl-quinolizine-3-carboxylic acid;
8-(3-amino- 1 -pyrrolidinyl)- 1 -cyclopropyl-9-ethyl-7-fluoro-4H-4-oxo-quinolizine-3- carboxylic acid;
1 -cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-8-(3-(l ,2,3-triazol- 1 -yl)- 1 -pyrrolidinyl)- quinolizine-3-carboxylic acid;
1 -cyclopropyl -7 -fluoro-4H-9-methyl-4-oxo-8-(cw-3-amino-4- methyl- 1 -pyrrolidinyl)- quinolizine-3-carboxylic acid;
8-(2-aminoethyl)-l-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid; 8-(3-(ethylaminomethyl)pyrroUdinyl)- 1 -cyclopropyl-7-fluoro-4H-9-methyl-4-oxo- quinolizine-3-carboxylic acid;
8-(3-( 1 -aminoethy pyrrolidinyl)- 1 -cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-
3-carboxylic acid; l-cyclopropyl-7-fluoro-4H-9-methyl-8-(2-methyl-2,8-diaza-8-bicyclo[4.3.0]nonyl)-4-oxo- quinolizine-3-carboxylic acid; l-cyclopropyl-7-fluoro-4H-8-((lS,4S)-2,5-diaza-bicyclo[2.2.1]heptan-2-yl)-9-methyl-4- oxo-quinolizine-3-carboxylic acid; 1 -cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-8-(3-(2-pyridinyl)- 1 -pyrrolidinyl)-quinolizine-
3-carboxylic acid;
8-((lR*,2S*,6R*)-2-amino-8-azabicyclo[4.3.0]nonan-8-yl))-l-cyclopropyl-7-fluoro-4H-
9-methyl-4-oxo-quinolizine-3-carboxylic acid; 8-((lR*,2R*,6R*)-2-amino-8-azabicyclo[4.3.0]nonan-8-yl))-l-cyclopropyl-7-fluoro-4H-
9-methyl-4-oxo-quinolizine-3-carboxylic acid;
8-((la,5a,6a)-6-amino-3-azabicyclo[3.1.0]hexan-3-yl))-l-cyclopropyl-9-methyl-7-fluoro-
4H-4-oxo-quinolizine-3-carboxylic acid;
8-(trαnj-3-amino-4-fluoro- 1 -pyrrolidinyl))- 1 -cyclopropyl- 9-methyl-7-fluoro-4H-4-oxo- quinolizine-3-carboxylic acid;
1 -cyclopropyl -7 -fluoro-4H-8-( 1 -homopiperazinyl))-9-methyl-4-oxo-quinolizine-3- carboxylic acid;
7,9-difluoro-4H-8-(4-methylpiperazinyl)-4-oxo- 1 -phenyl-quinolizine-3-carboxylic acid;
8-(spiro- 1 ,3-dioxacyclopentane[2.3]- 1 -piperidinyl)- 1 -cyclopropyl-7-fluoro-4H-9-methyl- 4-oxo-quinolizine-3-carboxylic acid ;
8-(3-amino-4-methoxypyrrolidinyl)-l-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo- quinolizine-3-carboxylic acid;
8-(4-amino-4-methylpyrrolidinyl)-l-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-
3-carboxylic acid; 8-(4-(2-hydroxyethyl)piperidinyl)- 1 -cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-
3-carboxylic acid ;
8-(4-(methoxymethyl)piperidinyl)-l-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-
3-carboxylic acid ;
8-(3-amino-3-methylpiperidinyl)-l-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine- 3-carboxyUc acid;
8-(3-pyrrolylpiperidinyl)-l-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3- carboxylic acid ;
8-(3-aminopiperidinyl)-l-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3- carboxylic acid; 8-(3-amino-3-methylpyrrolidinyl)- 1 -cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-
3-carboxylic acid;
8-(3-amino-4-( 1 ',3 '-dioxolanyl)pyrrolidinyl)- 1 -cyclopropyl-7-fluoro-4H-9-methyl-4-oxo- quinolizine-3-carboxylic acid;
8-(3-amino-4-hydroxy-pyrroUdinyl)-l-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo- quinolizine-3-carboxylic acid;
8-(4-( 1 -(N-ethylamino)methyl)piperidinyl)- 1 -cyclopropyl-7-fluoro-4H-9-methyl-4-oxo- quinolizine-3-carboxylic acid; l-cyclopropyl-7-fluoro-8-(3-hyαroxy-4-methylaminopyrrolidinyl)-4H-9-methyl-4-oxo- quinolizine-3-carboxylic acid;
8-(3-aminomethylpiperidinyl)-l-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3- carboxylic acid; 8-(2-aminomethyl-4-morpholinyl)- 1 -cyclopropyl -7 -fluoro-4H-9-methyl-4-oxo-quinolizine-
3-carboxylic acid;
8-(3-( 1 -(methylamino)methypiperidinyl)- 1 -cyclopropyl-7-fluoro-4H-9-methyl-4-oxo- quinolizine-3-carboxylic acid;
8-(3-(methyl(methylenedioxy)methyl)piperidinyl)-l-cyclopropyl-7-fluoro-4H-9-methyl-4- oxo-quinolizine-3-carboxylic acid;
8-(3-(S )-aminopiperidinyl)- 1 -cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3- carboxylic acid;
8-(3-(S)-(N-ethyl-N-methylamino)piperidinyl)-l-cyclopropyl-7-fluoro-4H-9-methyl-4- oxo-quinolizine-3-carboxyhc acid ; l-cyclopropyl-8-(4-(2'-(N-methylamino)methyl- 1 ',3'-dioxolanyl)piperidinyl)-7-fluoro-9- methyl-4-oxo-4H-quinolizine-3-carboxylic acid; l-cyclopropyl-8-(3-aza-6-amino-6-methylbicyclo[3.3.0]octan-l-yl)-7-fluoro-9-methyl-4- oxo-4H-quinolizine-3-carboxylic acid; l-cyclopropyl-8-(3-fluoromethylpiperidinyl)-7-fluoro-9-methyl-4-oxo-4H-quinolizine; l-cyclopropyl-8-(4-(N,N-dimethyl)aminopiperidinyl)-7-fluoro-9-methyl-4-oxo-4H- quinolizine-3-carboxylic acid; l-cyclopropyl-8-(6-amino-3-azabicyclo[3.3.0]octyl)-7-fluoro-9-methyl-4-oxo-4H- quinolizine-3-carboxylic acid; l-cyclopropyl-8-((2-aza-4-(dimethylaminomethyl)bicyclo[4.3.0]non-2-yl)-7-fluoro-9- methyl-4-oxo-4H-quinolizine carboxylic acid; l-cyclopropyl-8-(3-aza-6-(L-alanylamino)-6-methylbicyclo[3.3.0]octane)-7-fluoro-9- methyl-4-oxo-4H-quinolizine carboxylic acid;
(3R, 1 R)-8-(3-( 1 -(N-methyl)amino)propyl)pyrrolidinyl)- 1 -cyclopropyl-7-fluoro-9-methyl-
4-oxo-4H-quinohzine-3-carboxylic acid; (3R, 1 S)-8-(3-( 1 -amino-2-methoxyethyl)pyrrolidinyl)- 1 -cyclopropyl-7-fluoro-9-methyl-4- oxo-4H-quinolizine-3-carboxylic acid;
8-(3-(S)-(acetylamino)pyrrolidinyl)-l-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo- quinolizine-3-carboxylic acid;
8-(3-carbamoylpiperidinyl)-l-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3- carboxylic acid;
8-(3-hydroxypiperidinyl)-l-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3- carboxylic acid; 8-(3-hydroxymethylpiperidinyl)-l-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3- carboxylic acid;
8-(3-(R)-hydroxypiperidinyl)-l-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3- carboxylic acid; (3R)-9-fluoro-3-methyl-10-(piperazin-l-yl)-2H, 3H, 6H -6-oxo-pyrano[2.3.4- ij]quinolizine-5-carboxyUc acid; l-cyclopropyl-8-(S,S-2,8-diaza-8-bicyclo[4.3.0]nonyl)-7-fluoro-4H-9-methyl-4-oxo- quinolizine-3-carboxylic acid; l-cyclopropyl-8-(R,R-2,8-diaza-8-bicyclo[4.3.0]nonyl)-7-fluoro-4H-9-methyl-4-oxo- quinolizine-3-carboxylic acid;
1 -cyclopropyl-8-( 1 -amino-3-aza-bicyclo[3.1.0]hexan-3-yl)-7-fluoro-4H-9-methyl-4-oxo- quinolizine-3-carboxylic acid;
8-(3-amino-3-fluoromethyl- 1 -pyrrolidinyl)- 1 -cyclopropyl-7-fluoro-4H-9-methyl-4-oxo- quinolizine-3-carboxylic acid; 8-(3-aminomethyl-3-fluoro-l -pyrrolidinyl)- l-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo- quinolizine-3-carboxylic acid;
8-(3-(S)-hydroxy- 1 -pyrrolidinyl)- 1 -cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-
3-carboxylic acid;
8-(3-(R)-hydroxy-l-pyrrolidinyl)-l-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine- 3-carboxylic acid;
8-(7-(S)-amino-5-aza-spiro[2.4]heptan-5-yl)-l-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo- quinolizine-3-carboxylic acid hydrochloride;
8-(7-(R)-arnino-5-aza-spiro[2.4]heptan-5-yl)-l-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo- quinolizine-3-carboxylic acid hydrochloride; 8-(3-(l-amino-2,2,2-trifluoroethyl)pyrrolidinyl)-l-cyclopropyl-7-fluoro-4H-9-methyl-4- oxo-quinolizine-3-carboxylic acid;
8-(3-(S*)-(l-(S*)-amino-2,2,2-trifluoroethyl)pyrrolidinyl)-l-cycloρropyl-7-fluoro-4H-9- methyl-4-oxo-quinolizine-3-carboxyhc acid;
8-(3-aminoxypyrrolidinyl)-l-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3- carboxylic acid;
8-(3-(R)-aminoxypyrrolidinyl)-l-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3- carboxylic acid;
8-(3-(S)-arninoxypyrrolidinyl)-l-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3- carboxylic acid; 8-(octahydropyrrolo[3,2-b]pyridin-l-yl)-l-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo- quinolizine-3-carboxylic acid; 8-(tra W-3-amino-4-fluoromethylpyrrodin- 1 -yl)- 1 -cyclopropyl-7-fluoro-4H-9-methyl-4- oxo-quinolizine-3-carboxylic acid;
8-(cw-3-amino-4-fluoromethylpyrrodin- 1 -yl)- 1 -cyclopropyl-7-fluoro-4H-9-methyl-4-oxo- quinolizine-3-carboxylic acid; 8-(8-amino-6-azaspiro[3.4]oct-6-yl)-l-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo- quinolizine-3-carboxylic acid;
8-(2-aminomethyl-4-hydroxypyrrolidin- 1 -yl)- 1 -cyclopropyl-7-fluoro-4H-9-methyl-4-oxo- quinolizine-3-carboxylic acid;
8-(3-(R)-(aminomethyl)morpholin-l-yl)-l-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo- quinolizine-3-carboxylic acid;
8-(3-(R)-(L-alanylamino)piperidinyl)-l-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo- quinolizine-3-carboxylic acid;
8-(3-(5-aminooctahydroindol- 1 -yl)- 1 -cyclopropyl-7-fluoro-4H-9-methyl-4-oxo- quinolizine-3-carboxylic acid; 8-(3-(2-piperidyl)piperidin-l-yl)-l -cyclopropyl -7-fluoro-4H-9-methyl-4-oxo-quinolizine-
3-carboxylic acid;
8-(5-amino-decahydroisoquinolin-2-yl)-l-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo- quinolizine-3-carboxylic acid;
8-(2,7-diazabicyclo[3.3.0]oct-7-yl)-l-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo- quinolizine-3-carboxylic acid;
8-(3,7-diazabicyclo[3.3.0]oct-3-yl)-l-cyclopropyl-7-fiuoro-4H-9-methyl-4-oxo- quinolizine-3-carboxylic acid;
8-(3-carboxypyrrolidin- 1 -yl)- 1 -cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3- carboxylic acid; 8-(3-(2,2,2-trifluoroethyl)aminopyrrolidin- 1 -yl)- 1 -cyclopropyl-7-fluoro-4H-9-methyl-4- oxo-quinolizine-3-carboxylic acid;
8-(3-(2-fluoroethyl)aminopyrrolidin- 1 -yl)- 1 -cyclopropyl-7-fluoro-4H-9-methyl-4-oxo- quinolizine-3-carboxylic acid;
8-(3-((2-fluoroethyl)aminomethyl)pyrrohdin- 1 -yl)- 1 -cyclopropyl-7-fluoro-4H-9-methyl-4- oxo-quinolizine-3-carboxylic acid;
8-(3-(S)-(2-fluoroethyl)aminopyιτolidin- 1 -yl)- 1 -cyclopropyl-7-fluoro-4H-9-methyl-4-oxo- quinolizine-3-carboxylic acid;
8-(3-(R)-(2-fluoroethyl)aminopyrrolidin- 1 -yl)- 1 -cyclopropyl-7-fluoro-4H-9-methyl-4-oxo- quinolizine-3-carboxylic acid; 8-(3a-amino-octahydroisoindol-2-yl)-l-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo- quinolizine-3-carboxylic acid; 8-(6-amino-2-aza-spiro[3.3]non-2-yl)-l-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo- quinolizine-3-carboxylic acid (Isomer (I));
8-(3-amino-3-trifluoromethylpyrrolidin- 1-yl)- 1 -cyclopropyl-7-fluoro-4H-9-methyl-4-oxo- quinolizine-3-carboxylic acid; 8-(3-(S)-hydroxymethylazetidin-l-yl)-l-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo- quinolizine-3-carboxylic acid ;
8-(3-aminomethyl-3-trifluoromethyl-pyrrolidin- 1 -yl)- 1 -cyclopropyl-7-fluoro-4H-9-methyl-
4-oxo-quinolizine-3-carboxylic acid;
8-(octahydropyrrolo[3.4-c]pyrid-2-yl)-l-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo- quinolizine-3-carboxylic acid;
8-(3-(cyclopropylamino)pyrrolidin- 1 -yl)- 1 -cyclopropyl-7-fluoro-4H-9-methyl-4-oxo- quinolizine-3-carboxylic acid;
8-(6-amino-2-aza-spiro[3.3]non-2-yl)-l-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo- quinolizine-3-carboxylic acid (Isomer (II)); 8-(2,7-diazabicyclo[3.3.0]oct-7-yl)-l-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo- quinolizine-3-carboxylic acid Isomer A;
8-(2,7-diazabicyclo[3.3.0]oct-7-yl)-l-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo- quinolizine-3-carboxylic acid Isomer B;
8-(3-(R)-(hydroxymethyl)pyrrolidin- 1 -yl)- 1 -cyclopropyl-7-fluoro-4H-9-methyl-4-oxo- quinolizine-3-carboxylic acid;
8-(3-(S)-(hydroxymethyl)pyrrolidin- 1 -yl)- 1 -cyclopropyl-7-fluoro-4H-9-methyl-4-oxo- quinolizine-3-carboxylic acid;
8-(2-(R)-(hydroxymethyl)pyrrolidin-l-yl)-l-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo- quinolizine-3-carboxylic acid; 8-(2-(S)-(hydroxymethyl)pyrroUdin-l-yl)-l-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo- quinolizine-3-carboxylic acid;
8-(2-(R)-aminomethyl-pyrrolidin- 1 -yl)- 1 -cyclopropyl-7-fluoro-4H-9-methyl-4-oxo- quinolizine-3-carboxylic acid;
8-(2-(S)-aminomethyl-pyrrolidin- 1 -yl)- 1 -cyclopropyl-7-fluoro-4H-9-methyl-4-oxo- quinolizine-3-carboxylic acid;
8-(3-(R)-( 1 -aminocyclopropyl)pyrrolidinyl)- 1 -cyclopropyl-7-fluoro-9-methyl-4-oxo-4H- quinolizine-3-carboxylic acid;
8-(3-(S)-( 1 -aminocyclopropyl)pyrrolidinyl)- 1 -cyclopropyl-7-fluoro-9-methyl-4-oxo-4H- quinolizine-3-carboxylic acid 8-(3-(l -amino- l-cyclopropyl-methyl)pyrrolidinyl)-l-cyclopropyl-7-fluoro-9-methyl-4-oxo-
4H-quinolizine-3-carboxylic acid 8-(3-(R)-(pyrrolidin-2-(S)-yl)pyrrolidin-l-yl)-l-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H- quinolizine-3-carboxylic acid;
8-(3-(aminomethyl)azetidin-l-yl)-l-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-
3-carboxylic acid; (8-(3-amino-4-methyl-piperidin- 1 -yl)- 1 -cyclopropyl-7-fluoro-9-methyl-4-oxo-4H- quinolizine-3-carboxylic acid; and
8-(3-(7-amino-5-azaspiro[2.4]heptan-5-yl)-l-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H- quinolizine-3-carboxylic acid;
8-(7-(S)-amino-5-aza-spiro[2.4]heptan-5-yl)-l-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo- quinolizine-3-carboxylic acid;
8-(7-(R)-amino-5-aza-spiro[2.4]heptan-5-yl)-l-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-. quinolizine-3-carboxylic acid;
8-(trα w-3-(S)-amino-4-(R)-cyclopropylpyrrolidin- 1 -yl)- 1 -cyclopropyl-7-fluoro-4H-9- methyl-4-oxo-quinolizine-3-carboxylic acid; 8-(trα/u-3-(R)-amino-4-(S)-cyclopropylpyrrolidin- 1-yl)- l-cyclopropyl-7-fluoro-4H-9- methyl-4-oxo-quinolizine-3-carboxyUc acid;
8-(trα/w-3-(S)-amino-4-(R)-methylpyrrolidin- 1 -yl)- 1 -cyclopropyl-7-fluoro-4H-9-methyl-4- oxo-quinolizine-3-carboxylic acid;
8-(trα/w-3-(R)-amino-4-(S)-methylpyrrolidin-l-yl)-l-cyclopropyl-7-fluoro-4H-9-methyl-4- oxo-quinolizine-3-carboxylic acid;
8-(cw-3-(S)-amino-4-(S)-cyclopropylpyrrolidin- 1 -yl)- 1 -cyclopropyl-7-fluoro-4H-9- methyl-4-oxo-quinolizine-3-carboxylic acid;
8-(cw-3-(R)-amino-4-(R)-cyclopropylpyrrolidin- 1 -yl)- 1 -cycloproρyl-7-fluoro-4H-9- methyl-4-oxo-quinolizine-3-carboxyUc acid; 8-(trα/w-3-amino-4-ethylpyrrolidin-l-yl)-l-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo- quinolizine-3-carboxylic acid diastereomer A;
8-(trαrt5-3-amino-4-ethylpyrrolidin- 1 -yl)- 1 -cyclopropyl-7-fluoro-4H-9-methyl-4-oxo- quinolizine-3-carboxylic acid diastereomer B;
8-(c 5-3-amino-4-ethylpyrrodin- 1 -yl)- 1 -cyclopropyl -7 -fluoro-4H-9-methyl-4-oxo- quinolizine-3-carboxylic acid diastereomer A;
8-(c/s-3-amino-4-ethylpyrrodin- 1 -yl)- 1 -cyclopropyl-7-fluoro-4H-9-methyl-4-oxo- quinolizine-3-carboxylic acid diastereomer B; 8-(c 5-3-(S)-amino-4-(S)-methylpyrrodin- 1 -yl)- 1 -cyclopropyl-7-fluoro-4H-9-methyl-4- oxo-quinolizine-3-carboxylic acid; and 8-(cw-3-(R)-amino-4-(R)-methylpyrrodin- 1 -yl)- 1 -cyclopropyl-7-fluoro-4H-9-methyl-4- oxo-quinohzine-3-carboxylic acid; as well as the pharmaceutically acceptable salts, esters and amides thereof. Preferred among the above representative compounds of the invention are the following:
8-(3-(aminomethyl)pyrrolidinyl)-l-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-
3-carboxylic acid; 8-(3(S)-amino- 1 -pyrroUdinyl)- 1 -cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3- carboxylic acid;
8-(3-amino- 1 -pyrrolidinyl)- 1 -cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3- carboxylic acid;
(3R,lS)-8-(3-(l-amino)propyl)pyrrolidinyl)-l-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H- quinolizine-3-carboxylic acid;
8-(3-( 1 -aminobutyl)pyrrolidinyl)- 1 -cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-
3-carboxylic acid;
(3R, 1 S)-8-(3- ( 1 -amino-2-methoxyethyl)pyrrolidinyl)- 1 -cyclopropyl-7-fluoro-9-methyl-4- oxo-4H-quinolizine-3-carboxyhc acid; 1 -cyclopropyl-7-fluoro-9-methyl-4-oxo-8-(4-amino- 1 -piperdinyl)-4H-quinolizine-3- carboxylic acid;
1 -cyclopropyl-7-fluoro-9-methyl-4-oxo-8-(4-(aminomethyl)- 1 -piperdinyl)-4H-quinolizine-
3-carboxylic acid;
1 -cyclopropyl-7-fluoro-9-methyl-4-oxo-8-(3-amino- 1 -piperdinyl)-4H-quinolizine-3- carboxylic acid;
8-(3-(S)-aminopiperidinyl)-l-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3- carboxylic acid; l-cyclopropyl-8-(3-aza-6-amino-6-methylbicyclo[3.3.0]octan-l-yl)-7-fluoro-9-methyl-4- oxo-4H-quinolizine-3-carboxylic acid; l-cyclopropyl-8-(6-amino-3-azabicyclo[3.3.0]octyl)-7-fluoro-9-methyl-4-oxo-4H- quinolizine-3-carboxylic acid;
8-(( 1 R*,2S*,6R*)-2-amino-8-azabicyclo[4.3.0]nonan-8-yl))- 1 -cyclopropyl-7-fluoro-4H-
9-methyl-4-oxo-quinolizine-3-carboxylic acid;
8-((lR*,2R*,6R*)-2-amino-8-azabicyclo[4.3.0]nonan-8-yl))-l-cyclopropyl-7-fluoro-4H- 9-methyl-4-oxo-quinolizine-3-carboxylic acid;
8-(3-( 1 -aminoethyl)pyrrolidinyl)- 1 -cyclopropyl -7 -fluoro-4H-9-methyl-4-oxo-quinolizine-
3-carboxylic acid;
(8-(3-( 1 -amino- 1 -methylethyl)pyrrolidinyl)- 1 -cyclopropyl-7 -fluoro- 9- methyl-4-oxo-4H- quinolizine-3-carboxylic acid; (3R, 1 S)-8-(3-( l-(N-methyl)amino)propyl)pyrrolidinyl)- 1 -cyclopropyl-7-fluoro-9-methyl-
4-oxo-4H-quinolizine-3-carboxylic acid; 8-(3-aminopiperidinyl)-l-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3- carboxylic acid;
8-(3-( 1 -aminocyclopropyl)pyrrolidinyl)- 1 -cyclopropyl-7-fluoro-9-methyl-4-oxo-4H- quinolizine-3-carboxylic acid; (3S , 1 R)-8-(3-( 1 -aminoethyl)pyrrolidinyl)- 1 -cyclopropyl-7-fluoro-9-methyl-4-oxo-4H- quinolizine-3-carboxylic acid;
(3R, 1 S)-8-(3-( 1 -aminoethyl)pyrrolidinyl)- 1 -cyclopropyl-7-fluoro-9-methyl-4-oxo-4H- quinolizine-3-carboxylic acid;
(3R, 1 R)-8-(3-( 1 -aminoethyl)pyrrolidinyl)- 1 -cyclopropyl-7-fluoro-9-methyl-4-oxo-4H- quinolizine-3-carboxylic acid; l-cyclopropyl-8-(S,S-2,8-diaza-8-bicyclo[4.3.0]nonyl)-7-fluoro-4H-9-methyl-4-oxo- quinolizine-3-carboxylic acid; l-cyclopropyl-8-(R,R-2,8-diaza-8-bicyclo[4.3.0]nonyl)-7-fluoro-4H-9-methyl-4-oxo- quinolizine-3-carboxylic acid; l-cyclopropyl-8-(l-amino-3-aza-bicyclo[3.1.0]hexan-3-yl)-7-fluoro-4H-9-methyl-4-oxo- quinolizine-3-carboxylic acid;
8-(3-amino-3-fluoromethyl- 1 -pyrrolidinyl)- 1 -cyclopropyl -7-fluoro-4H-9-methyl-4-oxo- quinolizine-3-carboxylic acid;
8-(traAW-3-amino-4-fluoromethylpyrrodin- 1 -yl)- 1 -cyclopropyl-7-fluoro-4H-9-methyl-4- oxo-quinolizine-3-carboxylic acid;
8-(cw-3-amino-4-fluoromethylpyrrodin-l-yl)-l-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo- quinolizine-3-carboxylic acid;
8-(3-(S)-(2-fluoroethyl)aminopyrrolidin- 1 -yl)- 1 -cyclopropyl-7-fluoro-4H-9-methyl-4-oxo- quinolizine-3-carboxylic acid; 8-(3-(R)-(2-fluoroethyl)aminopyrrolidin- 1 -yl)- 1 -cyclopropyl-7-fluoro-4H-9-methyl-4-oxo- quinolizine-3-carboxylic acid;
8-(3-(R)-(hydroxymethyl)pyrroUdin- 1 -yl)- 1 -cyclopropyl-7-fluoro-4H-9-methyl-4-oxo- quinolizine-3-carboxylic acid;
8-(2-(R)-aminomethyl-pyrrolidin- 1 -yl)- 1 -cyclopropyl-7-fluoro-4H-9-methyl-4-oxo- quinolizine-3-carboxylic acid;
(8-(3-amino-4-methyl-piperidin- 1 -yl)- 1 -cyclopropyl-7-fluoro-9-methyl-4-oxo-4H- quinolizine-3-carboxylic acid;
8-(3-(7-amino-5-azaspiro[2.4]heptan-5-yl)-l-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H- quinolizine-3-carboxylic acid; 8-(7-(S)-amino-5-aza-spiro[2.4]heptan-5-yl)- 1 -cyclopropyl-7-fluoro-4H-9-methyl-4-oxo- quinolizine-3-carboxylic acid; 8-(7-(R)-aιnino-5-aza-spiro[2.4]heptan-5-yl)-l-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo- quinolizine-3-carboxylic acid;
8-(tr w-3-(S)-amino-4-(R)-cyclopropylpyrrolidin-l-yl)-l-cyclopropyl-7-fluoro-4H-9- methyl-4-oxo-quinolizine-3-carboxylic acid; 8-(trαAW-3-(R)-amino-4-(S )-cyclopropylpyιτolidin- 1 -yl)- 1 -cyclopropyl-7-fluoro-4H-9- methyl-4-oxo-quinolizine-3-carboxylic acid;
8-(trø/w-3-(S)-amino-4-(R)-methylpyrrolidin- 1 -yl)- 1 -cyclopropyl-7-fluoro-4H-9-methyl-4- oxo-quinolizine-3-carboxylic acid;
8-(trα/ιs-3-(R)-amino-4-(S)-methylpyιτolidin- 1 -yl)- 1 -cyclopropyl-7-fluoro-4H-9-methyl-4- oxo-quinolizine-3-carboxylic acid;
8-(cw-3-(S)-amino-4-(S)-cyclopropylpyrrolidin- 1 -yl)- 1 -cyclopropyl-7-fluoro-4H-9- methyl-4-oxo-quinolizine-3-carboxylic acid;
8-(cw-3-(R)-amino-4-(R)-cyclopropylpyrrolidin- 1 -yl)- 1 -cyclopropyl-7-fluoro-4H-9- methyl-4-oxo-quinolizine-3-carboxylic acid; 8-(trαrtly-3-amino-4-ethylpyrroUdin- 1 -yl)- 1 -cyclopropyl-7-fluoro-4H-9-methyl-4-oxo- quinolizine-3-carboxylic acid diastereomer A;
8-(trα/w-3-amino-4-ethylpyrrolidin- 1 -yl)- 1 -cyclopropyl-7-fluoro-4H-9-methyl-4-oxo- quinolizine-3-carboxylic acid diastereomer B;
8-(cw-3-amino-4-ethylpyrrodin- 1 -yl)- 1 -cyclopropyl-7-fluoro-4H-9-methyl-4-oxo- quinolizine-3-carboxylic acid diastereomer A;
8-(c/s-3-amino-4-ethylpyrτodin- 1 -yl)- 1 -cyclopropyl-7-fluoro-4H-9-methyl-4-oxo- quinolizine-3-carboxylic acid diastereomer B; 8-(cw-3-(S)-amino-4-(S)-methylpyrrodin- 1 -yl)- 1 -cyclopropyl-7-fluoro-4H-9-methyl-4- oxo-quinolizine-3-carboxylic acid; and 8-(cw-3-(R)-amino-4-(R)-methylpyrrodin- 1 -yl)- 1 -cyclopropyl-7-fluoro-4H-9-methyl-4- oxo-quinolizine-3-carboxylic acid; as well as the pharmaceutically acceptable salts, esters and amides thereof.
Especially preferred among the representative compounds of the present invention are the following: 8-(3(S)-amino- 1 -pyrrolidinyl)- 1 -cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3- carboxylic acid;
8-(3-amino- 1 -pyrrolidinyl)- 1 -cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3- carboxylic acid;
(3R, 1 S)-8-(3-(l -amino-2-methoxyethyl)pyrrolidinyl)- 1 -cyclopropyl-7-fluoro-9-methyl-4- oxo-4H-quinolizine-3-carboxylic acid;
(8-(3-( 1 -amino- 1 -methylethyl)pyrrolidinyl)- 1 -cyclopropyl-7-fluoro-9-methyl-4-oxo-4H- quinolizine-3-carboxylic acid; 8-(3-(l-aminocyclopropyl)pyrrolidinyl)-l-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H- quinolizine-3-carboxylic acid;
(3R, 1 S)-8-(3-( 1 -aminoethyl)pyrrolidinyl)- 1 -cyclopropyl-7-fluoro-9-methyl-4-oxo-4H- quinolizine-3-carboxylic acid; l-cyclopropyl-8-(S,S-2,8-diaza-8-bicyclo[4.3.0]nonyl)-7-fluoro-4H-9-methyl-4-oxo- quinolizine-3-carboxylic acid; l-cyclopropyl-8-(R,R-2,8-diaza-8-bicyclo[4.3.0]nonyl)-7-fluoro-4H-9-methyl-4-oxo- quinolizine-3-carboxylic acid; l-cyclopropyl-8-(l-amino-3-aza-bicyclo[3.1.0]hexan-3-yl)-7-fluoro-4H-9-methyl-4-oxo- quinolizine-3-carboxylic acid;
8-(3-amino-3-fluoromethyl- 1 -pyrrolidinyl)- 1 -cyclopropyl-7-fluoro-4H-9-methyl-4-oxo- quinolizine-3-carboxylic acid;
8-(trflAW-3-amino-4-fluoromethylpyrrodin- 1 -yl)- 1 -cyclopropyl-7-fluoro-4H-9-methyl-4- oxo-quinolizine-3-carboxylic acid; 8-(cw-3-amino-4-fluoromethylpyrrodin- 1 -yl)- 1 -cyclopropyl-7-fluoro-4H-9-methyl-4-oxo- quinolizine-3-carboxylic acid;
8-(3-(S)-(2-fluoroethyl)aminopyrrolidin- 1 -yl)- 1 -cyclopropyl-7-fluoro-4H-9-methyl-4-oxo- quinolizine-3-carboxylic acid;
8-(3-(R)-(2-fluoroethyl)aminopyrrolidin- 1 -yl)- 1 -cyclopropyl-7-fluoro-4H-9-methyl-4-oxo- quinolizine-3-carboxylic acid;
8-(3-(R)-(hydroxymethyl)pyrrolidin-l-yl)-l-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo- quinolizine-3-carboxylic acid;
8-(2-(R)-aminomethyl-pyrrolidin- 1 -yl)- 1 -cyclopropyl-7-fluoro-4H-9-methyl-4-oxo- quinolizine-3-carboxylic acid; (8-(3-amino-4-methyl-piperidin- 1 -yl)- 1 -cyclopropyl-7-fluoro-9-methyl-4-oxo-4H- quinolizine-3-carboxylic acid;
8-(3-(7-amino-5-azaspiro[2.4]heptan-5-yl)-l-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H- quinolizine-3-carboxylic acid;
8-(7-(S)-amino-5-aza-spiro[2.4]heptan-5-yl)-l-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo- quinolizine-3-carboxylic acid;
8-(7-(R)-amino-5-aza-spiro[2.4]heptan-5-yl)-l-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo- quinolizine-3-carboxylic acid;
8-(trfl t -3-(S)-amino-4-(R)-cyclopropylpyrrolidin- 1 -yl)- 1 -cyclopropyl-7-fluoro-4H-9- methyl-4-oxo-quinolizine-3-carboxyhc acid; 8-(trα«s-3-(R)-amino-4-(S)-cyclopropylpyrrolidin- 1 -yl)- 1 -cyclopropyl-7-fluoro-4H-9- meιhyl-4-oxo-quinolizine-3-carboxylic acid; 8-(trα w-3-(S)-amino-4-(R)-methylpyrrolidin-l-yl)-l-cyclopropyl-7-fluoro-4H-9-methyl-4- oxo-quinolizine-3-carboxylic acid;
8-(trfl/w-3-(R)-amino-4-(S)-methylpyrrolidin- 1 -yl)- 1 -cyclopropyl-7-fluoro-4H-9-methyl-4- oxo-quinolizine-3-carboxylic acid; 8-( -3-(S)-amino-4-(S)-cyclopropylpyrrolidin- 1 -yl)- 1 -cyclopropyl-7-fluoro-4H-9- methyl-4-oxo-quinolizine-3-carboxylic acid;
8-(cw-3-(R)-amino-4-(R)-cyclopropylpyrrolidin- 1 -yl)- 1 -cyclopropyl-7-fluoro-4H-9- methyl-4-oxo-quinolizine-3-carboxylic acid;
8-(tra w-3-amino-4-ethylpyrrolidin- 1 -yl)- 1 -cyclopropyl-7-fluoro-4H-9-methyl-4-oxo- quinolizine-3-carboxylic acid diastereomer A;
8-(trα w-3-amino-4-ethylpyrrolidin- 1 -yl)- 1 -cyclopropyl-7-fluoro-4H-9-methyl-4-oxo- quinolizine-3-carboxylic acid diastereomer B;
8-(cw-3-amino-4-ethylpyrrodin- 1 -yl)- 1 -cyclopropyl-7-fluoro-4H- 9- methyl -4-oxo- quinolizine-3-carboxylic acid diastereomer A; 8-(cw-3-amino-4-ethylpyrrodin- 1 -yl)- 1 -cyclopropyl-7-fluoro-4H-9-methyl-4-oxo- quinolizine-3-carboxylic acid diastereomer B;
8-(cw-3-(S)-amino-4-(S)-methylpyτrodin- 1-yl)- 1 -cyclopropyl-7-fluoro-4H-9-methyl-4- oxo-quinolizine-3-carboxylic acid; and
8-(cw-3-(R)-amino-4-(R)-methylpyrrodin- 1 -yl)- 1 -cyclopropyl-7-fluoro-4H-9-methyl-4- oxo-quinolizine-3-carboxylic acid; as well as the pharmaceutically acceptable salts, esters and amides thereof.
It will be observed above and elsewhere in the disclosure that numerous asymmetric centers may exist in the compounds of the present invention which will be found in the R or S configurations. Except where otherwise noted, the present invention contemplates the various stereoisomers and mixtures thereof.
A number of defined terms are used herein to designate particular elements of the present invention. When so used, the following meanings are intended:
The term "alkanoyl of from one to eight carbons" refers to a radical of the formula -C(0)R15 where Rl5 JS hydrogen or an alkyl radical of from one to eight carbon atoms including, but not limited to, acetyl and pivaloyl.
The term "alkyl" refers to saturated, straight- or branched-chain hydrocarbon radicals containing between one and ten carbon atoms including, but not limited to, methyl, ethyl, propyl, isopropyl, n-butyl, tert-butyl and neopentyl.
The terms "alpha-amino acid" and "polypeptide residue" refer, respectively, to a single amino acid and two to five amino acids each joined by amide (peptide) bonds. The amino acids may be any of the naturally-occurring amino acids such as valine, phenylalanine and glycine or synthetic alpha-amino acids such as cyclohexylalanine, and further may be in either the L or D configuration or a mixture of the two isomers. Preferably, amino acid substituents are optically active and have the L configuration.
The term "amino(loweralkyl)" refers to a loweralkyl radical having appended thereto at least one amino substituent which in turn is optionally substituted with one or two loweralkyl radicals or an alpha-amino acid or polypeptide residue. Examples of amino(loweralkyl) groups include aminoethyl, aminomethyl and N,N-dimethylaminoethyl.
The term "aminooxy" refers to an amino group, optionally substituted once or twice with loweralkyl or halo(loweralkyl), which is appended to the rest of the molecule via an oxygen atom; (e.g. -O-NR'R" wherein R' and R" are hydrogen, loweralkyl or halo(loweralkyl).
The term "aminothioloweralkoxy" refers to a thioloweralkoxy radical having appended thereto an amino group, as for example aminothiomethoxy and 2-aminothioethoxy.
The term "aromatic group" refers to a C6-to-C10 cyclic radical which is aromatic according to Huckel's rule. Examples of aromatic groups include carbocyclic aromatic radicals such as phenyl and naphthyl as well as nitrogen-containing aromatic heterocyclic radicals, defined below.
The term "aryl(loweralkyl)" refers to a loweralkyl radical having appended thereto an aromatic hydrocarbon group, as for example benzyl and phenylethyl. The term "aryl(loweralkyl)amino" refers to an amino radical having appended thereto an aryl(loweralkyl) group. Examples of aryl(loweralkyl)amino groups include benzylamino and phenylethylamino.
The term "aryl(loweralkyl)oxy" refers to an aryl(loweralkyl) radical which is joined to the rest of the molecule via an ether linkage (i.e., through an oxygen atom). Examples of aryl(loweralkyl)oxy radicals include benzyloxy and phenylethyloxy.
The term "aryloxy" refers to an aromatic hydrocarbon radical which is joined to the rest of the molecule via an ether linkage (i.e., through an oxygen atom), as for example phenoxy.
The term "bicycloalkyl" refers to a radical comprising a bridged, saturated or unsaturated hydrocarbon ring system having between five and nine carbon atoms in which two non-adjacent carbon atoms of a first ring are linked by an alkylene bridge of between one and three additional carbon atoms, the bicycloalkyl radical being optionally substituted with between one and three additional radicals selected from among aryl(loweralkyl), alkoxycarbonyl, loweralkyl, halo(loweralkyl), amino(loweralkyl), hydroxy-substituted loweralkyl, hydroxy, loweralkoxy, halogen, and amino, (loweralkyl)amino or alkanoylamino of from one to eight carbon atoms in which the amino group may be further substituted with alkanoyl of from one to eight carbons, an alpha-amino acid or a polypeptide. Examples of bicycloalkyl radicals include, but are not limited to, norbornyl, bicylo[2.2.1]hept-2-enyl and bicyclo[l.l.l]pentanyl.
The term "bicyclic nitrogen-containing heterocyclic group" refers to a radical comprising a bicyclic ring system in which the the rings are of the (a) fused, (b) bridged or (c) spiro form. Fused-ring bicyclic nitrogen-containing heterocyclic groups are those in which a first nitrogen-containing heterocycle or aromatic heterocycle has fused to it a second saturated or unsaturated carbocyclic or heterocyclic ring of between three and six atoms of which zero, one or two are heteratoms selected from S, O, and N. Both the first and the second ring may be optionally substituted with between one and three additional radicals A2 independently selected from among loweralkyl, halo(loweralkyl), hydroxy- substituted loweralkyl, hydroxy, halogen, amino(loweralkyl), alkanoylamino of from one to eight carbons, phenyl and -NR17R18 where RC and Rl8 are independently hydrogen or loweralkyl or, when one is hydrogen, the other is an alpha-amino acid or a polypeptide residue. Examples of fused-ring bicyclic nitrogen-containing heterocychc radicals are those having 5:3, 5:4, 5:5, 5:6 and 6:5 ring systems and include, but are not limited to, radicals of the formulae
Bridged-ring bicyclic nitrogen-containing heterocyclic groups are those selected the formulae
and unsaturated derivatives thereof, where j and k are independently one, two or three, and Al is a carbon atom or a heteroatom selected from S, O and N, optionally substituted at any position with between one and three additional radicals A is as previously defined.
Spiro-ring bicyclic nitrogen-containing heterocyclic groups are those in which a first nitrogen-containing heterocycle or aromatic heterocycle to which is joined, by a single shared carbon atom, a second carbocyclic or heterocyclic ring of between three and six atoms of which zero, one or two are heteratoms selected from S, O, and N. Either the first or the second ring may be substituted with between one and three additional radicals A , where A is as previously defined. Examples of spiro-ring bicyclic nitrogen-containing heterocyclic radicals include, but are not limited to, those having the formulae
The term "cyclic ether" refers to a 4- to 6-membered monocyclic hydrocarbon radical containing an oxygen ring atom and joined to the rest of the molecule via any of the carbon atoms including, but not limited to, oxetane. The term "cycloalkenyl of from four to eight carbons" refers to a mono- unsaturated monocyclic hydrocarbon radical having from four to eight carbon atoms in the ring, including, but not limited to, cyclobutenyl, cyclopentenyl, cyclohexenyl and cycloheptenyl, and optionally substituted with between one and three additionals radicals selected from among aryl(loweralkyl), alkoxycarbonyl, loweralkyl, halo(loweralkyl), amino(loweralkyl), hydroxy-substituted loweralkyl, hydroxy, loweralkoxy, halogen, amino, loweralkylamino, and amino, (loweralkyl)amino or alkanoylamino of from one to eight carbon atoms in which the amino group may be further substituted with alkanoyl of from one to eight carbons, an alpha-amino acid or a polypeptide.
The term "cycloalkyl of from three to eight carbons" refers to a saturated monocychc hydrocarbon radical having from three to eight carbon atoms in the ring and optionally substituted with between one and three additional radicals selected from among aryl(loweralkyl), alkoxycarbonyl, loweralkyl, halo(loweralkyl), amino(loweralkyl), hydroxy-substituted loweralkyl, hydroxy, loweralkoxy, halogen, and amino, (loweralkyl)amino or alkanoylamino of from one to eight carbon atoms in which the amino group may be further substituted with alkanoyl of from one to eight carbons, an alpha- amino acid or a polypeptide. Examples of cycloalkyl radicals include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, 1-fluoro-cyclopropyl, 2-fluorocyclopropyl and 2-aminocyclopropyl. The term "cycloalkyl(amino)" refers to an amino group substituted with at least one cycloalkyl group, typically having from three to eight carbons.
The term "cycloalkyl(loweralkyl)" refers to a loweralkyl radical having appended thereto a cycloalkyl radical of from three to eight carbon atoms, which cycloalkyl radical may be optionally substituted as described above.
The term "fused" as used herein refers to two cyclic groups having two adjacent ring atoms in common.
The terms "halo" and "halogen" refer to a monovalent radical selected from among chloro (Cl), bromo (Br), fluoro (F) and iodo (I). The term "halo(loweralkyl)" refers to a loweralkyl radical having appended thereto between one and three halogen atoms. Examples of halo(loweralkyl) radicals include fluoromethyl, trifluoromethyl, 1-fluoroethyl, 2-fluoroethyl and 1,2-difluoroethyl.
The term "halo(loweralkyl)amino refers to an amino group substituted with at least one halo(loweralkyl) group. The term "halo(loweralkyl)amino(loweralkyl)" refers to an amino(loweralkyl) radical having appended thereto a halo(loweralkyl) group, as for example 2-fluoroethylaminomethyl.
The term "halo-substituted nitrogen-containing aromatic heterocycle" refers to a nitrogen-containing aromatic heterocycle radical having appended thereto between one and three halogen atoms including, but not limited to, 5-fluoro-2-pyrimidyl.
The term "hydroxy-substituted loweralkyl" refers to a loweralkyl radical having appended thereto between one and three hydroxyl groups, as for example hydroxymethyl and 2-hydroxyethyl.
The term "hydroxy-substituted (loweralkyl)amino" refers to a (loweralkyl)amino radical having appended thereto between one and three hydroxyl groups, as for example hydroxymethylamino and 2-hydroxyethylamino.
The term "imino" refers to a divalent radical of the formula =N-OH.
The term "loweralkenyl" refers to a straight- or branched-chain hydrocarbon radical containing between two and six carbon atoms and possessing at least one carbon- carbon double bond. Examples of loweralkenyl radicals include vinyl, allyl, 2- or 3- butenyl, 2-,3- or 4-pentenyl, 2-,3-,4- or 5-hexenyl and isomeric forms thereof.
The term "loweralkoxy" refers to a loweralkyl radical which is appended to the rest of the molecule via an ether linkage (i.e., through an oxygen atom), as for example methoxy, ethoxy, propoxy, tert-butoxy, pentyloxy, hexyloxy, isomeric forms thereof and the like. The term "loweralkoxycarbonyl" refers to a radical of the formula -C(O)R25 wherein R25 is a loweralkoxy group, as for example ethoxycarbonyl and methoxycarbonyl.
The term ""loweralkoxy(loweralkoxy)(loweralkyl)" refers to a loweralkoxy(loweralkyl) radical having appended thereto a loweralkoxy group, as for example methoxymethoxymethyl and ethoxymethoxymethyl
The term "loweralkoxy(loweralkyl)" refers to a loweralkyl radical having appended thereto a loweralkoxy group and optionally substituted with an additional amino radical, as for example methoxyethyl, ethoxymethyl and l-amino-2-methoxyethyl. The term "loweralkyl" refers to an alkyl radical containing one to six carbon atoms including, but not limited to, methyl, ethyl, propyl, isopropyl, n-butyl, tert-butyl and neopentyl.
The term "(loweralkyl)amino" refers to an amino radical substituted with between one and three loweralkyl radicals including, but not limited to, methylamino, ethylamino, dimethylamino, propylamino and ethylmethylamino.
The tern "loweralkynyl" refers to a straight- or branched-chain hydrocarbon radical containing between two and six carbon atoms and possessing at least one carbon- carbon triple bond. Examples of loweralkynyl radicals include ethynyl, 2-hexyn-l-yl, 3,3- dimethyl- 1 -butyn- 1 -yl and 3-methylbutyn-3-yl. The term "nitrogen-containing aromatic heterocycle" refers to a monocyclic aromatic radical having from five to seven ring atoms of which one ring atom is nitrogen; zero, one or two ring atoms are additional heteroatoms independently selected from S, O and N; and the remaining ring atoms are carbon, the radical being joined to the rest of the molecule via any of the ring atoms. Examples of nitrogen-containing aromatic heterocycles include pyridine, pyrazine, pyrimidine, pyrrole, pyrazole, imidazole, thiazole, oxazole, isooxazole, thiadiazole, oxadiazole and substituted derivatives thereof.
The term "nitrogen-containing heterocycle" refers to a saturated or unsaturated monocyclic ring system radical having from four to seven ring atoms of which one is nitrogen; zero, one or two are additional heteroatoms independently selected from S, O and N; and the remainder are carbon, the radical being joined to the rest of the molecule via any of the ring atoms and being optionally substituted, either on a nitrogen or a carbon atom, by an additional radical selected from among aryl(loweralkyl), alkoxycarbonyl, loweralkyl, halo(loweralkyl), amino(loweralkyl), hydroxy-substituted loweralkyl, hydroxy, loweralkoxy, halogen, amino, loweralkylamino, and amino, (loweralkyl)amino or alkanoylamino of from one to eight carbon atoms in which the amino group may be further substituted with alkanoyl of from one to eight carbons, an alpha-amino acid or a polypeptide. Examples of nitrogen-containing heterocycles include pyrrolidine, dihydropyrrole, isooxazolidine, oxazolidine, tetrhydropyridine, piperidine, piperazine, morpholine, thiomorpholine, aziridine and azetidine. The term "pharmaceutically acceptable cation" refers to a positively-charged inorganic or organic ion that is generally considered suitable for human consumption. Examples of pharmaceutically acceptable cations are hydrogen, alkali metal (hthium, sodium and potassium), magnesium, calcium, ferrous, ferric, ammonium, alkylammonium, dialkylammonium, trialkylammonium, tetraalkylammonium, diethanolammmonium, triethanolammonium, and guanidinium ions, and protonated forms of lysine, procaine and choline. Cations may be interchanged by methods known in the art, such as ion exchange. Where compounds of the present invention are prepared in the carboxylic acid form (that is, where R4 is hydrogen) addition of a base form of the cation, (such as a hydroxide or a free amine) will yield the appropriate cationic form.
By "pharmaceutically acceptable salts, esters and amides", as of the compounds of formula I, is meant those carboxylate salts, amino acid addition salts, esters and amides which are, within the scope of sound medical judgement, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, commensurate with a reasonable benefit/risk ratio, and effective for their intended use, as well as the zwitterionic forms thereof.
Pharmaceutically acceptable salts are well known in the art. For example, S. M Berge, et al. describe pharmaceutically acceptable salts in detail in Pharmaceutical Sciences. 66:1-19 (1977). 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-phenylpropionate, 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 or 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.
Examples of pharmaceutically acceptable, non-toxic esters of the present invention include Cl-to-C6 alkyl esters and C5-to-C7 cycloalkyl esters, although Cl-to-C4 alkyl esters are preferred. Esters of the compounds of formula I may be prepared according to conventional methods.
Examples of pharmaceutically acceptable, non-toxic amides of the present invention include amides derived from ammonia, primary Cl-to-C6 alkyl amines and secondary Cl-to-C6 dialkyl amines. In the case of secondary amines, the amine may also be in the form of a 5- or 6-membered heterocycle containing one nitrogen atom. Amides derived from ammonia, Cl-to-C3 alkyl primary amides and Cl-to-C2 dialkyl secondary amides are preferred. Amides of the compounds of formula I may be prepared according to conventional methods. It is intended that amides of the present invention include amino acid and peptide derivatives of the compounds of formula I as well.
As used herein, the term "pharmaceutically acceptable carrier" means a non-toxic, inert solid, semi-solid or liquid filler, diluent, encapsulating material or formulation auxiliary of any type. Some examples of the materials that can serve as pharmaceutically acceptable carriers are sugars, such as lactose, glucose and sucrose; starches such as corn 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 as propylene glycol; polyols such as glycerin, sorbitol, mannitol and polyethylene 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 substances used in pharmaceutical formulations. Wetting agents, emulsifiers and lubricants such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, releasing agents, coating agents, sweetening, flavoring and perfuming agents, and preservatives can also be present in the composition, according to the judgement of the formulator.
The term "prodrug", as of the compounds of formula I, refers to derivative compounds that are rapidly transformed in vivo to yield the parent compound of the formula I, as for example by hydrolysis in blood. T. Higuchi and V. Stella provide a thorough discussion of the prodrug concept in "Pro-drugs as Novel Delivery Systems", Vol 14 of the A.C.S. Symposium Series, American Chemical Society (1975). Examples of esters useful as prodrugs for compounds containing carboxyl groups can be found on pages 14-21 of "Bioreversible Carriers in Drug Design: Theory and Application", edited by E.B. Roche, Pergamon Press:New York (1987). It is intended that these references, and any others cited throughout this specification, are incorporated herein by reference.
The term "prodrug ester group" refers to any of several ester-forming groups that are hydrolyzed under physiological conditions. Examples of prodrug ester groups include pivoyloxymethyl, acetoxymethyl, phthalidyl, indanyl and methoxymethyl, as well as other such groups known in the art, including a (5-R-2-oxo-l,3-dioxolen-4-yl)methyl group. Other examples of prodrug ester groups can be found in the book "Pro-drugs as Novel Delivery Systems", by Higuchi and Stella, cited above. The term "protecting group" is well-known in the art and refers to substituents on functional groups of compounds undergoing chemical transformation which prevent undesired reactions and degradations during a synthesis; see, for example, T.H. Greene, "Protective Groups in Organic Synthesis", John Wiley & Sons, New York (1981). The term "substituted phenyl" refers to a benzene ring having between one and five non-hydrogen substituents, each independently selected from among halogen, hydroxy, loweralkoxy, loweralkyl, hydroxy-substituted loweralkyl, amino, (loweralkyl)amino, amino(loweralkyl) and nitrogen-containing heterocycle. Examples of substituted phenyl radicals include 2-fluorophenyl, 4-fluorophenyl and 2,4-difluorophenyl. The term "thioloweralkoxy" refers to a radical of the formula -SR35 where R35 is a loweralkyl group including, but not limited to, thiomethoxy and thioethoxy.
The term "thioloweralkoxy(loweralkyl)" refers to a loweralkyl radical having appended thereto a thioloweralkoxy group including, but not limited to, thiomethoxymethyl and thiomethoxyethyl. According to the methods of treatment of the present invention, the compounds of the invention may be administered alone or in combination or in concurrent therapy with other agents. When utilizing the compounds of the present invention for antimicrobial therapy, 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 of the disorder; activity of the particular compound used; the specific composition employed; the age, body weight, general health, sex and diet of the patient; the time of administration, route of administration, and rate of excretion of the specific compound employed; the duration of the treatment; drugs used in combination or coincidently with the specific compound employed; and like factors well known in the medical arts. The total daily dose of the compounds of this invention administered to a host in single or in divided doses can be in amounts, as for example from 0.1 to 200 mg/kg body weight or more usually from 0.25 to 100 mg/kg body weight. Single dose compositions may contain such amounts or submultiples thereof as make up the daily dose.
According to the pharmaceutical compositions of the present invention, the compounds of the invention may be administered orally, parenterally, by inhalation spray, rectally, or topically in unit dosage formulations containing conventional nontoxic pharmaceutically acceptable carriers, adjuvants, diluents and/or vehicles as desired. The term "parenteral" as used herein includes subcutaneous injections, intravenous, intramuscular, intrasternal injection or infusion techniques. Injectable preparations, as 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 or suspension in a nontoxic parenterally acceptable diluent or solvent, as for example 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 purpose 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.
In order to prolong the effect of a drug, it is often desirable to slow the absorption of a drug from subcutaneous or intramuscular injection. The most common way to accomplish this is to inject a suspension of crystalline or amorphous material with poor water solubility The rate of absorption of the drug becomes dependent on the rate of dissolution of the drug which is, in turn, dependent on the physical state of the drug, for example, the crystal size and the crystalline form. Another approach to delaying absoφtion of a drug is to administer the drug as a solution or suspension in oil. Injectable depot forms can also be made by forming microcapsule matrices of drugs and biodegradable polymers such as polylactide-polyglycolide. Depending on the ratio of drug to polymer and the composition of the polymer, the rate of drug release can be controlled. Examples of other biodegradable polymers include poly-orthoesters and polyanhydrides. Depot injectables can also be made by entrapping the drug in liposomes or microemulsions which are compatible with body tissues.
Suppositories for rectal or vaginal administration of the drug can be prepared by mixing the drug with a suitable nonirritating excipient such as cocoa butter and polyethylene glycol which are solid at ordinary temperature but will melt in the rectum or in the vagina and release the drug. Solid dosage forms for oral administration may include capsules, tablets, pills, powders, prills and granules. In such solid dosage forms the active compound may 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 as magnesium stearate and microcrystalUne cellulose. In the case of capsules, tablets and pills, the dosage forms may also comprise buffering agents. Tablets and piUs can additionaUy be prepared with enteric coatings and other release-controUing coatings.
Liquid dosage forms for oral administration may include pharmaceuticaUy acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs containing inert diluents commonly used in the art such as water. Such compositions may also comprise adjuvants, such as wetting agents; emulsifying and suspending agents; and sweetening, flavoring and perfuming agents. If desired, the compounds of the present invention can be incoφorated into slow release or targeted dehvery systems such as polymer matrices, Uposomes and microspheres. They may be sterilized, for example, by filtration through a bacteria- retaining filter, or by incoφorating sterilizing agents in the form of sterile solid compositions which can dissolve in sterile water, or some other sterile injectable medium immediately before use.
The active compounds can also be in micro-encapsulated form with one or more excipients as noted above.
Dosage forms for topical or transdermal administration of a compound of this invention further 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 formulations, 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, siUcones, 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 or substitutes therefor.
Transdermal patches have the added advantage of providing controUed deUvery of a compound to the body. Such dosage forms can be made by dissolving or dispersing the compound in the proper medium. Absoφtion enhancers can also be used to increase the flux of the compound across the skin. The rate can be controUed by either providing a rate controlUng membrane or by dispersing the compound in a polymer matrix or gel.
A further possibility for delivery and/or utiUzation of the compounds of the present invention is by chemical conjugation of the compounds with other antibacterials such as beta-lactams. Sirrular dual-action conjugates (between beta-lactams and quinolones) are proposed in the published European patent appUcation No. 597 303 of Dax, etal. (published on May 18, 1994) and the pubUshed international patent appUcation No. PCT/US92/08246 of White, et al. (Publication No. WO 93/07154, published on April 15, 1993). In the manner suggested by these references, a carbon-nitrogen bond or other covalent Unk may be formed between, for example, either an amino substituent at the C-8 position or a carboxylic acid group at the C-3 position of a compound of the present invention, and an alkyl or other group of a beta-lactam. In general, the compounds of the present invention are synthesized according to reaction Schemes I through XVIII presented below, in which Rl through Rl , A, X, Y and Z correspond to the groups defined in connection with formula (I), R is a loweralkyl group, X is a halogen atom, P is a protecting group and L is a suitable leaving group, as for example a halogen atom.
Certain abbreviations are used repeatedly in the specification which foUows. These include: BOC for t-butoxycarbonyl; (BOC)2 for di-t-butyl dicarbonate; CBZ for benzyloxy-carbonyl; DMF for dimethyl formamide; DMSO for dimethyl sulfoxide; HRMS for high resolution mass spectroscopy; LAH for Uthium aluminum hydride; LDA for Uthium diethyl amide; RaNi for Raney Nickel; and THF for tetrahydrofuran.
For the preparation of the compounds of formula (I) which are alpha-amino acid or peptide derivatives of amine groups at R2, the condensation of the amino group with amino acids and peptides may be effected in accordance with conventional condensation methods such as the azide method, the mixed acid anhydride method, the DCC (dicyclohexylcarbodumide) method, the active ester method ( p-nitrophenyl ester method, N-hydroxysuccinic acid imide ester method, cyanomethyl ester method and the like), the Woodward reagent K method, the DCC-HOBT (1-hydroxy-benzotriazole) method and the like. Classical methods for amino acid condensation reactions are described in "Peptide Synthesis", Second Edition, M. Bodansky, Y.S. Klausner and M.A. Ondetti (1976). It is contemplated that the amino acid coupling reaction could be carried out before or after the amino-containing group is incoφorated into the compound by displacement of the 7- fluorine atom of the appropriate intermediate.
As in conventional peptide synthesis, branched chain amino and carboxyl groups at alpha and omega positions in amino acids may be protected and deprotected if necessary. The protecting groups for amino groups which can be used involve, for example, benzyloxycarbonyl (Z), o-chloro-benzyloxycarbonyl((2-Cl)Z), p-nitrobenzyloxycarbonyl (Z(NO2)), p-methoxybenzyloxycarbonyl (Z(OMe)), t-butoxycarbonyl (Boc), t-amyloxycarbonyl (Aoc), isobornealoxycarbonyl, adamantyloxycarbonyl (Adoc), 2-(4-biphenyl)-2-propyloxy carbonyl (Bpoc), 9-fluorenyl-methoxycarbonyl (Fmoc), methylsulfonylethoxy carbonyl (Msc), trifluoroacetyl, phthalyl, formyl, 2- nitrophenylsulfenyl (Nps), diphenylphosphinothioyl (Ppt) and dimethylphosphino-thioyl (Mpt).
The examples of protecting groups for carboxyl groups involve, for example, benzyl ester (OBzl), cyclohexyl ester, 4-nitrobenzyl ester (OBzlNO2), t-butyl ester (OtBu), 4-pyridylmethyl ester (OPic) and the like.
In the course of the synthesis of certain of the compounds of the present invention, specific amino acids having functional groups other than amino and carboxyl groups in the branched chain such as arginine, cysteine, serine and the like may be protected, if necessary, with suitable protecting groups. It is preferable that, for example, the guanidino group (NG) in arginine be protected with nitro, p-toluenesulfonyl (Tos), benzyloxycarbonyl (Z), adamantyloxycarbonyl (Adoc), p-methoxybenzenesulfonyl, 4- methoxy-2,6-dimethyl-benzenesulfonyl (Mts) or the like; that the thiol group in cysteine be protected with benzyl, p-methoxybenzyl, triphenylmethyl, acetamidomethyl, ethylcarbamyl, 4-methylbenzyl (4-MeBzl), 2,4,6,-trimethylbenzyl (Tmb) or the like; and that the hydroxy group in serine may be protected with benzyl (Bzl), t-butyl, acetyl, tetrahydropyranyl (THP) or the like.
Scheme I
FCH2COOR+ HCOOH
10C 11A 12A
13A Scheme II
12B IIB
Scheme ITT
IV A2 Scheme TVB
Scheme IVC
Scheme VA
Scheme VB
VB2 Scheme VI
65 66
Scheme VTT
VII
77 Scheme VTU
3 R1 is not cyclopropyl
Scheme IX
79 4 (OH) or 6 (Q=COOEt)
80 81
via Schemes II, or VIII
86 87
via Schemes Nor VIII
Scheme XI
)
Scheme XTT
\
Scheme XITT
90 100 101
Scheme XIV
102 103 104
Scheme XV
108 109
Scheme XVT
Scheme XVTT
Scheme XVH
In accordance with reaction Scheme I, illustrated above, an alpha-halo acetate derivative of formula 1, such as ethyl 2-fluoroacetate, is condensed with a formate ester of formula 2 in the presence of a suitable base, as for example sodium ethoxide, in an inert solvent such as diethyl ether to to give an enolate compound of formula 3. Compounds of formula 3 are, in turn, converted to compounds of formula 5 by condensation with an amidine derivative of formula 4, in which R is an electron withdrawing group such as phenyl, trifluoromethyl, cyano, perfluoroalkyl, vinyl, substituted vinyl, fluorine, nitro, acetylene, substituted acetylene, alkoxycarbonyl, or a nitrogen-containing aromatic heterocycle. Compounds of formula 5 are reacted with an alkoxymethylene malonate derivative of formula 8 in the presence of a suitable strong base, for example Uthium dusopropylamide (LDA) or n-butyl lithium, preferably at a temperature below 0°C, and conveniently at -78°C to afford the compounds of formula 9A.
The compounds of formula 9A are cyclized in the presence of a base, as for example DBU or piperidine, or in the presence of an acid, such as sulfuric acid, in a solvent such as toluene, THF, ethanol or chlorobenzene, or by heating the compound in a solvent, as for example xylene, diglyme, triglyme, sulfolane or Dowtherm A® (a eutectic mixture of biphenyl and diphenyl ether) at a temperature greater than 120°C, to give the compounds of formula IOC. The esters IOC are converted into the esters 11 A via trøλwesterifϊcation with an alcohol suitable for selective hydrolysis, such as benzyl alcohol or 2-(trimethylsilyl)ethanol (TMSE), in the presence of a catalyst, as for example titanium tetraethoxide.
The 2-hydroxy compounds of formula 11 A are converted to the corresponding halo-derivatives of formula 12A by treatment with a halogenating agent, for example phosphorous oxychloride to afford the chloro derivative, optionally in an inert solvent at a temperature between about 20°C and 145°C, depending on the halogenating agent and the boiling point of the solvent if one is used, and conveniently at room temperature. The leaving group L in the compounds of formula 12A is then displaced by a nucleophile such as a nucleophilic amine, for example N-methylpiperazine or 2-methylpiperazine, to give the compounds of formula 13 A. The reaction may be conducted at a temperature from about 20°C to about 130°C in a suitable organic solvent such as pyridine, methylene chloride, chloroform or l-methyl-2-pyrrolidinone. It is desirable to carry out the reaction in the presence of an acid-acceptor such as triethylamine, potassium carbonate and the like, at a molar ratio of 1.0 to 2.0 moles of the acid acceptor per mole of compound of the formula 6. The amine can also be used as an acid acceptor in which case two or more equivalents of this reagent are used.
The benzyl ester group of compounds of formula 13 A is then removed by hydrogenolysis when R is benzyl, or with tetrabutylammonium fluoride when R is TMSE, to afford a compound of formula I.
In accordance with Scheme U above, the substituted acetonitrile compounds of formula 4B, where R 1 is an alkyl, cycloalkyl, halo(loweralkyl) group or a
(loweralkyl)amino group protected with a protecting group such as benzyloxycarbonyl, or may be an electron withdrawing group as described above for Scheme I, are reacted with diethyl carbonate and sodium hydride in an inert organic solvent, such as toluene, THF or the like, to give the substituted cyanoacetic acid ester of formula 5B. The cyano group of the compounds of formula 5B is then reacted with an inorganic acid, such as hydrochloric acid, in the presence of one equivalent of anhydrous alcohol, such as ethanol, followed by reaction with ammonia to give the substituted amidine ester of formula 6B, which is then condensed with an enolate compound of formula 7B, prepared in a manner similar to compounds of formula 3 in Scheme I, in the presence of a suitable base, for example triethylamine, in a polar solvent such as methanol to give the substituted hydroxy- pyrimidine ester compounds of formula 8B. The ester function of the compounds of formula 8B is converted into an aldehyde function by reduction, for example with a hindered aluminum hydride, such as diisobutylaluminum hydride or LiAlH(O-t-butyl)3, or with N,N-dimethyl-chloromethyleneiminium chloride in pyridine or diarninoaluminum hydride to produce a compound of formula 9B. This reaction may be conducted at a temperature below -20°C, and conveniently at -78°C in the presence of a aprotic solvent such as hexane, toluene, methylene chloride or THF.
The aldehyde compounds of formula 9B are reacted with a malonic acid diester, such as diethyl malonate, dibenzyl malonate, t-butyl malonate or di-t-butyl malonate, in the presence of a suitable base such as piperidine and a catalytic amount of an acid, such as acetic acid or sulfuric acid, in a polar solvent, such as ethanol, to afford the pyridopyrimidine compounds of formula 10B. The compounds of formula 10B are reacted with a suitable halogenating agent such as phosphoryl chloride at room temperature to afford the compounds of formula 1 IB. The halo group is displaced as discussed in reaction Scheme I to afford the compounds of formula 12B, which are in turn converted into the compounds of formula I as described in Scheme I for the conversion of compounds of formula 10 into compounds of formula I.
According to reaction Scheme HI illustrated above, 2-picoline-N-oxide is converted to a mixture of compounds of formulae 22 and 23 by treatment with a halogenating agent, for example phosphorus oxychloride, optionally in an inert solvent. The reaction may be run at a temperature between about 25°C and 125°C, depending on the halogenating agent selected. When the halogenating agent is phosphorus oxychloride the reaction temperature is preferably between 60°C and 120°C. A compound of formula 23 is, in turn, reacted with an alkoxymethylene malonate derivative of formula 8 in the presence of a suitably strong and hindered base, for example lithium dusopropylamide (LDA), preferably at a temperature below 0°C, and conveniently at -78°C to afford the compounds of formula 24. Compounds of formula 24 are cyclized by heating the compound in a solvent with a boiling point greater than 120°C, for example xylene, diglyme, triglyme, sulfolane or Dowtherm A® (a eutectic mixture of biphenyl and diphenyl ether), to afford compounds of formula 25. The leaving group in the 8-position of the quinolizinone compound of formula 25 is then displaced using 3-aminopyrrolidine with the primary amino group protected, for example with t-butoxycarbonyl. The protecting group is then removed to give the compounds of formula 26.
The esters of formula 26 are than converted to the carboxylic acids of formula UI as described in Scheme 1 for the conversion of compounds of formula 10 to compounds of formula I. Alternately, compounds of formula 23 are converted to compounds of formula 27, wherein Rl is alkyl, cycloalkyl or carbocyclic aryl(loweralkyl), by treatment with an alkyl, cycloalkyl or carbocyclic aryl(loweralkyl) halide in the presence of a suitable base such as LDA. Compounds of formula 23 are converted to compounds of formula 27, wherein Rl is a phenyl group as defined herein or an alkylamino group by conversion to the corresponding halomethyl compound and treatment of the halomethyl compound with an aryl metal compound such as phenyllithium as described above, or with an alkylamine such as methylamine as shown in reaction Scheme VA. The compounds of formula 27 are converted to the compounds of formula 29 by the sequence of reactions described above for the conversion of compounds of formula 25. The leaving group in the 8-position of the quinolizinone compound of formula 29 is then displaced, for example by a nucleophilic amine such as N-methylpiperazine or 2-methylpiperazine, to give the the compounds of formula 30. The reaction may be conducted at a temperature from about 20 °C to about 130°C in a suitable organic solvent such as pyridine, methylene chloride, chloroform or 1- methyl-2-pyrrolidinone. It is desirable to carry out the reaction in the presence of an acid- acceptor such as triethylamine, potassium carbonate and the like, at a molar ratio of 1.0 to 2.0 moles of the acid acceptor per mole of compound of the formula29. The amine can also be used as an acid acceptor in which case two or more equivalents of this reagent are used. In the case where R2 is a phenyl group as defined herein, compounds of formula
30 are formed by coupling the compound of formula 29 with an aryl metal compound, for example phenyllithium, to replace the 8-leaving group with an unsubstituted phenyl group. The coupling reaction is carried in a reaction-inert solvent, i.e., a solvent which does not interfere with the coupling reaction of the aryl metal compound with a compound of formula29. Suitable reaction-inert solvents include ethers, for example diethyl ether, dimethoxyethane and tetrahydrofuran (THF). Co-solvents may be used with ethers if desired. These co-solvents may be benzene, toluene, tetramethylethyleneamine (TMEDA) and hexamethyl-phosphoramide (HMPA). The aryl metal compounds may be prepared by known methods. For example, they may be prepared by direct lithium-halogen exchange of the corresponding aryl halide using n-butyl-, sec-butyl- or t-butyl-lithium followed by trα/wmetallation by a wide variety of salts by known methods such as described by E. Negishi in "Organometallics in Organic Sysnthesis", Vol. 1, page 104.
According to Scheme IV A illustrated above, a compound of formula 31 is treated with a malononic acid ester, for example diethyl malonate, in the presence of a suitable base such as sodium hydride in a polar nonprotic solvent such as an ether, for example diethyl ether or THF, to afford a compound of formula 32. Compounds of formula 32 are, in turn, decarboxylated, for example by heating them in strong mineral acid such as aqueous sulfuric acid, to afford the compounds of formula 33. The nitro-compound of formula 33 is reduced to the corresponding amino-compound of formula 34. The nitro group may be reduced by catalytic hydrogenation using standard techniques or by any of a variety of known reducing agents such as using a metal, for example zinc, tin or iron, in the presence if a mineral acid, usually hydrochloric acid. The amino-compound of formula 34 is converted to the corresponding fluoro-compound of formula 35 by treatment with ethyl nitrite and tetrafluoroboric acid, followed by treatment with potassium fluoride. The compound of formula 35 is then converted into the corresponding N-oxide of formula 36 by oxidation, for example using peracetic acid. The reaction is carried out in the range from about 20°C up to the reflux temperature of the solvent employed, preferably at about 50°C. The compound of formula 36 is nitrated to afford compounds of formula 37. The nitration reaction can be carried out using a variety of known nitrating agents, for example a mixture of nitric acid and sulfuric acid or a mixture of sulfuric acid and potassium nitrate, or by using nitronium salts such as nitronium trifluoromethanesulfonate. The nitro compound of formula 37 is, in turn, converted to the corresponding halo compound of formula 38 by treatment with mineral acid at ambient or elevated temperature as desired. For example, the compound of formula 37 is treated with aqueous hydrochloric acid at a temperature of about 100-120°C to afford the compound of formula 38 wherein L is Cl. The compound of formula 38 is, in turn converted to the compound of formula IV A 1 by reduction, for example using a metal such as iron or zinc in the presence of an acid such as acetic acid. The compound of formula IV A 1 is, in turn, converted to the compound of formula IV A2 by treatment with a suitable base, such as LDA, followed by treatment with a halogenating agent, for example N-chloro or N-bromo succinimide. Alternately, the compounds of formula IV A 1 are converted to compounds of formula IV A3, wherein R is alkyl, cycloalkyl or carbocyclic aryl(loweralkyl), by treatment with an alkyl, cycloalkyl or carbocyclic aryl(loweralkyl) halide in the presence of a suitable base such as LDA. The compounds of formula IV A3 are further treated with a a suitable base, such as LDA, followed by treatment with a halogenating agent, for example N-chloro or N-bromo succinimide to afford the compounds of formula IV A4. Compounds of formulae IV Al - IV A4 are key intermediates used in the synthesis of quinolizinone compounds.
According to Schemes IV B and IV C illustrated above, the compounds of formulae IV A3 and IV A4 are converted to the quinolizinone compounds of formula IV B and IV C, respectively, by the following series of reactions: (1) reaction with an alkoxymethylene malonate derivative of formula 8 in the presence of a suitably strong and hindered base, for example lithium dusopropylamide (LDA), preferably at a temperature below 0°C, and conveniently at -78°C, to afford the compounds of formulae 39 and 42, respectively (2) cyclization as discussed in reaction Scheme HI, to afford the compounds of formulae 40 and 43, respectively (3) displacement of the leaving group in the 8-position as discussed in reaction Scheme HI to afford the compounds of formulae 41 and 44, respectively and (4) hydrolysis or hydrogenolysis as discussed in reaction Scheme HI of the carboxylic acid ester to the corresponding carboxylic acids of formulae IV B and IV C, respectively.
According to Scheme V A illustrated above, compounds of formula IV A 1 are treated with a halogenating agent under suitable conditions for generating halogen radicals, for example using N-bromo- or N-chlorosuccinimide in the presence of a free radical initiator such as AIBN to afford the compounds of formula 45. The halogen on the alpha carbon atom is then displaced by a nucleophile, for example an alkoxide to give the compounds of formula 51 or an amine to give the compounds of formula 46. The amine function is protected during synthesis by converting it to the corresponding formamidine function affording compounds of formula 47. Compounds of formula 47 are reacted with an alkoxymethylene malonate derivative of formula 8 in the presence of a suitably strong and hindered base, for example Uthium dusopropylamide (LDA), preferably at a temperature below 0°C, and conveniently at -78 °C. The formamidine group is then removed by reaction with hydrazine and acetic acid to afford the compounds of formula 48. The compounds of formula 48 are cyclized as discussed in reaction Scheme HI, to afford the compounds of formula 49. The leaving group, L, is then displaced as discussed in reaction Scheme HI to afford the compounds of formula 50. The compounds of formula 50 are, in turn, converted to the compounds of formula V Al as discussed in reaction Scheme I.
The compounds of formula 51 are converted to the compounds of formula V A2 by the following series of reactions: (1) reaction with an alkoxymethylene malonate derivative of formula 8 in the presence of a suitably strong and hindered base, for example Uthium dusopropylamide (LDA), preferably at a temperature below 0°C, and conveniently at -78 °C, to afford the compounds of formula 52 (2) cyclization as discussed in reaction Scheme IH, to afford the compounds of formula 53 (3) displacement of the leaving group in the 8-position as discussed in reaction Scheme HI to afford the compounds of formula 54 and (4) conversion of the carboxyUc acid ester to the corresponding carboxylic acids of formula V A2. According to reaction Scheme V B Ulustrated above, compounds of formula IV A2 are converted to compounds of formulae V B 1 and V B2 by the same procedures discussed in reaction Scheme V A for the conversion of compounds of formula IV A 1 to compounds of formulae V Al and V A2. According to reaction Scheme VI illustrated above, perfluoroinated pyridine is converted to the compound of formula 66 by the procedures described in reaction Scheme IV A for the preparation of compounds of formula 33. Compounds of formula 66 are, in turn, converted to the compounds of formula VI A and VI B by the series of reactions discussed in reaction Scheme HI for the conversion of compounds of formula 23 to compounds of formula IH.
According to reaction Scheme VII Ulustrated above, compounds of formula IV A2 are reacted with a protected alcohol of formula 71 , in the presence of a suitable base such as LDA, to afford compounds of formula 72. The hydroxy protecting group is preferably a THP (tetrahydopyranyl) ether group. The compounds of formula 72 are, in turn, deprotected by standard methods to afford the compounds of formula 73. The compounds of formula 73 are cyclized, in the presence of a suitable non-nucleophUic base such as sodium hydride, to afford the compounds of formula 74. The compounds of formula 74 are then comverted to the compounds of formula 77 by the series of reactions described in reaction Scheme IV B for the conversion of the compounds of formula IV A3 to the compounds of formula IV B.
Compounds of formula I, wherein R^ contains a free primary amino group are synthesized according to reaction Scheme VHT illustrated above. In accordance with reaction Scheme VIH, an alpha-halo acetate derivative of formula 1, such as ethyl 2- fluoroacetate, is condensed with a formate ester of formula 2, in the presence of a suitable base, for example sodium ethoxide, in an inert solvent such as diethyl ether to give an enolate compound of formula 3. Compounds of formula 3 are, in turn, converted to compounds of formula 5 by condensation with an amidine derivative of formula 4, in the presence of a suitable base, for example triethylamine, in a polar solvent such as methanol. The hydroxy-substituted compounds of formula 5 are converted to the corresponding halo- derivatives of formula 6 by treatment with a halogenating agent, for example phosphorus oxychloride to afford the chloro derivative, optionaUy in an inert solvent at a temperature between about 20°C and 145°C, depending on the halogenating agent and the boiting point of the solvent if one is used. When phosphorus oxychloride is the halogenating agent, the reaction temperature is preferably between about 80°C and 100°C. The leaving group in the 5-position of the pyrimidine ring of compounds of formula 6 is then displaced by a nucleophile such as a nucleophiUc amine, for example N-methylpiperazine or 2- methylpiperazine, to give the the compounds of formula 7. The reaction may be conducted at a temperature from about 20°C to about 130°C in a suitable organic solvent such as pyridine, methylene chloride, chloroform or l-methyl-2-pyrrolidinone. It is desirable to carry out the reaction in the presence of an acid-acceptor such as triethylamine, potassium carbonate and the like, at a molar ratio of 1.0 to 2.0 moles of the acid acceptor per mole of compound of the formula 6. The amine can also be used as an acid acceptor in which case two or more equivalents of this reagent are used. The compounds of formula 7 are reacted with an alkoxymethylene malonate derivative of formula 8 in the presence of a suitably strong hindered base, for example Uthium dUsopropylamide (LDA), preferably at a temperature below 0°C, and conveniently at -78 °C to afford the compounds of formula 9. The compounds of formula 9 are cycUzed in the presence of a suitable hindered base, for example DBU, in an aprotic solvent, such as toluene, THF or chlorobenzene to give the compounds of formulalO. The cyclization is carried out at a temperature in the range of about 30°C to about 130°C, preferably at the reflux temperture of the reaction mixture. The compounds of formula 10 are hydrolyzed in the presence of a suitable base such as sodium or potasium hydroxide to afford the compounds of formula 78. The compounds of formula 78 are, in turn, chlorinated to afford the compounds of formula 10a using an appropriate chlorinating agent such as phosphorus oxychloride. The leaving group in the 8-position of the quinoUzinone compound of formula 10a is then displaced using a nucleophiUc amine such as 3- aminopyrToUdine (with the primary amino group protected, for example with t- butoxycarbonyl). The protecting group is then removed to give the compounds of formula 10b. The esters of formula 10b are then converted to the carboxylic acids of formula I. The conversion may be achieved by conventional hydrolysis or by converting a compound of formula 10b to the corresponding ester, via trα westerification with an alcohol suitable for selective hydrolysis, such as benzyl alcohol or 2-(rrimethylsilyl)ethanol (TMSE), in the presence of a catalyst, for example titanium tetraethoxide, and then, in turn, removing the alcohol group by hydrogenolysis when R is benzyl or tetrabutylammonium fluoride when R is TMSE to afford a compound of formula I.
Compounds of formula I where R^ is loweralkyl or halo(loweralkyl) are synthesized according to reaction Scheme EX. In accordance with reaction Scheme EX Ulustrated above, an alpha-halo acetate derivative of formula 1 , such as ethyl 2- fluoroacetate, is condensed with a compound of formula 78, where X may be a halogen or alkanoyl and R3 may be loweralkyl or halo(loweralkyl), for example acetyl chloride or ethyl trifluoroacetate, in the presence of a suitable base, for example sodium methoxide or sodium ethoxide, and in a suitable solvent, such as methanol, ethanol or ether, to give an alpha-fluoro beta-keto ester compound of formula 79. Compounds of formula 79 are then reacted with amidine compounds of formula 4 or formula 6, in which R* is an alkyl, halo(loweralkyl) or cycloalkyl group, or may be an electron withdrawing group such as phenyl, trifluoromethyl, cyano, perfluoroalkyl, vinyl, substituted vinyl, fluorine, nitro, acetylene, substituted acetylene, alkoxycarbonyl, or a nitrogen-containing aromatic heterocycle, in the presence of a suitable base, such as sodium methoxide or sodium ethoxide, in the presence of a suitable solvent, such as methanol or ethanol, to give compounds of formulae 81 or 80, respectively. Compounds of formula 80 may be substituted for compounds of formula 8B in Scheme H and converted via the reactions in that Scheme, described above, into compounds of formula I. Compounds of formula 81 may be substituted for compounds of formula 5 in Scheme I and converted into compounds of formula I via the reactions of Scheme I described above. Alternatively, the compounds of formula 81 may be substituted for compounds of formula 5 in Scheme VIH and converted via the reactions in that scheme, described above, into compounds of formula I.
Compounds of formula I where R^ is loweralkyl, cycloalkyl, carbocyclic aryl(loweralkyl), cycloalkyl(loweralkyl), phenyl, nitrogen-containing aromatic heterocycle, or nitrogen-containing heterocycle are synthesized according to reaction Scheme X. In accordance with reaction Scheme X iUusrrated above, an organo-metalUc derivative of formula 82, such as phenyl magnesium bromide, cyclopentyl magnesium bromide, or N- methylpiperidin-4-yl magnesium bromide is condensed with an alpha-haloacetate derivative of formula 83, where X may be a halogen or alkoxy group, such as ethyl 2-fluoroacetate or 2-fluoroacetyl chloride, in an anhydrous solvent, for example ether or THF, to produce the alpha-fluoro compounds of formula 84. Compounds of formula 84, may hi turn be reacted with a formate ester of formula 2, in the presence of a suitable base, for example sodium ethoxide, in an inert solvent such as diethyl ether to give an enolate derivative of formula 85. The compounds of formula 85 are in turn converted to compounds of formula 86 or 87 by condensation with an amidine derivative of formula 4 or 6, in which R* is loweralkyl, halo(loweralkyl) or cycloalkyl, or is an electron withdrawing group such as phenyl, trifluoromethyl, cyano, perfluoroalkyl, vinyl, substituted vinyl, fluorine, nitro, acetylene, substituted acetylene, alkoxycarbonyl, or a nitrogen-containing aromatic heterocycle, in the presence of a suitable base, for example triethylamine, in a polar solvent such as methanol. Compounds of formula 87 may be substituted for compounds of formula 7 in Scheme VIH, and converted via the reactions in that scheme, described above, into compounds of formula I. Compounds of formula 86 may be substituted for compounds of formula 9B in Scheme H and, by reaction with a malonic acid diester as described for Scheme II above, converted directly into compounds of formula 12B and, thence, into compounds of formula I.
Alternatively, compounds of formula I, where R^ is loweralkyl, cycloalkyl, carbocycUc aryl(loweralkyl), cycloalkyl(loweralkyl), phenyl, nitrogen-containing aromatic heterocycle, or nitrogen-containing heterocycle are synthesized according to reaction Scheme XI. An alpha-haloacetate derivative of formula 1 is condensed with an acid haUde or ester derivative of formula 88, for example acetyl chloride, benzoyl chloride, isonicotinoyl chloride, or 2,6-dimethylisonicotinoyl chloride, in an anhydrous solvent, for example ether, THF, anhydrous methanol or an hydrous ethanol, in the presence of a suitable base, such as sodium methoxide or NaN(TMS)2, to produce the beta-ketoester derivative of formula 91, which is converted into compounds of formula 92 in the presence of a suitable base, such as sodium methoxide or sodium ethoxide, in the presence of a suitable solvent, such as methanol, ethanol or ether, to give the hydroxy-substituted compounds of formulae 92 or 93. These compounds, in turn, are converted into the corresponding halo- derivatives of formulae 94 and 95 under conditions as described for conversion of compounds of formula 5 to compounds of formula 6 in Scheme VHI. The compounds of formulae 94 and 95 are then reacted with reducing agents such as zinc in acetic acid or hydrogen in the presence of catalytic agents such as Ni, Pd, or Pt in suitable solvents such as ethanol or methanol to produce the compounds of formula 86 and 87, which are converted as described in Scheme X into compounds of formula I.
In addition, the non-fluorinated derivatives of formula 90, where R2 is as described above, may be converted to the beta-ketoester derivatives of formula 91 using a reagent such as N-fluoropyridinium triflate, N-fluorosulfonyl amide, cesium fluorooxysulfate, or acetyl hypofluoride.
In accordance with Scheme XH, which iUustrates a process for preparing the desired compounds of formula Ic wherein Rl is cyclopropyl, commercially avaUable 3- chloro-2,4,5,6-tetrafluoropyridine (compound 88) is reacted with an alkali salt of t-butanol, such as for example, sodium t-butoxide or Uthium t-butoxide, in a polar organic solvent such as THF, first at from 10°C to -78°C for 1-4 hours, then at room temperature for 2-72 hours, to give the compound of formula 89 (isolated from a mixture of products by chromatography). The compound of formula 89 is then reacted with hydrogen over a noble catalyst, such as Pd/C in a sodium acetate buffer, to remove the chlorine and give the compound of formula 90 (also isolated from a mixture of products by chromatography). In the instance where R^ is alkyl, the compound of formula 90 is then reacted with a suitable alkyl halide, for example methyl halide or the like, hi the presence of a suitably strong and hindered base, for example Uthium dUsopropylamide (LDA), preferably at a temperature below 0°C, and conveniently at -78°C to afford the compounds of formula 91. In the instance where R^ is haloalkyl, for example fluoroalkyl, the compound of formula 90 is first reacted with a suitably strong and hindered base, for example lithium dusopropylamide (LDA), preferably at a temperature below 0°C, and conveniently at -78°C foUowed by reaction with formaldehyde to give the compound where R^ is hydroxymethyl which is then reacted with diaminosulfur trifluoride (DAST) in a non-polar solvent such as methylene chloride to give the compound of formula 91. Alternately, when the group is to be a difluoromethyl, for example, the compound of formula 90 is first reacted with a suitably strong and hindered base, for example lithium dusopropylamide (LDA), preferably at a temperature below 0°C, and conveniently at -78°C foUowed by reaction with DMF to form the intermediate compound wherein R" is CHO, and this intermediate is then reacted with DAST to prepare the compound of formula 91, wherein R6 is difluoromethyl. The compounds of formula 91 are then reacted with hydrazine under nitrogen at reflux temperature for 2-8 hours, and after removal of excess hydrazine the residue is dissolved in an organic solvent, such as methanol or benzene, for example, and air is then passed through the solution of the hydrazino product for 8-16 hours to give the compounds of formula 92. he compounds of formula 92 are then condensed with cyclopropyl acetonitrile in a polar organic solvent, such as THF, for example, in the presence of strong base, such as Uthium diethylamide (LDA) or lithium dusopropylamide, at -78°C for 1-4 hours and then at 0°C for 1-4 hours or NaNH2 at -5°C to -10°C for 1 to 8 hours in order to prepare compounds of formula 93. The compounds of formula 93 are then reacted with trifluoroacetic acid under nitrogen for 1-4 hours at ambient temperature to removed the protecting t-butoxide group, and the unprotected material is then reacted with POC13 in a suitable organic solvent, such as DMF or methylene chloride, for example, at ambient temperature for 8-24 hours in order to prepare the compounds of formula 94.
In an improved preparative method, regarded as a part of the present invention, the compounds of formula 89 may be converted directly to the compounds of formula 91 by treatment with a strong base, such as t-butyllithium or s-butyllithium, for example, in a polar solvent such as THF or the like for a period of from 0.5 to 3 hours, followed by reaction with methyl iodide at a temperature firstly below -50°C then at ambient temperature for a period of from 4 to 20 hours. The compounds of formula 91 may then be converted to the compounds of formula 92 by treatment with a hydride reducing agent, such as LAH or sodium bis-(2-methoxyethoxy)aluminum hydride (Red-Al™), for example, at from 0°C to ambient temperature for a period of from 8-24 hours. The resulting compounds of formula 93 are then reacted with POCI3 in an organic solvent such as DMF or methylene chloride, for example, at ambient temperature for a period of from 6-20 hours in order to prepare directly the compounds of formula 94.
The cyano compounds of formula 94 are converted to esters of formula 95 by treatment with anhydrous ethanolic HCI foUowed by treatment with H2O. The ester compounds of formula 95 are then reduced to the aldehyde compounds of formula 96 by reaction with Uthium aluminum hydride in THF at reduced temperatures for 0.5 -2 hours, followed by reaction with oxalyl chloride and DMSO in the presence of triethyl amine at -78°C for 0.25- 1.0 hours. The compounds of formula 96 are reacted with with a malonic acid diester, such as diethyl malonate, dibenzyl malonate, t-butyl malonate or di-t-butyl malonate, in the presence of a suitable base such as piperidine and a catalytic amount of an acid, such as acetic acid or sulfuric acid, in a polar solvent, such as ethanol, followed by isolation of the intemediate compounds of formula 97 with subsequent treatment thereof by heating in a polar, high-boUing solvent such as DMF or DMSO at reflux temperature or in Dowtherm A™ for a period of from 0.5 to 4 hours to form the pyridopyrimidine compounds of formula 98. The chloro group of the compounds 98 is displaced as discussed in reaction Scheme I to afford the compounds of formula 99, which are in turn converted into the compounds of formula Ic as described in Scheme I for the conversion of compounds of formula 13A into compounds of formula I.
In accordance with Scheme XHI, trifluoropyridine ether of formula 90 is reacted with a suitable strong base, for example, LDA, preferrably at a temperature below 0°C and convenientyly at -78°C, in an inert solvent such as THF, for example. The anion thus generated is then reacted with an alkyl borate, such as, for example, trimethylborate or triethylborate, foUowed by oxidation with hydrogen peroxide in the presence of base such as sodium hydroxide in situ to give the compound of formula 100, wherein R' is lower alkyl. Compound 100 is then alkylated with a suitable alkylating agent, such as an alkyl iodide or alkyl sulfate, for example methyl sulfate or ethyl iodide or the like, in the presence of a base such as sodium hydroxide, barium hydroxide, potassium carbonate, lithium carbonate, or the like, in a polar solvent, such as acetone, ethanol, DMF, THF, or the like, within a temperature range of room temperature to reflux temperature of the solvent, to give the compound of formula 101. Alternately, compound 101 can be obtained by treating compound 100 with an alcohol of the formula R^OH, wherein R^ is as described above, triphenylphosphine and diethyldiazocarboxylate in a solvent such as THF at a temperature in the range of 0°C to room temperture.
In accordance with Scheme XTV, commerciaUy available pentafluoropyridine of formula 102, is reacted with an alkali metal salt of t-butanol, for example, sodium t- butoxide or potassium t-butoxide, in an anhydrous organic solvent such as THF, at a temperature in the range of -78 °C to room temperature, to give the compound of formula 103. Compound 103 is then reacted with hydrazine at a temperature in the range of room temperature to reflux temperature, and in a solvent such as methanol, iso-propanol, ether, or the like, foUowed by bubbling air through the solution of the intermediate in a solvent such as benzene of toluene, in the presence of a base such as sodium hydroxide to give to compound of formula 104.
In accordance with Scheme XV, the pentafluoropyridine of formula 102 is dissolved in a solvent, such as for example, THF or methylene chloride, and reacted with a cyclic amine of the formula R^H, wherein R^ is as defined above, or, when R^ is substituted with a reactive group such as an amino group, a cycUc amine with suitably protected reactive substituents, in the presence iof a suitable base, such as a tertiary amine, such as for example triethylamine, at a temperature in the range of 0°C to room temperature. The reactant of formula 106, wherein R^6 is as defined above and TBS represents a tributylsUyl group, is generated from the corresponding iodide starting material by reaction with t-butyl lithium in ether at -78°C, and is reacted with compound 105 in a solvent such as THF or ether at -78°C to give the compound of formula 107. The protecting TBS group is removed from compound 107 by reaction with tetrabutylammonium fluoride in THF at room temperature to give the compound of formula 108. The trifluoro compound 108 is converted into the difluoro compound 109 by reacting compound 108 with hydrazine at reflux temperature in a solvent such as ether, propanol, or methoxymethyl ether, followed by treatment of an intermediate hydrazino product with CuSO4 in a solvent such as methanol, ethanol, or toluene, or alternately by reaction with air in the presence of a base such as NaOH. The monocycUc compound 109 is then converted into the bicycUc compound of formula 110 by reaction with NaH at reflux temperature in a solvent such as dioxane or THF. Compound 110 is then treated with a strong base, such as LDA at -78°C, for example, and condensed with diethyl ethoxymethylenemalonate to give an intermediate product which is cycUzed in the presence of a base such as DBU or piperidine/acetic acid, in a solvent such a ethanol or aqueous THF, at a temperature from room temperature to 60°C, to give the tricyclic ester of formula 111. The ester 111 is hydrolyzed to the acid of formula 112 with an alkaU metal hydroxide in aqueous THF, for example. Any protecting groups remaining onthe R2 or R16 groups may conveniently be removed at this point to give the desired compound of Formula I.
In accordance with Scheme XVI, an alternate method of preparing compounds 112 is given. Compound 103 (from Scheme XIV) is reacted with compound 106 (from Scheme XV) in a solvent such as THF or ether at -78°C to give a TBS-protected intermediate compound, from which theTBS group is removed by reaction with tetrabutylammonium fluoride in THF at room temperature to give the compound of formula 1 13. The trifluoro compound 113 is converted into the difluoro compound 114 by reaction with hydrazine at reflux temperature in a solvent such as ether, propanol, or methoxymethyl ether, foUowed by treatment of an intermediate hydrazino product with CuSO4 in a solvent such as methanol, ethanol, or toluene, or alternately by reaction with air in the presence of a base such as NaOH. The monocyclic compound 114 is then converted into the bicyclic compound of formula 115 by reaction with NaH at reflux temperature in a solvent such as dioxane or THF. Compound 115 is then treated with a strong base, such as LDA at -78°C, for example, and condensed with diethyl ethoxymethylenemalonate to give an intermediate product which is cycUzed in the presence of a base such as DBU or piperidine/acetic acid, in a solvent such a ethanol or aqueous THF, at a temperature from room temperature to 60°C, to give the tricycUc ester of formula 116. The protecting t-butoxy group is removed from compounds 1 16 by reaction with an acid, such as HCI or trifluoroacetic acid at room temperature, and optionally in a suitable solvent, such as methylene chloride or dioxane to give compound s 117. The free hydroxy group of compounds 117 is then reacted with POC13/DMF in a suitable solvent such as methylene chloride at room temperature to give the chloro compounds of formula 118. Compounds 118 are reacted with a cyclic amine of the formula R^H, wherein R^ is as defined above, or, when R^ is substituted with a reactive group such as an amino group, a cycUc amine with suitably protected reactive substituents, in the presence of a suitable base, such as a tertiary amine, such as for example triethylamine, in a suitable solven, such as acetonitrile or pyridine, at a reflux temperature to give the compounds 111. The ester group is hydrolyzed, and optional additional protecting groups removed, as described in Scheme XV. In accordance with Scheme XVII are prepared desired compounds of Formula I wherein R^ is amino Compounds of formula 91 are reacted with HN-P, wherein P are amino protecting groups, for example benzyl and p-methoxybenzyl groups, in a solvent such as ethanol or toluene, at elevated temperature to give compounds of formula 119. Compounds of formula 119 are treated according to the procedures as described in Schemes XII, XV and XVI above to provide compounds of formula 120. Deprotection of protected amino compounds of formula 120 by catalytic hydrogenation such as Pd-C in ethanol or methanol at room temperature, or by oxidation if R is p-methoxybenzyl with ammonium cerium nitrate, and the resulting compounds of formula 121 are hydrolyzed by a base such as LiOH or NaOH to give compounds of formula 122. In accordance with Scheme XVHI are prepared compounds of Formula I wherein the R2 group is a ring group attached via a carbon atom. Compounds of formula 123, wherein X is a leaving group such as chloride, bromide, iodide, fluoride or sulfonate, for example, is treated with an appropriately substituted malonate, wherein R, R' could be the same or different) are alkyl groups, such as diethyl and di-t-butyl malonate, in a polar solvent such as DMF, DMSO, or the like, in the presence of a strong base such as NaH, at a temperature between 0 to 60°C, to give compounds of formula 124. Decarboxylation of compounds of formula 124 under acidic conditions, such as trifluoroacetic acid and hydrogen chloride in a solvent such as methylene chloride, ethanol, water, or the like, foUowed by protection of the intermediate acid with an ester such as diphenylmethyl ester by treating with diphenyl diazomethane in a solvent such as methylene chloride or THF, gives the compounds of formula 125. Compounds of formula 125 are then cycUzed to compounds of formula 126 by reaction with Br(CH2)nB(CH2)mBr or I(CH2 )nB(CH2)mI or R substituted iodide or bromide, for example, wherein B is CH2, N, O or S, in the presence of a base such as NaH and in a solvent such as DMF, DMSO, or the like, at room temperature or elevated temperature. Alternately, conversion of compounds of formula 125 to the methylenyl intermediate by reacting with aqueous formaldehyde with a base such as sodium bicarbonate in a solvent such as DMF, foUowed by reacting with methanesulfonyl chloride and triethylamine. The methylenyl compound is then converted to compound 126 by cycUzation or dipolar addition with a suitable reagent, such as trimethylsulfonium iodide or diazomethane for cyclopropyl compound, in a solvent such as DMF, DMSO, or the like at 0 to 60°C in the presence of a suitable base such as NaH. Selective deprotection of the ester 'ROCO, such as using trifluoroacetic acid and anisol at room temperature for diphenylmethyl ester, foUowed by alkaUne hydrolysis of the other ester provides the desired compounds of formula 127, and foUowed by Curtius rearrangement when 'R2 is NH2. In the compounds of formulas 126 and 127, n and m may be from 0-4, n+m=l-4, B may be CH2, N, O or S; RD may be hydrogen, alkyl, amino, aminoalkyl, hydroxyl or alkoxyl groups, for example, or other substituents as described for substituent Y in subformula Ic above.
Representative of the chemical intermediates which are useful in the above syntheses, and which are regarded as a further aspect of the present invention, are the following compounds:
4-t-butoxy-3-chloro-2,5,6-trifluoropyridine; 4-t-butoxy-2,3,6-trifluoropyridine; 4-t-butoxy-2,3,6-trifluoro-5-methylpyridine; 4-t-butoxy-2,5-difluoro-3-methylpyridine; 2-(4-t-butoxy-5-fluoro-3-methyl-2-pyridinyl)cyclopropaneacetonitrile; 2-(4-chloro-5-fluoro-3-methyl-2-pyridinyl)cyclopropaneacetonitrile; 2-(4-chloro-5-fluoro-3-methyl-2-pyridinyl)cyclopropaneacetic acid; ethyl 2-(4-chloro-5-fluoro-3-methyl-2-pyridinyl)cyclopropaneacetate; 2-(4-chloro-5-fluoro-3-methyl-2-pyridinyl)cyclopropaneacetaldehyde; 2-(4-chloro-5-fluoro-3-methyl-2-pyridinyl)cyclopropaneethanol; 2-(2-(4-chloro-5-fluoro-3-methyl-2-pyridinyl)-2-cyclopropylethyUdinyl)- 1 ,3- propanedicarboxyUc acid, diethyl ester; and
8-chloro- l-cyclopropyl-7-fluoro-9-methyl-4-oxo-4h-quinoUzine-3-carboxyUc acid ethyl ester.
The foregoing may be better understood from the following examples, which are presented for the purpose of Ulustration and are not intended as a limitation upon the scope of the invention.
Example 1
3-Fluoro-9-(4-fluorophenyl)-2-(4-methylpiperazin- 1 -yl)- 6H-6-oxo-pyridoπ .2-alpyrimidine-7 -carboxylic acid
Step 1: 5-Fluoro-2-C4-fluorobenzylV4-hvdroxypyrimidine
Sodium hydride (4.36 g of 60% NaH in mineral oil, 107.6 mmol) was suspended, under a nitrogen atmosphere, in 125 mL of anhydrous diethyl ether in a 500 mL round-bottom flask fitted with a mechanical stirrer, a thermometer and a condenser. To this mixture, with vigorous stirring, was slowly added 6.28 mL (107.6 mmol) of anhydrous ethyl alcohol. After the evolution of gas ceased, a mixture of ethyl 2- fluoroacetate (10 mL, 102.5 mmol) and ethyl formate (12.5 mL, 153.7 mmol) was added, dropwise, to the ethoxide solution. The reaction mixture was cooled when necessary in order to maintain the reaction temperature between 18°C and 20°C. The reaction mixture was stirred, under a nitrogen atmosphere, at 18-20°C for 4.75 hours. The solvent was removed under aspirator pressure, fresh anhydrous diethyl ether was added to the residue and the ether solution was concentrated under reduced pressure to afford, as a solid residue, the sodium enolate of ethyl 2-fluoro-3-oxo-2-propanecarboxylate, as described by E.EUdk and M. Imbeaux-Oudotte in βull S≤c Chim. 1165-1169, 1975. To this residue was added 20.3 g (107.6 mmol) of 4-fluorobenzylamidine hydrochloride, foUowed by 250 mL of methanol and 28.8 mL (205 mmol) of triethylamine (TEA). The reaction mixture was heated, with stirring, at reflux temperature for 16 hours and then concentrated in vacuo. The residue was triturated with hexane and the hexane was decanted. Water was added to the residue and the aqueous mixture was acidified with glacial acetic acid and extracted with 4 X 150 mL of methylene chloride. The combined organic extract was washed with 200 mL of water and concentrated in vacuo. The residue was recrystaUized twice from ethyl acetate containing Norite® charcoal to afford the title compound, m.p. 169-170°C; MS DCI-NH3 M/Z: 223 (M+H)+; 1H NMR (DMSO-d6) d 3.87 (s, 2H), 7.14 (m, 2H), 7.33 (m, 2H), 7.98 (d, IH). Analysis calculated for C11H8F2N2O: C, 59.46; H, 3.63; N, 12.61. Found: C, 59.08; H, 3.70; N, 12.57.
Step 2: 4-Chloro-5-fluoro-2-( -fluorobenzylVpyrimidine
A mixture of 1.93 g (8.7 mmol) of 5-fluoro-2-(4-fluorobenzyl)-4- hydroxypyrimidine, from Step 1, and 15 mL of phosphorus oxychloride was heated in an oU bath at 90°C for 1.5 hours and then concentrated in vacuo. The residue was triturated with 75 mL of ice water and the aqueous mixture was adjusted to pH 8 - 9 by the addition of soUd sodium bicarbonate. The mixture was extracted with 3 X 70 mL of methylene chloride. The combined organic extracts were dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to a light brown residue. The residue was purified by flash chromatography on a 230-400 mesh sUica gel column (4.8 X 14.6 cm) eluted with hexane:methylene chloride (1:1 v/v) to afford 1.94 g (90% yield) of the title compound; MS DCI-NH3 M/Z: 241 (M+H)+; 1H NMR (CDCI3) d 4.22 (s, 2H), 7.00 (m, 2H), 7.30 (m, 2H), 8.48 (s, IH).
Step 3: 5-Ruoro-2-(4-fluorobenzyl V4-(4-methylpiperazin- 1 -vIVpyrimidine
A mixture of 0.48 g (2 mmol) of 4-chloro-5-fluoro-2-(4-fluorobenzyl)-pyrimidine from Step 2 and 1.53 mL (14 mmol) of 4-methylpiperazine in 10 mL of methylene chloride was stirred at ambient temperature for 1.5 hours. The reaction mixture was concentrated in vacuo and the residue was dissolved in methylene chloride. The resultant solution was washed with 4 X 30 mL of water, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to give 0.59 g (95% yield) of the titie compound as an oil; *H NMR (CDCI3) d 2.32 (s, 3H), 2.47 (t, 4H), 3.78 (t, 4H), 3.99 (s, 2H), 6.97 (m, 2H), 7.29 (m, 2H), 7.97 (d, IH). The product was carried on to the next step without purification.
Step 4: Diethyl 2-ethoxy-3-(4-fluorophenyl)-3-[5-fluoro-4- (4-methvpiperazin- 1 -vDpyrimidin-2-yll-propane- 1.1 -dicarboxylate
A solution of 0.35 mL (2.5 mmol) of diisopropylamine in 5 mL of anhydrous tetrahydrofuran (THF) was prepared under a nitrogen atmosphere and cooled in an ice/water bath. To this solution was added via syringe, 1.0 mL of a 2.5 M solution of n- butylUthium (2.5 mmol) in hexane. The solution was stirred for 15 minutes at 0°C and then cooled to -78 °C. To the mixture at -78°C, was added a solution of 0.7 g (2.3 mmol) of 5- fluoro-2-(4-fluorobenzyl)-4-(4-methylpiperazin-l-yl)-pyrimidine, from Step 3, in 5 mL of anhydrous THF and a dark red-colored solution was formed. The solution was stirred at -78°C for 1 hour and then 0.46 mL (2.3 mmol) of ethyl 2-carboethoxy-3-ethoxy-2- propenecarboxylate was added. Stirring was continued at -78°C for 3 hours and the reaction mixture turned a Ught yeUow color. The reaction mixture was poured into 30 mL of water, with 6 g of soUd ammonium chloride. The aqueous mixture was extracted with 4 X 50 mL of methylene chloride. The combined organic extract was dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was dissolved in 300 mL of methylene chloride. The resultant solution was washed with a 50 mL portion of water, followed by a 75 mL portion of water, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to afford the titie compound; MS DCI-NH3 M/Z: 521 (M+H)+; lH NMR (CDCI3) d 0.84 (2 X t, 3H), 1.18 (t, 3H), 1.28 (t, 3H), 2.33 (s, 3H), 2.50 (m, 4H), 3.36-3.53 (m, 2H), 3.83 (s, 4H), 3.96-4.22 (m, 4H), 4.42 (t, IH), 4.98 (dd, IH), 6.95 (m, 2H), 7.48 (m, 2H), 7.99 (d, IH).
Step 5 : Ethyl 3-fluoro-9-(4-fluorophenyl)-2-(4-methylpiperazin- 1 -yl) -6H-6-oxo-pyridor 1 ,2-alpyrimidine-7-carboxylate
A solution of 0.57 g (1.1 mmol) of diethyl 2-ethoxy-3-(4-fTuorophenyl)-3-[5- fluoro-4-(4-methypiperazin- 1 -ylpyrimidin-2-yl]-propane- 1 , 1-dicarboxylate, from Step 4, and 0.2 mL of l,8-diazabicyclo[5.4.0]undec-7-ene (DBU) in 200 mL of toluene was heated at reflux temperature, with stirring, for 20.5 hours. During the first 0.5 hours, 125 mL of toluene was removed via Dean Stark trap and 100 mL of fresh toluene was added through a dropping funnel. Water (75 mL) was added to the reaction mixture and stirring was continued at ambient temperature for 3 hours. The organic layer was separated and washed with 75 mL of water. The combined aqueous layers were extracted with 3 X 75 mL of toluene. The organic layers were all combined, dried over anhydrous magnesium sulfate, fUtered and concentrated in vacuo. The residue (0.32 g) was purified on a 70-230 mesh sUica gel column (2.4 X 43 cm) eluted with ethyl alcoho chloroform (1:10 v/v) to afford 0.26 g (56% yield) of the title compound, m.p. 202-204°C; MS DCI-NH3 M/Z: 429 (M+H)+; IH NMR (CDCI3) d 1.40 (t, 3H), 2.33 (s, 3H), 2.51 (m, 4H), 3.93 (m, 4H), 4.40 (q, 2H), 7.08 (t, 2H), 7.50 (m, 2H), 8.43 (s, IH), 9.20 (d, IH). Step 6: Benzyl 3-fluoro-9-(4-fluorophenyl)-2-(4-methylpiperazin-l-yl) -6H-6-oxo-pyridoll.2-a1pyrimidine-7 -carboxylate
A mixture of 0.11 g (0.26 mmol) of ethyl 3-fluoro-9-(4-fluorophenyl)-2-(4- methylpiperazin-l-yl)-6H-6-oxo-pyrido[l,2-a]pyrimidine-7-carboxylate, from Step 5, 50 mL of dry benzyl alcohol and 0.05 mL of titanium tetraethoxide was heated, with stirring, at 100°C for 22 hours. The benzyl alcohol was removed by distillation under reduced pressure and the residue was dissolved in 75 mL of methylene chloride. To this solution was added 5 mL of saturated aqueous lithium fluoride solution and the resultant mixture was stirred at ambient temperature for 20 minutes. The layers were separated and the organic layer was dUuted with 75 mL of methylene chloride and washed with 20 mL of water. The aqueous layer was extracted with 25 mL of methylene chloride and the methylene chloride layer from this extraction was combined with the organic layer. The combined organic layers were dried over anhydrous magnesium sulfate, filtered and concentrated. The residue (0.18 g) was chromatographed on a 70-230 mesh silica gel column ( 1.8 X 34 cm) eluted with ethanolxhloroform (1:13 v/v) to afford 87 mg (67% yield) of the title compound; 1H NMR (CDCI3) d 2.33 (s, 3H), 2.52 (m, 4H), 3.94 (m, 4H), 5.40 (s, 2H), 7.08 (s, 2H), 7.27 (m, 5H), 8.44 (s, IH), 9.21 (d, IH). The product was carried on to the next step without further purification.
Step 7: 3-Fluoro-9-(4-fluorophenyl)-2-(4-methylpiperazin-l-yl)- 6H-6-oxo-pyridor 1 ,2-alpyrimidine-7 -carboxylic acid
Benzyl 3-fluoro-9-(4-fluorophenyl)-2-(4-methylpiperazin- 1 -yl)-6H-6-oxo- pyrido[l,2-a]pyrimidine-7 -carboxylate (87 mg, 0.177 mmol), from Step 6, was dissolved in 20 mL of ethyl acetate. To this solution was added 20 mg of 10% palladium on carbon and the resultant mixture was hydrogenated at ambient temperature, under 4 atmospheres of hydrogen, for approximately 19 hours. The catalyst was removed by filtration and washed with 400 mL of ethyl acetate The filtrate was concentrated in vacuo to give 65.2 mg of solid. The solid was purified by chromatography on a 70-230 mesh sUica gel column (1.8 X 18.5 cm) eluted with chloroform:methanol:acetic acid:water (100:25:5:2.5 v/v/v/v). The fractions containing the desired product were combined and concentrated. Toluene was added to the residue and evaporated in vacuo. Chloroform was then added to the residue and evaporated in vacuo to afford the title compound as a yeUow solid, m.p. 225-230°C; MS DCI-NH3 M/Z: 401 (M+H)+; 1H NMR (CDCI3) d 1.68 (brs, IH), 2.33 (s, 3H), 2.53 (brs, 4H), 3.98 (brs, 4H), 7.10 (t, 2H), 7.48 (m, 2H), 8.57 (s, IH), 9.08 (d, 2H). Analysis calculated for C20H18F2N4O3+O.75H2O: C, 58.03; H, 4.75; N, 13.54. Found: C, 57.98; H, 4.32; N, 13.22. Example 2
3-Ruoro-9-(4-fluorophenyl)-2-(4-methylpiperazin- 1 -yl)- 6H-6-oxo-pyridoπ .2-alpyrimidine-7-carboxylic acid
Step 1 : Ethyl 3-fluoro-9-(4-fluorophenyl)-2-hydroxy- 6H-6-oxo-pyridor 1.2-alpyrimidine-7 -carboxylate
To a stirred solution of 0.87 g (2.05 mmol) of ethyl 3-fluoro-9-(4-fluorophenyl)- 2-(4-methylpiperazin- 1 -yl)-6H-6-oxo-pyrido[ 1 ,2-a]pyrimidine-7-carboxylate, the product of Step 5 of Example 1 , in 54 mL of THF/water (1:1) was added 6 mL of 1 N aqueous sodium hydroxide solution. The reaction mixture was stirred at ambient temperature for 6 hours and then was allowed to stand overnight at ambient temperature. The soUd was filtered and dried to give the title compound; 1H NMR (d6-DMSO) d 1.23 (t, 3H), 4.15 (q, 2H), 7.17 (m, 2H), 7.52 (m, 2H), 7.91 (s, IH), 8.77 (d, IH).
Step 2: Ethyl 2-chloro-3-fluoro-9-(4-fluorophenyl)- 6H-6-oxo-pyridor 1.2-alpyrimidine-7-carboxylate
A mixture of 55.7 mg of ethyl 3-fluoro-9-(4-fluorophenyl)-2-hydroxy-6H-6-oxo- pyrido[l, 2- a]pyrimidine-7 -carboxylate from Step 1 and 0.5 mL of phosphorus oxychloride was stirred and heated at 90°C for 1.25 hours. The mixture was evaporated under reduced pressure to yield the title compound which can be reacted with amines without purification. A pure sample of the title compound is obtained by treatment of the crude product with aqueous sodium bicarbonate solution and extracting the aqueous mixture with methylene chloride. The organic solution is concentrated and chromatographed on siUca gel eluting with ethyl acetate.
Step 3 : Ethyl 3-fluoro-9-(4-fluorophenyl)-2-(4-methylpiperazin- 1 -yl)- 6H-6-oxo-pyridoI 1.2-alpyrimidine-7-carbox ylate
FoUowing the procedures described in Step 3 of Example 1, ethyl 2-chloro-3- fluoro-9-(4-fluorophenyl)-6H-6-oxo-pyrido[l,2-a]pyrimidine-7-carboxylate from Step 2 is reacted with 4-methylpiperazine to afford the titie compound. Step 4: Benzyl 3-fluoro-9-(4-fluorophenyl)-2-(4-methylpiperazin- 1 -yl)- 6H-6-oxo-pyridor 1.2-alpyrimidine-7 -carboxylate
A mixture of 0.11 g (0.26 mmol) of ethyl 3-fluoro-9-(4-fluorophenyl)-2-(4- methylpiperazin-l-yl)-6H-6-oxo-pyrido[l,2-a]pyrimidine-7-carboxylate, from Step 3, 50 mL of dry benzyl alcohol and 0.05 mL of titanium tetraethoxide was heated, with stirring, at 100°C for 22 hours. The benzyl alcohol was removed by distillation under reduced pressure and the residue was dissolved in 75 mL of methylene chloride. To this solution was added 5 mL of saturated aqueous lithium fluoride solution and the resultant mixture was stirred at ambient temperature for 20 minutes. The layers were separated and the organic layer was dUuted with 75 mL of methylene chloride and washed with 20 mL of water. The aqueous layer was extracted with 25 mL of methylene chloride and the methylene chloride layer from this extraction was combined with the organic layer. The combined organic layers were dried over anhydrous magnesium sulfate, fUtered and concentrated. The residue (0.18 g) was chromatographed on a 70-230 mesh silica gel column (1.8 X 34 cm) eluted with ethanolxhloroform (1:13 v/v) to afford 87 mg (67% yield) of the title compound; lH NMR (CDCI3) d 2.33 (s, 3H), 2.52 (m, 4H), 3.94 (m, 4H), 5.40 (s, 2H), 7.08 (s, 2H), 7.27 (m, 5H), 8.44 (s, IH), 9.21 (d, IH). The product was carried on to the next step without further purification.
Step 5: 3-Fluoro-9-(4-fluorophenyl)-2-(4-methylpiperazin-l-yl)- 6H-6-oxo-pyridoπ ,2-alpyrimidine-7 -carboxylic acid
Benzyl 3-fluoro-9-(4-fluorophenyl)-2-(4-methylpiperazin- 1 -yl)-6H-6-oxo- pyrido[l,2-a]pyrimidine-7 -carboxylate (87 mg, 0.177 mmol), from Step 4, was dissolved in 20 mL of ethyl acetate. To this solution was added 20 mg of 10% palladium on carbon and the resultant mixture was hydrogenated at ambient temperature, under 4 atmospheres of hydrogen, for approximately 19 hours. The catalyst was removed by filtration and washed with 400 mL of ethyl acetate The filtrate was concentrated in vacuo to give 65.2 mg of solid. The solid was purified by chromatography on a 70-230 mesh sUica gel column (1.8 X 18.5 cm) eluted with chloroform:methanol:acetic acid:water (100:25:5:2.5 v/v/v/v). The fractions containing the desired product were combined and concentrated. Toluene was added to the residue and evaporated in vacuo. Chloroform was then added to the residue and evaporated in vacuo to afford the title compound as a yeUow solid, m.p. 225-230°C; MS DCI-NH3 M/Z: 401 (M+H)+; 1H NMR (CDCI3) d 1.68 (brs, IH), 2.33 (s, 3H), 2.53 (brs, 4H), 3.98 (brs, 4H), 7.10 (t, 2H), 7.48 (m, 2H), 8.57 (s, IH), 9.08 (d, 2H). Analysis calculated for C20H 18F2N4O3+O.75H2O: C, 58.03; H, 4.75; N, 13.54. Found: C, 57.98; H, 4.32; N, 13.22. Examples 3-38
By foUowing the procedures described in Example 2 and using the appropriate amine, Examples 3-20, as disclosed in Table 1 , may be prepared which have the general formula
Likewise, Examples 21-38, as also disclosed in Table 1, may be prepared by using the appropriate amine and 2,4-difluorobenzylamidine instead of 4-fluoro- benzylamidine to produce the general formula
The amines are protected and deprotected as described in Example 58 Example 39
9-Cyclopropyl-3-fluoro-2-(4-methylpiperazin- 1 -yl)- 6H-6-oxo-pyridoπ .2-alpyrimidine-7-carboxylic acid
Step 1. 2-CvcIopropyl-3-hvdroxyacryhc acid
A 1.1 M solution of diethylzinc (350 mL) in an oven-dried system under positive nitrogen atmosphere is coled in an ice bath. Vinyl acetic acid (17 mL, 200 mmol) is added dropwise with stirring, foUowed by 24 mL (300 mmol) of diiodomethane. The reaction mixture is stirred overnight at ambient temperature. The reaction mixture is then cautiously poured into 500 mL of 1 N aqueous hydrochloric acid solution and the aqueous mixture is extracted with diethyl ether. The organic layer is dried over anhydrous sodium sulfate, filtered and concentrated. The residue is vacuum distilled to give cyclopropylacetic acid.
The cyclopropylacetic acid (15 g, 150 mmol) in a flask protected from moisture is cooled in an ice bath and 13.2 mL (180 mmol) of thionyl chloride is added dropwise with stirring. After the addition is complete, the reaction mixture is warmed to ambient temperature and then to 50°C. The reaction mixture is heated at 50°C for 1 hour and then cooled in an ice bath. Absolute ethanol (26 mL, 450 mmol) is added dropwise with stirring to the reaction mixture. After the addition is complete, the reaction mixture is stirred at ambient temperature overnight. The reaction mixture is diluted with 500 mL of methylene chloride and then washed with 200 mL of 5% aqueous sodium bicarbonate solution. The organic layer is dried over anhydrous sodium sulfate, filtered and the ethyl ester of cyclopropylacetic acid is obtained by distillation.
2-Cyclopropyl-3-hydroxyacrylic acid (12.8 g, 100 mmol), from Step 1, is dissolved in 150 mL of dry dimethoxyethane in an oven-dried system under positive nitrogen atmosphere. The resultant solution is cooled in an ice bath and 4.4 g of 60% sodium hydride in mineral oU is added. The mixture is stirred for several hours at approximately 0°C and then for several hours at ambient temperature. The reaction mixture is cooled in an ice bath and 8.9 mL (110 mmol) of ethyl formate in 90 mL of dry dimethoxyethane is added dropwise with stirring. After the addition is complete, the reaction mixture is stiιτed overnight at ambient temperature. The reaction mixture is then cautiously poured into 300 mL of saturated aqueous ammonium chloride solution and extracted with ethyl acetate. The ethyl acetate solution is dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to afford the title compound. Step 2. Ethyl 5-Cvclopropyl-2.6-dihvdroxy-nicotinic acid
A solution of 11.5 (88 mmol) of monoethyl malonate monoamide in 25 mL of dry THF is cooled in an ice bath and is treated with 10.7 g (95 mmol) of potassium t-butoxide. The reaction mixture is stirred at 0-5 °C for 1 hour. A solution of 12.5 g (80 mmol) of 2- cyclopropyl-3-hydroxyacryUic acid, from Step 1, in 20 mL of dry THF is added dropwise with stirring. The reaction mixture is then warmed to ambient temperature and then heated at reflux overnight. The reaction mixture is poured into brine and is extracted with ethyl acetate. The organic layer is dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to afford the title compound.
Step 3. Ethyl 5-cvclopropyl-2.6-dichloro-nicotinic acid
Ethyl 5-cyclopropyl-2,6-dihydroxy-nicotinic acid (15.6 g, 70 mmol) from Step 2, 1,2-dichloroethane (25 mL), anhydrous DMF (2 mL) and phosphoryl chloride (14.3 mL, 150 mmol) are combined in a system under positive nitrogen atmosphere, The reaction mixture is stirred at ambient temperature for 24 hours then diluted with 1,2-dichloroethane. The reaction mixture is then washed with 5% aqueous sodium bicarbonate solution and brine. The organic layer is dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to afford the title compound.
Step 4. 2-Chloro-5-cyclopropyl-6- N-((4,5dimethoxy- 2-nitro-phenvDmethoxycarbonyl)amino-nicotinic acid
Ethyl 5-Cyclopropyl-2,6-dichloro-nicotinic acid (11.2 g, 50 mmol) from Step 3 is dissolved in 15 mL of anhydrous DMF. To this solution is added 25 mL of concentrated ammonium hydroxide and the reaction mixture is heated at reflux overnight. The reaction mixture is cooled to ambient temperature, dUuted with water and extracted with 1 ,2- dichloroethane. The organic layer is dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue is dissolved in 250 mL of 1,2-dichloroethane and 200 mL of 10% aqueous sodium carbonate solution. The reaction mixture is cooled in an ice bath and 16.5 g (60 mmol) of 3,4-dimethoxy-6-nitrobenzylchloroformate is added. The reaction mixture is stirred at 0-5 °C for 1 hour. The layers are separated and the aqueous layer is extracted with 1,2-dichloroethane. The combined organic layers are dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. Step 5: 2-Chloro-5-cyclopropyl-6- N-((4,5dimethoxy-2-nitro- phenyl)methoxycarbonyl -N-( -fluoroacetvDamino-rricotinic acid
2-Chloro-5-cyclopropyl-6- N-((4,5dimethoxy-2-nitro-phenyl)methoxycarbonyl)- amino-nicotinic acid (14.4 g, 30 mmol) from Step 4 is dissolved in 20 mL of dry THF in an oven-dried system under positive nitrogen atmosphere. The reaction mixture is cooled in an ice bath and 1.3 g of 60% sodium hydride in mineral oU is added. The reaction mixture is stired at 0-5 °C for 1 hour and 3.2 g (33 mmol) of alpha-fluoroacetyl chloride in 5 mL of dry THF is added dropwise with stirring. After the addition is complete, the reaction mixture is slowly warmed to ambient temperature and stirred overnight at ambient temperature. The reaction mixture is then poured into brine and extracted with ethyl acetate. The ethyl acetate solution is dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. to afford the title compound.
Step 6: 2-Chloro-5-cyclopropyl-6- N-((4,5dimethoxy-2-nitro-phenyl)methoxy- carbonylVN-(2-fluoro-3-hvdrox v- 1 -oxo- 1 -prop-2-enyl amino-nicotinic acid
Sodium hydride ()880 mg of 60% NaH in mineral oU) is suspended in 10 mL of dry THF. The suspension is cooled in an ice bath and 10.7 g (20 mmol) of 2-chloro-5- cyclopropyl-6- N-((4,5dimethoxy-2-nitro-phenyl)methoxycarbonyl)-N-(2-fluoroacetyl)- amino-nicotinic acid, from Step 5, in 150 mL of dry THF is added dropwise with stirring. After the addition is complete, the reaction mixture is stirred at 0-5°C for 1 hour. Ethyl formate (1.78 mL, 22 mmol) in 25 mL of dry THF is added dropwise with stirring. After the addition is complete, the reaction is stirred overnight at ambient temperature and then poured into 10% aqueous ammonium chloride solution. The aqueous mixture is extracted with ethyl acetate. The organic layer is dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to afford the title compound.
Step 7 : Ethyl 9-cyclopropyl- 1 -((4,5dimethoxy-2-nitro-phenyl)methoxycarbonyl)3- fluoro-2-hvdroxy-6H-6-oxo-pyridor 1.2-alpyrimidine-7-carboxylate
A solution of 8.5 g (15 mmol) of 2-Chloro-5-cycloρropyl-6- N-((4,5dimethoxy- 2-nitro-phenyl)methoxycarbonyl)-N-(2-fluoro-3-hydroxy- 1 -oxo- 1 -prop-2-enyl)amino- nicotinic acid, from Step 6, is dissolved in 200 mL of dioxane/water (1:1). To this solution is added 4.1 g (30 mmol) of potassium carbonate. The reaction mixture is heated at reflux with stirring overnight and then cooled to ambient temperature. The reaction mixture is then diluted with water and extracted with ethyl acetate. The organic layer is dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to afford the title compound. Step 8: Ethyl 9-cyclopropyl-3-fluoro-2-chloro-6H- 6-oxo-pyridori.2-alpyrimidine-7 -carboxylate
Ethyl 9-cyclopropyl- 1 -((4,5dimethoxy-2-nitro-phenyl)methoxy-carbonyl)3- fluoro-2-hydroxy-6H-6-oxo-pyrido[l,2-a]pyrimidine-7-carboxylate (5.3 g, 10 mmol) from Step 7 is dissolved in 75 mL of 2: 1 dioxane:water and the resultant solution is iUuminated with 320 nm Ught for 30 min. The reaction mixture is extracted with ethyl acetate. The organic layer is dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue is purified by siUca gel chromatography to afford the product of Step 7 with the nitrogen protecting group removed. This product is dissolved in 1,2-dichloroethane and tretaed with phosphorous oxychloride at ambient temperature for 18 hours. The reaction mixture is dUuted with 1,2-dichloroethane and is washed with saturated aqueous sodium bicarbonate solution and brine. The organic layer is dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to afford crude title compound which is purified by recrystallization from ethyl alcohol.
Step 9: Ethyl 9-cyclopropyl-3-fluoro-2-(4-methylpiperazin-l-yl)- 6H-6-oxo-pyridor 1.2-alpyrimidine-7 -carboxylic acid
FoUowing the procedures described in Step 3 of Example 1, ethyl 9-cyclopropyl- 3-fluoro-2-chloro-6H-6-oxo-pyrido[l,2-a]pyrimidine-7-carboxylate from Step 8 is reacted with 4-methylpiperazine to afford the title compound.
Step 10: 9-Cyclopropyl-3-fluoro-2-(4-methylpiperazin-l-yl)- 6H-6-oxo-pyridoπ .2-a1pyrimidine-7 -carboxylic acid
FoUowing the procedures described in Steps 5 - 7 of Example 1, Ethyl 9- cyclopropy l-3-fluoro-2-(4-methylpiperazin- 1 -yl)-6H-6-oxo-pyrido[ 1 ,2-a]pyrimidine-7- carboxylic acid is converted to the title compound.
Examples 40-57
By foUowing the procedures described in Example 39 and replacing 4- methylpiperazine in Step 4 with the appropriate amine, Examples 40 - 57 may be prepared as disclosed in Table 2 wherein the compounds have the general formula
The amines are protected and deprotected as described in Example 58 Example 58 8-(3- Amino- 1 -pyrrolidinyl 4H-quinolizin-4-one-3-carboxyUc acid hydrochloride
Step 1. 4-Chloro-2-picoline
To 34.5 mL (0.37 mol) of phosphorus oxychloride, under a nitrogen atmosphere, was added 20.0 g (0.19 mol) of 2-picoline-N-oxide (commerciaUy avaUable from Aldrich Chemical Company) in small portions. The reaction temperature slowly increased during the addition to ~60°C. After the addition was complete, the reaction mixture was a homogeneous dark red solution and the reaction temperature was 80°C. This solution was heated at 120°C for 1.5 hours. The reaction mixture was concentrated under reduced pressure in order to remove most of the phosphorus oxychloride and the concentrate was poured into ice water. The aqueous mixture was allowed to stand for 2 hours at ambient temperature and then was extracted with diethyl ether. The ether extract was discarded. The aqueous layer was adjusted to pH 8.0 with potassium carbonate and then extracted with ethyl acetate. The organic extract was dried over anhydrous sodium sulfate, fUtered and concentrated under reduced pressure. The Uquid concentrate was distilled to afford 8.737 g of a mixture of the title compound and the isomeric 6-chloro-2-picoline as a clear colorless liquid, b.p. 70°C (25 mm Hg). This product was combined with another sample of the same mixture prepared separately by the same procedure. The isomeric products were inseparable by distillation. The combined products (12.905 g) were dissolved in 750 mL of ethyl alcohol. To the resultant solution was added, dropwise, concentrated nitric acid solution until a white precipitate formed and the pH of the supernatant solution was 1. The precipitate was removed by filtration and dissolved in water. The resultant aqueous solution was adjusted to neutral pH with sodium bicarbonate and then extracted with methylene chloride. The organic extract was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford 7.487 g of the title compound. ]H NMR (CDCI3) d 2.55 (s, 3H), 7.12 (dd, IH, J=3 Hz, 6 Hz), 7.18 (d, IH, J=3 Hz), 8.40 (d, IH, J=6 Hz).
Step 2. Diethyl 2-ethoxy-3-(r5-fluoropyridin-2-yl)-propane-l.l-dicarboxylate
Lithium dUsopropylamide (LDA: 16 mL of a 1.5 M solution in hexane) was added to 8 mL of dry THF, under a nitrogen atmosphere, and the resultant solution was cooled to -70°C in a isopropyl alcohol/dry ice bath. To the cooled solution of LDA, was added dropwise, over a 30 minute period, a solution of 2.5 g (19.6 mmol) of 4-chloro-2- picoUne, from Step 1, in 20 mL of dry THF. The solution turned a very dark red color. After stirring the dark red solution for 0.5 hours at -70°C, a solution of 4.04 mL (19.6 mmol) of ethoxymethylenemalonate in 18 mL of dry THF was added dropwise over a 30 minute period. The reaction solution turned from dark red to orange. After stirring for 0.5 hours at -70°C, the reaction solution was allowed to warm to -20°C and was stirred at -20°C for 1 hour. The reaction was quenched at -20°C by the addition of 1.3 mL of glacial acetic acid and the cooUng bath was removed. After 20 minutes the reaction solution was poured into 5% aqueous sodium bicarbonate solution. The aqueous mixture was extracted with methylene chloride and the organic extract was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue (8.03 g) was purified by chromatography on a sUica gel column (-120 g of Siθ2) eluted with 0.5% methanol in methylene chloride to afford 4.59 g (68% yield) of the title compound.
Step 3. Ethyl 8-chloro-4H-quinolizin-4-one-3-carboxylate
80 mL of Dowtherm A® in a 3-neck flask equipped with a thermometer, an addition funnel and an air-cooled condenser was heated to 235°C, under nitrogen, using a heating mantel. A solution of 4.26 g (12.4 mmol) of diethyl 2-ethoxy-3-(5-fluoropyridin- 2-yl)-propane-l,l-dicarboxylate, from Step 2, in 45 mL of Dowtherm A® was added, dropwise over a 1.5 hours period, through the addition funnel to the heated stirring Dowtherm A®. After the addition was complete, the resultant solution was heated at ~200°C for 1 hour and then was cooled to ambient temperature. The black-green-colored solution was then poured into 500 mL of hexane and a precipitate formed. The precipitate was collected by filtration, washed with 5 X 100 mL of hexane and dried to afford 1.487 g (48% yield) of the title compound.
Step 4. Ethyl 8-(3-(N-t-butoxycarbonyl)amino-.l-pyrroUdinyl)- 4H-quinolizin-4-one-3-carboxylate
Ethyl 8-chloro-4H-quinolizin-4-one-3-carboxylate (1.0 g, 3.97 mmol), from Step 3, was dissolved in 20 mL of dry pyridine under a nitrogen atmosphere. To the resultant solution was added a solution of 1.85 g (9.92 mmol) of 3-(N-t- butoxycarbonylamino)pyrrolidine in 5 mL of dry pyridine and the reaction mixture was heated at 70°C for 4.5 hours. The reaction mixture was then concentrated in vacuo in order to remove all of the pyridine. The dry residue (3.124 g) was purified by chromatography on siUca gel eluted with 2% methanol in methylene chloride to afford 0.889 g (56% yield) of the title compound. Step 5: 8-(3-Amino-l-pyrrolidinyl)-4H-quinoUzin- 4-one-3-carboxyUc acid hydrochloride
A solution of 0.889 g (2.2 mmol) of ethyl 8-(3-(N-t-butoxycarbonyl)amino-l- pyrroUdinyl)-4H-quinolizin-4-one-3-carboxylate, from Step 4, in 20 mL of trifluoroacetic acid (TFA) was stirred for 2 hours at ambient temperature. The TFA was evaporated in vacuo and the residue was dissolved in 200 mL of methanol. To the resultant solution was added 4.5 g of strongly basic ion exchange resin and the mixture was stirred at ambient temperature for 1 hour. The mixture was filtered and the filtrate was concentrated under reduced pressure to afford crude ethyl 8-(3-amino-l-pyrroUdinyl)-4H-quinoUzin-4-one-3- carboxylate as a residue. The residue was dissolved in 5 mL of THF and 11 mL of a 1 M aqueous solution of sodium hydroxide was added. The reaction mixture was heated at 60°C for 1 hour and then the reaction temperature was increased to 85°C in order to evaporate the THF. The concentrated reaction solution was dUuted with 20 mL of water and the pH of the resultant solution was adjusted to 1 - 2 with concentrated hydrochloric acid. The aqueous solution was concentrated in vacuo. The residue was crystaUized from ethyl alcohol: isopropyl alcoho water (4:4:1 v/v/v) and recrystalUzed from ethyl alcohol/water to afford 0.388 g (57% yield) of the title compound, m.p.225-230°C; MS DCI-NH3: 274 (M-C1)+ 90%, 230 ((M-Cl)-CO2H)+ base; IR (KBr): 3420 (OH), 1650 (C=O) cm'1; lH NMR (TFA) d 2.8-3.1 (m, 6H), 4.62 (m, IH), 7.06 (s, IH), 7.4 (d, 2H, J=9 Hz), 8.14 (d, IH, J=9 Hz), 9.06 (d, IH, J=9 Hz). Analysis calculated for
C14H16CIN3O3+I/3H2O: C, 53.21; H, 5.10; N, 13.30. Found: C, 53.58; H, 5.38; N, 13.30.
Example 59 8-(r3-('N-Norvalyl)amino-pyrrolidinylV4H-quinolizin-4-one-3-carboxylic acid
3-Amino-l-benzylpyιτolidine (I. Sumio and T. Matsuo, Japanese Kokai JP 5328161, published March 16, 1978) is coupled to N-t-butoxycarbonyl norvaline (Boc- nVal) using conventional N-hydroxysuccinimide coupling procedures. The 1 -benzyl group is removed by hydrogenolysis in methanol using paUadium on carbon catalyst. The 3-(N- Boc-norvalyl)aminopyrrolidine is then reacted with ethyl 8-chloro-4H-quinolizin-4-one-3- carboxylate, the product of Step 3 of Example 58, as described in Step 4 of Example 58, replacing 3-(N-t-butoxycarbonylamino)pyrrolidine with 3-(N-Boc- norvalyl)aminopyrroUdine, to give 8-(3-(N-norvalyl)amino-pyrrolidinyl)-4H-quinoUzin-4- one-3-carboxyUc acid with the nitrogen of the amino acid protected with a Boc group. The Boc protecting group is removed by standard hydrolysis using trifluoroacetic acid and dUute aqueous hydrochloric acid.
Using the procedure outlined in Example 59, or any of the other conventional condensation methods listed above, other amino acid derivatives of the compounds of this invention having an amino group can be prepared. Examples of amino acids which can be coupled, either alone or in combination with one and other, include naturaUy occurring amino acids such as glycine, alanine, leucine, isoleucine, methionine, phenylalanine, valine, and the like, as weU as synthetic amino acids such as cyclohexylala.nine, cyclohexylglycine, aminopentanoic acid, and the like.
Example 60 8-ChIoro-4-H-quinoUzin-4-one-3-carboxylic acid
Step 1: Ethyl 8-chloro-4H-quinolizin-4-one-3-carboxylate
35 mL of Dowtherm A® in a 3-neck flask equipped with a thermometer, an addition funnel and an air-cooled condenser was heated to 230-235°C, under positive nitrogen pressure, using a heating mantel. A solution of 2.7 g (7.85 mmol) of diethyl 2- ethoxy-3-(5-fluoropyridin-2-yl)-propane-l,l-dicarboxylate, the product of Step 2 of Example 58, in 45 mL of Dowtherm A® was added, dropwise over a 1.5 hours period, through the addition funnel to the heated stirring Dowtherm A®. After the addition was complete, the resultant solution was heated at ~200°C for 40 minutes and then was cooled to ambient temperature. The black-green-colored solution was then poured into 600 mL of hexane and a precipitate formed. The precipitate was collected by filtration, washed with 2 X 150 mL of hexane and dried to afford 1.15 g (58% yield) of the title compound, m.p. 153-154°C.
Step 2: 8-Chloro-4-H-quinolizin-4-one-3-carboxylic acid
Ethyl 8-chloro-4H-quinolizin-4-one-3-carboxylate (125 mg, 0.5 mmol) was suspended in 5 mL of 0.5 N aqueous sodium hydroxide solution. The reaction mixture was heated to 65 °C and 2 mL of THF was added. After the reaction mixture was stirred at 65°C for 1 hour, the THF was distilled from the mixture. Stirring was continued for 2 hours at 65°C and then the reaction mixture was allowed to cool to ambient temperature. The aqueous mixture was adjusted to pH 2 with 3 mL of 1.0 N aqueous hydrochloric acid solution and diluted with 10 mL of water. The precipitate was coUected by filtration, washed with 2 X 15 mL of water and dried in vacuo to afford 100 mg (89% yield) of the title compound, m.p. 229-230°C. The product was recrystaUized from ethyl alcohol and dried in vacuo to afford 50 mg (44.5% yield) of the title compound, m.p. 237-238°C; MS DCI-NH3: 224 (M+H)+, 241 (M+NH4)+; IR (KBr): 3430 (OH), 1740 (C=O) cm"l; 1H NMR (CDCI3) d 6.89 (d, IH, J=6.9 Hz), 7.30 (dd, IH, J=2.1 Hz, J=6.6 Hz), 7.71 (d,
IH, J=2.1 Hz), 8.64 (d, IH, J=6.9 Hz), 9.25 (d, IH, J=6.6 Hz). Analysis calculated for C10H6CINO3: C, 53.71; H, 2.70; N, 6.26. Found: C, 54.27; H, 2.86; N, 6.23.
Example 61 8-f4-methyTpiperazin- l-yl)-4H-quinolizin-4-one-3-carboxylic acid hydrochloride
Step 1: Ethyl 8-f 4-methylpiperazin- 1 -ylV4H-quinolizin-4-one-3-carboxylate
Ethyl 8-chloro-4H-quinolizin-4-one-3-carboxylate (755 mg, 3.0 mmol), the product of Step 3 of Example 58, was suspended in 12 mL of dry pyridine under a nitrogen atmosphere. To the resultant solution was added 6.0 mL (6.0 mmol) of N- methylpiperazine and the reaction mixture was heated at 70°C for 8 hours. The reaction mixture was then concentrated in vacuo in order to remove aU of the pyridine. The dry residue (3.124 g) was dissolved in 125 mL of methylene chloride and the methylene chloride solution was washed with 125 mL of saturated sodium chloride solution (brine). The aqueous layer was extracted with 125 mL of methylene chloride and the combined methylene chloride solutions were dried over anhydrous sodium sulfate, fUtered and concentrated and dried in vacuo to afford 1.01 g of the title compound.
Step 2: 8-(4-methylpiperazin-l-yl)-4H-quinolizin- 4-one-3-carboxylic acid hydrochloride
A mixture of 0.865 g (2.75 mmol) of ethyl 8-(4-methylpiperazin-l-yl)-4H- quinolizin-4-one-3-carboxylate, from Step 1, in 12 mL of THF and 16.5 mL of a 0.5 N aqueous solution of sodium hydroxide was heated, with stirring, at 75°C for 8 hours. The THF was removed from the reaction mixture by distiUation during the reaction. The concentrated reaction mixture was cooled to ambient temperature and adjusted to pH 2.0 with 10.5 mL of 1 N aqueous hydrochloric acid solution. The aqueous solution was concentrated in vacuo to remove ~80% of the water and the concentrate was dUuted with 50 mL of 95% ethyl alcohol. The solid was coUected by filtration, washed with 2 X 5 mL of ethyl alcohol and dried in vacuo to afford the desired productThe product was recrystaUized from ethyl alcohol/water (3:1 v/v) to afford 0.332 g (37% yield) of the title compound, m.p.257-258°C; MS DCI-NH3: 288 (M-C1)+ 90%, 244 ((M-Cl)-CO2H)+ base, 270 (M-Cl-H2θ)+; IR (KBr): 3420 (OH), 1645 (C=O) cπrl; 1H NMR (TFA) d 3.20 (m, 3H), 3.52 (dd, 2H, J=10 Hz), 4.02 (m, 4H), 4.63 (d, 2H, J=12 Hz), 7.41 (m, 2H), 7.65 (d, IH, J=7.5 Hz), 8.26 (d, IH, J=9 Hz), 9.18 (d, IH, J=7.5 Hz). Analysis calculated for C15H18CIN3O3+O.5H2O: C, 54.14; H, 5.75; N, 12.62. Found: C, 54.23; H, 5.54; N, 12.64.
Example 62 8-(3- Amino- 1 -pyrrolidinyl)- 1 -ethyl-4H-quinoUzin-4-one-3-carboxylic acid hydrochloride
Step 1: 4-Chloro-2-propyl-pyridine
A 1.5 M solution of LDA in hexane (100 mL, 150 mmol) was cooled to -60°C in an isopropyl alcohol/dry ice bath. To the stirred LDA solution, under nitrogen, was added, dropwise over a 0.5 hours period, a solution of 17.466 g (137 mmol) of 4-chloro-2- picoUne (the product of Step 1 of Example 58) in 80 mL of dry THF. The reaction mixture was stirred for 0.5 hours at -60°C and then a solution of 10.95 mL (137 mmol) of ethyl iodide in 30 mL of dry THF was added, dropwise over a 20 minute period. After the reaction mixture was stirred at -60°C for 0.5 hours, the cooling bath was allowed to slowly (1.5 hours) warm to -30°C. According to TLC analysis on sUica gel eluted with 5% methanol in methylene chloride, the reaction had gone to completion. The reaction mixture was poured into cold brine and the aqueous mixture was extracted with methylene chloride. The organic extract was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was distilled to afford 12.667 g (60% yield of the titie compound, b.p. 77-80°C (10 mm Hg).
Step 2. Diethyl 2-ethoxy-3-r4-chloro-2-pyridvn-pentane- 1.1 -dicarboxylate
A solution of 12.6 mL (89.9 mmol) of diisopropylamine in 20 mL of anhydrous tetrahydrofuran (THF) was prepared under a nitrogen atmosphere and cooled in an ice/water bath. To this solution was added, dropwise over a 30 minute period, 36 mL of a 2.5 M solution of n-butyUithium (90 mmol) in hexane. The solution was stirred for 30 minutes at 0°C and then cooled to -60°C. To the amine solution at -60°C, was added, dropwise over a 30 minute period, a solution of 12.66 g (81.9 mmol) of 4-chloro-2- propyl-pyridine, from Step 1, in 100 mL of anhydrous THF and a dark red-colored solution was formed. The solution was stirred at -60°C for 0.5 hours and then 16.55 mL (81.9 mmol) of ethyl 2-carboethoxy-3-ethoxy-2-propenecarboxylate was added, dropwise over a 30 minute period. Stirring was continued at -60°C for 0.5 hours and at -20°C for 1.5 hours. The reaction mixture was poured into cold brine and the aqueous mixture was extracted with methylene chloride. The combined organic extract was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to afford 35.48 g of the title compound. The product was carried on to the next step without purification.
Step 3. Ethyl 8-chloro- 1 -ethyl-4-H-quinoUzin-4-one-3-carboxylate
A solution of 35.48 g (99.2 mmol) of diethyl 2-ethoxy-3-[4-chloro-2-pyridyl]- pentane-l,l-dicarboxylate, from Step 2, in 1 L of xylene was heated at 150°C, with stirring, for 24 hours and then concentrated in vacuo. The residue was washed with a mixture of hexane and cyclohexane to afford 14.867 g (54% yield) of the title compound as a green soUd; MS DCI-NH3 M/Z: 280 (M+H)+, 246 (M-C1)+, 217 (M-Cl-Et)+; 1H NMR (CDCI3) d 1.31 (t, 3H, J=7.5 Hz), 1.43 (t, 3H, J=7.2 Hz), 2.78 (q, 2H, J=7.5 Hz), 4.43 (q, 2H, J=7.2 Hz), 7.10 (dd, IH, J=2.4 Hz, 8.1 Hz), 7.70 (d, IH, J=2.4 Hz), 8.32 (s, IH), 9.40 (d, IH, 8.1Hz).
Step 4. Ethyl 8-(3-(N-t-butoxycarbonyl)amino-l-pyrroUdinyl)- l-ethyl-4H-quinolizin-4-one-3-carboxylate
Ethyl 8-chloro-l-ethyl-4H-quinolizin-4-one-3-carboxylate (1.20 g, 4.3 mmol), from Step 3, was dissolved, under a nitrogen atmosphere, in 15 mL of dry pyridine. To the resultant solution was added 1.04 g (5.59 mmol) of 3-(N-t-butoxycarbonylamino- pyrrolidine) and 1.8 mL (12.9 mmol) of dry triethylamine and the reaction mixture was heated at 60°C for 12 hours. The reaction mixture was then concentrated in vacuo in order to remove all of the pyridine. Ethyl alcohol (4 mL) was added to the dry residue. The mixture was filtered to give 0.421 g of the desired product as a solid. The filtrate was concentrated and the residue purified by flash chromatography on sUica gel eluted with 2% methanol in methylene chloride, followed by 5% methanol in methylene chloride to afford an additional 1.273 g of the desired product. The title compound was obtained in 92% yield (1.694 g) as a yellow solid and taken on to the next step.
Step 5. 8-(3-Amino-l -pyrroUdinyl)- l-ethyl-4H- quinolizin-4-one-3-carboxylic acid hydrochloride
A solution of 1.694 g (3.94 mmol) of ethyl 8-(3-(N-t-butoxycarbonyl)-amino-l- pyrroUdinyl)-l-ethyl-4H-quinolizin-4-one-3-carboxylate, from Step 4, in 25 mL of trifluoroacetic acid (TFA) was stirred for 2 hours at ambient temperature. The TFA was evaporated in vacuo and the residue was dissolved in 200 mL of methanol. To the resultant solution was added 25 g of strongly basic ion exchange resin and the mixture was stirred at ambient temperature for 2 hours. The mixture was filtered and the filtrate was concentrated under reduced pressure to afford 1.146 g (88% yield) of ethyl 8-(3-amino-l-pyrroUdinyl)- l-ethyl-4H-quinolizin-4-one-3-carboxylate as a residue. The residue was dissolved in 6 mL of THF and 10.5 mL of a 1 M aqueous solution of sodium hydroxide was added. The reaction mixture was heated at 60°C for 2 hours and then the reaction temperature was increased to 90°C for 2 hours, in order to evaporate the THF. The concentrated reaction solution was poured into water and the pH of the resultant solution was adjusted to ~2 with concentrated hydrochloric acid. The soUd was filtered to afford 0.365 g (31% yield) of the title compound, m.p.l96-198°C; MS DCI-NH3: 302 (M-C1)+ base, 258 ((M-Cl)-CO2H)+ 25%; IR (KBr): 3440 (OH), 2960, 1650 (OO), 1500, 1360, 1280 cm" 1; 1H NMR (TFA) d 1.41 (t, 3H, J=7.5 Hz), 2.39 (q, 2H, J=7.5), 2.70 (m, 3H), 4.0 (m, 3H), 4.53 (m, IH), 6.93 (d, IH, J=1.5 Hz), 7.33 (dd, IH, J=9 Hz, 1.5 Hz), 7.93 (s, IH), 9.08 (d, IH, J=9 Hz). Analysis calculated for CI6H20CIN3O3: C, 56.98; H, 5.97; N, 12.44. Found: C, 56.83; H, 6.00; N, 11.93.
Example 63 8-(3-f Alanyl)amino-pyτrolidinyl)- 1 -ethyl-4H-quinolizin-4-one-3-carboxylic acid
3-Amino-l-benzylpyrrolidine (I. Sumio and T. Matsuo, Japanese Kokai JP
5328161, published March 16, 1978) is coupled to N-t-butoxycarbonyl alanine (Boc-Ala) using conventional N-hydroxysuccinimide coupling procedures. The 1 -benzyl group is removed by hydrogenolysis in methanol using palladium on carbon catalyst. The 3-(N- Boc-alanyl)aminopyrroUdine is then reacted with ethyl 8-chloro-l -ethyl -4H-quinoUzin-4- one-3-carboxylate, the product of Step 3 of Example 62, as described in Step 4 of Example 62 replacing 3-(N-t-butoxycarbonylaminopyrrolidine) with 3-(N-Boc- alanyl)aminopyrrolidine, to give 8-(3-(N-alanyl)amino-pyrrolidinyl)-4H-quinoUzin-4-one- 3-carboxyUc acid with the nitrogen of the amino acid protected with a Boc group. The Boc protecting group is removed by standard hydrolysis using trifluoroacetic acid and dUute aqueous hydrochloric acid.
Using the procedure outlined in Example 63, or any of the other conventional condensation methods listed above, other amino acid derivatives of the compounds of this invention having an amino group can be prepared. Examples of amino acids which can be coupled, either alone or in combination with one and other, include naturally occurring amino acids such as glycine, alanine, leucine, isoleucine, methionine, phenylalanine, valine, and the like, as weU as synthetic amino acids such as cyclohexylalanine, cyclohexylglycine, aminopentanoic acid, and the like.
Example 64 1 -Ethyl-8-(3-methyl- 1 -piperazinyl)-4H-quinoUzin-4-one-3-carboxylic acid hydrochloride
Step 1. Ethyl l-ethyl-8- -methyl- 1 -piperazinyl 4H-quinolizin-4-one-3-carboxylate
Ethyl 8-chloro-l-ethyl-4H-quinoUzin-4-one-3-carboxylate (558 mg, 2.0 mmol), the product of Step 3 of Example 62, was dissolved in 10 mL of dry pyridine under a nitrogen atmosphere. To the resultant solution was added 600 mg (6.0 mmol) of 2- methylpiperazine and the stirred reaction mixture was heated at 65°C for 3 hours. The reaction mixture was aUowed to cool to ambient temperature and then concentrated in vacuo in order to remove aU of the pyridine. The residue was dissolved in 60 mL of methylene chloride and the methylene chloride solution was washed with 60 mL of water. The aqueous layer was extracted with 2 X 60 mL of methylene chloride and the combined methylene chloride solutions were dried over anhydrous sodium sulfate, fUtered and concentrated and dried in vacuo to afford 690 mg of the title compound. The product was carried on to the next step without purification.
Step 2. l-Ethyl-8-(3-methyl-l-piperazinyl)-4H- quinolizin-4-one-3-carboxylic acid hydrochloride
To a suspension of 0.686 g (2 mmol) of ethyl l-ethyl-8-(3-methyl-l- piperazinyl)-4H-quinolizin-4-one-3-carboxylate, from Step 1, in 8 mL of THF was added 8.0 mL of a 1.0 N aqueous sodium hydroxide solution and the reaction mixture was heated, with stirring, at 65°C for 3 hours. The THF was removed from the reaction mixture by distiUation during the reaction. The concentrated reaction mixture was cooled to ambient temperature and adjusted to pH 1-2 with 16 mL of 1 N aqueous hydrochloric acid solution. The aqueous solution was concentrated in vacuo to remove the water and the residue was suspended in 10 mL of water. The soUd was collected by filtration and dried in vacuo to afford the 385 mg (55% yield) of the title compound, m.p.>295°C; MS DCI- NH3: 316 (M-C1)+ ; IR (KBr): 3420 (OH), 1720 (C=O) cπr1; 1H NMR (TFA) d 1.50 (t, 3H, J=7.5 Hz), 1.70 (d, 3H, J=6 Hz), 3.00 (q, 2H, J=7.5 Hz), 3.70-4.10 (m, 6H), 4.55 (m, IH), 4.60 (m, IH), 7.40 (d, IH, J=3.0 Hz), 7.68 (dd, IH, J=3.0 Hz, 8.4 Hz), 8.18 (s, IH), 9.19 (d, IH, J=8.4 Hz). Analysis calculated for C17H22CIN3O3+H2O: C, 55.21; H, 6.54; N, 11.36. Found: C, 55.19; H, 6.07; N, 11.34. Example 65 1 -Ethyl-8-f 4-methylpiperazin- 1 -ylV4H-quinoUzin-4-one-3-carboxyUc acid hydrochloride
Step 1. Ethyl l-ethyl-8-f4-methylpiperazin-l-yl)-4H-quinolizin-4-one-3-carboxylate
Ethyl 8-chloro-l-ethyl-4H-quinoUzin-4-one-3-carboxylate (279 mg, 1.0 mmol), the product of Step 3 of Example 62, was dissolved in 5 mL of dry pyridine under a nitrogen atmosphere. To the resultant solution was added 2 mL (2.0 mmol) of N- methylpiperazine and the stirred reaction mixture was heated at 85°C for 2.5 hours. The reaction mixture was aUowed to cool to ambient temperature and then concentrated in vacuo in order to remove aU of the pyridine. The residue was dissolved in 50 mL of methylene chloride and the methylene chloride solution was washed with 50 mL of 5% aqueous sodium bicarbonate solution. The aqueous layer was extracted with 3 X 50 mL of methylene chloride and the combined methylene chloride solutions were dried over anhydrous sodium sulfate, filtered and concentrated and dried in vacuo to afford 343 mg of the titie compound, m.p. 94-96°C; MS DCI-NH3: 344 (M+H)+.
Step 2. l-Ethyl-8-(4-methylpiperazin-l-yl)-4H- quinolizin-4-one-3-carboxylic acid hydrochloride
To a solution of 171 mg (0.5 mmol) of ethyl l-ethyl-8-(4-methylpiperazin-l-yl)-
4H-quinolizin-4-one-3-carboxylate, from Step 1, in 4 mL of THF was added 4.0 mL of a 1.0 N aqueous sodium hydroxide solution and the reaction mixture was heated, with stirring, at 75°C for 4.5 hours. The reaction mixture was cooled to ambient temperature and adjusted to pH 2 with 5 mL of 1 N aqueous hydrochloric acid solution. The aqueous solution was concentrated in vacuo to ~5 mL and the solid was coUected by filtration and dried in vacuo to afford 120 mg (68% yield) of the title compound, m.p. 293-294°C (dec); MS DCI-NH3: 316 (M-C1)+ 90%, 272 ((M-Cl)-CO2H)+ base; IR (KBr): 3420 (OH), 1695 (OO), 1640 (OO) cm"1; !H NMR (TFA) d 1.47 (t, 3H, J=7.5 Hz), 3.00 (q, 2H, J=7.5 Hz), 3.23 (s, 3H), 3.55 (dd, 2H, J=9 Hz), 4.12 (m, 4H), 4.65 (d, 2H, J=15 Hz), 7.40 (s, IH), 7.67 (d, IH, J=9 Hz), 8.18 (s, IH), 9.20 (d, IH, J=7.5 Hz). Analysis calculated for C17H22CIN3O3: C, 56.59; H, 6.42; N, 1 1.64. Found: C, 56.86; H, 6.19; N, 11.60. Example 66 4-Chloro-5-fluoro-2-picoline
Step 1. 2-f 5-Nitro-2-pyridvI)- 1.3-propanedicarboxylate
Sodium hydride (20.2 g of NaH suspended in hexane, 0.504 mol) was suspended, under a nitrogen atmosphere, in 600 mL of anhydrous THF in a 3-neck 2 L round-bottom flask equiped with an addition funnel and a mechanical stirrer. The suspension was cooled to 0°C in an ice bath. A solution of 71.8 mL (0.473 mol) of diethyl malonate in 60 mL of anhydrous THF was added dropwise to the sodium hydride suspension over a 1 hour period. After the addition and the evolution of hydrogen gas were complete, the reaction mixture was stirred for 20 min at 0°C. A solution of 50 g (0.315 mol) of 2-chloro-5-nitropyridine in 150 mL of anhydrous THF was added dropwise to the mixture, over a 25 min period. The ice bath was removed and the deep red-colored solution was stirred at ambient temperature for 48 hours. These procedures were repeated on the same scale. The two solutions containing the product were concentrated to ~ 500 mL and poured into a mixture of 1 L of 10% aqueous sodium bicarbonate solution and 1 L of brine. The aqueous mixture was extracted with 3 X 500 mL of methylene chloride. The combined organic extract was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to a soUd residue. The residue was crystaUized from ethyl alcohol and the crystals were washed with hexane to yield 140 g (79% yield) of the title compound as a bright yellow soUd; MS DCI-NH3 M/Z: 283 (M+H)+ base, 253 ((M+H)-C2H5)+ base; *H NMR (CDCI3) d 1.30 (t, 6H, J=7.5 Hz), 4.26 (q, 2H, J=6.0 Hz), 4.29 (q, 2H, J=6.0 Hz), 5.08 (s, IH), 7.77 (dd, IH, J=9.0 Hz, 0.6 Hz), 8.49 (dd, IH, J=3.0 Hz, 9.0 Hz), 9.38 (dd, IH, J=3.0 Hz, 9.0 Hz).
Step 2. 5-Nitτo-2-picoUne
A suspension of 102.0 g (0.361 mol) of 2-(5-nitro-2-pyridyl)-l,3- propanedicarboxylate, from Step 1, in 600 mL of 20% aqueous sulfuric acid solution was heated at 95°C for 24 hours. The resultant solution was poured onto 1 kg of ice and the aqueous mixture was adjusted to a pH within the range pH 10 - 12 with 50% aqueous sodium hydroxide solution. The precipitate was filtered and dissolved in ethyl acetate. The ethyl acetate solution was dried over anhydrous sodium sulfate, filtered and concentrated to a solid residue. The residue was washed with hexane. The hexane was removed by filtration and the soUd was dried to afford 45.86 g (92% yield) of the title compound; 1H NMR (CDCI3) d 2.71 (s, 3H), 7.36 (d, IH, J=9.0 Hz), 8.37 (dd, IH, J=3.0 Hz, 9.0 Hz), 9.33 (d, IH, J=3.0 Hz).
Step 3. 5-Amino-2-picoUne
The product of Step 2, 5-nitro-2-picoline (45.86, 0.332 mol), was dissolved in
200 mL of methanol and 1.15 g of 10% palladium on carbon was added to the resultant solution. The reaction mixture was hydrogenated at ambient temperature under 4 atmospheres of hydrogen. The paUadium catalyst was removed by filtration through a 45 μ MUUpore® filter and the filtrate was concentrated in vacuo to afford 33.96 g (95% yield) of the title compound as a tan solid; 1H NMR (CDCI3) d 2.42 (s, 3H), 3.54 (brs, 2H), 6.91 (m, 2H), 8.00 (m, IH).
Step 4. 5-Fluoro-2-picoUne
A solution of 5-amino-2-picoline (20 g, 0.185 mol), from Step 3, in 105 mL of ethyl alcohol was cooled to 0°C. Tetrafluoroboric acid (55 mL of a 48% solution in water) was added to the cold 5-aminopicoUne solution and the flask containing the resultant solution was weighed. Ethyl nitrite was bubbled through the cold solution until 13.88 g (0.185 mol) had been added. The addition took place over a 1.25 hours period. After the addition was complete the reaction solution was aUowed to sit at 0°C for 15 min, during which time, the excess ethyl nitrite evaporated from the solution. Diethyl ether (120 mL) was added to the reaction mixture to ensure complete precipitation of the tetrafluoroborate salt. After 30 minutes at 0°C, the mixture was filtered. The filter cake was washed with 200 mL of diethyl ether, foUowed by 300 mL of hexane. The soUd was transferred to a 1 L beaker containing approximately 300 mL of hexane and 10.75 g (0.185 mol) of potassium fluoride. The mixture was heated to 40°C over a 4.5 hours period. The orange- colored soUd was converted to a black oily soUd. The hexane was decanted and the residue was cooled to 0°C. The cold residue was triturated with approximately 200 mL of 50% sodium hydroxide. The mixture was combined with material obtained from dupUcate runs of the preceeding procedures and the combined aqueous mixtures were steam distiUed. The aqueous distiUate coUected between 92°C and 100°C was extracted with two portions of methylene chloride. The combined methylene chloride extract was dried over anhydrous sodium sulfate, filtered and added to the (hexane) distillate which was coUected between 62°C and 65 °C. The product was carried on to the next step in solution. Step 5. 5-Fluoro-2-picohne-N-oxide
To the solution of 5-fluoro-2-picoline obtained in Step 4, at 0°C, was added, with vigorous stirring, a cold solution of 40% peracetic acid (prepared by carefully adding 50 mL of 30% hydrogen peroxide solution to 150 mL of glacial acetic acid). The reaction mixture was heated at reflux temperature (50°C) for 4 days and then poured into 600mL of ice water. The aqueous mixture was adjusted to pH 9 by the addition of potassium carbonate and then was stirred at ambient temperature for 4 hours. The aqueous solution was continuously extracted with methylene chloride for 24 hours and the methylene chloride extract was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to afford 30.8 g (22% yield) of the title compound; MS DCI-NH3 M/Z: 128
(M+H)+ base; *H NMR (CDCI3) d 2.48 (s, 3H), 7.00 (ddd, IH), 7.22 (dd, IH), 8.22 (dd, IH).
Step 6. 5-Fluoro-4-nitro-2-picoline-N-oxide
The reaction was carried out in a flask vented to a gas scrubber containing aqueous sodium hydroxide solution. The product of Step 5, 5-fluoro-2-picoline-N-oxide (1.0 g, 7.86 mmol) was cooled to 0°C and concentrated sulfuric acid (4.2 mL) was slowly added, with stirring. Solid potassium nitrate (1.27 g, 12.5 mmol) was then added to this mixture at 0°C, in smaU portions over a 45 minute period. The reaction mixture was aUowed to warm to ambient temperature and was stirred at ambient temperature for 1 hour. Not aU of the potassium nitrate had dissolved and the reaction mixture was heated at 50°C for 0.5 hours and then at 100°C for 18 hours. The homogeneous reaction solution was poured over ice and the resultant aqueous solution was adjusted to pH 9 with soUd potassium carbonate. The aqueous solution was then extracted with 3 X 80 mL of methylene chloride. The combined organic extract was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give 1.084 g (80% yield) of the title compound as a yellow solid, m.p. 107-108°C; MS DCI-NH3 M/Z: 190 (M+NH4)+ 10%, 173 (M+H)+ 30%, 157 (M-O)+ 50%; lH NMR (CDCI3) d 2.48 (s, 3H), 8.05 (d, IH, J=9.0 Hz), 8.31 (d, IH, J=6.0 Hz).
Step 7. 4-Chloro-5-fluoro-2-picoline-N-oxide
The product of Step 6, 5-fluoro-4-nitro-2-picoUne-N-oxide (3.56 g, 20.6 mmol) was dissolved in 30 mL of concentrated (37.5%) aqueous hydrochloric acid. The resultant solution was heated, with stirring, at 110°C for 48 hours and then concentrated in vacuo. Water (30 mL) was added to the residue and the resultant aqueous solution was adjusted to pH 9-10 with sodium carbonate. The aqueous solution was then extracted with 3 X 50 mL of methylene chloride and the combined organic extract was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The product was crystaUized from hexane to afford 1.8 g (55% yield) of the title compound, m.p. 92-93°C; MS DCI-NH3 M/Z: 179 (M+NH4)+ 30%, 162 (M+H)+ base, 146 (M-O)+ 60%; 1H NMR (CDCI3) d 2.46 (s, 3H), 7.30 (d, IH, J=9.0 Hz), 8.26 (d, IH, J=4.5 Hz); IR (chloroform solution) 1605 (N- O), 1180 (C-F) cm"1. Analysis calculated for C6H5CIFNO: C, 44.61; H, 3.12; N, 8.62. Found: C, 44.89; H, 3.25; N, 9.40.
Step 8. 4-Chloro-5-fluoro-2-picoline
4-Chloro-5-fluoro-2-picoline-N-oxide (12.43 g, 76.93 mmol), from Step 7, was dissolved in 52 mL of glacial acetic acid in a 3-necked flask equiped with a mechanical stirrer, a condenser and a thermometer. Iron powder (6.45 g, 115.5 mmol) was added to the solution at ambient temperature and the reaction mixture was carefuUy heated to 35- 40°C. After 10 min at 30°C, an exothermic reaction took place which caused the reaction temperature to rise to 120°C and the reaction mixture became a very dark brown-colored solution. The flask was trα/wferred to a cold water bath and the temperature of the solution brought down to ambient. The reaction mixture was then poured over ice. The resultant aqueous mixture was adjusted to pH 9 with potassium carbonate and steam distiUed. The aqueous distillate collected at 92-96°C was extracted with three portions of methylene chloride. The combined organic extract was dried over anhydrous sodium sulfate, filtered and distilled to afford 15.91 g (71% yield) of the title compound, b.p. 138-140°C; MS GC¬ MS M/Z: 146 (M+H)+; ]H NMR (CDCI3) d 2.53 (s, 3H), 7.23 (d, IH, J=6.0 Hz), 8.37 (s, IH).
Example 67 3.4-Dichloro-5-fluoro-2-picoline
To 0.87 g (6 mmol) of 4-chloro-5-fluoro-2-picoline, the product of Example 66, in 20 mL of chloroform cooled to -45°C, is added 0.75 mL of t-butylhypochlorite. The reaction mixture is stirred at -45°C for 2 hours and at 0°C for 2 hours. The reaction mixture is then poured into water and the resultant aqueous mixture is extracted with methylene chloride. The organic solution is dried over anhydrous magnesium sulfate, fUtered, concentrated under reduced pressure and distUled to afford the title compound. Example 68 3-Bromo-4-chloro-5-fluoro-2-picoline
4-Chloro-5-fluoro-2-picoline, the product of Example 66, is treated with bromine in fuming sulfuric acid containing 65% sulfur trioxide for 7 hours at 80°C as described by L. van der Does and H.J. Hertog in Rec Trav Chim 81: 864 (1965) to afford the title compound.
Example 69 4-Chloro-3.5-difluoro-2-picoUne
4-Chloro-5-fluoro-2-picoline is treated with 1.1 equivalents of acetyl hypofluorite as described by O. Lerman,, et al. J Org Chem.49: 806-813 (1984) to afford the title compound.
Example 70
4-Chloro-5-fluoro-2-propyl-pyridine
Diisopropylamine (924 μL, 6.59 mmol) was dissolved in 9 mL of dry THF and the resultant solution was cooled to 0°C in an ice bath. n-ButyUithium (3.07 mL of a 2.05 M solution in THF, 6.29 mmol) was added via syringe to the amine solution and the resultant solution was stirred for 30 minutes at 0°C. The Uthium diisopropylamide (LDA) solution was then cooled to -50°C in an isopropyl alcohol/dry ice bath. To the cold LDA solution was added, dropwise from an addition funnel, over a 15 min period, a solution of 4-chloro-5-fluoro-2-picoline (435 μL, 3.0 mmol), the product of Example 64, in 9 mL of THF. The reaction solution turned dark orange-brown in color. The reaction solution was stirred at a temperature in the range -50°C to -45°C for 5 hours and then was cooled over a 15 min period to -78°C. Ethyl iodide (792 μL, 9.9 mmol) was added in one portion and the reaction solution was stirred at -78°C for 20 min. The reaction was then quenched by pouring the reaction solution into 60 mL of 10% aqueous ammonium chloride solution. The aqueous mixture was extracted with 2 X 50 mL of methylene chloride. The combined organic extract was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo and the residue was distiUedto afford the title compound, b.p. 80-82°C (12 mm Hg); MS DCI-NH3 M/Z: 174 (M+H)+ 40%; 1H NMR (CDCI3) d 0.96 (t, 3H, J=7.5 Hz), 1.73 (spt, 2H, J=7.5 Hz), 2.73 (t, 2H, J=7.5 Hz), 7.21 (d, IH, J=6.0 Hz), 8.38 (s, IH). Example 71 3.4-Dichloro-5-fluoro-2-propyl-pyridine
By foUowing the procedures described in Example 67 and replacing 4-chloro-5- fluoro-2-picoUne (the product of Example 66) with 4-chloro-5-fluoro-2-propyl-pyridine (the product of Example 70), the title compound can be prepared.
Example 72 3-Bromo-4-chloro-5-fluoro-2-propyl-pyridine
By foUowing the procedures described in Example 68 and replacing 4-chloro-5- fluoro-2-picoUne (the product of Example 66) with 4-chloro-5-fluoro-2-propyl-pyridine (the product of Example 70), the title compound can be prepared.
Example 73 4-Chloro-3.5-difluoro-2-propyl-pyτidine
By foUowing the procedures described in Example 69 and replacing 4-chloro-5- fluoro-2-picoUne (the product of Example 66) with 4-chloro-5-fluoro-2-propyl-pyridine
(the product of Example 70), the title compound can be prepared.
Example 74
1 -Ethyl-7-fluoro-8-(4-methylpiperazin- 1 -yl)- 4H-quinoUzin-4-one-3-carboxylic acid hydrochloride
By foUowing the procedures described in Step 2 of Example 62 and in Example
65 and replacing 4-chloropicoline with 4-chloro-5-fluoro-picoline (the product of Example 66), the titie compound can be prepared.
Example 75 1 -Ethyl-7-fluoro-8-(3-methyl- 1 -piperazinyl)-
4H-quinolizin-4-one-3-carboxylic acid hydrochloride
By foUowing the procedures described in Step 2 of Example 62 and in Example 65 and replacing 4-chloropicoline with 4-chloro-5-fluoro-picoline (the product of Example 66), and replacing N-methylpiperazine with 2-methylpiperazine, the title compound can be prepared. Example 76
8-(3- Amino- 1 -pyrrolidinyl)- 1 -ethyl-7-fluoro-4H- quinoUzin-4-one-3-carboxyUc acid hydrochloride
Following the procedures described in Example 62, replacing 4-chloropicoUne with 4-chloro-5-fluoro-picoline (the product of Example 66), the title compound is prepared.
Example 77 9-Chloro-l-ethyl-7-fluoro-8-(4-methylpiperazin-l-yl)-
4H-quinolizin-4-one-3-carboxylic acid hydrochloride
FoUowing the procedures described in Step 2 of Example62 and in Example 65, replacing 4-chloropicoline with 3,4-dichloro-5-fluoro-picoUne (the product of Example 67), the title compound is prepared.
Example 78
9-Chloro- 1 -ethyl-7-fluoro-8-(3-methyl- 1 -piperazinyl)- 4H-quinolizin-4-one-3-carboxylic acid hydrochloride
FoUowing the procedures described in Step 2 of Example 62 and in Example 65, replacing 4-chloropicoUne with 3,4-dichloro-5-fluoropicoline (the product of Example 67), and replacing N-methylpiperazine with 2-methylpiperazine, the title compound is prepared.
Example 79
8-(3- Amino- 1 -pyrroUdinyl)-9-chloro- 1 -ethyl-7- fluoro-4H-quinolizin-4-one-3-carboxylic acid hydrochloride
Following the procedures described in Example 62, replacing 4-chloropicoUne with 3,4-dichloro-5-fluoropicoline (the product of Example 67), the title compound is prepared. Example 80
9-Bromo-l-ethyl-7-fluoro-8-(4-methylpiperazin-l-yl)- 4H-quinolizin-4-one-3-carboxyUc acid hydrochloride
FoUowing the procedures described in Step 2 of Example 62 and in Example 65, replacing 4-chloropicoline with 3-bromo-4-chloro-5-fluoropicoline (the product of Example 68, the title compound is prepared.
Example 81 9-Bromo- 1 -ethyl-7-fluoro-8-(3-methyl- 1 -piperazinyl)-
4H-quinoUzin-4-one-3-carboxyIic acid hydrochloride
FoUowing the procedures described in Step 2 of Example 62 and in Example 65, replacing 4-chloropicoline with 3-bromo-4-chloro-5-fluoro-picoline (the product of Example 68), and replacing N-methylpiperazine with 2-methylpiperazine, the title compound is prepared.
Example 82
8-(3- Amino- 1 -pyrroUdinyl)-9-bromo- 1 -ethyl-7-fluoro- 4H-quinolizin-4-one-3-carboxylic acid hydrochloride
Following the procedures described in Example 62, replacing 4-chloropicoUne with 3-bromo-4-chloro-5-fluoro-picoUne (the product of Example 68), the title compound is prepared.
Example 83
7,9-Difluoro- 1 -ethyl-8-(4-methylpiperazin- 1 -yl)- 4H-quinolizin-4-one-3-carboxylic acid hydrochloride
FoUowing the procedures described in Step 2 of Example 62 and in Example 65, replacing 4-chloropicoUne with 4-chloro-3,5-difluoropicoline (the product of Example 69), the titie compound is prepared. Example 84
7,9-Difluoro- 1 -ethyl-8-(3-methyl- 1 -piperazinyl)- 4H-quinoUzin-4-one-3-carboxyhc acid hydrochloride
FoUowing the procedures described in Step 2 of Example 62 and in Example 65, replacing 4-chloropicoUne with 4-chloro-3,5-difluoropicoline (the product of Example 69), and replacing N-methylpiperazine with 2-methylpiperazine, the title compound is prepared.
Example 85 8- (3- Amino- 1 -pyrroUdinyl)-7,9-difluoro- 1 -ethyl-
4H-quinolizin-4-one-3-carboxylic acid hydrochloride
Following the procedures described in Example 62, replacing 4-chloropicoUne with 4-chloro-3,5-difluoropicoline (the product of Example 69), the title compound is prepared.
Example 86 l-Cyclopropyl-7-fluoro-8-(4-methylpiperazin-l-yl)- 4H-quinoUzin-4-one-3-carboxyUc acid hydrochloride
FoUowing the procedures described in Steps 1 and 2 of Example 62 and in
Example 65, replacing 4-chloropicoline with 4-chloro-5-fluoropicoUne (the product of
Example 66), and replacing ethyl iodide with cyclopropyl iodide, the title compound is prepared.
Example 87
1 -Cyclopropyl-7-fluoro-8-(3-methyl- 1 -piperazinyl)- 4H-quinolizin-4-one-3-carboxylic acid hydrochloride
FoUowing the procedures described in Steps 1 and 2 of Example 62, replacing 4- chloropicoUne with 4-chloro-5-fluoropicoUne (the product of Example 66) and replacing ethyl iodide with cyclopropyl iodide, and the procedures described in Example 65, replacing N-methylpiperazine with 2-methylpiperazine, the title compound is prepared. Example 88
8-(3- Amino- 1 -pyrrolidinyl)- 1 -cyclopropyl-7-fluoro- 4H-quinolizin-4-one-3-carboxyUc acid hydrochloride
Following the procedures described in Example 62, replacing 4-chloropicoUne with 4-chloro-5-fluoropicoline (the product of Example 66), and replacing ethyl iodide with cyclopropyl iodide, the title compound is prepared.
Example 89 9-Chloro- l-cyclopropyl^-fluoro-S-^-methylpiperazin- l-vπ^H-quinolizin^-one-S-carboxylic acid hydrochloride
FoUowing the procedures described in Steps 1 and 2 of Example 62, replacing 4- chloropicoUne with 3,4-dichloro-5-fluoropicoUne (the product of Example 67) and replacing ethyl iodide with cyclopropyl iodide, and the procedures described in Example 65, the title compound is prepared.
Example 90
9-Chloro- 1 -cyclopropyl-7-fluoro-8-(3-methyl- 1 - piperazinvD-4H-quinolizin-4-one-3-carboxyUc acid hydrochloride
FoUowing the procedures described in Steps 1 and 2 of Example 62, replacing 4- chloropicoUne with 3,4-dichloro-5-fluoropicoUne (the product of Example 67) and replacing ethyl iodide with cyclopropyl iodide, and the procedures described in Example 65, replacing N-methylpiperazine with 2-methylpiperazine, the title compound is prepared.
Example 91
8-(3- Amino- 1 -pyrroUdinyl )-9-chloro- 1-cyclopropyl- 7-fluoro-4H-quinolizin-4-one-3-carboxylic acid hydrochloride
Following the procedures described in Example 62, replacing 4-chloropicoUne with 3,4-dichloro-5-fluoropicoUne (the product of Example 67) and replacing ethyl iodide with cyclopropyl iodide, the title compound is prepared. Example 92
9-Bromo- 1 -cyclopropyl-7-fluoro-8-(4-methylpiperazin- l-yl)-4H-quinolizin-4-one-3-carboxylic acid hydrochloride
FoUowing the procedures described in Steps 1 and 2 of Example 62, replacing 4- chloropicoline with 3-bromo-4-chloro-5-fluoropicoUne (the product of Example 68) and replacing ethyl iodide with cyclopropyl iodide, and the procedures described in Example 65, the title compound is prepared.
Example 93
9-Bromo-l-cyclopropyl-7-fluoro-8-(3-methyl-l- piperazinyl1-4H-quinolizin-4-one-3-carboxyUc acid hydrochloride
FoUowing the procedures described in Steps 1 and 2 of Example 62, replacing 4- chloropicoline with 3-bromo-4-chloro-5-fluoropicoUne (the product of Example 68) and replacing ethyl iodide with cyclopropyl iodide, and the procedures described in Example 65, replacing N-methylpiperazine with 2-methylpiperazine, the title compound is prepared.
Example 94 8-(3-Aιr-ino-l-pyπoUdinyl)-9-bromo-l-cyclopropyl-
7-fluoro-4H-quinoUzin-4-one-3-carboxylic acid hydrochloride
FoUowing the procedures described in Example 62, replacing 4-chloropicoUne with 3-bromo-4-chloro-5-fluoropicotine (the product of Example 68) and replacing ethyl iodide with cyclopropyl iodide, the title compound is prepared.
Example 95
1 -Cyclopropyl -7 ,9-difluoro-8-(4-methylpiperazin- 1 -yl) -4H-quinolizin-4-one-3-carboxyIic acid hydrochloride
FoUowing the procedures described in Steps 1 and 2 of Example 62, replacing 4- chloropicoUne with 4-chloro-3,5-difluoropicoUne (the product of Example 69) and replacing ethyl iodide with cyclopropyl iodide, and the procedures described in Example 65, the title compound is prepared. Example 96
1 -Cyclopropyl-7,9-difluoro-8-(3-methyl- 1 -piperazinyl)- 4H-quinoUzin-4-one-3-carboxyUc acid hydrochloride
FoUowing the procedures described in Steps 1 and 2 of Example 62, replacing 4- chloropicoUne with 4-chloro-3,5-difluoropicoUne (the product of Example 69) and replacing ethyl iodide with cyclopropyl iodide, and the procedures described in Example 65, replacing N-methylpiperazine with 2-methylpiperazine, the titie compound is prepared.
Example 97
8-(3-Amino- 1 -pyrrolidinyl)- l-cyclopropyl-7,9-difluoro- 4H-quinolizin-4-one-3-carboxylic acid hydrochloride
Following the procedures described in Example 62, replacing 4-chloropicoUne with 4-chloro-3,5-difluoropicoUne (the product of Example 69) and replacing ethyl iodide with cyclopropyl iodide, the title compound is prepared.
Example 98
7-Fluoro- 1 -methylamino-8-(4-methylpiperazin- 1 -yl)- 4H-quinolizin-4-one-3-carboxylic acid hydrochloride
Step 1. 4-Chloro-5-fluoro-alpha-bromo-2-picohne
4-Chloro-5-fluoro-2-picoline (2.9 g, 20 mmol), the product of Example 66, was dissolved in 50 mL of 1 ,2-dichloroethane in a dry flask. The resultant solution was heated, with stirring, to 75°C and 4.09 (23 mmol) of N-bromosuccinimide was added, followed by 100 mG (0.7 mmol) of 2,2-azobisisobutyronitrUe (AIBN), a free radical initiator. After the reaction mixture was stirred at 75°C for 24 hours, it was dUuted with 450 mL of methylene chloride and washed with 3 X 400 mL of water. The organic layer was separated and dried over anhydrous sodium sulfate, fUtered and concentrated under reduced pressure. The residue was dried in vacuo to give 3.5 g (69% yield) of the title compound as an amber oil; IH NMR (CDC13) d 4.50 (s, 2H), 7.54 (d, IH), 8.44 (s, IH).
Step 2. 4-Chloro-5-fluoro-2-(N-methylaminomethylVpyridine
4-Chloro-5-fluoro-alpha-bromo-2-picoline (1.37 g, 6.1 mmol), from Step 1 was dissolved in 15 mL of methanol in a pressure tube. Methylamine (3 mL of 40% aqueous solution) was added to the tube and the tube was sealed. The reaction mixture was stirred at ambient temperature for 26 hours and then the solvent was removed under reduced pressure. To the residue was added 50 mL of 10% aqueous sodium carbonate solution and the resultant aqueous mixture was extracted with 3 X 50 mL of methylene chloride. The organic combined extract was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressur. The residue was dried in vacuo to give 754 mg g (70% yield) of the title compound; MS DCI-NH3 M/Z: 175 (M+H)+ base; 1H NMR (CDCI3) d 2.50 (s, 3H), 3.90 (s, 2H), 7.47 (d, IH), 8.42 (s, IH).
Step 3. N-(4-chloro-5-fluoro-2-pyridyl)methyl-N- methyl-N-(2.2-dimethylethvI)-formamidine
4-Chloro-5-fluoro-2-(N-methylaminomethyl)-pyridine (650 mg, 3.72 mmol), from Step 2 was dissolved in 15 mL of toluene. To the resultant solution was added 2.3 mL (15 mmol) of N,N-dimethyl-N-(2,2-dimethylethyl)-formamide, followed by 40 mg (0.3 mmol) of ammonium sulfate. The reaction mixture was heated at reflux temperature, with stirring, for 28 hours and then allowed to cool to ambient temperature. The solvent was removed under reduced pressure and the residue dried in v acuo to give 560 mg (59% yield) of the title compound; MS DCI-NH3 M/Z: 175 (M+H)+ 73%, 203 ((M+H)-C1-F)+ base; *H NMR (CDCI3) d 1.17 (s, 3H), 1.19 (s, 9H), 2.83 (d, 2H), 4.47 (s, IH), 7.43
(d, IH, J=3 Hz), 8.40 (dd, IH), J=3 Hz, 1.5 Hz).
Step 4. Diethyl 2-ethoxy-3-(5-fluoropyridin-2-yl)-3-[N-methyl- N-C2".2"-dimethylethv methylaminol-propane- 1.1 -dicarboxylate
Lithium dUsopropylamide (LDA: 16 mL of a 1.5 M solution in hexane) is added to 8 mL of dry THF, under a nitrogen atmosphere, and the resultant solution is cooled to -70°C in a isopropyl alcohol/dry ice bath. To the cooled solution of LDA, is added dropwise, over a 30 minute period, a solution of 3.41 g (19.6 mmol) of N-(4-chloro-5- fluoro-2-pyridyl)methyl-N-methyl-N-(2,2-dimethylethyl)-formamidine, from Step 3, in 25 mL of dry THF. After stirring the solution for 0.5 hours at -70°C, a solution of 4.04 mL (19.6 mmol) of ethoxymethylenemalonate in 18 mL of dry THF is added dropwise over a 30 minute period. The reaction solution turns from dark red to orange. After stirring for 0.5 hours at -70°C, the reaction solution is aUowed to warm to -20°C and is stirred at -20°C for 1 hour. The reaction is quenched at -20°C by the addition of 1.3 mL of glacial acetic acid and the cooUng bath is removed. After 20 minutes the reaction solution is poured into 5% aqueous sodium bicarbonate solution. The aqueous mixture is extracted with methylene chloride and the organic extract is dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue is purified by chromatography on a sUica gel column to afford the title compound.
Step 5. Diethyl 2-ethoxy-3-(5-fluoropyridin-2-yl)-3- methylamino-propane- 1.1 -dicarboxylate
A solution of 2 mmol (0.8 g) of diethyl 2-ethoxy-3-(5-fluoropyridin-2-yl)-3-[N- methyl-N-(2",2"-dimethylethyl)methylamino]-propane-l,l-dicarboxylate, from Step 4, 16 mmol of hydrazine and 6 mml of glacial acetic acid in 20 mL of 95% ethyl alcohol is heated at 50°C under nitrogen for approximately 15 hours. Upon coohng, the solvent is removed in vacuo and the residue extracted with diethyl ether. The ether solution is washed with saturated aqueous sodium bicarbonate solution, dried over anhydrous sodium sulfate, and concentrated in vacuo to afford the title compound.
Step 6. Ethyl 8-chloro-7-fluoro- 1 -methylamino-4H-quinolizin-4-one-3-carboxylate
80 mL of Dowtherm A® in a 3-neck flask equipped with a thermometer, an addition funnel and an air-cooled condenser is heated to 235°C, under nitrogen, using a heating mantel. A solution of 3.9 g (12.4 mmol) of diethyl 2-ethoxy-3-(5-fluoropyridin-2- yl)-3-methylamino-propane-l,l-dicarboxylate, from Step 5, in 45 mL of Dowtherm A® is added, dropwise over a 1.5 hours period, through the addition funnel to the heated stirring Dowtherm A®. After the addition is complete, the resultant solution is heated at ~200°C for 1 hour and then is cooled to ambient temperature. The solution is then poured into 500 mL of hexane and a precipitate forms. The precipitate is collected by filtration, washed with 5 X 100 mL of hexane and dried to afford the titie compound.
Step 7. Ethyl 7-fluoro-l-methylamino-8-(4-methylpiperazin- l-yl)-4H-quinolizin-4-one-3-carboxylate
Ethyl 8-chloro-7-fluoro- 1 -methylamino-4H-quinoUzin-4-one-3-carboxylate (899 mg, 3.0 mmol), the product of Step 6, is suspended in 12 mL of dry pyridine under a nitrogen atmosphere. To the resultant solution is added 6.0 mL (6.0 mmol) of N- methylpiperazine and the reaction mixture is heated at 70°C for 8 hours. The reaction mixture is then concentrated in vacuo in order to remove aU of the pyridine. The dry residue is dissolved in 125 mL of methylene chloride and the methylene chloride solution is washed with 125 mL of brine. The aqueous layer is extracted with 125 mL of methylene chloride and the combined methylene chloride solutions are dried over anhydrous sodium sulfate, filtered and concentrated and dried in vacuo to afford the title compound. Step 8. 8-(4-methylpiperazin-l-yl)-4H-quinolizin- 4-one-3-carboxyhc acid hydrochloride
A mixture of 1 g (2.75 mmol) of ethyl 7-fluoro-l-methylamino-8-(4- methylpiperazin-l-yl)-4H-quinoUzin-4-one-3-carboxylate, from Step 7, in 12 mL of THF and 16.5 mL of a 0.5 N aqueous solution of sodium hydroxide is heated, with stirring, at 75°C for 8 hours. The THF is removed from the reaction mixture by distiUation during the reaction. The concentrated reaction mixture is cooled to ambient temperature and adjusted to pH 2.0 with 10.5 mL of 1 N aqueous hydrochloric acid solution. The aqueous solution is concentrated in vacuo to remove -80% of the water and the concentrate is diluted with 50 mL of 95% ethyl alcohol. The solid is coUected by filtration, washed with 2 X 5 mL of ethyl alcohol and dried in vacuo to afford the desired product.
Examples 99-116
By foUowing the procedures described in Example 98 and replacing N- methylpiperazine in Step 7 with the appropriate amine as shown, Examples 99-116 are prepared as disclosed in Table 3 wherein the compounds have the general formula
Table 3
Example No. F Example No. β'
* The amines are protected and deprotected as described in Example 58 Example 117
7,9-Difluoro- 1 -methylamino-8-(4-methylpiperazin- 1-yl)- 4H-quinoUzin-4-one-3-carboxyUc acid hydrochloride
By foUowing the procedures described in Example 98 and replacing 4-chloro-5- fluoro-2-picoUne (the product of Example 66) with 4-chloro-3,5-difluoro-2-picoline (the product of Example 69), the titie compound is prepared.
Examples 118-135
By following the procedures described in Example 98, replacing 4-chloro-5- fluoro-2-picoUne (the product of Example 66) with 4-chloro-3,5-difluoro-2-picoline (the product of Example 69) and replacing N-methylpiperazine with the appropriate amine as shown, Examples 118-135 are prepared as disclosed in Table 4 wherein the compounds have the general formula
Table 4
Example No. β2
The amines are protected and deprotected as described in Example 58
- in Example 136
1 -Ethyl-8-(4-methylpiperazin- 1 -yl)-6,7,9-trifluoro- 4H-quinoUzin-4-one-3-carboxyUc acid hydrochloride
Step 1. 3.4.5.6-Tertrafluoro-2-picoline
2,3,4,5,6-Pentafluoropyridine (commerciaUy avaUable from Aldich Chemical Co.) is oxidized to the corresponding N-oxide foUowing the procedures described in Step 6 of Example 66. The 2,3,4,5,6-pentafluoropyridine N-oxide is treated at ambient temperature with one equivalent of methylmagnesium iodide in diethyl ether as described by F. Binns and H. Suschitsky in Chemical Communications. 750-751 (1970) and J Chem Soc (C). 1223-1231 (1771). The reaction mixture is treated with aqueous ammonium chloride and extracted with diethyl ether. The ether solution is dried over anhydrous magnesium sulfate, filtered and concentated under reduced pressure and the crude product is chromatographed on sUica gel to afford 2-methyl-3,4,5,6-tetrafluoropyridine N-oxide (3,4,5,6-tetrafluoro-2-picoline). The N-oxide is then reduced to afford the title compound by the procedures described in Step 8 of Example 66.
Step 2. 2-Pτopyl-3.4.5.6-tetrafluoropyridine
A 1.5 M solution of LDA in hexane (100 mL, 150 mmol) is cooled to -60°C in an isopropyl alcohol/dry ice bath. To the stirred LDA solution, under nitrogen, is added, dropwise over a 0.5 hours period, a solution of 22.617 g (137 mmol) of 3,4,5,6- tetrafluoro-2-picoline, the product of Step 1, in 80 mL of dry THF. The reaction mixture is stirred for 0.5 hours at -60°C and then a solution of 10.95 mL (137 mmol) of ethyl iodide in 30 mL of dry THF is added, dropwise over a 20 minute period. After the reaction mixture is stirred at -60°C for 0.5 hours, the cooling bath is allowed to slowly (1.5 hours) warm to -30°C. The reaction mixture is poured into cold brine and the aqueous mixture is extracted with methylene chloride. The organic extract is dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue is distilled to afford the titie compound.
Step 3. Diethyl 2-ethoxy-3-[3,4,5,6-tetrafluoro- 2-pyridyll-pentane- 1.1 -dicarboxylate
A solution of 12.6 mL (89.9 mmol) of diisopropylamine in 20 mL of anhydrous tetrahydrofuran (THF) is prepared under a nitrogen atmosphere and cooled in an ice/water bath. To this solution is added, dropwise over a 30 minute period, 36 mL of a 2.5 M solution of n-butyUithium (90 mmol) in hexane. The solution is stirred for 30 minutes at 0°C and then cooled to -60°C. To the amine solution at -60°C, is added, dropwise over a 30 minute period, a solution of 15.82 g (81.9 mmol) of 2-propyl-3,4,5,6- tetrafluoropyridine, from Step 2, in 100 mL of anhydrous THF. The resultant solution is stirred at -60°C for 0.5 hours and then 16.55 mL (81.9 mmol) of ethyl 2-carboethoxy-3- ethoxy-2-propenecarboxylate is added, dropwise over a 30 minute period. Stirring is continued at -60°C for 0.5 hours and at -20°C for 1.5 hours. The reaction mixture is poured into cold brine and the aqueous mixture is extracted with methylene chloride. The combined organic extract is dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to afford 35.48 g of the title compound. The product is carried on to the next step without purification.
Step 4. Ethyl l-ethyl-6.7.8.9-tetrafluoro-4-H-quinolizin-4-one-3-carboxylate
A solution of 40.61 g (99.2 mmol) of diethyl 2-ethoxy-3-[4-chloro-2-pyridyl]- pentane- 1,1-dicarboxylate, from Step 3, in 1 L of xylene is heated at 150°C, with stirring, for 24 hours and then concentrated in vacuo. The residue is washed with a mixture of hexane and cyclohexane to afford the title compound.
Step 5: Ethyl l-ethyl-8-(4-methylpiperazin-l-yl)-6,7,9- trifluoro-4H-quinolizin-4-one-3-carboxylate
Ethyl 8-chloro- 1 -ethyl-6,7,8,9-tetrafluoro-4H-quinolizin-4-one-3-carboxylate (317 mg, 1.0 mmol), from Step 4, is dissolved in 5 mL of dry pyridine under a nitrogen atmosphere. To the resultant solution is added 2 mL (2.0 mmol) of N-methylpiperazine and the stirred reaction mixture is heated at 85°C for 2.5 hours. The reaction mixture is aUowed to cool to ambient temperature and then concentrated in vacuo in order to remove aU of the pyridine. The residue is dissolved in 50 mL of methylene chloride and the methylene chloride solution is washed with 50 mL of 5% aqueous sodium bicarbonate solution. The aqueous layer is extracted with 3 X 50 mL of methylene chloride and the combined methylene chloride solutions are dried over anhydrous sodium sulfate, filtered and concentrated and dried in vacuo to afford the titie compound. Step 6. l-Ethyl-8-(4-methylpiperazin-l-yl)-6,7,9-trifluoro- 4H-quinoUzin-4-oήe-3-carboxyUc acid hydrochloride
To a solution of 199 mg (0.5 mmol) of ethyl l-ethyl-8-(4-methylpiperazin-l-yl)- 6,7,9-trifluoro-4H-quinoUzin-4-one-3-carboxylate, from Step 5, in 4 mL of THF is added 4.0 mL of a 1.0 N aqueous sodium hydroxide solution and the reaction mixture is heated, with stirring, at 75°C for 4.5 hours. The reaction mixture is cooled to ambient temperature and adjusted to pH 2 with 5 mL of 1 N aqueous hydrochloric acid solution. The aqueous solution is concentrated in vacuo to -5 mL and the solid is coUected by filtration and dried in vacuo to afford the titie compound.
Example 137
8-(3- Amino- 1 - 1 -pyrroUdinyl)- 1 -ethyl-6,7,9-trifluoro- 4H-quinoUzin-4-one-3-carboxylic acid hydrochloride
Step 1. Ethyl 8-(3-(N-t-butoxycarbonyl)amino-l-pyrroUdinyl)- ; l-ethyl-6.7.9-trifluoro-4H-quinolizin-4-one-3-carboxylate
Ethyl 6,7,8,9-tetrafluoro-l-ethyl-4H-quinolizin-4-one-3-carboxylate (1.26 g, 3.97 mmol), from Step 3 of Example 136, is dissolved in 20 mL of dry pyridine under a nitrogen atmosphere. To the resultant solution is added a solution of 1.85 g (9.92 mmol) of 3-(N-t-butoxycarbonylamino)pyrroUdine in 5 mL of dry pyridine and the reaction mixture is heated at 70°C for 4.5 hours. The reaction mixture is then concentrated in vacuo in order to remove all of the pyridine. The dry residue (3.124 g) is purified by chromatography on siUca gel to afford the title compound.
Step 2. 8-(3- Amino- 1 -pyrroUdinyl)- l-ethyl-6,7,9-trifluoro- 4H-quinoUzin-4-one-3-carboxylic acid hydrochloride
A solution of 1.11 g (2.2 mmol) of ethyl 8-(3-(N-t-butoxycarbonyl)amino-l- pyrrolidinyl)-l-ethyl-6,7,9-trifluoro-4H-quinoUzin-4-one-3-carboxylate, from Step 1, in 20 mL of trifluoroacetic acid (TFA) is stirred for 2 hours at ambient temperature. The TFA is evaporated in vacuo and the residue is dissolved in 200 mL of methanol. To the resultant solution is added 4.5 g of strongly basic ion exchange resin and the mixture is stirred at ambient temperature for 1 hour. The mixture is fUtered and the filtrate is concentrated under reduced pressure to afford crude ethyl 8-(3-amino-l-pyπolidinyl)-l-ethyl-6,7,9- trifluoro-4H-quinolizin-4-one-3-carboxylate as a residue. The residue is dissolved in 5 mL of THF and 11 mL of a 1 M aqueous solution of sodium hydroxide is added. The reaction mixture is heated at 60°C for 1 hour and then the reaction temperature is increased to 85°C in order to evaporate the THF. The concentrated reaction solution is diluted with 20 mL of water and the pH of the resultant solution is adjusted to 0 with concentrated hydrochloric acid. The aqueous solution is concentrated in vacuo. The residue is crystalUzed from ethyl alcoholasopropyl alcohobwater (4:4: 1 v/v/v) and recrystallized from ethyl alcohol/water to afford the title compound.
Example 138 l-Ethyl-8-f3-('N-norvalyl')amino-pyrroUdinylV4H-quinoUzin-4-one-3-carboxylic acid
3-Amino-l-benzylpyrrolidine (I. Sumio and T. Matsuo, Japanese Kokai JP
5328161, published March 16, 1978) is coupled to N-t-butoxycarbonyl norvaline (Boc- nVal) using conventional N-hydroxysuccinimide coupling procedures. The 1 -benzyl group is removed by hydrogenolysis in methanol using paUadium on carbon catalyst. The 3-(N- Boc-norvalyl)aminopyrroUdine is then reacted with ethyl 6,7,8,9-tetrafluoro-l-ethyl-4H- quinolizin-4-one-3-carboxylate, as described in Step 1 of Example 137, replacing 3-(N-t- butoxycarbonylamino)pyrroUdine with 3-(N-Boc-norvalyl)aminopyrroUdine, to give 1- ethyl-8-(3-(N-norvalyl)amino-pyrrolidinyl)-4H-quinoUzin-4-one-3-carboxylic acid with the nitrogen of the amino acid protected with a Boc group. The Boc protecting group is removed by standard hydrolysis using trifluoroacetic acid and dilute aqueous hydrochloric acid.
Using the procedure outlined in Example 138, or any of the other conventional condensation methods listed above, other amino acid derivatives of the compounds of this invention having an amino group can be prepared. Examples of amino acids which can be coupled, either alone or in combination with one and other, include naturaUy occurring amino acids such as glycine, alanine, leucine, isoleucine, methionine, phenylalanine, valine, and the like, as weU as synthetic amino acids such as cyclohexylalanine, cyclohexylglycine, aminopentanoic acid, and the like.
Examples 139-155
By foUowing the procedures described in Example 136 or Example 137 and replacing N-methylpiperazine or 3-(N-t-butoxycarbonylamino)pyrroUdine with the appropriate amine as shown, Examples 139-155 are prepared as disclosed in Table 5 in which the compounds have the general formula
Table 5
The amines are protected and deprotected as described in Example 58 Example 156
11,12-Dihydro-7-fluoro- 12-methyl-8-(4-methyl- 1 -piperazinyl)- 4H-pyranori.j1quin-oUzin-4-one-3-carboxylic acid
Step 1. 4-Chloro-3.5-difluoro-2-("l-f2-tetrahydropyranvI)oxy-2-propyl)pyridine
A solution of 12.8 g (150 mmol) of 2-chloro-l -propanol is dissolved in 200 mL of acetone. To the resultant solution are added 40 g of anhydrous ferric chloride and 30 g (200 mmol) of sodium iodide. The reaction mixture is stirred at room temperature for 24 hours and then filtered to remove sodium chloride. The solvent is evaporated to afford the corresponding 2-iodo-l -propanol. The iodo alcohol is dissolved in 200 mL of methylene chloride and is treated with 20.5 mL (225 mmol) of 3,4-dihydro-2H-pyran and 50 mg of p- toluenesulfonic acid. The reaction mixture is stirtred at room temperature for several hours and then poured into 200 mL of 5% aqueous sodium bicarbonate solution. The aqueous mixture is extracted with methylene chloride. The methylene chloride solution is dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford the THP-protected 2-iodo-l -propanol.
A solution of 4-chloro-3,5-difluoro-2-methylpyridine (16.5 g, 100 mmol) in 150 mL of dry THF under a positive nitrogen atmosphere is treated with 73 mL of 1.5 M. Uthium dusopropylamine (LDA) at -78°C. After stirring at -78°C for 30 minutes, a solution of 27.0 g (100 mmol) of the THP-protected l-iodo-2-propanol in 150 mL of THF is added dropwise with stirring. The reaction mixture is stirred at -78°C for several hours and then is slowly warmed to -20°C. The reaction is quenched by pouring the reaction mixture into 400 mL of saturated aqueous ammonium chloride solution. The aqueous layer is separated and extracted with methylene chloride. The combined organic layers are dried over anhydrous sodium sulfate, fUtered and concentrated under in vacuo to afford the title compound.
Step 2. 4-Chloro-3.5-difluoro-2-f 1 -hydroxy-2-propyl pyridine
The product of Step 1 is dissolved in 200 mL of 2: 1 THF:water and to this solution is added 6 mL of acetic acid. The reaction mixture is heated at 45 °C for approximately 5 hours. The THF is removed under reduced pressure and the aqueous reaction mixture is adjusted to a pH in the range of 8 to 9 with 10% sodium carbonate and is then extracted with methylene chloride. The organic layer is dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to afford the title compound. Step 3. 8-Chloro-3.4-dihvdro-7-fluoro-3-methyl-2H-pyranor3.2-blpyridine
The product of Step 2 (15.5 g, 75 mmol) is dissolved in 100 mL of dry THF in an oven-dried system under positive nitrogen atmosphere. The reaction mixture is cooled in ice and 3.2 g (80 mmol) of 60% sodium hydride is added. The reaction mixture is warmed to room temperature and then heated at reflux temperature overnight with stirring. The reaction mixturte is cooled to room temperature and poured into brine. The aqueous mixture is extracted with ethyl acetate. The organic layer is dried over anhydrous magnesium sulfate, fUtered and concentrated in vacuo to afford the titie compound.
Step 4. Diethyl 2-(8-chloro-3,4-dihydro-7-fluoro-3-methyl- 2H-pyranor3.2-blpyridin-4-yD-2-ethoxy- 1.1 -ethanedicarboxylate
FoUowing the procedure described in Step 2 of Example 62, the product of Step 3 is treated with ethyl 2-carboethoxy-3-ethoxy-2-propenecarboxylate and LDA to afford the title compound.
Step 5. Ethyl 8-chloro- 11,12-dihydro-7-fluoro- 12-methyl- 4H-pyranori.jlquin-olizin-4-one-3-carboxylate
FoUowing the procedures described in Step 3 of Example 62, the product of Step 4 is heated in refluxing Dowtherm A® to afford the desired cyclized product.
Step 6. Ethyl 11,12-dihydro-7-fluoro- 12-methyl-8- (4-methyl- l-piperazinylV4H-pyranori1jlqum-olizin-4-one-3-carboxylate
FoUowing the procedures described in Step 1 of Example 65, the product of Step 5 is reacted with N-methylpiperazine to afford the title compound.
Step 7. 1 l,12-Dihydro-7-fluoro- 12-methyl-8- (4-methyl- l-piperazinyπ-4H-pyranori.jlquin-olizin-4-one-3-carboxylic acid
FoUowing the procedures described in Step 2 of Example 65, the tUe compound is prepared. Example 157
2-(3-Aminopyιτolidin-l-yl)-9-cyclopropyl-3-fluoro-6H- 6-oxo-pyridori.2-alpyrimidine-7-carboxyUc acid hydrochloride salt
Step 1. 2-Cvclopropyl-2-ethoxycarbonylacetamidine hydrochloride
Into a stirred solution of 38.72 g (0.253 mol) of ethyl 2-cyano-2- cyclopropylacetate (preparation described by R.W.J. Carney and J. Wojtkunski, Org. Prep. Proced. Int., 5_, 25 (1973)) in 17.7 mL (0.303 mol) of anhydrous ethanol under a dry N2 atmosphere was introduced 10.0 g (0.274 mol) of gaseous hydrogen chloride with ice cooling. The mixture was allowed to warm to room temperature and stand for 72 hours. The reaction was diluted with 100 mL of anhydrous ethanol, 70 mL of ammonia in ethanol (4.17 M) was added slowly at room temperature and the reaction was stirred for 3 hours. The reaction mixture was filtered to remove the ammonium chloride, and the solvent was removed to afford the title compound as a viscous off-white oil, which was taken directly to the next step.
Step 2. 2-Cyclopropyl-2-(5-fluoro-4-hydroxypyrimidin-2-yl)acetic acid methyl ester and 2-cyclopropyl-2-(5-fluoro-4- hvdroxypyrimidin-2-yl)acetic acid ethyl ester
A mixture of 0.253 mol of the compound from Step 1 , 0.254 mol of the sodium salt of ethyl 2-fluoro-3-hydroxy-2-propenoate (prepared as described by E. Elkik and M. Imbeaux-Oudotte, Bull. Soc. Chim. Fr., 5-6 pt 2. 1165 (1975)) and 37.0 ml (0.265 mol) of triethylamine in 250 mL of anhydrous methanol was heated at reflux under a dry N2 atmosphere for 17 hours. The solvent was removed, 200 mL of water added and the residue acidified to pH 5 with acetic acid. This mixture was then extracted with methylene chloride. The extract was washed with water, dried over anhydrous magnesium sulfate, and the solvent was removed by evaporation under vacuum to give a dark brown oil. The product was purified by column chromatography on sUica gel eluting with 1 : 1 ethyl acetate: hexane to afford 22.8 g of the methyl ester title compound as a pale yeUow viscous oU and 6.45 g of the ethyl ester title compound as a pale yeUow viscous oil.
Methyl ester: MS M/Z: 227 (M+H). NMR (CDCI3): d 0.43 (IH, m), 0.52 (IH, m), 0.65 (IH, m), 0.77 (IH, m), 1.42 (IH, m), 2.97 (IH, d, J=10 Hz), 3.80 (3H, s), 7.88 (IH, d, J=3 Hz), 11.8 (IH, b). IR: (neat) 1740, 1690, 1615 cm"1. Analysis calculated for oHi iFN2θ3*l/4 H2O: C, 52.06; H, 5.02; N, 12.14. Found: C, 52.45; H, 4.94; N, 11.76. Ethyl ester: MS M/Z: 258 (M+NH4). NMR (CDCI3): d 0.47 (IH, m), 0.54 (IH, m), 0.66 (IH, m), 0.74 (IH, m), 1.31 (3H, t, J=7 Hz), 1.34 (IH, m), 2.96 (IH, d, J=10 Hz), 4.27 (2H, m), 7.83 (IH, d, J=3 Hz), 11.0 (IH, b): IR: (neat) 1735, 1682, 1605 cm"1. Analysis calculated for Cl ιHl3FN2θ3»0.3 H2O: C, 53.78 H, 5.58; N, 11.40. Found: C, 54.05; H, 5.59; N, 1 1.11.
Step 3. 2-Cyclopropyl-2-(5-fluoro-4-hvdroxypyrimidin-2-yl)acetaldehvde
To a solution of 4.960 g (21.9 mmol) of the methyl ester compound from Step 2 in 40 mL of toluene stirred at -70°C under a dry N2 atmosphere was added 46.0 mL of IN dusobutylaluminum hydride in toluene (46 mmol). The reaction was stirred for 40 min and then quenched by the addition of 5 mL of acetic acid. The mixture was aUowed to warm to room temperature, and the reaction was extracted with ethyl acetate. The extract was washed with water (3x), dried over anhydrous magnesium sulfate and concentrated under vacuum to afford 2.230 g of the title compound as a white soUd. This compound was used directly in the next step.
MS M/Z: 214 (M+NH4). NMR:(CDCl3) d 0.48 (m, 2H), 0.91 (m, 2H), 1.35 (m, 1H0, 7.40 (d, IH, J=10 Hz), 7.75 (d, IH, J=4 Hz), 9.61 (br s, IH), 13.64 (d, IH, J=10 Hz). IR (KBr) 1695, 1660, 1635 cm" 1.
Step 4. 9-Cyclopropyl-3-fluoro-2-hydroxy-6H-6-oxo- pyridoπ.2-alpyrimidine-7-carboxylic acid benzyl ester
A 2.230 g (11.37 mmol) sample of the compound from Step 3 was dissolved in 100 mL of anhydrous ethanol. To this was added 3.5 mL (14.00 mmol) of dibenzyl malonate, 2.5 mL of piperidine and 0.25 mL of acetic acid. This reaction mixture under a dry N2 atmosphere was heated under reflux conditions for 3 hours and stirred at room temperature overnight. The solvent was removed by evaporation, the residue was dissolved in methylene chloride which was washed with water and dried over anhydrous magnesium sulfate. The solvent was removed by evaporation under vacuum to give a yeUow oU, which was purified by column chromatography on siUca gel, eluting with 1 :5: 100 acetic acid:methanol:methylene chloride. Removal of the solvent afforded 1.800 g of the title compound as a pale yellow soUd, mp 225.5-226.5°C. MS M/Z 355 (M+H). NMR:(CDCl3) d 0.64 (m, 2H), 1.08 (m, 2H), 1.62 (m, IH), 5.37 (s, 2H), 7.35-7.48 (m, 5H), 8.28 (s, IH), 9.00 (d, IH, J=6 Hz). IR (KBr) 1720, 1700, 1690 cm"1. Analysis calculated for C19H15FN2O.W/4 H2O: C, 63.60; H, 4.35; N, 7.81. Found: C, 63.54; H, 4.08; N, 7.78. Step 5. 2-Chloro-9-cyclopropyl-3-fluoro-6H-6-oxo- pyridori.2-alpyrimidine-7-carboxylic acid benzyl ester
A mixture of 0.200 g (0.564 mmol) of the compound from Step 4, 0.50 mL of DMF, 0.60 mL of phosphorous oxychloride and 10 mL of methylene chloride was stirred under a dry N2 atmosphere at room temperature for 4 hours. Ice was added to react with the excess phosphorous oxychloride. The mixture was extracted with methylene chloride, which was washed with water, then the solvent was dried over anhydrous magnesium sulfate and the solvent was removed by evaporation under vacuum to yield the titie compound as an orange residue. This compound was taken directly to the next step.
Step 6. 2-(3-(N-t-butoxycarbonyl)aminopyrrolidin- l-yl)-9-cyclopropyl-3- fluoro-6H-6-oxo-pyridorL2-alpyrimidine-7-carboxyUc acid benzyl ester
The 0.564 mmol sample of the compound from the previous step was dissolved in 5 mL of dry methylene chloride and cooled to 0°C. To this solution was added 0.45 g of 3-(N-t-butoxycarbonyl)aminopyrroUdine, and the reaction mixture was stirred at room temperature overnight The solvent was removed by evaporation under vacuum, and the product was purified by column chromatography on siUca gel, eluting with 10% methanol in methylene chloride to afford 0.295 g of the titie compound as a yellow soUd, mp 159- 160°C. MS M/Z 523 (M+H). NMR:(CDCl3) d 0.60 (m, 2H), 0.87 (m, 2H), 1.46 (s, 9H), 1.90-2.40 (m, 2H), 3.70-4.45 (m, 5H), 4.94 (br s, IH), 5.37 (s, 2H), 7.29 (m, IH), 7.37 (m, 2H), 7.50 (m, 2H), 7.99 (br s, IH), 9.10 (d IH, J=10 Hz). IR (KBr) 1715, 1685, 1660 cm'1. Analysis calculated for C28H31FN4O5* 1/2 H2O: C, 63.44; H, 6.08; N, 10.57. Found: C, 63.39; H, 6.13; N, 10.83.
Step 7. 2-(3-(N-t-butoxycarbonyl)aminopyrroUdin-l-yl)-9-cyclopropyl- 3-fluoro-6H-6-oxo-pyridor 1.2-alpyrimidine-7-carboxylic acid
To a 0.135 g (0.259 mmol) sample of the benzyl ester from Step 6 in 20 mL of methanol and 2 mL of THF was added 2.0 mL of 98% formic acid and 0.05 g of 10% Pd/C. This mixture was stirred under a dry N2 atmosphere at room temperature for 37 min. The catalyst was removed by filtration, and the solvent was removed under vacuum. The crude product was purified by column chromatography on siUca gel, eluting with 1:5:100 acetic acid:methanol:methylene chloride to afford the titie compound as a yeUow soUd after removal of the solvent. This product was taken directly to the next step. Step 8. 2-(3-AminopyπOUdin-l-yl)-9-cyclopropyl-3-fluoro- 6H-6-oxo-pyridori.2-a1pyrimidine-7-carboxyUc acid hydrochloride salt
The sample of the compound from the previous step was reacted with 10 mL of 4N HCI in dioxane under a dry N2 atmosphere at room temperature 3 hours. The solvent was removed, the yeUow solid was dissolved in distilled water. The yellow solution was filtered and freeze-dried to afford 0.0681 g of the title compound as a yellow soUd, mp 234°C, (dec). MS M/Z 333 (M-Cl). NMR: (CDCI3) d 0.64 (m, 2H), 0.96 (m, 2H), 2.20-2.65 (m, 3H), 3.58-4.35 (m, 5H), 7.80 (d, IH, J=10 Hz), 9.05 (br s, IH), IR (KBr) 1665, 1620 cm-1.
Example 158
2-(3-Aminopyrrolidin- 1 -yl)-9-cyclopropyl-3-fluoro- 6H-6-oxo-pyridori .2-alpyrimidine-7-carboxylic acid
Step 1. 9-Cyclopropyl-3-fluoro-2-hydroxy-6H-6- oxo-pyridori.2-alpyrimidine-7-carboxyUc acid t-butyl ester
A 0.247 g (1.262 mmol) sample of 2-cyclopropyl-2-(5-fluoro-4- hydroxypyrimidin-2-yl)acetaldehyde, from Example 157 Step 3 above, was dissolved in 20 mL of ethanol, and 0.290 mL of ethyl t-butyl malonate, 0.5 mL of piperidine and 0.05 mL of acetic acid were added. The reaction was heated under a dry N2 atmosphere at reflux for 25 hours, the solvents were removed by evaporation and the product was purified by column chromatography on siUca gel, eluting with 1:10:100 acetic acid:methanol:methylene chloride. Removal of the solvent afforded 0.287 g of the title compound as a pale yeUow soUd, mp >265°C. MS M/Z 321 (M+H). NMR: (CDCI3 + CD3OD) d 0.61 (m, 2H), 1.06 (m, 2H), 1.58 (s, 9H), 1.72 (m, IH), 8.07 (s, IH), 8.93 (d, IH, J=6 Hz). IR (KBr)1720, 1525 cm-1.
Step 2. 2-Chloro-9-cyclopropyl-3-fluoro-6H-6- oxo-pyridoπ.2-alpyπmidine-7-carboxylic acid t-butyl ester
A mixture of 0.100 g (0.312 mmol) of the compound from Step 1, 0.29 mL of
DMF, 0.33 mL of phosphorous oxychloride and 10 mL of methylene chloride was stirred under a dry N2 atmosphere at room temperature for 1 hour. After workup as described in Example 157 Step 5, the title compound was obtained as a orange solution in methylene chloride. This compound was taken directly to the next step. Step 3. 2-(3-(N-t-butoxycarbonyl)aminopyrroUdin-l-yl)-9-cyclopropyl- 3-fluoro-6H-6-oxo-pyridoπ.2-alpyrimidine-7-carboxylic acid t-butyl ester
To the 0.312 mmol sample in methylene chloride from the previous step at room temperature was added several smaU portions of 3-(N-t-butoxycarbonyl)aminopyrroUdine untU the color of the reaction turned from orange to light yellow. The solution was concentrated to leave a yellow residue. The product was purified by column chromatography on siUca gel, eluting with 10:100 methanol: methylene chloride to afford 0.132g of the title compound as a yellow soUd after removal of the solvent. This compound was taken directly to the next step.
Step 4. 2-(3-aminopyrrolidin-l-yl)-9-cyclopropyl-3-fluoro-6H-6- oxo-pyridor 1.2-alpyrimidine-7-carboxylic acid
The boc-protected t-butyl ester from Step 4 was hydrolyzed by reacting the 0.132 g sample with 1 mL of 4N HCI in dioxane under a dry N2 atmosphere . The solvent was removed, the yellow solid was dissolved in water and the solution adjusted to pH 7-8, and extracted with methylene chloride. The reaction was incomplete at this point, so the soUd was redissolved in 5 mL of trifluoroacetic acid and the reaction stirred at room temperature overnight. The solvent was removed by evaporation. The residue was redissolved and extracted as above, then the product was purified by column chromatography on sUica gel, eluting with 2:5:20:100 wateπacetic acid:methanol:methylene chloride to afford 0.0515 g of the title compound as a yeUow soUd.
Example 159
9-(2,4-Difluorophenyl)-3-fluoro-2-(4-methylpiperazin- 1 -yl)- 6H-6-oxopyridoπ .2-alpyrimidine-7-carboxylic acid
Step 1. 2-(2.4-Difluorophenyl)-acetamidine hydrochloride
Into a solution of 49.44 g (0.323 mol) of 2,4-difluorophenylacetonitrile (commercially avaUable) in 20.8 mL (0.354 mol) of ethanol cooled to 0°C in an ice bath and stirred under a dry N2 atmosphere was added 14.61 g (0.400 mol) of gaseous HCI. After 20 min the reaction mixture solidified, this was then aUowed to warm to room temperature and held at this temperature for 72 hours. To the mixture was then added 140 mL of ethanol, followed by 150 mL (0.42 mol) of 4.2 M ammonia in ethanol. This mixture was stirred for an additional 3 hours at room temperature and filtered. The solvent was removed from the filtrate by evaporation to afford 65.7 g of the title compound as a white solid, mp 163-164°C. NMR: (DMSO-d6) d 3.72 (s, 2H), 7.16 (m, IH), 7.33 (m, IH), 7.50 (m, IH), 8.95 (broad, 4H). This compound was taken directly to the next step.
Step 2. 2-(2.4-Difluorobenzyl)-5-fluoro-4-hydroxypyrimidine
A mixture of 68.0 g ( 0.33 mol) of the compound from Step 1, 0.34 mol of the sodium salt of ethyl 2-fluoro-3-hydroxy-2-propenoate (prepared as described by E. Elkik and M. Imbeaux-Oudotte, Bull. Soc. Chim. Fr., 5-6 pt 2. 1165 (1975)), 300 mL of anhydrous methanol and 50 mL of triethylamine was heated at reflux under a dry N2 atmosphere for 23 hours. The solvent was removed by evaporation under vacuum, 200 mL of water added and the mixture acidified to pH 3-4 with 10% HCI. This mixture was then extracted with methylene chloride. The solvent was washed with water, dried over anhydrous magnesium sulfate, and the solvent was removed by evaporation under vacuum to give a dark oil which solidified upon standing. The solid was washed with ethyl acetate, ethyl acetate/hexane and hexane to afford 29.8 g of the titie compound as a white solid, mp 155-156°C. A second crop of 10.2 g of product was obtained from the filtrates after chromatography on siUca gel, eluting with 2.5% methanol in methylene chloride. MS M/Z: 258 (M=NH4), 241 (M+H). NMR: (CDCI3) d 4.02 (s, 2H), 6.88 (m, 2H), 7.33 (m, IH), 7.89 (d, IH, J=3 Hz). IR (KBr): 1690, 1605 cm -1. Analysis calculated for C11H7F3N2O: C, 55.00; H, 2.94; N, 11.67. Found: C, 54.63; H, 2.98; N, 11.50.
Step 3. 4-Chloro-2-(2.4-difluorobenzyl)-5-fluoropyrimidine
A mixture of 1.000 g (4.16 mmol) of the compound from Step 2, 3.40 mL (43.7 mmol) of DMF and 3.90 mL (43.7 mmol) of phosphorous oxychloride in 15 mL of methylene chloride was stirred under a dry N2 atmosphere at ambient temperature for 2 hours, then quenched with water and ice. The mixture was then extracted with methylene chloride, which was washed with water, dried, filtered and concentrated to yield the title compound as a yellow oil. MS M/Z: 259 (M+H). NMR: (CDCI3) d 4.27 (s, 2H), 6.83 (m, 2H), 7.27 (m, IH), 8.48 (s, IH). This compound was taken directly to the next step.
Step 4. 2-(2.4-Difluorobenzyl)-5-fluoro-4-(4-methylpiperazin-l-yl pyrimidine
To the 4.16 mmol of the compound from Step 3 in 10 mL of methylene chloride was added 3 mL of N-methylpiperidine and the mixture was stirred under a dry N2 atmosphere at room temperature for 1 hour. The solvent was removed by evaporation, and the product was purified by column chromatography on siUca gel eluting with 5% methanol in methylene chloride. The solvent was removed by evaporation to afford 1.229 g of the title compound as a pale yeUow oil, MS M/Z: 323 (M+H). NMR: (CDCI3) d 2.32 (s, 3H), 2.46 (t, 4H, J+7 Hz), 3.75 (t, 4H, J=7 Hz), 4.05 (s, 2H), 6.80 (m, 2H), 7.25 (m, IH), 7.99 (d, IH, J=7 Hz). Analysis calculated for C16H17F3N4: C, 59.61; H, 5.32; N, 17.38. Found: C, 59.63; H, 5.31; N, 17.31.
Step 5. 3-(2,4-Difluorophenyl)-2-ethoxy-3-(5-fluoro-4-(4-methylpiperidin- l-yDpyrimidin-2-yDpropane-l.l-dicarboxyUc acid diethyl ester
FoUowing the procedure of Step 4 Example 1 the compound from Step 4 above (0.74 g, 2.3 mmol), 1.0 mL (2.5 mmol) of a 2.5 M solution of n-butyllithium in hexane and 0.35 mL of diisopropylamine was reacted with 0.46 mL ethyl 2-carboethoxy-3-ethoxy- 2-propenecarboxylate, to afford after work-up 1.22 g of the title compound as an oil. This material was further purified by column chromatography over sUica gel, eluting with 5% ethanol in ethyl acetate to give 0.774 g of an oil; MS M/Z: 539 (M+H). NMR: (CDCI3) d 0.87 (m, 3H), 1.22 (m, 6H), 2.34 (s, 3H), 2.50 (m, 4H), 3.52 (m, 2H), 3.81 (m, 4H), 4.16 (m, 5H), 4.82 (m, IH), 4.99 (m, IH), 6.78 (m, 2H), 7.59 (m, IH), 8.01 (m, IH).
Step 6. 9-(2,4-Difluorophenyl)-3-fluoro-2-(4-methylpiperazin-l-yl)- 6H-6-oxopyridori.2-alpyrimidine-7-carboxylic acid ethyl ester
To a 1.847 g (3.43 mmol) sample of the compound from Step 5 dissolved in 40 mL of anhydrous ethanol was added 1.5 mL of piperidine and 0.05 mL of acetic acid, and the reaction was heated at reflux conditions under a dry N2 atmosphere for 3 hours. The solvent was removed by evaporation to leave a yeUow soUd which was purified by column chromatography over siUca gel, eluting with 0.5:10:100 28% aq. NH4θH:methanol:methylene chloride to afford after removal of the solvent 1.282 g of the title compound as a yeUow solid, mp 193-195°C. MS M/Z: 447 (M+H). NMR: (CDCI3) d 1.40 (t, 3H, J=7 Hz), 2.33 (s, 3H), 2.50 (m, 4H), 3.89 (m, 4H), 4.39 (q, 2H, J=7 Hz), 6.91 (m, 2H), 7.33 (m, IH), 8.37 (s, IH), 9.16 (d, IH, J=10 Hz). IR (KBr): 1725, 1685, 1660 cm"1. Analysis calculated for C22H2lF3N4θ3»0.5 H2O: C, 58.02; H, 4.87; N, 12.30. Found: C, 58.15; H, 4.70; N, 12.15.
Step 7. 9-(2,4-Difluorophenyl)-3-fluoro-2-(4-methylpiperazin-l-yl)- 6H-6-oxopyridoπ.2-alpyrimidine-7-carboxylic acid benzyl ester
A mixture of a 1.166 g (2.61 mmol) sample of the ethyl ester compound from Step 1 , 150 mL of dry benzyl alcohol and 0.5 mL of titanium tetramethoxide was heated under a dry N2 atmosphere with stirring at reflux conditions for 17 hours. The solvent was removed by distillation at 100°C under reduced pressure in a kugelrohr apparatus. The product was purified by column chromatography on sUica gel, eluting with 0.5:10:100 28% aq. NH4θH:methanol:methylene chloride to afford after removal of the solvent 0.895 g of the titie compound as a yellow soUd, mp 207-208 °C. MS M/Z: 509 (M+H). NMR: (CDCI3) d 2.33 (s, 3H), 2.50 (m, 4H), 3.88 (m, 4H), 5.38 (s, 2H), 6.90 (m, 2H), 7.30- 7.50 (m, 6H), 8.37 (s, IH), 9.17 (d, IH, J=10 Hz). IR (KBr): 1730, 1685, 1660 cm'1.
Step 8. 9-(2,4-Difluorophenyl)-3-fluoro-2-(4-methylpiperazin-l-yl)- 6H-6-oxopyridori.2-alpyrimidine-7-carboxyUc acid
A 0.300 g (0.590 mmol) sample of the benzyl ester from Step 7 was dissolved in 40 mL of dry methanol and 0.1 g of 10% Palladium on carbon was added. Four mL of 98% formic acid was added and the mixture stirred under a dry N2 atmosphere for 20 min. The catalyst was removed by filtration through diatomaceous earth, and the solvent was removed under vacuum. The product was purified by column chromatography on sUica gel, eluting with 1:10: 100 acetic acid:methanol:methylene chloride give a yeUow soUd. This material was washed with pH 7.5 sodium bicarbonate solution, followed by water rinse to afford 0.178 g of the titie compound as a yeUow solid, mp 246-248°C (dec). MS M/Z: 419 (M+H). NMR: (CDCI3 + CD3OD) d 2.34 (s, 3H), 2.53 (m, 4H), 3.85-4.00 (m, 4H), 6.90 (m, 2H), 7.32 (m, IH), 8.49 (s, IH), 9.07 (d, IH, J=9 Hz). IR (KBr): 1720, 1660 cm'1. Analysis calculated for C20H17F3N4O3: C, 57.42; H, 4.10; N, 13.39. Found: C, 57.21; H, 4.08; N, 13.21.
Example 160 2-(3-(N-t-butoxycarbonyl)aminopyrroUdin- 1 -yl)-9-(2,4-difluorophenyl)-
3-fluoro-6H-6-oxopyridori .2-alpyrimidine-7 -carboxylic acid
Step 1. 3-(2,4-Difluorophenyl)-2-ethoxy-3-(5-fluoro-4- hvdroxypyrimidin-2-y0propane-l,l-dicarboxylic acid diethyl ester
A 4.804 g (20.0 mmol) sample of 2-(2,4-Difluorobenzyl)-5-fluoro-4- hydroxypyrimidine (prepared as described in Step 2 Example 159 above) was dissolved in 150 mL of dry THF and cooled to -78 °C with stirring under a dry N2 atmosphere. To this was slowly added 16.40 mL of 2.5 N n-butyllithium in hexane, and the mixture was stirred for 30 min. Then 4.85 mL (24 mmol) of diethyl ethoxymethylenemalonate was added and the mixture stirred for an additional 30 min at -78°C. The reaction mixture was quenched with 10% HCI until the mixture was at pH 3, whereupon it was then extracted with ethyl acetate. This was dried over anhydrous magnesium sulfate and the solvent was removed by evaporation under vacuum to afford the title compound as a yeUow oil. This material was taken directly to the next step.
Step 2. 9-(2,4-Difluorophenyl)-3-fluoro-2-hydroxy-6H-6- oxopyridori.2-alpyrimidine-7-carboxyUc acid ethyl ester
The compound from Step 1 was dissolved in 80 ml of ethanol, 2 mL of piperidine and 0.2 mL of acetic acid was added and the mixture heated at reflux (bath temperature at 90°C) for 16 hours under a dry N2 atmosphere. The solvent was removed by evaporation, and the residue was washed with methanol and methylene chloride to give 4.794 g of a pale yeUow solid. The washings were concentrated and the residue was purified by column chromatography on sUica gel, eluting with 2:10:100 acetic acid:methanol:methylene chloride to afford an additional 2.220 g of the title compound as a pale yeUow soUd, mp 239-240°C. MS M/Z: 382 (M+NH4), 365 (M+H). NMR:(DMSO-d6) d 1.23 (t, 3H, J=7 Hz), 4.14 (q, 2H, J=7 Hz), 7.08 (m, IH), 7.21 (m, IH), 7.40 (m, IH), 7.83 (s, IH), 8.74 (d, IH, J=8 Hz). IR (KBr) 1710, 1675, 1620 cm'1.
Step 3. 9-(2,4-Difluorophenyl)-3-fluoro-2-hydroxy-6H- 6-oxopyridoiπ.2-alpyrimidine-7-carboxylic acid benzyl ester
To a 7.000 g sample of the ethyl ester compound from Step 2 dissolved in 200 mL of benzyl alcohol was added 0.70 mL of titanium tetraethoxide and the mixture heated with stirring at 100°C for 2.5 hours under a dry N2 atmosphere. The reaction was diluted with methylene chloride, then washed once with 1 N HCI and three times with water, and the solvent was dried over anhydrous magnesium sulfate and removed by evaporation under vacuum to leave a yellow solid. This material was washed with ether and dried under vacuum to afford 6.655 g of the title compound as a yellow solid, mp 218-219°C. MS M/Z 427 (M+H). NMR:(DMSO-d6) d 5.26 (s, 2H), 7.15-7.45 (m, 8H), 8.00 (s, IH), 9.00 (d, IH, J=7 Hz). IR (KBr) 1710, 1675, 1620 cm'1.
Step 4. 2-(3-(N-t-butoxycarbonyl)aminopyrroUdin-l-yl)-9-(2,4-difluorophenyl)- 3-fluoro-6H-6-oxopyridori.2-alpyrimidine-7-carboxylic acid benzyl ester
A 1.200 g (2.815 mmol) sample of the compound from Step 3 was dissolved in 45 mL of methylene chloride and 2.50 mL of DMF and 2.95 mL of POCI3 were added. The reaction was stirred under a dry N2 atmosphere at room temperature for 2.5 hours, then quenched with ice and water. The mixture was extracted with methylene chloride, and the solvent was washed with water until the acidity of the rinse water was above pH 3. The solvent was then dried with magnesium sulfate and an excess of 2-(N-t- butoxycarbony-lamino)pyrroUdine was added and allowed to react. The solution was then concentrated and the product was purified by column chromatography over sUica gel eluting with 0.5:5: 100 cone ammonium hydroxide:methanol:methylene chloride. The solvent was removed to afford 1.579 g of the title compound as a light yeUow crystalline soUd, mp 103-104°C. MS M/Z: 595 (M+H). NMR: (CDCI3) d 1.45 (s, 9H), 1.85-2.30 (m, 2H), 3.42-4.35 (m, 5H), 4.65 (br s, IH), 5.38 (s, 2H), 6.89 (m, 2H), 7.30-7.50 (m, 6H), 8.35 (s, IH), 9.15 (d, IH, J=9 Hz), 9.16 (d, IH, J=9 Hz). IR (KBr): 1735, 1710, 1660 cm'1.
Step 5. 2-(3-(N-t-butoxycarbonyl)aminopyrrotidin- l-yl)-9-(2,4-difluorophenyl)- 3-fluoro-6H-6-oxopyridoπ .2-alpyrimidine-7-carboxyUc acid
A 1.769 g sample of the compound from Example 160 Step 4 was dissolved in 80 mL of dry methanol, and the benzyl ester was removed by reacting with 4.0 mL of 98% formic acid in the presence of 0.200 g of 10% Pd/C under a dry N2 atmosphere . After filtration and evaporation of the solvent, the product was purified by column chromatography on sUica gel, eluting with 1:10:100 acetic acid:methanol:methylene chloride to afford, after removal of the solvent, 1.125 g of the title compound as a yellow solid, mp 209.5-210.5°C. MS M/Z: 505 (M+H). NMR: (CDCI3/CD3OH) d 1.45 (s,
9H), 1.90-2.30 (m, 2H), 3.50-4.35 (m, 5H), 6.91 (m, 2H), 7.32 (m, IH), 8.44 (s, IH), 9.03 (d, IH, J=8 Hz), 9.04 (d, IH, J=8 Hz). IR (KBr): 1714, 1662, 1620 cm" 1.
Example 161 2-(3- Aminopyrrolidin- 1 -yl)-9-(2,4-difluorophenyl)-3-fluoro-
6H-6-oxopyridoπ .2-alpyrimidine-7 -carboxylic acid
A 0.100 g, (0.198 mmol) sample of 2-(3-(N-t-butoxycarbonyl)-aminopyrrolidin- 1 -yl)-9-(2,4-difluorophenyl)-3-fluoro-6H-6-oxopyrido[ 1 ,2-a]pyrimidine-7 -carboxylic acid, from Example 160 Step 5, was dissolved in a smaU volume of 4 N HCI in dioxane and stirred at room temperature for 3 hours under a dry N2 atmosphere. The solvent was removed by evaporation under vacuum to yield a yeUow soUd, which was dissolved in water and neutralized to pH 7 with 5% sodium bicarbonate solution. The resulting precipitate was filtered off, washed with water and dried to afford 0.075 g of the titie compound as a yellow solid, mp >250°C. MS M/Z: 405 (M+H). NMR: (DMSO) d 1.90- 2.30 (m, 2H), 3.00-4.10 (m, 5H), 7.16 (m, 2H), 7.30 (m, IH), 8.18 (s, IH), 9.17 (d, IH, J=8 Hz), 9.18 (d, IH, J=8 Hz). IR (KBr): 1715, 1660 cm"1. Analysis calculated for Ci9Hi5F3N4O3«1.25 H2O: C, 53.46; H, 4.07; N, 13.12. Found: C, 53.64; H, 3.70; N, 12.80.
Example 162
2-(3- Aminopyrrolidin- 1 -yl)-9-(2,4-difluorophenyl)-3-fluoro- 6H-6-oxopyridori.2-alpyrimidine-7-carboxyhc acid trifluoroacetic acid salt
A 0.879 g (2.174 mmol) sample of 2-(3-aminopyrrolidin-l-yl)-9-(2,4- difluorophenyl)-3-fluoro-6H-6-oxopyrido[l,2-a]pyrimidine-7-carboxyUc acid, from Example 161, was dissolved in 10 mL of trifluoroacetic acid, then the excess acid was removed by evaporation under vacuum. The yellow residue was dissolved in 600 mL of water with containing 1 mL of trifluoroacetic acid, the solution was fUtered through sintered glass and freeze dried to afford 0.876 g of the titie compound as a light yeUow solid; mp 191-192°C (dec). MS M/Z: 405 (M+H). NMR (CD3OH): d: 2.102.55 (m, 2H), 3.75-4.20 (m, 5H), 7.05 (m, 2H), 7.50 (m, IH), 8.30 (s, IH), 9.19 (d, IH), J=8 Hz). IR (KBr): 1720, 1660, 1620 cm-1. Analysis calculated for C21H16F6N4O5.H2O: C, 47.02; H, 3.38; N, 10.45. Found: C, 47.36; H, 3.07; N, 10.36.
Example 163
9-Cyclopropyl-3-fluoro-2-(4-methylpiperazin-l-yl)- 6H-6-oxo-pyridoπ .2-alpyrimidine-7-carboxylic acid
Step 1. 2-Chloro-9-cyclopropyl-3-fluoro-6H-6-oxo- pyridoπ.2-alpyrimidine-7-carboxylic acid benzyl ester
To a 0.100 g (0.282 mmol) sample of 9-cyclopropyl-3-fluoro-2-hydroxy-6H-6- oxo-pyrido[l,2-a]pyrimidine-7-carboxylic acid benzyl ester, prepared as described in Example 157 Step 4, was added 5 mL of methylene chloride, 0.275 mL of DMF and 0.33 mL of phosphorous oxychloride, and the reaction was stirred 5 hours at room temperature under a dry N2 atmosphere. The solution was cooled to 0°C, and ice was added to destroy the excess phosphorous oxychloride. This mixture was then extracted with methylene chloride which was dried over anhydrous magnesium sulfate The solvent was removed by evaporation under vacuum to afford the title compound as an orange soUd. NMR (CDCI3): d 4.27 (s, 2H), 6.83 (m, 2H), 7.27 (m, 2H), 8.48 (s, IH). This material was taken directly to the next step. Step 2. 9-Cyclopropyl-3-fluoro-2-(4-methylpiperazin-l-yl)- 6H-6-oxo-pyridori.2-alpyrimidine-7-carboxylic acid benzyl ester
The compound from the previous step was dissolved in 2.5 mL of methylene chloride and 0.5 mL of N-methylpiperazine was added with cooling. The reaction was stirred at room temperature overnight. The solvent was removed by evaporation and the product was purified by column chromatography on siUca gel, eluting with 10% methanol in methylene chloride. The solvent was removed to afford 0.107 g of the title compound as a yellow solid. Recrystallization from methanol gave yellow needles, mp 194-195°C. MS M/Z 437 (M+H). NMR:(CDCl3) d 0.62 (m, 2H), 0.88 (m, 2H), 2.12 ( , IH), 2.57 (s, 3H), 2.59 (t, 4H, J=7 Hz), 4.07 (t, 4H, J=7 Hz), 5.38 (s, 2H), 7.28 (m, IH), 7.36 (m, 2H), 7.51 (m, 2H), 8.04 (s, IH), 9.16 (d, IH, J=10 Hz). IR (KBr): 1715, 1685, 1660 cm"1. Analysis calculated for C24H25FN4O3* 1/4 H2O: C, 65.37; H, 5.83; N, 12.70. Found: C, 65.21; H, 5.53; N, 12.59.
Step 3. 9-Cyclopropyl-3-fluoro-2-(4-methylpiperazin-l-yl)- 6H-6-oxo-pyridor 1.2-alpyrimidine-7 -carboxylic acid
To a 0.050 g (0.115 mmol) sample of the benzyl ester compound from the previous step was added 10 mL of methanol, 1 mL of 98% formic acid and 0.04 g of 10% Pd/C, and the mixture was stirred under Argon for 30 min at room temperature. The solution was diluted with methylene chloride, filtered through diatomaceous earth and the solvent was removed to leave a yeUow residue. The product was purified by column chromatography on sUica gel, eluting with 1:10:100 acetic acid:methanol:methylene chloride. After removal of the solvent, 0.0345 g of the titie compound was obtained as a yellow solid, mp 219-220°C. MS M/Z 347 (M+H). NMR:(CDCl3) d 0.67 (m, 2H), 0.95 (m, 2H), 2.18 (m, IH), 2.39 (s, 3H), 2.65 (t, 4H, J=6 Hz), 4.13 (m, 4H), 8.11 (s, IH), 9.02 (d, IH), J=10 Hz). IR (KBr): 1720, 1660, 1620 cm" 1. Analysis calculated for CπHi9FN4θ3»0.6 CH3COOH: C, 57.17; H, 5.64; N, 14.65. Found: C, 57.60; H, 5.79; N, 14.13.
Example 164
9-Cyclopropyl-3-fluoro-2-(piperazin- 1 -yl)-6H-6- oxo-pyridoπ .2-alpyrimidine-7 -carboxylic acid
Step 1. 2-Chloro-9-cyclopropyl-3-fluoro-6H-6- oxo-pyridori.2-alpyπrnidine-7-carboxyUc acid t-butyl ester
A mixture of 0.100 g (0.312 mmol) of 9-cyclopropyl-3-fluoro-2-hydroxy-6H-6- oxo-pyrido[l,2-a]pyrimidine-7-carboxylic acid t-butyl ester from Example 158 Step 1, 0.29 mL of DMF, 0.33 mL of phosphorous oxychloride and 10 mL of methylene chloride was stirred under a dry N2 atmosphere at room temperature for 1 hour. After workup as described in Example 157 Step 5, the title compound was obtained as a orange solution in methylene chloride, which was taken directly to the next step.
Step 2. 9-Cyclopropyl-3-fluoro-2-(piperazin-l-yl)-6H-6- oxo-pyridori.2-alpyrimidine-7-carboxylic acid t-butyl ester
The sample from Step 1 in 5 mL of methylene chloride was added dropwise to a solution of 0.289 g piperazine in 10 mL of methylene chloride stirred under a dry N2 atmosphere. The resulting yellow solution was concentrated to give a yeUow residue, which was purified by column chromatography on siUca gel, eluting with 0.5: 10: 100 cone ammonium hydroxide:methanol:methylene chloride, to afford after removal of the solvent 0.068 g of the title compound as a yellow soUd. This material was taken directly to the next step.
Step 3. 9-Cyclopropyl-3-fluoro-2-(piperazin-l-yl)-6H-6- oxo-pyridor 1.2-alpyrimidine-7-carboxylic acid
The sample of the compound from the previous step was reacted with 10 mL of 4N HCI in dioxane under a dry N2 atmosphere at room temperature overnight. The solvent was removed, the yellow solid was dissolved in distiUed water, adjusted to pH 7-8 with saturated sodium carbonate solution, and the solution extracted with methylene chloride. The extracts were washed with water, dried, concentrated, and chromatographed on siUca gel to afford 0.043 g of the title compound as a yellow soUd, mp 198-199°C. MS M/Z 333 (M+H). NMR:(CDCl3) d 0.67 (m, 2H), 0.94 (m, 2H), 2.19 (m, IH), 3.08 (t, 4H, J=6 Hz), 4.08 (m, 4H), 8.11 (s, IH), 9.01 (d, IH, J=10 Hz). IR (KBr): 1710, 1660 cm"1. Analysis calculated for Ci6Hi7FN4θ3»0.1 H2O: C, 57.36; H, 5.20; N, 16.72. Found: C, 57.69; H, 5.22; N, 16.31. Example 165
9-Cyclopropyl-3-fluoro-2-(morpholin- 1 -yl)-6H-6- oxo-pyridoll.2-alpyrimidine-7 -carboxylic acid
Step 1. 9-Cyclopropyl-3-fluoro-2-(morpholin-l-yl)-6H-6- oxo-pyridori.2-alpyrimidine-7-carboxyUc acid benzyl ester
To a 0.150 g (0.396 mmol) sample of 2-chloro-9-cyclopropyl-3-fluoro-6H-6- oxo-pyrido[l,2-a]pyrimidine-7-carboxylic acid benzyl ester, prepared as in Example 164 Step 1 , dissolved in anhydrous methylene chloride and cooled to 0°C and stirred under a dry N2 atmosphere was added 0.042 mL (0.483 mmol) of morpholine dropwise. The color changed from orange to yellow, and the reaction was complete in 15 min. The solvent was removed by evaporation, and the product was purified by column chromatography on sUica gel, eluting with 2:10:100 acetic acid:methanol:methylene chloride. The solvent was removed to afford the title compound as a yeUow solid. This was taken directly to the next step. NMR:(CDCl3) d 0.62 (m, 2H), 0.89 (m, 2H), 2.11 (m, IH), 3.87 (t, 4H), J=6 Hz), 4.07 (t, 4H, J=6 Hz), 5.39 (s, 2H), 7.29 (m, IH), 7.37 (m, 2H), 7.51 (m, 2H), 8.07 (s, IH), 9.19 (d, IH, J=10 Hz).
Step 2. 9-Cyclopropyl-3-fluoro-2-(morpholin-l-yl)-6H-6- oxo-pyridor 1.2-alpyrimidine-7-carboxyUc acid
The benzyl ester product from the previous step was dissolved in 20 mL of anhydrous methanol and stirred with 0.020 g of 10% Pd/C catalyst under 1 atm. Hydrogen at room temperature for 5 hours. The catalyst was removed by filtration, and the solvent was removed under vacuum to afford 0.100 g of the title compound as a yeUow soUd, mp >260°C. MS M/Z 334 (M+H). NMR:(CDCl3) d 0.68 (m, 2H), 0.95 (m, 2H), 2.19 (m, IH), 3.90 (t, 4H, J=6 Hz), 4.10 (t, 4H, J=6 Hz)., 8.15 (s, IH), 9.06 (d, IH, J=10 Hz). IR 1720, 1660, 1620 cm"1. Analysis calculated for Ci6Hi6FN3θ4*H2θ: C, 54.70; H, 5.16; N, 11.96. Found: C, 55.01; H, 4.71; N, 11.62.
Example 166
9-(2,4-Difluorophenyl)-3-fluoro-2-(3-(N-(S)-noiΥalyl)aιτunopyιτotidin-l-yl)- 6H-6-oxopyridoπ.2-a1pyrimidine-7-carDoxylic acid hydrochloride salt
Step 1. 2-(3-AminopyrroUdin-l-yl)-9-(2,4-difluorophenyl)-3-fluoro- 6H-6-oxopyridon.2-a1pyrimidine-7 -carboxylic acid benzyl ester
A 1.579 g (2.655 mmol) sample of the 9-(2,4-difluorophenyl)-3-fluoro-2-(3-(N- t-butoxycarbonyl)aminopyrrolidin- l-yl)-6H-6-oxopyrido[ 1 ,2-a]pyrimidine-7-carboxylic acid benzyl ester, from Example 160 Step 4, was dissolved in 5 mL of trifluoroacetic acid and stirred at room temperature for 1 hour under a dry N2 atmosphere. The solvent was removed by evaporation under vacuum to yield the deprotected title product as a yeUow solid, which was taken directly to the next step. Mp 185-186°C. NMR (CDCI3): d 1.75- 2.19 (m, 2H), 3.33-4.07 (m, 5H), 5.38 (s, 2H), 6.87 (m, 2H), 7.32 (m, 4H), 7.48 (m, 2H), 8.33 (s, IH), 9.13 (apparent d, IH, J=9 Hz).
Step 2. 2-(3-(N-(N-Benzyloxycarbonyl)norvalyl)aminopyrrolidin-l-yl)-
9-(2,4-difluorophenyl)-3-fluoro-6H-6- oxopyridoπ.2-a1pyrimidine-7-carboxylic acid benzyl ester
The sample from the previous step was suspended in 50 mL of THF and dnsopropylethylamine was added with stirring at room temperature until a homogeneous solution resulted. Then 0.885 g (2.66 mmol) of the N-benzyloxycarbonyl protected (s)- norvatine succinamide was added and stirred at room temperature for 1 hour under a dry N2 atmosphere. Another 0.050 g of the protected norvaUne was added, and the solution was stirred for another 0.5 hours. The reaction was diluted with methylene chloride, washed with water (4x), and the organic solvent dried over anhydrous magnesium sulfate and removed by evaporation under vacuum. This product was purified by column chromatography on sUica gel, eluting with 5% methanol in methylene chloride, to afford 1.678 g of the title compound as a yeUow crystalUne solid after removal of the solvent. Mp 103-105°C. MS M/Z: 728 (M+H). NMR: (CDCI3) d 0.90 (t, 3H, J=7 Hz), 1.39-2.30 (m, 6H), 3.30-4.40 (m, 5H), 4.85-5.40 (m, 5H), 6.75-7.40 (m, 13 H), 8.15-8.80 (m, 2H). IR (KBr): 1700, 1660 cm" 1. Analysis calculated for C39H36F3N5O6O.25 H2O: C, 63.97; H, 5.02; N, 9.56. Found: C, 64.19; H, 5.1 1; N, 9.50. Step 3. 9-(2,4-Difluorophenyl)-3-fluoro-2-(3-(N-(S)- norvalyl)aminopyrroUdin- 1 -yl)-6H-6- oxopyridoπ.2-alpyrimidine-7-carboxylic acid hydrochloride salt
A 1.515 g sample (2.0822 mmol) sample of the compound from the previous step was dissolved in 80 mL of methanol, and 4.0 mL of 98% formic acid and 0.2 g of 10% Pd/C was added. The mixture was stirred at room temperature for 1.7 hours under a dry N2 atmosphere, filtered and concentrated to leave a yellow soUd residue. This soUd was dissolved in methanol and filtered through sintered glass, then the solvent was removed to leave a yellow solid. This soUd was dissolved in 50 mL of methanol, 3 mL of cone HCI was added and the solvent evaporated off. The residue was dissolved in 200 mL of water, filtered again through sintered glass, and the solution was freeze-dried to afford 0.969 g of the title product as a yellow solid, mp 192-194°C. MS M/Z: 504 (M+H). NMR: (CD3OD) d 0.96 (m, 3H), 1.90-2.35 (m, 6H), 3.50-4.60 (m, 5H), 7.02 (m, 2H), 7.48 (m, IH), 8.22 (br s, IH), 8.35 (br s, 2H), 9.09 (m, IH). IR (KBr): 1710, 1665, 1610 cm" 1. Analysis calculated for C24H25F3N5θ4*2 H2O: C, 50.05; H, 5.07; N, 12.16. Found: C, 50.00; H, 4.56; N, 12.03.
Example 167
2-(3-(N-(S)-Alanyl)aminopyrrolidin- 1 -yl)-9-(2,4-difluorophenyl)- 3-fluoro-6H-6-oxopyridoπ.2-alpyrirrύdine-7-carboxylic acid hydrochloride
Step 1. 2-(3-(N-(N-Benzyloxycarbonyl)alanyl)aminopyrroUdin-
1 -yl)-9-(2,4-difluorophenyl)-3-fluoro-6H-6-oxopyrido[ 1 ,2- alpyrimidine-7-carboxylic acid benzyl ester
A 0.982 g ( 1.986 mmol) sample of 9-(2,4-difluorophenyl)-3-fluoro-2-(3- anrrinopyπolidin-l-yl)-6H-6-oxopyrido[l,2-a]pyrimidine-7-carboxytic acid benzyl ester, prepared as described in Example 166 Step 1, was suspended in 40 mL of THF and 0.700 g (2.196 mmol) of the N- benzyloxycarbonyl protected (S)-alanine succinamide was added.The mixture was stirred at room temperature for 2 hour under a dry N2 atmosphere. The reaction solvent was evaporated off, then the residue was dissolved in methylene chloride, which was washed with water (3x). The organic solvent was dried over anhydrous magnesium sulfate and removed by evaporation under vacuum. This product was purified by column chromatography on sUica gel, eluting with 5% methanol in methylene chloride, to afford, after removal of the solvent, 1.318 g of the title compound as a yeUow crystalUne soUd, mp 104-107°C. MS M/Z 700 (M+H). NMR: (CDCI3) d
1.43 (m, 3H), 1.95-2.30 (m, 2H), 3.40-4.40 (m, 5H), 4.75-5.35 (M, 5H), 6.77 (m, 2H), 7.10-7.40 (m, IH), 8.18-8.40 (m, 2H). IR (KBr): 1720, 1660 cm -1. Analysis calculated for C37H32F3N5O6-1/2 H2O: C, 62.71; H, 4.69; N, 9.88. Found: C, 63.04; H, 4.49; N, 9.92
Step 2. 2-(3-(N-(S)-Alanyl)aminoρyrrolidin-l-yl)-9-(2,4-difluorophenyl)- 3-fluoro-6H-6-oxopyridori.2-alpyrimidine-7-carboxyUc acid hydrochloride
A 1.262 g (1.804 mmol) sample of the compound from the previous step was suspended in 80 mL of methanol and 4.0 mL of 98% formic acid and 0.200 g of 10% Pd/C was added with stirring. The mixture was stirred at room temperature for 1.7 hours, then 40 ml of THF was added and the mixture stirred for 0.3 hours longer under a dry N2 atmosphere, filtered and concentrated to leave a yellow soUd residue. This was dissolved in 500 mL of water and 4 mL of cone HCI was added, then the solution was filtered through sintered glass and freeze-dried to afford 0.877 g of the titie compound as a yellow soUd, mp 198-200° C (dec). MS M/Z 476 (M-Cl). NMR: (DMSO-d6) d 1.33 (apparent t, 3H, J=7 Hz), 1.90-2.30 (m, 2H), 3.35-4.40 (m, 6H), 7.17 (m, IH), 7.32 (m, IH), 7.58 (m, IH), 8.20 (d, IH), 9.19 (m, IH), 13.45 (br, IH). IR (KBr): 1715, 1665, 1620 cm"1. Analysis calculated for C22H2lClF3N5θ4«1.5 H2O: C, 49.03; H, 4.48; N, 12.99. Found: C, 49.18; H, 4.17; N, 12.53.
Example 168
2-(3-(N-(S)-Alanyl-(S)-alanyl)aminopyrrolidin-l-yl)-9-(2,4-dtfluorophenyl)- 3-fluoro-6H-6-oxopyridor 1.2-alpyrimidine-7-carboxylic acid hydrochloride
Step 1. 2-(3-(N-(N-Benzyloxycarbonyl)-(S)-alanyl-(S)- alanyl)aminopyrrolidin- 1 -yl)-9-(2,4-difluorophenyl)-3-fluoro- 6H-6-oxopyridoπ.2-alpyrimidine-7-carboxyUc acid benzyl ester
A 0.905 g (1.830 mmol) sample of 9-(2,4-difluorophenyl)-3-fluoro-2-(3- aminopyrrolidin-l-yl)-6H-6-oxopyrido[l,2-a]pyrimidine-7-carboxyUc acid benzyl ester, prepared as described in Example 166 Step 1, was suspended in 10 mL of DMF and 0.700 g (2.196 mmol) of the N-benzyloxycarbonyl protected (S)-alanyl-(S)-alanine. The mixture was stirred at 0°C and 0.530 g of l-ethyl-3-[3-α!imethylaminopropyl]carbodtimide hydrochloride (ED AC) and 0.370 g of 1 -hydroxybenzotriazole hydrate (HOBT) was added. The mixture was stirred for 30 min at 0°C, then at room temperature for 2 hours. The solvent was removed in a kugelrohr apparatus, then the residue was dissolved in methylene chloride, washed 2x with water, washed 2x with saturated sodium bicarbonate solution, then 2x again with water and dried over magnesium sulfate. The solvent was removed by evaporation, and the product was purified by column chromatography on silica gel, eluting with 10% methanol in methylene chloride to afford 1.187 g of the titie product as yellow crystals, mp 123-126°C. MS M/Z 771 (M+H). NMR: (CDCI3) d 1.37 (m, 6H), 1.92-2.18 (m, 2H), 3.58-4.48 (m, 5H), 4.76-5.00 (m, 2H), 5.30 (s, 2H), 5.32 (s, 2H), 6.80 (m, 2H), 7.10-7.45 (m, IH), 8.23 and 8.30 (two s, IH), 8.87 and 8.93 (two d, lH, J=8 Hz). IR (KBr): 1720, 1660 cm-1. Analysis calculated for C4()H37F3N6θ7» 1/2 H2O: C, 61.62; H, 4.91; N, 10.78. Found: C, 61.51; H, 4.71; N, 10.75.
Step 2. 2-(3-(N-(S)-Alanyl-(S)-alanyl)aminopyrroUdin-l-yl)- 9-(2,4-difluorophenyl)-3-fluoro-6H- 6-oxopyridoπ.2-alpyrimidine-7 -carboxylic acid hydrochloride
A 1.131 g (1.467 mmol) sample of the compound from Step 1 was dissolved in 80 mL of methanol and 4.0 mL of 98% formic acid and 0.2 g of 10% Pd/C was added. The mixture was stirred 1 hour at room temperature under a dry N2 atmosphere, filtered, and concentrated to leave a yellow residue. This was dissolved in 500 mL of distiUed water and 3 mL of cone HCI was added, then the solution was filtered though sintered glass, and freeze-dried to afford 0.729 g of the titie compound as a pale yellow solid, mp 217-219°C (dec). MS M/Z 547 (M-Cl). NMR: (DMSO-d6) d 1.24 (m, 3H), 1.32 (d, 3H, J=7 Hz), 1.80-2.20 (m, 2H), 3.40-4.50 (m, 7H), 7.17 (m, IH), 7.31 (m, IH), 7.57 (m, IH), 8.20 (br, 4H), 8.47 (m, IH), 8.66 (m, IH), 9.19 (m, IH), 13.45 (br, IH). IR (KBr): 1710, 1660, 1630 cm"1.
Example 169
2-((2S,4S)-4-Acetamido-2-methylpyrrolidin-l-yl)-9-(2,4-difluorophenyl)- 3-fluoro-6H-6-oxopyridoπ .2-a1pyrimidine-7-carboxylic acid
Step 1. 2-((2S,4S)-4-Acetamido-2-methylpyrroUdin-l-yl)-9-(2,4-
D difluorophenyl)-3-fluoro-6H-6-oxopyrido[ 1 ,2- alpyrimidine-7-carboxylic acid benzyl ester
A 0.200 g (0.469 mmol) sample of 9-(2,4-difluorophenyl)-3-fluoro-2-hydroxy-
6H-6-oxopyrido[l,2-a]pyrimidine-7 -carboxylic acid benzyl ester, from Example 160 Step 3, was dissolved in 5 mL of methylene chloride and 0.42 mL of DMF and 0.49 mL of POCI3 were added. The reaction was stirred under a dry N2 atmosphere at room temperature for 3.5 hours, then quenched with ice and water. The mixture was extracted with methylene chloride, and the solvent was washed with water until the acidity of the rinse water was above pH 3. The solvent was then dried with magnesium sulfate and 0.120 g (0.656 mmol) of (2S,4S)-4-acetamido-2-methylpyrrolidine (prepared as described by Rosen, T., et al., J. Med. Chem., 3.1, 1598-1611 (1988)) in 10 mL of methylene chloride and 2 mL of triethylamine was added and allowed to react. The solution was then concentrated and the product was purified by column chromatography over sUica gel eluting with 1:10:100 acetic acid:methanol:methylene chloride. The solvent was removed to afford 0.205 g of the titie compound as yeUow crystals, mp 117-119°C. [a]=-122.6° (25°C, D, c=0.05, CHCI3). MS M/Z 551 (M+H). NMR: (CDCI3) d 1.10 (d, 3H, J=7 Hz), 1.85-2.25 (m, 2H), 2.10 (s, 3H), 4.05 (m, 2H), 4.23 (m, IH), 4.80 (m, IH), 5.06 (d, IH, J=13 Hz), 5.27 (d, IH, J=13 Hz), 6.79 (m, 2H), 7.20-7.40 (m, 6H), 7.76 (br, IH), 8.21 (s, IH), 8.80 (d, IH, J=9 Hz). IR (KBr): 1725, 1660 cm"1. Analysis calculated for C29H25F3N4O4Η2O: C, 61.26; H, 4.79; N, 9.85. Found: C, 61.59; H, 4.37; N, 9.72.
Step 2. 2-((2S,4S)-4-Acetarnido-2-methylpyrroUdin-l-yl)-9-(2,4-difluorophenyl)- 3-fluoro-6H-6-oxopyridori ■2-alpyrimidine-7-carboxylic acid
To a 0.198 g (0.359 mmol) sample of the compound from Step 1 in 20 mL of methanol was added 1 mL of 98% formic acid and 0.1 g of 10% Pd/C. The mixture was stirred at room temperature under a dry N2 atmosphere for 1.25 hours. The mixture was filtered, and the filtrate concentrated to leave a yeUow residue. The product was purified by column chromatography on siUca gel, eluting with 1:10:100 acetic acid:methanol:methylene chloride to afford 0.126 g of the title compound as a yellow soUd, after removal of the solvent, mp 163-164°C. [a]=-50.2° (23°C, D, c=0.5, CHCI3). MS M/Z 461 (M+H). NMR: (CDCI3 + CD3OD) d 1.09 and 1.39 (two d, 3H, J=6 Hz), 1.92-2.15 (m, 2H), 2.00 (s, 3H), 3.97 (m, IH), 4.16 (m, IH), 4.32 (m, IH), 4.72 (m, IH), 6.90 (m, 2H), 7.25 (m, IH), 8.17 and 8.31 (two s, IH), 8.93 and 8.97 (two d, IH, J=8 Hz). IR (KBr): 1720, 1660, 1035 cm"1. Analysis calculated for C22Hl9F3N4θ4»H2θ: C, 55.23; H, 4.42; N, 11.71. Found: C, 55.25; H, 4.20; N, 11.21.
Example 170
9-(2,4-Difluorophenyl)-3-fluoro-2-(3-hydroxypyrroUdin- 1 -yl)- 6H-6-oxopyridoπ .2-alpyrimidine-7 -carboxylic acid
Step 1. 9-(2,4-Difluorophenyl)-3-fluoro-2-(3-hydroxypyrroUdin-l-yl)- 6H-6-oxopyridon.2-alpyrimidine-7-carboxylic acid benzyl ester
A 0.200 g (0.469 mmol) sample of 9-(2,4-difluorophenyl)-3-fluoro-2-hydroxy- 6H-6-oxopyrido[l,2-a]pyrimidine-7-carboxylic acid benzyl ester, from Example 160 Step 3, was dissolved in 5 mL of methylene chloride and 0.42 mL of DMF and 0.49 mL of POCI3 were added. The reaction was stirred under a dry N2 atmosphere at room temperature for 3.5 hours, then quenched with ice and water. The mixture was extracted with methylene chloride, and the solvent was washed with water until the acidity of the rinse water was above pH 3. The solvent was then dried with magnesium sulfate and 0.1 mL of 3-pyrroUdinol was added and allowed to react. The solution was then concentrated and the product was purified by column chromatography over siUca gel eluting with 1:10:100 acetic acid:methanol:methylene chloride. The solvent was removed to afford 0.183 g of the title compound as yellow crystals, mp 105-107°C. MS M/Z 496 (M+H). NMR: (CDCI3) d 2.00-2.16 (m, 2H), 3.55-3.68 (m, 2H), 3.96-4.16 (m, 2H), 4.18 and 4.55 (m, IH), 5.36 and 5.38 (two s, 2H), 6.90 (m, 2H), 7.30-7.48 (m, 6H, 8.33 (s, IH), 9.08 and 9.14 (two d, IH, J=6 Hz). IR (KBr): 1725, 1690, 1660 cm'1. Analysis calculated for C26H2θF3N3θ4'3/4 H2O: C, 61.36; H, 4.26; N, 8.26. Found: C, 60.97; H, 3.67; N, 7.98.
Step 2. 9.-(2,4-Difluorophenyl)-3-fluoro-2-(3-hydroxypyrroUdin-l-yl)- 6H-6-oxopyridori .2-alpyrimidine-7-carboxyUc acid
To a 0.166 g (0.334 mmol) sample of the compound from Step 1 in 20 mL of methanol and 15 mL of DMF was added 2 mL of 98% formic acid and 0.12 g of 10% Pd/C. The mixture was stirred at room temperature under a dry N2 atmosphere for 1.33 hours. The mixture was filtered, and the filtrate concentrated, removing the DMF in a kugelrohr apparatus, to leave a yeUow residue. The product was purified by column chromatography on sUica gel, eluting with 1:10:100 acetic acid:methanol:methylene chloride to afford 0.088 g of the title compound as a yellow soUd, after removal of the solvent, mp 168-170°C (dec). MS M/Z 406 (M+H). NMR: d 2.00-2.15 (m, 2H), 3.55- 3.70 (m, 2H), 3.97-4.12 (m, 2H), 4.50-4.60 (m, IH), 6.93 (m, 2H), 7.35 (m, IH), 8.43
(s, IH), 9.01 and 9.04 (two d, IH, J=4 Hz). IR (KBr): 1715, 1665, 1625 cm"1.
Analysis calculated for Ci9Hi4F3N3θ4»l/2 H2O: C, 55.08; H, 3.65; N, 10.14. Found:
C, 55.10; H, 3.53; N, 10.04.
Example 171 2-((2S,4S)-4-Amino-2-methylpyrrolidin-l-yl)-9-(2,4-difluorophenyl)-
3-fluoro-6H-6-oxopyridori.2-alpyrimidine-7-carboxylic acid hydrochloride
Step 1. (2S.4S)-4-acetamido-2-methylpyrroUdine
A 6.000 g (24.760 mmol) sample of (2S, 4S)-4-acetamido-l-(t-butoxy- carbonyl)-2-methylpyrrolidine, prepared as described by Rosen, T., et al., J. Med. Chem., 3ft, 1598-1611 (1988), was dissolved in 30 mL of 4N HCI in dioxane and stirred at room temperature for 24 hours to remove the boc group. The solvent was removed by evaporation to give the hydrochloride salt of this compound as a white soUd, which was taken directly to the next step.
Step 2. (2S. 4S V4-acetamido- l-benzyl-2-methylpyrroUdine
This salt from the previous step was suspended in 27 mL of methylene chloride, 8.4 mL of triethylamine was added and the mixture stirred for 10 min. Next was added 3.2 mL (26.9 mmol) of benzyl bromide and the mixture heated at reflux for 5 hours. The mixture was dUuted with methylene chloride, which was washed 3x with water, dried over, magnesium sulfate, and evaporated to leave the 1 -benzyl protected compound as a white solid, which was taken directly to the next step.
Step 3. (2S. 4S)-4-amino-l-benzyl-2-methylpyrrolidine hydrochloride
The acetyl group was removed from the compound from the previous step by heating at reflux for 6 hours in 6N HCI. Removal of the solvent gave the soUd product which was taken directly to the next step.
Step 4. (2S . 4S 1 -benzyl-4-t-butoxycarbonylamino-2-methylpyrrolidine
The sample from the previous step was dissolved in 10 mL of water and 35 mL of methanol. To this solution stirred at 0°C was added 5.2 mL of triethylamine and 4.21 g of di-t-butyl dicarbonate. The reaction was stirred for 2 hours at 0°C and then at room temperature for 19 hours. The solvent was removed by evaporation, the residue dissolved in methylene chloride, which was washed with water and concentrated. The product was purified by column chromatography on silica gel, eluting with 0.5:5: 100 cone ammonium hydroxide:methanol:methylene chloride to give the titie compound as a white soUd after removal of the solvent. This material was taken directly to the next step.
Step 5. (2S. 4SV4-t-butoxycarbonylamino-2-methylpyrrolidine
The sample from the previous step was dissolved in 150 mL of methanol, 0.90 g of 10% Pd/C was added and the mixture shaken under 4 atm of hydrogen at room temperature for 13 hours. The mixture was concentrated, the catalyst was removed by filtration, and the solvent removed to afford 3.081 g of the title compound as a white solid. MS M/Z 201 (M+H). NMR (CDCI3): d 1.15 (d, 3H, J=6 Hz), 1.44 (s, (H), 1.54-1.63 (m, 2H), 1.75 (m, IH), 2.64 (dd, IH, J=5, J=12 Hz), 3.26 (m, IH), 3.38 (dd, IH, J=7, J=12 Hz), 4.12 (br, IH), 4.63 (br, IH). IR (KBr): 1685 cm"1.
Step 6. 2-((2S,4S)-4-t-butoxycarbonylamino-2- methylpyrrolidin-l-yl)-9-(2,4-difluorophenyl)-3-fluoro- 6H-6-oxopyridori.2-alpyrimidine-7 -carboxylic acid benzyl ester
A 1.500 (3.518 mmol) sample of 9-(2,4-difluorophenyl)-3-fluoro-2-hydroxy- 6H-6-oxopyrido[l, 2- a]pyrimidine-7 -carboxylic acid benzyl ester, from Example 160 Step 3, was dissolved in 40 mL of methylene chloride and 3.20 mL of DMF and 3.70 mL of POCI3 were added. The reaction was stirred under a dry N2 atmosphere at room temperature for 2.25 hours, then quenched with ice and water. The mixture was extracted with methylene chloride, and the solvent was washed with water until the acidity of the rinse water was above pH 3. The solvent was then dried with magnesium sulfate and 1.06 g (0.656 mmol) of (2S,4S)-4-t-butoxycarbonylamino-2-methylpyrrolidine, from Step 5 above, in 50 mL of methylene chloride and 7 mL of triethylamine was added and aUowed to react The solution was then concentrated and the product was purified by column chromatography over sUica gel eluting with 0.5:10:100 cone ammonium hydroxide:methanol:methylene chloride. The solvent was removed to afford 1.856 g of the title compound as yellow crystals, mp 106-107°C. [a]=+13.4 (23°, D, c=0.5, CHCI3).
MS M/Z 609 (M+H). NMR: (CDCI3) d 1.11 (two d, 3H, J=7 Hz), 1.45 and 1.55 (two s, 9H), 1.90-2.10 (m, 2H), 3.60-4.60 (m, 5H), 5.39 (s, IH), 6.89 (m, 2H), 7.34-7.50 (m, 6H), 8.34 and 8.36 (two s, IH), 9.16 and 9.19 (two d, IH, J=9 Hz). IR (KBr): 1715, 1690, 1660 cm"1. Analysis calculated for C32H3lF3N4θ5» 1/2 H2O: C, 62.23; H, 5.22; N, 9.07. Found: C, 62.44; H, 5.20; N, 9.16.
Step 7. 2-((2S,4S)-4-Amino-2-methylpyrrolidin- l-yl)-9-(2,4-drfluorophenyl)- 3-fluoro-6H-6-oxopyridoπ .2-alpyrimidine-7-carboxylic acid
To a 1.814 g (2.981 mmol) sample of the compound from Step 6 dissolved in 80 mL of methanol and 10 mL of THF was added 8 mL of 98% formic acid and 1 g of 10% Pd/C. The mixture was stirred at room temperature under a dry N2 atmosphere for 2.3 hours. The mixture was filtered, and the filtrate concentrated to leave a yellow residue. The product was purified by column chromatography on sUica gel, eluting with 1:10:100 acetic acid:methanol:methylene chloride to afford 1.513 g of the title compound as a yeUow soUd, after removal of the solvent. The compound was taken directly to the next step. Step 8. 2-((2S,4S)-4-Amino-2-methylpyrrolidin- l-yl)-9-(2,4-difluorophenyl)- 3-fluoro-6H-6-oxopyridori.2-alpyrimidine-7-carboxyUc acid hydrochloride
The 1.528 g sample of the compound from the previous step was dissolved in 20 mL of 4N HCI in dioxane and stirred at room temperature for 3.5 hours. The solvent was removed, the residue redissolved in 500 mL of water, 0.5. mL of cone HCI was added, and the solution freeze-dried to afford 1.147 g of the titie compound as a yeUow solid, mp 204°C (dec). [a]=+35.4° (22°C, D, c=0.5, CH3OH). MS M/Z 419 (M-Cl). NMR: (CD3OD) d 1.16 and 1.41 (two d, 3H, J=7 Hz), 2.15-2.31 (m, 2H), 3.75-4.40 (m, 4H), 7.04 (m, 2H), 7.46 (m, IH), 8.25 and 8.30 (two s, IH), 9.11 and 9.21 (two d, IH, J=9 Hz). IR (KBr): 1710, 1660, 1630 cm"1. Analysis calculated for
C20Hl8F3ClN4θ3»H2θ: C, 50.80; H, 4.26; N, 11.85. Found: C, 50.98; H, 4.10; N,
11.85.
Example 172
2-(3-Aminopyrrolidin-l-yl)-3-fluoro-9-(2,3,4,5,6-pentafluorophenyl)- 6H-6-oxopyridori.2-alpyrimidine-7-carboxylic acid hydrochloride salt
Step 1. 2-(2.3.4.5.6-PentafluorophenylVacetamidine hydrochloride
Into a solution of 26.72 g (0.129 mol) of pentafluoroacetonitrile (commerciaUy available) in 8.30 mL of anhydrous ethanol cooled to 0°C and stirred under a dry N2 atmosphere was introduced gaseous HCI, until the mixture solidified. The reaction was allowed to stand for 96 hours, then 60 mL of ethanol and 30.7 mL of 4.2 N HCI in ethanol (0.124 M) was added, and the slurry was stirred at room temperature for 2 hours. The mixture was filtered through sintered glass, and the filtrate was concentrated under vacuum to afford the titie compound as a brownish solid, which was taken directly to the next step.
Step 2. 5-Fluoro-4-hvdroxy-2-(2.3.4.5.6-pentafluorobenzyl')pyrimidine
A mixture of the compound (0.129 mol) from Step 1 , 0.135 mol of the sodium salt of ethyl 2-fluoro-3-hydroxy-2-propenoate (prepared as described by E. Elkik and M. Imbeaux-Oudotte, Bull. Soc. Chim. Fr., 5-6 pt 2. 1165 (1975)), 150 mL of anhydrous methanol and 25 mL of triethylamine was stirred under a dry N2 atmosphere for 24 hours. The solvent was removed by evaporation under vacuum and the residue was dissolved in methylene chloride and washed (lx) with 10% HCI and (lx) with water, then dried over anhydrous magnesium sulfate, and the solvent was removed by evaporation under vacuum to give a dark oU which solidified upon standing. This solid was washed with 1 :2 ethyl acetate exane to afford 4.843 g of the title compound as a white solid, mp 161-162°C. The filtrate was concentrated and extracted with 1 :4 ethyl acetate±exane to leave a second crop of 4.454 g of product Additional product was obtained by chromatography of the residue, for a total yield of 19.20 g of product. MS M/Z 312 (M+NH4). NMR (CDCI3): d 4.15 (apparent s, 2H), 7.80 (d, IH, J=3 Hz), 13.38 (br s, IH). IR (KBr): 3440, 1685, 1660, 1610 cm"1.
Step 3. 2-Ethoxy-3-(5-fluoro-4-hydroxy-3-(2,3,4,5,6- pentafluorophenyl)propane-l.l-dicarboxylic acid diethyl ester
The compound from Step 2 above (0.294 g, 1.00 mmol) was dissolved in 10 mL of THF and cooled to -78°C with stirring, then 0.82 mL (2.05 mmol) of a 2.5 M solution of n-butyUithium in hexane was added and the resulting yeUow solution was stirred for 30 min. To this was added 0.243 mL (1.2 mmol) of ethyl 2-carboethoxy-3-ethoxy-2- propenecarboxylate with stirring for 15 min. The reaction was quenched with 10% HCI, aUowed to warm to room temperature and extracted with ethyl acetate. The extract was washed (2x) with brine, and the solvent dried over magnesium sulfate and concentrated to afford the title compound as an oU, which was taken directly to the next step.
Step 4. 9-(2,3,4,5,6-ρentafluorophenyl)-3-fluoro-2-hydroxy-6H- 6-oxopyridoπ.2-alpyrimidine-7 -carboxylic acid ethyl ester
The compound from Step 3 above was dissolved in 10 mL of ethanol, 0.2 mL of cone sulfuric acid was added and the solution was heated at reflux for 18 hours. The solvent was removed and the residue washed with ether to afford 0.222 g of the title compound as a yellow solid, mp 235-236C. MS M/Z 419 (M+H), 436 (M+NH4). IR (KBr): 3440 (br), 1710, 1680, 1615 cm"1. NMR (CDCI3) d 1.38 (t, 3H), J=7 Hz), 4.37 (q, 2H, J=7 Hz), 8.23 (s, IH), 9.05 (d, IH, J=6 Hz).
Step 5. 3-Fluoro-2-hydroxy-9-(2,3,4,5,6-pentafluorophenyl)-6H- 6-oxopyridori.2-alpyrimidine-7-carboxylic acid benzyl ester
A 1.000 g (2.391 mmol) sample of the compound from Step 4 was dissolved in 25 mL of benzyl alcohol, 0.09 mL of titanium tetraethoxide was added and the mixture was stirred at 90°C for 20 hours. The reaction was diluted with methylene chloride, washed (lx) with 10% HCI and concentrated in a rotary evaporator. The crude product was purified in a kugelrohr apparatus to yield a yellow solid, which was washed with ether and dried to afford 0.457 g of the title compound, which was taken directly to the next step. Step 6. 2-(3-(N-t-Butoxycarbonyl)aminopyrroUdin-l-yl)- 3-fluoro-9-(2,3,4,5,6-pentafluorophenyl)-6H-6- oxopyridori.2-alpyrimidine-7-carboxylic acid benzyl ester
A 0.400 g (0.833 mmol) sample of the compound from Step 5 was dissolved in 10 mL of methylene chloride and 0.746 mL of DMF, and 0.870 mL of POCI3 were added and stirred under a dry N2 atmosphere at room temperature for 1.7 hours. The reaction was quenched with ice and the mixture extracted with methylene chloride which was washed (2x) with water. The organic layer was added to a stirred solution of 0.235 g (1.2 mmol) of 2-(N-t-butoxycarbonylamino)pyrrolidine in 4 mL of triethylamine. The solvent was removed by evaporation, and the product was purified by column chromatography on sUica gel, eluting with 2.5: 100 methanol:methylene chloride . Removal of the solvent afforded 0.353 g of the title product as a yellow crystaUine solid, mp 107-108°C. MZ M/Z 649 (M+H). NMR (CDCI3) d 1.44 (s, 9H), 1.90-2.30 (m, 2H), 3.40-4.65 (m, 5H), 5.38 (s, 2H), 7.35 (m, 3H), 7.48 (m, 2H), 8.34 (s, IH), 9.14 and 9.15 (two d, IH, J=9 Hz).
Step 7. 2-(3-(N-t-Butoxycarbonyl)aminopyrrolidin-l-yl)-3-fluoro-9-(2,3,4,5,6- pentafluorophenyl)-6H-6-oxopyridor 1.2-alpyrimidine-7-carboxylic acid
A 0.335 g ( 0.516 mmol) sample of the compound from Step 6 was dissolved in 40 mL of dry methanol, and the benzyl ester was removed by reacting with 2.0 mL of 98% formic acid in the presence of 0.100 g of 10% Pd/C, stirring under a dry N2 atmosphere for .0.25 hours. After filtration and evaporation of the solvent, the product was purified by column chromatography on siUca gel, eluting with 1:15:100 acetic acid:methanol:methylene chloride to afford, after removal of the solvent, the title compound as a yellow soUd, which was taken directly to the next step.
Step 8. 2-(3-Aminopyrrolidin- 1 -yl)-3-fluoro-9-(2,3,4,5,6-pentafluorophenyl)- 6H-6-oxopyridori.2-alpyrimidine-7-carboxylic acid hydrochloride salt
The compound from the previous step was dissolved in 10 mL of 4 N HCI in dioxane and stirred at room temperature for 0.7 hours, after which the solvent was removed under vacuum. The residue was dissolved in water which was filtered through sintered glass and freeze-dried to afford 0.232 g of the title compound as a yellow solid, mp 202-204°C. MS M/Z 459 (M-Cl). NMR (CD3OD): d 2.12-2.54 (m, 2H), 3.70-4.36 (m, 5H), 8.42 (s, IH), 9.21 (d, IH, J=9 Hz). IR (KBr): 1715, 1660, 1630 cm"1. Analysis calculated for Ci9Hi2F6N4θ3»HCl»0.5H2θ: C, 45.30; H, 2.80; N, 11.12. Found: C, 45.46; H, 2.39; N, 10.57.
Example 173 2-((2S, 4S)-4-(N-(S)-Alanyl-(S)-alanyl)amino-2- methylpyrrolidin- 1 -yl)-9-(2,4-difluorophenyl)-3-fluoro-6H- 6-oxopyridoπ.2-alpyrimidine-7-carboxyUc acid hydrochloride
Step 1. 2-((2S,4S)-4-amino-2-methylpyrrolidin- 1 -yl)-9-(2,4-difluorophenyl)- 3-fluoro-6H-6-oxopyridoπ.2-alpyrimidine-7-carboxylic acid benzyl ester
FoUowing the procedure described in Example 166 Step 1, replacing the boc- protected benzyl ester compound with a 2.345 mmol sample of 2-((2S,4S)-4-t- butoxycarbonylamino-2-methylpyrrolidin-l-yl)-9-(2,4-difluorophenyl)-3-fluoro-6H-6- oxopyrido[l,2-a]pyrimidine-7-carboxyUc acid benzyl ester, from Example 171 Step 6, the boc protecting group was removed to afford 1.06 g of the titie compound.
Step 2. 2-((2S, 4S)-4-(N-(N_Benzoyloxycarbonyl)-(S)-alanyl-
(S)-alanyl)amino-2-methylpyrroUdin- 1 -yl)-9-(2,4-difluorophenyl)- 3-fluoro-6H-6-oxopyridori.2-alpyrimidine-7-carboxylic acid benzyl ester
FoUowing the procedure of Example 168 Step 1 , replacing the benzyl ester compound of that example with 1.06 g of the compound from Step 1 above, 0.98 g of the title compound was prepared.
Step 3. 2-((2S, 4S)-4-(N-(S)-Alanyl-(S)-alanyl)amino- 2-methylpyrroUdin- 1 -yl)-9-(2,4-difluorophenyl)-3-fluoro- 6H-6-oxopyridori.2-alpyrimidine-7-carboxyUc acid hydrochloride
Following the procedure of Example 168 Step 2, replacing the boc-protected benzyl ester compound of that example with the compound from Step 2 above, 0.66 g of the title compound was prepared. Mp 198-200°C. MS M/Z 561 (M-Cl). NMR (CD3OD): d 1.14 and 1.40 (two d, 3H, J=7 Hz), 1.34 and 1.35 (two d, 3H, J=7 Hz), 1.50 and 1.51 (two d, 3H, J=7 Hz), 1.96-2.11 (m, 2H), 3.50-4.60 (m, 6H), 7.40 (m, 2H), 7.47 (m, IH), 8.26 and 8.29 (two s, IH), 9.12 and 9.16 (two d, IH, J=9 Hz). Example 174
9-(2,4-Difluorophenyl)-3-fluoro-2-hydroxy-4-methyl-6H- 6-oxopyrido 1.2-alpyrimidine-7-carboxyUc acid ethyl ester
Step I . 2-(2.4-Difluororjenzyl)-5-fluoro-4-hydroxy-6-methylpyrimidine
A mixture of 8.6 g (0.0445 mmol) of 2-(2,4-difluorophenyl)-acetamidine hydrochloride, prepared as in Example 159 Step 1, and 6.1 g (0.0405 mmol) of ethyl 2- fluoro-3-oxo-butanoate (prepared as described by E. O. Bergmann, S. Cohen, and I. Shahak, J. Chem .Soc, 3278. (1959)), in 30 mL of anhydrous methanol and 10.1 mL of a 2.5% solution of sodium methoxide was heated at reflux under a dry N2 atmosphere for 16 hours. The solvent was removed by evaporation under vacuum, and the residue was washed with water, then 200 mL of water added and the mixture was acidified and the resulting precipitate was fUtered off. The aqueous solution was then extracted (3x) with methylene chloride. The solvent was washed with water, dried over anhydrous magnesium sulfate, and the solvent was removed by evaporation under vacuum to give a dark soUd. The solid was washed with ethyl ether and dried, then combined with the earlier precipitate which was recrystaUized from methanohether to afford 4.51 g of the title compound. MS M/Z 272 (M+NH4). NMR: (CDCI3) d 2.22 (d, 3H, J=4 Hz), 3.92 (s, 2H), 6.92 (m, 2H), 7.30 (m, IH).
Step 2. 3-(2,4-Difluorophenyl)-2-ethoxy-3-(5-fluoro-4-hydroxy- 6-methylpyrimidin-2-yl)propane-l.l-dicarboxylic acid diethyl ester
A 0.615 g (2.42 mmol) sample of the compound from Step 1 above was dissolved in THF and cooled to -78°C with stirring under a dry N2 atmosphere. To this was slowly added 1.98 mL of 2.5 N n-butyUithium in hexane, and the mixture was stirred for 30 min. Then 0.586 mL (2.9 mmol) of diethyl ethoxymethylenemalonate was added at -78 °C and the mixture stirred for an additional 15 min at room temperature. The reaction mixture was quenched with 10% HCI untU the mixture was about pH 3, whereupon it was then extracted with ethyl acetate. This was dried over anhydrous magnesium sulfate, and the solvent was removed by evaporation under vacuum to afford 1.6 g of the title compound as a yellow oil. This material was taken directly to the next step. Step 3. 9-(2,4-Difluorophenyl)-3-fluoro-2-hydroxy-4-methyl- 6H-6-oxopyridori.2-alpyrimidine-7-carboxyUc acid ethyl ester
The compound from Step 2 was dissolved in toluene, 0.62 mL of DBU was added and the mixture heated at reflux in a flask equipped with a Dean-Stark condenser for 16 hours under a dry N2 atmosphere. The mixture was removed from the heat and stirred with 70 mL of water for 2 hours. After separation, the organic phase was dried over magnesioum sulfate, and the solvent was removed by evaporation. The residue was purified by column chromatography on siUca gel, eluting with 1:5:100 acetic acid:methanol:methylene chloride to afford 0.175 g of the title compound as a yeUow solid. MS M/Z: 379 (M+H). NMR:(DMSO-d6) d 1.21 (t, 3H, J=7 Hz), 2.07 (d, 3H, J=4 Hz), 4.10 (q, 2H, J=7 Hz), 7.03 (m, IH), 7.16 (m, IH), 7.38 (m, IH), 7.66 (s, IH).
Examples 175-178
By foUowing the procedures described in Example 174 and substituting the appropriate ester for ethyl 2-fluoro-3-oxobutyrate, Examples 175-178 may be prepared as disclosed in Table 6 (where R = ethyl and R1 = 2,4-difluorophenyl).
Table 6
Examples 179-195
By foUowing the procedures described in Example 160 Steps 3, 4 and 5 and Example 161, and replacing 2-(N-t-butoxycarbonylamino)pyrroUdine in Step 4 with the appropriate N-methyl- or boc-protected amine, Examples 179-195 may be prepared as disclosed in Table 7 (where R1 = 2.4-difluorophenyl). Table 7
Example No. R2 R5
NH2
180 -CH2F
185 ft CH2NHCH2CH3 -CH2F 186 ft CH2NHCH2CH3 -CHF2
187 ft CH2 'NHCH2CH3 _Cp3
f—
192 CH3-N N-
-CH3
193 CH3-N N-
-CH2F
194 CH3-N N-
-CHF2 —
195 CH3-N N-
-CF3 Examples 196-240
By foUowing the procedures described in Example 160 Steps 3, 4 and 5 and Example 161, replacing 2-(N-t-butoxycarbonylamino)pyrrolidine in Step 4 with the appropriate substituted or boc-protected amine and replacing 9-(2,4-difluoro-phenyl)-3- fluoro-2-hydroxy-6H-6-oxopyrido[l,2-a]pyrimidine-7-carboxylic acid benzyl ester with the compound containing the appropriate R group (as described in Examples 2 and 39), Examples 196-240 may be prepared as disclosed in Table 8.1 to 8.3 in which: R1 is 4- fluorophenyl (Table 8.1), 2,4-difluorophenyl (Table 8.2) or cyclopropyl (Table 8.3); and R5 is hydrogen.
Table 8.1
R ! = 4-fluorophenyl. R5 = H:
Example No. Example No
202 HN N- 209
CH CH, NH2Y>
CH3O"^
R = cyclopropyl. R^ = H:
Example No. _B2 Example No FT
Examples 241-250 By following the procedures of Example 157 Steps 2-8, replacing 2-cyclopropyl- 2-ethoxycarbonylacetamidine hydrochloride in Step 2 with the compound containing the appropriate R1 group (refer to compound 6B in Scheme II), and replacing the 3-(N-t- butoxycarbonyl)aminopyrroUdine in Step 6 with the appropriately protected amine, examples 241-250 may be prepared as disclosed in Table 9, above, (in which R^ is hydrogen).
Example No. FT R1
/ — \
246 N N-
^
248 — ^ CH3
N N-
249 N N- F3C~
250 N N- FCH2CH2- Examples 251-252
By foUowing the procedures of Example 157, steps 2-8, replacing replacing 2- cyclopropyl-2-ethoxycarbonylacetamidine hydrochloride in Step 2 with 2-(N- benzoyloxycarbonyl-N-methylarnino)-2-ethoxycarbonylacetamidine hydrochloride , and replacing the 3-(N-t-butoxycarbonyl)aminopyrroUdine in Step 6 with the appropriately protected amine, Examples 251-252 may be prepared as disclosed in Table 10 (in which R^ = H).
Table 10
Example No. R2 R1 ,
252 HN N- CH3NH-
Example 253 8-(3- Amino- 1 -pyrroUdinyl)- 1 -cyclopropy l-7-fiuoro-9- methyl-4-oxo-4H-quinolizine-3-carboxylic acid
Step 253a. 4-t-Butoxy-3-chloro-2.5.6-trifluoropyridine
To 250 mL of a THF solution containing 106 g (0.571 mmol) of a mixture of 4- chloro-tetrafluoropyridine and 3-chloro-tetrahydropyridine (approx 70:30 ratio, from
Aldrich Chemical Co.) at -78°C was added a solution of 38.3 g (0.399 mmol) of sodium t- butoxide in 350 mL of THF, and the solution was stirred for 2 hours at -78°C and at ambient temperature for 16 hours. The mixture was poured into 500 mL of hexane, and this mixture was filtered through celite and the filtrate concentrated. The residue was purified by flash chromatography, eluting first with hexane, then ethyl acetate:hexane (1:4), to separate the desired titie product from the mixture of products. MS 238, 240 (M+H)+; IH NMR (CDCI3) θ: 1.52 (d, J=2Hz); 19F NMR (CDCI3, CFCI3 as reference) θ: 73.75 (dd, Jι=14.2, J2=23.2 Hz), 89.71 (dd, Ji=14.2, J2=21.98 Hz); 152.42 (apparent t, J=22 Hz). Step 253b. 4-t-Butoxy-2.3.6-trifluoropyridine
To the product from Step 253a above (24.92 g, 0.104 mmol) in 100 mL of methanol was added 2.5 g of Pearlman's catalyst (Aldrich Chemical Co.), and the mixture was stirred at ambient temperature for 14 hours under and atmosphere of hydrogen. An additional 2.5 g of catalyst was added, and the mixture was stirred for another 22 hours. The mixture was filtered, the filtrate was concentrated, and the residue was extracted with hexane/ether. After filtration, the solvent was removed by evaporation, and the residue was purified by flash chromatography (ethyl acetate:hexane 1:16) to yield 12.05 g of the title product. MS 206 (M+H)+, 233 (M+18)+; IH NMR (CDCI3) 3: 1.52 (s, 9H), 6.51 (m, IH); 19F NMR (CDCI3, CFCI3 as reference) d: 72.60 (dd, J]=14.3, J2=21.0 Hz), 89.74 (dd, Jι=14.3, J2=21.0 Hz), 164.68 (dt, Jι=4.2, J2=21.0 Hz).
Step 253c. 4-t-Butoxy-2.3.6-trifluoro-5-methylpyridine
A freshly prepared solution of lithium diethylamide (LDA) (58.21 mmol) in 30 mL of THF at -78°C was added to 10.0 g (48.74 mmol) of the product from Step 253b in 50 mL of THF at -78°C, and the reaction was stirred for 50 min. To the reaction mixture was added 4.3 mL (69.07 mmol) of methyl iodide, and the mixture was stirred at -78°C for 1 hour and stirred at ambient temperature for 16 hours. The reaction was quenched with saturated NH4CI solution, extracted with hexane, and the extracts washed with water, dried over MgSO4 and concentrated to give the title product as a pale yeUow oU, which was taken directly to the next step. MS (220) (M+H)+; IH NMR (CDCI3) d: 1.47 (m, 9H), . 2.12 (m, 3H). 19F NMR (CDCI3, CFCI3 as reference) d: 75.91 (dd apparent, Jι=15.0, J2=22.1 Hz), 93.17 (dd apparent, J 1=15.0, J2=22.1 Hz), 156.54 (m).
Step 253d. 4-t-Butoxy-2.5-difluoro-3-methylpyridine
A sample of the product from Step 253c above (48.74 mmol) and 13.5 mL of hydrazine monohydrate were dissolved in 150 mL of n-propanol. The reaction was stirred at reflux temperature under nitrogen for 4 hours. The volatiles were removed, and the residue was dissolved in methylene chloride, which was washed with water and dried over MgSOφ The solvent was removed to give the intermediate hydrazine product as a yellow liquid, which was dissolved in 110 mL of methanol. To this was added 20 mL of 20% NaOH and air was passed through the solution for 16 hours. The solvents were removed at 30°C under vacuum. The residue was dissolved in methylene chloride, which was washed with water and dried over MgSO4. The solvent was removed and the crude product purified by flash chromatography, eluting with ethyl acetate:hexane 1:16 to give the title product as a colorless liquid after removal of the solvents. MS (202) (M+H)+; IH NMR (CDCI3) d: 1.43 (d, 9H, J=1.5 Hz), 2.18 (d, 3H, J=1.5 Hz), 7.85 (br s, IH); l°F NMR (CDCI3, CFCI3 as reference) d: 73.37 (d, J=24.5 Hz), 142.17 (d, J=24.5 Hz).
Step 253e. 2-(4-t-Butoxy-5-fluoro-3-methyl-2-pyridinyl)cyclopropaneacetonitrile
A sample of the product from Step 253d above (40.8 mmol) was dissolved in 50 mL of THF and cooled to -78°C. To this was added a freshly prepared solution of LDA (0.103 mmol) in 50 mL of THF at -78°C, and the reaction was stirred for 1 hour. The reaction was then stirred at 0°C for 1 hour, quenched with saturated NH4CI solution and extracted with ether. The extracts were washed with saturated NaCl solution, dried over MgSO4, and concentrated. The residue was purified by flash chromatography, eluting with 1 :4 ethyl acetate: hexane, to yield 10.33 g of the title product after removal of the solvent. MS 263 (M+H)+; IH NMR (CDCI3) d: 0.50 (m, 2H), 0.63 (m, IH), 0.73 (m, IH), 1.60 (m, IH), 1.43 (d, 9H, J=2 Hz), 2.29 (s, 3H), 3.76 (d, IH, J=8 Hz), 8.30 (d, IH, J=3 Hz). IR (neat) 2240, 1580, 1470 cm"1.
Step 253f. 2-(4-Chloro-5-fluoro-3-methyl-2-pyridinyl)cyclopropaneacetonitrile
A sample of the product from Step 253e above (5.21 g, 19.86 mmol) was dissolved in 50 mL of trifluoroacetic acid, the reaction was stirred under nitrogen for 1 hour at ambient temperature, and the material concentrated to dryness. The residue was dissolved in a mixture of 15.6 mL of DMF and 90 mL of methylene chloride. This solution was cooled in a water bath as 18.8 mL (19.86 mmol) of POCI3 was added, then the reaction was stirred at ambient temperature for 16 hours. The reaction was quenched by pouring it into ice water, and the mixture was extracted with methylene chloride. The aqueous solution was adjusted to pH7 with NaOH and re-extracted with methylene chloride. The extracts were combined and washed with water, dried over MgSO4 and concentrated. The residue was purified by flash chromatography with 1 :4 ethyl acetate:hexane to give 3.26 g of the titie product as a colorless liquid after removal of the solvents. MS 225, 227 (M+H)+; IH NMR (CDCI3) θ: 0.48 (m, IH), 0.59 (m, IH), 0.66 (m, IH), 0.77 (m, IH), 1.50 (m, IH), 2.48 (s, 3H), 3.80 (d, IH, J=8 Hz), 8.39 (s, IH). IR (neat) 2240, 1570, 1460 cm" 1. Step 253 . Ethyl Σ-^-chloro-S-fluoro-S-methyl-Σ-pyridinvDcvclopropaneacetate
A sample of the product from Step 253f above (3.26 g, 14.51 mmol) was dissolved in 10 mL of ethanol, and gaseous HCI was introduced until 4 g had been dissolved. The solution was heated to reflux, and 0.36 mL of water was added, then the mixture was stirred for 1 hour. The reaction was cooled, then poured into water, and the mixture was adjusted to pH7 with NaHCO3. The mixture was then extracted with methylene chloride, which was washed with water, dried over MgSO4 and concentrated. The residue was triturated with 1:4 ethyl acetate:hexane, and filtered. The filtrate was concentrated and the residue was purified by flash chromatography with 1 :4 ethyl acetate:hexane to give 2.262 g of the title product after removal of the solvent MS 272, 274 (M+H)+; IH NMR (CDCI3) d: 0.12 (m, IH), 0.38 (m, IH), 0.53 (m, IH), 0.76 (m, IH), 1.20 (t, 3H, J=7 Hz), 1.67 (m, IH), 2.40 (s, 3H), 3.23 (d, IH, J=9 Hz), 4.16 (q, 2H, J=7 Hz), 8.36 (s, IH).
Step 253h. 2-('4-Chloro-5-fluoro-3-methyl-2-pyridiny cvclopropane-acetaldehvde
A sample of the product from Step 253g above (1.73 g, 6.37 mmol) was dissolved in 10 mL of THF and stirred with water bath cooling and 3.2 mmol of LiAlH4 (LAH) was added. The mixture was stirred at ambient temperature for 1 hour, then poured into water. This mixture was extracted with ether, the extracts were washed, dried and concentrated to give 1.48 g of a colorless oU. This oil was dissolved in 10 mL of methylene chloride and added to a solution of 3.8 mL (7.6 mmol) of oxalyl chloride and 1.1 mL of DMSO (15.5 mmol) in 15 mL of methylene chloride stirred at -78°C. The solution was stirred for 15 min, and 4.4 mL (31.6 mmol) of triethylamine was added. The stirring was continued at -78°C for 5 min and at -10°C for 10 min. The reaction was quenched with water, and extracted with methylene chloride. The extract was washed, dried and concentrated to give 1.49 g of the crude title product which was taken directly to the next step without further purification. MS 228, 230 (M+H)+; IH NMR (CDCI3) d: 0.25 (m, IH), 0.35 (m, IH), 0.60 (m, IH), 0.75 (m, IH), 1.53 (m, IH), 2.38 (s, 3H), 3.19 (dd, IH, J=3, J=9 Hz), 8.37 (s, IH), 9.86 (d, IH, J=3 Hz).
Step 253i. 8-Chloro- 1 -cyclopropyl-7-fluoro-9-methyl-4-oxo- 4H-quinoUzine-3-carboxylic acid ethyl ester
A sample of the product from Step 253h above (6.37 mmol) was dissolved in 50 mL of ethanol, and to this were added 1.5 mL of piperidine, 1.5 mL of acetic acid, and 5 mL of diethyl malonate (32.9 mmol). The reaction was heated at reflux under nitrogen for 4 hours. The solvents were then removed, and the residue was dissolved in ether. The ether was washed with water and brine, then dried over MgSO4 and concentrated Purification in a kugelrohr apparatus gave 2.4 g of the crude condensation product This intermediate product was dissolved in 20 ML of of Dowtherm A™, and this solution was added to 100 mL of Dowtherm A™ heated to 235°C. The reaction was then stirred at 220°C for 45 min. After cooUng, the product was separated from the solvent by flash chromatography, eluting with hexane to remove the solvent and then with 1 :4 ethyl acetate hexane to remove the product. In this manner 1.065 g of the tifle product was obtained after removal of the solvent. MS 324, 326 (M+H)+; IH NMR (CDCI3) 9: 0.75 (m, 2H), 1.07 (m, 2H), 1.42 (t, 3H, J=7 Hz), 2.31 (m, IH), 3.08 (s, 3H), 4.42 (q, 2H, J=7 Hz), 8.40 (s, IH), 9.44 (d, IH, J=6 Hz).
Step 253j. 8-(3-(N-BOC-amino)pyrrolidinyl)-l-cyclopropyl- 7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid ethyl ester
A sample of the product from Step 253i above (0.500 g, 1.544 mmol) was dissolved in 20 mL of anhydrous acetonitrile, and 0.600 g of sodium bicarbonate and 0.600 g (3.22 mmol) of 3(S)-(BOC-amino)pyrrolidine were added. The mixture was heated at reflux under nitrogen for 7 hours, then the solvent was removed and the residue was redissolved in methylene chloride. This solution was washed with water, 5% HCI, water, and concentrated.. The residue was purified by flash chromatography, eluting with 100:10 methylene chloride:methanol, followed by 100:10:0.5 methylene chloride: methanol:NH4θH. Removal of the solvent gave 0.778 g of the title product, which was taken directly to the next step.
Step 253k. 8-(3-(N-BOC-amino)pyrrolidinyl)-l-cyclopropyl- 7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid
A sample of the product from Step 253j above (0.778 g, 1.645 mmol) was dissolved in 20 mL of THF, 0.570 g of LiOH«H2O and 10 mL of water were added, and the mixture was stirred under nitrogen for 3 hours. The THF was removed under vacuum, and the residue was adjusted to a pH between 2 and 4 with 1 N HCI. The solid was collected, and the filtrate was extracted with methylene chloride and washed and concentrated to give additional product The combined soUds were purified by flash chromatography eluting with 100:5:1 methylene chloride:methanol:acetic acid to yield 0.698 g of the title product after removal of the solvent. This material was taken directly to the next step.
Step 2531. 8-(3-aminopyrroUdinyl)-l-cyclopropyl-7-fluoro- 9-methyl-4-oxo-4H-quinolizine-3-carboxyUc acid hydrochloride
A sample of the product from Step 253k above (0.697 g, 1.564 mmol) was dissolved in 17 mL of anhydrous methylene chloride, 5.0 mL of 4 N HCI in dioxane was added, and the reaction was stirred for 1.75 hours. Ether was added, and the precipitate was coUected by filtration and washed with ether. The solid was dissolved in water, filtered through a sintered glass funnel, and freeze-dried to give the title product as a yeUow solid, mp 230-232°C (dec). MS 346 (M-C1)+; IH NMR (DMSO) d: 0.58(m, 2H), 0.99
(m, 2H), 2.15 (m, IH), 2.31 (m, 2H), 2.63 (s, 3H), 3.77 (m, 2H), 3.99-4.06 (m, 3H),
7.94 (s, IH), 8.39 (br s, 3H), 9.10 (d, IH, J=l l Hz), 13.85 (br s); IR 3440, 1695, 1610 cm" -1
Example 254
8-(3-(aminomethyl)pyrroUdinyl)- 1 -cyclopropyl-7-fluoro- 9-methyl-4-oxo-4H-quinoUzine-3-carboxylic acid hydrochloride
The 3-(BOC-amino)pyrrolidine of Step 253j above was replaced by 3-BOC- aminomethylpyrroUdine and the reaction product was carried forward as in Steps 253 K and 2531, above, to prepare 0.085 g of the title compound. MS 360 (M-C1)+; IH NMR (DMSO) θ: 0.60 (m, 2H), 0.99 (m, 2H), 1.81 (m, IH), 2.18 (m, IH), 2.30 (m, IH), 2.60 (s, 3H), 2.98 (m, 2H), 3.66-3.81 (m, 5H), 7.90 (s, IH), 8.09 (br s, 3H), 9.06 (d, IH, J=l l Hz), 13.85 (br s, IH).
Example 255
8-(2S,4S-4-amino-2-methylpyrrolidinyl)- 1 -cyclopropyl- 7-fluoro-9-methyl-4-oxo-4H-quinoUzine-3-carboxylic acid hydrochloride
The 3-BOC-aminopyιτoUdine of Step 253j above was replaced by (2S,4S)-4- (BOC-amino)-2-methylpyrroUdine and the reaction product was carried forward as in Steps 253K and 2531, above, to prepare 0.071 g of the title compound. MS 360 (M-C1)+; IH NMR (DMSO) 3: 0.51 (m, IH), 0.63 (m, IH), 0.90 (m, IH), 1.09 (m, IH), 1.17 (d, 3H, J=6 Hz), 2.01 (m, IH), 2.40 (m, 2H), 2.64 (s, 3H), 3.40 (m, IH), 3.98 (m, IH), 4.31 (m, IH), 4.61 (m, IH), 8.00 (s, IH), 9.17 (d, IH, J=l l Hz). Example 256
8-(3-aιτrinoazetidinyl)-l-cyclopropyl-7-fluoro-9-methyl- 4-oxo-4H-quinolizine-3-carboxylic acid hydrochloride
The 3-BOC-aminopyrroUdine of Step 253j above was replaced by 3-(BOC- amino)azetidine and the reaction product was carried forward as in Steps 253K and 2531, above, to prepare 0.094 g of the title compound. MS 332 (M-C1)+; IH NMR (DMSO) 3: 0.61 (m, 2H), 1.00 (m, 2H), 2.30 (m, IH), 2.61 (s, 3H), 4.15 (m, IH), 4.56 (m, 2H), 4.86 (m, 2H), 7.89 (s, IH), 8.51 (br s, 3H), 9.13 (d, IH, J=10 Hz).
Example 257
8-(3(S)-aminopyrrolidinyl)- 1 -cyclopropyl-7-fluoro- 9-methyl-4-oxo-4H-quinoUzine-3-carboxyUc acid hydrochloride
The 3-BOC-aminopyrrolidine of Step 253j above was replaced by 3(S)-(BOC- amino)pyrroUdine and the reaction product was carried forward as in Steps 253K and 2531, above, to prepare 0.087 g of the title compound. MS 346 (M-C1)+; IH NMR (DMSO) 3: 0.59 (m, 2H), 0.99 (m, 2H), 2.14 (m, IH), 2.31 (m, 2H), 2.63 (s, 3H), 3.76 (m, 2H), 3.98-4.07 (m, 3H), 7.94 (s, IH), 8.36 (br s, 3H), 9.11 (d, IH, J=l l Hz).
Example 258 l-cyclopropyl-7-fluoro-9-methyl-4-oxo-8-(3-methyl- l-piperazinyl)-4H-quinolizine-3-carboxylic acid hydrochloride
The 3-BOC-aminopyrrolidine of Step 253j above was replaced by
2-methylpiperazine (Aldrich Chemical Co.), and the reaction product was carried forward as in Steps 253K and 2531, above, to prepare 225 mg of the title compound, mp > 300°C. IR (KBr): 3420, 1720, 1650 cm" 1. MS 360 (M-C1)+. l NMR (CD3OD) 3: 0.75 (m, 2H), 1.10 (m, 2H), 1.40 (d, 3H, J=7.5 Hz), 2.90 (s, 3H), 3.45 (m, 3H), 3.71 (m, 4H), 8.23 (s, IH), 9.40 (d, IH, J=12 Hz). Calc. for Ci9H23ClFN3θ3»1.25 H2O: C, 54.55; H, 6.14; N, 10.04; Found: C, 54.78; H, 5.78; N, 10.05. Example 259 l-cyclopropyl-7-fluoro-9-methyl-4-oxo-8-piperazinyl- 4H-quinoUzine-3-carboxylic acid hydrochloride
The 3-BOC-aminopyrroUdine of Step 253j above was replaced by piperazine
(Aldrich Chemical Co.), and the reaction product was carried forward as in Steps 253K and 2531, above, to prepare 75 mg of the title compound, mp = 279-280°C. IR (KBr): 3420, 1710, 1650, 1610 cm"1. MS 346 (M-C1)+. 1H NMR (CD3OD) 9: 0.72 (m, 2H), 2.43 (m, IH), 2.92 (s, 3H), 3.43 (m, 4H), 3.72 (m, 4H), 8.25 (s, IH), 9.30 (d, IH, J=12 Hz). Calc. for Ci8H2lClFN3θ3»1.5 H2O: C, 55.32; H, 5.67; N, 10.75; Found: C, 55.52; H, 5.49; N, 10.59.
Example 260 l-cyclopropyl-7-fluoro-9-methyl-8-(2-((N-methyl)aminomethyl)- 4-morphoUnyl)-4-oxo-4H-quinoUzine-3-carboxylic acid hydrochloride
Step 260a. l-N-benzyl-S-fchloromethvPmorpholine
A mixture of 1.5 g (10 mmol) of N-benzyl-ethanolamine (Aldrich Chemical Co.) and 7.8 mL of epichlorohydrin was heated at 40°C for 30 min. The reaction was cooled, and the excess epichlorohydrin was removed with a rotary evaporator. The residue was dried under vacuum, dissolved in 30 mL of cone. H2SO4, and the mixture heated at 150°C for 30 min. The reaction was quenched by pouring onto ice, and the pH was adjusted with NaOH to pH 13. The basic solution was extracted with toulene (3x), and the extracts were dried over Na2SO4, fUtered, and the solvent remove under vacuum. The residue was dried under vacuum to yield 193 mg of the titie product.
Step 260b. 1 -N-benzyl-3-f fN-methylamino)methyl')-morphoUne
A thick-walled glass tube was charged with 8.83 g of N-benzyl-3- (chloromethyl)morpholine, from step 260a above, dissolved in 15 mL of methanol. The tube and its contents were cooled and 25 mL of anhydrous methylamine was added. The tube was sealed and heated at 100°C for 24 hours. The seal was broken, and the solvent was removed under vaccum. The residue was dUuted with 100 mL of 10% Na2CO3, then extracted 3x with methylene chloride. The extract was dried over Na2SO4, filtered, and the solvent was removed on a rotary evaporator to yield 8.6 g of the tifle product. Step 260c. l-N-benzyl-3-(CN-BOC-N-methylamino")methyl -mo hoUne
To a dry flask under positive N2 atmosphere was added 8.6 g (39 mmol) of the l-N-benzyl-3-((N-methylamino)methyl)-morpholine, from step 260b above, in 100 mL of dry methylene chloride. The solution was cooled in an ice bath and 8.6 mL (64.3 mmol) of triethylamine and 12.7 g (58.5 mmol) of di-t-butyldicarbonate was added. The reaction mixture was stirred at 0-5 °C for 30 min, then warmed to room temperature and stirred for 72 hours. The reaction contents were dUuted with 100 mL of methylene chloride, which was then washed with water and dried over Na2SO4. The solution was fUtered, the solvent was removed on a rotary evaporator, and the residue dried under vacuum to afford 12.4 g of crude title product. The product was purified by column chromatography to yield 7.4 g of the title product as a colorless oil. Anal Calc. for Cl 1H22N2O3: C, 67.47; H, 8.81;,N, 8.74; Found: C, 67.00; H, 8.53; N, 8.66.
Step 260d. 2-fN-BOC-N-methyl-aιτunomethyl)morphoUne
A 1.10 g (3.43 mmol sample of l-N-benzyl-3-((N-BOC-N- methylamino)methyl)-morphoUne, from step 260c above, was dissolved in 100 mL of methanol. To this was added 500 mg of 20%Pd/C, and the mixture was stirred at room temperature under 4 arm of H2 for 16 hours. The catalyst was removed by filtration, the solvent was removed with a rotary evaporator, and the residue was dried under vacuum to yield 794 mg of the title product as a colorless oU.
Step 260e. 1 -cyclopropyl-7 -fluoro- 9-methyl-8-(2-((N-methyl)aminomethyl)- 4-morphoUnyl)-4-oxo-4H-quinolizine-3-carboxylic acid hydrochloride
The 3-BOC-aminopyrroUdine of Step 253j above was replaced by 2-(N-BOC-N- methyl-aminomethyl)morpholine (from step 260d above)and the reaction product was carried forward as in Steps 253K and 2531, above, to prepare 280 mg of the titie compound, mp = 208-210°C. IR (KBr): 3420, 1720, 1700, 1650 cm" 1. MS 390 (M- Cl)+. !H NMR (CD3OD) 3: 0.70 (m, 2H), 1.10 (m, 2H), 2.38 (m,lH), 2.78 (s, 3H),2.90 (s, 3H), 3.10-3.30 (m, 2H), 3.50-4.15 (m, 7H), 8.12 (s, IH), 9.20 (d, IH, J=14 Hz). Calc. for C2θH25ClFN3θ4«2H2θ: C, 52.01; H, 6.33; N, 9.10; Found: C, 51.90; H, 5.92; N, 9.09. Example 261 l-cyclopropyl-7-fluoro-9-methyl-4-oxo-8-(l,2,3,4- tetrahvdro-2-isoquinoUnyl)-4H-quinolizine-3-carboxylic acid
The 3-BOC-aminopyrrolidine of Step 253j above was replaced by 1,2,3,4- tetrahydroisoquinoUne (Aldrich Chemical Co.), and the reaction product was carried forward as in Steps 253K and 2531, above, to prepare 315 mg of the title compound, mp = 214-215°C. IR (KBr): 3420, 1730, 1680 cm"1. MS 393 (M+H)+. lR NMR (CDCI3) 3: 0.70 (m, 2H), 1.08 (m, 2H), 2.30 (m,lH), 2.85 (s, 3H),3.10 (dd, 2H, J=6 Hz), 3.75 (m,
2H), 4.60 (s, 2H), 7.28 (m, 4H), 8.40 (s, IH), 9.22 (d, IH, J=12 Hz). Calc. for
C23H2lFN2θ3»1.25 H2O: C, 66.58; H, 5.71; H, 6.75; Found: C, 66.56; H, 5.26; N,
6.62.
Example 262 l-cyclopropyl-7-fluoro-9-methyl-4-oxo-8-(4-amino-l-piperdinyl)-
4H-quinoUzine-3-carboxylic acid hydrochloride
Step 262a. N-benzyl-4-(N-hydroxyimino')piperidine
A 3.78 g (20 mmol) sample of N-benzyl-4-oxo-piperidine (Aldrich Chemcial Co.) was dissolved in 50 mL of methanol. To this solution was added 4.16 g (60 mmol) of hydroxylamine hydrochloride and 5.2 g NaHCO3 (62 mmol) (Dissolved in 80 mL of water and added in 5 mL portions). The mixture was then stirred at room temperature for 18 hours. The mixture was filtered, and the solvent was removed from the filtrate on a rotary evaporator to give 3.05 g of the titie product, mp 127-128°C.
Step 262b. l-N-benzyl-4-aminopiperidine
A 2.04 g (9.98 mmol) sample of the oxime from step 262a above was dissolved in 200 mL of methanol and reduced with 10 g of Raney nickel under 4 atmosphere of H2 at room temperature for 4 hours. The catalyst was removed by filtration, and the solvent was removed on a rotary evaporator. The residue was dried under vacuum to yield 1.79 g of the titie product MS M/Z: 191 (M+H)+.
Step 262c. l-N-benzyl-4-BOC-aminopiperidine
In a dry system under N2 pressure was introduced 1.78 g of the l-N-benzyl-4- aminopiperidine, from step 262b above, dissolved in 9 mL of dry methylene chloride. To this was added 1.6 mL (12 mmol) of triethylamine and 2.45 g (11.2 mmol) of di-t- butyldicarbonate. The reaction mixture was stirred at room temperature for 96 hours. The contents were dUuted with 125 mL of methylene chloride and washed with water. The organic layer was dried over Na2SO4, filtered, and the solvent removed on a rotary evaporator. The residue was dried under vacuum to yield 2.45 g of the title product as an off-white solid. The crude product was purified by column chromatography on silica gel, eluting with 2% methanol in methylene chloride. Removal of the solvent gave 1.74 g of product, which was the recrystaUized from ethanol, and dried under vacuum, mp. 121- 122°C. Anal. calc. for C17H25N2O2: C, 70.31; H, 9.02; N, 9.65; Found: C, 70.26; H, 9.02; N, 9.55.
Step 262d. 4-BOC-aminopiperidine
The benzyl group was removed from the product of step 262c by the procedure described for Example 260d above, to afford the title product.
Step 262e. l-cyclopropyl-7-fluoro-9-methyl-4-oxo-8-(4-amino-l- piperdinyl')-4H-quinolizine-3-carboxylic acid hydrochloride
The 3-BOC-aminopyrroUdine of Step 253j above was replaced by 4-(BOC- amino)-methylpiperidine, from step 262d above, and the reaction product was carried forward as in Steps 253K and 2531, above, to prepare 480 mg of the title compound, mp = 231-232°C. IR (KBr): 3420, 1700, 1610 cm"1. MS 360 (M-C1)+ 1H NMR (CD3OD) 3: 0.70 (m, 2H), 1.08 (m, 2H), 1.85 (m,lH), 2.10 (m, IH), 2.18 (m, 2H), 2.35 (m, 2H), 2.87 (s, 3H), 3.50 (m, 2H), 3.70 (m, IH), 8.16 (s, IH), 9.22 (d, 2H, J=9 Hz). Calc. for Cl9H23ClFN3O3«0.75 H2O: C, 55.75; H, 6.03; H, 10.26; Found: C, 55.70; H, 6.07; N, 10.36.
Example 263 l-cyclopropyl-7 -fluoro- 9-methyl-4-oxo-8-(3-amino-l- piperdinylV4H-quinoUzine-3-carboxylic acid hydrochloride
The 3-BOC-aminopyrrolidine of Step 253j above was replaced by 3-amino- piperidine hydrochloride (Aldrich Chemical Co.), which was neutralized with triethylamine, and the reaction product was carried forward as in Steps 253K and 2531, above, to prepare 250 mg of the titie compound, mp = 222-223°C. IR (KBr): 3400, 1700, 1680 cm" 1. MS 360 (M-C1)+. lU NMR (CD3OD) 3: 0.70 ( , 2H, J=6 Hz), 1.10 (m, 2H, J=6 Hz), 1.70 (m,2H), 2.05 (m, 3H), 2.30 (m, 2H), 2.40 (m, 2H), 2.87 (s, 3H), 3.90 (m, IH), 8.18 (s, IH), 9.20 (d, IH, J=9 Hz). Calc. for Ci9H23ClFN3θ3«2 H2O: C, 52.84; H, 6.30; H, 9.73; Found: C, 52.62; H, 6.62; N, 9.36.
Example 264 l-cyclopropyl-7-fluoro-9-methyl-4-oxo-8-(4-(aιτιinomethyl)- l-piperdinyl)-4H-quinolizine-3-carboxyUc acid hydrochloride
The 3-BOC-aminopyrroUdine of Step 253j above was replaced by 4-(amino- methyl)piperidine (Aldrich Chemical Co.), and the reaction product was carried forward as in Steps 253K and 2531, above, to prepare 157 mg of the title compound, mp > 300°C. IR (KBr): 3410, 1720, 1660 cm"1. MS 374 (M-C1)+. 1H NMR (CD3OD) 3: 0.70 (m, 2H), 1.08 (m, 2H), 1.55 (m, IH), 1.95 (m, 2H), 2.42 (m, 2H), 2.83 (s, 3H), 2.95 (m, 3H), 3.40 (m, 2H), 3.60 (m, 2H), 8.18 (s, IH), 9.22 (d, IH, J=9 Hz). Calc. for C20H25C1FN3O3»1.75 H2O: C, 54.42; H, 6.51; H, 9.52; Found: C, 53.92; H, 6.85; N, 9.73.
Example 265
1 -cyclopropyl-7-fluoro-9-methyl-4-oxo-8-(5-amino- 1 ,2,3,4- tetrahvdro-2-isoquinolinyl)-4H-quinolizine-3-carboxylic acid hydrochloride
Step 265a. 5-amino-1.2.3.4-tetrahvdroisoquinoline
A 1.0 g (0.69 mmol) sample of 5-aminoisoquinoline (Aldrich Chemical Co.) was dissolved in 100 mL of methanol and reduced with 250 mg Ptθ2 catalyst at 25°C under 4 atmospheres of H2 for 8 hours. The catalyst was removed by filtration, the solvent was removed on a rotary evaporator, and the residue was dired under vacuum to give 1.01 g of crude product The material was crystaUized from i-propanol and dried under vacuum, yield 602 mg. mp = 153-154°C. MS M/Z: 149 (M+H)+, 166 (M+NH4)+.
Step 265b. l-cyclopropyl-7-fluoro-9-methyl-4-oxo-8-(5-amino- 1,2,3,4- tetrahvdro-2-isoquinoIinyl)-4H-quinolizine-3-carboxylic acid hydrochloride
The 3-BOC-aminopyrrolidine of Step 253j above was replaced by 5-amino- 1,2,3,4-tetrahydroisoquinoline, prepared in step 265a above, and the reaction product was carried forward as in Steps 253K and 2531, above, to prepare 507 mg of the titie compound, p = 185-187°C. IR (KBr): 3380, 1710, 1650 cm"1. MS 408 (M-C1)+, 390 (M+NH4-CD+ 1H NMR (CD3OD) 3: 0.72 (m, 2H, J=6, J=3 Hz), 1.10 (m, 2H, J=3 Hz), 2.40 (m, IH), 2.90 (s, 3H), 3.07 (dd, 2H, J=7.5 Hz), 3.90 (dd, 2H, J=7.5, J=3
Hz), 4.74 (s 2H), 7.28 (m, 2H), 7.35 (m, IH, J=9 Hz), 8.17 (s, IH), 9.25 (d, IH, J=12
Hz). Calc. for C23H23ClFN3θ3«0.75 H2O: C, 60.39; H, 5.40; H, 9.19; Found: C,
60.38; H, 5.16; N, 9.10. Example 266 l-cyclopropyl-7-fluoro-9-methyl-4-oxo-8-(4-(l-pyrrolyl)- 1 -piperidinyl)-4H-quinoUzine-3-carboxylic acid
The 3-BOC-aminopyrrolidine of Step 253j above was replaced by 4-(l- pyπτolyl)piperidine (prepared from N-benzyl-4-hydroxypiperidine by mesylation foUowed by displacing the mesyl group with pyrrole and removing the benzyl group), and the reaction product was carried forward as in Steps 253K and 2531, above, to prepare 386 mg of the title compound, mp = 268-269°C. IR (KBr): 3420, 1720, 1660 cm"1. MS 427 (M+NH4)+, 410 (M+H)+. lH NMR (CD3OD) 3: 0.70 (m, 2H), 1.03 (m, 2H), 2.14 (m, 4H), 2.40 (m, IH), 2.90 (s, 3H), 3.60 (m, 4H), 4.18 (m, IH), 6.08 (dd, 2H, J=3 Hz), 6.84 (dd, 2H, J=3 Hz), 8.37 (s, IH), 9.25 (d, IH, J=12 Hz). Calc. for C23H24FN3θ3^1.25 H2O: C, 63.95; H, 6.18; H, 9.73; Found: C, 63.60; H, 6.61; N, 9.43.
Example 267 l-cyclopropyl-8-(c«-3.5-dimethyl-l-piperazinyl)-7-fluoro- 9-methyl-4-oxo-4H-quinoUzine-3-carboxylic acid hydrochloride
The 3-BOC-aminopyιτolidine of Step 253j above was replaced by c/'.s-3,5- dimethy-Ipiperazine (Aldrich Chemical Co.) and the reaction product was carried forward as in Steps 253j and 253k, above, to prepare 0.46 g of the title compound. IR (KBr): 3450, 1720, 1650, 1610 cm"1. MS 374 (M-C1)+. 1H NMR (DόDMSO) 3: 0.70 (m, 2H), 1.04 (m, 2H), 1.30 (d, 6H, J=7 Hz), 2.41 (m, IH), 2.80 (s, 3H), 3.40-3.65 (m, 6H), 8.03 (s, IH), 9.26 (d, IH, J=9Hz), 9.60 (br s, IH). Calc. for C2θH25ClFN3θ3»0.75 H2O: C, 56.74; H, 6.31; N, 9.92; Found: C, 56.66; H, 6.21; N, 9.74.
Example 268 l-cyclopropyl-8-(2,7-α azabicyclo[3.3.0]oct-2-yl)-7-fluoro- 9-methyl-4-oxo-4H-quinoUzine-3-carboxylic acid hydrochloride
The 3-BOC-aminopyrrolidine of Step 253j above was replaced by 7-BOC-2,7- diaza[3.3.0]octane (prepared according to US Patent 5,071,999) and the reaction product was carried forward as in Steps 253j, k, and 1, above, to prepare 0.34 g of the title compound. IR (KBr): 3400, 1700, 1650, 1605 cm"1. MS 372 (M-C1)+. !H NMR (D6DMSO) 3: 0.60 (m, 2H), 0.91 (m, IH), 2.03-2.10 (m, 3H), 2.36 (m, IH), 2.68 (s, 3H), 3.19 (m, IH), 3.49 (m, 2H), 4.15 (m, IH), 5.50 (m, IH), 7.98 (s, IH), 9.14 (d, IH, J=10 Hz), 9.40 (br s, IH). Calc. for C20H24CI2FN3O3: C, 54.06; H, 5.44; N, 9.46; Found: C, 53.86; H, 5.48; N, 9.63.
Example 269 l-cyclopropyl-8-(2,8-diaza-8-bicyclo[4.3.0]nonyl)-7-fluoro- 9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid hydrochloride
The 3-BOC-aminopyrrolidine of Step 253j above was replaced by 8-BOC-2,8- diaza[4.3.0]nonane (prepared according to US 5,059,597), and the reaction product was carried forward as in Steps 253K and 2531, above, to prepare 0.50 g of the title compound. IR (KBr): 3400, 1690, 1650, 1600 cm" 1. MS 386 (M-C1)+. 1H NMR (D6DMSO) 3: 0.56 (m, IH), 0.62 (m, IH), 0.93 (m, IH), 1.07 (m, IH), 1.60-1.80 (m, 4H), 2.28-2.32 (m, 2H), 2.67 (s, 3H), 2.72 (m, IH), 2.94 (m, IH), 3.70 (m, 2H), 3.91 (m, IH), 4.03 (m, IH), 4.35 ( , IH), 7.93 (s, IH), 8.90 (br s, IH), 9.10 (d, IH, J=l l Hz), 9.48 (br s, IH), 13.85 (br s, IH). Calc. for C21H26CI2FN3O3: C, 55.03; H, 5.72; N, 9.17; Found: C, 54.75; H, 5.82; N, 9.38.
Example 270
1 -cyclopropy l-7-fluoro-9-methyl-4-oxo-8-(3 (S )-( 1 - pyrrolyl)- 1 -pyrroUdinyl)-4H-quinolizine-3-carboxylic acid
A mixture of 25 mg 8-(3(S)-aminopyrrolidinyl)- 1 -cyclopropyl-7-fluoro-9-methyl-
4-oxo-4H-quinolizine-3-carboxylic acid hydrochloride (from Example 257) and 40 mg of sodium acetate in 0.7 mL of ethyl acetate was heated to 100°C. To this solution was added 0.009 mL of dimethoxy tetrahydrofuran dropwise, and the reaction was stirred at 110°C for 5 min, then quenched by addition of water. The mixture was extracted twice with methylene chloride, and the extract was washed with water, dried over MgSO4 and concentrated. The residue was purified by preparative TLC, eluting with 100:10 chloroform:methanol, to give 13.6 mg of the title product as a yellow solid after removal of the solvent MS 395 (M-C1)+. lH NMR (CDCI3) 3: 0.67 (m, 2H), 1.00 (m, 2H), 2.20 (m, IH), 2.46 (m, IH), 2.56 (m, IH), 2.66 (s, 3H), 3.89 (m, IH), 3.99 (m, 2H0, 4.15 (m, IH), 4.86 (m, IH), 6.23 (t, 2H, J=2 Hz), 6.79 (t, 2H, J=2 hz), 8.32 (s, IH), 9.15 (d, IH, J=10 Hz), 13.83 (br, IH). Example 271 l-cyclopropyl-7-fluoro-8-(3-hydroxy- 1 -pyrrolidinyl)- 9-methyl-4-oxo-4H-quinoUzine-3-carboxyUc acid hydrochloride
The 3-BOC-aminopyrroUdine of Step 253j above was replaced by 3-hydroxy- pyrrolidine (Aldrich Chemical Co.), and the reaction product was carried forward as in Steps 253j and 253k above, to prepare 0.15 g of the title compound. IR (KBr): 3425, 1690, 1650, 1600 cm" 1. MS 346 (M+H)+. 1H NMR (DMSO-d6) 3: 0.59 (m, 2H), 0.93 (m, IH), 1.03 (m, IH), 1.96-2.01 (m, 3H), 2.29 (m, IH), 2.49 (s, 3H), 3.43 (m, IH), 3.69 (m, IH), 4.01 (m, 2H), 4.42 (m, IH), 5.15 (d, IH, J=3 Hz), 7.89 (s, IH), 9.05 (d, IH, J=l l Hz), 13.86 (br s, IH). Calc. for C18H19FN2O4: C, 62.42; H, 5.53; N, 8.09; . Found: C, 62.20; H, 5.55; N, 8.09.
Example 272 l-cyclopropyl-7-fluoro-8-(4-methyl- 1 -piperazinyl)-
9-methyl-4~oxo-4H-quinoUzine-3-carboxylic acid hydrochloride
The 3-BOC-aminopyrroUdine of Step 253j above was replaced by 1- methylpiperazine (Aldrich Chemical Co.), and the reaction product was carried forward as in Steps 253j and 253k, above, to prepare 0.15 g of the title compound, mp = 210-216°C (dec). MS 360 (M-C1)+. 1H NMR (CDCI3) 3: 0.70 (m, 2H), 1.02 (m, 2H), 2.28 (m, IH), 2.40 (s, 3H), 2.60 (m, 4H), 2.79 (s, 3H), 3.48 (m, 4H), 8.37 (s, IH), 9.21 (d, IH, J=9 Hz).
Example 273
1 -cyclopropyl- 9-chloro-7-fluoro-8-(3-amino- 1 -pyrroUdinyl)- 4-oxo-4H-quinolizine-3-carboxylic acid trifluoroacetic acid salt
The 4-t-butoxy-2,3,6-trifluoro-5-methylpyridine of Step 253d above was replaced by 4-t-butoxy-3-chloro-2,5,6-trifluoropyridine (from step 253a above), and the methanol solvent was replace by benzene, and the reaction product was carried forward as in Steps 253d-l above, and the 4N HCI in dioxane of Step 2531 was replaced with trifluoroacetic acid, to prepare 0.13 g of the titie compound. MS 366 (M-CF3CO2)+. 1H NMR (D6-DMSO) 3: 0.58 (m, 2H), 0.97 (m, 2H), 2.11 (m, IH), 2.31 (m, IH), 2.44 (m, IH), 3.83 (m, IH), 3.97 (m, 2H), 4.10 (m, IH), 4.20 (m, IH), 8.09 (s, IH), 8.09 (br, 3H), 9.18 (d, IH, J=l l Hz). Calc. for Ci7Hi7ClFN3θ3:«CF3COOH«0.5 H2O: C, 46.69; H, 3.92; N, 8.60; Found: C, 46.62; H, 3.64; N, 8.45. Example 274
8-(3-amino- 1 -pyrrolidinyl)- l-cyclopropyl-7,9-difluoro- 4-oxo-4H-quinolizine-3-carboxylic acid hydrochloride
Step 274a. 4-t-butoxy-2.3.5.6-tetrafluoropyridine
A 158.5 g (0.938 mmol) sample of pentafluoropyridine (Aldrich Chemical Co.) was dissolved in 600 mL of THF and cooled to -78°C. To this was added 88.29 g (0.919 mmol) of sodium-t-butoxide in 800 mL of THF over a 30 min period, with stirring and whUe maintaining the temperature at -78°C. The mixture was stirred for another 30 min at this temperature, then the temperature of the bath was raised to -20°C, and the reaction was stirred at this temperature for 64 hours. The reaction mixture was removed from the cold bath and diluted with 1.5 L of ether, then fUtered through a diatomaceous earth filter aid. The solvent was removed under vacuum to leave a yeUow oU. The oU was purified by vacuum distiUation to afford 141.34 g of the titie product.
Step 274b. 4-t-butoxy-2.3.5-trifluoropyridine
A 20.0 g (0.089 mmol) sample of the product from step 274a above was dissolved in 100 mL of absolute ethanol, and 26.08 mL (0.538 mol) of hydrazine monohydrate was added. The reaction was stirred for 1 hour at room temperature and 1 hour at reflux. The solvent was removed under vacuum. The residue was dissolved in ether and washed with water and brine. The organic phase was dried over MgSO4, and the solvent was removed under vacuum to yield a yeUow solid. This material was dissolved in 120 mL of toluene, 60 mL of 20% sodium hydroxide was added, and air was bubbled through the stirred solution for 18 hours. To the reaction was added 100 mL of ether, and the organic phase was separated, washed with water and brine, and dried over MgSO4. Removal of the solvent and purification of the residue with flash chromatography on siUca gel, eluting with 1: 16 ethyl acetate.-hexane, gave 14.6 g of the titie product as a reddish liquid.
Step 274c. 8-(3-amino- 1 -pyrrolidinyl)- 1 -cyclopropy 1-7 ,9-difluoro- 4-oxo-4H-quinolizine-3-carboxylic acid hydrochloride
Replacing the 4-t-butoxy-2,5-difluoro-3-methylpyridine of step 253e with the 4-t- butoxy-2,3,5-trifluoropyridine from step 274b above, and carrying the product forward according to the procedures of Steps 253e-l, 76 mg of the title compound was prepared. MS M/Z: 350 (M-C1)+. lU NMR (D6-DMSO) 3: 0.65 (m, 2H), 0.90 (m, 2H), 2.15-2.30 (m, 3H, 3.95-4.00 (m, 3H), 4.18 (m, 2H), 7.81 (s, IH), 8.46 (br, 3H), 9.17 (d, IH, J=9 Hz).
Example 275
8-(3-amino- 1 -pyrrolidinyl)- 1 -cyclopropyl-7-fluoro- 9-methoxy-4-oxo-4H-quinolizine-3-carboxyUc acid hydrochloride
Step 275a. 4-t-butoxy-2.3.6-trifluoro-5-hydroxypyridine
A 11.16 g (54.39 mmol) sample of 4-t-butoxy-2,3,6-trifluoropyridine, from
Example 253 step b above, was dissoved in 50 mL of THF, and the solution was cooled to -78°C. To this solution was added LDA (65.6 mmol) with stirring for 30 min, during which a solid preciptated. To this mixture was added 7.5 mL of rrimethoxyborane, with stirring for 25 min at -78°C. To this mixture was added 10 mL of acetic acid, and the mixture was stirred and allowed to warm to room temperature. Next was added 100 mL of 30% hydrogen peroxide and 100 mL of 2N sodium hydroxide while cooUng in an ice bath. The mixture was then stirred at room temperature for 16 hours, and quenched with saturated NH4CI solution. The mixture was extracted with ether, and the extract was washed with brine and dried over MgSO4. The solvent was removed under vacuum, and the residue was purified by flash chromatography on siUca gel, eluting with 1:8 ethyl acetate:hexane. Removal of the solvent gave 9.769 g of the title product as a colorless liquid.
Step 275b. 4-t-butoxy-2.3.6-trifluoro-5-methoxypyridine
To a solution of 237 mg ( 1.07 mmol) of 4-t-butoxy-2,3,6-trifluoro-5- hydroxypyridine, from step 275a above, in 3 mL of anhydrous THF was added 335 mg (1.277 mmol)of triphenyl phosphine and 0.060 mL (1.48 mmol) of methanol. To this solution was added 0.200 mL (1.270 mmol) of DEAD dropwise at room temperature. The reaction was complete in 10 min, so the solvents were removed under vacuum and the residue was purified by flash chromatography on siUca gel, eluting with 1:16 ethyl acetate:hexane to give 215.6 mg of the title product as a colorless Uquid after removal of the solvent. Step 275c. 8-(3-amino-l -pyrroUdinyl)- l-cyclopropyl-7-fluoro- 9-methoxy-4-oxo-4H-quinolizine-3-carboxyUc acid hydrochloride
Replacing the 4-t-butoxy-2,3,6-trifluoro-5-methylpyridine of Example 253 step c with the 4-t-butoxy-2,3,6-trifluoro-5-methoxypyridine of step 275b above and carrying the product forward according to the procedures of Steps 253d-l, 120 mg of the title compound was prepared. MS M/Z: 362 (M-C1)+. IR (KBr): 3440, 1799, 1650, 1610 cm" 1. 1H NMR (D6-DMSO) 3: 0.62 (m, 2H), 0.91 (m, 2H), 2.12 (m, IH), 2.29 (m, IH), 2.39 (m, IH), 3.62 (s, 3H), 3.81 (m, IH), 3.94 (m, 2H), 4.06 (m, 2H), 7.79 (s, IH), 8.30 (br, 3H), 9.13 (d, IH, J=10 Hz), 13.79 (br, IH). Calc. for Cl8H2θFN3θ4«2HCM).5H2θ: C, 48.77; H, 5.23; N, 9.48; Found: C, 48.65; H, 5.19; N, 9.56.
Example 276
1 -cyclopropyl-7-fluoro-9-methyl-8-(3 (S)-methylamino- 1 -pyrrolidinylV4-oxo-4H-quinolizine-3-carboxylic acid hydrochloride
Step 276a. l-N-benzyl-3fSWBOC-aminoVpyrroUdine
A 4.2 g sample of (3S)-3-BOC-aminopyrroUdine (TCI America) and 4.7 mL of triethylamine were dissolved in 75 mL of methylene chloride at room temperature. To this solution was added 2.95 mL of benzyl bromide dropwise, and the reaction was heated at reflux for 6 hours. After cooling, the solution was washed with water, and the solvent was dried and evaporated to give 5.10 g of the titie product as a white soUd.
Step 276b. l-N-benzyl-3 S)-("methylaminoVpyrroUdine
The 5.10 g sample of l-N-benzyl-3(S)-(BOC-amino)-pyrroUdine, from step 276a above, was dissolved in 25 mL of THF, and 55.6 g of LiAlH4 (1.0 M in THF) was added. The mixture was stirred and heated at reflux for 4 hours. The reaction was quenched with water, and the mixture was extracted with methylene chloride. The solvent was washed with water, dried over MgSO4, and removed on a rotary evaporator to yield 2.43 g of the title product.
Step 276c. l-N-benzyl-3fSUN-BOC-N-methylaminoVpyHθUdine
A 2.43 g sample of l-N-benzyl-3(S)-(methylamino)-pyrrolidine, from step 276b above, was dissolved in 100 mL of a 4: 1 methanokwater mixture, and 3.34 g of di-t-butyl dicarbonate was added in portions. The reaction was stirred at room temperature for 6 hours. The methanol was removed under vacuum, and the aqueous residue was extracted with methylene chloride. The solvent was washed with water, dried over MgSO4 and removed under vacuum. The residue was purified by chromatography over silica gel, eluting wtih 100:5:0.5 methylene chloride:methanol:NH4θH to give 3.23 g of the titie product.
Step 276d. CSVCN-BOC-N-methylaminoVpyrroIidine
The product from step 276c was treated according to the procedure of Example
171 step 5 to remove the benzy protecting group and afford 2.24 g of the title product as a white solid.
Step 276e. l-cyclopropyl-7-fluoro-9-methyl-8-(3(S)-methylamino- 1 -pyrrolidinyl 4-oxo-4H-quinolizine-3-carboxylic acid hydrochloride
FoUowing the procedure of Example 253 step j, replacing the 3-BOC- aminopyrroUdine of that example with the 3(S)-(N-BOC-N-methylamino)-pyrroUdine from step 276d above, and carrying the reaction product forward according to the procedures of Example 253 steps k and 1, a 452 mg sample of the title product was obtained. MS: 360 (M-C1)+. IR (KBr): 3450, 1710, 1650, 1610 cm" 1. lH NMR (d6-DMSO): 0.62 (m, 2H), 1.00 (m, 2H), 2.26 (m, IH), 2.33 (m, 3H), 2.65 (s, 6H), 3.75 (m, IH), 3.90 (m, 2H), 4.05 (m, 2H), 7.94 (s, IH), 9.12 IH, J=10 Hz), 9.18 ( br s, 2H), 13.86 (br s, IH). Anal. Calc. for Ci9H22FN3θ3'HCl«H2θ: C, 55.14; H, 6.09; N, 10.15; Found: C, 55.29; H, 5.99; N, 10.18. Example 277 l-cyclopropyl-7-fluoro-9-methyl-8-(3(R)- amino- 1 -pyrroUdinyl)- 4-oxo-4H-quinolizine-3-carboxylic acid hydrochloride
Step 277a. l-N-benzyl-3(R)-fBOC-amino)-pyrrolidine
FoUowing the procedure of Example 276 step a, replacing the (3S)-3-BOC- aminopyrrolidine of step 276a with (3R)-3-BOC-aminopyrroUdine (TCI America), the titie compound was prepared.
Step 277b. 3fRV(BOC-amino)pyrrolidine
The benzyl group was removed from the product of step 277a by the procedure of step 276d above, to give the title product
Step 277c. l-cycloρroρyl-7-fluoro-9-methyl-8-(3(R)-amino-l- pyrrolidinyl)-4-oxo-4H-quinoUzine-3-carboxylic acid hydrochloride
FoUowing the procedure of Example 253 step j, replacing the 3-(BOC- amino)pyrroUdine of that example with the 3(R)-(BOC-amino)-pyrrolidine from step 277b above, and carrying the reaction product froward according to the procedures of Example 253 steps k and 1, a 452 mg sample of the title product was obtained. MS: 346 (M-C1)+. IR (KBr): 3440, 1700, 1650, 1610 cm"1. ]H NMR (d6-DMSO): 0.59 (m, 2H), 1.00 (m, 2H), 2.15 (m, IH), 2.31 (m, 2H), 2.63 (s, 3H), 3.76 (m, 2H), 4.00-4.07 (m, 3H), 8.40 (br, 3H), 9.10 (d, IH, J=l l Hz). Ci8H2θFN3θ3.HCl»H2θ: C, 54.07; H, 5.80; N, 10.51; Found: C, 54.19; H, 5.65; N, 10.37.
Example 278
(3R)-9-fluoro-3-methyl- 10-(4-methyl- 1 -piperazinyl)-2H,3H,6H- 6-oxo-pyranoI2.3.4-ij1quinolizine-5-carboxylic acid hydrochloride
Step 278a. (S 1 -bromo-2-methyl-3-Ct-butyldimethylsilyloxy)propane
To a 9.59 g (62.67 mmol) sample of (S)-(+)-3-bromo-2-methyl-l -propanol (Aldrich Chemical Co.) in 40 mL of DMF was added 4.27 g (62.720 mmol) of imidazole, and the solution was cooled to 0°C. To this cooled solution was added 9.45 g (62.69 mmol) of t-butyldimethylsilyl chloride, and the solution was stirred at room temperature for 16 hours. The reaction solution was poured into water, which was extracted with hexane. The organic layer was washed with water, satd. brine, dried over MgSO4, and concentrated. The residue was distiUed in a kugelrohr apparatus (0.2 mm Hg, 50°C) to yield 15.00 g of the title product as a colorless Uquid.
Step 278b. (S)-l-iodo-2-methyl-3 -(t-butyldimethylsilyloxy)propane
A 15.00 g sample of the product from the proceeding step was dissolved in 100 mL of acetone, and 42.00 g (5 eq) of Nal was added. This mixture was heated at reflux under N2 for 9 hours. The mixture was cooled, filtered, and the filtrate was concentrated. The residue was dissolved in hexane, and the solution was again filtered and concentrated to yield 16.62 g of a colorless Uquid. This material was distiUed in a kugelrohr apparatus (0.2 mm Hg, 60°C) to give 16.479 g of the title product as a colorless liquid. MS: 315 (M+H)+. IH NMR (CDCI3) 3: 0.07 (s, 6H), 0.90 (s, 9H, 0.95 (d, 3H, J=7 Hz), 1.65 (m, IH), 3.29 (m, 2H), 3.40 (m, IH), 3.54 (m, IH).
Step 278c. l-C2.3.5.6-tetrafluoro-4-pyridyl)-4-methylpiperazine
A 25.10 g sample (0.148 mmol) of pentafluoropyridine (Aldrich Chemical Co.) and 23.0 mL (0.165 mmol) of triethylamine were dissolved in 150 mL of HPLC grade methylene chloride. To this solution 17.3 mL (0.156 mmol) of N-methylpiperazine were added slowly dropwise at 0°C. The solution was stirred for 16 hours at 0°C, then washed with water, dried over MgSO4 and concentrated to give 36.95 g of the title product as a colorless oil, which solidifed upon standing. MS: 250 (M+H)+. 1H NMR (CDCI3) 3: 2.36 (s, 3H), 2/53 (m, 4H), 3.52 (m, 4H).
Step 278d. (R)-2-methyl-3-(4-(4-methylpiρerazinyl)-3,5,6- trifluoro-2-pyridinyl)- 1 -propanol
A 5.03 g (16.00 mmol) sample of (S)-l-iodo-2-methyl-3-(t-butyldimethyl- silyloxy)propane, from step 278b above, was dissolved in 32 mL of ether and cooled to -78°C. To this solution was added 19.8 mL (33.66 mmol) of t-buthyllithium (1.7 M in pentane), and the temperature was maintained at -78°C whtie stirring for 40 min. The temperature was raised to 0°C, and stirring was continued for 30 min. This solution was designated the "lithium compound" and was utiUzed below. In a separate flask 3.99 g (16.01 mmol) of l-(2,3,5,6-tetrafluoro-4-pyridyl)-4-methylpiperazine, from step 278c above, was dissolved in 50 mL of THF. To the latter solution at -78°C was added via cannula the solution of the lithium compound. The reaction was stirred at -78°C for 5 min and at room temperature for 30 min. The reaction was quenched by addition of satd. NH4CI, and extracted with ether. The extract was washed with satd. brine, dried over MgSO4, and concentrated. The residue was dissolved in 30 mL of THF, and 16.5 mL of tetrabutlyammonium fluoride (1 N in THF) was added. The mixture was stirred for 16 hours and concentrated. The residue was slurried with water and extracted with methylene chloride. The organic phase was washed wtih water, dried over MgSO4, and concentrated. The residue was purified by flash chromatography on sUica gel, eluting with 100:5:0.5 methylene chloride:methanol:NH4θH to give 4.037 g of the title product as a colorless viscous oil. MS: 304 (M+H)+. H NMR (CDCI3) 3: 0.95 (d, 3H, J=6.6 Hz), 2.11 (m, IH), 2.35 (s, 3H), 2.53 (m, 4H), 2.63 (m, IH), 2.71 (m, IH), 137-3.50 (m, 6H). Anal calc for C14H20F3N3O: C, 55.44; H, 6.65; N, 13.72; Found: C, 55.10; H, 6.24; N, 13.72. [a]D=+7.80° (26°, c=1.68, methylene chloride).
Step 278e. (R)-2-methyl-3-(4-(4-methylpiperazinyl)- 3.5.-difluoro-2-pyridinyl)-l-propanol
A 4.349 g (14.337 mmol) sample of 2-methyl-3-(4-(4-methylpiperazinyl)-3,5,6- trifluoro-2-pyridinyl)-l -propanol, from step 278d above, was dissolved in 20 mL of n- propanol, 3.50 mL (72.15 mmol) of hydrazine hydrate was added, and the reaction was heated at reflux under N2 for 17 hours. Another 1.5 mL of hydrazine hydrate was added, and the reflux was continued for 15 hours. The solution was concentrated on a rotary evaporator, and the residue was slurried in water, then extracted with methylene chloride. The solvent was washed with water, dried over MgSO4, and concentrated to give 4.60 g of the title product as a viscous oil. This intermediate hydrazino compound was dissolved in 300 mL of water, and a solution of 29.78 g of CuSO4 in 400 mL of water was added by pipet over a 15 min period. The reaction was then heated at reflux under N2 for 50 min.. The reaction was cooled to ambient temperature and the soultion was made basic with NH4OH. The solution was extracted with methylene chloride, which was washed with water, dried over MgSO4 and concentrated. The residue was purified by flash chromatography on sUica gel, eluting with 100:5:0:5 methylene chloride:methanol:NH4θH, to give 3.605 g titie product. MS: 286 (M+H)+. 1H NMR (CDCI3) 3: 0.96 (d, 3H, J=6.6 Hz), 2.14 (m, IH), 2.35 (s, 3H), 2.52 (m, 4H), 2.80 (m, 2H), 3.35-3.41 (m, 5H), 3.51 (m, IH), 8.01 (d, IH, J=3.3 Hz). Anal. calc. for C14H21F2N3O: C, 58.93; H, 7.42; N, 14.73; Found: C, 58.59; H, 7.22; N, 14.31. Step 278f. 3(R)-7-fluoro-3-methyl-8-(4-methyl-l- piperazinyl)-2.3-dihvdro-4H-pyranor3.2-blpyridine
A 3.557 g (12.465 mmol) sample of 2-methyl-3-(4-(4-methylpiperazinyl)-3,5,- difluoro-2-pyridinyl)- 1 -propanol, from step 278e above, was dissolved in 30 mL of dioxane and added to a dispersion of 1.12 g (37.33 mmol) of NaH (50% dispersion) in 100 mL of dioxane. The mixture was heated at reflux for 19 hours, then concentrated to dryness. The residue was slurried with water, and extracted with ether. The extract was washed with satd. brine, dried over MgSO4, and concentrated. The residue was purified by flash chromatography on sUica gel, eluting with 100:5:0:5 methylene chloride:methanol:NH4θH, to afford 2.299 g of the title product. MS: 266 (M+H)+. 1H NMR (CDCI3) 3: 1.07 (d, 3H, J=6.6 Hz), 2.21 (m, IH), 2.38 (s, 3H), 2.49 (m, IH), 2.57 (m, 4H), 2.94 (m, IH), 3.37 (m, 4H), 3.67 (dd, IH, J=9.6, 10.3 Hz), 4.23 (m, IH), 7.90 (d, IH, J=3.3 Hz). Anal calc. for C14H20FN3O: C, 63.38; H, 7.60; N, 15.84; Found: C, 63.58; H, 7.60; N, 15.84.
Step 278g. 3(R)-9-fluoro-3-methyl-10-(4-methyl-l-piperazinyl)- 2H.3H.6H-6-oxo-pyranor2.3.4-ijlquinolizine-5-carboxylic acid, ethyl ester
A 132.7 mg (0.500 mmol) sample of 3(R)-7-fluoro-3-methyl-8-(4-methyl-l- piperazinyl)-2,3-dihydro-4H-pyrano[3.2-b]pyridine, from step 278f above, was dissolved in 5 mL of THF and cooled to -78°C. To this solution was added 0.22 mL of n-butyl lithium (0.55 mmol, 2.5 M in hexane), and the reaction was stirred at -78°C for 30 min. To the reaction vessel was added 0.120 mL (0.594 mmol) of diethoxy ethoxymethylenemalonate, and the reaction was stirred for 5 min at -78°C and at room temperature for 15 min. The solvent was removed, and the residue was dissolved in ethanol. To this was added 1.0 mL of piperidine and 0.2 mL of acetic acid, and the solution was heated at reflux for 16 hours. The solvents were removed, and the residue was dissolved in methylene chloride. This solution was washed with water, dried over MgSO4, and concentrated. The residue was triturated with 50:50 etheπhexane, and the soUd was isolated, and the filtrate purified by chromatography on siUca gel, eluting with 100:5:0:5 methylene chloride:methanol:NH4θH, to afford a total of 88.9 mg of the titie product. MS: 390 (M+H)+. IR 3440, 1710, 1630 cm" 1. lH NMR (CDCI3) 3: 1.34 (d, 3H, J=7 Hz), 1.42 (t, 3H, J=7 hz), 2.37 (s, 3H), 2.56 (m, 4H), 3.12 (m, IH), 3.55 (m, 4H), 4.02 (dd, IH, J=l l, 6 Hz), 4.28 (dd, IH, J=l l, 4 Hz), 4.41 (q, 2H, J=7 Hz), 8.03 (s, IH), 9.06 (d, IH, J=9 Hz). Anal calc. for C20H24FN3O4: C, 61.69; H, 6.21; N, 10.79; Found: C, 61.42; H, 5.89; N, 10.65. [a]o=-37.14° (25°C, c=0.28, methylene chloride).
Step 278h. 3(R)-9-fluoro-3-methyl-10-(4-methyl-l-piperazinyl)- 2H.3H.6H-6-oxo-pyranor2.3.4-ij1quinolizine-5-carboxylic acid
A 657 mg (1.687 mmol) sample of 3(R)-9-fluoro-3-methyl-10-(4-methyl-l- piperazinyl)-2H,3H,6H-6-oxo-pyrano[2.3.4-ij]quinolizine-5-carboxyUc acid, ethyl ester, from step 278g above, was dissolved in 6 mL of THF and 142 mg of LiOH»H2θ and 3 mL of water were added. The mixture was heated at 60°C under N2 for 80 min. The solvent was removed under reduced pressure, and the aqueous residue was diluted with additional water and extracted with methylene chloride. The aqueous solution was then neuraUzed to ph& with 10% HCI, and extracted with methylene chloride. The extract was washed with water, dried over MgSO4 and concentrated to dryness. The residue was dissolved in methylene chloride, which was then filtered through a sintered glass funnel. The filtrate was concentrated to dryness, and the residue was triturated with 1:1 etheπhexane to give 494.2 mg of the title product as a yellow soUd after drying. MS: 362 (M+l)+. IR 3440, 1720, 1640, 1610 cm-i. lU NMR (CDCI3) 3: 1.37 (d, 3H, J=7 Hz), 2.39 (s, 3H), 2.60 (m, 4H), 3.19 (m, IH), 3.61 (m, 4H), 4.06 (dd, IH, J=6.3, 10.6 Hz), 4.34 (dd, IH, J=3.6, 10.6 Hz), 8.15 (s, IH), 8.94 (d, IH, J=8.8 Hz), 13.86 (br, IH). Anal calc. for C18H20FN3O4 •0.5H2O: C, 59.09; H, 5.65 ; N, 11.48; Found: C, 59.25; H, 5.59; N, 11.39.
Step 278i. 3(R)-9-fluoro-3-methyl-10-(4-methyl-l-piperazinyl)-2H,3H,6H- 6-oxo-pyranor2.3.4-iilquinolizine-5-carboxyUc acid hydrochloride
A 200 mg sample of the free base from the previous step was dissolved in 15 mL of methylene chloride, and 0.75 mL of 1 M HCI in ether was added. Additional ether was added to precipitate the product, which was collected by filtration. The soUd was dissolved in water, and the solution was fUtered through sintered glass. The filtrate was freeze-dried to give 213.1 mg of the title product as a yellow soUd. MS: 362 (M-C1)+. IR 3440, 1700, 1637, 1603 cm-i. lH NMR (DMSO-d6) 3: 1.29 (d, 3H, j=7 Hz), 2.76 (s, 3H), 3.15- 3.36 (m, 5H), 3.74 (m, 4H), 4.18 (dd, IH, J=5.7, 10.7 Hz), 4.38 (dd, IH, J=3.7, 10.7 Hz), 8.03 (s, IH), 9.02 (d, IH, J=8.8 Hz). Anal calc. for C18H20FN3O4 «HCl«H2θ: C, 51.99; H, 5.57; N, 10.08; Found: C, 51.91; H, 5.33; N, 10.03. [a]D=-24.2° (24°C, 0.33, methanol). Example 279
3(S)-9-fluoro-3-methyl-10-(4-methyl-l-piperazinyl)- 2H.3H.6H-6-oxo-pyranor2.3.4-ijlquinolizine-5-carboxyUc acid hydrochloride
Step 279a. 2fRV3-('t-butyldimethylsUyl')oxy-2-methvI-l -propanol
A 24.39 g (265 mmol) sample of Q .)-(-)-methyl 3-hydroxy-2-methylpropionate (Aldrich Chemical Co.) and 15.46 g (227 mmol) of imidazole were dissolved in 120 mL of DMF. The solution was stirred at 0°C under N2 and 34.23 g (227 mmol) of t- butyldimethyl-sUyl chloride was added in several portions. The reaction was stirred at 0°C for 1 hour and room temperature for 22 hours, then poured into water. The mixture was extracted with hexane, and the extract was washed with water, dried over MgSO4, and concentrated to give 52.51 g of the protected intermediate. The intermediate was dissolved in 100 mL of THF and added via cannula to a flask containing 475 mL of DIBAL in 200 mL of THF at -78°C, then stirred for 15 min. The reaction was then warmed to 0° rapidly and stirred for 2 hours. The reaction was quenched by slowly pouring it into 1 L of satd. Na2SOφ The mixture was filtered through a filter aid. The organic phase was separated and reserved. The aqueous phase was extracted with ether. The organic phases were combined, washed with satd. brine, dried over MgSO4 and concentrated to give a yellow Uquid. This material was distiUed in a kugelrohr apparatus at 0.2 mmHg and 70°C to yield 19.50 g of the title product. [a]D=-8.12° (26°C, c=2.02, CH2C12). 1H NMR (CDCI3) 3: 0.07 (s, 6H), 0.84 (d, 3H, J=7 Hz), 0.90 (s, 9H), 1.94 (m, IH), 2.81 (br, IH), 3.54- 3.62 (m, 3H), 3.74 (m, IH).
Step 279b. 20 )-3-ft-butyldimethylsilyl)oxy-l-iodo-2-methylpropane
A 19.50 g (95.41 mmol) sample of 2(R)-3-(t-butyldimethylsilyl)oxy-2-methyl-l- propanol, from step 279a above, was dissolved in 100 mL of methylene chloride and 26.6 mL (191 mmol) of triethylamine was added. The solution was cooled to 0°C, 11.0 mL (142 mmol) of methansulfonyl chloride was added, and the reaction was stirred for 1 hour. Stirring was discontinued, and the reaction was held at -20°C for 16 hours. The reaction was quenched with 5% NaHCO3, then extracted with methylene chloride. The extract was washed with water, dried over MgSO4 and concentrated. The residue was chromatographed of siUca gel, eluting with melthylene chloride, and the solvent was removed to give 25.95 g of the mesylated intermediate. This intermediate was dissolved in 100 mL of acetone, and 55 g of Nal was added. The mixture was heated at reflux for 10 hours, then cooled, diluted with hexane, and filtered. The filtrate was concentrated, the residue redissolved and refUtered, and again concentrated. The residue was distiUed in a kugelrohr apparatus at 0.2 mmHg and 60°C to yield 18.22 g of the title product. [a]D=- 9.39° (25°C, c=2.46, CH2C12). MS: 332 (M+18)+, 315 (M+H)+. 1H NMR (CDCI3) 3: 0.07 (s, 6H), 0.60 (s, 9H), 0.96 (d, 3H, J=7 Hz), 1.64 (m, IH), 3.29 (m, 2H), 3.40 (m, IH), 3.53 (m, IH).
Step 279c. 3(S)-9-fluoro-3-methyl- 10-(4-methyl- l-piperazinyl)-2H,3H,6H- 6-oxo-pyranoI2.3.4-ijlquinolizine-5-carboxyUc acid hydrochloride
FoUowing the procedure of Example 278d, substituting the 2(R)-3-(t- butyldimethylsilyl)oxy- 1 -iodo-2-methylpropane of step 279b above for the 2(S)-3-(t- butyldimethylsUyl)oxy-l-iodo-2-methylpropane of step 278d, and carrying the product forward according to Example 278 steps f-i, the title product was prepared. MS 362 (M- Cl)+. IR (KBr): 3440, 1710, 1635, 1610 cm-1. 1H NMR (DMSO-d6) 3: 1.29 (d, 3H, J=7 Hz), 2.82 (s, 3H), 3.18 (m, 2H), 3.27 (m, IH), 3.48 (m, 2H), 3.69 (m, 2H), 3.86 (m, 2H), 4.19 (dd, IH, J=6, 11 Hz), 4.49 (dd, IH, J=4, 11 Hz), 8.03 (s, IH), 9.03 (d, IH, J=9 Hz), 11.09 (br, IH), 13.96 (br, IH). Anal calc for
Ci8H20FN3O4.HCM.5H2O: C, 50.89; H, 5.69; N, 9.89; Found: C, 50.50; H, 5.46; N, 9.72.
Example 280
9-fluoro-10-(l-morpholinyl)-2H,3H,6H-6-oxo-pyrano- I2.3.4-iilquinolizine-5-carboxylic acid
Step 280a. 3-("t-butyldimethylsilyloxy)-l-iodopropane
A mixture of 44.28 g (175 mmol) sample of l-bromo-3-(t- butyldimethylsilyloxy)-propane (prepared according to Wilson and Zucker, J. Org. Chem, 22:2571 (1988)) and 100 g of Nal in 200 mL of acetone was heated at reflux for 20 hours, filtered and concentrated. The residue was dissolved in hexane, re-filtered and concentrated. The residue was distilled in a kugelrohr apparatus (0.2-0.3 mm Hg, 60°C) to give 46.87 g of the tifle product This material was distiUed under reduced pressure, and the pure product coming over at 53-57°C and 0.3 mm Hg was collected. MS: 301 (M+H)+. lH NMR (CDCI3) 3: 0.70 (s, 6H), 0.90 (s, 9H), 1.99 (m, 2H), 3.28 (t, 2H, J=7 Hz), 3.66 (t, 2H, J=6 Hz). Step 280b. 9-fluoro-10-(l-morpholinyl)-2H,3H,6H-6-oxo- pyranor2.3.4-ijlquinolizine-5-carboxylic acid
FoUowing the procedure of Example 278d, replacing the (2S)-3-(t-butyldimethyl- silyloxy)-l-iodo-2-methylpropane of that step with the 3-(t-butyldimethylsilyloxy)-l-iodo- propane from step 280a above, and carrying the product forward according to the procedures of Examples 278d-h, 20 mg of the titie product was obtained. MS: 335 (M+l)+. IR (KBr): 3440, 1705, 1630, 1610 cm-1. lH NMR (CDCI3) 9: 3.13 (t, 3H, J=5.5 Hz), 3.58 (m, 4H), 3.85 (m, 4H), 4.42 (t, 2H, J=5.5 Hz), 8.08 (s, IH), 8.94 (d, IH, J=8.8 Hz). Anal. Calc. for Ci6Hi5FN2θ4«l/8H2θ: C, 57.10; H, 14.57; N, 8.32; Found: C, 57.07; H, 14.32; N, 8.23.
Example 281
(3R)-10-(3-amino-l-pyrrolidinyl)-9-fluoro-3-methyl- 2H.3H.6H-6-oxo-pyranof2.3.4-iilquinolizine-5-carboxylic acid
Step 281a. f2RV3-f4-t-butoxy-3.5.6-trifluoro-2-pyridinyI>2-methyl-l -propanol
A 9.38 g (29.85 mmol) of (S)-l-iodo-2-methyl-3-(t-butyldimethylsilyloxy)- propane, from Step 278b above, was dissolved in 50 mL of ether and reacted with 36.9 mL (1.7 M in pentane, 62.73 mmol) of t-butyl lithium at -78°C for 40 min and at 0°C for 30 min. This solution was cooled to -78°C again and added to a stirred solution of 6.70 g (30.02 mmol) sample of 4-t-butoxy-2,3,5,6-tetrafluoropyridine, from Example 274a above, in 40 mL of ether at -78°C. The reaction was stirred for 5 min, the dry ice bath was removed, and the reaction was stirred at room temperature for 64 hours. The reaction was quenched with satd.NH4Cl, and the mixture was extracted with ether. The extract was washed wtih satd. brine, dried over MgSO4 and concentrated. The residue was dissoved in 20 mL of THF, and 30 mL of a IN solution of tetrabutylammonium fluoride was added. The reaction was stirred for 5 hours and concentrated. The residue was dissolved in ether, which was washed with water, brine, dried over MgSO4, and concentrated to dryness. The residue was flash chromatographed on siUca gel, eluting with 1 :3 acetone:hexane to give 5.21 g of the title product as a colorless liquid after removal of the solvent. MS: 278 (M+H)+. lH NMR (CDCI3) 3: 0.93 (d, 3H, J=7 Hz), 1.44 (s, 9H), 1.83 (t, IH, J=7 Hz), 2.15 (m, IH), 2.67 (m, IH), 2.8 (m, IH, 3.50 (m, 2H). Anal. Calc. for Cl3Hl8F3NO2*l/4H2O: C, 55.41; H, 6.62; N, 4.97; Found: C, 55.17; H, 6.30; N, 4.61. Step 281b. ('2RV3-(,4-t-butoxy-3.5-difluoro-2-pyridinyD-2-methyl-l -propanol
Following the procedure of Example 274b, replacing the reactant from step 278a with (2S)-3-(4-t-butoxy-3,5,6-trifluoro-2-pyridinyl)-2-methyl-l-propanol, from step 281a above, 3.44 g of the title product was prepared. MS: 260 (M+H)+. 1H NMR (CDCI3) 3: 00.93 (d, 3H, J=7 Hz), 1.42 (m, 9H), 2.16 (m, IH), 2.86 (m, 2H), 2.96 (t, IH, J=7 Hz), 3.40 (m, IH), 3.53 (m, IH), 8.21 (m, IH). Anal. Calc. for C13H19F2NO2: C, 60.22; H, 7.39; N, 5.40; Found: C, 60.15; H, 7.46; N, 5.22.
Step 281c. 3(R)-7-fluoro-3-methyl-8-(t-butyloxy)-2, 3-dihydro-4H-pyranor3.2-blpyridine
A 3.29 g (12.69 mmol) sample of (2R)-3-(4-t-butoxy-3,5-difluoro-2-pyridinyl)- 2-methyl-l -propanol, from step 281b above, was dissolved in 100 mL of dioxane and added to a dispersion of 0.570 g (19.00 mmol) of NaH (80% dispersion) in 100 mL of dioxane. The mixture was heated at reflux for 4 hours, then concentrated to dryness. The residue was slurried with water, and extracted with ether. The extract was washed with satd. brine, dried over MgSO4, and concentrated. The residue was purified by flash chromatography on sUica gel, eluting with 1 :2 ethyl acetete exane, to afford 2.722 g of the title product. MS: 240 (M+H)+. 1H NMR (CDCI3) 3: 1.08 (d, 3H, J=6.5 Hz), 1.40 (d, 9H, J=lHz), 2.22 (m, IH), 2.55 (m, IH), 2.99 (m, IH), 3.69 (dd, IH, J=9, 10 Hz), 4.21 (m, IH), 8.01 (d, IH, J=l Hz). Anal calc. for C13H18FNO2: C, 66.25; H, 7.58; N, 5.85; Found: C, 66.35; H, 7.49; N, 6.04.
Step 28 Id. 3(R)-9-fluoro-10-hydroxy-3-methyl-2H,3H,6H- 6-oxo-pyranoI2.3.4-ijlquinolizine-5-carboxyIic acid, ethyl ester
A 400 mg (1.671 mmol) sample of 3(R)-7-fluoro-3-methyl-8-(t-butyloxy)-2,3- dihydro-4H-pyrano[3.2-b]pyridine, from step 281c above, was dissolved in 5 mL of THF and cooled to -78°C. To this solution was added a solution of 0.80 mL of n-butyl lithium (2.0 mmol, 2.5 M in hexane) and 0.28 mL of LDA (2.00 mmol) (prepared at -78°C and warmed to 0°C for 15 min), and the reaction was stirred at -78 °C for 30 min. To the reaction vessel was added 0.400 mL of diethoxy ethoxymethylenemalonate, and the reaction was stirred for 5 min at -78°C and at room temperature for 15 min. 1.7 mL of NNTMS2 (IN in THF) was added, the reaction was warmed to room temperature, then quenched with satd. NH4C1. The mixture was extracted with ether, which was washed, dried over MgSO4 and concentrated. The solvent was removed, and the residue was dissolved in 10 mL of ethanol. To this was added 0.5 mL of DBU and thereaction was refluxed for 2 hours, then concentrated to dryness. The residue was dissolved in methylene chloride, which was then washed with 10% citric acid, water, dried over MgSO4, and concentrated. The residue was purified by chromatography on sUica gel, eluting with 100: 10 methylene chloride:methanol. To the residue of the desired fraction was added 3 mL of trifluoroacetic acid, and the mixture was concentrated immediately. The residue was washed with ether to leave 307.4 mg of the titie product as a yeUow soUd. MS: 308 (M+H)+. lU NMR (DMSO-d6) 3: 1.25 (d, 3H, J=7 Hz), 1.27 (t, 3H, J=7 hz), 3.19 (m, IH), 4.10 (dd, IH, J=5, 10 Hz), 4.22 (q, 2H, J=7 Hz), 4.33 (dd, IH, J=4, 10 Hz), 9.00 (d, IH, J=8 Hz).
Step 28 le. 3(R)-10-chloro-9-fluoro-3-methyl-2H,3H,6H- 6-oxo-pyranor2.3.4-ijlquinolizine-5-carboxylic acid, ethyl ester
A 276.1 mg (0.899 mmol) sample of 3(R)-9-fluoro-10-hydroxy-3-methyl- 2H,3H,6H-6-oxo-pyrano[2.3.4-ij]quinolizine-5-carboxylic acid, ethyl ester, from step 28 Id above, was dissolved in 5 mL of methylene chloride, and 0.71 mL (9.17 mmol) of DMF and 0.85 mL of POCI3 (9.12 mmol) were added. The reaction was stirred for 15 hours and quenched with water and ice. The mixture was extracted with methylene chloride, and the extract was washed with water, dried over MgSO4 and concentrated. The residue was purified by flash chromatography on sUica gel, eluting with 10:1 methylene chloride:methanol to afford 180.6 mg of the titie product as a yeUow solid after removal of the solvent. MS: 326, 328 (M+H)+. lH NMR (CDCI3) 3: 1.40 (d, 3H, J=5 hz), 1.43 (t, 3H, 7 Hz), 3.22 (m, IH), 4.21 (dd, IH, J=6, 10 Hz), 4.45 (m, 3H), 8.25 (s, IH), 9.09 (d, IH, J=6 Hz).
Step 28 If. 3(R)-10-(3-(N-BOC)amino-l-pγrrolidinyl)-9-fluoro-3-methyl- 2H.3H.6H-6-oxo-pyranor2.3.4-ijlquinolizine-5-carboxylic acid, ethyl ester
A 130.9 mg (0.402 mmol) sample of 3(R)-10-chloro-9-fluoro-3-methyl- 2H,3H,6H-6-oxo-pyrano[2.3.4-ij]quinolizine-5-carboxylic acid, ethyl ester, from step 28 le above, was dissolved in 5 mL of acetonitrile. To this solution was added 0.24 mL of DBU and 120 mg (0.644 mmol) of 3-(N-BOC)aminopyrrolidine (TCI America, Inc.), and the reaction was heated at reflux for 8 hours. The solvent was removed, and the residue was dissolved in methylene chloride which was washed with water. The solvent was removed and the residue was purified by flash chromatography on sUica gel, eluting with 100:10:0.5 methylene chloride:methanol:NH4θH to afford 187.6 mg of the title product as a yellow solid Step 281g. 3(R)-10-(3-(N-BOC)amino-l-pyrroUdinyl)-9-fluoro- 3-methyl-2H.3H.6H-6-oxo-pyranor2.3.4-ijlquinolizine-5-carboxylic acid
A 187.6 mg (0.394 mmol) sample of 3(R)-10-(3-(N-BOC)amino-l-pyιτoUdinyl)- 9-fluoro-3-methyl-2H,3H,6H-6-oxo-pyrano[2.3.4-ij]quinoUzine-5-carboxylic acid, ethyl ester, from step 28 If above, was dissolved in 4 mL of THF and 70 mg of LiOH»H2θ in 2 mL of water was added. The mixture was stirred under N2 for 8 hours at 60°C. The pH was adjusted to 6.5 with IN HCI, and the mixture was extracted wtih methylene chloride. The extract was washed with water, dried over MgSO4 and concentrated. The residue was purified by flash chromatography on sUica gel, eluting with 100:10:1 methylene chloride.-methanol.-acetic acid to afford 144 mg of the title product as a yeUow soUd. MS: 448 (M+H)+. IR (KBr): 3440, 1710, 1640, 1610 cm"1. lH NMR (CDCI3) 3: 1.32 (d, 3H, J=7 Hz), 1.47 (s, 9H), 2.00 (m, IH), 2.18 (m, IH), 3.11 (m, IH), 3.85 (m, IH), 3/987 (m, 2H), 4.10-4.16 (m, 2H), 4.26 (m, IH), 4.32 (m, IH), 5.06 (m, IH), 7.92 (s, IH), 8.80 (d, IH, j=10 Hz). Anal calc. for C22Hi6FN3θ6»H2θ: C, 56.77; H, 6.06; N, 9.03; Found: C, 56.70; H, 5.80; N, 8.81.
Step 281h. 3(R)-10-(3-amino-l-pyrrolidinyl)-9-fluoro-3-methyl-2H,3H,6H- 6-oxo-pyranor2.3.4-ij1quinolizine-5-carboxyUc acid hydrochloride
A 115.7 mg (0.259 mmol) sample of 3(R)-10-(3-(N-BOC)amino-l-pyrroUdinyl)-
9-fluoro-3-methyl-2H,3H,6H-6-oxo-pyrano[2.3.4-ij]quinolizine-5-carboxylic acid, from step 28 lg above, was dissolved in 3 mL of 4N HCI in dioxane, and the reaction was stirred for 1.5 hours at room temperature. The solution was concentrated to dryness, and the residue was dried in a vacuum. The residue was dissolved in water, filtered though sintered glass, and freeze-dried to give 97.3 mg of the title product as a yellow solid. MS: 348 (M-C1)+. IR (KBr): 3440, 1690, 1640, 1600 cm"1. 1H NMR (DMSO-d6) 3: 1.27 (d, 3H, J=7 Hz)), 2.10 (m, IH), 2.22 (m, IH), 3.20 (m, IH), 3.88 (m, IH), 3.99 (m, 2H), 4.10-4.16 (m, 3H), 4.27 (m, IH), 7.82 (s, IH), 8.95 (d, IH, J=10 Hz). Anal calc. for Cl7Hi8FN3θ4«0.5H2θ«2HCl: C, 47.57; H, 4.93; N, 9.79; Found: C, 47.72; H, 4.81; N, 9.58. Step 281 i. 3(R)- 10-(3-amino- 1 -pyrrolidinyl)-9-fluoro-3-methyl-2H,3H,6H- 6-oxo-pyranoI2.3.4-ij1quinoUzine-5-carboxylic acid
A 50 mg sample of the hydrochloride salt from step 28 lh was dissolved in 5 mL of water, and satd. NaHCO3 was adde until the solution was pH 7. The solid (27.8 mg) was coUected by filtration, and the filtrate was extracted with 10% methanol in methylene chloride and methylene chloride. The extract was washed, dried and concentrated to afford a second crop of product. MS: 348 (M+H)+. IR (KBr): 3440, 1650, 1640, 1600 cm"1. lH NMR (DMSO-d6) 3: 1.25 (d, 3H, J=7 Hz), 1.68 (m, IH), 1.95 (m, IH), 3.16 (m, IH), 3.55 (m, 2H), 3.94-4.05 (m, 4H), 4.25 (m, IH), 7.74 (s, IH), 8.89 (d, IH, J=l l Hz). Anal calc. for Cl7Hi8FN3θ4*1.5H2θ: C, 54.54; H, 5.57; N, 11.23; Found: C, 54.78; H, 5.31; N, 11.05.
Example 282
3(R)-10-(3-aminomethyl-l-pyrrolidinyl)-9-fluoro-3-methyl-2H,3H,6H- 6-oxo-pyranoI2.3.4-ijlquinoUzine-5-carboxylic acid hydrochloride
FoUowing the procedure of Example 28 If, replacing the the 3-(BOC- amino)pyrrolidine of that step with 3-(BOC-amino)methylpyrroUdine (prepared according to EP Published appUcation 0106489), and carrying the product forward according to steps 28 lg and h, 118 mg of the title compound was prepared. MS: 362 (M-C1)+. IR (KBr): 3440, 1640, 1600 cm"1. 1H NMR (DMSO-d6) 3: 1.25 (d, 3H, J=7 Hz), 1.72 (m, IH), 2.10 (m, IH), 2.53 (m, IH), 2.94 (m, 2H), 3.16 (m, IH), 3.76 (m, IH), 3.96 (m, 2H), 4.05 (m, 2H), 4.25 (m, IH), 7.77 (s, IH), 8.12 (br, 4H), 8.90 (d, IH, J=10 Hz), 13.92 (br, IH). Anal calc. for Ci8H26FN3θ4«2HCl: C, 49.78; H, 5.11; N, 9.68; Found: C, 49.90; H, 5.04; N, 9.74.
Example 283
3(R)- 10-((2S ,4S)-4-amino-2-methyl- 1 -pyrrolidinyl)-9-fluoro- 3-methyl-2H.3H.6H-6-oxo-pyranor2.3.4-ij1quinolizine-5-carboxylic acid hydrochloride
FoUowing the procedure of Example 28 If, replacing the the 3-(BOC- amino)pyrrolidine of that step with (2S,4S)-4-BOC-amino-2-methylpyrrolidine (from Example 171, step 5), and carrying the product forward according to steps 28 lg and h, 57 mg of the title compound was prepared. MS: 362 (M-C1)+. IR (KBr): 3440, 1700, 1635, 1610 cm" 1. lH NMR (DMSO-d6) 3: 1.20 (d, 3H, J=6 Hz), 1.28 (d, 3H, J=7 Hz), 1.92 (m, IH), 2.37 (m, IH), 3.22 (m, IH), 3.77 (m, IH), 3.91 (m, IH), 4.09 (m, IH), 4.34 (m, 2H), 4.82 (m, IH), 7.88 (s, IH), 8.28 (br, 4H), 9.00 (d, IH, J=10 Hz), 13.94 (br, IH). Anal calc. for Ci8H26FN3θ4*2HCl: C, 49.78; H, 5.11; N, 9.68; Found: C, 49.78; H, 5.04; N, 9.73.
Example 284
3(R)-9-fluoro-10-(3-hydroxy-l-pyrroUdinyl)-3-methyl-2H,3H,6H- 6-oxo-pyranoI2.3.4-ij1quinolizine-5-carboxylic acid
FoUowing the procedure of Example 28 If, replacing the the 3-(BOC- amino)pyrrolidine of that step with (3-hydroxypyrrolidine (Aldrich Chemical Co.), and carrying the product forward according to step 28 lg, 69 mg of the tifle compound was prepared. MS: 349 (M+H)+. lH NMR (DMSO-d6) 3: 1.24, 1.26 (two d, 3H, J=6 Hz), 1.80 (m, 2H), 3.16 (m, IH), 3.69 (m, IH), 3.92 (m, IH), 4.06 (m, 3H), 4.26 (dd, IH, J=10, 4 Hz), 4.36 (m, IH), 5.09 (d, IH, J=3 Hz), 7.76 (s, IH), 8.90 (d, IH, J=10 Hz), 13.94 (br, IH). Anal calc. for C17H17FN2O5: C, 58.62; H, 4.92; N, 8.04; Found: C, 58.23; H, 4.91; N, 7.81.
Example 285
9-fluoro- 10-(4-methyl- 1 -piperazinyl)-2H,3H,6H-6-oxo- pyranor2.3.4-ijlquinolizine-5-carboxylic acid hydrochloride
Step 285a. 9-fluoro-10-(4-methyl-l-piperazinyl)-2H,3H,6H- 6-oxo-pyranoI2.3.4-ijlquinolizine-5-carboxylic acid
FoUowing the procedure of Example 281f, replacing the the 3-(BOC- amino)pyrroUdine of that step with N-methylpiperazine (Aldrich Chemical Co.), and carrying the product forward according to step 28 If and Example 278 step h, 69 mg of the title compound was prepared. MS: 348 (M+H)+. 1H NMR (CDCI3) 3: 2.39 (s, 3H), 2.57 (m, 4H), 3.12 (t, 2H, J=6 Hz), 3.60 (m, 4H), 4.40 (t, 2H, J=6 Hz), 8.10 (s, IH), 8.94 (d, IH, J=9 Hz), 13.87 (s, IH). Anal calc. for C17H18FN3O4O.5H2O; C, 57.30; H, 5.37; N, 11.79; Found: C, 57.71; H, 5.23; N, 11.41.
Step 285b. 9-fluoro- 10-(4-methyl- 1 -piperazinyl)-2H,3H,6H-6- oxo-pyranoI2.3.4-ijlquinolizine-5-carboxylic acid hydrochloride
FoUowing the procedure of Example 278i, replacing the compound of step 278h with the 9-fluoro- 10-(4-methyl- 1 -piperazinyl)-2H,3H,6H-6-oxo-pyrano[2.3.4- ij]quinolizine-5-carboxylic acid, from step 285a above, the title compound was prepared. Examples 286-296
Following the procedures of Steps 253j, 253k and 2531 (if required), above, replacing the 3-BOC-aminopyrroUdine of Step 253j with the reagent shown, the compounds of Examples 286-296 are prepared as shown in Table 11, below.
Table 11
(continued . . . )
Ex.No. Reagent E __
286 1,3-dimethylpiperazine H*C-N N-
287 3-(N-BOC-N-methyl)aminopiperidine
288 2-(N-BOC-aminomethyl)morpholine
289 3(S)-(N-BOC-N-methylamino)-pyrroUdine
290 3-((N-BOC-N-methylamino)methyl)-pyrrolidine
291 3-((N-BOC-N-ethylamino)methyl)-pyrroUdine
292 2-BOC-octahydropyrrolo[3,4-c]pyrrole
293 5-BOC-octahydropyrrolo[3,4-c]pyridine [ | "" N
294 cw-3-BOC-amino-4-methylpyrrotidine
295 trα« -3-BOC-amino-4-methylpyrrolidine
296 7-amino-5-azaspiro[2.4]heptane
Example 297
8-(2S ,4S-4-amino-2-methylpyrrolidinyl)- 1 -cyclopropyl-7-fluoro- 9-ffluoro)methyl-4-oxo-4H-quinolizine-3-carboxyUc acid hydrochloride
FoUowing the procedure of Example 253c, reacting the product of Step 253b with LDA at -78 °C, then adding formaldehyde and stirring until the reaction is complete, foUowed by reaction of the newly formed intermediate with diethylaminosulfur trifluoride (DAST) in methylene chloride to form the intermediate product 4-t-butoxy-2,3,6-trifluoro- 5-(fluoro)-methylpyridine, and carrying this product through the remaining steps as in Example 253d-l, the title compound is prepared.
Example 298
8-(3-Dimethylaminopyrrolidinyl)-l-cyclopropyl-7-fluoro- 9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid, acetic acid salt
A 81 mg sample of 8-chloro-l-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H- quinolizine-3-carboxyUc acid ethyl ester, from Example 253i above, was dissolved in 2.5 mL of dry pyridine under a nitrogen atmosphere. To this solution was added a solution of 114 g of 3-(dimethylamino)pyrrolidine in 2.5 mL of pyridine, and the reaction mixture was heated at 60°C for 39 hours. The pyridine was removed under vacuum, and the residue was stirred with IN NaOH in TΗF/water for at 60°C for 6 hours. The solution was made acidic with acetic acid, and the product was extracted with chloroform. After drying over MgSO4, the solvent was removed, and the residue was purified by chromatography on sUica gel, eluting with 100:40:20:8 chloroform: methanol: acetic acid:water to give the titie product, mp 165-170°C (dec). MS 374 (M+H)+; 1H NMR (D6-DMSO) 3: 0.53 (m, 2H), 0.82-1.08 (m, 2H), 1.75 (s, 3H), 2.22 (s, 6H), 2.08-2.33 (m, 2H), 2.74 (m, 2H), 3.44-3.94 (m, 5H), 8.01 (br s, IH), 8.90 (br s, IH).
Example 299
(3R)-8-(3-Dimethylaminopyrrolidinyl)- 1 -cyclopropyl-7-fluoro- 9-methyl-4-oxo-4H-quinolιzine-3-carboxylic acid hydrochloride
Following the procedure of Example 298, replacing the 3-(dimethylamino)- pyrrolidine with (3R)-3-(dimethylamino)pyrroUdine, the titie compound was prepared, mp 146-148°C. MS 374 (M+H)+; 1H NMR (D6-DMSO) 3: 0.64 (m, 2H), 1.02 (m, 2H), 2.23-2.43 (m, 3H), 2.66 (s, 3H), 2.83 (s, 6H), 3.78-4.17 (m, 5H), 7.95 (s, IH), 9.12 (d, IH, J=l l Hz), 11.14 (br s, IH), 13.83 (br s, IH).
Example 300
(3R, 1 S)-8-(3-( 1 -Aminoethyl)pyrrolidinyl)- 1 -cyclopropyl-7-fluoro- 9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid hydrochloride
A sample of 8-chloro-l-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinoUzine-3- carboxylic acid ethyl ester, from Example 253i above, was dissolved in anhydrous acetonitrile, reacted with (3R,lS)-3-(l-(t-butoxycarbonylamino)ethyl)pyrroUdine (prepared as described by Schroeder et al., J. Heterocyclic Chem., 29: 1481-1498 (1992)), and carried forward as described in Example 253k-l to give the title product, mp 250-255°C (dec). MS 374 (M+H)+; l NMR (D6-DMSO) 3: 0.59 (m, 2H), 1.00 (m, 2H), 1.29 (d, 3H, J=6 Hz), 1.77 (m, IH), 2.13 (m, IH), 2.29 (m, IH), 2.41 (m, IH), 2.64 (s, 3H), 3.57 (s, IH), 3.76 (m, 3H), 3.94 (m, IH), 7.91 (s, IH), 8.17 (brs, 3H), 9.07 (d, IH, J=l l Hz), 13.83 (brs, IH). Example 301
(3S, lR)-8-(3-( 1 -Aminoethyl)pyrrolidinyl)- 1 -cyclopropyl-7-fluoro- 9-methyl-4-oxo-4H-quinoUzine-3-carboxylic acid hydrochloride
A 0.44 g sample of 8-chloro- l-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H- quinolizine-3-carboxylic acid ethyl ester, from Example 253i above, and 1.51 g of NaHCO3 were dissolved in 40 mL of anhydrous acetonitrile, reacted with (3S,lR)-3-(l-(t- butoxycarbonylamino)ethyl)pyrroUdine (1.06 g, prepared as described by Schroeder etal., J. Heterocyclic Chem., 29: 1481-1498 (1992)), and carried forward as described in Example 253k-l to give the titie product, mp 235-240°C (dec). MS 374 (M+H)+; 1H NMR (D6-DMSO) 3: 0.59 (m, 2H), 1.00 (m, 2H), 1.29 (d, 3H, J=6 Hz), 1.76 (m, IH), 2.13 (m, IH), 2.28 (m, IH), 2.41 (m, IH), 2.63 (s, 3H), 3.30 (m, IH), 3.74 (m, 3H), 3.94 (m, IH), 7.90 (s, IH), 8.16 (br s, 3H), 9.07 (d, IH, J=l l Hz).
Example 302
(3R, 1 R)-8-(3-( 1 - Aminoethyl)pyrroUdinyl)- 1 -cyclopropyl-7-fluoro- 9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid hydrochloride
A 0.35 g sample of 8-chloro-l-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H- quinolizine-3-carboxylic acid ethyl ester, from Example 253i above, and 0.73 g of sodium bicarbonate were dissolved in 24 mL of anhydrous acetonitrile, reacted with (3R,lR)-3-(l- (t-butoxycarbonylamino)ethyl)-pyrrolidine (0.51 g, prepared as described by Schroeder et al., J. Heterocyclic Chem., 2£: 1481-1498 (1992)), and carried forward as described in Example 253k-l to give the title product. mp 220-222°C. MS 374 (M+H)+; 1H NMR (D6-DMSO) 3: 0.61 (m, 2H), 0.94 (m, IH), 1.07 (m, IH), 1.28 (d, 3H, J=6 Hz), 1.82
(m, IH), 2.27 (m, 2H), 2.46 (m, IH), 2.62 (s, 3H), 3.57 (s, IH), 3.92 (m, IH), 7.90 (s, IH), 8.17 (br s, 3H), 9.07 (d, IH, J=l l Hz), 13.84 (brs, IH).
Example 303 l-cyclopropyl-8-((R,S)-3-fluoropyrrolidine)-7-fluoro-
9-methyl-4-oxo-4H-quinolizine-3 - carboxylic acid
Step 303a. N-CBZ-rR.SV3-hvdroxypyrrolidine
(R,S)-3-hydroxypyrrolidine (1.0 g, 0.011 mmol) was dissolved in ethyl acetate (50 mL) and to this solution at room temperature was added N-
(benzyloxycarbonyl)succinimide (2.86 g, 0.011 mmol). The mixture was stirred overnight then partitioned between dilute aqueous HCI and ethyl acetate. The aqueous phase was extracted with ethyl acetate (2x). The organics were combined, dried (MgSO4) and concentrated in vacuo. The crude product was purified by flash chromatography on sUica gel (ethyl acetate-hexane) to give the desired compound as a clear oil, 2.1 g, 83%. MS (DCI/NH3) m/z: 222 (M+H)+, 239 (M+NH4) - 1H NMR (CDCI3) d: 1.85-2.10 (m, 2H), 3.37-3.65 (m, 4H), 4.44-4.55 (m, IH), 5.15 (s,2H), 7.28-7.45 (m, 5H).
Step 303b. N-CBZ-fR.SV3-fhιoropyrrolidine
The compound from step 303a above (32.0 lgm, 9.10mmole) was dissolved in anhydrous CH2CI2 (40 mL) and cooled under nitrogen to -78 C. To the cold solution was added in one portion via syringe diethylaminosulfur trifluoride (DAST) (1.32 mL, 10.0 mmol), and the resulting solution was stirred overnight at room temperature. The product was isolated by concentrating the reaction mixture in vacuo with flash chromatography of the residue on silica gel(ethyl acetate-hexane) to give a clear oU, 1.53gm, 75%. MS (DCI/NH3) m/z: 224 (M+H)+, 241 (M+NH4)+ !H NMR (CDCI3) 3: 1.83-2.15 (m,lH), 2.16-2.35 (m, IH), 3.43-3.90 ( m, 4H), 5.21-5.24 (m, 2.5H) 5.28-5.36, (m, 0.5H), 7.28-7.5 (m,5H).
Step 303c fR.SV3-fluoropyrrolidine hydrochloride
The compound from step 303b above (1.53 g, 6.85 mmol) was dissolved in methanol (50 mL) to which was added 5% Pd/BaSO4 (0.5g). The mixture was vacuum degassed (3x) then exposed to a low pressure atmosphere of hydrogen (balloon) at room temperature for 4 hours. The reaction was terminated by vacuum filtration to remove catalyst. The filtrate was cooled in an ice bath, then HCI gas was bubbled into the cold solution for one minute. The resulting solution was concentrated in vacuo, and the residue was triturated with ethyl acetate-ether. The solid was coUected by vacuum filtration to give 0.659 g, 76%, of the hydrochloride as an off white solid. !HNMR (CD3OD) d: 2.1-2.46 (m, 2H), 3.33-3.65 (m, 4H), 5.43 (db.t, IH, JF,H=51 HZ).
Step 303d. l-cyclopropyl-8-((R,S)-3-fluoropyrroUdine)-7-fluoro- 9-methyl-4-oxo-4H-quinolizine-3-carboxyUc acid
The N-boc-3-aminopyrrolidine of Example 253j above was replaced by the (R,S)-3-fluoro pyrrolidine hydrochloride of step 303c above (0.66 g, 5.24 mmol), and the reaction product was carried forward as previously described to give 0.326 g (65%) of the title compound as a bright yeUow solid, mp 227.5-230°C (dec). MS (DCI/NH3) m/z: 349 (M+H)+. l NMR( CDCI3) d: 0.58-0.78 (cm, 2H), 0.85-0.98, (cm,lH) 1.04-1.16 (cm, IH), 2.03-2.53 (cm, 3H), 2.67 (s,3H), 3.60-3.86 (cm, 2H), 4.05-4.26 (cm, 2H), 5.43 (db.t, IH, JF,H=52HZ), 7.26 (s,lH), 8.26 (s, IH), 8.26 (s,lH), 9.08 (d, IH, J=10.5Hz), 13.8 (br.s., IH). Calc. for C18H18N2O3F2 : %C, 62.05; H, 5.22; N, 8.04. Found: %C, 62.06; H, 5.22; N, 7.86.
Example 304
8-(4-( 1 -piperidyl)- 1 -piperidyl)- 1 -cyclopropyl-7-fluoro- 9-methyl-4-oxo-4H-quinoUzine-3-carboxylic acid
A 70 mg sample of 8-chloro-l-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H- quinoUzine-3-carboxylic acid ethyl ester, from Example 253i above, was dissolved in 2 mL of anhydrous acetonitrile, reacted with 4-(l-piperidyl)piperidine (70 mg, 0.4 mmol, Aldrich Chem. Co.), and carried forward as described in Example 253j-k to give the title product. MS 428 (M+H)+; 1H NMR (CDCI3) 3: 0.69 (m, 2H), 1.02 (m, 2H), 1.18 (m, 4H), 2.27 (n, IH), 2.78 (s, 3H), 2.72 (m, IH), 3.35 (m, 3H), 3.55 (m, IH), 3.75 (m, IH), 8.36 (s, IH), 9.20 (d, IH). Anal. Calcd for O24H30N3O3F.I.5 H2O: C, 63.42; H, 7.32; N, 9.24; Found: C, 62.99; H, 7.04; N, 8.78.
Example 305
8-(4-( 1-piperidyl)- 1 -piperidyl)- 1 -cyclopropyl-7-fluoro- 9-methyl-4-oxo-4H-quinoUzine-3-carboxyUc acid trifluoroacetic acid salt
A 100 mg sample of 8-chloro-l-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H- quinoUzine-3-carboxylic acid ethyl ester, from Example 253i above, was dissolved in 3 mL of anhydrous acetonitrile, reacted with 4-(4-piperidyl)-piperidine (0.24 g, 0.93 mmol, obtained from Aldrich Chem. Co.), carried forward as described in Example 253j-k and converted to the TFA salt by the procedure of Example 162 to give the titie product. MS 428 (M+H)+; !H NMR (CDCI3) 3: 0.69 (m, 2H), 1.03 (m, 2H), 1.70 (m, 2H), 1.87 (m, 2H), 1.98 (m, 2H), 2.14 (m, 2H), 2.27 (m, IH), 2.77 (s, 3H), 2.91 (m, 2H), 3.33 (m, 2H), 3.54 (m, 4H), 8.37 (s, IH), 9.21 (d, IH). Anal. Calcd for C24H30N3O5F4.I.5 H2O: C, 54.93; H, 6.03; N, 7.39; Found: C, 54.97; H, 5.39; N, 7.24. Example 306
8-(4-(2-pyridyl)- 1 -piperazinyl)- 1 -cyclopropyl- 7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid
A 60 mg sample of 8-chloro- l-cyclopropyl-7 -fluoro- 9-methyl-4-oxo-4H- quinoUzine-3-carboxylic acid ethyl ester, from Example 253i above, was dissolved in 2 mL of anhydrous acetonitrile, reacted with 4-(2-pyridyl)piperazine (63.5 mg, 0.39 mmol, Aldrich Chem. Co.), and carried forward as described in Example 253j-k to give the titie product. MS 423 (M+H)+; !H NMR (CDCI3) 3: 0.71 (m, 2H), 1.05 (m, 2H), 2.30 (m, IH), 2.86 (s, 3H), 3.59 (m, 4H), 3.78 (m, 4H), 6.76 (m, 2H), 7.57 (m, IH), 8.25 (m, IH), 8.40 (s, IH), 8.25 (d, IH), 13,83 (bs, IH). Anal. Calcd for C23H23N4O3F.I.5 H2O: C, 61.46; H, 5.83; N, 12.46; Found: C, 61.76; H, 5.54; N, 11.64.
Example 307 8-((2-amino)thioethoxy)- 1 -cyclopropy 1-7-fluoro-
9-methyl-4-oxo-4H-quinoUzine-3-carboxylic acid trifluoroacetic acid salt
A 50 mg sample of 8-chloro-l-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H- quinoUzine-3-carboxylic acid ethyl ester, from Example 253i above, was dissolved in 2 mL of anhydrous acetonitrile, reacted with N-BOC-2-aminothiol (57.4 mg, 0.32 mmol, prepared by standard procedures from the unprotected compound obtained from Aldrich Chem. Co.), carried forward as described in Example 253j-k, deprotected as in step 2531, and converted to the TFA salt by the procedure of Example 162 to give the title product. MS 337 (M+H)+; 1H NMR (d6-DMSO) 3: 0.74 (m, 2H), 1.08 (m, 2H), 3.04 (t, 2H), 3.16 (s, 3H), 3.33 (t, 2H), 8.27 (s, IH), 9.32 (d, IH), 13.8 (br, IH).
Example 308
(3R, 1 S)-8-(3-( 1 -amino)propyl)pyrroUdinyl)- 1 -cyclopropyl- 7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid hydrochloride
A 147 mg sample of 8-chloro-l-cyclopropyl-7 -fluoro- 9- methyl-4-oxo-4H- quinoUzine-3-carboxylic acid ethyl ester, from Example 253i above, was dissolved in 3 mL of anhydrous acetonitrile, reacted with (3R,lS)-3-(l-BOC-amino)propyl)pyrroUdine (326 mg, 1.13 mmol, prepared as described by Hayakawa et al., U.S. Patent 5,098,912, issued March 24, 1992, using modifications for chiral products described by Plummer, et al.
Tetr. Lett.24:7529-32 (1993)), and carried forward as described in Example 253J-1 to give the title product. MS (high resolution) found: 388.2039; calc: 388.2036 (M+H)+; 1H NMR (D6-DMSO) 3: 0.60 (m, 2H), 1.00 (t, 3H), 1.01 (m, 2H), 1.63 (m, 2H), 2.13 (m,
IH), 2.29 (m, 2H), 3.73 (m, 3H), 3.95 (m, IH), 7.96 (s, IH), 8.00 (b m, 2H), 9.08 (d,
IH), 13.83 (b s, IH). Anal. Calcd for C21H27N3O3FOO.5 H2O: C, 58.13; H, 6.74;
N, 9.68; Found: C, 58.24; H, 6.51; N, 9.71.
Example 309
(3R,lS)-8-(3-(l-(N-methyl)amino)propyl)pyrrolidinyl)-l-cyclopropyl- 7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid hydrochloride
A 492.9 mg sample of 8-chloro- 1 -cyclopropyl-7-fluoro-9-methyl-4-oxo-4H- quinoUzine-3-carboxylic acid ethyl ester, from Example 253i above, was dissolved in 8 mL of anhydrous acetonitrile, reacted with (3R,lS)-3-(l-(N-methyl)amino)propyl)pyτrolidine (501 mg, 3.53 mmol, prepared as described by Hayakawa et al., U.S. Patent 5,098,912, issued March 24, 1992, using modifications for chiral products described by Plummer, et al. Tetr. Lett. 24:7529-32 (1993)), and carried forward as described in Example 253 j-1, omitting the deprotecting step, to give the title product MS 402 (M+H)+; 1H NMR (D6- DMSO) 3: 0.61 (m, 2H), 0.98 (t, 3H), 1.00 (m, 2H), 1.75 (m, 5H), 2.15 (m, IH), 2.30 (m, IH), 2.59 (s, 3H), 2.63 (s, 3H), 3.66 (m, IH), 3.77 (m, 2H), 3.95 (m, IH), 7.90 (s, IH), 8.60 (bs, 2H), 9.08 (d, IH), 13.83 (bs, IH) Anal. Calcd for C22H29N3O3FC1* H2O: C, 57.95; H, 6.85; N, 9.22; Found: C, 58.24; H, 6.58; N, 9.30.
Example 310
(3R, 1 S)-8-(3-( 1 -aιrdno-3-methylpropyl)pyrrotidinyl)- 1 -cyclopropyl- 7-fluoro-9-methyl-4-oxo-4H-quinoUzine-3-carboxylic acid hydrochloride
A 171 mg sample of 8-chloro-l -cyclopropyl-7 -fluoro- 9- methyl -4-oxo-4H- quinoUzine-3-carboxylic acid ethyl ester, from Example 253i above, was dissolved in 4 mL of anhydrous acetonitrile, reacted with (3R,lS)-3-(l-amino-3-methylpropyl)pyrroUdine (400 mg, 1.32 mmol, prepared as described by Plummer etal., Tetr. Lett.24:7529-32 (1993), and carried forward as described in Example 253j-l, omitting the deprotection reaction, to give the title product. MS (high resolution) found: 402.2174; calc: 402.2193 (M+H)+; 1H NMR (D6-DMSO) 3: 0.60 (m, 2H), 0.95 (d, 3H), 1.06 (d, 3H), 1.75 (m, IH), 2.13 (m, IH), 2.29 (m, 2H), 2.50 (s, 3H), 3.66 (m, 3H), 3.78 (m, IH), 3.97 (m, IH), 7.88 (s, IH), 9.08 (d, IH), 13.82 (bs, IH). Anal. Calcd for C22H29N3O3FC1* 0.75 H2O: C, 58.53; H, 6.81; N, 9.31; Found: C, 58.88; H, 6.70; N, 9.26. Example 311
8-(3-( 1 -aminocyclopropyl)pyrrolidinyl)- 1 -cyclopropy 1-7-fluoro- 9-methyl-4-oxo-4H-quinoUzine-3-carboxyUc acid hydrochloride
A 98 mg sample of 8-chloro- l-cyclopropyl-7 -fluoro- 9-methyl-4-oxo-4H- quinoUzine-3-carboxylic acid ethyl ester, from Example 253i above, was dissolved in 2 mL of anhydrous acetonitrile, reacted with l-(N-BOC-amino)cyclopropyl)pyιτolidine (172 mg, 0.76 mmol, prepared as described by Hayakawa etal., U.S. Patent 5,098,912, issued March 24, 1992), and carried forward as described in Example 253j-l to give the title product. MS (high resolution) found: 386.1893; calc: 386.1880 (M+H)+; 1H NMR (D6- DMSO) 3: 0.60 (m, 2H), 0.91 (m, 5H), 1.04 (m, IH), 1.67 (m, IH), 2.04 (m, IH), 2.29 (m, 2H), 2.61 (s, 3H), 3.70 (m, 3H), 3.93 (m, IH), 7.90 (s, IH), 8.43 (bs, 2H), 9.08 (d, IH), 13.82 (s, IH). Anal. Calcd for C22H29N3O3FCI: C, 59.55; H, 6.12; N, 9.80; Found: C, 59.78; H, 5.97; N, 9.69.
Example 312
(3R, 1 S)-8-(3-( 1 -amino-2-hydroxyethyl)pyrroUdinyl)- 1 -cyclopropyl- 7-fluoro-9-methyl-4-oxo-4H-quinoIizine-3-carboxylic acid hydrochloride
Step 312a. f S VN-BOC-O-(methoxymethyl)serine methyl ester
A 7 g (31.96 mmol) sample of ((S)-N-BOC-serine methyl ester (obtained from Aldrich) was dissolved in CH2CI2 and cooled in an ice bath. To this stirred solution was added dropwise 2.83 g (35.16 mmol) of methoxymethyl chloride, followed by dropwise addition of 4.544 g (6.12 mL, 35.16 mmol) of dUsopropylethylamine. After all reagents were added the reaction was stirred for 16 hours at room temperature. The solution was washed with 0.5 % HCI, satd. NaHCO3, H2O, and brine, dried over MgSO4 and filtered. The solvent was removed to leave a yellow oU. The residue was purified by chromatography on sitica gel, eluting with 15-20% ethyl acetate:hexane to afford 6 g of title product after removal of the solvent. MS 264 (M+H)+; lH NMR (CDCI3) 3: 1.47 (s, 9H), 3.31 (s, 3H), 3.74 (dd, IH), 3.79 (s, 3H), 4.00 (dd, IH), 4/45 (b M, IH), 4.60 (s, 2H), 5.43 (b m, IH).
Step 312b. 2-('BOC-aminoV3-(methoxymethoxy)-l -propanol
A solution of the compound from step 312a above (5.202 g, 19.78 mmol) in 15 mL of THF was added dropwise to a cooled (ice bath) suspension of 570 mg (14.84 mmol) of LAH in 15 mL of THF under N2 atmosphere. The mixture was stirred for 1.5 hours, the reaction was quenched with water and 50% NaOH, filtered, and the filtrate evaporated to obtain the crude product A yellow oU was obtained, which was purified by chromatography on siUca gel, eluting with 35-40% ethyl acetate: hexane to give 3.475 g of the title product as a colorless oU. MS 236 (M+H)+
Step 312c 2-fBOC-am o)-3-(methoxymethoxy)-l-propanal
To a solution of the compound from step 312b above (3.47 g, 14.77 mmol) in 7 mL of DMSO cooled to 0°C was added dropwise 6.8 mL (48.74 mmol) of triethylamine. Pyridine»Sθ3 complex (7.05 g, 44.31 mmol) was dissolved in 27 mL of DMSO and added to the first solution, and the reaction was stirred for one hour after the addition was complete. The solution was poured into 120 mL of cold brine, and the mixture was washed 3x with ethyl acetate. The extract was washed with water, dried over MgSO4, filtered and the solvent was removed under vacuum to give 6 g of a yellow oU, which was taken directly to the next step.
Step 312d. 4-(BOC-amino)-5-fmethoxymethoxy)-2-pentenoic acid ethyl ester
To a solution of the compound from step 312c above (14.77 mmol) in 42 mL of CH2CI2 and cooled in an ice bath was added dropwise 5.454 g (15.66 mmol) of (carboethoxymethylene)triphenylphosphorane in 56 mL of CH2CI2. After addition was complete, the reaction was stirred for 16 hours at room temperature. The solvent was removed, and the residue purified by column chromatography on sUica gel, eluting with 10% ethyl acetate:hexane, to give 2.763 g of a colorless oil. MS 304 (M+H)+; 1H NMR (CDCI3) 3: 1.25 (t, 3H), 1.47 (s, 9H), 3.36 (s, 3H), 3.67 (dd, IH), 3.73 (dd, IH), 3.72 (m, IH), 4.20 (q, 2H), 4.62 (s, 2H), 5.99 (dd, IH), 6.93 (dd, IH).
Step 312e. 4-(BOC-amino)-5-(methoxymethoxy)- 3-(nitromethyl)-pentanoic acid ethyl ester
To a solution of the compound from step 312d above (2.76 g, 9.71 mmol) in 8 mL of nitromethane cooled in an ice bath was added 7 mL (6.934 g, 45.55 mmol) of 1,8- diazabicyclo[5.4.0]undec-7-ene dropwise under N2. The mixture was warmed to room temperature and stirred for 16 hours. The solution was diluted with CH2CI2 and extracted with water, 10% HCI, 10% NaHCO3, water and brine. The solution was dried over MgSO4, and the solvent was removed. The residue was chromatographed on sUica gel, eluting with 10-15% ethyl acetate:hexane, and the solv: -i was removed to give 2.01 g of the title product as a white solid. MS 365 (M+H)+; lκ NMR (CDCI3) 3: 1.27 (t, 3H), 1.47 (s, 9H), 2.46 (dd, IH), 2.98 (br, IH), 3.38 (s, 3H), 3.58 (ddd, IH), 3.76 (dd, IH), 3.97 (b m, IH), 4.16 (q, IH), 4.53 (dd, IH), 4.62 (s, 2H), 4.67 (dd, IH), 4.99 (b d, IH).
Step 312f. 4-(BOC-amino)-5-(methoxymethoxy)- 3-(aminomethyl)-pentanoic acid ethyl ester
Two g of the compound from step 312e above was dissolved in 200 mL of ethanol and hydrogenated at 4 Atm over 4 g of Raney nickel catalyst for 24 hours. The catalyst was removed by filtration and the solvent was evaporated. The residue was taken directly to the next step.
Step 312g. N-BOC-2-(methoxymethoxyVl-(5-oxo-3-pyHolidinyl)-ethylarrune
The residue from step 312f above was dissolved in 150 mL of ethanol and heated at reflux for 8 hours. The solvent was removed, the residue was chromatographed on sUica gel, eluting with 4% methanol/methylene chloride. Removal of the solvent gave 1.36 g of titie product. MS 289 (M+H)+; 1H NMR (CDCI3) 3: 1.47 (t, 3H), 2.17 (dd, IH), 2.38 (dd, IH), 2.78 (m, IH), 3.31 (t, IH), 3.46 (s, 3H), 3.46 (t, IH), 3.59 (m, 2H), 3.81 (b t, IH), 4.62 (s, 2H), 4.94 (br d, IH), 5.43 (br, IH).
Step 312h. N-BOC-2-('methoxymethoxyVl-('5-thioxo-3-pyιτolidinyπ-ethylamine
A 500 mg (1.74 mmol) sample of the compound from step 312g above and 387 mg (0.957 mmol) of Lawesson's reagent were dissolved in 4 mL of THF and stirred under N2 for 3 hours. The solvent was removed, and the residue was dissolved in CH2CI2 and chromatographed on siUca gel, eluting with 35% ethyl acetate exane. Removal of the solvent left 500 mg of product. MS 305 (M+H)+; 1H NMR (CDCI3) 3: 1.47 (s, 9H), 2.71 (dd, IH), 2.89 (m, IH), 3.00 (dd, IH), 3.37 (s, 3H), 3.53 (dd, 2H), 3.66 (m, 2H), 3.83 (b m, IH), 4.61 (s, 2H), 4.98 (b d, IH).
Step 312i. N-BOC-2-fmethoxymethoxyV3-pyrrolid;'iyl)-ethylamine acetic acid salt
A 250 mg (0.825 mmol) sample of the compound from step 312h above and 1.57g (6.6 mmol) of NiC12»6H2θ were dissolved in 10 mL of a 1:1 mixture of methanol and THF, and the solution was cooled to -78°C and stirred under N2. A 749 mg (19.8 mmol) sample of NaBH4 was added in portions, and the mixture was stirred for 2 hours. The solvents were removed under vacuum, and dissolved in 20% methanol in chloroform. The solution was filters and the solvent removed. The residue was chromatographed on sUica gel, eluting with 1:1:1:1 n-butanol:ethyl acetate :H2θ: acetic acid to provide 349 mg of title product. MS 275 (M+H)+; lU NMR (D2O) 3: 1.44 (s, 9H), 3.03 (m, IH), 3.30 (m, IH), 3.40 (s, 3H), 3.48 (m, IH), 3.60 (t, 2H), 3.75 (m, IH).
Step 312j. (3R, 1 S)-8-(3-( 1 -amino-2-hydroxyethyl)pyrrolidinyl)- 1 -cyclopropyl- 7-fluoro-9-methyl-4-oxo-4H-quinoUzine-3-carboxylic acid hydrochloride
A 107 mg (0.33 mmol) sample of 8-chloro-l-cyclopropyl-7-fluoro-9-methyl-4- oxo-4H-quinolizine-3-carboxyUc acid ethyl ester, from Example 253i above, was dissolved in 2.5 mL of anhydrous acetonitrile, reacted with the compound from step 312i above (0.825 mmol), and carried forward as described in Example 253j-l to give 74 mg of the title product. ]H NMR (D6-DMSO) 3: 0.60 (m, 2H), 0.94 (m, IH), 1.05 (m, IH), 1.78 (m, IH), 2.05 (m, IH), 2.19 (m, 2H), 2.60 (s, 3H), 3.57 (m, IH), 3.73 (m, 3H), 3.92 (m, IH), 5.41 (m, IH), 7.91 (s, IH), 9.09 (d, IH), 13.83 (br s, IH).
Example 313
(8-(3-( 1 -amino- 1 -methylethyl)pyrroUdinyl)- 1 -cyclopropyl-7-fluoro- 9-methyl-4-oxo-4H-quinoUzine-3-carboxyUc acid hydrochloride
A 150 mg sample of 8-chloro-l-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H- quinoUzine-3-carboxylic acid ethyl ester, from Example 253i above, was dissolved in 2 mL of anhydrous acetonitrile, reacted with 1 -amino- l-methylethyl)pyrroUdine (155 mg, 0.77 mmol, prepared by standard method from the free base described by Hayakawa et ai, U.S. Patent 5,098,912, issued March 24, 1992), and carried forward as described in Example 253k-l to give the title product. MS (high resolution) found: 388.2047; calc: 388.2036 (M+H)+; 1H NMR (D6-DMSO) 9: 0.60 (m, 2H), 0.94 (m, IH), 1.07 (m, IH), 1.33 (s, 3H), 1.34 (s, IH), 2.83 (m, IH), 2.07 (m, IH), 2.19 (m, 2H), 2.63 (s, 3H), 3.60 (b t, IH), 3.68 (b t, IH), 3.81 (m, IH), 3.93 (m, IH), 7.90 (s, IH), 8.1 1 (b s, IH), 9.08 (d, IH), 13.83 ( b s, IH). Anal. Calcd for C21H27N3O3FCM.5 H2O: C, 55.93; H, 6.71; N, 9.32; Found: C, 56.07; H, 6.71; N, 8.95. Example 314
8-(3-( 1 -aminobutyl)pyrrolidinyl)- 1 -cyclopropyl-7-fluoro- 9-methyl-4-oxo-4H-quinoUzine-3-carboxyUc acid hydrochloride
Step 314a. 4-(BOC-amino)-3-(nitromethyl)-heptanoic acid ethyl ester
FoUowing the procedure of Example 312 step b, substituting DL-N-BOC- norvaUne methyl ester (prepared from norvaUne by standard methods) for the compound of step 312a thereof, and carrying the product forward via the procedures of Example 312 steps c-e, the title compound was prepared.
Step 314b. 4-(BOC-amino)-3-("nitromethyl)-heptanol
Repeating the procedure of example 312 step b, substituting 4-(BOC-amino)-3- (nitromethyl)-heptanoic acid ethyl ester (1.3 g, 3.91 mmol), from step 314a above, for the compound of step 312a thereof, the titie compound was prepared. MS 291 (M+H)+; 1H NMR (CDCID3) 9: 0.93 (t, 3H), 1.45 (s, 9H), 1.48 (m, 5H), 1.77 (m, IH), 2.53 (m, IH), 3.79 (m, 3H), 4.33 (m, IH), 4.38 (dd, IH), 4.49 (dd, IH).
Step 314c 4-fBOC-aιτuno)-3-(nitromethyl)-heptanol. O-mesityl ether
A 610 mg (2.03 mmol) sample of the compound from step 314c above was dissolved in 2 mL of CH2CI2, and the solution was cooled to - 10°C. To this was added dropwise 289 mg (0.195 mL, 2.52 mmol) of methanesulfonyl chloride and 319 mg (3.15 mmol) of triethylamine. The solution was stirred for 2 hours at 0-10°C. The solution was diluted with CH2CI2 and washed, once with water, once with 5% NaHCO3, and once with brine. The solvent was dried over MgSO4 and filtered, and the solvent was removed to give 720 mg of the titie product as an oU.
Step 314d. 3-C 1 -(N-BOC-amino butvnpyrrolidine
The 720 mg sample of the product from step 314c was dissolved in 50 mL of methanol and hydrogenated over 360 mg of 10% Pd/C catalyst at 4 Atm and room temperature for 24 hours. MS 2243 (M+H)+; 1H NMR (CD3OD) 9: (0.94 (t, 3H), 1.34 ( , 3H), 1.44 (s, 9H), 1.48 (m, IH), 1.70 (m, IH), 2.13 (m, IH), 2.37 (q, IH), 3.04 ( , IH), 3.22 (m, IH), 6.71 (b d, IH). Step 314e. 8-(3-(l-aminobutyl)pyrroUdinyl)-l-cyclopropyl-7-fluoro- 9-methyl-4-oxo-4H-quinolizine-3-carboxyUc acid hydrochloride
A 238 mg sample of 8-chloro-l-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H- quinoUzine-3-carboxylic acid ethyl ester, from Example 253i above, was dissolved in 5 mL of anhydrous acetonitrUe, reacted with 3-(l-(N-BOC-amino)butyl)pyrroUdine (620 mg, 1.83 mmol, prepared in step 314d above), and carried forward as described in Example 253J-1 to give the titie product. MS (high resolution) found: 402.2199; calc: 402.2193 (M+H)+; lH NMR (D6-DMSO) 9: 0.60 (m, 2H), 0.89 (m, 4H), 1.05 (m, IH), 1.49 (m, 5H), 1.17 (m, IH), 2.14 (m, IH), 2.27 (m, IH), 2.62 (s, 3H), 3.77 (m, 4H), 3.94 (m, IH), 7.89 (s, IH), 8.54 (b m, IH), 9.07 (d, IH), 11.47 (br, IH).
Examples 315-323
Following the procedures of Steps 253j, 253k and 2531 above, replacing the 3- BOC-aminopyrrolidine of Step 253j with the reagent shown, the compounds of Examples 315-323 are prepared as shown in Table 12, below.
Table 12
Ex. No. Reagent R^
Example 324 l-cyclopropyl-7-fluoro-9-methyl-4-oxo-8-(trfl/w-4-trifluoromethyl- 3-aminopyrroUdinyl)-4H-quinolizine-3-carboxylic acid hydrochloride
Step 324a. trα/»,-N-benzyl-4-trifluoromethvI-3-pyrrolidinecarboxyUc acid ethyl ester
Trifluoroacetic acid (3 mL, 1 N in CH2CI2) was added to a stirred solution of trans-ethyl trifluorocrotonate (4.969 g ) and N-benzyl-N- methoxymethyl)trimethylsilylamine (7.00 g, prepared according to Chem. Pharm. Bull., 22:2762 (1985)) in 30 mL of CH2CI2 at 0°C, and the mixture was stirred for 2 hours. After dUution with CH2CI2, the solution was washed with satd. NaHCO3 solution and water, dried over MgSO4 and concentrated under vacuum to give a pale yeUow liquid (8.75 g).
Step 324b. trα«.γ-N-benzyl-4-trifluoromethyl-3-pyπOUdinecarboxylic acid
A sample (4.739 g ) of this Uquid was hydrolyzed with 1.98 g of LiOH»H2θ in
THF:H2θ (25 mL, 1.5:1) at 60°C to give after workup 3.64 g of the intermediate as a solid.
Step 324c trQ/i.v-l-benzyl-3-(BOC-aminoV4-rrifluoromethylpyrrolidine
A sample of the intermediate from 324b (3.64 g), diphenylphosphoryl azide (3.50 mL), t-butanol (40 mL), triethylamine (2.3 mL) and 40 mL of dioxane were mixed and heated at reflux under N2 for 17 hours. The solvents were removed under vacuum. The residue was dissolved in CH2CI2, washed with satd. NaHCO3 solution and water, dried over MgSO4 and concentrated under vacuum. The product was purified by chromatography on siUca gel, eluting with 100:5:5 CH2CI2 :methanol: NH4OH to afford 1.77 g of the titie compound.
Step 324d. trαn.y-3-(BOC-amino)-4-trifluoromethylpyrrolidine
The compound from step 324c above (1.55 g) was hydrogenated in 50 mL of methanol over 0.45 g of 10% Pd/C catalyst under 4 Atm of H2 for 3.5 days. The catalyst was removed by filtration, and the solvent was removed to afford the titie compound as a white solid (1.09 g). Step 324e. 1 -cyclopropyl-7-fluoro-9-methyl-4-oxo-8-(trαw-4-trifluorornethyl- 3-aminopyrroUdinyl -4H-quinoUzine-3-carboxylic acid hydrochloride
FoUowing the procedure of Example 253 steps k and 1, replacing the 3-BOC- aminopyrroUdine of Example 253j with the compound from step 325d above, the title compound was prepared (97 mg). MS: 414 (M+l)+; 1H NMR (D6-DMSO) 9: 0.63 (m, 2H), 1.01 (m, 2H), 2.39 (m, IH), 2.70 (s, 3H), 3.59 (m, IH), 3.81 (m, 2H), 4.11-4.25 (m, 3H), 8.01 (s, IH). Anal. Calcd for C19Hi9N3O3F4.HCM.25 H2O: C, 48.31; H, 4.80; N, 8.90; Found: C, 48.45; H, 4.63; N, 8.53.
Example 325 l-cyclopropyl-7-fluoro-9-methyl-4-oxo-8-(trα/JS-4-ttifluoromethyl-3- aminomethylpyrrolidinyl)-4H-quinolizine-3-carboxyUc acid hydrochloride
Step 325a. trα/iγ-l-benzyl-3- hvdroxymethyl)-4-trifluoromethylpyrrolidine
A sample of the compound from Example 324 step a above (4.02 g) was dissolved in 10 mL of THF, then LAH (8.0 mL, 1.0 N in THF) was added, and the solution was stirred for 30 min at room temperature. The reaction was quenched, and the product was extracted to give 3.36 g of the title product after removal of the solvent.
Step 325b. tra ,-l-benzyl-3-('aminomethyl">-4-trifluoromethylpyrrolidine
The compound from step 325a above (3.36 g), triphenylphosphine, and phthaUmide were dissolved in 50 mL of THF, and DEAD (2.05 mL) was added dropwise to the above solution at room temperature. The reaction was complete almost immediately, and the solvents were removed. The residue was dissolved in 50 mL of ethanol, 0.65 mL of NH2NH2»H2θ was added, and the reaction was heated at reflux under N2 for 3 hours. The solution was cooled to room temperature, 5 mL of cone HCI was added, and the mixture was filtered. The filtrate was concentrated, and the residue was dissolved in 10% HCI and extracted (6x) with CH2CI2. The aqueous layer was then adjusted to pH 11 with NaOH and extracted with CH2CI2, which was washed with H2O, dried over MgSO4 and concentrated. The residue was dissolved in 7:25 H2θ:methanol, (BOQ2O was added, and the reaction stirred at room temperature for 30 min. The methanol was removed under vacuum, and the aqueous residue was extracted with CH2CI2 • The extract was washed with H2O, dried over MgSO4 and concentrated. The residue was purified by chromatography on siUca gel, eluting with 1 :4 ethyl acetate exane, to give the title compound as a white solid. Step 325c trα -3-(BOC-aminomethylV4-trifluoromethylpyrroUdine
The compound from step 325b above was hydrogenated according to the procedure of Example 324 step d to afford the title compound as a white soUd.
Step 325d. l-cyclopropyl-7-fluoro-9-methyl-4-oxo-8-(trfl«5'-4-trifluoromethyl- 3-aminomethylpyrrolidinylV4H-quinoUzine-3-carboxyUc acid hydrochloride
FoUowing the procedure of Example 253 step j above, substituting the compound from step 325c above for the 3-BOC-aminopyrroUdine thereof, and carrying the reaction product forward as in Example 253 steps k and 1 above, a 77 mg sample of the title product was prepared. MS: 428 (M+l)+; !H NMR (D6-DMSO) 9: 0.63 (m, 2H), 1.02 (m, 2H), 2.36 (m, IH), 2.69 (s, 3H), 2.80 (m, IH), 3.08 (m, 2H), 3.69 (m, IH), 3.83 (m, IH), 3.94-4.06 (m, 3H), 7.99 (s, IH), 9.17 (d, IH, J=10 Hz). Anal. Calcd for C20H21N3O3F4 'HCW^O: C, 49.85; H, 5.02; N, 8.72; Found: C, 49.86; H, 5.10; N, 8.93.
Example 326
3(S)- 1 -cyclopropyl-7-fluoro-9-methyl-4-oxo-8-(3-(N-(S)- norvalylamino pyrroUdinylV4H-quinoUzine-3-carboxyUc acid hydrochloride
FoUowing the procedure of Example 166, replacing the starting pyrido- pyrimidine material thereof with the product of Example 253 step j, the title compound was prepared. MS: 445 (M+l)+; Anal. Calcd for C23H29N4O4F »1.5 HC1»0.75 H2O: C, 53.88; H, 6.29; N, 10.93; Found: C, 53.87; H, 6.10; N, 11.10.
Example 327
3(S)- 1 -cyclo ropyl-7-fluoro-9-methyl-4-oxo-8-(3-(N-(S)- alanylamino')pyιτolidinvI)-4H-quinolizine-3-carboxylic acid hydrochloride
FoUowing the procedure of Example 167, replacing the starting pyrido- pyrimidine material thereof with the product of Example 253 step j, 97 mg of the titie compound was prepared. MS: 417 (M+l)+; 1H NMR (D6-DMSO) 9: 0.60 (m,2H), 1.00 (m, 2H), 1.35 (d, 3H, J=7 Hz), 2.00 (m, IH), 2.20-2.31 (m, 2H), 2.62 (s, 3H), 3.56 (m, IH), 3.80 (m, 2H), 3.93-4.06 (m, 2H), 4.43 (m, IH), 7.91 (s, IH), 8.19 (br, 3H), 8.91 (d, IH, J=6 Hz), 9.09 (d, IH, J=10.5 Hz), 13.85 (br, IH). Anal. Calcd for C21H25N4O4F «2 HCI: C, 51.54; H, 5.56; Found: C, 51.50; H, 5.48. Example 328
3(S)-l-cyclopropyl-7-fluoro-9-methyl-4-oxo-8-(3- ^-(S)-alanyl-(S)- alanylamino)pyrroUdinylV4H-quinolizine-3-carboxyUc acid hydrochloride
FoUowing the procedure of Example 168, replacing the starting pyrido- pyrimidine material thereof with the product of Example 253 step j, 680 mg of the title compound was prepared. MS: 488 (M-C1)+; 1H NMR (D6-DMSO) 9: 0.60 (m, 2H), 1.00 (m, 2H), 1.23 (d, 3H, J=7.5 Hz), 1.33 (d, 3H, J=7.0 Hz), 1.98 (m, IH), 3.85-4.01 (m, 4H), 4.314.37 (m, 2H), 7.91 (s, IH), 8.13 (br, 3H), 8.47 (d, IH, J=6.0 Hz), 8.65 (d, IH, J=7.5 Hz), 9.10 (d, IH, J=10.5 Hz). Anal. Calcd for C24H30N5O5F »3 HCM).5 H2O: C, 46.18; H, 5.57; N, 11.22; Found: C, 46.34; H, 5.77; N, 11.52.
Example 329 l-cyclopropyl-7-fluoro-6-methyl-4-oxo-8-(3-aminopyrroUdinyl)- 4H-quinolizine-3-carboxylic acid hydrochloride
Step 329a. 4-t-butoxy-3-chloro-2.5-difluoro-6-('trimethylsilylmethyl)pyridine
To a stirred solution of 4-t-butoxy-3-chloro-trifluoropyridine (7.55 g, prepared as in Example 253 step a above) in 200 mL of THF at -78°C was added trimethylsUylmethyl Uthium (1.0 M in pentane, 66 mL) dropwise, and the resulting solution was stirred for 1 hour. The reaction was quenched with satd NaCl solution, and the mixture was extracted with ether. The extract was washed with brine, dried over MgSO4 and concentrated. The residue was purified by chromatography on siUca gel, eluting with 1:32 ethyl acetate: hexane to give 6.26 g of title compound.
Step 329b. 4-t-butoxy-2.5-difluoro-6-(trimethylsilylmethvPpyridine
The compound from step 329a above was dissolved in 100 mL of ethyl acetate, and 15 mL of triethylamine and 1.3 g of 10% Pd/C were added. The mixture was shaken under 4 Atm of H2 for 24 hours. The catalyst was removed, and the filtrate was concentrated. The residue was purified with column chromatography on sUica gel, eluting with 1:32 ethyl acetate±exane to give 4.38 g of a colorless liquid. Step 329c 2.5-difluoro-4-t-butoxy-6-methylpyridine
A 1.00 g sample of the compound from step 329b above was dissolved in 10 mL of THF, BH4NF (1.0 M in THF, 3.7 mL) was added, and the reaction was stirred at room temperature for 2.5 hours. The solvent was removed, and the residue was dissolved in ether, which was then washed with water, brine, and dried over MgSO4. Removal of the solvent and purification of the residue by chromatography on sUica gel, eluting with 1:32 ethyl acetate exane, gave 0.68 g of the titie compound as a colorless Uquid.
Step 329d. l-cyclopropyl-7-fluoro-6-methyl-4-oxo-8-(3- aminopyrrolidinv -4H-quinoUzine-3-carboxylic acid hydrochloride
Following the procedure of Example 253 step e, replacing the 3-methylpyridine compound thereof with the 6-methyl compound form step 329c above, and carrying the product forward according to steps 253e-l, a 31 mg sample of the title compound was prepared. MS: 346 (M-C1)+; 1H NMR (D6-DMSO) 9: 0.53 (m, 2H), 0.99 (m, 2H), 1.87 (m, IH), 2.20 (m, IH), 2.34 (m, IH), 2.87 (d, 3H, J=5.5 Hz), 3.76-4.02 (m, 5H), 6.92 (d, IH, J=9 Hz), 7.72 (s, IH), 8.38 (br, 3H). Anal. Calcd for C18H20N3O3F •HCM.5 H2O: C, 52.88; H, 5.92; N, 10.28; Found: C, 52.60; H, 5.98; N, 10.18.
Example 330 1 -cyclopropyl-7-fluoro-4H-8-( 1 -imidazolyl)-
9-methyl-4-oxo-quinolizine-3-carboxylic acid hydrochloride
Following the procedure of Example 253 step j, replacing the 3-t-BOC- aminopyrroUdine thereof with imidazole, and carrying the product forward as in Example 253 step k, the title compound was prepared. HRMS: (M+H)+ calcd: 328.1097; found: 328.1110 1H NMR (CDCI3) 9: 0.90 (m, 2H), 1.18 (m, 2H), 2.40 (m, IH), 2.83 (s, 3H), 7.15 (s, IH), 7.39 (s, IH), 7.71 (s, IH), 8.66 (s, IH), 9.43 (d, IH, J=6 Hz).
Example 331 8-(3-amino- 1 -pyrrolidinyl)- 1 -ethyl-7-fluoro-4H-4-oxo-
9-methvI-quinolizine-3-carboxylic acid hydrochloride
FoUowing the procedure of Example 253 step e, replacing the cyclopropylacetonitrile compound thereof with propionitrile, and carrying the product forward as in Example 253 steps e-1, the title compound was prepared. MS: 334 (M-C1)+; lH NMR (D6-DMSO) 9: 2.28 (m, 3H), 2.22 (m, IH), 2.52 (m, 4H), 2.96 (m, 2H), 3.88- 4.18 (m, 5H), 8.01 (s, IH), 9.05 (d, IH, J=10 Hz). Anal. Calcd for Ci7H2θ 3θ3FCl« HC1« 1.5 H2O: C, 51.45; H, 6.10; N, 10.59; Cl, 8.93; Found: C, 51.51; H, 5.90; N, 10.78; Cl, 8.91.
Example 332
8-(3-amino-l -pyrroUdinyl)- l-cyclopropyl-9-ethyl- 7-fluoro-4H-4-oxo-quinolizine-3-carboxyUc acid hydrochloride
Following the procedure of Example 253 step c, replacing the methyl iodide thereof with ethyl iodide, and carrying the product forward as in Example 253 steps 253d- 1, the title compound was prepared. MS: 360 (M-C1)+; 1H NMR (D6-DMSO) 9: 0.52 (m, 2H), 0.87 (t, 3H, J=6 Hz), 0.98 (m, 2H), 2.20 (m, 2H), 2.33 (m, IH), 3.20 (m, 2H), 3.65-3.96 (m, 5H), 7.95 (s, IH), 8.43 (br, 3H), 9.07 (d, IH, J=10.5 Hz), 13.83 (br, IH). Anal. Calcd for C19H22N3O3F .1.25 HCI* 1.5 H2O: C, 53.95; H, 6.01; N, 9.93; Found: C, 53.82; H, 5.87; N, 10.18.
Example 333 l-cyclopropyl-7-fluoro-4H-9-methyl- oxo-8-(3-(l,2,3-triazol-l-yl)- 1 -pyrrolidinyl)-quinolizine-3-carboxylic acid
Step 333a. l-benzyl-3-π.2.3-triazol-l-yl)pyrrolidine
A solution of 3-azido-l-benzylpyrroUdine (2.30 g) and trimethylsilylacetylene (8.0 mL) in 15 mL of toluene was heated at reflux for 18 hours. The solvents were removed to give an oUy residue. The residue was dissolved in 20% HCI and heated at reflux for 16 hours. The solution was cooled, made basic with NaHCO3, and extracted with methylene chloride. The organic layer was washed with water, dried over MgSO4 and concentrated. The crude product was purified by chromatography on sUica gel, eluting with CH2CI2 :methanol:NH4OH 100:10:1.
Step 333b. 3-f 1.2.3-triazol- 1 -vnpyrrolidine
The compound from step 333a was dissolved in methanol and hydrolyzed by hydrogenation for 16 hours with a catalyst of 10% Pd/C. The mixture was filtered, and the solvent was removed to give 1.00 g of the product. Step 333c l-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo- 8-f 3-f 1.2.3-triazol- 1 -yl 1 -pyrroUdinylVquinoUzine-S-carboxyUc acid
FoUowing the procedure of Example 253 step j, replacing the 3-BOC- aminopyπτ>Udine thereof with the compound from step 333b, and carrying the product forward as in Example 253 steps j & k, the title compound was prepared, mp 183-186°C. MS: 398 (M-C1)+; 1H NMR (D6-DMSO) 9: 0.61 (m, 2H), 0.99 (m, 2H), 2.31 (m, IH), 2.56 (m, 2H), 2.62 (s, 3H), 3.84 (m, IH), 3.99 (m, IH), 4.10 (m, IH), 4.36 (m, IH), 5.46 (m, IH), 7.80 (s, IH), 7.92 (s, IH), 8.32 (s, IH), 9.11 (d, IH, J=l l Hz). Anal. Calcd for C20H20N5O3F: C, 60.45; H, 5.07; N, 17.62; Found: C, 60.46; H, 5.20; N, 17.63.
Example 334 l-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-8-(cz.y-3- amino-4-methyl-l-pyπ-oUdinyiyquinolizine-3-carboxyuc acid hydrochloride
FoUowing the procedure of Example 253 step j, replacing the 3-BOC- aminopyrroUdine thereof with s-3-BOC-aπύno-4-methylpyrroUdine, and carrying the product forward as in Example 253 steps j-1, the title compound was prepared. MS: 360 (M-C1)+; 1H NMR (D6-DMSO) 9: 0.60 (m, 2H), 0.99 (m, 2H), 1.18 (d, 3H, J=7 Hz), 2.30 (m, IH), 2.62 (s, 3H), 3.48-4.00 (m, 6H), 7.94 (s, IH), 8.40 (m, 3H), 9.10 (d,
IH, J= 10.5 Hz). Anal. Calcd for Ci9H22N3O3F.HCM.25 H2O: C, 54.55; H, 6.14; N, 10.04; Found: C, 54.62; H, 6.10; N, 10.08.
Example 335 8-(2-aminoethyl)-l-cyclopropyl-7-fluoro-4H-9-methyl-
4-oxo-quinolizine-3-carboxylic acid hydrochloride
FoUowing the procedure of Example 253 step j, replacing the 3-BOC- aminopyrroUdine thereof with 2-aminoethylamine, and carrying the product forward as in Example 253 steps j-1, the titie compound was prepared. MS: 320 (M-C1)+; ] H NMR (D2O) 3: 0.60 (m, 2H), 1.02 (m, 2H), 2.02 (m, IH), 2.64 (s, 3H), 3.40 (m, 2H), 3.99 (m, 2H), 7.40 (s, IH), 8.80 (d, IH, J=10.5 Hz). Anal. Calcd for Cl6Hl8N3θ3F»HCM).85 H2O: C, 51.78; H, 5.62; N, 11.32; Found: C, 51.79; H, 5.31; N, 11.15. Example 336
8-(3-(ethylaminomethyl)pyrroUdinyl)- 1 -cyclopropyl- 7-fluoro-4H-9-metnyl-4-oxo-quinoUzine-3-carboxylic acid hydrochloride
FoUowing the procedure of Example 253 step j, replacing the 3-BOC- aminopyrrolidine thereof with 3-((N-BOC-N-ethyl)arnino)methylpyrrolidme, and carrying the product forward as in Example 253 steps j-1, the title compound was prepared. MS: 388 (M-C1)+; lH NMR (CD3OD) 3: 0.60-0.68 (m, 2H), 1.05 (m, 2H), 1.37 (m, 3H), 1.91 (m, IH), 2.31 (m, 2H), 2.68 (s, 3H), 2.69 (m, IH), 3.15 (m, 2H), 3.33 (m, 2H), 3.75-3.96 (m, 4H), 8.01 (s, IH), 9.03 (d, IH, J=10.5 Hz). Anal. Calcd for
C2lH26N3θ3F«1.25 HCI.H2O: C, 55.92; H, 6.54; N, 9.32; Found: C, 56.18; H, 6.32; N, 9.27.
Example 337 8-(3-(l-aminoethyl)pyrroUdinyl)-l-cyclopropyl-7-fluoro-
4H-9-methyl-4-oxo-quinolizine-3-carboxyUc acid hydrochloride
FoUowing the procedure of Example 253 step j, replacing the 3-BOC- aminopyrroUdine thereof with 3-(N-BOC-aminoethyl)pyrroUdine, and carrying the product forward as in Example 253 steps j-1, the title compound was prepared. MS: 374 (M-C1)+; Anal. Calcd for C20H24N3O3F.HCl.H2O: C, 56.14; H, 6.36; Found: C, 56.27; H, 6.14.
Example 338 l-cyclopropyl-7-fluoro-4H-9-methyl-8-(2-methyl-2,8-diaza- 8-bicvclor4.3.01nonyl)-4-oxo-quinolizine-3-carboxylic acid hydrochloride
Following the procedure of Example 253 step j, replacing the 3-BOC-amino- pyrrolidine thereof with 2-methyl-2,8-diaza-bicyclo[4.3.0]nonane, and carrying the product forward as in Example 253 steps j-1, the title compound was prepared. MS: 400 (M-C1)+; 1H NMR (DMSO-d6) 3: 0.65 (m, 2H), 0.92 (m, IH), 1.09 (m, IH), 1.80-1.95 (m, 5H), 2.31 (m, IH), 2.69 (s, 3H), 2.83 (m, 5H), 3.61-4.34 (m, 5H), 7.90 (s, IH), 9.10 (d, IH, J=10.5 Hz). Anal. Calcd for C22H26N3O3F.I.25 HC1.0.5 H2O: C, 58.20; H, 6.27; N, 9.25; Found: C, 58.09; H, 6.27; N, 9.25. Example 339 l-cyclopropyl-7-fluoro-4H-8-((lS,4S)-2,5-diaza- bicycloI2.2. llheptan-2-v -9-methyl-4-oxo-quinolizine-3-carboxylic acid hydrochloride
Following the procedure of Example 253 step j, replacing the 3-BOC-amino- pyrrolidine thereof with (lS,4S)-2,5-diaza-5-BOC-bicyclo[2.2.1]heptane (prepared according to J. Med Chem., 22:1598 (1988)), and carrying the product forward as in Example 253 steps j-1, the titie compound was prepared. MS: 358 (M-C1)+; 1H NMR (DMSO-d6) 3: 0.59 (m, IH), 0.93 (m, IH), 1.06 (m, IH), 2.05 (m, IH), 2.31 (m, 2H), 2.59 (s, 3H), 3.45 (m, 2H), 3.61 (m, IH), 4.09 (m, IH), 4.51 (m, IH), 4.96 (m, IH), 7.97 (s, IH), 9.07 (br, IH), 9.20 (d, IH, J=10.5 Hz), 9.54 (br, IH). Anal. Calcd for C19H20N3O3F.I.5 HCI* 1.0 H2O: C, 53.06; H, 5.51; N, 9.77; Found: C, 53.19; H, 5.37; N, 9.58.
Example 340 l-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-8-(3-(2-pyridinyl)- l-pyrrolidinyl)-quinolizine-3-carboxylic acid hydrochloride
Following the procedure of Example 253 step j, replacing the 3-BOC-amino- pyrroUdine thereof with 3-(2-pyridinyl)pyrrolidine, and carrying the product forward as in Example 253 steps j-1, the titie compound was prepared. MS: 408 (M-C1)+; 1H NMR (DMSO-d6) 3: 0.60 (m, 2H), 0.99 (m, 2H), 2.30-2.40 (m, 2H), 2.60 (m, IH), 2.64 (s, 3H), 3.86-4.16 (m, 4H), 7.80 (m, IH), 7.90 (s, IH), 9.07 (d, IH, J=l l Hz). Anal. Calcd for C23H23N3O3F .HCI.H2O: C, 55.43; H, 5.26; N, 8.43; Found: C, 55.69; H, 4.97; N, 8.52.
Example 341
8-((lR 2S 6R*)-2-amino-8-azabicyclo[4.3.0]nonan-8-yl))- 1 -cvclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid hydrochloride
Step 341a. lR*.2S*.6R*-2-BOC-amino-8-azabicvclo!4.3.01nonane
Two mL of 1.0 N trifluoracetic acid was added to a stirred solution of 2.o mL of cyclohexane and 4.92 g of N-benzyl-N-(methoxymethyl)-trimethylsUylmethylamine in 20 mL of methylene chloride at 0°C. The mixture was stirred at room temperature for 16 hours, then diluted with methylene chloride. The solution was washed with NaHCO3 and water, then dried over MgSO4. Removal of the solvent left an oUy residue. The residue was dissolved in 65 mL of methanol, after which were a . d 2.2 g of NH2OH»HCl, 10 mL of 10% NaOH, and 6.5 mL of methylene chloride, and the reaction was heated at 60°C for 3 hours. The solvents were removed, and the residue was dissolved in methylene chloride, which was washed with water, dried over MgSO4 and concentrated to give an oil. The oil was dissolved in 50 mL of THF, 1.57 g of LAH were added, and the mixture was heated at reflux for 2 hours. The reaction was quenched with water, the soUd was removed, and the filtrate was concentrated. The concentrate was dissolved in 40 mL of methanol and 10 mL of water. To this solution was added 5.0 g of (BO 2O and the reaction was stirred for 16 hours. The methanol was removed under vacuum, and the residue was extracted with methylene chloride. The extract was washed with water, dried over MgSO4 and concentrated to give an oil. The oU was purified by chromatography on siUca gel, eluting with 100:5:0.5 methylene chloride:methanol:NH4θH to give 0.36 g of the 1R*,2S*,6R* isomer and 2.22 g of the 1R*,2R*,6R* isomer of the title compound. The 1R*,2S*,6R* isomer was stirred with 0.12g Of 10%Pd/C in 25 mL of methanol under 4 Atm of H2 for 48 hours. The catalyst was filtered off, and the solvent was removed to give the titie compound.
Step 341b. 8-((lR*,2S*,6R*)-2-amino-8- azabicyclo[4.3.0]nonan-8-yl))-l-cyclopropyl-7-fluoro- 4H-9-methyl-4-oxo-quinolizine-3-carboxyUc acid hydrochloride
FoUowing the procedure of Example 253 step j, replacing the 3-BOC- aminopyrrolidine thereof with lR*,2S*,6R*-2-BOC-amino-8-azabicyclo[4.3.0]nonane, prepared in step 341a above, and carrying the product forward as in Example 253 steps j-1, the title compound was prepared. MS: 400 (M-C1)+; 1H NMR (DMSO-d6) 3: 0.63 (m, 2H), 0.94 (m, IH), 1.05 (m, IH), 1.42-1.62 (m, 4H), 1.97 (m, IH), 2.31 (m, 2H), 2.62 (s, 3H), 2.67 (m, IH), 3.19 (m, IH), 3.54 (m, IH), 3.82 (m, IH), 4.00 (m, 2H), 7.89 (s, IH), 8.18 (br, 3H), 9.06 (d, IH, J=l 1 Hz). Anal. Calcd for C22H26N3O3F .1.25 HCI.1.5 H2O: C, 55.55; H, 6.43; N, 8.83; Found: C, 55.40; H, 6.38; N, 8.72.
Example 342
8-((lR*,2R*,6R*)-2-amino-8-azabicyclo[4.3.0]nonan-8-yl))-l-cyclopropyl- 7-fluoro-4H-9-methyl-4-oxo-quinolιzine-3-carboxylic acid hydrochloride
Step 342a. lR*.2R*.6R*-2-BOC-amino-8-azahicvclor4.3.01nonane
Removing the N-benzyl group from the lR*,2R*,6R*-isomer of Example 341 step a, the title compound was prepared.
Step 341b. 8-((lR*,2R*,6R*)-2-amino-8-azabicyclo[4.3.0]nonan-8-yl))- 1 -cyclopropyl-7-fluoro-4H-9-methyl-4-oxo- quinoUzine-3-carboxylic acid hydrochloride
Following the procedure of Example 253 step j, replacing the 3-BOC-amino- pyπoUdine thereof with lR*,2R*,6R*-2-BOC-amino-8-azabicyclo[4.3.0]nonane, prepared in step 342a above, and carrying the product forward as in Example 253 steps j-1, the title compound was prepared. MS: 400 (M-C1)+; 1H NMR (DMSO-d6) 3: 0.53-0.61 (m, 2H), 0.95-1.06 (m, 2H), 1.30 (m,2H), 1.60 (m, 2H), 1.81 (m, 2H), 2.29 (m, IH), 2.49 (m, IH), 2.64 (s, 3H), 2.77 (m, IH), 3.32-3.49 (m, 3H), 4.16 (m, 2H), 7.91 (s, IH), 8.33 (br, 3H), 9.06 (d, IH, J=10 Hz). Anal. Calcd for C22H26N3O3F .1.0 HCM.25 H2O: C, 57.64; H, 6.49; N, 9.17; Found: C, 57.70; H, 6.80; N, 9.18.
Example 343
8-((la,5a,6a)-6-aπύno-3-azabicyclo[3.1.0]hexan-3-yl))-l-cyclopropyl- 9-methvI-7-fluoro-4H-4-oxo-quinolizine-3-carboxylic acid hydrochloride
Following the procedure of Example 253 step j, replacing the 3-BOC-amino- pyrrolidine thereof with la,2a,6a-2-BOC-amino-8-azabicyclo[4.3.0]hexane, prepared according to U.S. Patent 5,298,629, and carrying the product forward as in Example 253 steps j-1, the title compound was prepared. MS: 358 (M-C1)+; 1H NMR (DMSO-d6) 3: 0.61 (m, 2H), 1.01 (m, 2H), 2.12 (br s, 2H), 2.33 (m, IH), 2.62 (s, 3H), 3.81 (m, 5H), 7.97 (s, IH), 8.46 (br s, 3H), 9.11 (d, IH, J=10.5 Hz), 13.83 (br, IH). Anal. Calcd for C19H20N3O3F .1.5 HCl.0.5 H2O: C, 54.19; H, 5.39; N, 9.98; Found: C, 54.43; H, 5.28; N, 9.87. Example 344
8-(trαrt£-3-amino-4-fluoro- 1 -pyrrolidinyl))- 1 -cyclopropyl-9-methyl- 7-fluoro-4H-4-oxo-quinolizine-3-carboxylic acid hydrochloride
Step 344a. l-CBZ-3.4-epoxy-pyrroUdine
l-CBZ-3-pyrroline (20g) was dissolved in 200 mL of CH2CI2. MCPBA (50- 60% pure, 61.5 g) in 500 mL of CH2CI2 was added to the above solution at 0°C, and the reaction was stirred at 45°C for 18 hours. The reaction mixture was filtered, and the filtrate was treated with NaHSO3 (ca. 5 g). The solution was then poured into 1 L of 1 N NaOH, the mixture was shaken, and the organic phase was separated, washed with water, dried over MgSO4 and concentrated. The residue was taken directly to the next step.
Step 344b. trflns-3-azido-l-benzyloxycarboxy-4-hvdroxypyrrolidine
The compound from step 344a above was dissolved in 250 mL of acetone. NaN3 (20.16 g) in 200 mL of water was added, and the reaction was stirred at 60°C for 18 hours. The reaction mixture was poured into satd. NaCl solution, and the mixture was extracted (3x) with CH2CI2. The extract was washed with water, dried over MgSO4 and concentrated. The residue was purified by column chromatography on sUica gel, eluting with 3% methanol in CH2CI2 to yield 5.92 g of the product
Step 344c trfl^y-azido-l-benzyloxycarboxy-4-fluoropyrrolidine
The compound from step 344b above was dissolved in 15 mL of CH2CI2 and cooled to -78°C. DAST (0.82 mL) was added, and the reaction was stirred at room temperature for 16 hours. The solvent was removed, the residue dissolved in ethyl acetate, and the solution was washed with satd NaHCO3, brine, and dried over mgso4. The solvent was removed, and the residue was purified by column chromatography on sUica gel, eluting with 1% methanol in CH2CI2 to yield 0.88 g of the title compound. 1H NMR (CDCI3) 3: 3.62 (m, 4H), 4.22 (br d, IH, J=l l Hz), 4.99 (br d, IH, J=51 Hz), 5.16 (s, 2H), 7.36 (m, 5H). Step 344d. trα^-3-fBOC-aminoV4-fluoropyrroUdine
The compound from step 344c was stirred with Raney Ni in methanol under 4 Atm H2 for 9 hours. The catalyst was removed by filtration. The filtrate was concentrated, and the residue was treated with (BOC)2θ and the reaction was stirred for 16 hours. The methanol was removed under vacuum, and the residue was extracted with methylene chloride. The extract was washed with water, dried over MgSO4 and concentrated. The residue was purified by chromatography on sUica gel, eluting with 100:5:0.5 methylene chloride:methanol:NH4θH to give the 1-benzyloxycarboxy compound. This protecting group was removed by hydrogenolysis over Pd/C under H2 for 30 min. The catalyst was removed, and the filtrate was concentrated to give the title compound (331 mg). MS: 205 (M-C1)+; 1H NMR (CDCI3) 3: 1.46 (s, (H), 2.67 (dd, J=4.5, 12 Hz, IH), 3.04 (ddd, J=4.5, 14, 36 Hz, IH), 3.18 (dd, J=14, 25 Hz, IH), 3.44 (dd, J=7.5, 12 Hz, IH), 4.08-4.12 (m, IH), 4.49 (br s, IH), 4.98 (br d, J=53 Hz, IH).
Step 344e. 8-(trα/w-3-aιτrino-4-fluoro-l -pyrroUdinyl))- 1-cyclopropyl- 9-methyl-7-fluoro-4H-4-oxo-quinoUzine-3-carboxylic acid hydrochloride
Following the procedure of Example 253 step j, replacing the 3-BOC-amino- pyrroUdine thereof with the compound from step 344d above, and carrying the product forward as in Example 253 steps j-1, the title compound (44 mg) was prepared. MS: 364 (M-C1)+; HRMS: calc for C18H19N3O3F2 (M_C1)+: 364.1473; found: 364.1480. lH NMR (DMSO-d6) 3: 0.62 (m, 2H), 1.00 (m, 2H), 2.36 (m, IH), 2.68 (s, 3H), 3.77 (m, IH), 3.93 (m, IH), 4.11 (m, IH), 4.31-4.41 (m, IH), 5.50 (br d, J=51 Hz, IH), 7.99 (s, IH), 8.69 (br s, 3H), 9.16 (d, J=9 Hz, IH), Anal. Calcd for C18H19N3O3F2 «1.3 HCl.2.0 H2O: C, 48.39; H, 5.48; N, 9.40; Found: C, 48.12; H, 5.58; N, 9.63.
Example 345 l-cyclopropyl-7-fluoro-4H-8-(l-homopiperazinyl))-9-methyl- 4-oxo-quinolizine-3-carboxylic acid, acetic acid salt
Following the procedure of Example 298, replacing the 3-(dimethylamino)- pyrrolidine thereof with the homopiperazine, the title compound was prepared, mp 195- 198°C (dec). MS: 360 (M+H)+; lU NMR (DMSO-d6) 3: 0.55 (m, 2H), 0.98 (m, 2H), 1.83 (s, 6H), 2.26-2.38 (m, 2H), 2.69 (br s, 3H), 2.89 (m, 4H), 8.08 (br s, IH), 9.04 (br s, IH). Example 346
7,9-difluoro-4H-8-(4-methylpiperazinyl)-4-oxo-l-phenyl- quinoUzine-3-carboxyUc acid hydrochloride
Step 346a. l-f2.3.5.6-tetrafluoro-4-pyridinyl)-4-methylpiperazine
To a cold solution of pentafluoropyridine (16.1 g, 95.2 mmol) and triethyl amine (11.1 g, 110 mmol) in 150 mL of CH2CI2 a solution of N-methylpiperazine (10.0 g, 100 mmol) in 50 mL of CH2CI2 was added dropwise. The solution was stirred for 2 hours, then stirred for 16 hours at room temperature. The solution was extracted with water and washed with brine, and the organic layer was dried over MgSO4 and concentrated to give 23.25 g of the product. MS: 250 (M+H)+; NMR (CDCI3) 3: 2.35 (s, 3H), 2.55 (m, 4H), 3.5 (m, 4H).
Step 346b. l-f2-hydrazino-3.5.6-trifluoro-4-pyridinyl)-4-methylpiperazine
To a solution of the compound from step 346a above (23.24 g, 93.2 mmol) in
500 mL of ethanol was added 37.34 g (746 mmol) of hydrazine hydrate, and the reaction was heated at reflux for 16 hours. The solvent was removed, and the residue was dissolved in CH2CI2. The solution was washed with water, dried over MgSO4, filtered and the solvent removed under vacuum. The residue was triturated with ether, and collected by filtration to obtain 17.42 g of light yeUow soUd. mp 174-5°C. MS: 262
(M+H)+; lH NMR (CDCI3) 3: 2.35 (s, 3H), 2.52 (m, 4H), 3.42 (m, 4H), 3.76 (s, 2H), 5.68 (s, IH). Anal. Calcd for C10H14N5F3: C, 45.97; H, 5.40; N, 26.81; Found: C, 45.99; H, 5.34; N, 26.65.
Step 346c l- 2.3.5-trifluoro-4-pyridinyl')-4-methylpiperazine
A suspension of 17.36 g (66.4 mmol) of the compound from step 346b above in 200 mL of ethanol and 20 mL of 20% NaOH was stirred and air was bubbled through for 16 hours. The mixture was poured into brine, and this mixture was extracted with CH2CI2. The extract was dried over MgSO4, filtered, and the solvent was removed to give 13.40 g of a soUd. The residue was purified by chromatography on siUca gel, eluting with ethyl acetate, to afford 11.54 g of pure titie product. MS: 232 (M+H)+; 1H NMR (CDCI3) 3: 2.34 (s, 3H), 2.52 (m, 4H), 3.46 (m, 4H), 7.66 (m, IH). Anal. Calcd for C10H12N3F3: C, 51.94; H, 5.23; N, 18.18; Found: C, 51.63; H, 4.92; N, 17.73. Step 346d. 2-f3.5-difluoro-4-f4-methylpiperazinyl)-2-pyridiny -phenylacetonitrile
A solution of LDA (99.4 mmol, 66.3 mL, 1 M in cyclohexane) in 50 mL of THF was prepared and cooled at -78 °C for 15 min. To this solution was added in a dropwise manner a solution of 8.87 g (75.7 mmol) of phenylacetonitrile in 35 mL of THF. The reaction was stirred at -78°C for 15 min, then 0°C for 30 min. The solution was then cooled to -60°C and a solution of the compound from step 346c in 35 mL of THF was added dropwise. The reaction mixture was stirred for 1 hour at -60°C and at 0°C for 3 hours. The reaction contents were poured into excess NH4CI solution, and the mixture was extracted with CH2CI2. The extract was washed with brine, dried over MgSO4 and filtered, and the solvent was removed. The residue was purified by chromatography on siUca gel, eluting with 1:20 methanokchloroform, to yield 10.24 g of the title compound. MS: 329 (M+H)+; 1H NMR (CDCI3) 3: 2.35 (s, 3H), 2.52 (m, 4H), 3.41 (m, 4H), 5.43 (s, IH), 7.35 (m, 3H), 7.45 (m, 2H), 8.13 (m, IH). Anal. Calcd for C18H18N4F2O.5 H2O: C, 64.95; H, 5.57; N, 16.83; Found: C, 62.51; H, 5.50; N, 16.96.
Step 346e. l-f2-benzyl-3.5-difluoro-4-pyridinylV4-methylpiperazine
To a solution of the compound from step 346d above (8.55 g, 26mmol) in 50 mL of ethanol was rapidly added 13.6 mL of cone H2SO4. After an initial temperature rise, the solution was stirred at room temperature for 2hr, then at reflux for 48 hours. The reaction solution was cooled and poured into H2O, adjusted to a basic pH with solid
K2CO3 and extracted with CH2CI2. The extract was dried over MgSO4 and fUtered, and the solvent was removed. The residue was purified by chromatography on silica gel, eluting with ethyl acetate to afford 3.57 g of the titie compound. MS: 304 (M+H)+; 1H NMR (CDCI3) 3: 2.35 (s, 3H), 2.52 (m, 4H), 3.40 (m, 4H), 4.07 (m, 2H), 7.20 (m, IH), 7.30 (m, 4H), 8.05 (m, IH).
Step 346f. 4-(3,5-difluoro-4-(4-methylpiperazin- l-yl)-2-pyridinyl)- 2-ethoxycarbonyl-4-phenyl-2-butenoic acid ethyl ester
To 30 mL of THF cooled to -60°C was slowly added 5.8 mL of butyl lithium (14.5 mmol, 2.5 M in hexane), and the solution was stirred for 10 min. To this first solution was added dropwise a solution of 3.52 g (116 mmol) of the compound from step 346e above in 15 mL of THF. The reaction mixture was stirred for 10 min, then a solution of 3.4 mL (16.8 mmol) of diethyl ethoxymethylenemalonate in 15 mL of THF was added dropwise. The reaction was stirred for 0.5 hours at -60°C, then for 2 hours at room temperature. The reaction solution was poured into a 15% aq. NH4CI solution, and the mixture was extracted with CHCI3. The extract was dried over MgSO4 and fUtered, and the solvent was removed. The residue was purified by chromatography on sUica gel, eluting with ethyl acetate to afford 4.09 g of the title compound. MS: 520 (M+H)+; Anal. Calcd for C27H35F2N3O5: C, 62.41; H, 6.79; N, 8.09; Found: C, 62.58; H, 6.63; N, 8.07.
Step 346g. 7,9-difluoro-4H-8-(4-methylpiperazinyl)-4-oxo- l-phenyl-quinolizine-3-carboxyUc acid, ethyl ester
A 3.16 g (6.08 mmol) sample of the compound from step 346f above was dissolved in 20 mL of DMSO, and the solution was heated at reflux for 1 hour. The solution was poured into aq. 5% NaHCO3 solution, and the mixture was extracted with CHCI3. The extract was washed with brine, dried over MgSO4 and filtered, and the solvent was removed. The residue (2.23 g) was purified by chromatography on siUca gel, eluting with 4: 1 :0.1 ethyl acetate:ethanol:TEA to yield 681 mg of the titie compound. MS: 428 (M+H)+; !H NMR (CDCI3) 3: 1.40 (m, 3H), 2.40 (m, 2H), 2.58 (m, 5H), 3.10 (m, 2H), 4.38 (m, 2H), 7.40 (m, 6H), 8.12 (s, IH), 9.30 (m, IH).
Step 346h. 7,9-difluoro-4H-8-(4-methylpiperazinyl)-4-oxo- l-phenyl-quinoUzine-3-carboxyUc acid hydrochloride
A solution of the compound from step 346g above (623 mg, 1.46 mmol) in 30 mL of THF was diluted with 15 mL of water. The suspension was cooled in an ice bath for 15 min, then LiOH«H2θ (183 mg, 4.37 mmol) was added, the reaction was stirred for 1 hour with cooling, then for 16 hours at room temperature. TLC showed the reaction to be incomplete, so an additional 123 mg of LiOH»H2θ was added, and the reaction was stirred for 24 hours. The reaction contents were poured into H2O, and 1.3 mL of acetic acid were added. Solid NaHCO3 was added untU the solution was basic, and the mixture was extracted with CHCI3 containing a smaU amount of DMF. The extract was dried over MgSO4 and filtered, and the solvent was removed. Excess DMF was removed by co- distillation with toluene. The residue was suspended in water and carefully acidified with 0.5 M HCI. The solution was frozen, and the water removed by freeze-drying. The soUd was triturated with ether, coUected by filtration, and dried for 48 hours at 50°C in vacuum to yield 171 mg of the titie compound, mp 230°C (dec). MS: 400 (M+H)+; 1H NMR (DMSO-d6) 3: 2.73 (m, 3H), 2.80 (m, 4H), 3.70 (m, 4H), 7.40 (m, 6H), 7.93 (m, IH), 9.33 (m, IH), 11.0 (m, IH). Anal. Calcd for C21H20N3O3F2.H2O: C, 55.57; H, 4.89; N, 9.26; Found: C, 55.89; H, 4.62; N, 8.99.
Example 347 Scaled-Up Preparation of 8-(3(S)-aminopyrrolidinyl)- 1 -cyclopropyl-
7-fluoro-4H-9-methyl-4-oxo-quinoUzine-3-carboxylic acid hydrochloride
Step 347a. 4-t-butoxy-3-chloro-2.5.6-trifluoropyridine
A 927.55 g (5.0 mol) sample of 3-chloro-2,4,5,6-tetrafluoropyridine (from Fluorochem Ltd.) was dissolved in 4 L of anhydrous THF, and the solution was cooled to -10°C. To this solution was added 429 (5.36 mol) of lithium t-butoxide in portions over a 1-hr period, while maintaining the temperature between -5°C to -10°C. The reaction was stirred for 2 hours at -10°C, the cooling bath was removed, and the solution was warmed to room temperature over a 3 hours period. The THF was removed under reduced pressure. The residue was dissolved in 6 L of ether, and the solution was washed with 4x1 L of water. The ether solution was dried over MgSO4, and the ether was removed under reduced pressure to give 1123.44 g of the crude product. The crude product was purified by chromatography, eluting with hexane. bp 43-47 °C/0.6 mm Hg.
Step 347b. 4-t-butoxy-3-methyl-2.5.6-trifluoropyridine
A 499 g (2.08 mol) sample of the compound from step 347a above was dissolved in 4 L of THF and cooled to -70°C. WhUe maintaining a N2 atmosphere, 1.6 L of sec- butyllithium (2.08 mol, 1.3 M) was added, and the reaction mixture was stirred for 1 hour. Iodomethane (129.6 mL, 2.08 mol) was added rapidly dropwise, whUe maintaining the temperature below -50°C. The mixture was stirred whUe allowing the temperature to rise, and the stirring was continued for 16 hours. The reaction was quenched with 1 L of water while cooling with an ice bath, then 2 L of hexane were added, the phases mixed well, and the layers separated. The organic layer was concentrated on a rotary evaporator. The residue was dissolved in hexane, dried over MgSO4, filtered and concentrated to give 496 g of title compound, which was taken directly to the next step. Step 347c 4-t-butoxy-2.5-difluoro-3-methylpyridine
Lithium aluminum hydride (56.7 g, 1.42 mol) was added to 6 L of THF, and the suspension was stirred under N2- The temperature was adjusted to 0 to -5°C, and 476.5 g (2.27 mol) of the compound from step 347b above (dissolved in 750 mL of THF) was added in a stream over a 15 min period. The mixture was stirred at room temperature for 16 hours, then 500 mL of hexane was added. The reaction was then quenched while maintaining an internal temperature of 10-20°C by adding 57 mL of H2O, 57 mL of 15% NaOH solution, and 171 mL of H2O, in that order. The mixture was filtered, and the filter cake was washed with THF and hexane. The filtrate was concentrated on a rotary evaporator with a bath temperature of 35°C. The residue was purified by column chromatography on siUca gel, eluting with hexane and 5% ethyl acetate in hexane to afford 141 g of the title compound. DistiUation at 80-90°C and 1 mm Hg gave 103.4 g of the pure product.
Step 347d. Alternate preparation of 4-t-butoxy-2.5-difluoro-3-methylpyridine
A 476.5 g (2.27 mmol) sample of the compound from step 347b above was dissolve in 6 L of THF and stirred under N2- The temperature of the solution was adjusted to 0 to 5°C, and a solution of sodium bis-(2-methoxyethoxy)aluminum hydride in toluene (750 mL, 3.4 M, 2.5 mol) was added rapidly dropwise over 1 hour. The reaction mixture was stirred at room temperature for 16 hours, and 500 mL of hexane was added. The reaction was then quenched while maintaining an internal temperature of <25°C by careful addition of 500 mL of H2O. The organic layer was decanted, and the soUds were washed thoroughly with hexane. The solvents were combined and concentrated on a rotary evaporator, with a bath temperature of 55°C. The 440 g of crude product was twice purified by chromatography over siUca gel, eluting with hexane and 3% ethyl acetate in hexane to give 137.5 of the pure titie compound.
Step 347e. 2-f4-t-butoxy-5-fluoro-3-methyl-2-pyridinylV2-cvclopropylacetonitrile
Dtisopropylamine (445 mL, 3.18 mol) was dissolved in 1.5 L of anhydrous THF and stirred under N2- The solution was cooled to -40°C, and n-butylUthium (1.274 L, 3.18 mole, 2.5 M in hexane) was added at a rate such that the internal temperature was maintained at -40 to -20°C. The solution was warmed to -10°C, then cooled to -70°C. Cyclopropylacetonitrile (257 g, 3.17 mmol) was added dropwise to maintain the temperature below -68°C, then the solution was stirred for 35 min. A sample of 4-t- butoxy-2,5-difluoro-3-methylpyridine, from step 347c or 347d above, was dissolved in 1.2 L of anhydrous THF. To this solution was added in a dropwise manner the first solution containing the Uthium salt of cyclopropylacetonitrile, at a rate that the internal temperature remained below -70°C. The solution was stirred at -78°C for 1 hour, then aUowed to warm to 0°C. The reaction was quenched by adding 1 L of satd aq. NH4CI solution and IL of H2O. The organic layer was separated. The aqueous layer was extracted with ethyl acetate. The organic layers were combined, washed with brine, dried with MgSO4, and concentrated on a rotary evaporator to give an oil residue. The oil was distiUed at 0.2 mm Hg at 25-35°C to remove low boiUng impurities and residual cyclopropylacetonitrile. The residue was twice chromatographed on sUica gel, eluting with 7% ethyl acetate in hexane to afford 646 g of pure titie compound. MS: 263 (M+H)+; 1H NMR (CDCI3) 9: 0.50 (m, 2H), 0.64 (m, IH), 0.75 (m, IH), 1.43 (d, J= 1.5 Hz, 9H), 1.50 (m, IH), 2.29 (s, 3H), 3.76 (d, J=7.5 Hz, IH), 8.31 (s, IH).
Step 347f. 2-f4-chloro-5-fluoro-3-methyl-2-pyridinyl)-2-cyclopropylacetonitrile
To a cooled (0°C) solution of the compound from step 347e above (189.78 g, 0.72 mol) in 1.6 L of CH2CI2 and 270 mL of DMF was added 300 mL (3.2 mol) of POCI3, and the reaction was stirred for 12 hours. Another 25 mL (0.27 mol) of POCI3 was added, and the reaction stirred for an additional 12 hours. The reaction mixture was then poured into H2O, and this mixture was stirred for 1 hour. The organic material was extracted with CH2CI2, which was washed with H2O, sat aq NaHCO3 solution, H2O, dried over MgSO4, filtered and evaporated under vacuum to afford 129.3 g of the titie compound as an oil. MS: 225, 227 (M+H)+, 191. lH NMR (CDCI3) 9: 0.48 (m, IH), 0.58 (m, IH), 0.66 (m, IH), 0.77 (m, IH), 1.50 (m, IH), 2.49 (s, 3H), 3.80 (d, J=8 Hz, IH), 8.39 (s, IH).
Step 347g. 2-(4-chloro-5-fluoro-3-methyl-2-pyridinyl)- 2-cvclopropylacetic acid, ethyl ester
To IL of ethanol saturated with ca. 400 g HCI gas and stirred under N2 and cooled to 0°C was added a solution of 135.8 (0.6 mol) of the compound from step 347f in 90 mL of ethanol, and the reaction was stirred for 3 hours at 0°C. To this solution was added 90 mL of H2O, and the reaction mixture was heated at 80°C for 2 hours. The mixture was poured over ice to make a total volume of 4 L. The solution was neutraUzed with 50% NaOH to pH 8 whUe maintaining the temperature below 0°C. The soUd was filtered off, redissolved in CH2CI2, and the residual water layer removed. The organic layer was dried over MgSO4 and evaporated to leave a tan soUd (134.4 g). MS: 272 (M+H)+; lH NMR (CDCI3) 9: 0.12 (m, IH), 0.38 (m, IH), 0.54 (m, IH), 0.75 (m, IH), 1.20 (t, J=7.5 Hz, 3H), 1.68 (m, IH), 2.40 (s, 3H), 3.24 (d, J=9.3 Hz, IH), 4.16 (q, J=7.5 Hz, 2H), 8.36 (s, IH).
Step 347h. 2-f4-chloro-5-fluoro-3-methyl-2-pyridinyl)-2-cyclopropylethanol
A solution of the compound from step 347g above (130.72 g, 0.48 mol) in 530 mL of anhydrous THF was stirred under N2 at -78°C. To this was added a solution of LiAlH4 (480 mL, 1 M in THF, 0.48 mol) dropwise while maintaining the temperature below -60°C. The reaction was stirred at -78°C for 2 hours. The reaction was quenched by addition of H2O (16 mL), 15% NaOH (16 mL and H2O (46 mL), and the mixture was stirred for 1 hour at room temperature. The soUd was removed by filtration and washed with ether. The combined organic were washed with brine, dried over MgSO4, filtered and evaporated under vacuum to afford the title compound (108.6 g) as a white soUd. MS: 230 (M+H)+, 196; lH NMR (CDCI3) 9: 0.21 (m, 2H), 0.44 (m, IH), 0.60 (m, IH), 1.21 (m, IH), 2.39 (s, 3H), 2.56 (m, IH), 3.52 (br s, IH), 4.02 (m, 2H), 8.31 (s, IH).
Step 347i. 2-f4-chloro-5-fluoro-3-methyl-2-pyridinyl)-2-cyclopropylacetaldehyde
Anhydrous DMSO (80 mL, 1.14 mol) was dissolved in 900 mL of anhydrous CH2CI2, and stirred under N2. The solution was cooled to -78°C, and a solution of oxalyl chloride (2.0 M, 284 mL, 0.569 mol) in CH2CI2 was added over a 20 min period while holding the internal temperature below -60°C and stirred for 35 min longer. The compound from step 346h (109 g, 0.475 mol) was dissolved in 400 mL of anhydrous CH2CI2 and added dropwise to the first solution, whUe holding the internal temperature below -60°C. The reaction mixture was stirred for 30 min, and triethylamine (327 mL, 2.34 mol) was added dropwise over 10 min. The reaction was stirred as the internal temperature was raised to -10°C. The reaction was quenched with 500 mL of H2O, and the organic layer was isolated, washed with H2O, dried over MgSO4 and evaporated to give 109.64 g of the titie compound. MS: 228 (M+H)+; lH NMR (CDCI3) 9: 0.24 (m, IH), 0.35 (m, IH), 0.59 (s, IH), 0.76 (m, IH), 1.55 (m, IH), 2.38 (s, 3H), 3.19 (dd, J=2.7, 9 Hz, IH), 8.37 (s, IH), 9.87 (d, J=2,7 Hz, IH). Step 347j. 4-(4-chloro-5-fluoro-3-methyl-2-pyridinyl)- 4-cvclopropyl-2-ethoxycarbonyl-2-butenoic acid ethyl ester
The compound from step 347i above (109.68 g, 0.48 mol) was dissolved in 1.3 L of absolute ethanol and stirred under N2- To this solution was added diethylmalonate (351 mL, 2.31 mol), piperidine (45.5 mL, 0.46 mol) and acetic acid (45.5 mL, 0.79 mol). The solution was heated at reflux for 8 hours and cooled to room temperature. The solvent was removed with a rotary evaporator, and the residue was dissolved in ethyl acetate. This solution was washed with water, brine, dried over MgSO4 and concentrated to give an oUy residue. The residue was distilled in a short-path distillation apparatus at 0.2 mm Hg and 25-56°C to remove excess diethyl malonate and volatile impurities. The residual oil was taken directly to the next step.
Step 347k. 8-chloro-l-cyclopropyl-7-fluoro-4H-9-methyl- 4-oxo-quinolizine-3-carboxylic acid, ethyl ester
The compound from step 347j above was dissolved in 400 mL of anhydrous
DMSO and heated at reflux for 1 hour. The hot reaction mixture was slowly poured into rapidly stirred ice water (3 L). The product was filtered off and washed with water (3L) and hexane (1.5 L). The product was dried in a vacuum oven for 16 hours to afford 105 g of the titie compound as a yeUow crystalUne solid. MS: 324 (M+H)+; 1H NMR (CDCI3) 3: 0.75 (m, 2H), 1.06 (m, 2H), 1.43 (t, 3H), 2.32 (m, IH), 3.09 (s, 3H), 4.43 (q, 2H), 8.39 (s, IH), 9.43 (dd, J=l, 6 Hz, IH).
Step 3471. 8-(3(S)-(BOC-amino)pyrroUdinyl)-l-cyclopropyl- 7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxyIic acid, ethyl ester
A 93.1 g (0.29 mmol) sample of the compound from step 347k above was dissolved in 1.24 L of acetonitrile, and 137 g (0.72 mol) of 3(S)-(BOC-amino)pyrrolidine and 113 g (1.45 mol) of NaHCO3 were added. The mixture was heated at reflux under N2 for 1 hour. The reaction mixture was cooled to 25°C, and 700 mL of H2O were added. The mixture was extracted with ethyl acetate, and the solvent was washed with water, IN HCI, water and brine. The solvent was dried over MgSO4 and concentrated to a thick tar. MS: 474 (M+H)+; !H NMR (CDCI3) 3: 0.60 (m, 2H)0.95 (m, 2H), 1.41 (t, 3H), 1.42 (m, 2H), 1.46 (s, 9H), 2.60 (s, 3H), 3.50 (m, IH), 3.82 (m, IH), 3.95 (m, IH), 4.49 (q, 2H), 4.79 (br s, IH), 8.2 (s, IH), 9.25 (d, IH). Step 347m. 8-(3(S)-(BOC-amino)pyrroUdinyl)-l-cyclopropyl- 7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxyUc acid
The material from step 3471 above was dissolved in 900 L of THF, and 550 mL of water and 107.5 g (2.56 mol) of LiOH«H2θ were added. The mixture was heated at reflux under N2 for 1 hour. The mixture was diluted by pouring into a mixture of 1 L of THF and 0.5 L of water, with addition of ice to assist cooling. Cone HCI was added with vigorous mixing to bring the acidity to pH 4, whUe holding the internal temperature below 15°C. The yellow precipitate was filtered off, then dissolved in CH2CI2. The solution was washed with water until the washings tested neutral, then dried over MgSO4 and concentrated. MS: 446 (M+H)+; lH NMR (CDCI3) 3: 0.69 (m, 2H), 1.02 (m, 2H), 1.48 (s, 9H), 2.12 (m, 2H), 2.30 (m, IH), 2.62 (s, 3H), 3.60 ( , IH), 3.79 (m, IH), 3.96 (m, 2H), 4.38 (br s, IH), 5.11 (br s, IH), 8.13 (s, IH), 8.99 (d, IH), 13.82 (s, IH).
Step 347n. 8-(3(S)-amino)pyrroUdinyl)-l-cyclopropyl- 7-fluoro-4H-9-methyl-4-oxo-quinoUzine-3-carboxylic acid hydrochloride
A 140 g sample of the compound from step 347m above was dissolved in 1.2 L of CH2CI2, and 1.0 L of 1.0 M HCI in acetic acid was added over 5 min. The mixture was stirred under N2 for 1 hour at room temperature. The product was collected by filtration and washed with CH2CI2 until colorless. The solid was dried in a vacuum oven (50°C, 10 mm Hg) for 48 hours. This material (307.45 g) was added to 3.8 L of absolute ethanol pre-warmed to 70°C. To the mixture was added 1.23 L of H2O, and the mixture was heated to boiling and stirred until all soUd dissolved. Stirring was discontinued, seed crystals were added, and the solution aUowed to cool to room temperature. The mixture was then cooled at 0°C for 12 hours and at -25°C with stirring for 2 hours. The product was filtered off and washed with chiUed absolute ethanol. The solid was dried in vacuum for 48 hours to give the title product (261 g) as a yellow solid. MS: 346 (M-C1)+; 1H NMR (CD3OD) 3: 0.69 (m, 2H), 1.06 (m, 2H), 2.26 (m, 2H), 2.52 (m, IH), 2.73 (s, 3H), 3.88 (m, 2H), 4.05 (m, 2H), 4.18 (m, IH), 4.88 (br s, IH), 8.03 (s, IH), 9.02 (d, J=10.8 Hz, IH). Example 348
8-(spiro-l,3-dioxacyclopentane[2.3]-l-piperidinyl)- l-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinoUzine-3-carboxylic acid
Step 348a. N-CBZ-3-hvdroxypiperidine
A sample of 3-hydroxypiperidine HCI (50.0 g) was dissolved in a smaU amount of water and the solution was cooled to 0°C in an ice bath. The HCL was neutraUzed by slow addition of 363 mL of 1 M NaOH. An additional 1.2 eq of 1 M NaOH was added quickly, and 52 mL of benzyl chloroformate in 20 mL of ether was added dropwise, then the solution was stirred for 4 hours at 0°C. The solution was diluted with 600 mL of water and extracted with methylene chloride. The organic extract was dried over Na2SO4, filtered, and taken to dryness to afford 89.2 g of the titie compound.
Step 348b. N-CBZ-3-oxo-piperidine
A 30.0 g sample of N-CBZ-3-hydroxypiperidine, from step 348a above, was dissolved in 250 mL of DMSO, and the solution was cooled to 0°C. To this solution, stirred at 0°, was added 142 mL of triethylamine, and next was added dropwise a solution of 60.88 g of pyridine»Sθ3 complex dissolved in 250 mL of DMSO. The cooUng bath was removed, and the reaction mixture was stirred at room temperature for 20 hours. The reaction mixture was dUuted with water, and the mixture was extracted with methylene chloride. The extract was dried over Na2SO4, filtered, and taken to dryness. The DMSO was distilled off under reduced pressure, and the residue purified by distiUation in a kugelrohr apparatus to yield 26.53 g of the title compound.
Step 348c spiro- 1.3-dioxacyclopentaner2.31piperidine
A 10.0 g sample of N-CBZ-3-oxo-piperidine, from step 348b above, was dissolved in 10 mL of toluene and 5.98 mL of ethylene glycol and 0.408 g of p- toluenesulfonic acid were added. The solution was stirred at 130°C for 96 hours, then poured into 5% NaHCO3 solution. The mixture was extracted with methylene chloride, the extract was dried over Na2SO4, then the solvent was removed under vacuum and the residue was distilled in a kugelrohr apparatus to give 7.30 g of the title compound. Step 348d. 8-(spiro-l,3-dioxacyclopentane[2.3]-l-piperidinyl)- l-cvclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid
FoUowing the procedure of Example 253 step j, replacing the 3-BOC- aminopyrrolidine thereof with spiro- l,3-dioxacyclopentane[2.3]piperidine, from step 348c above, and carrying the product forward as in Example 253 steps j-k, the title compound was prepared (245 mg). mp 184-187°C. MS: 403 (M+l)+; l NMR (CDCI3) 3: 0.69 (m, 2H), 1.03 (m, 2H), 1.88 (m, 2H), 1.99 (m, 2H), 2.28 (m, IH), 2.82 (s, 3H), 3.35 (m, 4H), 3.97 (m, 4H), 8.36 (s, IH), 9.20 (d, IH, J=3 Hz), 13.91 (s, IH). Anal. Calcd for C21H23N2O5F .0.5 H2O: C, 61.31; H, 5.88; N, 6.81; Found: C, 61.41; H, 5.91; N, 6.62.
Example 349
8-(3-amino-4-methoxypyrrolidinyl)- 1 -cyclopropyl- 7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid hydrochloride
Step 349a. N-CBZ-pyrroUne
A 50.0 g sample of pyrroline (Aldrich) was dissolved in 868 mL of IM NaOH, and the solution was cooled to 0°C. Benzyl chloroformate (103.29 mL) was dissolved in 100 mL of ether and added to the solution of pyrroline dropwise over a 1 hour period. The solution was stirred for 4 hours at 0°C, then dUuted with 500 mL of water and extracted with methylene chloride. The extracts were combined, dried of Na2SO4, filtered, and evaporated to dryness to yield 144.6 g of the title compound.
Step 349b. N-CBZ-3.4-epoxy-Pyrrolidine
In a dry system under N2 a 15.0 g sample of N-CBZ-pyrroline, from step 349a above, was dissolved in 200 mL of methylene chloride, and the solution was cooled to 0°C. To this solution was added 46.3 g of m-chloroperbenzoic acid dissolved in 500 mL of methylene chloride dropwise over a 1 hour period. The reaction mixture was then heated at 45 °C for 18 hours, then recooled to 0°C. To the cool solution was added 3 g of sodium bisulfite, and the mixture was stirred for 1 hour and poured into 1 L of 1 N NaOH. The organic layer was washed with water, dried over Na2SO4, filtered and evaporated to afford 14.5 g of the title compound. Step 349c. N-CBZ-3-azido-4-hydroxy-pyrrolidine
A 16.18 g sample of N-CBZ-3,4-epoxy-pyrroUdine was dissolved in 145 mL of acetone. A 14.39 g sample of sodium azide was dissolved in 130 mL of water and added to the acetone solution. The reaction mixture was stirred at 60°C for 16 hours, then poured into 400 mL of satd. NaQ solution. The quenched reaction mixture was extracted with methylene chloride, which was dried over Na2SO4, fUtered and evaporated. The residue was purified by flash chromatography over siUca gel to afford 21.40 g of the title compound.
Step 349d. N-CBZ-3-azido-4-methoxy-pyrrolidine
A 3.36 g sample of NaH was suspended in 60 mL of THF in a dry flask under N2 and cooled to 0°C. A 20.0 g sample of N-CBZ-3-azido-4-hydroxy-pyrrolidine, from step 349c above, was dissolved in 200 mL of THF, and this solution was added dropwise to the suspension of NaH. The reaction mixture was stirred for 30 min at 0°C, 30 min at room temperature, and recooled to 0°C. To this solution was added dropwise a solution of 5.70 mL of methyl iodide in 60 mL of THF. The reaction mixture was stirred at 0°C for 30 min and at room temperature for 23.5 hours. The reaction mixture was poured into 500 mL of 5% NH4CI solution, and the mixture was extracted with methylene chloride. The extract was dried over Na2SO4, filtered and evaporated. The residue was purified by flash chromatography over sUica gel to afford 8.99 g of the title compound.
Step 349e. N-CBZ-3-amino-4-methoxy-pyrrolidine
A 8.98 g sample of N-CBZ-3-azido-4-methoxy-pyrrolidine, from step 349d above, was dissolved in 100 mL of methanol and hydrogenated at room temperature under 4 Atm of H2 in the presence of 6.8 g of RaNi for 4 days in a sealed bomb. The catalyst was removed by filtration, and the methanol was evaporated. The residue was dissolved in methylene chloride, dried over Na2SO4, and fUtered. The solvent was removed to yield 5.60 g of the titie compound.
Step 349f. N-CBZ-3-fBOC-aminoV4-methoxy-pyrrolidine
A 5.60 g sample of N-CBZ-3-(BOC-amino)-4-methoxy-pyrrolidine was dissolved in 120 mL of methylene chloride in a dry flask under N2 and cooled to 0°C. To this were added 6.61 mL of triethylamine and 7.76 g of di-t-butyl dicarbonate dissolved in 50 mL of methylene chloride (dropwise). The reaction mixture was stirred at )°C fro 1 hour and at room temperature for 24 hours. The reaction was quenched by addition to water. The mixture was extracted with methylene chloride. The extract was dried over Na2SO4, filtered and evaporated to yield 6.88 g of crude product. The residue was purified by flash chromatography over sUica gel to afford 1.97 g of pure title compound.
Step 349g. 3-fBOC-amino1-4-methoxy-pyrroUdine
A 1.97 g sample of N-CBZ-3-(BOC-amino)-4-methoxy-pyrroUdine, from step 349f above, was hydrogenated over 0.2 g of 10% Pd/C in 100 mL of methanol under 4 Atm of H2 at room temperature for 24 hours. The catalyst was removed by filtration, the solvent was removed to yield 1.28 g of title compound.
Step 349h. 8-(3-amino-4-methoxypyrrolidinyl)-l-cyclopropyl- 7-fluoro-4H-9-methyl-4-oxo-quinoUzine-3-carboxylic acid hydrochloride
FoUowing the procedure of Example 253 step j, replacing the 3-BOC- aminopyrrolidine thereof with 3-(BOC-amino)-4-methoxypyrrolidine, from step 349g above, and carrying the product forward as in Example 253 steps j-1, the title compound was prepared (369 mg). MS: 376 (M+l)+; 1H NMR (CD3OD) 3: 0.71 (m, 2H), 1.88 (m, 2H), 2.30 (m, IH), 2.74 (s, 3H), 3.51 (s, 3H), 3.84 (m, 2H), 3.98 (m, IH), 4.24 (m, 3H), 8.02 (s, IH), 9.02 (d, IH, J=3.5 Hz). Anal. Calcd for C19H23N3O4CIF.4 H2O: C, 46.16; H, 6.46; N, 8.68; Found: C, 47.53; H, 6.06; N, 9.36.
Example 350
8-(4-amino-4-methylpyrroUdinyl)- 1 -cyclopropyl-7-fluoro- 4H-9-methyl-4-oxo-quinoUzine-3-carboxylic acid hydrochloride
Step 350a. N-CBZ-4-hvdroxypiperidine
A 35.43 g of 4-hydroxypiperidine was suspended in 420 mL of 1 M NaOH, and cooled to 0°C. To this stirred solution was added 50.0 mL of benzyl chloroformate dissolved in 100 mL of ether dropwise over a 1 hour period. The reaction mixture was stirred for 3 hours, diluted with 200 mL of water, and extracted with methylene chloride. The extract was dried over Na2SO4, filtered and evaporated to afford the title compound. Step 350b. N-CBZ-4-oxopiperidine
A 43.1 g sample of N-CBZ-4-hydroxypiperidine, from step 350a above, was dissolved in 370 mL of DMSO in a dry flask under N2 and cooled to 0°C. To this solution was added 204 mL of triethyl amine, then a solution of 87.5 g of pyridine»SO3 in 370 mL of DMSO was added dropwise over a period of 1 hour. The reaction was stirred for 24 hours at room temperature, then quenched by addition to 1 L of NaCl solution. The mixture was extracted with methylene chloride. The extract was dried over Na2SO4, filtered and evaporated. The residue was chromatographed of a siUca gel column to afford 11.49 g of the title compound.
Step 350c N-CBZ-4-hvdroxy-4-methylpiperidine
A 58 mL sample of methyl magnesium bromide was placed into a dry flask under N2 containing 450 mL of dry ether cooled to -20°C. A 25.00 g sample of N-CBZ-4- oxopiperidine, from step 350b above, was dissolved in 100 mL of dry ether and added to the reaction vessel dropwise over a 1 hour period. The reaction mixture was stirred for 1 hour, then warmed to room temperature over a 2.5-hour period. The reaction was quenched by dropwise addition of an excess of satd NH4CI solution. The layers were separated, and the aqueous layer was extracted with ether. The organic layers were combined, dried over Na2SO4, filtered and evaporated. The residue was distilled in a kugelrohr apparatus to yield 44.3 g of the title compound.
Step 350d. N-CBZ-4-facetylamino)-4-methylpiperidine
A solution of 270 mL of 90% sulfuric acid and 34 mL of acetonitrile was prepared and cooled to 0°C. A 44.3 g sample of N-CBZ-4-hydroxy-4-methylpiperidine, from step 350c above, dissolved in acetonitrile was added dropwise to the stirred solution in the reaction vessel over a 2 hours period. The reaction mixture was stirred an additional 45 min at 0°C and 2.5 hours without cooling. The reaction mixture was poured over 1 kg of ice, and the mixture was adjusted to pH 12-13 with 50% NaOH. This mixture was extracted with ethyl acetate. The organic layers were combined, dried over Na2SO4, filtered and evaporated to give the titie compound (101.5 g) as a white solid. Step 350e. N-CBZ-4-amino-4-methylpiperidine
A 53 g sample of N-CBZ-4-(acetylamino)-4-methylpiperidine, from step 350e above, was dissolved in 202 mL of 12 M HCI and heated at 115°C for 90 hours. The reaction mixture was poured over 800 g of ice. This mixture was extracted with methylene chloride. The organic layers were combined, dried over Na2SO4, filtered and evaporated to give 37.6 g of the titie compound.
Step 350f. N-CBZ-4-fBOC-aminoV4-methylpiperidine
In a dry flask under N2 a 37.6 g sample of N-CBZ-4-amino-4-methylpiperidine, from step 350e above, was dissolved in 220 mL of CC14, 51.3 mL of triethylamine was added, and 52.2 g of di-t-butyl dicarbonate was added in small portions. The solution was stirred at 38°C for 20 hours, then washed with water. The organic solvent was dried over Na2SO4, fUtered and evaporated to give 23.71 g of titie compound.
Step 350g. 4-fBOC-amino)-4-methylpiperidine
A 23.71 g sample of N-CBZ-4-(BOC-amino)-4-methylpiperidine, from step 350f above, was hydrogenated as described in Example 349g above to give 15.7 g of title compound.
Step 350h. 8-(4-amino-4-methylpyrroUdinyl)-l -cyclopropyl -7-fluoro- 4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid hydrochloride
FoUowing the procedure of Example 253 step j, replacing the 3-BOC- aminopyrroUdine thereof with 4-(BOC-amino)-4-methylpyrroUdine (Aldrich) and carrying the product forward as in Example 253 steps j-1, the title compound was prepared (513 mg). mp 205-207°C. MS: 374 (M+l)+; lH NMR (CD3OD) 3: 0.71 (m, 2H), 1.08 (m, 2H), 1.54 (s, 3H), 2.00 (m, 4H), 2.38 (m, IH), 2.87 (s, 3H), 3.60 (m, 4H), 8.20 (s, IH), 9.27 (d, IH, J=3 Hz). Anal. Calcd for C20H25N3O3CIF.3 H2O: C, 51.78; H, 6.73; N, 9.06; Found: C, 51.64; H, 6.39; N, 9.01. Example 351
8-(4-(2-hydroxyethyl)piperidinyl)- 1 -cyclopropyl- 7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid
FoUowing the procedure of Example 253 step j, replacing the 3-BOC- aminopyrroUdine thereof with 1-piperidineethanol, obtained from Aldrich, and carrying the product forward as in Example 253 steps j-k, the titie compound was prepared (270 mg). MS: 389 (M+l)+; lU NMR (CD3OD) 3: 0.73 (m, 2H), 1.09 (m, 2H), 2.40 (m, IH), 2.93 (s, 3H), 3.42 (m, 4H), 3.54 (m, IH), 3.75 (m, 2H), 3.78 (m, 4H), 3.96 (m, 2H), 8.29 (s, IH), 9.32 (d, IH, J=3.3). Anal. Calcd for C20H24N3O4F.2.5 H2O: C, 55.29; H, 6.73; N, 9.67; Found: C, 55.08; H, 6.02; N, 9.56.
Example 352
8-(4-(methoxymethyl)piperidinyl)- 1 -cyclopropy 1- 7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid
Step 352a. N-CBZ-4-methoxymethoxypiperidine
A 4.00 g sample of N-CBZ-4-hydroxypiperidine, prepared as in Example 350a above, was dissolved in 45 mL of methylene chloride, and 11.85 mL of dUsopropylethylamine was added. To this solution was then added 3.87 mL of chloromethyl methyl ether dropwise over 10 min. The reaction mixture was stirred at room temperature for 17 hours, diluted with 50 mL of methylene chloride, and washed with 0.5 M phosphoric acid, 5% NaHCO3 and water. The solvent was dried over Na2SO4, filtered and evaporated to give 4.43 g of the title compound.
Step 352b. 4-methoxymethoxypiperidine
A 4.43 g sample of N-CBZ-4-methoxymethoxypiperidine, from step 352a above, was hydrogenated as described in Example 349g above to give 2.15 g of titie compound.
Step 352c 8-(4-(methoxymethyl)piperidinyl)-l-cyclopropyl- 7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid
FoUowing the procedure of Example 253 step j, replacing the 3-BOC-amino- pyrroUdine thereof with 4-methoxymethylpiperidine, from step 352b above, and carrying the product forward as in Example 253 steps j-k, the titie compound was prepared (270 mg). mp 128-130°C. MS: 405 (M+l)+; lH NMR (CD3OD) 3: 0.69 (m, 2H), 1.03 (m, 2H), 1.68 (m, 3H), 1.98 (m, IH), 2.12 (m, IH), 2.27 (m, IH), 2.79 (s, 3H), 3.28 (m,
IH), 3.37 (m, 3H), 3.65 (m, IH), 3.79 (m, IH), 4.71 (m, 2H), 8.38 (s, IH), 9.20 (d,
IH, J=12 Hz), 13.88 (s, IH). Anal. Calcd for C21H25N2O5F.O.5 H2O: C, 61.02; H,
6.11; N, 6.87; Found: C, 61.01; H, 6.34; N, 6.78.
Example 353
8-(3-amino-3-methylpiperidinyl)- 1 -cyclopropyl- 7-fluoro-4H-9-methyl-4-oxo-quinoUzine-3-carboxylic acid hydrochloride
Step 353a. N-benzyl-3-hvdroxy-3-methylpiperidine
To a dried system under N2 was added 400 mL of dry ether and 32.2 mL of methyl magnesium bromide, and the solution was cooled to -30°C. To this solution was added dropwise a solution of 16.626 g of N-benzyl-3-piperidone (Aldrich) in 50 mL of dry ether. The reaction mixture was then stirred at room temperature for 4 hours. The reaction was quenched by dropwise addition of satd NH4CI solution with cooUng until the suspended solid separated. An additional 300 mL of 10% NH4CI solution was then added, and the layers were separated. The aqueous layer was washed with ether, the organic solution and extracts were combined, dried over Na2SO4, filtered and evaporated. The residue was distiUed in a kugelrohr apparatus to give 17.942 g of the title compound.
Step 353b. N-benzyl-3-facetylaminoV3-methylpiperidine
A 21.961 g sample of N-benzyl-3-hydroxy-3-methylpiperidine, prepared as in step 353a above, was dissolved in 16.8 mL of acetonitrUe and added dropwise over 1.5 hours to 134 mL of vigorously stirred 90% sulfuric acid cooled to 0°C. The reaction mixture was stirred for an additional 15 min at 0°C, and at room temperature for 6 hours. The reaction was quenched by pouring the reaction mixture over ice. This solution was adjusted to pH 12 with 50% NaOH solution and was then extracted with methylene chloride. The extract was dried over Na2SO4, fUtered and evaporated to yield 19.2 of the title compound.
Step 353c N-benzyl-3-amino-3-methylpiperidine
The sample of N-benzyl-3-(acetylamino)-3-methylpiperidine from the previous step was stirred with 100 mL of cone. HCI at 110°C for 36 hours. The reaction mixture was poured over 800 g of ice. This mixture was extracted with methylene chloride. The organic layers were combined, dried over Na2SO4, filtered and evaporated to give the title compound.
Step 353d. N-benzyl-3-fBOC-amino)-3-methylpiperidine
The N-benzyl-3-amino-3-methylpiperidine of the previous step was reacted with di-t-butyl dicarbonate according to the procedure of Example 350f above, and the title compound was isolated.
Step 353e. 3-fBOC-amino)-3-methylpiperidine
A 3.32 g sample of N-benzyl-3-(BOC-amino)-3-methylpiperidine was hydrogenated according to the procedure of Example 350f above, and 2.50 g of the titie compound was isolated.
Step 353f. 8-(3-amino-3-methylpiperidinyl)-l-cyclopropyl- 7-fluoro-4H-9-methyl-4-oxo-quinoUzine-3-carboxylic acid hydrochloride
FoUowing the procedure of Example 253 step j, replacing the 3-BOC- aminopyrrolidine thereof with 3-(BOC-amino)-3-methylpiperidine, from step 353e above, and carrying the product forward as in Example 253 steps j-1, the title compound was prepared (225 mg). MS: 373 (M+l)+; 1H NMR (CD3OD) 3: 0.69 (m, 2H), 1.05 (m, 2H), 1.53(m, 3H), 1.80 (m, IH), 2.23 (m, 2H), 2.86 (m, 3H), 3.23 (m, 2H), 3.41 (m, 2H), 3.72 (m, 2H), 8.68 (m, 2H), 8.15 (m, IH), 9.01 (m, IH), 13.64 (s, IH). Anal. Calcd for C2θH25N3θ3ClF.H2θ: C, 56.14; H, 6.36; N, 9.82; Found: C, 55.73; H, 6.43; N, 9.48.
Example 354
8-(3-pyrrolylpiperidinyl)- 1 -cyclopropyl-7-fluoro- 4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid
Step 354a. N-CBZ-3-fmethanesulfonyloxy)piperidine
A 4.0 g sample of N-CBZ-3-hydroxypiperidine (prepared from 3- hydroxypiperidine by standard methods) was dissolved in 25 mL of methylene chloride and cooled to 0°C. To this was added 3.55 mL of triethylamine, then a solution of 1.77 mL of methanesulfonylchloride in 4 mL of methylene chloride was added dropwise. The reaction mixture was stirred at 0°C for 15 min and at room temperature for 1.5 hours. The reaction was quenched by dUution with methylene chloride and extraction with 15% NaHCO3 solution. The layers were separated, and the organic layer dried over Na2SO4, filtered and evaporated to give 5.02 g of the title compound.
Step 354b. N-CBZ-3-pyrrolylpiperidine
A 5.02 g sample of the N-CBZ-3-(methanesulfonyloxy)piperidine from step 354a above was dissolved in 8.89 g of pyrrole and heated at 100°C for 20 hours. Excess pyrrole was removed under vacuum, and the residue was washed with 5% NaHCO3 solution, water, dried over Na2SO4, filtered and taken to dryness. The residue was purified by flash chromatography on siUca gel, eluting with 0-1% methanol in methylene chloride to afford 0.500 g of the tifle compound.
Step 354c 3-pyrrolylpiperidine
A 612 mg sample of N-CBZ-3-pyrrolylpiperidine, from step 354b above, was hydrogenated according to the procedure of Example 350f above, and 500 mg of the titie compound was isolated.
Step 354d. 8-(3-pyrrolylpiperidinyl)-l-cyclopropyl- 7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxyUc acid
FoUowing the procedure of Example 253 step j, replacing the 3-BOC- aminopyrroUdine thereof with 3-pyrrolylpiperidine, from step 354c above, and carrying the product forward as in Example 253 steps j-k, the titie compound was prepared (157 mg). mp 182-185°C. MS: 410 (M+l)+; 1H NMR (CD3OD) 3: 0.71 (m, 2H), 1.03 (m, 2H), 1.93 (m, 2H), 2.26 (m, 3H), 2.78 (s, 3H), 2.91-3.78 (m, 6H), 6.19 (m, 2H), 6.77 (m, 2H), 8.23 (s, IH), 9.15 (d, IH, J=12 Hz), 13.09 (s, IH). Anal. Calcd for
C23H24N3O3F.2.25 H2O: C, 61.39; H, 5.83; N, 9.34; Found: C, 61.40; H, 5.63; N, 8.94.
Example 355
8-(3-aminopiperidinyl)- 1 -cyclopropyl-7-fluoro- 4H-9-methyl-4-oxo-quinoUzine-3-carboxyUc acid hydrochloride
Step 355a. fR)-3-amino-2-piperidone
A sample of D-ornithine methyl ester hydrochloride was dissolved in 240 mL of methanol, and stirred with 75 g of an anion exchange resin in the OH" form for 4 hours at room temperature. The suspension was filtered, and the filtrate was taken to dryness. The residue was distiUed in a kugelrohr apparatus to yield 7.59 g of the title compound.
Step 355b. R)-3-aminopiperidine
A 7.49 g sample of (R)-3-amino-2-piperidone, from step 355a above, was dissolved in 140 mL of THF, and the solution was cooled to 0°C. To this solution was carefully added in smaU portions 3.00 g of Uthium aluminum hydride. The reaction mixture was stirred at room temperature for 2 hours. The reaction was quenched with water and NaOH, fUtered, and the filter cake was extracted with THF. The solution was dried over Na2SO4, filtered, and evaporated to dryness. The residue was purified by distiUation.
Step 355c 8-(3-aminopiperidinyl)-l-cyclopropyl-7-fluoro- 4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid hydrochloride
FoUowing the procedure of Example 253 step j, replacing the 3-BOC- a inopyrroUdine thereof with 3-aminopiperidine, from step 355b above, and carrying the product forward as in Example 253 steps j-1, the title compound was prepared (376 mg). MS: 360 (M+l)+; 1H NMR (CD3OD) 3: 0.71 (m, 2H),1.09 (m, 2H), 1.67-2.44 (m, 10H), 3.82 (d, 2H, J=12 Hz), 8.20 (s, IH), 9.25 (d, IH, J=9 Hz). Anal. Calcd for C19H23N3O3CIF.H2O: C, 55.14; H, 6.09; N, 10.15; Found: C, 55.50; H, 6.37; N, 9.26.
Example 356
8-(3-amino-3-methylpyιτolidinyl)- 1 -cyclopropyl- 7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid hydrochloride
Following the procedure of Example 253 step j, replacing the 3-BOC-amino- pyrroUdine thereof with 3-(BOC-amino)-3-methylpyrroUdine, and carrying the product forward as in Example 253 steps j-1, the title compound was prepared (255 mg). MS: 360 (M+l)+; 1H NMR (CD3OD) 3: 0.69 (m, 2H), 1.07 (m, 2H), 1.63 (s, 3H), 2.31 (m, 3H), 2.74 (s, 3H), 3.95 (m, 4H), 8.12 (s, IH), 9.14 (d, IH, J=9 Hz). Anal. Calcd for C19H23N3O3C1F.H2O: C, 55.14; H, 6.09; N, 10.15; Found: C, 55.08; H, 6.01; N, 9.77.
Example 357
8-(3-amino-4-( 1 ',3'-dioxolanyl)pyrrolidinyl)- 1 -cyclopropyl- 7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid hydrochloride
Step 357a. N-CBZ-3-amino-4-hvdroxy-pyrrolidine
A 27.1 g sample of N-CBZ-3-azido-4-hydroxy-pyrroUdine, prepared as in step 349c above, was hydrogenated for 24 hours under the conditions of example 349e above, and 25.4 g of the titie compound was obtained.
Step 357b. N-CBZ-3-fCBZ-aminoV4-hvdroxy-pyrroUdine
A 25.4 g sample of N-CBZ-3-azido-4-hydroxy-pyrrolidine, from step 357a above, was dissolved in 129 mL of 1 M NaOH, and the solution was cooled to 0°C. A 15.35 mL sample of benzyl chloroformate was dissolved in 20 mL of ethanol, and this solution was added dropwise to the vigorously stirred solution of the pyrrolidine over a 40 min period. The reaction mixture was stirred at 0°C for 4 hours, then the reaction was quenched by pouring into 200 mL of water. This mixture was extracted with methylene chloride, which was dried over Na2SO4, filtered, and evaporated to dryness. The residue was purified by column chromatography on siUca gel, eluting with 0.5-3.5% methanol in methylene chloride to yield 18.77 g of the titie compound.
Step 357c N-CBZ-3-fCBZ-aminoV4-pyrrolidinone
In a dry vessel under N2 was place 385 mL of methylene chloride, and the solvent was cooled to 0°C. To this was added 17.32 mL of DMSO, then 21.89 mL of phenyl dichlorophosphate was added dropwise over a 30 min period. Next was added 34.03 mL of triethylamine over a 30 min period. To this solution was added a solution of N-CBZ-3-(CBZ-amino)-4-hydroxy-pyrrolidine, from step 357b above, in 100 mL of methylene chloride in a dropwise manner over a 45 min period. The reaction mixture was stirred at 0°C for 1 hour and at room temperature for 20 hours. The reaction was quenched by pouring it into 20% NaCl solution. The mixture was extracted with methylene chloride, which was dried over Na2SO4, filtered, and evaporated to dryness. The excess DMSO was removed under vacuum with heating, and the residue was purified by column chromatography on siUca gel, eluting with 0 to 1 % methanol in methylene chloride to give 9.2 of the title compound.
Step 357d. N-CBZ-3-fCBZ-aminoV4-fl'-3-dioxolanylvnpyrroIidine
A0.932 g sample of N-CBZ-3-(CBZ-amino)-4-pyrrolidinone, from step 357c above, was dissolved in 17 mL of toluene and 0.353 mL of ethylene glycol and 24 mg of p-toluenesulfonic acid were added. The reaction mixture was stirred at 110°C for 20 hours, then the reaction was quenched by addition of 5% NaHCO3 solution. The mixture was extracted with methylene chloride, which was dried over Na2SO4, filtered, and evaporated to dryness. The residue was purified by column chromatography on silica gel, eluting with 2% methanol in methylene chloride to afford 578 mg of the title compound.
Step 357e. 3-amino-4-f -3-dioxolanylyl)pyrrolidine
A 2.68 g sample of N-CBZ-3-(CBZ-amino)-3-methylpiperidine was hydrogenated for 7 days according to the procedure of Example 350f above, and 937 mg of the title compound was isolated.
Step 357f. 8-(3-amino-4-( ,3'-dioxolanyl)pyrrolidinyl)- 1-cyclopropyl- 7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid hydrochloride
FoUowing the procedure of Example 253 step j, replacing the 3-BOC- aminopyrrolidine thereof with 3-amino-4-( ,3'-dioxolanyl)pyrrolidine, from step 357d above, and carrying the product forward as in Example 253 steps j-1, the title compound was prepared (324 mg). MS: 404 (M+l)+; 1H NMR (CD3OD) 3: 0.69 (m, 2H), 1.06 (m, 2H), 2.33 (m, IH), 2.75 (s, 3H), 3.88-4.02 (m, 4H), 4.16 ( , 4H), 4.21 (m, IH), 8.16 (s, IH), 9.21 (d, IH, J=9 Hz). Anal. Calcd for C20H23N3O5CIF.H2O.HCI: C, 48.59; H, 5.30; N, 8.50; Found: C, 48.80; H, 4.87; N, 8.52. Example 358
8-(3-amino-4-hydroxy-pyrrolidinyl)- 1 -cyclopropyl- 7-fluoro-4H-9-methyl-4-oxo-quinoUzine- 3-carboxylic acid hydrochloride
Step 358a. N-CBZ-3-azido-4-fmethoxymethoxy)pyrroUdine
A sample of N-CBZ-3-azido-4-hydroxypyrrolidine, prepared as in Example 349c above, was dissolved in 20 mL of methylene chloride, 5.02 mL of dnsopropylethylamine was added, and 1.64 mL of methoxymethyl chloride was added dropwise over a 15 min period, with cooling as necessary to maintain the temperature at ambient. The reaction mixture was stirred at room temperature for 18 hours, then washed with 0.5 M phosphoric acid, 5% NaHCO3, dried over Na2SO4, filtered, and evaporated to dryness. The residue was purified by flash chromatography on siUca gel, eluting with 0.5% methanol in methylene chloride to yield 1.58 g of the title compound.
Step 358b. N-CBZ-3-amino-4-fmethoxymethoxy)pyrrolidine
A 2.23 g sample of N-CBZ-3-azido-4-(methoxymethoxy)pyrrolidine, prepared as in step 358a above, was dissolved in 200 mL of ethyl acetate and hydrogenated at room temperature under 4 Atm of H2 in the presence of RaNi for 24 hours in a sealed bomb. The catalyst was removed by filtration, and the solvent was removed under vacuum to give the title product.
Step 358c N-CBZ-3-(BOC-amino)-4-fmethoxymethoxy pyrrolidine
A 2.04 g sample of N-CBZ-3-amino-4-(methoxymethoxy)pyrrolidine, from step 358b above, was dissolved in 20 mL of methylene chloride, and the solution was cooled to 0°C. To this solution was added 2 mL of triethylamine, then 2.38 mL of di-t- butyl dicarbonate dissolved in 5 mL of methylene chloride. The reaction mixture was stirred for 30 min at 0°C, at room temperature for 24 hours, and at 40°C for 8 hours, then quenched by pouring into 10% NaCl solution. The mixture was extracted with methylene chloride, which was dried over Na2SO4, filtered, and evaporated to dryness. The residue was purified by column chromatography on sUica gel, eluting with 1 % methanol in methylene chloride to give 1.35 g of the title compound. Step 358d. 3-fBOC-aιrdnoV4-fmethoxymethoxy)pyrrolidine
A 1.35 g sample of N-CBZ-3-(BOC-arnino)-4-(methoxymethoxy)pyrrolidine, from step 358c above, was hydrogenated for 12 days according to the procedure of Example 350f above, and 874 mg of the title compound was isolated.
Step 358e. 8-(3-amino-4-hydroxy-pyrroUdinyl)-l-cyclopropyl- 7-fluoro-4H-9-methvI-4-oxo-quinoUzine-3-carboxylic acid hydrochloride
Following the procedure of Example 253 step j, replacing the 3-BOC-amino- pyrroUdine thereof with 3-amino-4-hydroxypyrrolidine from step 358d above, and carrying the product forward as in Example 253 steps j-1, the title compound was prepared (125 mg). MS: 362 (M+l)+; 1H NMR (CD3OD) 3: 0.69 (m, 2H), 1.08 (m, 2H), 2.31 (m,
IH), 2.73 (s,3H), 3.69-4.53 (m, 7H), 8.08 (s, IH), 9.10 (m, 2H). Anal. Calcd for
CI8H21N3O4CIF.I.5H2O: C, 50.89; H, 5.69; N, 9.89; Found: C, 51.38; H, 5.65; N,
9.73.
Example 359
8-(4-( 1 -(N-ethylamino)methyl)piperidinyl)- 1 -cyclopropyl- 7-fluoro-4H-9-methyl-4-oxo-quinolιzine-3-carboxylic acid hydrochloride
Step 359a. 4-fN-BOC-N-ethylaminomethyDpyridine
A 4.00 g sample of 4-(N-ethylaminomethyl)pyridine (Aldrich) was dissolved in 50 mL of methylene chloride, and the solution was cooled to 0°C. To his solution was added 8.19 mL of triethylamine and then 8.01 g of di-t-butyl dicarbonate dissolved in 10 mL of methylene chloride was added dropwise. The reaction mixture was stirred for 1 hour at 0°C and at room temperature for 30 min, then quenched by pouring into 10% NaCl solution. The mixture was extracted with methylene chloride, which was dried over Na2SO4, filtered, and evaporated to dryness. The residue was purified by flash chromatography on siUca gel, eluting with 1% methanol in methylene chloride to yield 5.52 g of the title compound.
Step 359b. 4-fN-BOC-N-ethylaπύnomethvDpiperidine
A 5.50 g sample of 4-(N-BOC-N-ethylaminomethyl)pyridine, prepared as in step 359a above, was dissolved in 200 mL of ethyl acetate and hydrogenated at room temperature under 4 Atm of H2 in the presence of RaNi for 24 hours in a sealed bomb. The catalyst was removed by filtration, and the solvent was removed under vacuum to give 1.80 g of the titie product.
Step 359c 8-(4-(l-(N-ethylamino)methyl)piperidinyl)-l-cyclopropyl- 7-fluoro-4H-9-methyl-4-oxo-quinoUzine-3-carboxylic acid hydrochloride
Following the procedure of Example 253 step j, replacing the 3-BOC-amino- pyrτolidine thereof with 4-(N-BOC-N-ethylaminomethyl)piperidine, prepared in step 359b above, and carrying the product forward as in Example 253 steps j-1, the title compound was prepared (488 mg). MS: 402 (M+l)+; 1H NMR (CD3OD) 3: 0.69 (m, 2H), 1.07 (m, 2H), 1.36 (t, J=7.5 Hz, 3H), 1.91 (m, 4H), 2.36 (m, IH), 2.84 (s, 3H), 2.97 (3.37 (m, 8H), 3.41 (m, IH), 8.20 (s, IH), 9.26 (d, J=9 Hz, IH). Anal. Calcd for C22H29N3O3C1F.0.5H2O: C, 59.12; H, 6.77; N, 9.40; Found: C, 58.74; H, 6.63; N, 9.28.
Example 360 l-cyclopropyl-7-fluoro-8-(3-hycbOxy-4-methylaminopyrrolidinyl)- 4H-9-methyl-4-oxo-quinoUzine-3-carboxylic acid hydrochloride
Step 360a. N-CBZ-3-cvano-4-hvdroxypyrrolidine
A sample of N-CBZ-3,4-epoxypyrroUdine, prepared as in Example 349b above, was dissolved in 100 mL of ethanol and added to a solution of 9.88 g of MgSO4 and 13.41 g of NaCN in 195 mL of water. The reaction mixture was stirred at 65 °C for 20 hours., cooled, filtered, and extracted with methylene chloride, which was dried over Na2SO4, fUtered, and evaporated to dryness to afford 9.0 g of the title compound.
Step 360b. N-CBZ-3-aminomethyl-4-hydroxypyrrolidine
A 13.97 g sample of N-CBZ-3-cyano-4-hydroxypyrrolidine, prepared as in step 360a above, was dissolved in 210 mL of methanol containing 40 mL of triethylamine and hydrogenated at room temperature under 4 Atm of H2 in the presence of RaNi for 24 hours in a sealed bomb. The catalyst was removed by filtration, and the solvent was removed under vacuum to give 14.38 g of the titie product.
Step 360c N-CBZ-3-fBOC-aminomethvIV4-hvdroxypyrrolidine
A 2.73 g sample of N-CBZ-3-aminomethyl-4-hydroxypyrroUdine, from step 360b above, was dissolved in 20 mL of methylene chloride, and the solution was cooled to 0°C. To this solution was added 2.86 g of di-t-butyl dicarbonate dissolved in 3 mL of methylene chloride, and the reaction mixture was stirred at 0°C for 1 hour and at room temperature for 18 hours. The reaction was quenched by pouring into 250 mL of water, and the mixture was extracted with methylene chloride, which was dried over Na2SO4, filtered, and evaporated to dryness. The residue was purified by flash chromatography on sUica gel to afford the titie compound.
Step 360d. 3-hvdroxy-4-methylaminopyrrolidine
A sample of N-CBZ-3-(BOC-aminomethyl)-4-hydroxypyrroUdine, from step 360c above, was hydrogenated over 10% Pd/C in 100 mL of methanol under 4 Atm of H2 at room temperature for 24 hours. The catalyst was removed by filtration, the solvent was removed to yield 610 mg of title compound.
Step 360e. 1 -cyclopropyl-7-fluoro-8-(3-hydroxy-4-methylaminopyrroUdinyl)- 4H-9-methyl-4-oxo-quinolizine-3-carboxyUc acid hydrochloride
FoUowing the procedure of Example 253 step j, replacing the 3-BOC- aminopyrroUdine thereof with 3-hydroxy-4-methylaminopyrroUdine, from step 360d above, and carrying the product forward as in Example 253 steps j-1, the title compound was prepared (540 mg). MS: 376 (M+l)+; 1H NMR (CD3OD) 3: 0.68 (m, 3H), 0.99 (m, 2H), 2.29 (m, IH), 2.70 (s, 3H), 3.55-4.58 (m, 9H), 8.09 (s, IH), 9.02 (d, J=9 Hz, IH). Anal. Calcd for C19H23N3O4CIF.2H2O: C, 50.95; H, 6.08; N, 9.38; Found: C, 50.88; H, 5.77; N, 9.01.
Example 361 8-(3-aminomethylpiperidinyl)- 1 -cyclopropyl-7-fluoro-
4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid hydrochloride
Step 361a. 3-fN-BOC-aminomethyl)pyridine
Under dry N2, 15.69 g of di-t-butyldicarbonate was dissolved in 100 mL of CH2C12- The flask and contents were cooled in an ice bath, and to this was added a solution of 6.12 g of 3-(aminornethyl)pyridine in CH2CI2 dropwise with stirring. The solution was stirred at 0-5°C for 30 min, then stirred at room temperature for 72 hours. The reaction was diluted with additional CH2CI2 (100 mL), then washed with 250 mL of water. The water was back-extracted with CH2CI2, and the organic layers were combined and dried over Na2SO4. The solution was filtered, and the solvent was removed on a rotary evaporator to give 13 g of title compound.
Step 361b. 3-fN-BOC-aminomethyl)piperidine
A 10.13 g sample of the compound from step 361a above was dissolved in 250 mL of methanol and reduced over 5 g of 5% Rh/C catalyst at room temperature under 4 Atm or H2 for 18 hours. The catalyst was removed by filtration, and the solvent was removed under vacuum. The product was recrystaUized from ethyl acetate,. and dried under high vacuum to give 3.8 g of product, mp. 64-65°C.
Step 361c 8-(3-aminomethylpiperidinyl)-l-cyclopropyl-7-fluoro- 4H-9-methyl-4-oxo-quinolizine-3-carboxylιc acid hydrochloride
FoUowing the procedure of Example 253 step j, replacing the 3-BOC- aminopyrroUdine thereof with 3-(N-BOC-aminomethyl)piperidine, prepared in step 361b above, and carrying the product forward as in Example 253 steps j-1, the title compound was prepared (301 mg). mp 207-208°C. MS: 374 (M+l)+; 1H NMR (CD3OD) 3: 0.70 (m, 2H), 1.05 (m, 2H), 1.45 (m, 2H), 1.90 (m, 2H), 2.10 (m, 2H), 2.35 (m, IH), 2.84 (s, 3H), 3.00 (m, 2H), 3.20 (m, IH), 3.30 (m, 2H), 8.09 (s, IH), 8.32 (s, IH), 9.17 (d, IH, J=12 Hz). Anal. Calcd for C20H25N3O3C.F-l.5H2O: C, 50.75; H, 6.18; N, 8.88; Found: C, 50.53; H, 6.20; N, 9.03.
Example 362
8-(2-aminomethyl-4-morpholinyl)- 1 -cyclopropyl-7-fluoro- 4H-9-methyl-4-oxo-quinoUzine-3-carboxylic acid hydrochloride
Step 362a. N-benzyl-2-chloromethylmorphoUne
A flask was charged with 1.5 g (10 mmol) of N-benzyl-ethanolamine, 7.8 mL of epichlorohydrin (71 mmol). The reaction mixture was heated at 40°C for 30 min, then cooled to room temperature. The excess epichlorohydrin was removed under vacuum, and the residue was dissolved in 30 mL of cone H2SO4. The solution was heated at 150°C for 30 min and poured onto 50 g of ice. The solution was adjusted to pH 13 with NaOH, and the mixture was extracted with toluene. The solution was dried over Na2SO4, filtered, the solvent removed, and the residue dried under vacuum to give 193 mg of the title compound. MS m/z: 226, 228 (M+H)+. Step 362b. 2-fN-benzyl-morpholiny -N-methylphthaUmide
An oven-dried system under positive N2 pressure was charged with 900 mg (4 mmol) of N-benzyl-3-chloromethylmorphoUne dissolved in 20 mL of DMSO. To this was added 1.48 g (8 mmol) of potassium phthalimide. The reaction mixture was stirred at 100°C for 96 hours, then cooled to room temperature and poured into 50 mL of water. The mixture was extracted with methylene chloride, the extract washed with water, and the organic layer was dried over Na2SO4. The solution was filtered, the solvent was removed under vacuum, and the product was dried under vacuum to give 1.18 g of the title compound. The material was recrystaUized from ethanol, separated by filtration, and dried under vacuum to give 884 mg of pure title compound.
Step 362c 4-benzyl-2-aminomethylmorpholine
A system under positive N2 pressure was charged with 160 mg of 3-(N-benzyl- morpholinyl)-N-methylphthaUmide, from step 362b above, suspended in 4 mL of ethanol. To this was added 50 μL of hydrazine hydrate, and the reaction mixture was stirred at room temperature for 3 hours and at 70°C for 24 hours. The reaction mixture was cooled to room temperature and dUuted with 10 mL of water. The mixture was filtered, and the aqueous layer was adjusted to pH 12 with NaOH and extracted with methylene chloride. The organic extract was dried over Na2SO4, filtered, and the solvent was removed and the product was dried under vacuum to give 72 mg of the title compound.
Step 362d. 4-benzyl-2-fBOC-aminomethyl)morpholine
An oven-dried system protected from moisture was charged with 198 mg of 1- benzyl-3-aminomethylmorpholine, prepared as in step 362c above, dissolved in 2 mL of methylene chloride. To this solution was added 250 mg of di-t-butyl-dicarbonate. The reaction mixture was stirred at room temperature for 24 hours, diluted with 30 mL of methylene chloride, and dried over Na2SOφ The mixture was fUtered, and the solvent was removed under vacuum. The residue was purified with preparative TLC on siUca gel, developing with 9% methanol in methylene chloride and collecting the band at Rf=0.48. The product was removed from the sUica gel with 300 mL of 10% methanol in methylene chloride, and the solvent was removed under vacuum to give 173 mg of the titie compound. MS: 307 (M+l)+. Step 362e. 2-fBOC-aminomethy morphoUne
A 50 mg sample of 4-benzyl-2-(BOC-aminomethyl)morphoUne, from step 362d above, was dissolved in 5 mL of methanol and the benzyl group was removed by hydrogenation over under 4 Atm of H2 over 25 mg of Pd/C at room temperature for 48 hours. The catalyst was fUtered off, and the solvent was removed to give 33 mg of the title compound.
Step 362f. 8-(2-aminomethyl-4-morphoUnyl)-l-cyclopropyl-7-fluoro- 4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid hydrochloride
FoUowing the procedure of Example 253 step j, replacing the 3-BOC- aminopyrroUdine thereof with 2-(BOC-aminomethyl)morphoUne, prepared as in step 362e above, and carrying the product forward as in Example 253 steps j-1, the title compound was prepared (287 mg). mp 209-210°C. MS: 376 (M+l)+, 393 (M+NH4)+; l NMR (CD3OD) 3: 0.70 (dd, 2H, J=4.5, 1.5 Hz), 1.09 (dd, 2H, J=1.5, 4.5 Hz), 2.38 (m, IH), 2.88 (s, 3H), 3.05 (m, 2H), 3.20 (m, 2H), 3.40 (m, 2H), 3.50 (m, 2H), 3.90 (m, 2H), 4.10 (dd, IH, J=1.5, 12 Hz), 8.03 (s, IH), 8.15 (s, IH), 9.23 (d, IH, J=9 Hz), Anal. Calcd for C19H23N3O4CIF.2.25 H2O: C, 50.45; H, 6.13; N, 9.29; Found: C, 50.63; H, 6.17; N, 9.11.
Example 363
8-(3-( 1 -(methylamino)methypiperidinyl)- 1 -cyclopropyl-7-fluoro- 4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid hydrochloride
Step 363a. 3-fN-BOC-N-methylamino methyl)pyridine
To a dry flask under N2 was added 84.7 mg (2.2 mmol) of NaH (minoil washed with dry hexane) and 2 mL of dry THF. The mixture was cooled in an ice bath and 416 mg of 3-(N-BOC-aminomethyl)piperidine, from Example 361b above, in 4 mL of dry THF was added dropwise. The mixture was stirred at 0-5°C for 1 hour after addition was complete, and 0.125 mL of methyl iodide was added. The mixture was stirred at 0-5°C for 30 min, then warmed to room temperature and stirred for 24 hours. The reaction was quenched by pouring it into 30 mL of satd NaCl solution, and the mixture was extracted with 3x30 mL of methylene chloride. The organic extracts were combined, dried over Na2SO4, fUtered and concentrated on a rotary evaporator to give 430 mg of title compound. Step 363b. 3-fN-BOC-N-methylamino)methv piperidine
A 1.16 g sample of the compound from step 361a above was dissolved in 50 mL of methanol and reduced over 1.16 g of 5% Rh/C catalyst at room temperature under 4 Atm or H2 for 18 hours. The catalyst was removed by filtration, and the solvent was removed under vacuum. The product was recrystaUized from ethyl acetate, and dried under high vacuum to give 1.18 g of product MS m/z: 229 (M+H)+.
Step 363c 8-(3-(l-(methylamino)methypiperidinyl)-l-cyclopropyl- 7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid hydrochloride
Following the procedure of Example 253 step j, replacing the 3-BOC-amino- pyrroUdine thereof with 3-(N-BOC-N-methylamino)methyl)piperidine prepared according to step 363a above, and carrying the product forward as in Example 253 steps j-1, the titie compound was prepared (535 mg). mp 246-247°C. MS: 388 (M+l)+; 1H NMR (CD3OD) 3: 0.70 (dd, 2H, J=4.5 Hz), 1.07 (dd, 2H, J=7.8 Hz), 1.50 (m, 2H), 1.90 (m, 4H), 2.10 (m, 2H), 2.21 (m, IH), 2.72 (s, 3H), 2.85 (s, 3H), 3.00 (m, 2H), 8.10 (s, IH), 8.32 (s, IH), 9.18 (d, IH, J=9 Hz), Anal. Calcd for C21H27N3O3CIF. H2O: C, 57.08; H, 6.61; N, 9.51; Found: C, 56.93; H, 6.68; N, 10.23.
Example 364 8-(3-(methyl(methyleneα oxy)methyl)piperidmyl)-l-cyclopropyl-
7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid hydrochloride
Following the procedure of Example 253 step j, replacing the 3-BOC-amino- pyrrolidine thereof with 3-(methyl(methylenedioxy)methyl)piperidine prepared according to European Patent AppUcation 342, 675, and carrying the product forward as in Example 253 steps j-k, the title compound was prepared (443 mg). mp 117-118°C. MS: 419 (M+l)+; ! H NMR (CDCI3) 3: 0.70 (m, 2H), 1.03 (m, 2H), 1.40 (m, 2H), 1.71 (m, 6H), 2.80 (s, 3H), 3.10 (dt, IH, J=3, 12 Hz), 8.04 (dd, 2H, J=7.5 Hz), 8.32 (s, IH), 9.18 (d, IH, J=12 Hz); Anal. Calcd for C22H27N2O5F: C, 63.15; H, 6.50; N, 6.69; Found: C, 63.02; H, 6.42; N, 6.64. Example 365
8-(3-(S)-aminopiperidinyl)- 1 -cyclopropyl-7-fluoro- 4H-9-methyl-4-oxo-quinolizine-3-carboxykc acid hydrochloride
FoUowing the procedure of Example 253 step j, replacing the 3-BOC- aminopyrroUdine thereof with 3-(S)-(N-BOC-amino)piperidine and carrying the product forward as in Example 253 steps j-1, the title compound was prepared (500 mg). mp 220- 221°C. MS: 360 (M+l)+, 377 (M+NH4)+; 1H NMR (CD3OD) 3: 0.70 (m, 2H, J=6 Hz), 1.10 (m, 2H, J=6 Hz), 1.72 (m, 2H), 2.05 (m, 3H), 2.28 (m, 2H), 2.40 (m, 2H), 2.86 (s, 3H), 3.90 (m, IH), 8.18 (s, IH), 9.22 (d, IH, J=9 Hz); Anal. Calcd for
C19H23N2O5CIF.I.5 H2O: C53.97; H, 6.20; N, 9.94; Found: C, 54.28; H, 6.61; N, 8.85.
Example 366 8-(3-(S)-(N-ethyl-N-methylamino)piperidinyl)- 1 -cyclopropyl -
7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid
Step 366a. fSV3-acetylamino-l-benzylpyrrolidine
To 1.30 g (7.38 mmol) of 3-amino-l-benzylpyrrolidine and 1.7 mL (12 mmol) of triethylamine in 25 mL of ethyl acetate stirred at room temperature was added 1.1 mL (12 mmol) of acetic anhydride, and the reaction was stirred for 1 hour. The solvent was removed, and the residue was treated with 1:1 20% K2Cθ3:brine, then extracted with methylene chloride. The organic extract was dried over Na2SO4, fUtered, the solvent was removed under vacuum, and the residue was dried under high vacuum for 16 hours to give 1.71 g of the titie compound. MS: 219 (M+l)+; Anal. Calcd for C13H18N2O: C68.69; H, 8.42; N, 12.32; Found: C, 68.75; H, 8.00; N, 12.27.
Step 366b. fSV3-ethylamino-l-benzylpyrrolidine
To 1.70 g (7.4 mmol) of the compound from step 366a above in 20 mL of THF was added 850 mg of Uthium aluminum hydride, and the mixture was stirred at room temperature for 72 hours. The reaction was quenched with water and NaOH, stirred for 1 hour, fUtered, and the filter cake was extracted with methylene chloride. The aqueous layers were extracted with methylene chloride, and the organic extracts were combined. The solution was dried over Na2SO4, filtered, and the solvent was removed under vacuum to give 1.71 g of the title compound. 1H NMR (CDCI3) 3: 1.09 (t, 3H), 1.30-1.51 (m, IH), 1.48-1.53 (m, IH), 2.06-2.21 (m, IH), 2.34 (dd, IH), 2.58 (q, 2H), 2.47-2.68 (m, 2H), 2.77 (dd, IH), 3.26-3.37 (m, IH), 3.50 (s, 2H), 7.19-7.40 (m, 5H).
Step 366c fSV3-fN-BOC-N-ethylaminoVl-benzylρyrrolidine
To a 1.7 g sample of the compound from step 366b above dissolved in 3 mL of methylene chloride was added 1.94 g (8.9 mmol) of butoxycarbonyl anhydride, and the reaction was stirred for 16 hours. The solvent was removed under vacuum, and the residue was chromatographed on siUca gel, eluting with 1;1 hexane:ethyl acetate to give 1.8 g of the title compound. MS: 305 (M+l)+; 1H NMR (CDCI3) 3: 1.11 (t, 3H), 1.44 (s, 9H), 3.25 (q, 2H), 7.24-7.47 (m, 5H). Anal. Calcd for CI8H28N2O2: C68.00; H, 9.35; N, 8.81; Found: C, 68.05; H, 8.73; N, 8.85.
Step 366d. fSV3-fN-ethyl-N-methylamino)-l-benzylpyrrolidine
To a 1.8 g (5.9 mmol) sample of the compound from step 366c above in 20 mL of THF was added 800 mg of LAH, and the reaction was stirred for 48 at reflux conditions. The reaction was cooled to room temperature, and 0.8 mL of water was added dropwise with stirring, followed by 0.8 mL of 15% NaOH simUarly, and finaUy 2.4 mL of water, and the mixture was stirred for 2 hours at room temperature. The mixture was filtered, the filter cake washed with methylene chloride, the filtrate concentrated under vacuum to give the crude title product This material was dissolved in acetic acid and filtered, methanol was added and the solvent removed, and the residue repeatedly dissolved in methanol and stripped. The residue was taken up in water, adjusted to pH 10-11 with K2CO3, saturated with NaCl, then this solution was extracted with 10% methanol in CHCI3. The extract was dried over Na2SO4, filtered and the solvent was removed to give 603 mg of the title product. MS: 219 (M+l)+; 1H NMR (CDCI3) 3: 1.06 (t, 3H), 1.93- 2.09 (m, IH), 2.20 (s, 3H), 2.28-2.60 (br, 4H), 2.66-2.77 (m, IH), 2.82 (dd, IH), 2.96-3.14 (m, IH), 3.60 (q, 2H), 7.18-7.41 (m, 5H).
Step 366e. fSV3-fN-ethyl-N-methylamino)pyrrolidine
A 1.3 g sample of the compound from step 366d above was dissolved in 50 mL of acetic acid and 0.5 mL of HCI, 0.13 g of 10% Pd/C was added and the sample hydrogenated under 4 Atm of H2. Additional amounts of catalyst and HCI were added before the reaction was complete. The solution was filtered, then the solvent was removed with repeated addition and removal of methanol. The residue was dissolved in water, which was adjusted to pH 10-11 with K2CO3, saturated with NaCl, and extracted repeatedly with 10% methanol in CHCI3. The extract was dried over Na2SO4, filtered, and taken to dryness to give 603 mg of the title compound. HRMS (M+l)+: calc: 129.1936; found, 129.1392.
Step 366f. 8-(3-(S)-(N-ethyl-N-methylamino)piperidinyl)- l-cvclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinoUzine-3-carboxylic acid
Following the procedure of Example 253 step j, replacing the 3-BOC-amino- pyrrolidine thereof with (S)-3-(N-ethyl-N-methylamino)-pyrrolidine from step 366e above and carrying the product forward as in Example 253 steps j-k, the title compound was prepared. MS: 416 (M+l)+; !H NMR (CDCI3) 3: 0.5-0.6 M, IH), 0.6-0.7 (m, IH), 0.8-
0.95 (m, 2H), 1.1 (t, 3H), 1.4 (t, 3H), 1.9-2.0 (m, IH), 2.1-2.2 (m, IH), 2.25 (s, 3H),
2.33 (s, 3H), 3.6-3.7 (m, 4H), 3.7-3.9 (m, IH), 3.9-4.0 (m, IH), 4.12 (dd, IH), 4.4 (q,
2H), 8.13 (s, IH), 9.25 (d, 2H).
Example 367
1 -cyclopropyl-8-(4-(2'-(N-methylamino)methyl- 1 ',3'-dioxolanyl)piperidinyl)- 7-fluoro-9-methyl-4-oxo-4H-quinoUzine-3-carboxylic acid hydrochloride
Step 367a. N-CBZ-4-f4'-bromomethyl-l'.3'-dioxolanyl piperidine
A 17.48 g sample of N-CBZ-4-oxopiperidine, prepared as in Example 350b above, was dissolved in 325 mL of toluene, and 16.40 mL of 3-bromo-l,2-propanediol and 713 mg of p-toluenesulfonic acid were added. The reaction mixture was heated at reflux (120-125°C) for 24 hours while collecting the water of reaction in a Dean-Stark trap. The reaction mixture was cooled to room temperature, then washed with 5% NaHCO3 and water, dried over Na2SO4, filtered, and taken to dryness. The residue was purified by flash chromatography on sUica gel, eluting with O-to-1.5% methanol in methylene chloride to yield 26.5 g of the title compound.
Step 367b. N-CBZ-4-f4'-fmethylaminomethyD- 1 '.3'-dioxolanyl)piperidine
A 7.29 g sample of N-CBZ-4-(4'-bromomethyl- ,3'-dioxolanyl)piperidine, from step 367a above, was heated with excess methylamine, and 3.427 g of the titie compound was isolated and purified. Step 367c N-CBZ-4-f4'-fN-BOC-N-methylaminomethyl r.3'-dioxolanvnpiperidine
A 3.43 g sample of N-CBZ-4-(4'-(methylaminomethyl)-l,,3'-dioxolanyl)- piperidine, from step 367b above, was dissolved in 30 mL of methylene chloride, to which was added 2.98 mL of triethylamine foUowed by dropwise addition of 3.50 g of di-t-butyl dicarbonate in 20 mL of methylene chloride. The reaction mixture was stirred at 35°C for 5 hours and at room temperature for 15 hours. The mixture was dUuted with methylene chloride and washed with water. The extract was dried over Na2SO4, filtered, and taken to dryness to obtain 4.29 g of title compound.
Step 367d. 4-f4'-f N-BOC-N-methylaminomethyl)- 1 ' '-dioxolanv piperidine
A sample of N-CBZ-4-(4'-(N-BOC-N-methylaminomethyl)-l',3'-dioxolanyl)- piperidine, from step 367c above, was hydrogenated over 10% Pd/C in 200 mL of methanol under 4 Atm of H2 at room temperature for 24 hours. The catalyst was removed by filtration, and the solvent was removed to yield the titie compound.
Step 367e. l-cyclopropyl-8-(4-(2'-(N-methylamino)methyl- ,3'-dioxolanyl)piperidinyl)-7-fluoro-9-methyl- 4-oxo-4H-quinoUzιne-3-carboxylic acid hydrochloride
Following the procedure of Example 253 step j, replacing the 3-BOC-amino- pyrrolidine thereof with 4-(4'-(N-BOC-N-methylaminomethyl)- 1 ',3'-dioxolanyl)- piperidine, prepared in step 367d above, and carrying the product forward as in Example
253 steps j-k, 199 mg of the title compound was prepared. IR (KBr) cm" 1 : 3300 (br),
2850 (br), 1700 (s), 1610 (m), 1530 (s), 790 (m). MS (CDI/NH3) m/z (M+H)+: 446 base. NMR (d6-DMSO): 9.18 (d, IH), 8.00 (s, IH), 3.69-4.57 (m, 4H), 2.95-3.25 (m, 5H), 2.76 (s, 3H), 2.48 (m, 3H), 2.40 (m, IH), 1.88 (m, 4H), 1.02 (m, 2H), 0.65 (m,
2H). Anal. Calcd for C23H29ClFN3θ5;.2 H2O: C53.33; H, 6.42; N, 8.11; Found: C,
53.62; H, 6.38; N, 8.32.
Example 368 l-cyclopropyl-8-(3-aza-6-amino-6-methylbicyclo[3.3.0]octan- 1 -yl)-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carbox ylic acid hydrochloride
Step 368a. -benzyl-3-aza-6-oxobicvclor3.3.01octane
A 32.69 g sample of N-methoxymethyl-N-(trimethylsUylmethyl)-benzylamine was dissolved in 30 mL of methylene chloride, and the solution was cooled to 0°C. To this solution was added 9.5 mL of 2-cyclopentene-l-one and 1.75 mL of trifluoroacetic acid, and the reaction mixture was stirred at 0°C for 0.5 hours and at room temperature for 24 hours. The reaction was quenched with water, and the mixture was extracted with methylene chloride, which was dried over Na2SO4, filtered, and taken to dryness to obtain 28.27 g of the title compound.
Step 368b. N-benzyl-3-aza-6-hydroxy-6-methylbicycloI3.3.01octane
In dry ether and under N2, the compound from step 368a was reacted with methyl magnesium bromide at -30°C. After standard workup, the title compound was isolated.
Step 368c. N-benzyl-3-aza-6-facetylaminoV6-meτhvIbicvclor3.3.01octane
The compound of step 368b was reacted with acetonitrile in the presence of concentrated sulfuric acid. The reaction was quenched with water, and the product was extracted into methylene chloride, which was dried over Na2SO4, fUtered, and taken to dryness to obtain the tifle compound.
Step 368d. N-benzyl-3-aza-6-amino-6-methylbicvcloI3.3.01octane
The acetyl group was removed from the compound of step 368c by reaction with cone HCI. The reaction mixture was made basic with NaOH, and the product was extracted into methylene chloride, which was dried over Na2SO4, fUtered, and taken to dryness to obtain the title compound.
Step 368e. N-benzyl-3-aza-6-fBOC-aminoV6-methylbicvclor3.3.01octane
The compound from step 368d was reacted with di-t-butyl dicarbonate in the presence of triethylamine. The reaction was quenched with water, and the product was extracted into methylene chloride, which was dried over Na2SO4, fUtered, and taken to dryness to obtain the title compound.
Step 368f. 3-aza-6-fBOC-aminoV6-methv1bicvclor3.3.01octane
The benzyl group was removed from the compound of step 368f by hydrogenation in the presence of Pd/C. The catalyst was removed by filtration, and the product was obtained by evaporation of the solvent. Step 368g. l-cyclopropyl-8-(3-aza-6-amino-6-methylbicyclo[3.3.0]octan-l-yl)- 7-fluoro-9-methyl-4-oxo-4H-quinoUzine-3-carboxylic acid hydrochloride
Following the procedure of Example 253 step j, replacing the 3-BOC-amino- pyrroUdine thereof with 3-aza-6-(BOC-amino)-6-methylbicyclo[3.3.0]-octane, from step 369g above, and carrying the product forward as in Example 253 steps j-k, 418 mg of the title compound was prepared. IR (KBr) cm" 1: 3340 (br), 2860 (br), 1700 (m), 1610 (m), 1430 (s), 1370 (m). MS (CDI/NH3) m/z (M+H)+: 400 base. NMR (CD3OD): 9.12 (m, IH), 8.03 (s, IH), 3.94 (m, 2H), 3.78 (m, IH), 3.57 (m, 2H), 2.83 (m, IH), 2.78 (m, 3H), 2.31 (m, IH), 1.88 (m, 2H), 2.19 (m, 2H), 1.50 (s, 3H), 1.07 (m, 2H), 0.68 (m, 2H). Anal. Calcd for C22H27CIFN3O3 .5 H2O Q57.62; H, 6.37; N, 9.06; Found: C, 58.02; H, 6.64; N, 9.23.
Example 369 l-cvclopropyl-8-f3-fluoromethylpiperidinyl)-7-fluoro-9-methyl-4-oxo-4H-quinolizine
Step 369a. N-BOC-3-hydroxymethylpiperidine
A sample of 3-hydroxymethylpiperidine (2.0g,17.4mmol) was suspended in 60 mL of water and cooled to 0C. Sodium bicarbonate (2.63g, 31mmol) was added in one portion, then benzyl chloroformate (2.60ml, 18.3mmol) was added dropwise in 10ml of diethyl ether. After stirring for 4 hours at 0C, the reaction was poured into 150ml water and extracted with methylene chloride (3X100ml). The combined organic layers were dried over sodium sulfate, then filtered and the filtrate evaporated to dryness to yield 3.74g (86%).
Step 369b. N-BOC-3-fluoromethylpiperidine
This compound from step 369a (3.74g, 15mmol) was then dissolved in 10ml of methylene chloride and added dropwise to a solution of diethylaminosulfur trifluoride (2.59ml, 19.5mmol) in 10ml of methylene chloride at -78C. After the addition, the reaction was stirred at room temperature for 16 hours. 10ml of water, then 30ml of IM sodium hydroxide was added dropwise to the reaction, then the product was extracted into methylene chloride (3X75ml). The combined organic layers were dried over sodium sulfate, filtered, and the filtrate was evaporated to dryness. The product was purified by flash chromatography (100% methylene chloride) to yield 2.42g (64%). Step 369c 3-fluoromethylpiperidine
The amine was deprotected under hydrogenation conditions in methanol using palladium on carbon (2g). After 16h at room temperature and 4atm, the catalyst was filtered off and the filtrate concentrated to yield: 808 mg (68%) of the desired amine.
Step 369d. l-cyclopropyl-8-(3-fluoromethylpiperidinyl)- 7-fluoro-9-methyl-4-oxo-4H-quinolizine
FoUowing the procedure of Example 253 step j, replacing the 3-BOC- aminopyrroUdine thereof with 3-fluoromethylpiperidine, from step 369d above, and carrying the product forward as in Example 253 steps j-k, 198 mg of the title compound was prepared. IR (KBr) cm"1: 2950 (br), 1650 (s), 1470 (s), 1440 (s), 1350 (m). MS (CDI/NH3) m/z (M+H)+: 377 base. NMR (CDCI3): 9.22 (d, IH, J=9 Hz), 8.37 (s, IH), 4.21-4.53 (m, 4H), 3.14-3.67 (m, 7H), 2.79 (s, 3H), 2.25 (m, IH), 1.04 (m, 2H), 0.72 (m, 2H). Anal. Calcd for C20H22F2N2O3: C, 63.82; H, 5.89; N, 7.44; Found: C, 63.35; H, 5.83; N, 6.85.
Example 370 l-cyclopropyl-8-(4-(N,N-dimethyl)aminopiperidinyl)- 7-fluoro-9-methyl-4-oxo-4H-quinoIizine-3-carboxylic acid hydrochloride
Step 370a. 4-fN.N-dimethyl)aminopiperidine
4-(N,N-dimethyl)aminopyridine (l.Og, 8.2mmol) was subjected to hydrogenation conditions in lOOml methanol using Rhodium (50 mg) at room temperature and 4atm for 72 hours. The catalyst was filtered off and the filtrate was evaporated to yield 100% of the desired amine.
Step 370b. l-cyclopropyl-8-(4-(N,N-dimethyl)aminopiperidinyl)- 7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid hydrochloride
Following the procedure of Example 253 step j, replacing the 3-BOC-amino- pyrrolidine thereof with 4-(N,N-dimethyl)aminopiperidine, from step 370a above, and carrying the product forward as in Example 253 steps j-k, 345 mg of the title compound was prepared. IR (KBr) cm" 1: 2950 (br), 1710 (m), 1610 (m), 1470 (s), 1440 (s). MS (CDI/NH3) m/z (M+H)+: 388 base. Anal. Calcd for C21H27CIFN3O3: C, 59.50; H, 6.42; N, 9.91; Found: C, 59.72; H, 6.69; N, 9.33.
Example 371 l-cyclopropyl-8-(6-amino-3-azabicyclo[3.3.0]octyl)-
7-fluoro-9-methyl-4-oxo-4H-quinoUzine-3-carboxylic acid hydrochloride
Step 371a. 3-aza-3-benzyl-6-fhydroxylimino)bicvclor3.3.01octane
A 3.24 sample of 3-aza-6-oxobicyclo[3.3.0]octane, prepared as in Example 368a above, was dissolved in 40 mL of THF. Hydroxylamine hydrochloride (3.14 g) was dissolved in 60 mL of water and 4.05 g of NaHCO3 was added to neutraUze the salt. The neutral hydroxylamine solution was added to the THF solution, and the reaction mixture was stirred vigorously at room temperature for 18 hours. The THF was removed from the mixture under vacuum, and the aqueous solution was extracted with methylene chloride, which was dried over sodium sulfate, filtered and evaporated to dryness to yield 2.80 g of the titie compound.
Step 371b. 3-aza-3-benzyl-6-aminobicvclor3.3.01octane
A 29.37 g sample of 3-aza-6-(hydroxyUmino)bicyclo[3.3.0]octane, prepared as in step 371a above, was dissolved in 1 L of methanol and hydrogenated at 4 Atm of H2 over 58.74 g of RaNi catalyst for 24 hours. The catalyst was filtered off, and the solvent was evaporated to afford the titie compound.
Step 371c. 3-aza-3-benzyl-6-fBOC-amino)bicycIor3.3.01octane
A 2.63 g sample of 3-aza-3-benzyl-6-aminobicyclo[3.3.0]octane, from step 371b above, was dissolved in 25 mL of methylene chloride, 3.39 mL of triethylamine was added, and the solution was cooled to 0°C. A 3.98 g sample of di-t-butyl dicarbonate was dissolved in 6 mL of methylene chloride and added dropwise to the first solution. The reaction mixture was stirred 30 min at 0°C and at room temperature for 18 hours, the quenched by rapid addition to water. The mixture was extracted with methylene chloride, which was dried over sodium sulfate, fUtered and evaporated to dryness. The residue was purified by column chromatography, eluting with 2% methanol in methylene chloride to afford the titie compound. Step 37 Id. 3-aza-6-fBOC-amino)bicvcloI3.3.01octane
The compound from step 37 lc above was dissolved in 150 mL of methanol and hydrogenated for 23 hours at room temperature and 4 Atm of H2 over 1.5 g of 10% Pd/C catalyst The catalyst was filtered off, and the solvent was evaporated to afford the titie compound.
Step 37 le. l-cyclopropyl-8-(6-amino-3-azabicyclo[3.3.0]octyl)- 7-fluoro-9-methyl-4-oxo-4H-quinoIizine-3-carboxylic acid hydrochloride
Following the procedure of Example 253 step j, replacing the 3-BOC-amino- pyrrolidine thereof with 6-(BOC-amino)-3-azabicyclo[3.3.0]octane, from step 37 Id above, and carrying the product forward as in Example 253 steps j-k, 298 mg of the final compound was prepared. IR (KBr) cm" 1: 2900 (br), 1700 (m), 1610 (m), 1430 (s), 1380 (m). MS (CDI/NH3) m/z (M+H)+: 386 base. NMR (CD3OD): 9.04 (d, IH, J=9 Hz), 7.97 (s, IH), 3.92 (m, 2H), 3.78 (m, 2H), 3.57 (m, IH), 3.15 (m, IH), 3.04 (m, IH), 2.76 (s, 3H), 2.29 (m, IH), 1.69-2.21 (m, 3H), 1.08 (m, 2H), 0.67 (m, 2H). Anal. Calcd for C21H25CIFN3O3.I.5 H2O. HCI: C, 51.97; H, 6.02; N, 8.66; Found: C, 52.07; H, 5.81; N, 8.48.
Example 372 l-cyclopropyl-8-((2-aza-4-(dimethylaminomethyl)bicyclo[4.3.0]non-2-yl)-
7-fluoro-9-methyl-4-oxo-4H-quinolizine carboxylic acid hydrochloride
Step 372a. 2-aza-4-dimethylaminomethvIbicvclor3.3.01nonane
A 1 g sample of 3-dimethylaminomethyUndole was hydrogenated over Pd/C in acetic acid/HCl, the catalyst removed by filtration, and the solvent dUuted with water, adjusted to pH 11, and extracted with ethyl acetate. The solvent was dried and evaporated to afford the title compound.
Step 372b. l-cyclopropyl-8-((2-aza-4- (dimethylaminomethyl)bicyclo[4.3.0]non-2-yl)- 7-fluoro-9-methyl-4-oxo-4H-quinolizine carboxylic acid hydrochloride
Following the procedure of Example 253 step j, replacing the 3-BOC-amino- pyrrolidine thereof with 2-aza-4-(dimethylaminomethyl)bicyclo[4.3.0]-nonane, from step 372a above, and carrying the product forward as in Example 253 steps j-k, 354 mg of the final compound was prepared. IR (KBr) cm"1: 3400 (br), 2950 (m), 2600 (br), 1720 (m), 1610 (m), 1430 (s), 1380 (m). MS (CDI/NH3) m/z (M+H)+: 442 base. NMR (CDCI3): 9.07 (d, IH, J=9 Hz), 8.28 (s, IH), 4.47 (m, IH), 4.04 (m, IH), 3.60 (m, IH), 3.18 (m, 2H), 2.75 (s, 3H), 2.49 (m, IH), 2.27 (m, IH), 1.26 (m, 2H), 1.00-1.90 (m, 9H), 2.91 (s, 6H), 0.70 (m, 2H). Anal. Calcd for C25H33CIFN3O3.I.25 H2O: C, 60.59; H, 7.73; N, 8.48; Found: C, 60.07; H, 7.71; N, 8.15.
Example 373 l-cyclopropyl-8-(3-aza-6-(L-alanylamino)-6-methylbicyclo[3.3.0]octane)- 7-fluoro-9-methyl-4-oxo-4H-quinolizine carboxyUc acid hydrochloride
A 50 mg sample of l-cyclopropyl-8-(3-aza-6-(L-alanylamino)-6-methylbicyclo- [3.3.0]octane)-7-fluoro-9-methyl-4-oxo-4H-quinoUzine carboxyUc acid hydrochloride, from Example 368, was dissolved in 3 mL of DMF, and the solution was cooled to 0°C. A 0.044 mL sample of diisopropylethylamine was added, followed by 35 mg of N-BOC-L- alanyl-N-hydroxysuccinimide, and the reaction was stirred at 0°C for 20 min and at room temperature for 48 hours. The solution was poured into a large volume of water, and the product was filtered off and dried. IR (KBr) cm"1: 2950 (br), 1680 (m), 1430 (s). MS (CDI/NH3) m/z (M+H)+: 471 base. Anal. Calcd for C25H32CIFN4O4Η2O: C, 57.19; H, 6.14; N, 10.67; Found: C, 57.16; H, 6.48; N, 9.90.
Example 374
(3R, 1 R)-8-(3-( 1 -(N-methyl)amino)propyl)pyrrolidinyl)- 1 -cyclopropyl- 7-fluoro-9-methyl-4-oxo-4H-quinoUzine-3-carboxylic acid hydrochloride
A sample of 8-chloro-l-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinoUzine-3- carboxylic acid ethyl ester, from Example 253i above, was dissolved in 8 mL of anhydrous acetonitrUe, reacted with (3R,lR)-3-(l-(N-methyl)amino)propyl)pyrroUdine (prepared as described by Hayakawa et al., U.S. Patent 5,098,912, issued March 24, 1992, using modifications for chiral products described by Plummer et ai, Tetr. Lett. 24:7529-32 (1993)), and carried forward as described in Example 253 j-1, omitting the deprotecting step, to give the title product. MS 402 (M+H)+; JH NMR (D6-DMSO) 3: 0.6-0.7 (m, 3H), 0.9 (t, 3H), 1-1.5 (m, 2H), 16-1.95 (m, 4H), 2.1-2.2 (m, IH), 2.6-2.65 (m, IH), 2.60 (s, 3H), 2.7 (s, 3H), 3.45-3.55 (m, IH), 3.7-3.75 (m, 2H), 3.95-4 (m, IH), 8.25 (s, IH), 9.1 (d, 2H). Examples 375-408
Following the procedures of Steps 253j, 253k and 2531 above, replacing the 3- BOC-aminopyrrolidine of Step 253j with the appropriate unprotected or BOC-protected reagent, the compounds of Examples 375-412 are prepared as shown in Table 13, below.
Table 13
Example # R2
29ά
H2N
Example 413
(3R,lS)-8-(3-(l-amino-2-methoxyethyl)pyrrolidinyl)-l-cyclopropyl- 7-fluoro-9-methyl-4-oxo-4H-quinoUzine-3-carboxylic acid hydrochloride
Step 413a. fS)-N-BOC-O-ft-butyldimethylsUv serine methyl ester
A 7 g (31.96 mmol) sample of ((S)-N-BOC-serine methyl ester (obtained from Aldrich) was dissolved in pyridine and cooled in an ice bath. To this stirred solution was added dropwise 5.54 g (36.76 mmol) of t-butyldimethylsUyl chloride (TBDMSC) dissolved in 40 mL of pyridine. After aU reagents were added the reaction was stirred for 4 hours at room temperature. An additional 0.5 g of TBDMSC was added and the reaction was stirred for an additional 2 hours. To the mixture was then added 2.5 equivalents of imidazole in 14 mL of DMF, and the reaction was stirred for 2 hours. The solvents were removed under reduced pressure, and the residue was dissolved in ethyl acetate, which was washed with water and brine. The solvent was removed to give the title compound as a yellow oil. MS 334 (M+H)+; lH NMR (CDCI3) 3: 0.11 (s, 6H), 0.86 (s, 9H), 1.46 (s, 9H), 3.74 (s, 3H), 3.82 (dd, IH), 4.04 (dd, IH), 4.36 (m, IH), 5.35 (br, IH).
Step 413b. fSV2-fBOC-aminoV3-ft-butyldimethylsilyloxyVl -propanol
A solution of the compound from step 413a above (9.6 g, 28.83 mmol) in 44 mL of THF was added dropwise to a cooled (ice bath) suspension of 570 mg (14.84 mmol) of LAH in 15 mL of THF under N2 atmosphere. The mixture was stirred for 1.5 hours, the reaction was quenched with water and 50% NaOH, filtered, and the filtrate evaporated to obtain the crude product. An oU was obtained, which was purified by chromatography on sUica gel, eluting with 15-20% ethyl acetate±exane to give 3.465 g of the title product as a colorless oil. MS 306 (M+H)+; lU NMR (CDCI3) 3: 0.08(s, 6H), 0.90 (s, 9H), 1.45 (s, 9H), 2.68 (br, IH), 3.68 (m, 2H), 3.81 (d, 2H), 3.85 (m, IH), 5.15 (br, IH).
Step 413c. fS)-2-fBOC-amino)-3-ft-butyldimethylsilyloxyVl-propanal
To a solution of the compound from step 413b above (3.47 g, 11.36 mmol) in 6 mL of DMSO cooled to 0°C was added dropwise 5.2 mL (37.49 mmol) of triethylamine. Pyridine»Sθ3 complex (5.424 g, 34.08 mmol) was dissolved in 21 mL of DMSO and added to the first solution, and the reaction was stirred for 1.5 hours after the addition was complete. The solution was poured into 120 mL of cold brine, and the mixture was washed 3x with ethyl acetate. The extract was washed with water, dried over MgSO4, filtered and the solvent was removed under vacuum to give 3.9 g of a yellow oil, which was taken directly to the next step.
Step 413d. fS)-4-fBOC-amino)-5-ft-butyldimethylsilyloxy)-2-pentenoic acid ethyl ester
To a solution of the compound from step 413c above (11.36 mmol) in 24 mL of
CH2CI2 and cooled in an ice bath was added dropwise 3.958 g (11.36 mmol) of (carboethoxymethylene)triphenylphosphorane in 13 mL of CH2CI2. After addition was complete, the reaction was stirred for 16 hours at room temperature. The solvent was removed, and the residue was purified by column chromatography on siUca gel, eluting with 3-10% ethyl acetate: hexane, to give 3.93 g of a colorless oil. MS 374 (M+H)+; 1H NMR (CDCI3) 3: 0.05 (d, 6H), 0.88 (s, 9H), 1.27 (t, 3H), 1.46 (s, 9H), 3.72 (m, 2H), 4.19 (q, 2H), 4.36 (br, IH), 5.98 (dd, IH), 6.91 (dd, IH).
Step 413e. (S)-4-(BOC-amino)-5-(t-butyldimethylsUyloxy)- 3-fnitromethyl)-pentanoic acid ethyl ester
To a solution of the compound from step 413d above (3.9 g, 10.46 mmol) in 6 mL of nitromethane cooled in an ice bath was added 1.56 mL (10.46 mmol) of 1,8- diazabicyclo[5.4.0]undec-7-ene dropwise under N2. The mixture was warmed to room temperature and stirred for 16 hours. The solution was diluted with CH2CI2 and extracted with water, 10% HCI, 10% NaHCO3, water and brine. The solution was dried over MgSO4, and the solvent was removed. The residue was chromatographed on sUica gel, eluting with 5-10% ethyl acetate:hexane, and the solvent was removed to give 3.6 g of the titie product as a white solid. MS 435 (M+H)+; 1H NMR (CDCI3) 3: 0.09 (s, 6H), 0.91 (s, 9H), 1.28 (t, 3H), 1.45 (s, 9H), 2.45 (dd, IH), 2.60 (dd, IH), 2.93 (m, IH), 3.68 (dd, IH), 3.78 (dd, IH), 3.84 (m, IH), 4.15 (q, 2H), 4.52 (dd, IH), 4.67 (dd, IH), 4.84.
Step 413f. (S)-4-(BOC-amino)-5-(t-butyldimethylsUyloxy)- S- aminomethvD-pentanoic acid ethyl ester
A 4.74 g sample of the compound from step 413e above was dissolved in 250 mL of ethanol and hydrogenated at 4 Atm over 14.2 g of Raney nickel catalyst for 24 hours. The catalyst was removed by filtration and the solvent was evaporated. The residue (mp 152-154°C) was taken directly to the next step. Step 413g. (S)-4-(l-(BOC-amino)-2- ft-butyldimethylsilyloxy)eτhyl)-2-oxo-4-pyrrolidine
The residue from step 413f above was dissolved in 150 mL of ethanol and heated at reflux for 8 hours. The solvent was removed, the residue was chromatographed on silica gel, eluting with 4% methanol/methylene chloride. Removal of the solvent gave the titie product.
Step 413h. (S)-4-( 1 -(BOC-amino)-2-(t-butyldimethyl- silyloxytethviy 1 -benzyl-2-oxopyrrolidine
A 200 mg (0.558 mg) sample of the compound from step 413g above was dissolved in 1 mL of THF and added dropwise to a 0°C suspension of NaH (47 mg, 1.172 mmol) in 2 mL of THF, and the reaction mixture was stirred for 1 hour. To this mixture was then added 124 mg of benzyl bromide, and the reaction was stirred at room temperature for 3 hours. The reaction was quenched with water, and the mixture was extracted with ethyl acetate. The organic phase was acidified with citric acid solution, and the mixture was extracted with ethyl acetate. The solvent was washed with brine and dried over MgSO4, filtered and evaporated. The residue was purified by column chromatography on sUica gel, eluting with 30-35% ethyl acetate: hexane, to give 168 mg of the title compound. MS 449 (M+H)+; H NMR (CDCI3) 3: 0.03 (s, 6 H), 0.87 (s, 9H), 1.42 (s, 9H), 2.26 (dd, IH), 2.52 (dd, IH), 2.58 (m, IH), 3.16 (br t, IH), 3.27 (dd,
IH), 3.61 (br m, 3H), 4.28 (d, IH), 4.59 (d, IH), 4.70 (d, IH), 7.23 (m, 2H), 7.32 (m, 3H).
Step 413i. fS)-4-fl-fBOC-aminoV2-hydroxyethyl)-l-benzvI-2-oxopyιτolidine
A 143 mg sample of the compound from step 413h above was dissolved in 1 mL of THF and reacted with 1 equivalent of tetra-n-butyl ammonium fluoride at room temperature for 1.5 hours. The solvent was removed, and the residue was dissolved in methylene chloride and purified by column chromatography on stiica gel, eluting with 5% methanol in methylene chloride, to give 110 mg of the title compound. MS 335 (M+H)+; H NMR (CDCI3) 3: 1.42 (s, 9H), 2.28 (m, IH), 2.59 (m, 3H), 3.15 (m, IH), 3.31 (m, IH), 3.61 (m, 2H), 3.70 (m, IH), 4.30 (d, IH), 4.58 (d, IH), 4.78 (d, IH), 7.23 (m, 2H), 7.32 (m, 3H). Step 413j. fSV4-fl-fBOC-aminoV2-methoxyethylVl-benzyl-2-oxopyrrolidine
A sample of the compound from step 413i above (7.34 mmol) was dissolved in 22 mL of THF and added to a suspension of 8.72 mg (16.148 mmol) of sodium methoxide in 40 mL of THF, and the reaction mixture was stirred at room temperature under nitrogen for 1 hour. To this solution was then added 3.958 g of methyl iodide in 5 mL of THF, and the reaction mixture was stiιτed for 16 hours. The solvents were removed under vacuum, and the residue was dissolved in ethyl acetate, which was washed with sodium thiosulfate and brine and dried over MgSO4, filtered and evaporated. The residue was dissolved in methylene chloride and purified by column chromatography on sUica gel, eluting with 5% methanol in methylene chloride, to give the titie compound. MS 349 (M+H)+; 1H NMR ' (CDCI3) 3: 1.42 (s, 9h), 2.28 (dd, IH), 2.56 (m, 3H), 3.14 (br t, IH), 3.28 (dd, IH), ' 3.30 (s, 3H), 3.37 (d, 2H), 3.71 (br, IH), 4.24 (dd, IH), 4.52 (dd, IH), 4.80 (d, IH), 7.23 (m, 2H), 7.31 (m, 3H).
Step 413k. fS)-4-fl-fBOC-aminoV2-methoxyethyl)-l-benzyl-2-thioxopyrrolidine
A 50 mg (0.14 mmol) sample of the compound from step 413j above and 29 mg (0.07 mmol) of Lawesson's reagent were dissolved in 0.3 mL of THF and stirred under N2 for 3 hours. The solvent was removed, and the residue was dissolved in CH2CI2 and chromatographed on siUca gel, eluting with 30% ethyl acetate:hexane. Removal of the solvent left 51 mg of product MS 365 (M+H)+; 1H NMR (CDCI3) 3: 1.41 (s, 9H), 2.64 (dd, IH), 2.87 (dd, IH), 3.16 (dd, IH), 3.29 (s, 3H), 3.36 (d, 2H), 3.55 (m, 2H), 3.70 (m, IH), 4.70 (d, IH), 4.83 (d, IH), 5.21 (d, IH), 7.33 (m, 5H).
Step 4131. fSV3-fl-fBOC-aminoV2-methoxyethylVl-benzylpyrrolidine
A 45.7 mg (0.125 mmol) sample of the compound from step 413k above and 239 mg ( 1.0 mmol) of NiC12»6H2O were dissolved in 2 mL of a 1: 1 mixture of methanol and THF, and the solution was cooled to -78°C and stirred under N2. A 114 mg (3.0 mmol) sample of NaBH4 was added in portions, and the mixture was stiired for 2 hours. The solvents were removed under vacuum, and dissolved in 20% methanol in chloroform. The solution was filtered and the solvent removed. The residue was chromatographed on sUica gel, eluting with 5%methanol in chloroform to provide 23 mg of title product MS 335 (M+H)+; *H NMR (CDCI3) 3: 1.45 (s, 9H), 2.01 (m, IH), 2.37 (m, IH), 2.49 (m, 2H), 2.61 (m, IH), 2.71 (m, IH), 3.32 (s, 3H), 3.35 (m, 2H), 3.44-3.67 (m, 4H), 7.23-7.33 (m, 5H). Step 413m. fS)-3-fl-fBOC-aιτύnoy2-methoxyethylVpyrroIidine
A 203 mg sample of the compound from step 4131 above was dissolved in 25 mL of methanol and hydrogenated at 4 Atm over 50 mg of 10% Pd/C catalyst for 22 hours. The catalyst was removed by filtration and the solvent was evaporated to give 160 mg of the title compound as a viscous oil. MS 245 (M+H)+; 1H NMR (CD3OD) 3: 1.43 (s, 9H), 1.92 (m, IH), 2.24 (m, IH), 2.43 (m, IH), 2.75 (m, IH), 2.90 (m, IH).
Step 413n. (3R, 1 S )-8-(3-( 1 -amino-2-methoxyethyl)pyrrolidinyl)- 1 -cyclopropyl- 7-fluoro-9-methyl-4-oxo-4H-quinoUzine-3-carboxylic acid hydrochloride
A 77 mg (0.238 mmol) sample of 8-chloro-l-cyclopropyl-7-fluoro-9-methyl-4- oxo-4H-quinolizine-3-carboxyUc acid ethyl ester, from Example 253i above, was reacted with the (S)-3-(l-(BOC-amino)-2-methoxyethyl)-pyrroUdine from step 413m above and carried forward as described in Example 253 steps j-1, to give 62 mg of the title product, mp. 62-64°C. HRMS calc: 404.1986; found: 404.1990 (M+H)+; 1H NMR (D6-DMSO) 3: 0.60 (m, 2H), 0.94, (m, IH), 2.13 (m, IH), 2.28 (m, 2H), 2.61 (s, 3H), 3.26 (s, 3H),
3.52 (m, 2H), 3.62 (dd, IH), 3.71 (m, 2H), 3.91 (m, IH), 7.91 (s, IH), 8.10 (br, 2H),
9.08 (d, IH).
Example 414
8-(3-(S)-(acetylamino)pyrrolidinyl)- 1 -cyclopropyl- 7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid
To a 290 mg sample of 8-(3-(S)-aminopyrroUdinyl)-l-cyclopropyl-7-fluoro-9-methyl-4- oxo-4H-quinolizine-3-carboxyUc acid, prepared from the HCI salt of Example 257 above, suspended in 4 mL of THF was added 0.342 mL of acetic anhydride dropwise with stirring. The reaction mixture was stirred for 3.5 hours, and the precipitate was separated by filtration dried under vacuum to give 196 mg of the title compound, mp. 116-117°C. MS 388 (M+H)+; !H NMR (CDCI3) 3: 0.65 (m, IH), 0.80 (m, IH), 1.00 (m, IH), 1.10 (m, IH), 2.03 (s, 3H), 2.20 (m, 2H), 2.35 (m, IH), 2.60 (s, 3H), 3.73 (m, 2H), 4.10 (m, 2H), 4.60 (m, IH), 7.48 (d, IH, J=6 Hz), 7.75 (s, IH), 8.83 (d, IH, J=12 Hz), 13.95 (s, IH). Analysis calculated for C20H22FN3O4.I.5 H2O: C, 58.60; H, 6.02; N, 10.25. Found: C, 58.89; H, 5.85; N, 10.02. Example 415
8-(3-carbamoylpiperidinyl)- 1 -cyclopropyl-7-fluoro- 4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid
Step 415a. 8-(3-carbamoylpiperidinyl)-l -cyclopropy 1- 7-fluoro-4H-9-methyl-4-oxo-quinoUzine-3-carboxylic acid, ethyl ester
A 971 mg sample of 8-chloro-l -cyclopropy 1-7-fluoro- 9- methyl-4-oxo-4H- quinoUzine-3-carboxyUc acid ethyl ester, prepared as in Example 253i above, was dissolved in 10 mL of DMF and placed in an oven-dried system under positive N2 atmosphere. To this was added 1.15 g of nicotinamide (Aldrich) and 0.900 mL of triethylamine. The reaction mixture was heated at 55°C with stirring for 24 hours. The reaction was quenched with water, and the mixture was extracted with methylene chloride. After washing with water, the organic solution was dried over Na2SO4 and fUtered. The solvent was removed under vacuum to give the title compound as a yellow solid (1.138 g).
Step 415b. 8-(3-carbamoylpiperidinyl)-l -cyclopropy 1- 7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxyhc acid
A 442 mg sample of the compound from step 415a above was hydrolyzed with
LiOH in TΗF/H2O and the titie product (308 mg) was isolated as described in Example 253 k. mp. 250-251°C. MS 388 (M+H)+; JH NMR (CDCI3) 3: 0.70 (m, 2H), 1.05 (m,
2H), 1.85 (m, 2H), 2.20 (m, 2H), 2.60 (m, IH), 2.72 (s, 3H), 3.25-3.50 (m, 4H), 3.60
(m, IH), 5.35 (s, IH), 5.80 (s, IH), 5.80 (s, IH), 8.25 (s, IH), 9.30 (d, IH, J=14 Hz),
13.90 (s, IH). Analysis calculated for C20H22FN2O4O.75 H2O: C, 59.92; H, 5.91; N,
10.48. Found: C, 60.18; H, 5.89; N, 10.62.
Example 416
8-(3-hydroxypiperidinyl)- 1 -cyclopropyl-7-fluoro- 4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid
A 2.0 g sample of 8-chloro-l-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H- quinoUzine-3-carboxyUc acid ethyl ester, prepared as in Example 253i above, was dissolved in 25 mL of DMF and placed in an oven-dried system under positive N2 atmosphere. To this was added 1.1 g of 3-hydroxypiperidine (Aldrich) and 1.8 mL of triethylamine. The reaction mbcture was heated at 55°C with stirring for 144 hours. The reaction was quenched with water, and the mixture was extracted with methylene chloride. After washing with water, the organic solution was dried over Na2SO4 and fUtered. The solvent was removed under vacuum to give the intermediate ester compound as an oU (3 g). MS 389 (M+H)+. This ester was purified by chromatography on sUica gel, after which the intermediate was hydrolyzed and the product isolated (1.34 g) as described in Example 415 above, mp. 232-233°C. MS 361 (M+H)+; 1H NMR (CDCI3) 3: 0.70 (m, 2H), 1.03 (m, 2H), 1.75 (m, 2H), 1.90 (m, IH), 2.08 (m, 2H), 2.28 (m, IH), 2.81 (s, 3H), 3.25 (m, 2H, J=3, 9 Hz), 3.38 (m, 2H), 3.62 (d, IH, J=12 Hz), 3.95 (s, IH), 4.70 (br s, IH), 8.32 (s, IH), 9.20 (d, IH, J=9 Hz), 14.90 (s, IH). Analysis calculated for Ci9H2lFN2θ4« H2O: C, 60.31; H, 6.13; N, 7.40. Found: C, 59.92; H, 5.79; N, 7.14.
Example 417
8-(3-hydroxymethylp_peridinyl)- 1 -cyclopropyl- 7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid
A 0.971 g sample of 8-chloro- l-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H- quinoUzine-3-carboxyUc acid ethyl ester, prepared as in Example 253i above, was dissolved in 10 mL of DMF and placed in an oven-dried system under positive N2 atmosphere. To this was added 1.04 g of 3-piperidinemethanol (Aldrich) and 0.900 mL of triethylamine. The reaction mixture was heated at 55°C with stirring for 72 hours. The reaction was quenched with water, and the mixture was extracted with methylene chloride. After washing with water, the organic solution was dried over Na2SO4 and fUtered. The solvent was removed under vacuum to give the intermediate ester compound as an oil (1.25 g). MS 403 (M+H)+. This ester was purified by chromatography on silica gel, after which the intermediate was hydrolyzed and the product isolated (785 mg) as described in Example 415 above, mp. 133-134°C. MS 375 (M+H)+; 1H NMR (CDCI3) 3: 0.70 (m, 2H), 1.03 (m, 2H), 1.30 (m, IH), 1.58 (m, 2H), 1.75-2.08 (m, 3H), 2.13 (m, IH), 2.90 (s, 3H), 3.15 (m, IH, J=1.5, 9 Hz), 3.30 (m, IH, J=1.5, 9 Hz), 3.50 (m, IH), 3.60 (m, IH), 3.70 (m, 2H), 8.30 (s, IH), 9.15 (d, 1H< J=10 Hz), 13.92 (s, IH). Analysis calculated for C20H23FN2O4. 0.25 H2O: C, 63.40; H, 7.39; N, 6.24. Found: C, 63.25; H, 7.29; N, 6.25.
Example 418
8-(3-(R)-hydroxypiperidinyl)- 1 -cyclopropyl- 7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid
A 0.971 g sample of 8-chloro-l-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H- quinoUzine-3-carboxyUc acid ethyl ester, prepared as in Example 253i above, was dissolved in 10 mL of DMF and placed in an oven-dried system under positive N2 atmosphere. To this was added 1.23 g of 3-(R)-(+)-hydroxypiperidine (Aldrich) and 0.900 mL of triethylamine. The reaction mixture was heated at 55°C with stirring for 72 hours. The reaction was quenched with water, and the mixture was extracted with methylene chloride. After washing with water, the organic solution was dried over Na2SO4 and fUtered. The solvent was removed under vacuum to give the intermediate ester compound as an oil (1.56 g). This ester was purified by chromatography on siUca gel, after which the intermediate was hydrolyzed and the product isolated (785 mg) as described in Example 415 above, mp. 192-193°C. MS 361 (M+H)+; 1H NMR (CDCl3) 3: 0.70 (m, 2H), 1.02 (m, 2H), 1.75 (m, 2H), 1.90 (m, IH), 2.05 (m, IH), 2.28 (m,
IH), 2.80 (s, 3H), 3.20 (m, 2H, J=2, 9 Hz), 3.38 (m, 2H), 3.62 (dt, IH, J=12, 1.5 Hz), 3.90 (m, IH), 4.60 (br s, IH), 8.34 (s, IH), 9.20 (d, IH, J=10 Hz), 13.85 (s, IH). Analysis calculated for C19H21FN2O4. 1.25 H2O: C, 59.60; H, 6.19; N, 7.32. Found: C, 59.30; H, 5.94; N, 7.29.
Example 419
(3R)-9-fiuoro-3-methyl- 10-(piperazin- 1 -yl)-2H, 3H, 6H-6-oxo-pyτanor2.3.4-ij1quinolizine-5-carboxylic acid hydrochloride
FoUowing the procedure of Example 28 If, replacing the 3-(BOC- amino)pyrrolidine of that step with N-BOC-piperazine and carrying the product forward according to steps 28 lg and h, the title compound was prepared. MS 348 (M+H)+; 1H NMR (DMSO-d6) 3: 12.9 (d, J=7 Hz, 3H), 3.25 (m, 4H), 3.31 (m, IH), 3.70 (m, 4H), 4.19 (dd, J=6, 11 Hz, IH), 4.37 (dd, J=4, 11 Hz, IH), 8.03 (s, IH), 9.04 (d, J=9 Hz, IH), 9.12 (br s, 2H). Analysis calculated for CπHi8FN3θ4* 2.0 H2O: C, 48.63; H, 5.52; N, 10.01. Found: C, 48.92; H, 5.57; N, 9.80.
Example 420 l-cyclopropyl-8-(S,S-2,8-diaza-8-bicyclo[4.3.0]nonyl)- 7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid hydrochloride
Step 420a. 6-fl-fS)-phenylethvI))-5.7-dihvdro-6H-pyrrolor3.4-b1pyridine-5.7-dione A 10 g sample of 2,3-pyridinedicarboxyUc anhydride (Aldrich) was dissolved in 100 mL of anhydrous THF and cooled to 0°C. To this solution was added 8.70 mL of (S)- (-)-alpha-methylbenzylamine. The solution was warmed to room temperature and stirred for 30 minutes, then 11.96 g of 1 , l'-carbonyldiimidazole was added. The reaction was stirred at room temperature under N2 for 20 hours. The solvent was removed, and the residue was dissolved in methylene chloride. The solvent was washed with water and dried over MgSO The solvent was removed under vacuum to give 15.344 g of the titie compound.
Step 420b. 8-fl-fSVphenylethylV2.8-diazobicvcloI4.3.01nonan-7.9-dione
A 15.344 g sample of the compound from step 420a above was hydrogenated in over Pd/C in 2-methoxyethanol at 4 atm H2 and 100°C for 22 hours. The catalyst and solvent were removed to give 10.12 g of the title compound.
Step 420c. 8-ffl-fSVphenylethylV2.8-diazobicvclor4.3.01nonane
A 10.12 g sample of the compound from step 420b was dissolved in 30 mL of THF, and this solution was added dropwise to a suspension of 3.13 g of LAH in 50 mL of anhydrous THF stirred at 0°C under N2- After addition was complete, the mixture was heated at reflux for 9 hours. The reaction was quenched at 0°C by sequential addition of 25 mL of H2O, 25 mL of 15% KOH and 25 mL of H2O. The solids were removed by filtration, and the filtrate was extracted with ether. The extract was dried over MgSO4, and the solvent was removed to give 7.98 g of the title compound.
Step 420d. 2-BOC-8-ffl-fSVphenvIethylV2.8-diazohicvclor4.3.01nonane
A 7.98 g sample of the compound from step 40c above was dissolved in 75 mL of 2:1 methanol:H2θ. The solution was cooled to 0°C, and 7.94 g of di-t-butyl dicarbonate was added. The mixture was then warmed to room temperature and stirred for 1 hour. The organic solvent was removed under vacuum, and the residue was slurried with methylene chloride. The organic phase was separated, washed and dried. The solvent was removed, and the residue was purified by chromatography on sUica gel, eluting with 100:5:0.5 methylene chloride:methanol:ammonium hydroxide, to give 4.6 g of the title compound as an oil. This material was separated into the 1,6-(R,R)- and 1,6-(S,S)- isomers by HPLC using a chiral support. The R,R- isomer had an [a]D of +31.9°C (23°, c=1.01, methanol); The S,S-isomer had an [a]D of -84.6°C (23°, c=1.04, methanol) (for additional information on assignment of isomers, refer to Poster #642, ICAAC 32nd Annual Meeting, 1994). Step 420e. fS.SV2-BOC-2.8-diazobicvclor4.3.01nonane
A 1.328 g sample of the S,S-isomer from step 420d above and 1.27 g of ammonium formate were dissolved in 40 mL of methanol. The flask was flushed with N2, 130 mg of 10% Pd/C was added, and the reaction mixture was heated at reflux for 1.5 hours. The solution was cooled and filtered, then the solvent was removed. The residue was dissolved in methylene chloride and fUtered again. The solvent was removed under vacuum to give the title compound (858 mg). [a]D -70.8°C (23°, c=1.30, methanol).
Step 420f. l-cycloρropyl-8-(S,S-2,8-diaza-8-bicyclo[4.3.0]nonyl)- 7-fluoro-4H-9-methyl-4-oxo-quinoUzine-3-carboxylic acid hydrochloride
Following the procedure of Example 253j, substituting 1.6-f S.SV2-BQC-2.8- diazobicyclo[4.3.0]nonane from step 420e above, for the BOC-aminopyrroUdine thereof, and carrying the product forward as in steps 253k and 1, the titie compound was prepared. [a]D -281.3°C (23°, c=0.52, methanol). MS 386 (M-C1)+; lH NMR (DMSO-d6) 3: 0.56 (m, IH), 0.62 (m, IH), 0.92 (m, IH), 1.07 (m, IH), 1.61-1.81 (m, 4H), 2.30 (m, IH), 2.56 (m, IH), 2.67 (s, 3H), 2.92 (m, IH), 3.25 (m, IH), 3.69 (m, 2H), 3.90 (m, IH), 4.06 (m, IH), 4.35 (m, IH), 7.92 (s, IH), 9.02 (br, IH), 9.09 (d, J=l l Hz, IH), 9.59 (br, IH). Analysis calculated for C21H24FN3O3.HCI. 1.25 H2O: C, 56.76; H, 6.24; N, 9.45. Found: C, 56.73; H, 6.05; N, 9.44.
Example 421 l-cyclopropyl-8-(R,R-2,8-diaza-8-bicyclo[4.3.0]nonyl)- 7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid hydrochloride
Step 421a. fR.RV2-BOC-2.8-diazobicvclor4.3.01nonane
Following the procedure of Example 420e above, a 1.864 g sample of the R,R- isomer from Example 420d above deprotected to give 1.219 g of the titie product. [a]D
+73.6°C (23°, c=1.15, methanol). Spectral data simUar to the compound of Example 420e was obtained.
Step 421b. l-cyclopropyl-8-(R,R-2,8-diaza-8-bicyclo[4.3.0]nonyl)- 7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid hydrochloride
Following the procedure of Example 253j, substituting (R,R)-2-BOC-2,8- diazobicyclo[4.3.0]nonane from step 421a above, for the BOC-aminopyrroUdine thereof, and carrying the product forward as in steps 253k and 1, the title compound was prepared. [a]D +275.1°C (23°, c=0.53, methanol). MS 386 (M-C1)+. 1H NMR (DMSO-d6) 3: 0.56 (m, IH), 0.62 (m, IH), 0.92 (m, IH), 1.08 (m, IH), 1.63-1.81 (m, 4H), 2.31 (m, IH), 2.56 (m, IH), 2.68 (s, 3H), 2.91 (m, IH), 3.25 (m, IH), 3.69 (m, 2H), 3.90 (m, IH), 4.06 (m, IH), 4.35 (m, IH), 7.92 (s, IH), 9.02 (br, IH), 9.09 (d, J=l l Hz, IH), 9.60 (br, IH). Analysis calculated for C21H24FN3O3.HCI. 1.5 H2O: C, 56.19; H, 6.29; N, 9.36. Found: C, 56.19; H, 6.15; N, 9.44.
Example 422 l-cyclopropyl-8-(l-amino-3-aza-bicyclo[3.1.0]hexan-3-yl)- 7-fluoro-4H-9-methyl-4-oxo-quinoUzine-3-carboxylic acid hydrochloride
Step 422a. l-cyclopropyl-8-(l-BOC-amino-3-aza-bicyclo[3.1.0]hexan-3-yl)- 7-fluoro-4H-9-methyl-4-oxo-quinoUzine-3-carboxylic acid, ethyl ester
A 660 mg sample of 8-chloro-l-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H- quinolizine-3-carboxylic acid ethyl ester, from Example 253i above, was placed in a flask, then 400 mg of l-(BOC-amino)-3-azabicyclobicyclo[3.1.0]hexane, prepared according to U.S. Patent No. 5,164,402, was dissolved in 15 mL of dry THF and added to the flask. Lastly 2.2 mL of triethylamine was added, and the solution was stirred at 5°C for 26 hours. The reaction was cooled, quenched with 15 mL of H2O, and the mixture was extracted with ethyl acetate. The organic extracts were dried over MgSO4, and the solvent was removed under vacuum. The residue was purified by chromatography on siUca gel, eluting with 3-5% methanol in methylene chloride, to give 350 mg of the titie compound. MS 486 (M+H)+. ΪH NMR (CDCI3) 3: 0.61 (m, 2H), 0.9-1.11 (m, 4H), 1.41 (t, J=7.5 Hz, 3H), 1.48 (s, 9H), 1.8 (br, IH), 2.19 (m, IH), 2.62 (s, 3H), 3.59 (d, J=10.5 Hz, IH), 3.73 (d, J=10.5 Hz, IH), 3.8 (br, IH), 4.0 (br, IH), 4.4 (q, J=7.5 Hz, 2H), 5.05 (br, IH), 8.21 (s, IH), 9.26 (d, J=10.5, IH).
Step 422b. l-cyclopropyl-8-(l-BOC-amino-3-aza-bicyclo[3.1.0]hexan-3-yl)- 7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid
FoUowing the procedure of Example 253k, substituting the compound of step
422a for the starting material thereof, the titie compound was prepared. MS 458 (M+H)+. lH NMR (CDCI3) 3: 0.67 (m, 2H), 1.0 (m, 3H), 1.1 (m, IH), 1.48 (s, 9H), 1.82 (br, IH), 2.22 (m, IH), 2.68 (s, 3H), 3.64 (d, J=10.5 Hz, IH), 3.79 (d, J=10.5 Hz, IH), 3.85 (br, IH), 4.05 (br, IH), 5.05 (br, IH), 8.35 (s, IH), 9.14 (d, J=10 Hz, IH), 13.86 (br, IH). Step 422c. l-cyclopropyl-8-(l-amino-3-aza-bicyclo[3.1.0]hexan-3-yl)- 7-fluoro-4H-9-methyl-4-oxo-quinoUzine-3-carboxylic acid hydrochloride
FoUowing the procedure of Example 2531, substituting the compound of step 422b for the starting material thereof, the title compound was prepared. MS 358 (M+H)+. lH NMR (DMSO-d6) 3: 0.62 (m, 2H), 0.98 (m, 3H), 1.31 (m, IH), 2.04 (m, IH), 2.37 (m, IH), 2.63 (s, 3H), 3.62 (m, IH), 3.8-4.0 (m, 3H), 8.01 (s, IH), 8.81 (br, 2H), 9.16 (d, J=10, IH), 13.82 (br, IH). Analysis calculated for C19H21FN3O3.HCI. 1.5 H2O: C, 54.22; H, 5.75; N, 9.98. Found: C, 54.10; H, 5.61; N, 9.86.
Example 423
8-(3-amino-3-fluoromethyl- 1 -pyrroUdinyl)- 1-cyclopropyl- 7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid hydrochloride
Step 423a. 2-fluoromethylpropenoic acid ethyl ester
A 2.632 g (20 mmol) sample of 2-hydroxymethylpropenoic acid ethyl ester
(prepared according to Villieras and Rambaud, Synthesis, 1982, 924) was dissolved in 35 mL of methylene chloride, and the solution was cooled to -78°C. To this solution was added 2.94 mL (22 mmol) of DAST, and the reaction mixture was stirred at -78°C for 30 minutes and at room temperature for 1 hour. The reaction was quenched with H2O (35 mL), and the layers were separated. The organic solution was washed with brine, dried over MgSO4, then the solvent was removed to give 2.343 g of the title compound. 1H NMR (CDCI3) 3: 1.32 (t, J=7.5 Hz, 3H), 4.26 (q, J=7.5 Hz, 2H), 5.08 (d, J=46 Hz, 2H), 5.93 (m, IH), 6.39 (m, IH).
Step 423b. l-benzyl-3-fluoromethyl-3-pyrrolidine carboxylic acid ethyl ester
A 739 mg (6 mmol) sample of the compound from step 423a and 1.327 g (6 mmol) of N-benzyl-N-(methoxymethyl)trimethylsilylmethylamine were dissolved in 4 mL of methylene chloride. This solution was cooled to 0°C, and 0.56 mL of IN trifluoroacetic acid in methylene chloride was added slowly. The reaction mixture was stirred for 75 minutes at 0-2°C. The solution was diluted with methylene chloride and washed with saturated NaHCO3 solution and water, then dried over MgSOφ The solvent was removed, and the residue was purified by chromatography on sUica gel, eluting with 4: 1 hexane:ethyl acetate, to obtain 875 mg of the title compound. MS 266 (M+H)+. 1H NMR (CDCI3) 3: 1.27 (t, J=7.5 Hz, 3H), 1.8 (m, IH), 2.25 (m, IH), 2.51 (m, IH), 2.75 (m, 3H), 3.62 (s, 2H), 4.20 (q, J=7.5 Hz, 2H), 4.45 (q, J=8.7 Hz, IH), 4.61 (q, J=8.7 Hz, IH), 7.3 (m, 5H).
Step 423c. 3-fluoromethyl-3-pyrrolidine carboxylic acid ethyl ester
A 875 mg sample of the compound from step 423b above and 1.04 g of ammonium formate were dissolved in 30 mL of ethanol. The flask was flushed with N2, 200 mg of Pd/C were added, and the mixture was heated at reflux for 15 minutes. The mixture was cooled, filter, and the solvent was removed to give 454 mg of the titie compound. MS 176 (M+H)+. 1H NMR (CDCI3) 3: 1.29 (t, J=7.5, 3H), 1.8 (m, IH), 2.15 (m, IH), 2.95 (m, 2H), 3.08 (m, IH), 3.32 (m, IH), 4.2 (q, J=7.5 Hz, 2H), 4.48 (m, IH), 4.63 (m, IH).
Step 423d. l-CBZ-3-fluoromethyl-3-pyrrolidine carboxyUc acid ethyl ester
A 450 mg sample of the compound from step 423c above was dissolved in 4 mL of 1 : 1 dioxane:water, 324 mg of Na2CO3 was added, and the solution was cooled to 0°C. To this solution was added dropwise 0.44 mL of benzyloxycarbonyl chloride, and the reaction mixture was stirred at 0°C for 45 minutes and at room temperature for 3 hours. The solution was diluted with ether, and the mixture was washed sequentiaUy with water, saturated NaHCO3, water and saturated brine. The ether layer was separated, and the solvent was removed. The residue was purified by chromatography on sUica gel, eluting with 1:3 ethyl acetate:hexane to give 666 mg of the title compound. MS 310 (M+H)+. 1H NMR (CDCI3) 3: 1.28 (t, J=7.5 Hz, 3H), 2.05 (m, IH), 2.32 (m, IH), 3.55 (m, 3H), 3.84 (dd, J=3, 12 Hz, IH), 4.22 (q, J=7.5 Hz, 2H), 4.48 (m, IH), 4.61 (m, IH), 5.14 (s, 2H), 7.35 (m, 5H).
Step 423e. l-CBZ-3-fluoromethyl-3-pyττolidinecarboxylic acid
A 550 mg sample of the compound from step 423d above was dissolved in 4 mL of THF, and the solution was cooled to 0°C. To this solution was added 173 mg of LiOH and 1 mL of H2O. The reaction mixture was stirred at room temperature for 3 hours, then acidified by the addition of IN HCI. The mixture was diluted with 40 mL of ethyl acetate, and the layers were separated. The organic solution was washed with water and saturated brine, and the solvent was removed. The residue was purified by chromatography on siUca gel, eluting with 10% methanol in methylene chloride to give 251 mg of the titie compound. MS 282 (M+H)+. 1H NMR (CDCI3) 3: 2.05 (m, IH), 2.35 (m, IH), 3.55 (m, 3H), 3.89 (m, IH), 4.5 (m, IH), 4.65 (m, IH), 5.12 (s, IH), 7.37 (m, 5H).
Step 423f. N-BOC-l-CBZ-3-fluoromethyl-3-pyrrolidineamine
A 715 mg sample of the compound from step 423e above was dried under vacuum and dissolved in 8 mL of distUled t-butanol. To this solution were added 0.71 mL of triethylamine and 0.81 mL of dppa, and the mixture was refluxed for 16 hours under a N2 atmosphere. The reaction mixture was cooled and diluted with ether, and the mixture was washed with water, saturated NaHCO3 and saturated brine. The solvent was removed, and the residue was purified by chromatography on sUica gel, eluting with 1 :4 ethyl acetate:hexane to give 587 mg of the titie compound. MS 353 (M+H)+. 1H NMR (CDCI3) 3: 1.44 (s, 9H), 2.1 (m, 2H), 3.55 (m, 4H), 4.48 (m, IH), 4.63 (m, IH), 5.12 (s, 2H), 7.35 (m, 5H).
Step 423 g. 3-fBOC-amino)-3-fluoromethylpyrrolidine
A 183 mg sample of the compound from step 423f above and 164 mg of ammonium formate were dissolved in 8 mL of ethanol. The flask was flushed with N2, 50 mg of Pd/C were added, and the mixture was heated at reflux for 20 minutes. The mixture was cooled and filtered, and the solvent was removed to give 101 mg of the titie compound. MS 219 (M+H)+. 1H NMR (CDCI3) 3: 1.45 (s, 9H), 1.6 (b, IH), 1.92 (m, 2H), 2.95 (m, 2H), 3.1 (m, 2H), 4.5 (d, J=48 Hz, IH), 4.75 (b, IH).
Step 423h. 8-(3-(BOC-amino)-3-fluoromethyl-l -pyrroUdinyl)- 1-cyclopropyl- 7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid ethyl ester
A 120 mg (0.37 mmol) sample of 8-chloro-l-cyclopropyl-7-fluoro-9-methyl-4- oxo-4H-quinoUzine-3-carboxyUc acid ethyl ester, from Example 253i above, was placed in a flask. To his flask was then added a solution of 95 mg of 3-(BOC-amino)-3- fluoromethylpyrrolidine, from step 423g above, dissolved in 3 mL of DMF, and 0.30 mL of triethylamine. The reaction mixture was heated at reflux for 16 hours, then the reaction was quenched with 4 mL of water. The mixture was cooled and extracted with ethyl acetate. The extract was dried over MgSO4, and the solvent was removed. The residue was purified by chromatography on siUca gel, eluting with 2-5% methanol in methylene chloride, to give 143 mg of the tile compound. MS 506 (M+H)+. 1H NMR (CDCI3) 3: 0.62 (m, 2H), 0.96 (m, 2H), 1.35 (m, IH), 1.42 (t, J=7.5 Hz, 3H), 1.46 (s, 9H), 2.2 (m, 2H), 2.35 (m, IH), 2.65 (s, 3H), 3.73 (m, IH), 3.85 (b, IH), 3.9 (m, IH), 4.4 (q, J=7.5 Hz, 2H), 4.65 (d, J=48 Hz, 2H), 4.85 (b, IH), 8.21 (s, IH), 9.29 (d, J=10.5 Hz, IH).
Step 423i. 8-(3-(BOC-amino)-3-fluoromethyl-l-pyrroUdinyl)-l-cyclopropyl- 7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid
FoUowing the procedure of Example 253k, substituting 143 mg of the compound of step 423h for the starting material thereof, 115 mg of the title compound was prepared.
Step 423j. 8-(3-amino-3-fluoromethyl- 1 -pyrroUdinyl)- 1-cyclopropyl- 7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxyIic acid hydrochloride
FoUowing the procedure of Example 2531, substituting 115 mg of the compound of step 423i for the starting material thereof, 95.5 mg of the titie compound was prepared.
MS 378 (M+H)+. l NMR (DMSO-d6) 3: 0.60 (m, 2H), 1.0 (m, 2H), 2.27 (m, 2H), 2.34 (m, IH), 2.67 (s, 3H), 3.85~(m, 2H), 4.04 (m, 2H), 4.78 (d, J=46 Hz, 2H), 7.97
(s, IH), 8.91 (b, 2H), 9.13 (d, J=10.5 Hz, IH), 13.85 (b, IH). Analysis calculated for
Ci9H2lF2N3θ3'2 HCI* 0.5 H2O: C, 49.68; H, 5.27; N, 9.15. Found: C, 49.66; H,
5.23; N, 8.91.
Example 424 8-(3-aminomethyl-3-fluoro- 1 -pyrroUdinyl)- 1 -cyclopropyl-
7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid
FoUowing the procedure of Example 253j, substituting 68 mg of 3-amino-3- fluoromethylpyrrotidine, prepared as in PCT patent appUcation WO9414794, for the BOC- aminopyrroUdine thereof, and carrying the product forward as in step 253k, the title compound was prepared (note rearrangement of positions of F and amino groups on the pyrrolidine ring). MS 378 (M+H)+. 1H NMR (DMSO-d6) 3: 0.6 (m, 2H), 0.9 (m, IH), 1.05 (m, IH), 1.25 (m, IH), 2.2-2.5 (m, 2H), 2.64 (s, 3H), 3.4 (m, 2H), 3.81 (m, 2H), 4.15 (m, 2H), 7.95 (s, IH), 8.4 (b, 2H), 9.1 (d, J=10.5 Hz, IH), 10.2 (s, IH). Example 425
8-(3-(S)-hydroxy-l-pyrroUdinyl)-l-cyclopropyl- 7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid
Step 425a. fS)-l-BOC-3-pyrrolidinol
A 9.8 g (55.2 mmol) sample of (S)-l-benzyl-3-pyrroUdinol was dissolved in 200 mL of ethanol, 1.96 g of 20% Pd/C was added, and the mixture was stirred under N2. To this mixture was added 17.4 g of ammonium formate, and the reaction mixture was stirred for 10 minutes at an internal temperature of 70°C. The reaction mixture was removed for the bath and cooled until gas evolution subsided. The mixture was cooled, then dUuted with methylene chloride. The solids were removed by filtration, and the filtrate was concentrated. The residue was suspended in 200 mL of methylene chloride, and 2.07 g of di-t-butyl dicarbonate was added with stirring and while holding the temperature at 19- 23°C. The mixture was stirred at room temperature for 16 hours. The organic solvent was removed under vacuum, and the residue was slurried with methylene chloride. The organic phase was separated, washed and dried. The solvent was removed, and the residue was purified by chromatography on siUca gel to give 8.94 g of the title compound as a colorless oil.
Step 425a. 8-(3-(S)-hydroxy-l -pyrrolidinyl)- 1-cyclopropyl- 7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid
FoUowing the procedure of Example 253j, substituting (S)-l-BOC-3- pyrroUdinol, from step 425a above, for the BOC-aminopyrrolidine thereof, and carrying the product forward as in step 253k, the title compound was prepared, mp. 240°C. MS 347 (M+H)+. lH NMR (DMSO-d6) 3: 0.6 (m, 2H), 0.95 (m, IH), 1.05 (m, IH), 2.0 (m, 2H), 2.3 (m, IH), 2.6 (s, 3H), 3.4 (d, IH), 3.7 (m, IH), 4.0 (m, 2H), 4.4 (br s, IH), 5.65 (d, IH), 7.9 (s, IH), 9.05 (d, IH), 18.5 (s, IH). Analysis calculated for C18H19FN2O4: C, 62.42; H, 5.53; N, 8.09. Found: C, 62.34; H, 5.38; N, 7.99.
Example 426
8-(3-(R)-hydroxy-l-pyιτoUdinyl)-l-cyclopropyl-7-fluoro- 4H-9-methyl-4-oxo-quinoUzine-3-carboxylic acid
FoUowing the procedures of Example 425, replacing the (S)- l-benzyl-3- pyrroUdinol with (R)-l-benzyl-3-pyrrolidinol, the title compound was prepared. mp.240°C. MS 347 (M+H)+. 1H NMR (DMSO-d6) 3: 0.6 (m, 2H), 0.95 (m, IH), 1.05 (m, IH), 2.0 (m, 2H), 2.3 (m, IH), 2.6 (s, 3H), 3.4 (d, IH), 3.7 (m, IH), 4.05 (m, 2H), 4.45 (br s, IH), 5.65 (d, IH), 7.9 (s, IH), 9.05 (d, IH), 18.5 (s, IH). Analysis calculated for C18H19FN2O4: C, 62.42; H, 5.53; N, 8.09. Found: C, 62.54; H, 5.56; N, 7.96.
Example 427
8-(7-(S)-amino-5-aza-spiro[2.4]heptan-5-yl)-l-cyclopropyl- 7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid hydrochloride
Step 427a. 7-amino-5-f 1 -fR phenylethv ^-oxo-S-azaspiroIΣ^lheptanes
Following the procedure of Kimura et al., J. Med. Chem., 22:3344-3352 (1994) the titie compound was prepared. The diastereomeric product was purified by chromatography on sUica gel, which resolved the compound into its 7-(S)- and 7-(R)- diastereomers. The 7-(S)- compound (the less polar isomer) was carried forward to the next step. The 7-(R)- compound was carried forward to the Example 428.
Step 427b. 7 fSVamino-5-fl-fRVphenylethylV5-azaspiroI2.41heptane
A sample of 7-(S)-amino-5-(l-(R)-phenylethyl)-4-oxo-5-azaspiro[2.4]heptane
(from step 427a, 15.3 g, 66.5 mmol, in freshly distilled THF (200 mL) was added dropwise to a cooled (ice bath) suspension of LAH (7.42 g) in dry THF (300 mL). The reaction was stirred and aUowed to warm to room temperature after addition of the starting material, then heated at reflux under N2 for 4 hours. The mixture was cooled to0°C, the H2O (7.5 mL), 20% NaOH (7.5 mL and H2O (22 mL) were added sequentially, with stirring, and the mixture was stirred at room temperature for 1 hour. The mixture was filtered, and the filter cake washed repeatedly. The combined filtrates were concentrated to afford the title compound as an oil (14.75 g). MS m/z 217 (M+H)+. Step 427c. 7-fS)-fBOC-aminoV5-fl-fRVphenylethyD-5-azaspiror2.41heρtane
The compound from step 427b (14.75 g, 79.8 mmol) was dissolved in methylene chloride (90 mL) and cooled, (BOQ2O was added in portions and the mixture was stirred at room temperature for 2 hours. The mixture was washed with water and brine, dried (MgSO4), filtered, and concentrated. The residue was purified by chromatography on siUca gel, eluting with 25% ethyl acetate in hexane to afford 18.1g white solid, 86% yield from lactam. X-ray crystallography confirms that it is an S-isomer at the pyrrolidine ring juncture. MS m/z 317 (M+H)+; NMR, (CDC13) ppm, 0.38(m, IH); 0.54(m, IH); 0.68(m, IH); 0.76(m, IH); 1.35(d,3H); 1.43(s, 9H); 2.30(d, IH); 2.48(d, IH); 2.79(d, 2H); 3.21(q, IH); 3.81(q, IH); 4.94(d, IH); 7.20-7.34(m, 5H)
Step 427d. 7-fS)-fBOC-amino)-5-azaspirol2.41 heptane
The 7-(S)-compound from step 427c was dissolved in ethanol and hydrogenated at 4 atm H2 over Pd/C at room temperature for 23 hours. The mixture was filtered, and the filtrate was concentrated. The residue was purified by chromatography on sUica gel, eluting with 15:85 ethyl acetate:hexane to give the title compound. MS m/z 213 (M+H)+.
Step 427e. 8-(7-(S)-(BOC-amino)-5-aza-spiro[2.4]heptan-5-yl)- l-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinoUzine-3-carboxylic acid
FoUowing the procedure of Example 253j, substituting the compound from step 427d above, for the BOC-aminopyrrolidine thereof, and carrying the product forward as in step 253k, the title compound was prepared.
Step 427f. 8-(7-(S)-amino-5-aza-spiro[2.4]heptan-5-yl)-l-cyclopropyl- 7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid hydrochloride
120 ml of IM HCI in acetic acid was added dropwise to the solution of the acid (18.57g; 39.43 mmol) in methyl chloride (80ml). The slightly reddish solution was stirred at room temperature for 1.5 hours. Yellow precipitate observed. TLC checked (4% MeOH/CH2θ2) showed no starting material. The solid was fUtered and washed several times with ether, dried at room temperature at 15mm Hg overnight obtained lOg of yellow solid. The filtrate was concentrated and dried on high vacuum (0.5 mmHg) for 2 hours and then titurated with ether. The solid thus obtained was stirred vigorously in ether, filtered and washed with ether, obtaining 4.6g of sUghtly brownish soUd. The two solid samples were combined and analyzed. MS 372 (M+H)+. NMR (DMSO) ppm: 0.49-1.18 (m, 8H); 2.29 (m, IH); 2.65 (s, 3H); 3.48 (m, IH); 3.81 (d, IH); 4.41 (m,2H); 7.93 (s,lH); 9.11 (d,lH); 13.83 (b, IH). Analysis calculated for C20H23N3O3FCI.H2O. C, 56.17; H, 5.31; N, 9.64. Found: C, 56.40; H, 5.91; N, 9.86.
Example 428 8-(7-(R)-amino-5-aza-spiro[2.4]heptan-5-yl)-l-cyclopropyl-
7-fluoro-4H-9-methyl-4-oxo-quinoUzine-3-carboxylic acid hydrochloride
FoUowing the procedure of Example 427b, substituting the 7-(R)-(BOC-amino)- 4-oxo-5-azaspiro[2.4]heptane, from step 427a, for the 7-(S)-isomer thereof, and carrying the product forward as in steps 427b-f, the tifle compound was prepared, mp. 200°C (dec). MS 372 (M+H)+. 1H NMR (DMSO-d6) 3: 0.6 (d, 2H), 1.0 (t, 2H), 1.1 (t,
2H),1.15 (t, IH), 2.15 (m, 2H), 2.3 (m, IH), 2.6 (s, 3H), 2.8 (br m, IH), 3.65 (m, IH), 3.8 (m, 2H), 4.15 (m, IH), 7.9 (s, IH), 8.6 (br s, 2H), 9.1 (d, IH) 13.85 (br s, IH). Analysis calculated for C20H22FN3O3.HCI.2 H2O: C, 54.12; H, 6.13; N, 9.47. Found: C, 54.21; H, 5.85; N, 9.38.
NMR (DMSO) ppm: 0.5-1.179 (m,8H); 2.31 (m, IH); 2.65 (s,3h), 3.51
(b,lH); 3.71 (d, IH); 4.34-4.47 (m, 2H); 7.95 (s,lH); 9.11 (d, IH); 13.82 (b.lH)
Example 429
8-(3-(R*)-(l-(S*)-amino-2,2,2-trifluoroethyl)pyrrolidinyl)- 1 -cvclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid hydrochloride
Step 429a. 1 -benzyl-3-f 1 -hydroxy-2.2.2-rrifluoroethylidene)-2-pyrrolidone
A 1.2 g sample of NaH was suspended in 30 mL of dry THF, and this suspension was stirred at room temperature. To this was added 3.5 g of 1 -benzyl -2- pyrrolidone (Aldrich), and the mixture was stirred at 65°C. To this mixture was next added 3.6 mL of ethyl trifluoroacetate in 10 mL of THF over a 25 minute period, and the reaction was heated at reflux for 3 hours. The reaction mixture was cooled, dUuted with ether and neutralized with 1 N HCI. The ether layer was separated, washed with brine, dried and taken to dryness. The residual oil was chromatographed on siUca gel, eluting with 1 : 1 ethyl acetate: hexane to give 2.06 g of the titie compound. MS 289 (M+H)+.
Step 429b. 1 -benzyl-3-f l-hydroxyimino-2.2.2-trifluoroethyl)-2-pyrrolidone
A 2.0 g sample of the compound from step 429a, 7.6 g of hydroxylamine HCI, 20 mL of pyridine and 40 mL of ethanol was heated at reflux for 4 hours. The solvents were removed under vacuum, and the residue was dissolved in methylene chloride. The solution was washed with water and brine, then dried and the solvent evaporated. The residue was azeotropically distiUed with toluene to remove the pyridine to give after drying 1.30 g of title compound. MS 287 (M+H)+.
Step 429c. l-benzyl-3-f l-amino-2.2.2-trifluoroethyl)-2-pyrrolidme
A 1.3 g sample of the compound from step 429c was dissolved in 20 mL of
THF, and 10 mL of IM LAH in THF was added. The mixture was heated at reflux for 4 hours. The reaction was quenched while stirring under a N2 atmosphere by the sequential addition of 0.4 mL H2O, 0.4 mL of 15% NaOH and 1.2 mL of H2O. The suspension was filtered, and the filtrate was washed with brine, dried and evaporated. The residue was then purified by chromatography on siUca gel, eluting with 5:95 methanokmethylene chloride to give 943 mg of titie compound. MS 259 (M+H)+.
Step 429d. 1 -benzyl-3-f l-fBOC-aminoV2.2.2-trifluoroethylV2-pyrroUdine
A 0.94 g sample of the compound from step 429c was dissolved in 5 mL of methylene chloride, and 0.8 g of di-t-butyl dicarbonate in 1 mL of methylene chloride was added. The mixture was stirred at room temperature for 16 hours. Another 0.4 g of di-t- butyl dicarbonate was then added, and the reaction was stirred for 24 hours. The solvent was removed, and the residue was chromatographed on sUica gel, eluting with 25:75 ethyl acetate:hexane. The product was resolved into two diastereomers by chromatography (they were arbitrarily assigned the relative stereochemistry 1S*,3R* and 1S*,3S*). Carrying the 1 S*,3R* compound forward the title compound was prepared.
Step 429e. 3-f l-fBOC-aminoV2.2.2-trifluoroethylV2-pyrrolidine
A 1.49 g sample of the compound from step 429d was dissolved in 100 mL of methanol, 0.9 g of 10% Pd/C was added, and the mixture was hydrogenated under 4 atm of H2 for 44 hours. The mixture was filtered, the filtrate was concentrated. The residue was triturated with acetonitrile, then filtered. The filtrate was concentrated to give 1.035 g of the title compound. MS 269 (M+H)+. Step 429f. 8-(3-(R*)-(l-(S*)-amino-2,2,2-trifluoroethyl)pyrrolidinyl)- l-cyclo-propyl-7-fluoro-4H-9-methyl-4- oxo-quinoUzine-3-carboxyUc acid hydrochloride
FoUowing the procedure of Example 253j, substituting the compound from step 429e above, for the BOC-aminopyrroUdine thereof, and carrying the product forward as in step 253k, then removing the BOC-group by hydrolysis as in Example 2531,with IN HCI in acetic acid, mp browned 160-163°C, decomposed at 180-183°C. MS 428 (M+H)+. 1H NMR (DMSO-d6) 3: 0.6 (d, 2H), 0.9 (m, IH), 1.1 (m, IH), 1.9 (m, IH), 2.3 (m, IH), 2.6 (s, 3H), 2.75 (m, IH), 3.7 (m, 2H), 4.0 (m, 2H), 4.4 (m, IH), 7.9 (s, IH), 9.1 (d, IH). Analysis calculated for C20H21F4N3O3.HCI.2 H2O: C,48.05; H, 5.24; N, 8.41. Found: C, 48.45; H, 5.20; N, 8.50.
Example 430
8-(3-(S *)-( 1 -(S *)-amino-2,2,2-trifluoroethyl)pyrrolidinyl)- 1 -cvclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid hydrochloride
Carrying the 1S*,3S* compound from Example 429d above forward as in Examples 429e and 253j, k and 1 the title compound was prepared, mp browned 205°C, melted at 213°C. MS 428 (M+H)+. 1H NMR (DMSO-d6) 3: 0.6 (d, 2H), 1.0 (m, 2H), 2.0 (m, IH), 2.3 (m, IH), 2.65 (s, 3H), 2.75 (m, IH), 3.75 (m, 2H), 4.0 (m, 2H), 4.4 (m, IH), 7.9 (s, IH), 9.1 (d, IH). Analysis calculated for C20H21F4N3O3.HCI.2.5 H2O: C47.20; H, 5.34; N, 8.26. Found: C, 47.14; H, 4.91; N, 8.55.
Example 431 8-(3-aminoxypyιτolidinyl)- 1 -cyclopropyl-7-fluoro-4H-
9-methyl-4-oxo-quinolizine-3-carboxylic acid hydrochloride
Step 4 1 a. 1 -BOC-3-pyrrolidinol
To a solution of 3.25 g of 3-pyrrolidinol in 25 mL of methylene chloride was added, with cooling, 5 mL of methylene chloride containing 8.2 g of di-t-butyl dicarbonate, and the mixture was stirred for 4 hours. The volatiles were removed under vacuum, and the residue was chromatographed on sUica gel, eluting with 7% methanol in methylene chloride to give 7.64 g of the title compound. Step 431b. N-fl-BOC-3-pyπ-oHdinoxy phthaUmide
To 50 mL of dry THF were added 5.17 g of the compound from 431a above, 9.7 g of triphenylphosphine, and 5.41 g of N-hydroxyphtahalimide. To this suspension, stirred and cooled to -20°C, was added 5.83 mL of DEAD, and the mixture was stirred for 1 hour at -20°C. The solution was quenched with water, then extracted with methylene chloride. The organic layer was dried and concentrated. The residue was chromatographed on sUica gel, eluting with 40:60 ethyl acetate:hexane to give 7.60 g of the title compound.
Step 431c. fl-BOC-3-pyrrolidinoxy amine
To a solution of 7.4 g of the compound from step 43 lb in 100 mL of methylene chloride was added 2.6 mL of hydrazine hydrate. The mixture was stirred at room temperature for 1 hour. The precipitate was removed by filtration, and the filtrate was washed with water, dried and evaporated to give 4.325 g of the title product as an oU.
S tep 431 d . 3-pyrrolidinoxyamine
A 4.318 g sample of the compound from step 431c was dissolved in 70 mL of dry methylene chloride, and 70 mL of 1 M HCI in acetic acid was added. The mixture was stirred for 30 minutes at room temperature. The precipitate was collected by filtration, washed and dried to give 3.41 g of the tile compound.
Step 431 e. 8-(3-aminoxypyrrolidinyl)- 1 -cyclopropyl-7-fluoro-4H- 9-methyl-4-oxo-quinolizine-3-carboxylic acid ethyl ester
A 0.25 g sample of the 3-pyrrolidinoxyamine from step 43 Id above and 1.06 mL of triethylamine were dissolved in 5 mL of dry THF, and the mixture was stirred at 55 °C for 7 hours. The reaction was quenched with water, and the mixture was extracted with ethyl acetate. The organic layer, wash washed with water, dried and evaporated. The residue was chromatographed on sUica gel, eluting with 100:7;0.7 methylene chloride:methanol:NH4OH to give 224 mg of the titie compound. Step 431 f . 8-(3-(BOC-aminoxy)pyrroUdinyl)- 1 -cyclopropyl- 7-fluoro-4H-9-methyl-4-oxo-quinoUzine-3-carboxylic acid ethyl ester
A mixture of 224 mg of the compound from step 43 le and 0.25 g of di-t-butyl dicarbonate were dissolved in 3 mL of methylene chloride, and the mixture was stirred for 4 days. The volatiles were removed, and the residue was taken directly to the next step.
Step 431g. 8-(3-(BOC-aminoxy)pyrroUdinyl)-l-cyclopropyl- 7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid
The material from the previous step, 4 mL of THF, 3 mL of water, 0.216 g of LiOH were combined, and the mixture was heated at 83°C for 3 hours. The mixture was acidified with IN HCI, and the precipitate was removed by filtration. The filtrate was washed with water and brine, then evaporated to give 245 mg of the title compound.
Step 431h. 8-(3-aminoxypyrrolidinyl)-l-cyclopropyl-7-fluoro- 4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid hydrochloride
A 200 mg sample of the compound from step 43 lg was dissolved in 23 mL of dry methylene chloride and treated with 1 N HCI in acetic acid at room temperature for 16 hours. The title compound was collected by filtration, washed with methylene chloride and dried, mp 158-161°C (dec). MS 362 (M+H)+. 1H NMR (DMSO-d6) 3: 0.6 (d, 2H), 0.9, (m, IH), 1.05 (m, IH), 2.3 (m, 3H), 2.6 (s, 3H), 3.65 (m, IH), 3.75 (m, IH), 4.0 (m, IH), 4.2 (m, IH), 5.0 (br s, IH), 7.9 (s, IH), 9.1 (d, IH), 11.1 (br s, 2H). Analysis calculated for Cl8H2θFN3θ4«HCi« H2O: C, 51.99; H, 5.57; N, 10.10. Found: C, 51.84; H, 5.33; N, 9.95.
Example 432
8-(3-(R)-aminoxypyrrolidinyl)- 1 -cyclopropyl-7-fluoro- 4H-9-methv1-4-oxo-quinolizine-3-carboxylic acid hydrochloride
FoUowing the procedures of Example 432, except substituting (S)-l-BOC-3- pyrrohdinol for the racemic starting material thereof, the title compound was prepared, mp 160-168°C (dec). MS 362 (M+H)+. 1H NMR (DMSO-dό) 3: 0.6 (d, 2H), 0.9, (m, IH), 1.05 (m, IH), 2.3 (m, 3H), 2.6 (s, 3H), 3.65 (m, IH), 3.8 (m, IH), 4.0 (m, IH), 4.15 (m, IH), 4.95 (br s, IH), 7.95 (s, IH), 9.1 (d, IH), 10.7 (br s, 2H). Analysis calculated for C18H20FN3O4.HCI. 0.75 H2O: C, 52.56; H, 5.51; N, 10.22. Found: C, 52.91; H, 5.57; N, 10.14. Example 433
8-(3-(S)-aminoxypyιτolidinyl)-l-cyclopropyl-7-fluoro- 4H-9-methyl-4-oxo-quinoUzine-3-carboxyUc acid hydrochloride
FoUowing the procedures of Example 432, except substituting (R)- 1 -BOC-3- pyrroUdinol for the racemic starting material thereof, the title compound was prepared, mp 160-168°C (dec). MS 362 (M+H)+. 1H NMR (DMSO-dό) 3: 0.6 (d, 2H), 0.9, (m, IH), 1.0 (m, IH), 2.3 (m, 3H), 2.6 (s, 3H), 3.65 (m, IH), 3.85 (br d, IH), 4.0 (m, IH), 4.15 (m, IH), 4.95 (br s, IH), 7.9 (s, IH), 9.1 (d, IH), 10.9 (br s, 2H). Analysis calculated for C18H20FN3O4ΗCI. 0.75 H2O: C, 52.56; H, 5.51; N, 10.22. Found: C, 52.98; H,
5.51; N, 10.16.
Example 434
8-(octahydropyrrolo[3,2-b]pyridin-l-yl)-l-cyclopropyl- 7-fluoro-4H-9-methyl-4-oxo-quinouzine-3-carboxylic acid hydrochloride
Step 434a. 3-nitro-2-pyridineacetic acid ethyl ester
A mixture of 25 g sample of diethyl malonate and 3 g of sodium was stirred at room temperature until the reaction was complete, then stirred at 120°C for 30 minutes. The mixture became a thick suspension, and 50 mL of toluene was added, followed by 17.17 g of 2-chloro-3-nitropyridine. The mixture was heated at reflux for 16 hours. The solvents were removed under vacuum, and the residue was dissolved in 50 mL of DMSO. To this solution was added 19.5 g of NaCl and 7.2 g of water, and the mixture was stirred at 160-170°C for 3 hours. The mixture was cooled and dUuted with ethyl acetate. The layers were separated, and the organic layer was washed with water, brine and dried over MgSO4. The solvent was removed, and the residue was chromatographed on siUca gel to give 11.3 g of the title compound. 1H NMR (CDCI3) 3: 8.8 (dd, IH), 8.45 (dd, IH), 7.5 (dd, IH), 6.35 (s, 2H), 4.15 (q, 2H), 1.25 (t, 3H).
Step 434b. 1.3-dihydropyrroloI3.2-blpyridin-2-one
A 6 g sample of the compound from step 434a was dissolved in ethanol and hydrogenated at 4 atm over Pd/C for 2 hours. The mixture was filtered, and the filtrate was evaporated to give the 3-amino compound. This intermediate was dissolved in 60 mL of 2 N HCI, and the solution was heated at reflux for 30 minutes. The mixture was neutralized with K2CO3 to pH7-8, and the mixture was extracted with 4:1 methylene chloride:i- propanol. The extract was dried, and the solvent was removed to give the title compound. lH NMR (CDCI3) 3: 8.05 (m, IH), 7.12 (m, 2H), 3.55 (s, 2H).
Step 434c. 4-fBOC-amino)-octahydropyιτoloI3.2-b1pyridin-2-one
A 2.8 g sample of the compound from step 434b was dissolved in 150 mL of acetic acid, and lg of PtO2 was added. The mixture was hydrogenated at 60 psi for 24 hours and at 2000 psi for 2 hours. The mixture was filtered, and the solvent was removed. The residue was dissolved in 10 mL of methanol, and 3 g NaHCO3, 5 mL of water and 6 g of di-t-butyl dicarbonate were added sequentiaUy. The mixture was stirred at room temperature for 4 hours. The mixture was dUuted with methylene chloride, .and the mixture was washed with water and brine. The solvent was dried and evaporated, and the residue was purified by chromatography on siUca gel, eluting with 7:100 methanokmethylene chloride to give 3.1 g of the title compound.
Step 434d. 4-fBOC-aminoVoctahydropyrrolor3.2-blpyridine
A 3.1 g sample of the compound from step 434c was dissolved in 20 mL of THF and heated with 2.6 g of Lawesson's Reagent at reflux for 2.5 hours. The solvent was removed, and the residue was chromatographed on siUca gel. The intermediate product thus obtained was dissolved in 40 mL of methanol, and 30 g of 50% Raney Ni in water was added. The mixture was stirred at room temperature for 30 minutes, then filtered. The solvent was removed to give 2.5 g of the title compound. 1H NMR (CDCI3) 3: 4.6-4.5 (m, IH), 4.40 (m, IH), 2.95-3.10 (m, 2H), 2.65-2.75 (m, IH), 1.90-2.0 (m, IH), 1.60- 1.70 (m, 4H), 1.45 (s, 9H), 1.30-1.40 (m, 2H).
S tep 434e. 8 -(octahydropyrrolo [3 ,2-b] pyridin- 1 -y 1)- 1 -cyclopropyl- 7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid hydrochloride
FoUowing the procedure of Example 253j, substituting the 4-(BOC-amino)- octahydropyrrolo[3,2-b]pyridine from step 434d for the BOC-amino-pyπoUdine thereof, and carrying the product forward as in steps 253k & 1, the title compound was prepared. MS 386 (M+H)+. ^H NMR (DMSO-d6) 3: 9.20 (d, IH), 8.0 (s, IH), 4.5 (m, IH), 4.40 (m, IH), 3.95 (m, IH), 3.20 (m, IH), 2.90 (m, IH), 2.70 (s, 3H), 2.4-2.6 (m, 3H), 2.10 (m, IH), 1.90 (m, 2H), 1.50 (m, 2H), 0.9-1.10 (m, 2H), 0.60 (m, 2H). Example 435
8-(trαn5-3-amino-4-fluoromethylpyrrodin- 1 -yl)- 1 -cyclopropyl- 7-fluoro-4H-9-methyl-4-oxo-quinoUzine-3-carboxylic acid hydrochloride
Step 435a. 4-fluoro-2-butenoic acid ethyl ester
A 1.6 g sample of ethyl fluoroacetate was dissolved in methylene chloride, and the mixture was cooled to -78°C. To this solution was added 1 equivalent of DIBAL (1.0 M in methylene chloride) during a 30 minute period. The reaction mixture was stirred for another 30 minutes, then the reaction mixture was warmed to room temperature and 1.1 equivalent of (triphenylphosphoran)ilidenylethyl acetate was added. The reaction mixture was stirred for 16 hours. The reaction was quenched by addition of methanol, and 5% citric acid solution. The mixture was extracted with methylene chloride, and the extract was dried and evaporated. The residue was distilled to yield a 3:1 mixture of the cis:trans isomers of the title compound.
Step 435b. l-benzyl-3-fluoromethyl-2-pyrrolidineacetic acid ethyl ester.
The compound (2.6 g, 20 mmol) from step 435a and 5 g of N-benzyl-N- (methoxymethyl)trimethylsilylamine were dissolved in 30 mL of dry methylene chloride. The solution was stirred at 0°C, and 1% trifluoroacetic acid was added dropwise. The mixture was then stiιτed for 1.5 hours at room temperature. The solvent was removed, and the residue chromatographed on stiica gel to give cis- and trans isomers of the titie compound.
Step 435c. tra/ -l-CBZ-3-fluoromethyl-2-pyrrolidineacetic acid ethyl ester.
The trans compound from step 435b was dissolved in 20 mL of ethanol, and 10 equivalents of ammonium formate and 170 mg of 10% Pd/C. The reaction mixture was heated at reflux and stirred for 30 minutes. The mixture was filtered, and the filtrate was evaporated. The residue was dissolved in 10 mL of dioxane and 2.5 mL of water, and 20% Na2CO3 was added. The mixture was cooled to 0°C, and 1.5 equivalents of benzoyloxycarbonyl chloride was added slowly. The reaction was stirred for 30 minutes, then dUuted with 100 mL of ether. The organic layer was separated, washed with brine and dried over MgSO4. The solvent was removed, and the residue was chromatographed on siUca gel to give 1.5 g of the title compound. 1H NMR (CDCI3) 3: 7.3-7.4 (m, 5H), 5.12 (s, 2H), 4.60 (m, IH), 4.10-4.20 (q, 2H), 3.60-3.90 (m, 3H), 3.30-3.40 (m,lH), 2.7-3.05 (m, 2H), 1.25 (t, 3H).
Step 435d. trα/«-2-fBOC-amino)-l-CBZ-3-fluoromethyl-pyrroUdine
A 1.5 g sample of the compound from step 435c was dissolved in 12 mL of
THF. The solution was cooled to 0°C, and 4 equivalents of LiOH in 3 mL of water were added. The mixture was stirred a 0°C for 2 hours, then diluted with water and acidified with 2 N HCI to pH 2. The mixture was extracted with ether, and the extract was washed with brine and dried. The solvent was removed, and the residue was chromatographed on sUica gel to give the intermediate acid. This compound was dissolved in 10 mL of anhydrous THF, and 1.1 equivalent of DPPA and 4 equivalents of triethylamine were added. The mixture was heated at reflux for 24 hours, then cooled. The solvent was removed, and the residue was chromatographed on siUca gel. 1H NMR (CDCI3) 3: 7.3- 7.4 (m, 5H), 5.12 (s, 2H), 6.4-4.60 ( , 3H), 4.05-4.10 (m, IH), 3.80-3.90 (m, IH), 3.65-3.75 (m, IH), 3.30-3.40 (m, IH), 3.20 (m, IH), 2.40-2.50 (m, IH), 1.95 (s, 9H).
Step 435e. traMS-2-fBOC-amino)-3-fluoromethyl-pyrrolidine
The compound from step 435d was hydrogenated with Pd/C in NMF and ethanol as in step 435c above, and the title compound was isolated.
Step 435f. 8-(trα«5-3-amino-4-fluoromethylpyrrodin-l-yl)-l-cyclopropyl- 7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid hydrochloride
Following the procedure of Example 253j, substituting the trαra-2-(BOC-amino)- 3-fluoromethyl-pyrroUdine from step 435e for the BOC-amino-pyrroUdine thereof, and carrying the product forward as in steps 253k & 1, the titie compound was prepared. MS 378 (M+H)+. 1H NMR (DMSO-d6) 3: 9.12 (d, IH), 7.95 (s, IH), 4.70-4.80 (m, IH), 4.55-4.65 (m, IH), 3.6-4.15 (m, 5H), 2.8-3.0 (m, IH), 2.65 (s, 3H), 2.3-2.4 (m, IH), 1.0 (m, 2H), 0.60 (m, 2H). Example 436
8-(cw-3-arnino-4-fluoromethylpyrrodin- 1-yl)- 1-cyclopropyl- 7-fluoro-4H-9-methyl-4-oxo-quinoUzine-3-carboxylic acid hydrochloride
FoUowing the procedure of Example 435c, replacing the trαw-isomer with the cώ-isomer from step 435b, and carrymg the product forward as in steps 435d-f, the title compound was prepared.
Example 437 8-(8-amino-6-azaspiro[3.4]oct-6-yl)- 1 -cyclopropyl-
7-fluoro-4H-9-methyl-4-oxo-quinoUzine-3-carboxylic acid hydrochloride
Step 437a. cvclobutvUdeneacetic acid ethvl ester
A 5 g sample of cyclobutanone was mixed with 1.1 equivalent of (carboethoxy- methyl)triphenylphosphorane in 20 mL of toluene. The mixture was heated at reflux for 16 hours, then filtered, and the filtrate was distiUed, with the title compound distUUng at 186- 188°C.
Step 437b. 8-(8-amino-6-azaspiro[3.4]oct-6-yl)-l-cyclopropyl- 7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid hydrochloride
FoUowing the procedures of Example 435b, replacing the compound of step 435a with the cyclobutyUdeneacetic acid ethyl ester from step 437a above, and carrying the product forward according to steps 435c-f, the titie compound was prepared. MS 386 (M+H)+. 1H NMR (DMSO-d6) 3: 9.10 (d, IH), 7.92 (s, IH), 6.1-4.25 (m, 2H), 3.9 (m, IH), 3.65-3.80 (m, 2H), 2.62 (s, 3H), 2.25-2.40 (m, IH), 1.85-2.20 (m, 3H), 0.9- 1.1 (m, 2H), 0.6 (m, 2H).
Example 438
8-(2-(R)-aminomethyl-4-(R)-hydroxypyrrolidin- 1 -yl)- 1 -cyclopropyl- 7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid hydrochloride
Step 438a. N-f f 1 -BOC^-fRVftributylsilyloxylpyiTolidinvnmethvnphthalimide
A 4.5 g (14 mmol) sample of l-BOC-2-(R)-hydroxymethyl-4-(R)-(tributyl- silyloxy)pyrrolidine, 2.50 g (17 mmol) of phthalimide and 4.46 g (17 mmol) of tiiphenylphosphine were dissolved in 30 mL of THF at room temperature. To this solution was added 2.94 g (17 mmol) of DEAD in THF dropwise, and the mixture was stirred for 3 hours. The solvent was removed under vacuum, and the residue was dissolved in 1 : 1 etheπethyl acetate. The solution was washed with water and brine and dried over MgSO4. The solvent was removed, and the residue was chromatographed on siUca gel to give the title compound.
Step 438b. N-ffl-BOC-4-fR)-hvdrox\φvιτolidinyl)methvnphthalimide
A 4.60 g sample of the compound from step 438a was dissolved in 20 mL of THF. Tetrabutylammonium fluoride (1 M in THF) was added dropwise while maintaining the solution at 0°C, the reaction was stirred at room temperature for 30 minutes. The mixture was dUuted with ethyl acetate, then washed with water, brine and dried. The solvent was removed to give the title compound.
Step 438c. N-ff4-fR)-hvdroxypyrrolidinyl)methyl)phthaUmide
A 2 g sample of the compound from step 438b was dissolved in 10 mL of methylene chloride, and 4 N HCI in dioxane was added. The mixture was stirred for 4 hours, and the product was collected by filtration.
Step 438d. N-ffl-CBZ-4-fRVhvdroxypyrrolidinyl)methvDphthaUmide
The compound from step 438c was dissolved in 10 mL of dioxane, and 3 g of
Na2CO3 was added. The mixture was stirred at 0°C for 30 minutes, then 1.1 equivalent of benzyl chloroformate was added dropwise. The reaction was stirred for 1 hour, and ethyl acetate was added. The water layer was separated, and the organic layer was washed and dried. The solvent was removed to give the title compound.
Step 438e. 2-fRVaminomethyl-l-CBZ-4-fR)-hydroxypyrrolidine
The compound from step 438d was dissolved in 20 mL of ethanol, and 1.2 equivalents of hydrazine hydrate was added. The mixture was heated at reflux for 2 hours, 6 N HCI was added, and the mixture was filtered. The filtrate was concentrated to give the title compound. Step 438f. 2-fRVfBOC-amino')methvI-l-CBZ-4-fRVhvdroxypyrrolidine
The compound of step 438e was treated with di-t-butyl dicarbonate and NaHCO3 in methanol/water as described above, to give the title compound.
Step 438g. 2-fRVfBOC-amino1methyl-4-fRVhvdroxypyrrolidine
The compound of step 438f was treated with ammonium formate and Pd/C using the procedure described above to five the titie compound.
Step 438h. 8-(2-(R)-aminomethyl-4-(R)-hydroxypyrrodin- 1 -yl)- 1 -cyclo.propyl- 7-fluoro-4H-9-methyl-4-oxo-quinoUzine-3-carboxylic acid hydrochloride
FoUowing the procedures of Example 435b, replacing the compound of step 435a with the 2-(BOC-amino)methyl-4-hydroxypyrroUdine from step 438g above, and carrying the product forward according to steps 435c-f, the titie compound was prepared. MS 376 (M+H)+. lH NMR (DMSO-d6) 3: 9.20 (d, IH), 8.0 (s, IH), 5.58 (m, IH), 4.60 (m, IH), 4.40 (m, IH), 3.88 (m, IH), 2.95 (m, 2H), 2.70 (s, 3H), 2.40 (m, 2H), 1.90 (m, IH), 0.90-1.10 (m, 2H), 0.60 (m, 2H).
Example 439
8-(3-(R)-(aminomethyl)morphoUn-l-yl)-l-cyclopropyl- 7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid hydrochloride
Step 439a. l-benzyl-3-fR)-fchloromethyl)morpholine
A 1.53 mL (10.8 mmol) sample of N-benzylethanolamine and 5.0 g (54 mmol) of (R)-(-)-epichlorohydrin were combined and heated at 40°C for 40 minutes, then the excess epichlorohydrin was removed by distiUation. The residue was dissolved in 2 mL of cone. H2SO4, and the mixture was heated at 140°C for 35 minutes. The reaction was quenched by pouring it onto ice, and the pH was adjusted with 20% NaOH to pH 10-12. The mixture was extracted with methylene chloride, and the solvent was dried, fUtered and concentrated to give the titie compound (0.971 g). MS 226 (M+H)+.
Step 439b. fRVN-ffl-benzylmorpholin-3-vDmethyl)phthalimide
A 971 mg sample of the compound from step 439a was dissolved in 20 mL of DMSO and 1.59 g of phthalimide was added. The reaction mixture was heated at 100°C for 72 hours. The reaction was quenched by pouring it into 250 mL of water. The mixture was extracted with methylene chloride, which was washed, dried and concentrated to give 1.65 g of the title compound.
Step 439c. fR)-l-benzyl-3-faminomethvDmorpholine
A 1.45 g sample of the compound from step 439b was dissolved in 30 mL of ethanol, 0.627 mL of hydrazine hydrate was added, and the mixture was stirred at room temperature for 18 hours. To this solution was added 13.2 mL of 1 N HCI, and the mixture was heated at 70°C for 6 hours. The reaction was quenched by the addition of water and fUtered. The filtrate was adjusted to pH 12 with 20% NaOH and extracted with methylene chloride. The extract was dried, filtered and concentrated to give 667 mg of the title compound. MS 207 (M+H)+.
Step 439d. fRVl-benzyl-3-fBOC-aminomethyDmoιpholine
The compound from step 439c (667 mg) was dissolved in 10 mL of methylene chloride, and the solution was cooled to 0°C. To this solution was added 0.901 mL of triethylamine, then 0.812 g of di-t-butyl dicarbonate in 4 mL of methylene chloride (dropwise). The reaction mixture was then stirred at room temperature for 20 hours. The solvent was removed, and the residue was purified by chromatography on silica gel to give 691 mg of the title compound.
Step 439e. fR)-3-fBOC-ammomethyl)morpholine
The compound from step 439d was hydrogenated in methanol over Pd/C at 4 atm at room temperature for 24 hours. The mixture was fUtered, and the solvent was evaporated to give 435 mg of the titie compound.
Step 439f. 8-(3-(R)-(aminomethyl)morphoUn-l-yl)-l -cyclopropy 1- 7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid hydrochloride
FoUowing the procedures of Example 435b, replacing the compound of step 435a with the (R)-3-(BOC-aminomethyl)morphoUne from step 439e above, and carrying the product forward according to steps 435c-f, the title compound was prepared. MS 376 (M+H)+. ! H NMR (DMSO-d6) 3: 0.66 (m, 2H), 1.04 (m, 2H), 2.41 (m, IH), 2.79 (s, 3H), 2.90 (m, IH), 3.08 (m, IH), 3.26 (m, 2H), 3.47 (m, IH), 3.57 (m, IH), 3.75 (m, IH), 3.96 (m, IH), 4.04 (m, IH), 8.01 (br s, 2H), 8.05 (s, IH), 9.25 (d, J=9 Hz, IH). Example 440
8-(3-(R)-(L-alany lamino )piperidinyl)- 1 -cyclopropy 1- 7-fluoro-4H-9-methyl-4-oxo-quinoUzine-3-carboxylic acid hydrochloride
Step 440a. 8-(3-(R)-(BOC-L-alanylamino)piperidinyl)- 1 -cyclopropyl- 7-fluoro-4H-9-methyl-4-oxo-quinoUzine-3-carboxylic acid hydrochloride
A 0.50 g sample of 8-(3-(R)-aminopiperidinyl)-l-cyclopropyl-7-fluoro-4H-9- methyl-4-oxo-quinolizine-3-carboxyUc acid hydrochloride, from Example 355 above, was dissolved in 15 mL of DMF, and the solution was cooled to 0°C. To this solution was added dropwise 0.484 mL of diisopropylethylamine, and the mixture was stirred for 10 minutes. To this solution was added 0.380 g of BOC-L-alanyl-N-hydroxy succinimide, the reaction was stirred for 20 minutes, then held without stirring at 4°C for 16 hours. This solution was poured into 150 mL of 1 N HCI, and the precipitate was collected and dried to yield 0.755 g of the title compound.
Step 440b. 8-(3-(R)-(L-alanylamino)piperidinyl)-l-cyclopropyl- 7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid hydrochloride
The compound from step 440a was stirred in 12 mL of 4 N HCI in dioxane at room temperature for 70 minutes. The solvent was removed, and the residue was triturated with ether. The soUd was collected and dried, then redissolved in ethanol, which was refiltered and dried to give 0.353 g of the title compound. MS 431 (M+H)+. 1H NMR (DMSO-d6) 3: 0.66 (m, 2H), 1.03 (m, 2H), 1.37 (d, 3H, J=7.5 Hz), 1.5-2.0 (m, 5H), 2.40 (m, IH), 2.78 (s, 3H), 3.12 (m, IH), 3.64 (m, 2H), 3.87 (m, 2H), 8.42 (d, IH, J=7.5 Hz), 9.22 (d, IH, J=7.5 Hz), 13.86 (s, IH). Analysis calculated .1.5H2O: C, 53.49; H, 6.12; N, 11.34. Found: C, 53.25; H, 6.15; N, 11.34.
Example 441
8-(3-(5-aminooctahydroindol- 1 -yl)- 1 -cyclopropy 1- 7-fluoro-4H-9-rnethyl-4-oxo-quinolizine-3-carboxylic acid hydrochloride
Step 441a. 5-aminooctahvdroindole
A 1.0 g sample of 5-aminoindole was hydrogenated at 4 atm H2 in 50 mL of acetic acid over 2 g of Pt2O at room temperature for 90 hours. The solution was filtered, and the solvent was removed. Step 441b. 8-(3-(5-aminooctahydroindol-l-yl)-l -cyclopropy 1- 7-fluoro-4H-9-methyl-4-oxo-quinoUzine-3-carboxyUc acid ethyl ester
FoUowing the procedure of Example 253j, substituting the 5- aminooctahydroindole from step 441a for the BOC-amino-pyrrolidine thereof, the titie compound was prepared.
Step 441c. 8-(3-(5-aminooctahydroindol-l-yl)-l-cyclopropyl- 7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid hydrochloride
The compound was from step 441b was treated with di-t-butyl dicarbonate in the presence of triethylamine. The resulting intermediate was treated with LiOH to hydrolyze the ester. The carboxylic acid compound was deprotected with HCI in dioxane, and the titie compound was isolated (0.136 g). MS 400 (M+H)+. 1H NMR (DMSO-d6) 3: 0.64 (m, 2H), 1.09 (m, 2H), 1.35 -3.04 (m, 11H), 2.12 (m, IH, 2.66 (s, 3H), 4.07 (m, 2H), 4.28 (m, 2H), 8.04 (s, IH), 9.18 (d, J=10.5, IH), 13.86 (s, IH). Analysis calculated for C22H27C.FN3O3.2H2O: C, 55.99; H, 6.41; N, 8.90. Found: C, 56.08; H, 6.45; N, 8.40.
Example 442 8-(3-(2-piperidyl)piperidin- 1 -yl)- 1 -cyclopropyl-7-fluoro-4H-
9-methyl-4-oxo-quinolizine-3-carboxylic acid hydrochloride
Step 442a. 1 -Boc-2-f 3-pyridyl)piperidine
Anabasine (0.300 g, Aldrich) was treated with di-t-butyl dicarbonate and triethylamine in methylene chloride for 5 hours. The reaction was quenched with water, and the mixture was extracted with methylene chloride. The extract was washed, dried and concentrated. The residue was purified by chromatography on sUica gel to give 0.36 g of the title compound.
Step 442b. l-BOC-2-f3-ρiperidvnpiperidine
The compound of step 442a was dissolved in 25 mL of acetic acid and hydrogenated under 4 atm of H2 over 0.36 g Pt2O for 17 hours. The mixture was filter, the solvent was removed, and the titie compound was dried under vacuum. Step 442c. 8-(3-(2-piperidyl)piperidin-l-yl)-l -cyclopropy 1- 7-fluoro-4H-9-methyl-4-oxo-quinoUzine-3-carboxylic acid hydrochloride
FoUowing the procedure of Example 253j, substituting the l-BOC-2-(3- piperidyl)piperidine from step 442b for the BOC-amino-pyrrolidine thereof, and carrying the product forward as in steps 253k & 1, the title compound was prepared. MS 465
(M+H)+. 1H NMR (DMSO-d6) 3: 0.72 (m, 2H), 1.07 (m, 2H), 1.52 (m, 2H), 1.79 (m, 3H), 1.97 (m, 3H), 2.28 (m, 2H), 2.38 (m, IH), 2.82 (m, 3H), 2.92 (m, 2H), 3.22 (m, 2H), 3.42 (m, 2H), 3.87 (m, 2H), 8.04 (s, IH), 9.05 (m, IH), 9.45 (m, IH). Analysis calculated for C24H32CIFN3O3: C, 62.13; H, 6.73; N, 9.06. Found: C, 61.49; H, 6.68; N, 8.91.
Example 443
8-(5-amino-decahydroisoquinoUn-2-yl)- 1 -cyclopropyl- 7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid hydrochloride
Step 443a. 5-amino-decahvdroisoquinoline
A 2 g sample of 5-aminoisoquinoline (Aldrich) was dissolved in 100 mL of methanol and hydrogenated at 4 atm of H2 at room temperature for 6 days over 0.9 g of 5% Rh/C. The mixture was filtered, and the solvent was removed to give the title compound.
Step 443b. 8-(5-amino-decahydroisoquinolin-2-yl)-l-cyclopropyl- 7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid hydrochloride
FoUowing the procedure of Example 253j, substituting the 5-amino- decahydroisoquinoUne from step 442b for the BOC-amino-pyrroUdine thereof, the condensed ester was produced. This compound was treated with di-t-butyl dicarbonate in the presence of triethylamine. The resulting intermediate was treated with LiOH to hydrolyze the ester. The carboxylic acid compound was deprotected with HCI in dioxane, and the title compound was isolated. MS 414 (M+H)+. 1H NMR (DMSO-d6) 3: 0.67 (m, 2H), 1.03, m, 2H), 1.30-2.25 (m, 11H), 2.40 (m, 1H),2.76 (s, 3H), 3.45-3.70 (m, 4H), 9.00 (m, IH), 9.20 (m, IH). Analysis calculated for C23H28FN3O3.HCl.H2O: C, 59.03; H, 6.46; N, 8.98. Found: C, 58.91; H, 6.77; N, 9.37. Example 444
8-(2,7-diazabicyclo[3.3.0]oct-7-yl)-l-cyclopropyl- 7-fluoro-4H-9-methyl-4-oxo-quinoUzine-3-carboxylic acid hydrochloride
Step 444a. 7-BOC-2-CBZ-2.7-diazabicvcloI3.3.01octane
A 1.06 g sample of 7-BOC-2,7-diazabicyclo[3.3.0]octane (prepared as in Example 268) was dissolved in 12 mL of 1 N NaOH, and the solution was cooled to 0°C. To this solution was added 1.43 mL of benzyl chloroformate in 10 mL of ether over a 10 minute period, and the mixture was stirred under N2 for 4 hours. The mixture was extracted with methylene chloride, and the extract was washed, dried and concentrated to give the titie compound (0.40 g).
Step 444b. 2-CBZ-2.7-diazabicvclor3.3.01octane
The compound from step 444a was dissolved in ethyl acetate and treated with 4 N HCI in dioxane to remove the BOC group. The solvent was removed, and the residue was dissolved in 5% NaHCO3. The mixture was washed with ethyl acetate, and the aqueous phase extracted with 1:3 i-propyl alcoho methylene chloride. The extract was washed with brine, dried and concentrated to give 0.600 g of the title compound.
Step 444c. 8-(2,7-diazabicyclo[3.3.0]oct-7-yl)-l-cyclopropyl-
7-fluoro-4H-9-methyl-4-oxo-quinolizine-)- 1 -cyclopropy 1-7 -fluoro- 4H-9-methyl-4-oxo-quinolizine-3-carboxyhc acid hydrochloride
FoUowing the procedure of Example 253j, substituting the 2-CBZ-2,7- diazabicyclo[3.3.0]octane from step 444b for the BOC-amino-pyrrolidine thereof, the condensed ester was produced. The ester was hydrolyzed according to the procedure of Example 253k, then the CBZ group was removed by hydrogenation over Pd/C, followed by formation and isolation of the salt according to the procedure of Step 2531. MS 372 (M+H)+. 1H NMR (DMSO-d6) 3: 0.62 (m, 2H), 1.00 (m, 2H), 1.98 (m,lH), 2.18 (m, IH), 2.35 (m, IH), 2.69 (s, 3H), 3.12 (m, IH), 3.27 (m, IH), 3.71 (m, 2H), 3.93 (m, IH), 4.05 (m, IH), 4.31 (m, IH), 8.00 (s, IH), 9.17 (d, J=12 Hz, IH). Analysis calculated for O20H22FN3O3.HCl.H2O: C, 56.40; H, 5.92; N, 9.87. Found: C, 56.57; H, 6.00; N, 9.69. Example 445
8-(3,7-diazabicyclo[3.3.0]oct-3-yl)-l-cyclopropyl- 7-fluoro-4H-9-methyl-4-oxo-quinoUzine-3-carboxylic acid hydrochloride
Step 445a. 3.7-dibenzyl-2.4-dioxo-3.7-diazabicyclor3.3.01octane
A 1.80 g (10 mmol) sample of N-benzylmaleimide and 2.38 g (10 mmol) of N- methoxymethyl-N-trimethylsilylmethyl-benzylamine were dissolved in methylene chloride, and the solution was cooled to 0°C. To this solution was added 1.00 mL (1.0 mmol) of 1.0 N TFA in methylene chloride dropwise over 5 minutes. The reaction was stirred for 3 hours, then another 238 mg of the amine reagent was added and the mixture was stirred at room temperature for 1 hour. The mixture was dUuted with 50 mL of methylene chloride and the solution was washed with 5% NaHCO3 and brine. The solution was dried and concentrated to give the title compound as a white solid.
Step 445b. 3-benzyl-2.4-dioxo-3.7-diazabicvclor3.3.01octane
The compound from step 445a (3.00 g, 9.38 mmol) was dissolved in 50 mL of methanol, 500 mg of 10% Pd/C was added, and the mixture was flushed with N2. To this mixture was added 2.96 g (46.87 mmol) of ammonium formate, and the reaction was stirred at 70°C under N2 for 1.25 hours. The mixture was diluted with methylene chloride and fUtered. The filtrate was washed with water and concentrated. The residue was redissolved in methylene chloride, rewashed, fUtered, and the solvent was removed to give 2.37 g of the titie compound.
Step 445c. 3-benzyl-3.7-diazabicvclor3.3.01octane
A 1.2 g (30.0 mmol) sample of LAH was suspended in ether under N2 at room temperature. A solution of the compound from step 445b (2.3 g, 10 mmol) in methylene chloride was added dropwise over 10 minutes whUe cooUng the vessel in a -10°C bath, and the mixture was stirred for 2 hours. The reaction was quenched by the sequential dropwise addition of 1.2 mL water, 1.2 mL 15% NaOH and 3.6 mL of water. The mixture was filtered, and the filtrate was concentrated to give 1.77 g of the title compound.
Step 445d. 3-benzyl-7-BOC-3.7-diazabicvcloI3.3.01octane
A 1.77 g of the compound from step 445c was dissolved in a 4: 1 mixture of methanol: water, and 2.29 g of di-t-butyl dicarbonate was added. The mixture was stirred at room temperature for 1.5 hours, and the solvents were removed. The residue was dissolved in methylene chloride, and the solution was washed with 5% NaHCCO3, brine, dried and concentrated. The residue was chromatographed on sUica gel to give 1.68 g of the title compound.
Step 445e. 3-BOC-3.7-diazabicvcloI3.3.01octane
The compound from step 445d was treated with ammonium formate and 10% Pd/C as in step 445 b for 30 minutes, and the title compound was isolated in a similar manner.
Step 445f. 8-(3,7-diazabicyclo[3.3.0]oct-3-yl)-l-cyclopropyl- 7-fluoro-4H-9-methyl-4-oxo-quinoUzine-3-carboxylic acid hydrochloride
FoUowing the procedure of Example 253j, substituting the 3-BOC-3 - diazabicyclo[3.3.0]octane from step 445e for the BOC-amino-pyrroUdine thereof, and carrying the product forward accordmg to steps 253k&l, the titie compound (552 mg) was obtained MS 372 (M+H)+. lH NMR (DMSO-d6) d: 0.61 (m, 2H), 0.99 (m, 2H), 2.33 (m, IH), 2.67 (s, 3H), 3.12 (m, 4H), 3.43 (m, 2H), 3.70 (m, 2H), 3.85 (m, 2H), 7.96 (s, IH), 9.12 (d, J=10 Hz, IH), 13.86 (br s, IH). Analysis calculated for C20H22FN3O3.HCl.H2O: C, 56.40; H, 5.92; N, 9.87. Found: C, 56.59; H, 5.80; N, 9.81.
Example 446
8-(3-carboxypyrrolidin- 1-yl)- 1 -cyclopropyl-7-fluoro- 4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid hydrochloride
Step 446a. l-benzylpyrrolidine-3-carboxylic acid methyl ester
4.3 g of methyl acrylate and 13.09 g of N-methoxymethyl-N- trimethylsilylmethyl-benzylamine were dissolved in 100 mL of methylene chloride, and the solution was cooled to 0°C. To this solution was added 5.00 mL of 1.0 N TFA in methylene chloride over a 10 minute period, and the reaction was stirred at room temperature for 16 hours. The mixture was washed with 5% NaHCO3 and brine, then concentrated. The residue was chromatographed on sUica gel to give 7.20 g of the title compound. Step 446b. l-benzylpyrroUdine-3-carboxylamide
The compound (2.02 g) from step 446a was dissolved in 50 mL of methanol, NH3 was bubbled in until the solution was saturated, and the solution was stirred under balloon pressure for 4 days. Additional NH3 was added, and the mixture stirred for 2 more days. The solvent was removed to give the title compound (1.60 g).
Step 446c. 3-carbamoyl-pyrrolidine
The compound (1.6 g) from step 446b was treated with ammonium formate and 10% Pd/C according to the procedure of step 445b for 1.75 hours, and the title compound was isolated in a simUar manner (200 mg).
Step 446d. 8-(3-carboxylpyrroUdin-l-yl)-l-cyclopropyl- 7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid
FoUowing the procedure of Example 253j, substituting the 3-carbamoyl- pyrroUdine (1.90 g) from step 446c for the BOC-amino-pyrrolidine thereof, and carrying the product forward as in step 253k the title compound was prepared (44 mg). MS 375
(M+H)+. 1H NMR (DMSO-d6) 3: 0.60 (m, 2H), 0.98 (m, 2H), 2.20 (m, 3H), 3.16 (m,
IH), 3.77 (m, 2H), 3.88 (m, 2H), 7.91 (s, IH), 9.07 (d, J=10 Hz, IH). Analysis calculated for C19H18FN2O5ΗCI.O.5H2O: C, 59.53; H, 5.26; N, 7.31. Found: C,
59.35; H, 5.06; N, 7.19.
Example 447
8-(3-(2,2,2-trifluoroethyl)aminopyrroUdin- 1 -yl)- 1 -cyclopropyl- 7-fluoro-4H-9-methyl-4-oxo-quinoUzine-3-carboxylic acid hydrochloride
Step 447a. 1 -benzyl-3-f2.2.2-trifluoroacetyl)aminopyrrolidine
A 3.52 g sample of N-benzyl-3-aminopyπolidine (prepared as in J. Med. Chem., 22:2521, 1990) was dissolved in 300 mL of methylene chloride, and the solution was cooled to )°C and flushed with N2. To this solution was added 4.85 mL of pyridine, then 8.45 mL of trifluoroacetic anhydride (dropwise over 10 minutes). The mixture was stirred at 0°C for 10 minutes and at room temperature for 20 minutes. The reaction mixture was washed with 5% NaHCO3 and brine, then filtered and concentrated to give 5.76 g of the title compound. Step 447b. l-benzyl-3-f2.2.2-trifluoroethyl aminopyrrolidine
A 2.64 g sample of the compound from step 447a was added dropwise to a suspension of 1.11 g of LAH in ether stirred under N2 at 0°C. After one hour, the reaction was stirred at room temperature for 6 hours. The reaction was quenched by sequential addition of 1.2 mL of water, 1.2 mL of 15% NaOH and 2.4 mL of water. The mixture was filtered, and the filtrate was concentrated to give 2.39 of the titie compound.
Step 447c. l-benzyl-3-fN-BOC-N-f2.2.2-trifluoroethyl)aminopyrrolidine
A 2.36 g sample of the compound from step 447b was treated with di-t-butyl dicarbonate in the THF/water, and the compound was isolated as in previous examples (e.g., Ex. 445e). Yield 1.81 g of the title compound.
Step 447d. 3-fN-BOC-N-f2.2.2-trifluoroethvnaminopyrroUdine
A 2.80 g sample of the compound from step 447c was treated with ammonium formate and 10% Pd/C according to the procedure of step 445b for 1.75 hours, and the titie compound was isolated (1.09 g).
Step 447e. 8-(3-(N-BOC-N-(2,2,2-trifluoroethyl)amino)- pyrrolidin- 1 -y 1)- 1 -cyclopropyl-7-fluoro-4H- 9-meτhyl-4-oxo-quinolizine-3-carboxylic acid hydrochloride
Following the procedure of Example 253j, substituting the 3-(N-BOC-N-(2,2,2- tiif oroethyl)aminopyrrolidine (0.646 g) from step 447d for the BOC-amino-pyrrolidine thereof, and carrying the product forward as in steps 253k&l the title compound was prepared (493 mg). MS 428 (M+H)+. 1H NMR (DMSO-d6) 3: 0.60 (m, 2H), 1.93 (m, IH), 2.10 (m, IH), 2.29 (m, IH), 2.60 (s, 3H), 3.54 (m, 2H), 3.75 (m, IH), 3.91 (m, 2H), 7.89 (s, IH), 9.06 (d, IH, J=10 Hz). Analysis calculated for C20H20F4N3O3ΗCI.O.25 H2O: C, 55.62; H, 5.02; N, 9.73. Found: C, 55.72; H, 4.83; N, 9.62Λ Example 448
8-(3-(2-fluoroethyl)aminopyrroUdin- 1 -yl)- 1 -cyclopropyl- 7-fluoro-4H-9-methyl-4-oxo-quinoUzine-3-carboxylic acid hydrochloride
Step 448a. l-benzyl-3-fN-BOC-N-f2-fluoroethyl)amino pyrrolidine
A 3.52 g (2.00 mmol) sample of N-benzyl-3-aminopyrrolidine (prepared as in J. Med. Chem., 22:2521, 1990) and 340 mg of NaHCO3 were dissolved in 5 mL of acetonitrile. This solution was flushed with N2 and 0.140 mL of l-bromo-2-fluoroethane (Aldrich) was added. The reaction was stirred at 50°C under N2 for 48 hours and at 70°C for 1.5 hours. This mixture was cooled, and then were added 5 mL of water, 5 mL of methanol and 873 mg of di-t-butyl dicarbonate. This reaction mixture was stirred for 7 hours, then diluted with methylene chloride. This mixture was washed with 5% NaHCO3 and brine. The organic layer was dried and concentrated to give the title compound.
Step 448b. 3-fN-BOC-N-f2-fluoroethvnamino')pyrrolidine
A 225 mg sample of the compound from step 448a was treated with ammonium formate and 10% Pd/C according to the procedure of step 445b for 1 hour, and the titie compound was isolated (190 mg).
Step 448c. 8-(3-(2-fluoroethyl)aminopyrrolidin-l-yl)-l-cyclopropyl- 7-fluoro-4H-9-methyl-4-oxo-quinoUzine-3-carboxylic acid hydrochloride
FoUowing the procedure of Example 253j, substituting the 3-(N-BOC-N-(2- fluoroethyl)amino)pyrroUdine (0.245 g) from step 448b for the BOC-amino-pyrrolidine thereof, and carrying the product forward as in steps 253k&l the title compound was prepared (76 mg). MS 392 (M+H)+. 1H NMR (DMSO-d6) 3: 0.61 (m, 2H), 1.00 (m, 2H), 2.33 (m, 3H), 3.38 (s, 3H), 3.54 (m, IH), 3.50 (m, IH), 3.80 (m, IH), 4.00 (m, 4H), 4.62 (m, IH), 4.87 (m, IH), 7.95 (s, IH), 9.13 (d, IH, J=10 Hz), 13.85 (br s, IH). Analysis calculated for C20H23F2N3O3 .HCIΗ2O: C, 53.87; H, 5.88; N, 9.42. Found: C, 53.75; H, 5.61; N, 9.45. Example 449
8-(3-((2-fluoroethyl)aminomethyl)pyrroUdin- 1 -yl)- 1 -cyclopropyl- 7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid hydrochloride
FoUowing the procedures of Example 448a-b, substituting l-benzyl-3-(BOC- amino)methylpyrrolidine (prepared according to J. Med. Chem., 1981:1320). then substituting that product for the BOC-amino-pyrrolidine forward foUowing the procedure of Example 352j of Example 253j, and following the procedure of 253j and carrying the product forward as in steps 253k&l the ύύe compound was prepared (85 mg). MS 406 (M+H)+. 1H NMR (DMSO-d6) 3: 0.60 (m, 2H), 1.01 (m, 2H), 1.84 (m, IH), 2.20 (m, IH), 2.29 (m, IH), 2.62 (s, 3H), 2.68 (m, IH), 3.16 (m, 2H), 3.78 (m, 4H), 4.80 (m, 2H), 7.91 (s, IH), 9.08 (d, IH, J=10 Hz). Analysis calculated for C20H25F2N3O3 •HC1.H2O: C, 54.84; H, 6.14; N, 9.14. Found: C, 54.23; H, 5.87; N, 8.95.
Example 450
8-(3-(S)-(2-fluoroethyl)aminopyrrolidin-l-yl)-l-cyclopropyl- 7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid hydrochloride
FoUowing the procedures of Example 448, beginning with the (S)-N-benzyl-3- aminopyrrolidine, the title compound (553 mg) was prepared.
MS 392 (M+H)+. IH NMR (DMSO-d6) 3: 0.62 (m, 2H), 1.00 (m, 2H), 2.32 (m, 3H), 2.64 (s, IH), 3.40 (m, IH), 3.48 (m, IH), 3.80 (m, IH), 4.01 (m, 4H), 4.83 (m, 2H), 7.93 (s, IH), 9.10 (d, IH, J=10 Hz), 13.85 (br s, IH). Analysis calculated for C20H23F2N3O3 .HCI.H2O: C, 53.87; H, 5.88; N, 9.42. Found: C, 53.88; H, 5.75; N, 9.30.
Example 451
8-(3-(R)-(2-fluoroethyl)aιτdnopyrroUdin-l-yl)-l-cyclopropyl- 7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid hydrochloride
FoUowing the procedures of Example 448, beginning with the (R)-N-benzyl-3- aminopyrrolidine, the title compound (601 mg) was prepared.
MS 392 (M+H)+. 1H NMR (DMSO-d6) 3: 0.61 (m, 2H), 1.00 (m, 2H), 2.32
(m, 3H), 2.64 (s, 3H), 3.40 (m, IH), 3.48 (m, IH), 3.80 (m, IH), 4.00 (m, 4H), 4.83 (m, 2H), 7.94 (s, IH), 9.11 (d, IH, J=10 Hz). Analysis calculated for C20H23F2N3O3
•HC1.H2O: C, 53.87; H, 5.88; N, 9.42. Found: C, 53.75; H, 5.61; N, 9.45. Example 452
8-(3a-amino-octahydroisoindol-2-yι)-l-cyclopropyl- 7-fluoro-4H-9-methyl-4-oxo-quinoUzine-3-carboxylic acid hydrochloride
Step 452a. 2-benzyl-3a-nitro-octahydroisoindole
A 1.27 g (10.0 mmol) sample of 1 -nitro- 1-cyclohexene (Aldrich) and 2.38 g (10.0 mmol) of N-benzyl-N-(methoxymethyl)-trimethylsUylmethylarnine were dissolved in methylene chloride, and the solution was flushed with N2 and cooled to 0°C. To this solution was added 10 mL of methylene chloride containing 1 N TFA over a 10 minute period, and the mixture was stirred at 0°C for 0.5 hour and at room temperature for 15 hours. An additional 479 mg (2 mmol) of N-benzyl-N-(methoxymethyl)-trimethylsilyl- methylamine were added, and the solution was stirred for 5 hours. The mixture was washed with 5% NaHCO3 and brine, dried and concentrated to give 2.935 g of the titie compound.
Step 452b. 2-benzyl-3a-amino-octahvdroisoindole
A 520 mg sample of the compound from step 452a was dissolved in 30 and treated with ammonium formate and 10% Pd/C according to the procedure of step 445b for 1 hour, and the title compound was isolated (550 mg).
Step 452c. 8-(3a-amino-octahydroisoindol-2-yl)-l-cyclopropyl- 7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid hydrochloride
FoUowing the procedure of Example 253j, substituting the 2-benzyl-3a-amino- octahydroisoindole (0.550 g) from step 448b for the BOC-amino-pyrroUdine thereof, then reacting the product with di-t-butyl dicarbonate in methanol, and carrying the BOC- protected product forward as in steps 253k&l the title compound was prepared (66 mg). MS 400 (M+H)+. ! H NMR (DMSO-dό) 3: 0.61 (m, 2H), 1.00 (m, 2H), 2.33 (m, 3H), 3.38 (s, 3H), 3.54 (m, IH), 3.50 (m, IH), 3.80 (m, IH), 4.00 (m, 4H), 4.62 (m, IH), 4.87 (m, IH), 7.95 (s, IH), 9.13 (d, IH, J=10 Hz), 13.85 (br s, IH). Analysis calculated for C22H26FN3O3 «HC1.2H2θ: C, 55.99; H, 6.62; N, 8.90. Found: C, 55.56; H, 6.30; N, 8.95. Example 453
8-(6-amino-2-aza-spiro[3.3]non-2-yl)-l-cyclopropyl- 7-fluoro-4H-9-methvI-4-oxo-quinohzine-3-carboxylic acid hydrochloride flsomer fl))
Step 453a. l-f2-bromoethyl)-2-oxo-cvclopentanecarboxyUc acid
A 4.68 g (30 mmol) sample of 2-oxo-cyclopentanecarboxyUc acid and 28.18 g (150 mmol) of 1,2-dibromoethane were dissolved in 100 mL of acetone. 20.73 g (150 mmol) of K2CO3 were added and the mixture was heated at reflux for 4 hours. The mixture was filtered and concentrated. The residue was chromatographed on sUica gel to give 4.52 g of the title compound.
Step 453b. 2-aza-2-benzyl-spiroI3.31nonan-1.6-dione
A 4.07 g sample of the compound from step 453a and 4.98 g of benzylamine were dissolved in 50 mL of toluene, and the mixture was heated at reflux for 8 hours in the presence of 14 g of 4A molecular sieves. To this mixture was added 36.6 mL of 2 M HCI, and the mixture was stirred at room temperature for 1 hour. The mixture was filtered, and the organic layer was separated and washed with 2 M HCI, dried and concentrated. The residue was chromatographed on sUica gel to give 1.69 g of the titie compound.
Step 453c. 2-aza-2-benzyl-spiroI3.31nonan-6-ol
A 1.18 g (4.85 mmol) sample of the compound from step 453b was dissolved in 15 mL of dry THF, and 14.6 mL (14.55 mmol) of LAH (1 M in ether) was added dropwise. The mixture was heated at reflux for 2 hours, then the reaction was quenched by the sequential dropwise addition of 0.55 mL water, 0.55 mL of 15% NaOH and 1.65 mL of water. The mixture was stirred for 1 hour and filtered. The filtrate was dried and concentrated to give 1.13 g of the titie compound.
Step 453d. 2-aza-2-benzyl-spiror3.31nonan-6-one
A 1.13 g sample of the compound from step 453c was dissolved in 35 mL of acetone, the solution was cooled to 0°Cm and 0.25 mL of H2SO4 was added. To this mixture was added Jones reagent dropwise, and the reaction was stirred at room temperature for 4 hours. Isopropanol was added, the acetone was removed under reduced pressure, and 6.5 mL of 6 M NaOH was added. The mixture was filter, and the filtrate was washed with water and brine, dried and concentrated to give 845 mg of the titie compound.
Step 453e. 6-amino-2-aza-2-benzyl-spiror3.31nonane
A 845 mg sample of the compound from step 453d, 173 mg of NaBH3CN and
2.84 g of ammonium acetate were dissolved in 120 mL of absolute methanol, and the mixture was stirred at room temperature for 16 hours. The mixture was concentrated, and 200 mL of methylene chloride were added. The solution was filtered, and the filtrate was washed with 5% NaHCO3, brine, dried and concentrated to give 853 mg of the title compound.
Step 453f. 6-fBOC-aminoV2-aza-2-benzyl-spiror3.31nonane
A 847 mg sample of the compound from step 453e was dissolved in 24 mL of methanol and 6 mL of water, and 1.61 g of di-t-butyl dicarbonate was added. The mixture was stirred at room temperature under N2 for 3 hours. The mixture was concentrated, and the residue was dissolved in methylene chloride. The solution was washed with 5% NaHCO3, dried and concentrated to give 1.40 g of the title compound.
Step 453g. 6-fBOC-amino)-2-aza-spiror3.31nonane
A 138 mg sample of the compound from step 453f was dissolved in 30 and treated with ammonium formate and 10% Pd/C according to the procedure of step 445b for 1 hour, and the titie compound was isolated (105 mg).
Step 453h. 8-(6-amino-2-aza-spiro[3.3]non-2-yl)-l-cyclopropyl- 7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid hydrochloride
FoUowing the procedure of Example 253j, substituting the 6-(BOC-amino)-2-aza- 2-benzyl-spiro[3.3]nonane (138 mg) from step 453g for the BOC-amino-pyrrolidine thereof, and carrying the product forward as in steps 253k&l the title compound was prepared (57 mg). Stereoisomers were separated by HPLC. Isomer (I): MS 400 (M+H)+. 1H NMR (DMSO-d6) 3: 0.62 (m, 2H), 1.00 (m, 2H), 1.65-2.35 (m, 1 IH), 2.63 (s, 3H), 3.47 (m, IH), 3.58 (m, IH), 3.81 (m, 2H), 3.92 (m, IH), 4.62 (m, IH), 7.93 (s, IH), 9.09 (d, IH, J=10 Hz). Analysis calculated for C22H26FN3O3 •HCM.5H2O: C, 57.08; H, 6.53; N, 9.08. Found: C, 56.85; H, 6.41; N, 8.84. Example 454
8-(3-aιrύno-3-trifluoromethylpyrrolidin- 1 -yl)- 1 -cyclopropyl- 7-fluoro-4H-9-methyl-4-oxo-quinoUzine-3-carboxylic acid hydrochloride
Step 454a. l-benzyl-3-trifluoromethylpyrroUdine-3-carboxylic acid
A 2.48 g sample of 2-(trifluoromethyl)acryUc acid was dissolved in 40 mL of dry methylene chloride, and a solution of 4.75 g of N-benzyl-N-(methoxymethyl)- trimethylsUylmethylamine in 20 mL of dry methylene chloride was added dropwise under N2 at 0°C. To this mixture was added 2 mL of trifluoroacetic acid, and the mixture was stirred for 2 hours at room temperature. The product was removed by filtration, washed and dried to give the titie product
Step 454b. l-benzyl-3-fBOC-amino -3-trifluoromethylpyrroUdine
A mixture of 1.42 g of the compound from step 454a, 1.71 g of diphenylphosphoryl azide, 12.3 g of t-butanol and 0.627 g of trimethyl amine was heated at reflux under N2 for 24 hours. The mixture was concentrated to dryness, and the residue was dissolved in methylene chloride. The solution was washed with satd. NaHCO3 and water, then concentrated. The residue was chromatographed on siUca gel to give 1.73 g of the title compound.
Step 454c. 3-fBOC-aminoV3-trifluoromethylpyrrolidine
A 413 mg sample of the compound from step 447c was treated with ammonium formate and 10% Pd/C according to the procedure of step 445b for 2 hours, and the title compound was isolated (282 mg).
Step 454d. 8-(3-amino-3-trifluoromethylpyrrolidin-l-yl)-l-cyclopropyl- 7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid hydrochloride
FoUowing the procedure of Example 253j, substituting the 3-(BOC-amino)-3- trifluoromethylpyrrolidine (227 mg) from step 453g for the BOC-amino-pyrrolidine thereof, and carrying the product forward as in steps 253k&l the titie compound was prepared (79 mg). MS 414 (M+H)+. 1H NMR (DMSO-d6) 3: 0.62 (m, 2H), 1.02 (m, 2H), 2.19 (m, IH), 2.35 (m, 2H), 2.65 (m, 3H), 3.78 (m, 2H), 4.19 (m, 2H), 7.97 (s, IH), 9.08 (d, IH, J=10 Hz). Example 455
8-(3-(S)-hydroxymethylazetidin- 1 -yl)- 1 -cyclopropyl- 7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid
FoUowing the procedure of Example 253j, substituting 3-(S)-hydroxymethyl- azetidine (540 mg) for the BOC-amino-pyrroUdine thereof, and carrying the product forward as in step 253k the title compound was prepared (102 mg). MS 347 (M+H)+. 1H NMR (DMSO-d6) '3: 0.59 (m, 2H), 0.86 (m, IH), 1.04 (m, IH), 2.26 (m, 2H), 2.60 (s, 3H), 3.61 (m, IH), 3.77 (m, IH), 4.23 (m, IH), 4.58 (m, IH), 4.91 (m, IH), 5.06 (m, IH), 7.86 (s, IH), 9.04 (d, IH, J=10 Hz). Analysis calculated for C18H19FN2O4 •0.25H2O: C, 61.62; H, 5.60; N, 7.98. Found: C, 61.71; H, 5.55; N, 7.81.
Example 456
8-(3-aminomethyl)-3-trifluoromethyl-pyrrolidin- 1 -yl)- 1 -cyclopropyl- 7-fluoro-4H-9-methyl-4-oxo-quinoUzine-3-carboxylic acid hydrochloride
Step 456a. l-benzyl-3-trifluoromethylpyrrolidine-3-carboxyUc acid
2-(Trifluoromethyl)acrylic acid (2.48 g, 20 mmol) was dissolved in 30 mL of dry methylene chloride, a solution of 4.75 g (20 mmol) of N-benzyl-N-(methoxymethyl)- trimethylsUylmethylamine in 20 mL of dry methylene chloride was added dropwise under N2 at 0°C. To this solution was added 2 mL of TFA, and the solution was stirred for 2 hours at room temperature. The white precipitate was coUected, washed and dried to give 3.22 g of the titie compound.
Step 456b. l-benzyl-3-trifluoromethylpyrrolidine-3-methanol
The compound from step 456a (2.32 g) was dissolved in 60 mL of dry THF, 1.12 eq of LAH (IN in dry THF) was added, and the reaction was stirred under N2 for 3 hours. The reaction was quenched by the sequential dropwise addition of 0.35 mL water, 0.35 mL of 15% NaOH and 1.3 mL of water, then the mixture was stirred for 1 hour and filtered. The filtrate was dried and concentrated to give 2.2 g of the title compound. Step 456c. 1 -benzyl-3-trifluoromethyl-3-f toluenesulfonyloxymethvDpyrroUdine
The compound from step 456b (1.61 g) was dissolved in dry pyridine, and the solution was cooled to 0°C. To this was added 1.458 g of p-toluenesulfonyl chloride in 4 mL of dry pyridine, and the reaction was stirred at 0-C for 4 days. The mixture was dUuted with 300 mL of methylene chloride, then washed with water and brine and dried. Removal of the solvent gave 2.81 g of the titie compound.
Step 456d. l-benzyl-3-trifluoromethyl-3-fazidomethyDpyrroUdine
The compound (2.43 g) from step 456c was dissolved in acetonitrile, then reacted with tetrabutylammonium azide at 80°C for 16 hours. The mixture was dUuted with methylene chloride, then washed with water and brine and dried. Removal of the solvent gave 0.751 g of the titie compound.
Step 456e. l-benzyl-3-fBOC-aminomethyl)-3-trifluoromethyl-pyrrolidine
The compound from step 456c ( 284 mg) and di-t-butyl dicarbonate (262 mg) were dissolved in anhydrous acetic acid and added to a suspension of Pd/C (29 mg) in 10 mL of dry acetic acid. The reaction was stirred at room temperature under N2 for 4 hours, then filtered The filtrate was washed with 5% NaHCO3 and brine, then dried and concentrated. The residue was purified by chromatography on sUica gel to give 172 mg of the titie compound.
Step 456f. 3-fBOC-aminomethylV3-trifluoromethyl-pyrrolidine
A 330 mg sample of the compound from step 447c was treated with ammonium formate and 10% Pd/C according to the procedure of step 445b for 2 hours, and the title compound was isolated (222 mg).
Step 456g. 8-(3-aιττinomethyl)-3-trifluoromethyl-pyrroUdin- 1 -yl)- 1 -cyclopropyl- 7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid hydrochloride
FoUowing the procedure of Example 253j, substituting 3-(BOC-aminomethyl)-3- trifluoromethyl-pyrrolidine from step 456f ( 182 mg) for the BOC-arnino-pyrroUdine thereof, and carrying the product forward as in steps 253k&l the title compound was prepared (47 mg). MS 428 (M+H)+. 1H NMR (DMSO-d6) 3: 0.63 (m, 2H), 1.02 (m, 2H), 2.32 (m, 3H), 2.55 (m, IH), 2.68 (s, 3H), 3.85 (m, 2H), 3.98 (m, 2H), 7.99 (s, IH), 9.16 (d, IH, J=12 Hz). Analysis calculated for C20H21F4N3O3 »HCM.75H2O: C, 48.49; H, 5.19; N, 8.48. Found: C, 48.48; H, 4.99; N, 8.49.
Example 457 8-(octahydropyrrolo[3.4-c]pyrid-2-yl)- 1 -cyclopropyl -7-fluoro-
4H-9-methyl-4-oxo-quinolizine-3-carboxyUc acid hydrochloride
Step 457a. N-benzyl-3.4-pyrroUdinedicarboxyUc acid diethyl ester
Diethyl glutaconate (7.44 g, 40 mmol) was dissolved in 60 mL of dry methylene chloride, and a solution of 9.52 g (40 mmol) of N-benzyl-N-(methoxymethyl)- trimethylsUylmethylamine in 20 mL of dry methylene chloride was added dropwise under N2 at 0°C. To this solution was added 2 mL of 1 N TFA in methylene chloride, and the solution was stirred for 2 hours at room temperature. The solution was washed with 5% NaHCO3 and brine, then dried and concentrated to give 12.48 g of the title compound.
Step 457b. 2-benzyl-4.6-dioxooctahydropyrrolor3.4-clpyridine
A solution of 9.00 mmol of Na in Uquid NH3 was prepared at -78°C. To this was added 15 mg of FeC13, and the reaction mixture was warmed to -40°C. To this solution, stirred under N2, a cooled (-40°C) solution of the compound (957 mg) from step 457a in THF was added over a 10 minute period, and the reaction mixture was stured at -33°C for 3 hours. Ammonium chloride (1.5 g) was added with stirring, then the mixture was warmed to room temperature and the excess ammonia was evaporated. To this was added 60 mL of water, and the mixture was extracted with methylene chloride. The extract was washed with brine, dried and concentrated. The residue was chromatographed on sUica gel to give 425 mg of the titie compound.
Step 457c. 2.5-dibenzyl-4.6-dioxooctahydropyrrolor3.4-clpyridine
To a mixture of 905 mg of K2CO3 and 400 mg of the compound from step 457b in 5 mL of DMF was added 308 mg of benzyl bromide, and the reaction mixture was stirred at room temperature under N2 for 6.5 hours. The mixture was diluted with ethyl acetate, which was washed with water and brine, dried and concentrated to give 610 mg of the titie compound. Step 457d. 5-benzyl-4.6-dioxooctahvdropyrroloI3.4-clpyridine
A 700 mg sample of the compound from step 447c was treated with ammonium formate and 10% Pd/C according to the procedure of step 445b for 2 hours, and the ti le compound was isolated (540 mg).
Step 457e. 5-benzyl-octahydropyrroloI3.4-clpyridine
A suspension of 266 mg of LAH in 10 mL of ether was stirred at 10°C under N2- To this suspension was added 540 mg of the compound from step 457d dissolved in 10 mL of methylene chloride. The mixture was stirred under N2 for 1.5 hours. The reaction was quenched by the sequential dropwise addition of 0.3 mL water, 0.3 mL of 15% NaOH and 0.6 mL of water, then the mixture was stirred for 1 hour and filtered. The filtrate was dried and concentrated to give 389 mg of the title compound.
Step 457f. 8-(octahydropyrrolo[3.4-c]pyrid-2-yl)- l-cyclopropyl-7-fluoro- 4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid hydrochloride
FoUowing the procedure of Example 253j, substituting 5-benzyl- octahydropyrrolo[3.4-c]pyridine from step 457e (330 mg) for the BOC-amino-pyrroUdine thereof, and carrying the product forward as in steps 253k&l the titie compound was prepared (22 mg). MS 386 (M+H)+. 1H NMR (DMSO-d6) 3: 0.60 (m, 2H), 0.98 (m, 2H), 1.78 (m, IH), 1.89 (m, IH), 2.27 (m, IH), 2.61 (s, 3H), 2.50-2.75 (m, 3H), 3.00 (m, IH), 3.17 (m, 2H), 3.65-4.00 (m, 4H), 7.90 (s, IH), 9.08 (d, IH, J=10 Hz).
Example 458
8-(3-(cyclopropylamino)pyrroUdin- 1 -yl)- 1 -cyclopropyl-7-fluoro- 4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid hydrochloride
Step 458a. l-benzyl-3-fcvclopropylmethyl)aminopyrrolidine
A sample (1.75 g 10 mmol) of l-benzyl-3-pyrroUdinone was dissolved in methylene chloride, and 1.44 g of anhydrous MgSO4 was added. The mixture was stirred under N2 at 0°C, and 634 mg of cyclopropylamine was added dropwise. The mixture was stirred at room temperature for 5 hours, then 10 mL of methanol foUowed by 534 mg of NaBH4 in smaU portions was added. The mixture was stirred for 1 hour, then dUuted with methylene chloride. The solution was washed with 5% NaHCO3 and brine, dried and concentrated to give 2.12 g of the title compound. Step 458b. l-benzyl-3-fN-BOC-N-fcvclopropylmethyl)amino)pyrrolidine
The compound from step 458 was treated with di-t-butyl dicarbonate in acetonitrile for 2 hours, and the title compound (2.11) g was obtained after extraction of the compound and chromatography on sUica gel.
Step 458c. l-benzyl-3-fN-BOC-N-fcvclopropylmethyl)amino)pyrrolidine
A 2.11 g sample of the compound from step 458b was treated with ammonium formate and 10% Pd/C according to the procedure of step 445b for 2 hours, and the title compound was isolated (1.92 mg).
Step 458d. 8-(3-(cyclopropylamino)pyιτoUdin-l-yl)-l -cyclopropy 1- 7-fluoro-4H-9-methyl-4-oxo-quinoUzine-3-carboxyIic acid hydrochloride
FoUowing the procedure of Example 253j, substituting l-benzyl-3-(N-BOC-N- (cyclopropylmethyl)amino)pyrrolidine from step 458c (1.13 g) for the BOC-amino¬ pyrrolidine thereof, and carrymg the product forward as in steps 253k&l the titie compound was prepared. MS 386 (M+H)+. lH NMR (DMSO-d6) 3: 0.60 (m, 2H), 0.81 (m, 2H), 1.00 (m, 4H), 2.34 (m, 3H), 2.64 (s, 3H), 2.83 (m, IH), 3.30 (m, IH), 4.06 (m, 4H), 7.93 (s, IH), 9.11 (d, IH, J=10 Hz).
Example 459
8-(6-aιτrino-2-aza-sp o[3.3]non-2-yl)-l-cyclopropyl-7-fluoro- 4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid hydrochloride flsomer fll))
The second stereoisomer (Isomer II) from Example 453 was also obtained by
HPLC. Isomer (II): MS 400 (M+H)+. 1H NMR (DMSO-d6) 3: 0.62 (m, 2H), 1.00 (m, 2H), 1.60-1.95 (m, 6H), 2.30 (m, 2H), 2.60 (s, 3H), 3.47 (m, IH), 3.52 (m, IH), 3.85 (m, 4H), 7.90 (s, IH), 9.09 (d, IH, J=10 Hz). Analysis calculated for C22H26FN3O3 •HCI.H2O: C, 58.21; H, 6.44; N, 9.26. Found: C, 58.00; H, 6.29; N, 8.86. Example 460
8-(2,7-diazabicyclo[3.3.0]oct-7-yι)-l-cyclopropyl-7-fluoro-4H- 9-methyl-4-oxo-quinoUzine-3-carboxylic acid hydrochloride / Isomer A
7-BOC-2-CBZ-2,7-diazabicyclo[3.3.0]octane was prepared according to the procedure of Example 444. This compound was separated by HPLC into two stereoisomers. Isomer A was carried forward according to the procedures of steps 444b and 444c to give the title compound (194 mg). MS 372 (M+H)+. 1H NMR (DMSO-d6) 3: 0.62 (m, 2H), 1.00 (m, 2H), 1.98 (m,lH), 2.18 (m, IH), 2.35 (m, IH), 2.69 (s, 3H), 3.12 (m, IH), 3.27 (m, IH), 3.71 (m, 2H), 3.93 (m, IH), 4.05 (m, IH), 4.31 (m, IH), 8.00 (s, IH), 9.17 (d, J=l 1 Hz, IH). Analysis calculated for C20H22FN3O3.HCM.75 H2O: C, 55.66; H, 6.08; N, 9.56. Found: C, 54.68; H, 5.73; N, 9.54.
Example 461 8-(2,7-diazabicyclo[3.3.0]oct-7-yl)-l-cycloρropyl-7-fluoro-4H-
9-methyl-4-oxo-quinolizine-3-carboxylic acid hydrochloride / Isomer B
7-BOC-2-CBZ-2,7-diazabicyclo[3.3.0]octane was prepared according to the procedure of Example 444. This compound was separated by HPLC into two stereoisomers. Isomer B was carried forward according to the procedures of steps 444b and 444c to give the title compound (263 mg). MS 372 (M+H)+. l NMR (DMSO-d6) 3: 0.62 (m, 2H), 1.00 (m, 2H), 1.98 (m,lH), 2.18 (m, IH), 2.36 (m, IH), 2.69 (s, 3H), 3.13 (m, IH), 3.28 (m, IH), 3.71 (m, 2H), 3.91 (m, IH), 4.04 (m, IH), 4.31 (m, IH), 8.00 (s, IH), 9.17 (d, J=l 1 Hz, IH). Analysis calculated for C20H22FN3O3.HCI.I.5 H2O: C, 55.24; H, 6.03; N, 9.66. Found: C, 55.37; H, 5.79; N, 9.59.
Example 462
8-(3-(R)-(hydroxymethyl)pyrrolidin- 1 -yl)- 1-cyclopropyl- 7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid hydrochloride
Step 462a. 1 -f 1 -fR phenylethvnpyrrolidine-3-f RV methanol
A 2.61 g (10 mmol) sample of 5-oxo-l-(l-(R)-phenylethyl-3-(R)-pyrroUdine carboxylic acid ethyl ester (prepared as described by D.R. Johnson et al., J. Heterocyclic Chem., 22:1481 (1992)) and 0.95 g of LAH were suspended in 20 mL of dry THF, and the reaction mixture was stirred at room temperature for 16 hours. The reaction was quenched by the sequential addition of water, 15% NaOH and water. The mixture was extracted with ether, which was washed, dried and concentrated to give the titie compound (1.8 g) as an oil. MS 206 (M+H)+. 1H NMR (CDCI3) 3: 1.4 (d, 3H), 1.6-1.7 and 1.9- 2.01 (m, 3H), 2.2-2.5 (m, 3H), 2.55-2.65 (tt, IH), 3.13-3.2 (1, IH), 3.5-3.57 (dd, IH), 3.7-3.76 (dd, IH), 7.2-7.32 (m, 5H).
Step 462b. 3-fR)-pyrrohdinemethanol
A sample of the compound from step 462a was dissolved in methanol, 10% Pd/C was added, and the mixture was hydrogenated at 4 atm H2 for 16 hours at room temperature. The solution was filtered, and the solvent was removed. The residue was taken directly to the next step.
Step 462c. 8-(3-(R)-(hydroxymethyl)pyrroUdin-l-yl)-l-cyclopropyl- 7-fluoro-4H-9-methyl-4-oxo-quinoUzine-3-carboxylic acid hydrochloride
FoUowing the procedure of Example 253j, substituting 3-(R)-pyrrolidinemethanol from step 462b for the BOC-amino-pyrrolidine thereof, and carrying the product forward as in steps 253k&l the title compound was prepared. MS 361 (M+H)+. 1H NMR (DMSO-d6) 3: 0.6-0.75 (m, 2H), 0.9-1.05 (m, 2H), 1.85-1.95 (m, IH), 2.1-2.2 (m, 2H), 2.45 (m, IH), 2.6 (s, 3H), 3.7-4.03 (m, 6H), 8.15 (s, IH), 9.02 (d, IH, J=12 Hz).
Example 463
8-(3-(S)-(hydroxymethyl)pyrrolidin- 1 -yl)- 1 -cyclopropyl- 7-fluoro-4H-9-methyl-4-oxo-quinoUzine-3-carboxylic acid hydrochloride
Step 463a. l-fl-fR)-phenylethyl')pyrroUdine-3-fS')-methanol
A 2.61 g (10 mmol) sample of 5-oxo-l-(l-(R)-phenylethyl-3-(S)-pyrrolidine carboxylic acid ethyl ester (prepared as described by D.R. Johnson et al., J. Heterocyclic Chem., 2^:1481 (1992)) and 0.95 g of LAH were suspended in 20 mL of dry THF, and the reaction mixture was stirred at room temperature for 16 hours. The reaction was quenched by the sequential addition of water, 15% NaOH and water. The mixture was extracted with ether, which was washed, dried and concentrated to give the titie compound as an oil. MS 206 (M+H)+. 1H NMR (CDCI3) 3: 1.39 (d, 3H), 1.7-1.8 and 1.94-2.07 (m, 3H), 2.2-2.46 (m, 3H), 2.97-3.05 (tt, IH), 3.12-3.2 (1, IH), 3.45-3.53 (dd, IH), 3.6-3.65 (dd, IH), 7.2-7.35 (m, 5H). Step 463b. 3-fSVpyrroUdinemethanol
A sample of the compound from step 462a was dissolved in methanol, 10% Pd/C was added, and the mixture was hydrogenated at 4 atm H2 for 16 hours at room temperature. The solution was filtered, and the solvent was removed. The residue was taken directly to the next step.
Step 463c. 8-(3-(S)-(hydroxymethyl)pyrroUdin-l-yl)-l-cyclopropyl- 7-fluoro-4H-9-methyl-4-oxo-quinoUzine-3-carboxylic acid hydrochloride
FoUowing the procedure of Example 253j, substituting 3-(R)-pyrrolidinemethanol from step 463b for the BOC-amino-pyrrolidine thereof, and carrying the product forward as in steps 253k&l the title compound was prepared. MS 361 (M+H)+. 1H NMR (DMSO-d6) 3: 0.6-0.75 (m, 2H), 0.9-1.05 (m, 2H), 1.85-1.9 (m, IH), 2.15-2.2 (m, 2H), 2.55-2.6 (s, IH), 2.65 (s, 3H), 3.65-3.85 (m, 6H), 8.19 (s, IH), 9.08 (d, 2H).
Example 464
8-(2-(R)-(hydroxymethyl)pyrrolidin-l-yl)-l-cyclopropyl- 7-fluoro-4H-9-methyl-4-oxo-quinoUzine-3-carboxylic acid hydrochloride
FoUowing the procedure of Example 253j, substituting 2-(R)-pyrrolidinemethanol (Aldrich) for the BOC-amino-pyrrolidine thereof, and carrying the product forward as in steps 253k&l the title compound was prepared. lH NMR (DMSO-d6) 3: 0.5-1.1 (m, 2H), 1.9-2.2 (m, 5H), 2.68 (s, 3H), 3.22 (s, IH), 3.62 (m, IH), 4.0 (m, 2H), 4.55 (m, IH), 7.95 (s, IH), 9.0 (d, 2H).
Example 465
8-(2-(S)-(hydroxymethyl)pyrrolidin- 1 -yl)- 1 -cyclopropyl- 7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid hydrochloride
FoUowing the procedure of Example 253j, substituting 2-(S)-pyrroUdinemethanol (Aldrich) for the BOC-amino-pyrrolidine thereof, and carrying the product forward as in steps 253k&l the title compound was prepared. 1H NMR (DMSO-d6) 3: 0.5-1.2 (m, 4H), 1.8-2.0 (m, 5H), 2.67 (s, 3H), 3.22 (m, IH), 3.65 (m, IH), 4.0 (m, 2H), 4.57 (m, IH), 7.9 (s, IH), 9.0 (d, 2H). Example 466
8-(2-(R)-aminomethyl-pyrrolidin- 1 -yl)- 1 -cyclopropyl- 7-fluoro-4H-9-methyl-4-oxo-quinoUzine-3-carboxylic acid hydrochloride
FoUowing the procedure of Example 253j, substituting 2-(R)-(BOC-amino- methyl)pyrrolidine (prepared as described in JP87-236335) for the BOC-amino-pyrroUdine thereof, and carrying the product forward as in steps 253k&l the title compound was prepared. MS 360 (M+H)+. lH NMR (DMSO-d6) 3: 0.61 (m, 2H), 0.92 ( , IH), 1.10 (m, IH), 1.87 (m, 2H), 2.06 (m, IH), 2.64 (s, 3H), 2.84 (m, IH), 2.94 (m, IH), 3.92 (m, IH), 4.53 (m, IH), 8.00 (s, IH), 9.18 (d, IH). HRMS (M+H)+: calculated for C19H23FN3O3: 360.1723; found:360.1713.
Example 467
8-(2-(S)-aminomethyl-pyrrolidin-l-yl)-l-cyclopropyl- 7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid hydrochloride
FoUowing the procedure of Example 253j, substituting 2-(S)-(BOC-amino- methyl)pyrrolidine (prepared as described in JP87-236335) for the BOC-amino-pyrroUdine thereof, and carrying the product forward as in steps 253k&l the titie compound was prepared. MS: 360 (M+H)+. lH NMR (DMSO-d6) 3: 0.60 (m, 2H), 0.92 (m, IH), 1.09 (m, IH), 1.87 (m, 2H), 2.06 (m, IH), 2.26 (m, IH), 2.35 (m, IH), 2.64 (s, 3H), 2.84 (m, IH), 2.97 (m, IH), 3.91 (m, IH), 4.54 (m, IH), 8.01 (s, IH), 9.16 (d, IH), 13.84 (b, IH). HRMS (M+H)+: calculated for C19H23FN3O3: 360.1723; found:360.1730.
Example 468
8-(3-(R)-( 1 -aminocyclopropyl)pyrrolidinyl)- 1 -cyclopropyl- 7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid hydrochloride
Step 468a. 4-(R)-(l-(BOC-amino)cyclopropyl)pyrroUdin-2-thione and 4-fS)- f l-fBOC-aminoteyclopropyl pyιτolidin-2-thione
A sample of 4-(l-(BOC-amino)cyclopropyl)-pyπOlidin-2-one (4.3 g,17.92 mmol, prepared as described by Hayakawa et al., U.S. Patent 5,098,912, issued March 24, 1992) and 3.987 g of La wesson's Reagent were suspended in 41 mL of THF, and the reaction mixture was stirred under N2 for 3 hours at room temperature. The solvent was removed, and the residue was dissolved in 1 % methanol in methylene chloride and purified by chromatography on silica gel to give 3.773 g of the title compound. MS: 257 (M+H)+. This compound was subjected to chiral HPLC to separate the R and S isomers. Step 468b. 3-fR)-f l-fBOC-aminolcvclopropyDpyrrolidme
A sample of the (R)-isomer (203 mg) from step 468a and 1.51 g of NiCL2«6H2O were dissolved in 10 mL of 1:1 methanohTHF, and the solution was cooled in an ice bath. To this was added 720 mg of NaBH4 in portions, and the reaction mixture was stirred at room temperature for 2 hours. The solvent was removed, and the residue was purified by chromatography on silica gel to give the title compound.
Step 468c. 8-(3-(R)-(l-aminocyclopropyl)pyrroUdinyl)-l-cyclopropyl- 7-fluoro-9-methvI-4-oxo-4H-quinoUzine-3-carboxylic acid hydrochloride
FoUowing the procedure of Example 253j, substituting 3-(R)-(l-(BOC-amino)- cyclopropyl)pyrrolidine from step 468b for the BOC-amino-pyrroUdine thereof, and carrying the product forward as in steps 253k&l the title compound was prepared. The spectroscopic data were simtiar to the racemic mixture of Example 311 above.
Example 469
8-(3-(S)-(l-aπύnocyclopropyl)pyrroUdinyl)-l-cyclopropyl- 7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid hydrochloride
Step 469a. 3-fS)-f l-fBOC-amino)cvclopropyl)pyrrolidine
A sample of the (S)-isomer (194 mg) from Example 468a above and 1.46 g of
NiCL2»6H2θ were dissolved in 10 mL of 1:1 methanohTHF, and the solution was cooled in an ice bath. To this was added 690 mg of NaBH4 in portions, and the reaction mbcture was stirred at room temperature for 2 hours. The solvent was removed, and the residue was purified by chromatography on sUica gel to give the title compound.
Step 469b. 8-(3-(S)-( 1 -aminocyclopropyl)pyrrolidinyl)- 1 -cyclopropyl- 7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid hydrochloride
FoUowing the procedure of Example 253j, substituting 3-(S)-(l-(BOC-amino)- cyclopropyl)pyrrolidine from step 468b for the BOC-amino-pyrroUdine thereof, and carrying the product forward as in steps 253k&l the title compound was prepared. The spectroscopic data were simtiar to the racemic mixture of Example 311 above. Example 470
8-(3-( 1 -amino- 1 -cyclopropyl-methyl)pyrrolidinyl)- 1 -cyclopropy 1- 7-fluoro-9-methyl-4-oxo-4H-quinoUzme-3-carboxylic acid hydrochloride
Step 470a. l-cyclopropyl-prop-2-ene-l-one
A sample (5 g, 59 mmol) of 1 -cyclopropyl methyl ketone (Aldrich) was dissolved in 59 mL of THF, and the solution was heated at reflux under N2, then cooled. Another solution 7.97 g of formaUn and 19.57 g of N-methylpyridinium trifluoroacetate was prepared. Half of the second solution was added to the cooled first solution, and this mixture was then heated at reflux for half an hour. The reaction mixture was then cooled, the second half of the second solution was added, and the reaction mixture heated at reflux for 7 hours. The mixture was cooled, and ether (100 mL) was added slowly with stirring, and a gummy precipitate was obtained. The gum was triturated with ethers. The ether solutions were combined and extracted with aqueous NaHCO3. The ether solution was dried, filtered and concentrated. The residue was triturated with ether, and the ether solution was again dried, fUtered and concentrated to give 4.60 g of the tifle compound.
Step 470b. fl-benzyl-pyrroldin-3-ylVcyclopropyI-methanone
A 2 g sample of the compound from step 470a and 4.94 g of N-benzyl-N- (methoxymethyl)-trimethylsUylmethylamine were dissolved in methylene chloride, and the solution was cooled in an ice bath. To this solution was added 2.1 mL of TFA (1 N in methylene chloride), and the reaction mixture was stirred at room temperature for 2 hours. The mixture was diluted with methylene chloride, and the solution was washed with NaHCO3, water and brine, then concentrated. The residue was purified by chromatography on silica gel to give 2.037 g of the title compound.
Step 470c. 1-f l-benzyl-pyrroldin-3-ylVl-cyclopropyl-methylamine
A 1 g sample of the compound from step 470b, 3.37 g of ammonium acetate and 274 mg of NaBH3CN were dissolved in 15 mL of methanol, 1.2 g of 4A molecular sieves were added, and the mixture was stirred at room temperature under N2 for 16 hours. The mixture was fUtered, the sieves washed with methanol, the wash and filtrate combined, and concentrated. The residue was dissolved in 100 mL of methylene chloride, and 30 mL of 15% NaOH was added. The organic phase and a second wash of the aqueous phase were combined and washed with water and brine, then dried over MgSO4. The solvent was removed, and the residue was chromatographed on siUca gel to give 460 mg of the title compound.
Step 470d. N-BOC-l-fl-benzyl-pyπ-oldin-3-yl)-l-cvclopropyl-methylamine
The compound from step 470c was treated with di-t-butyl dicarbonate in methylene chloride and triethylamine for 2 hours, and the title compound (640 mg) was obtained after chromatography on sUica gel.
Step 470e. 3- l-fBOC-aminoVl-cyclopropyl-methvDpyιτolidine
A sample (548 mg) of the compound from step 470d was dissolved in methanol,
140 mg of 10% Pd/C was added, and the mixture was hydrogenated at 4 atm H2 for 42 hours at room temperature. The solution was fUtered, and the solvent was removed to give 140 mg of the titie compound.
Step 470f. 8-(3-(l -amino- l-cyclopropyl-methyl)pyrrolidinyl)-l-cyclopropyl- 7 -fluoro- 9-methyl-4-oxo-4H-quinoUzine-3-carboxylic acid hydrochloride
FoUowing the procedure of Example 253j, substituting 3-(l-(BOC-amino)-l- cyclopropyl-methyl)pyrrolidine from step 470e for the BOC-amino-pyrroUdine thereof, and carrying the product forward as in steps 253k&l the titie compound was prepared. 1H NMR (DMSO-d6) 3: 0.46 (m, IH), 0.62 (m, 4H), 0.92 (m, IH), 1.03 (m, 2H), 1.82 (m, IH), 2.27 (m, 3H), 2.61 (s, 3H), 3.74 (m, 2H), 3.89 (m, 2H), 7.90 (s, IH), 9.07 (d, IH), 13.83 (br s, IH). HRMS (M+H)+: calculated for C22H27FN3O3: 400.2036; found: 400.2030.
Example 471
8-(3-(R)-(pyrrolidin-2-(S)-yl)pyrrolidin- 1 -yl)- 1 -cyclopropyl- 7-fluoro-9-methyI-4-oxo-4H-quinolιzine-3-carboxylic acid hydrochloride
Step 471a. 3-fRW l-BOC-2-fSVpyrrolidinylV4-nitrobutanol
A 7.5 g sample of ethyl 3-(R)-(l-BOC-2-(S)-pyrrolidinyl)-4-nitrobutanoate
(prepared according to the procedure of Hayakawa et al., U.S. Patent 5,098,912, issued March 24, 1992) was dissolved in 35 mL of ether and treated with 0.76 g of LAH. After careful quenching of the excess reagents, the tifle compound was extracted and purified by chromatography (4.5 g). Step 471b. 3-fRVf l-BOC-2-fSVpyrroUdinylV4-nitrohutanyl methylsulfonyl ether
A 3.5 g sample of the alcohol from step 47 la above was dissolved in 25 mL of methylene chloride and treated with methanesulfonyl chloride an TEA at 0°C for 2 hours. The reaction mixture was washed with NaHCO3 solution and water, and the solvent was removed. The residue was chromatographed on siUca gel to give 3 g of the title compound.
Step 471c. 3-fRVf l-BOC-pyrrolidin-2-fSVvnpyrroUdine
The ether compound from step 471a was treated by hydrogenation at 4 atm H2 over Pd/C in methanol to give the tile compound.
Step 47 Id. 8-(3-(R)-(pyrrolidm-2-(S)-yl)pyrrolidin- 1 -yl)- 1 -cyclopropyl- 7-fluoro-9-methyI-4-oxo-4H-quinolizine-3-carboxylic acid hydrochloride
FoUowing the procedure of Example 253j, substituting 3-(R)-(l-BOC-pyrrolidin- 2-(S)-yl)pyrrolidine from step 471c for the BOC-amino-pyrrolidine thereof, and carrying the product forward as in steps 253k&l the titie compound was prepared. MS 400 (M+H)+. 1H NMR (DMSO-d6) 3: 0.58-0.62 (m, 2H), 0.9-1.1 (m, 2H), 1.68-2.8 (m, 8H), 2.5 (s, 3H), 3.1-3.8 (m, 7H), 7.9 (s, IH), 9.08 (dd, 2H).
Example 472
8-(3-(aminomethyl)azetidin- 1-yl)- 1 -cyclopropyl -7-fluoro- 9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid hydrochloride
Step 472a. 3-fBOC-aminomethvD-l-diphenylmethyl-azetidine
A sample (0.6 g) of 3-aminomethyl-l-diphenylmethyl-azetidine (prepared according to Anderson and Lok, J. Org. Chem., 22:3393-5 (1972)) was treated with di-t- butyl dicarbonate in methylene chloride and triethylamine for 2 hours, and the title compound (450 mg) was obtained after chromatography on siUca gel. Step 472b. 3-fBOC-aminomethyl -azetidine
A sample of the compound from step 473a was treated with 4 atm of H2 in the presence of Pd/C in methanol at room temperature. The mixture was filtered, and the solvent was removed to give the titie compound.
Step 472c. 8-(3-(aminomethyl)azetidin-l-yl)-l-cyclopropyl-7-fluoro- 9-meτhyl-4-oxo-4H-quinolizine-3-carboxylic acid hydrochloride
FoUowing the procedure of Example 253j, substituting 3-(BOC-aminomethyl)- azetidine from step 472b for the BOC-amino-pyrroUdine thereof, and carrying the product forward as in steps 253k&l the title compound was prepared. MS 346 (M+H)+. 1H NMR (DMSO-d6) 3: 0.61 (m, 2H), 0.98 (m, 2H), 2.16 (m, IH), 2.60 (s, 3H), 3.01 (m, IH), 3.76 (m, IH), 4.41 (m, 2H), 4.69 (m, 2H), 7.88 (s, IH), 9.10 (d, IH).
Example 473 6- amino-8-(3-aιninopyrrotidinyl)- 1 -cyclopropyl -7 -fluoro-4H-
9-methvI-4-oxo-quinolizine-3-carboxylic acid hydrochloride
Step 473a. 4-t-Butoxy-6-dibenzylamino-2.5-difluoro-3-methylpyridine
4-t-Butoxy-2,5,6-trifluoro-3-methylpyridine from Step 253c above is reacted with dibenzylamine in ethanol at reflux temperature. Solvent is removed, and the residue is dissoved in methylene chloride and washed with water. The product is purified by column chromatography.
Step 473b. 6-m-benzylamino-8-(3-aminopyrrolidinyl)-l-cyclopropyl- 7-fluoro-4H-9-methyl-4-oxo-quinoUzine-3-carboxylic acid hydrochloride
FoUowing the procedure of Example 253e, replacing 4-t-butoxy-2,5-difluoro-3- methylpyridine with 4-t-butoxy-6-dibenzylaπύno-2,5-difluoro-3-methylpyridine from Step 473a above, and carrying the product forward as in Example 253 steps e-1, the titie compound is prepared.
Step 473c. 6-aιτ no-8-(3-arninopyrroUdinyl)-l-cyclopropyl- 7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid hydrochloride
A sample from Step 473d above is heated with ammonium formate in the presence of 10% Pd-C in ethanol. After the completion of the reaction, the mixture is fUtered and the filtrate is concentrated and treated with HCI in ether to give the titie compound.
Example 474 6-amino-8-(7-arcύno-5-azaspiro[2.4]heptan-5-yl)-l-cyclopropyl-
7-fluoro-4H-9-methyl-4-oxo-quinoUzine-3-carboxylic acid hydrochloride
Following the procedures of Example 473, replacing 3-BOC-aminopyrroUdine with 7-BOC-amino-5-azaspiro[2.4]heptane (prepared according to the procedures as described in J. Med. Chem. 1994, 2, 3344), and carrying the product forward the titie compound is prepared.
Example 475
6-amino-8-(2,8-diaza-8-bicyclo[4.3.0]nonyl)-l-cyclopropyl- 7-fluoro-4H-9-methyl-4-oxo-quinoUzine-3-carboxylic acid hydrochloride
Following the procedures of Example 473, replacing 3-BOC-aminopyrroUdine with 2,8-diazabicyclo[4.3.0]nonane (prepared according to US 5,059,597), and carrying the product forward the titie compound is prepared.
Example 476
6-amino-8-(3,5-ris-dimethylpiperazin- 1-yl)- 1 -cyclopropyl- 7.9-difluoro-4H-4-oxo-quinolizine-3-carboxylic acid hydrochloride
Following the procedure of Example 473a, replacing 4-t-butoxy-2,5,6-trifluoro-
3-methylpyridine with 4-t-butoxy-2,3,5,6-tertafluoropyridine from Example 274b above, and carrying the product forward as in Example 473b-c, replacing 3-BOC- aminopyrrolidine with 3,5- s-dimethylpiperazine and carrying the product forward the titie compound is prepared. Example 477
8- ( 1 -amino- 1 -cyclopropyl)- 1 -cyclopropy 1-7-fluoro- 9-methyl-4H-4-oxo-quinolizine-3-carboxylic acid hydrochloride
Step 477a. l-cyclopropyl-8-(diphenylmethoxycarbonylmethyl)- 7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid ethyl ester
To a suspension of NaH in DMF with ice bath cooUng is added di-t-butyl malonate. After the addition, 8-chloro- l-cyclopropyl-7 -fluoro- 9-methyl-4-oxo-4H- quinolizine-3-carboxylic acid ethyl ester from Example 253i above is added. The reaction is then heated to 50 to 60°C, and the mixture is poured into water and acidified. The product is extracted into methylene chloride and dried over MgSOφ The residue, after removal of the solvent, is dissolved in methylene chloride and trifluoroacetic acid at room temperature. The solvent is removed under vacuum, and the product is treated with diphenyldiazomethane in methylene chloride and methanol. When the reaction is finished, the solvents are removed under vacuum, and the product is purified by column chromatography to give the title compound.
Step 477b. l-cyclopropyl-8-(l-diphenylmethoxycarbony-l-vinyl)- 7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid ethyl ester
The product from Step 477a is heated with 35% formaldehyde in DMF in the presence sodium bicarbonate. When the reaction is complete, the product is extracted into methylene chloride, washed with water and dried over MgSOφ The solvent is removed, and the residue is dissolved methylene chloride. Triethylamine is added, foUowed by methanesulfonyl chloride with ice bath cooling. After the addition, the reaction is stirred at room temperature, then poured into water and acidified. The mbcture is extracted with ethylene chloride, and the solvent is removed to give the crude product, which is purified by column chromatography.
Step 477c. 1 -cyclopropyl-8-( 1 -diphenylmethoxycarbony- 1 -cyclopropyl)- 7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid ethyl ester
Trimethylsulfonium iodide is added to a stirred solution of NaH in DMSO at 0°C and the resulting solution is stirred at room temperature. The product from Step 477b above is added and mixture is stirred at 50°C. The mixture is quenched with water, and the product is extracted to give the titie compound.
Step 477d. l-cyclopropyl-8-(l-hydroxycarbonyl-l-cyclopropyl)- 7-fluoro-9-methyl-4-oxo-4H-quinoiizine-3-carboxylic acid ethyl ester
The product from Step 477d is dissolved in the mixture of anisol and trifluoroacedic acid and is stirred at room temperature. The solvents are removed and residue is purified by a column chromatography to give the title compound. Step 477e. l-cyclopropyl-8-(l-Bocamino-l-cyclopropyl)-7-fluoro- 9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid ethyl ester
A sample of the product from Step 477d is heated with diphenylphosphoryl azide, t-butanol, triethylamine and dioxane. The solvents is removed under vacuum. The residue is dissolved in methylene chloride, washed with water and dried over MgSO4 and concentrated under vacuum. The title compound is purified by chromatography on sUica gel.
Step 477f. l-cyclopropyl-8-(l -amino- l-cyclopropyl)-7-fluoro- 9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid hydrochloride
The product from Step 477e is treated by procedures as described in Example 253 k-1 to give the title compound.
Example 478 3(R)-10-(l-antino-l-cyclopropyl)-9-fluoro-3-methyl-2H,3H,6H-
6-oxo-pyranoI2.3.4-iilquinolizine-5-carboxylic acid hydrochloride
FoUow the procedures as described in Example 477, replacing 8-chloro-l- cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid ethyl ester with 3(R)-10-chloro-9-fluoro-3-methyl-2H,3H,6H-6-oxo-pyrano[2.3.4-ij]quinolizine-5- carboxylic acid ethyl ester from Example 28 le to give the titie compound.
Example 479
8-( 1 -amino- 1 -cyclopropyl)- 1 -cyclopropyl-7-fluoro- 9-methoxy-4H-4-oxo-quinolizine-3-carboxylic acid hydrochloride
FoUow the procedures as described in Example 477, replacing 8-chloro-l- cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinoUzine-3-carboxylic acid ethyl ester with 8- chloro- 1 -cyclopropyl-7-fluoro-9-methoxy-4H-4-oxo-quinolizine-3-carboxyUc acid ethyl ester from Example 275 to give the title compound. Example 480
8-( 1 -aminomethyl- 1 -cyclopropyl)- 1 -cyclopropyl-7-fluoro- 9-methyl-4H-4-oxo-quinolizine-3-carboxyUc acid hydrochloride
Step 480a. 8-(l -cyano- 1 -cyclopropyl)- 1-cyclopropyl- 7-fluoro-9-metnyl-4H-4-oxo-quinoUzine-3-carboxylic acid ethyl ester.
The product from Example 477d is treated with oxalyl chloride in methylene chloride foUowed by quenching with aqueous ammonia. Aqueous work up gives the amide, which is treated with POCI3 at room temperature to give the titie compound.
Step 480b. 8-(l-Bocaminomethyl-l -cyclopropyl)- 1 -cyclopropy 1- 7-fluoro-9-methyl-4H-4-oxo-quinolizine-3-carboxyUc acid ethyl ester
The product from Step 480a is treated with Raney Ni in ethanol under hydrogen. The residue after removal of the solvent is reacted with d-t-butyl dicarbonate in the mixture of methanol and water. Reaction is extracted into methylene chloride, washed with water and dried over MgSO4 and concentrated under vacuum. The title compound is purified by chromatography on sUica gel.
Step 480c. 8-( 1 -aminomethyl- 1 -cyclopropyl)- 1 -cyclopropyl-7-fluoro- 9-rnethyl-4H-4-oxo-quinolizine-3-carboxylic acid hydrochloride
The product from Step 480b is treated by procedures as described in Example 253 k-1 to give the title compound.
Examples 481-565
Following the procedures of Steps 253j, 253k and 2531 above, replacing the 3- BOC-aminopyrrolidine of Step 253j with the appropriate unprotected or BOC-protected reagent, the compounds of Examples 481-565 are prepared as shown in Table 13 A, below. In those cases wherein specific chiral isomers are indicated, the examples are to be understood as also representing the opposite stereoisomers and diasteromers thereof. Tabl 13A
Example 566 8-(trα/w-3-(S)-amino-4-(R)-cyclopropylyrrolidm- 1 -yl)- 1 -cyclopropyl-
7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid hydrochloride
Step 566a. l-benzyl-4-cyclopropylpyrroUdine-3-carboxyUc acid ethyl ester
Ethyl 3-cyclopropylacrylate (7.00 g, 50.0 mmol, prepared according to J. Org. Chem. 1987, 52, 2629) and N-benzyl-N-(methoxymethyl)trimethylsilylmethylamine (11.85 g, 50.0 mmol) were dissolved in methylene chloride (100 mL), and the solution was cooled to 0°C and flushed with N2. Trifluoracetic acid (5.0 mL, IN in methylene chloride) was added dropwise at 0°C over 10 minutes, and the reaction mixture was stirred under N2 for 2 hours while aUowing the reaction temperature to rise to room temperature. The mixture was stirred for an additional 18 hours, washed with 5% NaHCO3 and brine, dried (over Na2SO4) and concentrated. The residue was purified by chromatography on siUca gel, eluting with 1 :3 etheπhexane, to afford the title compound (9.30 g, oU).
Step 566b. l-benzyl-4-cyclopropylpyτrolidine-3-carboxylic acid
A sample of the compound from step 566a (5.46 g) was dissolved in methanol
(100 mL) and 15% aqueous NaOH (100 mL) was added dropwise at room temperature over 20 minutes. The mixture was stirred for 2.5 hours, and the methanol was removed under vacuum. The aqueous solution was then washed with methylene chloride, neutralized to pH 4 with 6N HCI, saturated with NaCl, and extracted with 1 :3 isopropanolrmetiiylene chloride. The extract was washed with brine, dried (over Na2SO4) and concentrated. The residue was vacuum dried to afford the titie compound (4.758 g). Step 566c. l-benzyl-3-('BOC-amino')-4-cyclopropylpyrroUdine
The compound from step 566b (4.70 g) was dissolved in t-butanol under N2. Triethylamine (5.34 mL, 38.4 mmol) and DPPA (6.08 g, 22.1 mmol) were added, and the mixture heated at 90°C under N2 for 24 hours. The solvent was removed, and the residue was purified by chromatography on sUica gel, eluting with 5% methanol in methylene chloride, to afford the title compound (4.77 g).
Step 566d. 3-("BOC-amino)-4-cvclopropylpyιτolidine
The compound from step 566c (6.952 g, 22 mmol) was dissolved in methanol (100 mL). The solution was flushed with N2, ammonium formate (6.93 g, 110 mmol) and 10% Pd/C (695 mg) were added, and the mixture was heated at 80°C for 26 hours. The mixture was cooled, diluted with methylene chloride and filtered. The solvent was removed to give the titie compound (5.80 g).
Step 566e. l-BenzyloxycarbonyI-3-fBOC-amino')-4-cvclopropyl
The compound from step 566d (2.0 g, 11.9 mmol) and K2CO3 (1.88 g, 17.8 mmol) were dissolved in 50% aqueous dioxane (40 mL), and the solution was flushed with N2 and cooled to 0°C. Benzyl chloroformate (2.43 g, 14.2 mmol) was added dropwise over 10 minutes, and the mixture was stirred under N2 at 0°C for 5 hours. The mixture was taken up in ether and washed with water, IN HCI, water and brine, then dried over Na2SO4. The solvent was removed, and the residue was purified by chromatography on sUica gel, eluting with 1:3 ethyl acetate:hexane to give the titie compound (1.96 g, oU).
The diastereomeric mixture was then separated by preparative HPLC (Chiralpak AS column eluted with 2.5 % ethanol in hexane) to give the pure 3-(S)-4-(R)- and 3-(R)-4- (S)- diastereomers of the titie compound.
Step 566f. 3-fSUBOC-am oV4-fRVcvclopropyrpyrrolidine
The 3-(S)-4-(R)-compound from step 566e was dissolved in methanol (40 mL). The solution was flushed with N2, ammonium formate (1.04 g, 16.5 mmol) and 10% Pd/C (208 mg) were added, and the mixture was heated at reflux for 1 hour. The mixture was cooled, diluted with methylene chloride and filtered. The solvent was removed to give the title compound (795 mg). Step 566g. 8-(trαrt5-3-(S)-amino-4-(R)-cyclopropylyrroUdin- 1 -yl)- 1 -cyclopropyl- 7-fluoro-4H-9-methyl-4-oxo-quinoUzine-3-carboxylic acid hydrochloride
FoUowing the procedure of Example 253j, substituting the 3-(S)-(BOC-amino)-4- (R)-cyclopropylpyrrolidme from step 566f for the BOC-amino-pyrrolidine thereof, and carrying the product forward as in steps 253k & 1, the title compound (3.20 g) was prepared. MS m/z 386 (M+H)+ 1H NMR (DMSO-d6) 3: 9.08 (IH, d, J=10.5 Hz), 7.93 (IH, s), 4.18 (IH, m), 4.07 (IH, m), 3.79 (2H, m), 3.62 (IH, m), 2.62 (3H, s), 2.33 (IH, m), 1.84 (IH, m), 1.00 (2H, m), 0.90 (IH, m), 0.61 (2H, m), 0.53 (2H, m), 0.38 (IH, m), 0.22 (IH, m). Analysis calculated for C21H24N3O3F «HCM 1/4H2O: C, 56.76; H, 6.24; N, 9.45. Found: C, 56.99; H, 6.13; N, 9.38.
Example 567
8-(trα/w-3-(R)-amino-4-(S)-cyclopropylyrrolidin-l-yl)-l-cyclopropyl- 7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid hydrochloride
Step 567a. 3-fR)-(BOC-amino)-4-fS)-cyclopropyrpyrrolidine
A sample of the 3-(R)-4-(S)-l-benzyloxycarbonyl-3-(BOC-amino)-4- cyclopropylpyrroUdine of step 566e (640 mg) was treated as in Example 566f to give the title compound (465 mg).
Step 566d. 8-(tra/i5-3-(R)-amino-4-(S)-cyclopropylyrroUdin-l-yl)-l-cyclopropyl- 7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid hydrochloride
FoUowing the procedure of Example 253j, substituting the 3-(R)-(BOC-amino)- 4-(S)-cyclopropylpyrroUdine from step 567a for the BOC-amino-pyrrolidine thereof, and carrying the product forward as in steps 253k & 1, the titie compound (318 mg) was prepared. MS m/z 386 (M+H)+. 1H NMR (DMSO-d6) d: 9.10 (IH, d, J=10.5 Hz),
7.95 (IH, s), 4.19 (IH, m), 4.07 (IH, m), 3.79 (2H, m), 3.62 (IH, m), 2.62 (3H, s),
2.33 (IH, m), 1.84 (IH, m), 1.00 (2H, m), 0.90 (IH, m), 0.61 (2H, m), 0.53 (2H, m), 0.38 (IH, m), 0.22 (IH, m). Analysis calculated for C21H24N3O3F .HCM 1/4H2O: C,
56.76; H, 6.24; N, 9.45. Found: C, 56.80; H, 6.12; N, 9.38. Example 568
8-(trα«j,-3-(S)-amino-4-(R)-methylyrroUdin- 1-yl)- 1 -cyclopropyl- 7-fluoro-4H-9-methyl-4-oxo-quinohzine-3-carboxylic acid hydrochloride
Step 568a. tran.T-3-fBOC-amino)- 1 -benzyl-4-methylpyrrolidine
trfl/i5-3-amino-l-benzyl-4-methylpyrrolidme (1.5 g, 41.3 mmol, prepared according to the procedures of Cesare, T.D., et al.. J. Med. Chem. 25: 4205-4213 (1992).) was dissolved in aqueous methanol at 0°C and treated with t-butyloxycarbonic anhydride (9.9 g), stirring for 16 hours. The product was collected by filtration as well as extraction with methylene chloride, and the titie compound was dried and taken directly to the next step.
Step 568b. trqns-3-(BOC-amino)-4-meτhylpyrroUdine
The compound from step 568a (8.65 g, 29.8 mmol) was dissolved in anhydrous methanol. The solution was flushed with N2, ammonium formate (9.39 g, 749 mmol) and 10% Pd/C (86.5 mg) were added, and the mixture was heated at 80°C for 2 hours. The mixture was cooled, diluted with methylene chloride and filtered. The solvent was removed to give the title compound (6.51 g). MS m/z 201 (M+H)+.
Step 568c. trαw.y-3-fBOC-aminoVl-CBZ-4-methylpyrroUdine
The compound from step 568b (6.51 g, 29.8 mmol) was dissolved in 90 mL of 50% aqueous dioxane, and K2CO3 (4.74g, 44.7 mmol) was added. The solution was stirred under N2 at 0°C, and benzyloxycarbonyl chloride (6.10 g, 35.76 mmol) was added dropwise over 15 minutes. The solution was stirred under N2 at 0°C for 5 hours, then dUuted with ether. The solution was washed with water and brine, dried and concentrated. The solvent was removed, and the residue was purified on sUica gel to give the titie compound (8.88 g, oil).
The enantiomers were separated by preparative chiral HPLC (Chiralpak AD column eluted with 5 % ethanol in hexane) to give the tr< ϊ-3-(S)-4-(R)- and trans-3-(R)-4- (S)- isomers of the titie compound.
Step 568d. trα«.v-3-('SVfBOC-aminoV4-(RVmethylpyrrolidine
The trfl W-3-(S)-(BOC-amino)-l-CBZ-4-(R)-methylpyrroUdine from step 568c (501 mg, 1.50 mmol) was dissolved in methanol (15 mL). The solution was flushed with N2, ammonium formate (472 mg, 7.50 mmol) and 10% Pd/C (100 mg) were added, and the mixture was stirred at room temperature for 26 hours. The mixture was cooled, dUuted with methylene chloride and filtered. The solvent was removed to give the titie compound (380 mg).
Step 568e. 8-(trflrt5-3-(S)-amino-4-(R)-methylyrrolidin-l-yl)-l-cyclopropyl- 7-fluoro-4H-9-methyl-4-oxo-quinoUzine-3-carboxylic acid hydrochloride
FoUowing the procedure of Example 253j, substituting the trύτιs-3-(S)-(BOC- amino)-4-(R)-methylpyιτoUdine from step 568d for the BOC-amino-pyrroUdine thereof, and carrying the product forward as in steps 253k & 1, the title compound (263 mg) was prepared. MS m/z 360 (M+H)+. 1H NMR (DMSO-d6) d: 9.07 (IH, d, J=10.8Hz), 7.93 (IH, s), 4.02 (2H, m), 3.89 (IH, m), 3.55 (2H, m), 2.63 (3H, s), 2.52 (IH, m), 2.31 (IH, m), 1.18 (3H, d, J=6.3 Hz), 0.99 (2H, m), 0.60 (2H, m). Analysis calculated for C19H22N3O3F •HCl^O: C, 55.14; H, 6.09; N, 10.15. Found: C, 54.98; H, 5.86; N, 9.91.
Example 569
8-(trα/w-3-(R)-amino-4-(S)-methylyrroUdin- 1 -yl)- 1 -cyclopropyl- 7-fluoro-4H-9-methyl-4-oxo-quinohzine-3-carboxylic acid hydrochloride
Step 569a. tra»,Y-3-("R)-('BOC-amino)-4-(,S)-methylpyrroUdine
The trα/w-3-(R)-(BOC-amino)-l-CBZ-4-(S)-methylpyrrolidine from Example 568c (501 mg, 1.50 mmol) was dissolved in methanol (15 mL). The solution was flushed with N2, ammonium formate (472 mg, 7.50 mmol) and 10% Pd/C (100 mg) were added, and the mixture was stirred at room temperature for 26 hours. The mixture was cooled, diluted with methylene chloride and filtered. The solvent was removed to give the title compound (380 mg).
Step 569b. 8-(trαn5-3-(R)-amino-4-(S)-methylyrrolidin- 1-yl)- 1-cyclopropyl- 7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid hydrochloride
FoUowing the procedure of Example 253j, substituting the trans -3-(R)-(BOC- amino)-4-(S)-methylpyrrolidine from step 569a for the BOC-amino-pyrrolidine thereof, and carrying the product forward as in steps 253k & 1, the title compound (246 mg) was prepared. MS m/z 360 (M+H)+. 1H NMR (DMSO-d6) 3: 9.11 (IH, d, J=10.5 Hz), 7.96 (IH, s), 4.02 (2H, m), 3.84 (IH, m), 3.55 (2H, m), 2.63 (3H, s), 2.50 (IH, m), 2.33 (IH, m), 1.17 (3H, d, J=6.3 Hz), 0.99 (2H, m), 0.60 (2H, m).
Example 570 8-(cw-3-(S)-amino-4-(S)-cyclopropylyrroUdin- 1 -yl)- 1 -cyclopropyl-
7-fluoro-4H-9-methyl-4-oxo-quinoUzine-3-carboxylic acid hydrochloride
Step 570a. ethyl N-benzyl-4-cvclopropyl-3-pyrrolinecarboxylate
Ethyl 3-cyclopropylpropiolate (2.76 g, 20.0 mmol, prepared by the method of Org. Syn., £6_:173 (1987)) and N-benzyl-N-(methoxymethyl)trimethylsilylmethylamine (4.76 g, 20.0 mmol) were dissolved in methylene chloride, cooled to 0°C and flushed with N2- TFA (2.0 mL, IN in methylene chloride) was added dropwise at 0°C over 10 minutes, and the mixture was stirred at 0°C under N2 for 2 hours and at room temperature for 22 hours. The mixture was washed with 5% aqueous NaHCO3 and brine, dried (Na2SO4) and concentrated. The residue was purified by chromatography on siUca gel, eluting with 1:2 to 1:1 ethyl acetate:hexane to give the titie compound (2.72g, oil).
Step 570b. fc/sVethyl N-benzyl-4-cyclopropyl-3-pyrrolidinecarboxylate
The compound from step 570a (2.72 g) was dissolved in ethanol and hydrogenated over Ptθ2 under 4 atm H2- The mixture was fUtered, the solvent was removed, and the residue was dried to afford the titie compound (2.36 g, oil).
Step 570c. (c/.vVefhyl 4-cvclopropyl-3-pyrrolidinecarboxylate
The compound from step 570b (2.36 g, 8.64 mmol) was dissolved in methanol (30 mL). The solution was flushed with N2, ammonium formate (2.72g, 43.2 mmol) and 10% Pd/C (300 mg) were added, and the mixture was stirred at 80°C for 3.5 hours. The mixture was cooled, diluted with methylene chloride and fUtered. The solvent was removed to give the titie compound (1.85 g).
Step 570d. Cc/ l-ethyl N-CBZ-4-cvclopropyl-3-pyrrolidinecarboxylate
The compound from step 570c (1.85 g, 10.1 mmol) was dissolved in 20 mL of 50% aqueous dioxane, and K2CO3 (1.59g, 15.0 mmol) was added. The solution was stirred under N2 at 0°C, and benzyloxycarbonyl chloride (2.04 g, 12.0 mmol) was added dropwise over 10 minutes. The solution was stirred under N2 at 0°C for 4 hours, then dUuted with ether. The solution was washed with water and brine, dried and concentrated. The solvent was removed, and the residue was purified on sUica gel to give the title compound (1.79 g, oil).
Step 570e. f s)-N-CBZ-4-cvclopropyl-3-pyrroUdinecarboxylic acid
The compound from step 570c (1.79 g, 5.65 mmol) was dissolved in methanol (40 mL) and 15% aqueous NaOH (40 mL) was added dropwise at room temperature over 10 minutes. The mixture was stirred for 4 hours, the methanol was removed under vacuum, and the aqueous residue was extracted with ether. The aqueous phase was neutralized to pH 3 with 6N HCI and extracted with methylene chloride. The extract was washed with brine, dried and concentrated to give the title compound (719 mg).
Step 570f. (c sV3-(ΩOC-an-rino)- 1 -CBZ-4-cyclopropylpyrrolidine
The compound from step 570d (648 mg, 2.24 mmol) was dissolved in t-butanol under N2. Triethylamine (0.623 mL, 4.48 mmol) and DPPA (740 mg, 2.69 mmol) were added, and the mixture heated at 90°C under N2 for 60 hours. The solvent was removed, and the residue was purified by chromatography on siUca gel, eluting with 1 :2 ethyl acetate hexane, to afford the titie compound (563 mg).
The racemic mixture was then separated by preparative HPLC (Chiralpak AS column elute with 2.5 % ethanol in hexane) to give the pure 3-(S)-4-(S)- and 3-(R)-4-(R)- enantiomers of the titie compound (146 mg) and (120 mg), respectively.
Step 570g. c/s-3-(S)-(BOC-amino)-4-(S)-cyclopropyIpyHθUdine
The (cw)-3-(S)-(BOC-amino)-l-CBZ-4-(S)-cyclopropylpyrrolidine from step
570e (143 mg, 0.397 mmol) was dissolved in methanol (10 mL). The solution was flushed with N2, ammonium formate (125 mg, 1.986 mmol) and 10% Pd/C (28.6 mg) were added, and the mixture was stirred at room temperature for 1 hour. The mixture was diluted with methylene chloride and filtered. The solvent was removed to give the titie compound. Step 570h. 8-(cw-3-(S -amino-4-(S)-cyclopropylyrrolidin-l-yl)-l-cyclopropyl- 7-fluoro-4H-9-methyl-4-oxo-quinoUzine-3-carboxylic acid hydrochloride
FoUowing the procedure of Example 253j, substituting the cw-3-(S)-(BOC- amino)-4-(S)-cyclopropylpyrrolidine from step 570f for the BOC-amino-pyrrolidine thereof, and carrying the product forward as in steps 253k & 1, the title compound (16 mg) was prepared. mp 240-242°C. MS m/z 386 (M+H)+. 1H NMR (DMSO-d6) 3: 9.11 (IH, d, J=l 1.4 Hz), 7.94 (IH, s), 4.18 (IH, m), 3.95 (2H, m), 3.81 (2H, m), 2.64 (3H, s), 2.32 (IH, m), 1.87 (IH, m), 0.98 (2H, m), 0.82 (IH, m), 0.59 (4H, m), 0.34 (IH, m), 0.28 (IH, m).
Example 571
8-(OT-3-(R)-amino-4-(R)-cyclopropylyrrolidin- 1 -yl)- 1 -cyclopropyl- 7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid hydrochloride
Step 571a. c .y-3-(R)-(BOC-amino)-4-(R)-cyclopropylpyrrolidine
The (cw)-3-(R)-(BOC-amino)-l-CBZ-4-(R)-cyclopropylpyrroUdine from step 570e (94 mg, 0.261 mmol) was dissolved in methanol (10 mL). The solution was flushed with N2, ammonium formate (82 mg, 1.305 mmol) and 10% Pd/C (19 mg) were added, and the mixture was stirred at room temperature for 1 hour. The mixture was cooled, diluted with methylene chloride and filtered. The solvent was removed to give the title compound (81 mg).
Step 571 b. 8-(cw-3-(R)-amino-4-(R)-cyclopropylyrrotidin- 1 -yl)- 1 -cyclopropyl- 7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid hydrochloride
FoUowing the procedure of Example 253j, substituting the c 5-3-(R)-(BOC- amino)-4-(R)-cyclopropylpyrroUdine from step 571a for the BOC-amino-pyrrolidine thereof, and carrying the product forward as in steps 253k & 1, the titie compound (54 mg) was prepared, mp 225 °C (dec). MS m/z 386 (M+H)+. lH NMR (DMSO-d6) 3: 9.11 (IH, d, J=l l.l Hz), 7.93 (IH, s), 4.18 (IH, m), 3.94 (2H, m), 3.81 (2H, m), 2.64 (3H, s), 2.34 (IH, m), 1.87 (IH, m), 1.05 (IH, m), 0.96 (IH, m), 0.82 (IH, m), 0.59 (4H, m), 0.35 (IH, m), 0.29 (IH, m). Example 572
8-(trα/w-3-amino-4-ethylpyrroUdin- 1 -yl)- 1 -cyclopropyl-7-fluoro- 4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid hydrochloride diastereomer A
Step 572a. 2-pentenoic acid ethyl ester
Propionaldehyde (5.8 g) and (carbethoxymethylene)triphenylphosphorane (35 g) were dissolved in methylene chloride (100 mL), and the mixture was refluxed overnight. The product was distiUed off from the reaction mixture.
Step 572b. trflAty-3-rBOC-aminoVl-CBZ-4-ethyl-pyrroUdine
Following the procedure of Example 435b, substituting the 2-pentenoic acid ethyl ester from step 572a above for the 4-fluoro-2-butenoic acid ethyl ester thereof, and carrying the product forward as in steps 435c and 435d, the title compound was prepared. The diastereomers were separated by chiral HPLC on a Chiralpak AS^M column, and diastereomer A (chirality not determined) was carried forward to the next step. 1H NMR (CDCI3) d: 7.4 (m, 5H), 5.18 (s, 2H), 6.4-4.60 (m, 3H), 4.30(m, IH), 3.60-3.80 (m, 3H), 3.10 (m, 2H), 1.95 (m, IH), 1.60 (m, IH), 1.30 (m, IH), 0.95 (t, 3H), 1.95 (s, 9H). Diastereomer B (chirality not determined) was carried forward to Example 573.
Step 572c. traw-3-(BOC-amino)-4-ethyI-pyrrolidine
The compound from step 2 was hydrogenated with Pd/C in ethanol as in step 435c above, and the titie compound was isolated.
Step 572d. 8-(trαtw-3-amino-4-ethylpyrroUdin-l-yl)-l-cyclopropyl- 7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid hydrochloride
Following the procedure of Example 435e, substituting the trα/w-3-(BOC-amino)- 4-ethyl-pyιτolidine from step 572c for the BOC-amino-pyrrolidine thereof, and carrying the product forward as in steps 253k & 1, the title compound was prepared. MS m/z 474 (M+H)+. 1H NMR (DMSO-d6) d: 9.10 (d, IH), 8.50 (s, IH), 4.10 (m, 2H), 3.50-3.80 (m, 3H), 2.60 (s, 3H), 2.30 (m, 2H), 1.7 (m, IH), 1.40 (m, IH), 1.0 (m, 5H), 0.6 (m, 2H). Example 573
8-(tr n5-3-amino-4-ethylpyrrolidin-l-yl)-l-cyclopropyl-7-fluoro-4H- 9-methyl-4-oxo-quinolizine-3-carboxyUc acid hydrochloride diastereomer B
Step 573a. trarø-3-(BOC-armno)-4-ethyl-pyrrolidine diastereomer B
The diastereomer B compound from step 572b was hydrogenated with Pd/C in ethanol as in step 435c above, and the titie compound was isolated.
Step 573b. 8-(trαws-3-amino-4-ethylpyrrotidin- 1 -yl)- 1 -cyclopropyl-7-fluoro-4H- 9-methyl-4-oxo-quinoUzine-3-carboxylic acid hydrochloride diastereomer B
Following the procedure of Example 435e, substituting the trαjw-3-(BOC-amino)- 4-ethyl-pyrroUdine diastereomer B compound from step 572c for the BOC-amino- pyrrotidine thereof, and carrying the product forward as in steps 253k & 1, the titie compound was prepared. MS m/z 474 (M+H)+. l NMR (DMSO-d6) d: 9.10 (d, IH), 8.50 (s, IH), 4.10 (m, 2H), 3.50-3.80 (m, 3H), 2.60 (s, 3H), 2.30 (m, 2H), 1.7 (m, IH), 1.40 (m, IH), 1.0 (m, 5H), 0.6 (m, 2H).
Example 574
8-(cw-3-amino-4-ethylpyrrolidin- 1 -yl)- 1 -cyclopropy 1-7 -fluoro- 4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid hydrochloride diastereomer A
Step 574a. 1 -CBZ-3-pyrroline
3-Pyrroline (Aldrich, 65% purity) was dissolved in a 1:1 mixture of dioxane and H2O. Na2CO3 was added. The reaction mixture was then flushed with N2 and cooled to 0 °C. Benzylchloroformate was added dropwise and the mixture was stirred at 0 °C for several hours. The reaction mixture was allowed to reach room temperature and was stirred for an additional 2 hours. Ethyl acetate was then added and the reaction mixture was washed with H2O and brine. The organic layer was dried over MgSO4, concentrated in vacuo and column chromatographed in a Hexane/EtOAc solution to afford the titie compound (65% purity).
Step 574b. 3.4-epoxy-l-CBZ-pyrroline
Five grams of crude l-CBZ-3-pyrroline from step 574a was dissolved in 25 mL of CH2CI2. 3-Chloroperoxybenzoic acid was added over 5 minutes. The reaction mixture was aUowed to stir at room temperature for 22 hours. The reaction mixture was then filtered, and filtrate was diluted with 30 mL of CH2CI2 and washed with Na2S2θ3 solution, NaHCO3 solution and H2O. The organic layer was dried over MgSO4, concentrated in vacuo, and chromatographed on siUca gel eluting with hexane/EtOAc solution. The title compound was obtained in 76% yield. MS m/z 220 (M+H)+. 1H
NMR (CDCI3) d: 3.35 (ddd, 2H), 3.65-3.70 (m, 2H), 3.80-3.90 (dd, 2H), 5.15 (d, 2H), 7.30-7.40 (m, 5H).
Step 574c. cis-3-( hvdroxy - 1 -CBZ-4-ethyl-pyrroUdine
The compound from step 574b (2.0 g) was dissolved in 20 mL of THF, and
CuCN (0.081 g) was added. The mixture was cooled to -70°C, and 5.5 mL of EtMgCl solution was then added over 20 minutes. The mixture was aUowed to warm to -50°C and was stiιτed at this temperature for 1 hour. The solution was then allowed to warm to -20 °C over the next hour. Finally, the solution was left to stir overnight and allowed to reach room temperature. The following morning, the reaction was quenched with 2N HCI.
EtOAc was added, and the layers were separated. The organic layer was washed with H2O and saturated NaCl solution, dried over MgSO4, concentrated in vacuo, and chromatographed on siUca gel to give the title compound in 88% yield. MS m/z 250 (M+H)+. lH NMR (CDCI3) d: 0.90-1.00 (t, 3H), 1.15-1.35 (m, IH), 1.45-1.65 (m, 3H), 1.90-2.05 (m, IH), 3.10-3.25 (m, IH), 3.25-3.40 (m, IH), 3.60-3.75 (m, 2H), 5.14 (s, 2H), 7.25-7.40 (m, 5H).
Step 574d. ri,v-3-fphthalimideVl-CBZ-4-ethyl-pyrrolidine
The compound from step 574b (5.22 g), PPh3 (8.24 g) and phthaUmide (4.0 g) were placed in a flask, flushed with N2, cooled to 0°C, and dissolved in 50 mL of THF. DEAD (4.3 mL) was then added dropwise over 25 minutes. The resultant solution was stirred for 51 hours at room temperature. The solvent was then removed in vacuo and the product was purified by column chromatography to give the titie compound in 86% yield. MS m/z 379 (M+H)+. 1H NMR (CDCI3) d: 0.85-0.95 (m, 2H), 1.15-1.40 (m, 3H), 2.37-2.53 (m, IH), 3.42 (t, IH), 3.75-4.00 (m, 2H), 4.10-4.35 (m, IH), 7.27-7.45 (m, 5H), 7.72-7.80 (m, 2H), 7.80-7.90 (m, 2H). Step 574e. ri.γ-3-fBOC-aminoVl-CBZ-4-ethyl-pyrrohdine
The compound from step 574c (6.56 g) was dissolved in EtOH, NH2NH2φH2θ (2.7 mL) was added and the mixture was refluxed for 5.5 hours. The reaction mixture was then cooled, fUtered, and the filtrate was concentrated in vacuo . The residue was dissolved in 20 mL of CH2CI2 and cooled to 0 °C. BOC2O (4.9 g), Et3N (3.0 mL), and a catalytic amount of DMAP were added and the mixture was aUowed to reach room temperature while stirring overnight. The following morning CH2CI2 was added, and the mixture was washed with NaHCO3 solution, H2O and brine. The organic layer was dried over MgSO4, concentrated in vacuo and column chromatographed in a hexane/EtOAc solution. The diastereomers were separated by chiral HPLC on a Chiralpak AS^M column. Diastereomer A was carried forward to the next step. MS m/z 349 (M+H)+. 1H NMR (CDCI3) d: 0.90-1.00 (td, 3H), 1.20-1.50 (m, 2H), 1.45 (s, 9H), 2.05-2.12 (m, IH), 3.01 (q, IH), 3.41 (t, IH), 3.51-3.71 (m, 2H), 4.24 (broad s, IH), 4.53 (broad s, IH), 5.13 (s, 2H), 7.18-7.40 (m, 5H). Diastereomer B was carried forward to Example 575.
Step 574f. c/s-3-fl3OC-aminoV4-ethyl-pyrrolidine
The compound from step 574d was hydrogenated with Pd/C in ethanol as in Example 435c, and the title compound was isolated. MS m/z 215 (M+H)+. 1H NMR (CDCI3) d: 0.90-1.00 (m, 3H), 1.42 (s, 9H), 2.00-2.10 (m, 2H), 2.50-2.60 (m, IH), 2.80-2.90 (m, IH), 3.15-3.25 (m, 2H), 4.12-4.25 (m, IH), 4.75-4.85 (m, IH).
Step 574g. 8-( -3-amino-4-ethylpyrrolidin- 1 -yl)- 1 -cyclopropyl-7-fluoro- 4H-9-methyl-4-oxo-quinolizine-3-carboxyUc acid hydrochloride
FoUowing the procedure of Example 253j, substituting the c -t-2-(BOC-amino)-3- ethyl-pyrrolidine from step 574e for the BOC-amino-pyrroUdine thereof, and carrying the product forward as in steps 253k & 1, the title compound was prepared. MS m/z 374 (M+H)+. ! H NMR (DMSO-d6) d: 13.80 (broad s, IH), 9.14 (d, IH), 8.42 (s, 2H), 7.78 (s, IH), 4.20-4.30 (m, IH), 385-3.95 (m, 2H), 3.78 (d, IH), 3.66 (t, IH), 2.61 (s, 3H), 2.33-2.5 (m, IH), 2.20-2.32 (m, IH), 1.39-1.61(m, 2H), 0.82-1.10 (m, 5H), 0.48-0.53 (m, 2H). Example 575
8-(cw-3-amino-4-ethylpyrroUdin- 1 -yl)- 1 -cyclopropyl-7-fluoro-4H- 9-methyl-4-oxo-quinoUzine-3-carboxylic acid hydrochloride diastereomer B
Step 575a. c/5,-3-fBOC-am o)-4-ethyl-pyrroUdine
The diastereomer B compound from Example 574d was hydrogenated with Pd/C in ethanol as in Example 435c, and the titie compound was isolated. MS m/z 215 (M+H)+. lH NMR (CDCI3) d: 0.90-1.00 (m, 3H), 1.42 (s, 9H), 2.00-2.10 (m, 2H), 2.50-2.60
(m, IH), 2.80-2.90 (m, IH), 3.15-3.25 (m, 2H), 4.12-4.25 (m, IH), 4.75-4.85 (m, IH).
Step 575b. 8-(cw-3-amino-4-ethylpyrrolidin- 1-yl)- l-cyclopropyl-7-fluoro-4H- 9-methyl-4-oxo-quinohzine-3-carboxylic acid hydrochloride
FoUowing the procedure of Example 253j, substituting the cw-2-(BOC-amino)-3- ethyl-pyrrolidine from step 575b for the BOC-amino-pyrrolidine thereof, and carrying the product forward as in steps 253k & 1, the title compound was prepared. MS m/z 374
(M+H)+. lH NMR (DMSO-d6) d: 13.80 (broad s, IH), 9.14 (d, IH), 8.42 (s, 2H), 7.78 (s, IH), 4.20-4.30 (m, IH), 385-3.95 (m, 2H), 3.78 (d, IH), 3.66 (t, IH), 2.61 (s, 3H), 2.33-2.5 (m, IH), 2.20-2.32 (m, IH), 1.39-1.61(m, 2H), 0.82-1.10 (m, 5H), 0.48-0.53 (m, 2H). Example 576
8-(cw-3-(S)-amino-4-(S)-methylpyrroUdin- 1 -yl)- 1 -cyclopropyl- 7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid hydrochloride
Step 576a. c/.γ-3-rBOC-amino)-4-methyl-pyrrolidine
cw-3-(BOC-amino)-4-methyl-l-benzylpyrroUdine (prepared according to the procedures of Cesare, T.D., et al., J. Med. Chem. 25: 4205-4213 (1992)) was hydrogenated with Pd/C in ethanol as in step 435c above, and the title compound was isolated. This compound was treated with benzyl chloroformate, the diastereomers were separated by chiral HPLC on a Chiralpak AS^M column, and the individual compounds were deprotected according to the procedures described in Example 568 steps c and d above. The 3S,4S-compound was carried forward to the next step. MS 201 (M+H)+. 1H NMR (CDCI3) d: 0.97 (d, 2H), 1.45 (s, 9H), 2.05 (s, 2H), 2.20-2.32 (m, IH), 2.50 (t, IH), 2.60-2.68 (dd, IH), 3.12-3.30 (m, 2H), 4.12 (s, IH), 4.63 (s, IH). The 3R,4R- compound was carried forward to the Example 576. Step 576b. 8-(c -3-(S)-amino-4-(S)-methylpyrrolidin- 1 -yl)- 1 -cyclopropyl- 7-fluoro-4H-9-methyl-4-oxo-quinoUzine-3-carboxylic acid hydrochloride
FoUowing the procedure of Example 253j, substituting the compound from step 576a for the BOC-amino-pyrrolidine thereof, and carrying the product forward as in steps 253k & 1, the title compound was prepared. MS 360 (M+H)+. 1H NMR (DMSO-d6) d: 13.84 (broad s, IH), 9.10 (d, IH), 8.36 (s, 2H), 7.94 (s, IH), 4.22-4.32 (m, IH), 3.70- 3.95 (m, 4H), 2.64 (s, 3H), 2.58-2.62 (m, IH), 2.25-2.37 (m, IH), 1.35 (d, 3H), 1.00- 1.10 (m, IH), 0.88-0.98 (m, IH), 0.50-0.78 (m, 2H).
Example 577
8-(cw-3-(R)-amino-4-(R)-methylpyrrolidin- 1 -yl)- 1 -cyclopropyl- 7-fluoro-4H-9-methyl-4-oxo-quinolιzιne-3-carboxylic acid hydrochloride
Step 577a. ris-3-fBOC-amino)-4-methyl-pyrrolidine
The 3R,4R compound from step 576a was hydrogenated with Pd/C in ethanol as in Example 435c, and the titie compound was isolated. MS m/z 201 (M+H)+. 1H NMR (CDCI3) d: 0.97 (d, 2H), 1.45 (s, 9H), 2.05 (s, 2H), 2.20-2.32 (m, IH), 2.50 (t, IH), 2.60-2.68 (dd, IH), 3.12-3.30 (m, 2H), 4.12 (s, IH), 4.63 (s, IH).
Step 577b. 8-(cw-3-amino-4-methylpyrrolidin-l-yl)-l-cyclopropyl- 7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid hydrochloride
FoUowing the procedure of Example 253j, substituting the compound from step 577a for the BOC-amino-pyrrolidine thereof, and carrying the product forward as in steps 253k & 1, the titie compound was prepared. MS m/z 374 (M+H)+. 1H NMR (DMSO-d6) d: 13.84 (broad s, IH), 9.10 (d, IH), 8.36 (s, 2H), 7.94 (s, IH), 4.22-4.32 ( , IH), 3.70-3.95 (m, 4H), 2.64 (s, 3H), 2.58-2.62 (m, IH), 2.25-2.37 (m, IH), 1.35 (d, 3H), 1.00-1.10 (m, IH), 0.88-0.98 (m, IH), 0.50-0.78 (m, 2H).
Example 578 In Vitro Assay of Antibacterial Activity
The in vitro antibacterial activity of the compounds of the present invention was demonstrated as foUows: Minimum inhibitory concentrations (MICs) were determined by the agar dilution method, in which twelve petri dishes were prepared, each containing successive aqueous 2-fold dilutions of the test compounds mixed with 10 mL of sterilized Brain Heart Infusion (BHI) agar. Each plate was inoculated with 1:100 (or 1:10 for slow- growing strains, primarily Micrococcus and Streptococcus) dUutions of up to 32 different microorganisms, using a Steers replicator block caUbrated to deliver approximately 10^ colony forming units (CFUs). The inoculated plates were incubated at from about 35°C to about 37°C for approximately 20-24 hours. In addition, a control plate using BHI agar containing no test compound was prepared and incubated at the beginning and at the end of each test. The quinolone antibacterial ciprofloxacin was used as a control ("Cnti").
After incubation, each petri dish was observed for the presence or absence of microorganism growth. The MIC was defined as the lowest concentration of test compound yielding no growth (a slight haze or sparsely isolated colonies at the inoculum spot) as compared to the growth control containing no test compound.
The results of the above tests, shown in Tables 14, 15 and 16 below, demonstrate that the compounds of the present invention are surprisingly effective in combating bacterial growth. Moreover, the 9-methyl quinolizinone compounds of the invention (in which A of formula (I) is =CR6- and R^ is methyl) are shown to have exceUent activity even against the ciprofloxacin-resistant pathogen Staphylococcus aureus 1775, demonstrating the potential usefulness of these compounds in treating infections not susceptible to this widely-used agent.
Table 14 In Vitro Antibacterial Activity (MIC Values in μg/ml)
Table 14 (continued') In Vitro Antibacterial Activity (MIC Values in μg/ml')
Table 14 (continued) In Vitro Antibacterial Activity (MIC Values in μg/ml')
Table 14 (continued) In Vitro Antibacterial Activity (MIC Values in μg/ml)
Table 15 In Vitro Antibacterial Activity (MIC Values in μg/ml)
Table 15 (continued) In Vitro Antibacterial Activity (MIC Values in μg/ml)
Table 15 (continued) In Vitro Antibacterial Activity (MIC Values in μg/ml)
Table 15 (continued) In Vitro Antibacterial Activity (MIC Values in μg/ml)
Table 15 (continued) In Vitro Antibacterial Activity (MIC Values in μg/ml)
Table 15 (continued) In Vitro Antibacterial Activity (MIC Values in μg/ml)
Table 15 (continued) In Vitro Antibacterial Activity (MIC Values in μg/ml)
Table 16 In Vitro Antibacterial Activity (MIC Values in μg/ml)
Table 16 (continued) In Vitro Antibacterial Activity (MIC Values in μg/ml)
Table 16 (continued) In Vitro Antibacterial Activity (MIC Values in μg/ml)
Table 16 (continued) In Vitro Antibacterial Activity (MIC Values in μg/ml)
Table 16 (continued) In Vitro Antibacterial Activity (MIC Values in μg/ml)
Table 16 (continued) In Vitro Antibacterial Activity (MIC Values in μg/ml)
Table 16 (continued) In Vitro Antibacterial Activity (MIC Values in μg/ml)
Table 16 (continued) In Vitro Antibacterial Activity (MIC Values in μg/ml)
Table 16 (continued) In Vitro Antibacterial Activity (MIC Values in μg/ml)
Table 16 (continued) In Vitro Antibacterial Activity (MIC Values in μg/ml)
Table 16 (continued) In Vitro Antibacterial Activity (MIC Values in μg/ml)
Table 16 (continued) In Vitro Antibacterial Activity (MIC Values in μg/ml)
Table 16 (continued) In Vitro Antibacterial Activity (MIC Values in μg/ml)
Table 16 (continued) In Vitro Antibacterial Activity (MIC Values in μg/ml)
Table 16 (continued) In Vitro Antibacterial Activity (MIC Values in μg/ml)
Table 16 (continued) In Vitro Antibacterial Activity (MIC Values in μg/ml)
Table 16 (continued) In Vitro Antibacterial Activity (MIC Values in μg/ml)
Table 16 (continued) In Vitro Antibacterial Activity (MIC Values in μg/ml)
Table 16 (continued) In Vitro Antibacterial Activity (MIC Values in μg/ml)
Table 16 (continued) In Vitro Antibacterial Activity (MIC Values in μg/ml)
Table 16 (continued) In Vitro Antibacterial Activity (MIC Values in μg/ml)
Table 16 (continued) In Vitro Antibacterial Activity (MIC Values in μg/ml)
Table 16 (continued) In Vitro Antibacterial Activity (MIC Values in μg/ml)
Table 16 (continued) In Vitro Antibacterial Activity (MIC Values in μg/ml)
Table 16 (continued) In Vitro Antibacterial Activity (MIC Values in μg/ml)
Table 16 (continued) In Vitro Antibacterial Activity (MIC Values in μg/ml)
Table 16 (continued) In Vitro Antibacterial Activity (MIC Values in μg/ml)
Table 16 (continued) In Vitro Antibacterial Activity (MIC Values in μg/ml)
Table 16 (continued) In Vitro Antibacterial Activity (MIC Values in μg/ml)
Certain compounds of the invention show particular superiority over compounds exemplified in previous applications. For example, compounds of Examples 420 and 566- 577 all possess MIC activity equal to or better (i.e., lower MIC value) than the criteria shown in Table 17, except for the Candida albicans organism, where the MIC data must be greater than 100. The comparative data for a ciprofloxacin standard are also given. These criteria were chosen because a compound possessing such an MIC profile shows exceptional promise of activity against a representative class of clinically troublesome organisms.
Table 17
Criteria of Superior In Vitro Antibacterial Activity (MIC Values in μg/ml)
The compounds from Examples 254, 257, 263, 271, and 341 also meet these criteria. However, these latter compounds are deemed inferior to the compounds of Examples 420 and 566-577 for the following reasons. The compound of Example 254: In-vitro cytotoxicity data obtained in a standard calf-thymus topoisomerase π assay was found not to meet the cytotoxicity criterion of 2 μg/mL.
The compound of Example 257: LD50 (IP) toxicity data obtained in a standard mouse model was found to be lower than the LD50 criterion of 50 mg/kg. The compound of Example 263: LD50 (IP) toxicity data obtained in a standard mouse model was found to be lower than the LD50 criterion of 50 mg/kg.
The compound of Example 271 : the solubility of this compound was found not to meet the solubility criterion of at lease 0.08 mg/mL. The compound of Example 341 : Whole-cell cytotoxicity data obtained in a standard Chinese Hamster ovarian assay was found not to meet the cytotoxicity criterion of 70 μg/mL.
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 of the invention, may be made without departing from the spirit and scope thereof.

Claims

WHAT IS CLAIMED IS:
1. A compound having the formula
or a pharmaceutically acceptable salt, ester or amide thereof, wherein
R1 in formula (I) is selected from (a) loweralkyl, (b) loweralkenyl, (c) halo(lower-alkyl), (d) loweralkoxy, (e) cycloalkyl of from three to eight carbon atoms, (f) phenyl, (g) substituted phenyl, (h) halo, (i) cyano, (j) nitro, (k) bicycloalkyl, (1) loweralkynyl, (m) loweralkoxycarbonyl, (n) nitrogen-containing aromatic heterocycle, (o) halo-substituted nitrogen-containing aromatic heterocycle, (p) a 4-, 5- or 6-membered cyclic ether, and (q) -NR7R8 where R7 and R8 are independently selected from the group consisting of hydrogen, loweralkyl and alkanoyl of from one to eight carbon atoms or, taken together with the nitrogen atom to which they are attached, R7 and R8 form a 5-, 6- or 7-membered heterocycle;
R2 in formula (I) is selected from (a) halogen, (b) loweralkyl, (c) loweralkenyl, (d) cycloalkyl of from three to eight carbons, (e) cycloalkenyl of from four to eight carbons, (f) loweralkoxy, (g) aryloxy, (h) aryl(loweralkyl)oxy, (i) aryl(loweralkyl), (j) cycloalkyl- (loweralkyl), (k) amino, (1) (loweralkyl)amino, (m) aryl(loweralkyl)-amino, (n) hydroxy- substituted (loweralkyl)amino, (o) phenyl, (p) substituted phenyl, (q) bicyclic nitrogen- containing heterocycle, (r) nitrogen-containing aromatic heterocycle, (s) nitrogen- containing heterocycle having the formula
(t) non-nitrogen-containing heterocycle having the formula where x is zero, one, two or three;
R9 is selected from the group consisting of (i) -(CH2)m- where where m is one, two or three, and (ii) -(CH2)nR13(CH2)p- where R13 is selected from -S-, -O- and -NH-, R10 is CH2, or when R9 is selected from option (i) may be O, S or N, n is one or two, and p is one or two; and R31 is -(CH2)qR32- where R32 is selected from -S- and -O-, and q is one, two or three; and Y is independently selected at each occurrence from the group consisting of: (i) loweralkyl,
(ii) hydroxy,
(iii) halogen,
(iv) halo(loweralkyl),
(v) hydroxy-substituted loweralkyl,
(vi) loweralkenylamino,
(vii) loweralkylamino,
(viii) loweralkoxy,
(ix) (loweralkoxy )loweralkylamino,
(x) loweralkoxy(loweralkyl),
(xi) loweralkoxy(loweralkoxy)(loweralkyl),
(xii) hydroxy-substituted loweralkyl,
(xiii) imino,
(xiv) alkoxycarbonyl,
(xv) carbamoyi,
(xvi) aryl(loweralkyl),
(xvii) aminoxy
(xviii) amino(loweralkyl),
(xix) halo(loweralkyl)amino,
(xx) halo(loweralkyl)amino(loweralkyl),
(xxi) thioloweralkoxy(loweralkyl),
(xxii) aminothioloweralkoxy,
(xxiii) cycloalkyl of from three to six carbon atoms, (xxiv) cycloalkyl(loweralkyl),
(xxv) cycloalkylamino,
(xxvi) phenyl,
(xxvii) substituted phenyl,
(xxviii) substituted phenyl(loweralkyl)
(xxix) nitrogen-containing aromatic heterocycle,
(xxx) -NR1 1R12 where R11 and R12 are independently selected from hydrogen and loweralkyl or, when one of R11 and R12 is hydrogen, the other is alkanoyl of from one to eight carbon atoms, an alpha-amino acid, or a polypeptide residue of from two to five amino acids, and
(xxxi) -C(R21)(R22)NH2 where R21 and R22 are independently selected from among hydrogen, loweralkyl, hydroxy-substituted loweralkyl, amino(loweralkyl), loweralkoxy- (loweralkyl), thioloweralkoxy (loweralkyl), cycloalkyl of from three to six carbon atoms, and loweralkyl substituted with nitrogen-containing aromatic heterocycle (or, taken together with the carbon atom to which they are attached, R21 and R22 form a ring structure selected from cycloalkyl of from three to six carbon atoms and nitrogen- containing heterocycle);
R3 is selected from the group consisting of hydrogen, halogen and loweralkoxy;
R4 is selected from the group consisting of hydrogen, loweralkyl, a pharmaceutically acceptable cation, and a prodrug ester group;
R5 is selected from the group consisting of (a) hydrogen, (b) halogen, (c) hydroxy, (d) loweralkyl, (e) halo(loweralkyl), (f) loweralkoxy, and (g) -NR13R14 where R13 and R14 are independently selected from the group consisting of hydrogen, loweralkyl, hydroxy- substituted loweralkyl, loweralkoxy(loweralkyl), and alkanoyl of from one to eight carbon atoms; and
A is =N- or =CR6-, where R6 is selected from the group consisting of (a) hydrogen, (b) halogen, (c) loweralkyl, (d) halo(loweralkyl), (e) hydroxy-substituted loweralkyl, (f) loweralkoxy(loweralkyl), (h) loweralkoxy, and (i) amino(loweralkyl); or, taken together with the atoms to which they are attached, R1 and R6 form a 6-membered saturated ring optionally containing an oxygen or a sulfur atom and optionally substituted with loweralkyl; provided that, when R5 is hydrogen and A is =CH-, R1 is not unsubstituted phenyl.
2. A compound according to Claim 1 wherein A is =CR6- and R6 is selected from the group consisting of halogen, loweralkyl, halo(loweralkyl), hydroxy-substituted loweralkyl, loweralkoxy(loweralkyl), loweralkoxy, and amino(loweralkyl).
3. A compound according to Claim 2 wherein R3 is halogen.
4. A compound according to Claim 3 wherein R5 is selected from the group consisting of hydrogen, loweralkyl, halo(loweralkyl), and -NR13R14 where R13 and R14 are as previously defined.
5. A compound according to Claim 4 wherein R1 is selected from the group consisting of cycloalkyl of from three to eight carbon atoms and substituted phenyl.
6. A compound according to Claim 5 wherein R6 is selected from the group consisting of halogen, loweralkyl, and loweralkoxy.
7. A compound according to Claim 6 wherein R2 is selected from the group consisting of bicyclic nitrogen-containing heterocycle and a nitrogen-containing heterocycle having the formula where R9, Y and x are as previously defined.
8. A compound according to Claim 7 wherein R2 is selected from the group consisting of
where Y and x are as previously defined.
9. A compound according to Claim 8 wherein x is one or two and Y is selected from the group consisting of -NR1 1R12 and -C(R21)(R22)NH2, where R11,
R12, R21 and R22 are as previously defined.
10. A compound according to Claim 2 wherein R6 is methyl.
1 1. A compound according to Claim 10 wherein R3 is halogen.
12. A compound according to Claim 11 wherein R5 is selected from the group consisting of hydrogen, loweralkyl, halo(loweralkyl), and -NR13R14 where R13 and R14 are as previously defined.
13. A compound according to Claim 12 wherein R1 is selected from the group consisting of cycloalkyl of from three to eight carbon atoms and substituted phenyl.
14. A compound according to Claim 13 wherein R2 is selected from the group consisting of bicyclic nitrogen-containing heterocycle and a nitrogen-containing heterocycle having the formula
where R9, Y and x are as previously defined.
15. A compound according to Claim 14 wherein R2 is selected from the group consisting of:
where Y and x are as previously defined.
16. A compound according to Claim 15 wherein x is one or two and Y is selected from the group consisting of -NR11R12 and -C(R21)(R22)NH2, where R11, R12, R21 and R22 are as previously defined.
17. A compound according to Claim 1 having the formula
or a pharmaceutically acceptable salt, ester or amide thereof, wherein
R2 is selected from the group consisting of bicyclic nitrogen-containing heterocycle and a nitrogen-containing heterocycle having the formula
and where R4, R9, Y and x are as previously defined.
18. A compound according to Claim 17 wherein R2 is selected from the group consisting of:
where Y and x are as previously defined.
19. A compound according to Claim 18 wherein x is one or two and Y is selected from the group consisting of -NR1 1R12 and -C(R21)(R22)NH2, where R1 1, R12, R21 and R22 are as previously defined.
20. A compound according to Claim 1 having the formula
or a pharmaceutically acceptable salt, ester or amide thereof, wherein
Z is selected from the group consisting of -CH2-, -O- and -S-, R16 is loweralkyl, and R2,
R3, R4 and R5 are as previously defined.
21. A compound according to Claim 20 wherein Z is -O- and R2 is a nitrogen- containing heterocycle having the formula
wherein R9, Y and x are as previously defined.
22. A compound according to Claim 1 selected from the group consisting of:
3-fluoro-9-(4-fluorophenyl)-2-(4-methylpiperazin-1-yl)-6(H)-6-oxo-pyrido[1,2- a]pyrimi dine-7-carboxylic acid;
9-(2,4-difluorophenyl)-3-fluoro-2-(4-methylpiperazin-1-yl)-6(H)-6-oxo-pyrido[1,2- a]pyrimidine -7-carboxylic acid;
3-fluoro-9-cyclopropyl-2-(4-methylpiperazin-1-yl)-6(H)-6-oxo-pyrido[1,2-a]pyrimidine-7- carboxylic acid;
8-(3-aminopyrrolidin-1-yl)-1-ethyl-4H-quinolizin-4-one-3-carboxylic acid;
2-(3-aminopyrrolidin-1-yl)-9-cyclopropyl-3-fluoro-6H-6-oxo-pyrido[1,2-a]pyrimidine-7- carboxylic acid;
2-(3-aminopyrrolidin-1-yl)-9-cyclopropyl-3-fluoro-6H-6-oxo-pyrido[1,2-a]pyrimidine-7- carboxylic acid; 9-(2,4-difluorophenyl)-3-fluoro-2-(4-methylpiperazin-1-yl)-6H-6-oxopyrido[1,2- a]pyrimidine-7-carboxylic acid;
2-(3-aminopyrrplidin-1-yl)-9-(2,4-difluorophenyl)-3-fluoro-6H-6-oxopyrido[1,2- a]pyrimidine-7-carboxylic acid;
2-(3-(N-t-butoxycarbonyl)aminopyrrolidin-1-yl)-9-(2,4-difluorophenyl)-3-fluoro-6H-6- oxopyrido[1,2-a]pyrimidine-7 -carboxylic acid;
2-(3-aminopyrrolidin-1-yl)-9-(2,4-difluorophenyl)-3-fluoro-6H-6-oxopyrido[1,2- a]pyrimidine -7-carboxylic acid;
9-cyclopropyl-3-fluoro-2-(4-methylpiperazin-1-yl)-6H-6-oxo-pyrido[1,2-a]pyrimidine-7- carboxylic acid;
9-cyclopropyl-3-fluoro-2-(piperazin-1-yl)-6H-6-oxo-pyrido[1,2-a]pyrimidine-7-carboxylic acid;
9-cyclopropyl-3-fluoro-2-(morpholin-1-yl)-6H-6-oxo-pyrido[1,2-a]pyrimidine-7- carboxyhc acid;
9-(2,4-difluorophenyl)-3-fluoro-2-(3-(N-(S)-norvalyl)aminopyrrolidin-1-yl)-6H-6- oxopyrido[1,2-a]pyrimidine-7-carboxylic acid;
2-(3-(N-(S)-alanyl)aminopyrrolidin-1-yl)-9-(2,4-difluorophenyl)-3-fluoro-6H-6- oxopyrido[1,2-a]pyrimidine-7-carboxylic acid;
2-(3-(N-(S)-alanyl-(S)-alanyl)aminopyrrolidin-1-yl)-9-(2,4-difluorophenyl)-3-fluoro-6H-
6-oxopyrido[1,2-a]pyrimidine-7-carboxylic acid;
2-((2S ,4S)-4-acetamido-2-methylpyrrolidin-1-yl)-9-(2,4-difluorophenyl)-3-fluoro-6H-6- oxopyrido[1,2-a]pyrimidine-7-carboxylic acid;
9-(2,4-difluorophenyl)-3-fluoro-2-(3-hydroxypyrrolin-1-yl)-6H-6-oxopyrido[1,2- a]pyrimidine-7 -carboxylic acid;
2-((2S,4S)-4-amino-2-methylpyrrolidin-1-yl)-9-(2,4-difluorophenyl)-3-fluoro-6H-6- oxopyrido[1,2-a]pyrimidine-7-carboxylic acid;
8-(3-amino-1-pyrrolidinyl)-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3- carboxyhc acid;
8-(3-(aminomethyl)pyrrolidinyl)-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-
3-carboxylic acid;
8-(2S,4S-4-amino-2-methylpyrrolidinyl)-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H- quinolizine-3-carboxylic acid;
8-(3-aminoazetidinyl)-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid;
8-(3(S)-aminopyrrolidinyl)-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3- carboxylic acid; 1-cyclopropyl-7-fluoro-9-methyl-4-oxo-8-(3-methyl-1-piperazinyl)-4H-quinolizine-3- carboxylic acid;
1-cyclopropyl-7-fluoro-9-methyl-4-oxo-8-piperazinyl-4H-quinolizine-3-carboxylic acid;
1-cyclopropyl-7-fluoro-9-methyl-8-(2-((N-methyl)aminomethyl)-4-morpholinyl)-4-oxo-
4H-quinolizine-3-carboxylic acid;
1-cyclopropyl-7-fluoro-9-methyl-4-oxo-8-(1,2,3,4-tetrahydro-2-isoquinolinyl)-4H- quinolizine-3-carboxyhc acid ;
1-cyclopropyl-7-fluoro-9-methyl-4-oxo-8-(4- amino- 1 -piperdinyl)-4H-quinolizine-3- carboxylic acid;
1-cyclopropyl-7-fluoro-9-methyl-4-oxo-8-(3-amino-1-piperdinyl)-4H-quinolizine-3- carboxylic acid;
1-cyclopropyl-7-fluoro-9-methyl-4-oxo-8-(4-(aminomethyl)-1-piperdinyl)-4H-quinolizine-
3-carboxyhc acid;
1-cyclopropyl-7-fluoro-9-methyl-4-oxo-8-(5-amino-1,2,3,4-tetrahydro-2-isoquinolinyl)-
4H-quinolizine-3-carboxylic acid;
1-cyclopropyl-7-fluoro-9-methyl-4-oxo-8-(4-(1-pyrrolyl)-1-piperidinyl)-4H-quinolizine-3- carboxylic acid;
1-cyclopropyl-8-(cis-3.5-dimethyl-1-piperazinyl)-7-fluoro-9-methyl-4-oxo-4H-quinolizine-
3-carboxylic acid;
1-cyclopropyl-8-(2,7-diaza-7-bicyclo[3.3.0]octyl)-7-fluoro-9-methyl-4-oxo-4H- quinolizine-3-carboxylic acid;
1-cyclopropyl-8-(2,8-diaza-8-bicyclo[4.3.0]nonyl)-7-fluoro-9-methyl-4-oxo-4H- quinolizine-3-carboxylic acid;
1-cyclopropyl-7-fluoro-9-methyl-4-oxo-8-(3(S)-(1-pyrrolyl)-1-pyrrolidinyl)-4H- quinolizine-3-carboxylic acid ;
1-cyclopropyl-7-fluoro-8-(3-hydroxy-1-pyrrolidinyl)-9-methyl-4-oxo-4H-quinotizine-3- carboxylic acid;
1-cyclopropyl-7-fluoro-8-(4-methyl-1-piperazinyl)-9-methyl-4-oxo-4H-quinolizine-3- carboxyhc acid;
1-cyclopropyl-9-chloro-7-fluoro-8-(3-amino-1-pyrrolidinyl)-4-oxo-4H-quinotizine-3- carboxylic acid trifluoroacetic acid;
8-(3-amino-1-pyrrolidinyl)-1-cyclopropyl-7,9-difluoro-4-oxo-4H-quinolizine-3-carboxylic acid;
8-(3-amino-1-pyrrolidinyl)-1-cyclopropyl-7-fluoro-9-methoxy-4-oxo-4H-quinolizine-3- carboxylic acid. 1-cyclopropyl-8-(2,7-diaza-7-bicyclo[3.3.0]oct-2-yl)-7-fluoro-9-methyl-4-oxo-4H- quinolizine-3-carboxylic acid;
1-cyclopropyl-8-(2,8-diaza-8-bicyclo[4.3.0]nonyl)-7-fluoro-9-methyl-4-oxo-4H- quinolizine-3-carboxylic acid;
1-cyclopropyl-7-fluoro-9-methyl-4-oxo-8-(3(S)-(1-pyrrolyl)-1-pyrrolidinyl)-4H- quinolizine-3-carboxylic acid;
1-cyclopropyl-7-fluoro-8-(3-hydroxy-1-pyrrolidinyl)-9-methyl-4-oxo-4H-quinotizine-3- carboxylic acid;
1-cyclopropyl-7-fluoro-8-(4-methyl-1-piperazinyl)-9-methyl-4-oxo-4H-quinolizine-3- carboxyhc acid;
1-cyclopropyl-9-chloro-7-fluoro-8-(3-amino-1-pyrrolidinyl)-4-oxo-4H-quinolizine-3- carboxylic acid;
8-(3-amino-1-pyrrolidinyl)-1-cyclopropyl-7,9-difluoro-4-oxo-4H-quinolizine-3-carboxylic acid;
8-(3-amino-1-pyrrolidinyl)-1-cyclopropyl-7-fluoro-9-methoxy-4-oxo-4H-quinolizine-3- carboxylic acid;
1-cyclopropyl-7-fluoro-9-methyl-8-(3(S)-methylamino-1-pyrrolidinyl)-4-oxo-4H- quinolizine-3-carboxylic acid;
1-cyclopropyl-7-fluoro-9-methyl-8-(3(S)-methylamino-1-pyrrolidinyl)-4-oxo-4H- quinolizine-3-carboxylic acid;
1-cyclopropyl-7 -fluoro- 9-methyl-8-(3(R)-amino- 1 -pyrrolidinyl)-4-oxo-4H-quinolizine-3- carboxylic acid;
(3S)-9-fluoro-3-methyl-10-(4-methyl-1-piperazinyl)-2H,3H,6H-6-oxo-pyrano[2.3.4- ij]quinolizine-5-carboxylic acid;
3(R)-9-fluoro-3-methyl-10-(4-methyl-1-piperazinyl)-2H,3H,6H-6-oxo-pyrano[2.3.4- ij]quinolizine-5-carboxylic acid;
9-fluoro-10-(1-morpholinyl)-2H,3H,6H-6-oxo-pyrano[2.3.4-ij]quinolizine-5-carboxylic acid;
(3S)-10-(3-amino-1-pyrrolidinyl)-9-fluoro-3-methyl-2H,3H,6H-6-oxo-pyrano[2.3.4- ij]quinolizine-5-carboxylic acid;
3(S)-10-(3-aminomethyl-1-pyrrolidinyl)-9-fluoro-3-methyl-2H,3H,6H-6-oxo- pyrano[2.3.4-ij]quinolizine-5-carboxylic acid;
3(S)-10-((2S,4S)-4-amino-2-methyl-1-pyrrolidinyl)-9-fluoro-3-methyl-2H,3H,6H-6-oxo- pyrano[2.3.4-ij]quinolizine-5-carboxylic acid;
3(S)-9-fluoro-10-(3-hydroxy-1-pyrrolidinyl)-3-methyl-2H,3H,6H-6-oxo-ρyrano[2.3.4- ij]quinolizine-5-carboxylic acid; 9-fluoro-10-(4-methyl-1-piperazinyl)-2H,3H,6H-6-oxo-pyrano[2.3.4-ij]quinolizme-5- carboxylic acid;
8-(2,4-dimethyl-1-piperazinyl)-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3- carboxylic acid;
8-(3-(methylamino)-1-piperazinyl)-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H- quinolizine-3-carboxylic acid;
8-(3-(methylamino)-1-morpholinyl)-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H- quinolizine-3-carboxylic acid;
8-(3-(S)-(methylamino)-1-pyrrolidinyl)-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H- quinolizine-3-carboxylic acid;
8-(3-(S)-(1-(methylamino)methyl)-1-pyrrolidinyl)-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-
4H-quinolizine-3-carboxylic acid;
8-(3-(S)-(1-(ethylamino)methyl)-1-pyrrolidinyl)-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-
4H-quinolizine-3-carboxylic acid;
8-(octahydropyrrolo[3,4-c]pyrrol-1-yl)-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H- quinolizine-3-carboxylic acid;
8-(octahydropyrrolo[3,4-c]pyridin-5-yl)-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H- quinolizine-3-carboxylic acid;
8-(cis-4-amino-3-methylpyrrolidinyl)-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H- quinolizine-3-carboxylic acid;
8-(trans-4-amino-3-methylpyrrolidinyl)- 1-cyclopropyl -7 -fluoro- 9- methyl-4-oxo-4H- quinolizine-3-carboxylic acid;
8-(3-methyl-4-spirocyclopropylpyrrolidinyl)-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H- quinolizine-3-carboxylic acid;
8-(2S,4S-4-amino-2-methylpyrrolidinyl)-1-cyclopropyl-7-fluoro-9-(fluoro)methyl-4-oxo- 4H-quinolizine-3-carboxylic acid;
8-(3-dimethylaminopyrrolidinyl)-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-
3-carboxylic acid;
(3R)-8-(3-dimethylaminopyrrolidinyl)-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H- quinolizine-3-carboxylic acid;
(3R,1S)-8-(3-(1-aminoethyl)pyrrolidinyl)-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H- quinolizine-3-carboxylic acid;
(3S,1R)-8-(3-(1-aminoethyl)pyrrolidinyl)-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H- quinolizine-3-carboxylic acid;
(3R,1R)-8-(3-(1-aminoethyl)pyrrolidinyl)-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H- quinolizine-3-carboxylic acid; 1-cyclopropyl-8-((R,S)-3-fluoropyrrolidine)-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3 - carboxylic acid;
8-(4-(1-piperidyl)-1-piperidyl)-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3- carboxylic acid;
8-(4-(1-piperidyl)-1-piperidyl)-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3- carboxylic acid;
8-(4-(2-pyridyl)-1-piperazinyl)-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3- carboxylic acid;
8-((2-amino)thioethoxy)-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3- carboxylic acid;
(3R,1S)-8-(3-(1-amino)propyl)pyrrolidinyl)-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H- quinolizine-3-carboxylic acid;
(3R,1S)-8-(3-(1-(N-methyl)amino)propyl)pyrrolidinyl)-1-cyclopropyl-7-fluoro-9-methyl-
4-oxo-4H-quinolizine-3-carboxylic acid;
(3R,1S)-8-(3-(1-amino-3-methylpropyl)pyrrolidinyl)-1-cyclopropyl-7-fluoro-9-methyl-4- oxo-4H-quinolizine-3-carboxylic acid;
8-(3-(1-aminocyclopropyl)pyrrolidinyl)-1-cyclopropy l-7-fluoro-9-methyl-4-oxo-4H- quinolizine-3-carboxylic acid;
(3R,1S)-8-(3-(1-amino-2-hydroxyethyl)pyrrolidinyl)-1-cyclopropyl-7-fluoro-9-methyl-4- oxo-4H-quinolizine-3-carboxylic acid;
(8-(3-(1-amino-1-methylethyl)pyrrolidinyl)-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H- quinolizine-3-carboxylic acid;
8-(3-(1-aminobutyl)pyrrolidinyl)-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-
3-carboxylic acid;
1-cyclopropyl-7-fluoro-9-methyl-4-oxo-8-(trans-4-trifluoromethyl-3-aminopyrrolidinyl)-
4H-quinolizine-3-carboxylic acid;
1-cyclopropyl-7 -fluoro- 9-methyl-4-oxo-8-(trans-4-trifluoromethyl-3- aminomethylpyrrolidinyl)-4H-quinolizine-3-carboxylic acid;
3(S)-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-8-(3-(N-(S)-norvalylamino)pyrrolidinyl)-4H- quinolizine-3-carboxylic acid;
3(S)-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-8-(3-(N-(S)-alanylamino)pyrrolidinyl)-4H- quinolizine-3-carboxylic acid;
3(S)-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-8-(3-(N-(S)-alanyl-(S)- alanylamino)pyrrolidinyl)-4H-quinolizine-3-carboxylic acid;
1-cyclopropyl-7-fluoro-6-methyl-4-oxo-8-(3-aminopyrrolidinyl)-4H-quinolizine-3- carboxylic acid; 1-cyclopropyl-7-fluoro-4H-8-(1-imidazolyl)-9-methyl-4-oxo-quinolizine-3-carboxylic acid;
8-(3-amino-1-pyrrolidinyl)-1-ethyl-7-fluoro-4H-4-oxo-9-methyl-quinolizine-3-carboxylic acid;
8-(3-amino-1-pyrrolidinyl)-1-cyclopropyl-9-ethyl-7-fluoro-4H-4-oxo-quinolizine-3- carboxylic acid;
1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-8-(3-(1,2,3-triazol-1-yl)-1-pyrrolidinyl)- quinolizine-3-carboxylic acid;
1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-8-(cis-3-amino-4-methyl-1-pyrrolidinyl)- quinolizine-3-carboxylic acid;
8-(2-aminoethyl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid;
8-(3-(ethylaminomethyl)pyrrolidinyl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo- quinolizine-3-carboxylic acid;
8-(3-(1-aminoethyl)pyrrolidinyl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-
3-carboxylic acid;
1-cyclopropyl-7-fluoro-4H-9-methyl-8-(2-methyl-2,8-diaza-8-bicyclo[4.3.0]nonyl)-4-oxo- quinolizine-3-carboxylic acid;
1-cyclopropyl-7-fluoro-4H-8-((1S,4S)-2,5-diaza-bicyclo[2.2.1]heρtan-2-yl)-9-methyl-4- oxo-quinolizine-3-carboxylic acid;
1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-8-(3-(2-pyridinyl)-1-pyrrolidinyl)-quinolizine-
3-carboxylic acid;
8-((1R*,2S*,6R*)-2-amino-8-azabicyclo[4.3.0]nonan-8-yl))-1-cyclopropyl-7-fluoro-4H-
9-methyl-4-oxo-quinolizine-3-carboxylic acid;
8-((1R*,2R*,6R*)-2-amino-8-azabicyclo[4.3.0]nonan-8-yl))-1-cyclopropyl-7-fluoro-4H-
9-methyl-4-oxo-quinolizine-3-carboxylic acid;
8-((1a,5a,6a)-6-amino-3-azabicyclo[3.1.0]hexan-3-yl))-1-cyclopropyl-9-methyl-7-fluoro-
4H-4-oxo-quinolizine-3-carboxylic acid;
8-(trans-3-amino-4-fluoro-1-pyrrolidinyl))-1-cyclopropyl-9-methyl-7-fluoro-4H-4-oxo- quinolizine-3-carboxylic acid;
1-cyclopropyl-7-fluoro-4H-8-(1-homopiperazinyl))-9-methyl-4-oxo-quinolizine-3- carboxylic acid;
7,9-difluoro-4H-8-(4-methylpiperazinyl)-4-oxo-1-phenyl-quinolizine-3-carboxylic acid;
8-(spiro-1,3-dioxacyclopentane[2.3]-1-piperidinyl)-1-cyclopropyl-7-fluoro-4H-9-methyl- 4-oxo-quinolizine-3-carboxylic acid ;
8-(3-amino-4-methoxypyrrolidinyl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo- quinolizine-3-carboxylic acid; 8-(4-amino-4-methylpyrrolidinyl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine- 3-carboxylic acid;
8-(4-(2-hydroxyethyl)piperidinyl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine- 3-carboxylic acid ;
8-(4-(methoxymethyl)piperidinyl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine- 3-carboxylic acid ;
8-(3-amino-3-methylpiperidinyl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine- 3-carboxylic acid;
8-(3-pyrrolylpiperidinyl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3- carboxylic acid ;
8-(3-aminopiperidinyl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3- carboxylic acid;
8-(3-amino-3-methylpyrrolidinyl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine- 3-carboxylic acid;
8-(3-amino-4-(1',3'-dioxolanyl)pyrrolidinyl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo- quinolizine-3-carboxylic acid;
8-(3-amino-4-hydroxy-pyrrolidinyl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo- quinolizine-3-carboxylic acid;
8-(4-(1-(N-ethylamino)methyl)piperidinyl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo- quinolizine-3-carboxylic acid;
1-cyclopropyl-7-fluoro-8-(3-hych-oxy-4-methylaminopyrrolidinyl)-4H-9-methyl-4-oxo- quinolizine-3-carboxylic acid;
8-(3-aminomethylpiperidinyl)- 1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3- carboxylic acid;
8-(2-aminomethyl-4-morpholinyl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-
3-carboxylic acid;
8-(3-(1-(methylamino)methypiperidinyl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo- quinolizine-3-carboxylic acid;
8-(3-(methyl(methylenedioxy)methyl)piperidinyl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4- oxo-quinolizine-3-carboxylic acid;
8-(3-(S)-aminopiperidinyl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3- carboxylic acid;
8-(3-(S)-(N-ethyl-N-methylamino)piperidinyl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4- oxo-quinolizine-3-carboxylic acid ;
1-cyclopropyl-8-(4-(2,-(N-methylamino)methyl- 1',3'-dioxolanyl)piperidinyl)-7-fluoro-9- methyl-4-oxo-4H-quinolizine-3-carboxylic acid; 1-cyclopropyl-8-(3-aza-6-amino-6-methylbicyclo[3.3.0]octan-1-yl)-7-fluoro-9-methyl-4- oxo-4H-quinolizine-3-carboxylic acid;
1-cyclopropyl-8-(3-fluoromethylpiperidinyl)-7-fluoro-9-methyl-4-oxo-4H-quinolizine;
1-cyclopropyl-8-(4-(N,N-dimethyl)aminopiperidinyl)-7-fluoro-9-methyl-4-oxo-4H- quinolizine-3-carboxylic acid;
1-cyclopropyl-8-(6-amino-3-azabicyclo[3.3.0]octyl)-7-fluoro-9-methyl-4-oxo-4H- quinolizine-3-carboxylic acid;
1-cyclopropyl-8-((2-aza-4-(dimethylaminomethyl)bicyclo[4.3.0]non-2-yl)-7-fluoro-9- methyl-4-oxo-4H-quinolizine carboxylic acid;
1-cyclopropyl-8-(3-aza-6-(L-alanylamino)-6-methylbicyclo[3.3.0]octane)-7-fluoro-9- methyl-4-oxo-4H-quinolizine carboxylic acid;
(3R,1R)-8-(3-(1-(N-methyl)amino)propyl)pyrrolidinyl)-1-cyclopropy1-7-fluoro-9-methyl-
4-oxo-4H-quinolizine-3-carboxylic acid;
(3R,1S)-8-(3-(1-amino-2-methoxyethyl)pyrrolidinyl)-1-cyclopropyl-7-fluoro-9-methyl-4- oxo-4H-quinolizine-3-carboxylic acid;
8-(3-(S)-(acetylamino)pyrrolidinyl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo- quinolizine-3-carboxylic acid;
8-(3-carbamoylpiperidinyl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3- carboxylic acid;
8-(3-hydroxypiperidinyl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3- carboxylic acid;
8-(3-hydroxymethylpiperidinyl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3- carboxylic acid;
8-(3-(R)-hydroxypiperidinyl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3- carboxylic acid;
(3R)-9-fluoro-3-methyl-10-(piperazin-1-yl)-2H, 3H, 6H -6-oxo-pyrano[2.3.4- ij]quinolizine-5-carboxylic acid;
1-cycloproρyl-8-(S,S-2,8-diaza-8-bicyclo[4.3.0]nonyl)-7-fluoro-4H-9-methyl-4-oxo- quinolizine-3-carboxylic acid;
1-cyclopropyl-8-(R,R-2,8-diaza-8-bicyclo[4.3.0]nonyl)-7-fluoro-4H-9-methyl-4-oxo- quinolizine-3-carboxylic acid;
1-cyclopropyl-8-(1-amino-3-aza-bicyclo[3.1.0]hexan-3-yl)-7-fluoro-4H-9-methyl-4-oxo- quinolizine-3-carboxylic acid;
8-(3-amino-3-fluoromethyl-1-pyrrolidinyl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo- quinolizine-3-carboxylic acid; 8-(3-aminomethyl-3-fluoro-1-pyrrolidinyl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo- quinolizine-3-carboxylic acid;
8-(3-(S)-hydroxy-1-pyrrolidinyl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-
3-carboxylic acid;
8-(3-(R)-hydroxy-1-pyrrolidinyl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-
3-carboxylic acid;
8-(7-(S)-amino-5-aza-spiro[2.4]heptan-5-yl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo- quinolizine-3-carboxylic acid hydrochloride;
8-(7-(R)-amino-5-aza-spiro[2.4]heptan-5-yl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo- quinolizine-3-carboxylic acid hydrochloride;
8-(3-(1-amino-2,2,2-trifluoroethyl)pyrrolidinyl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4- oxo-quinolizine-3-carboxylic acid;
8-(3-(S*)-(1-(S*)-amino-2,2,2-trifluoroethyl)pyrrolidinyl)-1-cycloproρyl-7-fluoro-4H-9- methyl-4-oxo-quinolizine-3-carboxylic acid;
8-(3-aminoxypyrrolidinyl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3- carboxylic acid;
8-(3-(R)-aminoxypyrrolidinyl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3- carboxylic acid;
8-(3-(S)-aminoxypyrrolidinyl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3- carboxylic acid;
8-(octahydropyrrolo[3,2-b]pyridin-1-yl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo- quinolizine-3-carboxylic acid;
8-(trans-3-amino-4-fluoromethylpyrrodin-1-yl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4- oxo-quinolizine-3-carboxylic acid;
8-(cis-3-amino-4-fluoromethylpyrrodin-1-yl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo- quinolizine-3-carboxylic acid;
8-(8-amino-6-azaspiro[3.4]oct-6-yl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo- quinolizine-3-carboxylic acid;
8-(2-aminomethyl-4-hydroxypyrrolidin-1-yl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo- quinolizine-3-carboxylic acid;
8-(3-(R)-(aminomethyl)morpholin-1-yl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo- quinolizine-3-carboxylic acid;
8-(3-(R)-(L-alanylamino)piperidinyl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo- quinolizine-3-carboxylic acid;
8-(3-(5-aminooctahydroindol-1-yl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo- quinolizine-3-carboxylic acid; 8-(3-(2-piperidyl)piperidin-1-yl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-
3-carboxylic acid;
8-(5-amino-decahydroisoquinolin-2-yl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo- quinolizine-3-carboxylic acid;
8-(2,7-diazabicyclo[3.3.0]oct-7-yl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo- quinolizine-3-carboxylic acid;
8-(3,7-diazabicyclo[3.3.0]oct-3-yl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo- quinolizine-3-carboxylic acid;
8-(3-carboxypyrrolidin-1-yl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3- carboxylic acid;
8-(3-(2,2,2-trifluoroethyl)aminopyrrolidin-1-yl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4- oxo-quinolizine-3-carboxylic acid;
8-(3-(2-fluoroethyl)aminopyrrolidin-1-yl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo- quinolizine-3-carboxylic acid;
8-(3-((2-fluoroethyl)aminomethyl)pyrrolidin-1-yl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4- oxo-quinolizine-3-carboxylic acid;
8-(3-(S)-(2-fluoroethyl)aminopyrrolidin-1-yl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo- quinolizine-3-carboxylic acid;
8-(3-(R)-(2-fluoroethyl)aminopyrrolidin-1-yl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo- quinolizine-3-carboxylic acid;
8-(3a-amino-octahydroisoindol-2-yl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo- quinolizine-3-carboxylic acid;
8-(6-amino-2-aza-spiro[3.3]non-2-yl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo- quinolizine-3-carboxylic acid (Isomer (I));
8-(3-amino-3-trifluoromethylpyrrolidin-1-yl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo- quinolizine-3-carboxylic acid;
8-(3-(S)-hydroxymethylazetidin-1-yl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo- quinolizine-3-carboxylic acid ;
8-(3-aminomethyl-3-trifluoromethyl-pyrrolidin-1-yl)-1-cyclopropy1-7-fluoro-4H-9-methyl-
4-oxo-quinolizine-3-carboxylic acid;
8-(octahydropyrrolo[3.4-c]pyrid-2-yl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo- quinolizine-3-carboxylic acid;
8-(3-(cyclopropylamino)pyrrolidin-1-yl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo- quinolizine-3-carboxylic acid;
8-(6-amino-2-aza-spiro[3.3]non-2-yl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo- quinolizine-3-carboxylic acid (Isomer (II)); 8-(2,7-diazabicyclo[3.3.0]oct-7-yl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo- quinolizine-3-carboxylic acid Isomer A;
8-(2,7-diazabicyclo[3.3.0]oct-7-yl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo- quinolizine-3-carboxylic acid Isomer B;
8-(3-(R)-(hydroxymethyl)pyrrolidin-1-yl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo- quinolizine-3-carboxylic acid;
8-(3-(S)-(hydroxymethyl)pyrrolidin-1-yl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo- quinolizine-3-carboxylic acid;
8-(2-(R)-(hydroxymethyl)pyrrolidin-1-yl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo- quinolizine-3-carboxylic acid;
8-(2-(S)-(hydroxymethyl)pyrrolidin-1-yl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo- quinolizine-3-carboxylic acid;
8-(2-(R)-aminomethyl-pyrrolidin-1-yl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo- quinolizine-3-carboxylic acid;
8-(2-(S)-aminomethyl-pyrrolidin-1-yl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo- quinolizine-3-carboxylic acid;
8-(3-(R)-(1-aminocyclopropyl)pyrrolidinyl)-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H- quinolizine-3-carboxylic acid;
8-(3-(S)-(1-aminocyclopropyl)pyrrolidinyl)-1-cyclopropy1-7-fluoro-9-methyl-4-oxo-4H- quinolizine-3-carboxylic acid;
8-(3-(1-amino-1-cyclopropyl-methyl)pyrrolidinyl)-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-
4H-quinolizine-3-carboxylic acid;
8-(3-(R)-(pyrrolidin-2-(S)-yl)pyrrolidin-1-yl)-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H- quinolizine-3-carboxylic acid;
8-(3-(aminomethyl)azetidin-1-yl)-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-
3-carboxylic acid;
(8-(3-amino-4-methyl-piperidin-1-yl)-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H- quinolizine-3-carboxylic acid; and
8-(3-(7-amino-5-azaspiro[2.4]heptan-5-yl)-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H- quinolizine-3-carboxylic acid;
8-(7-(S)-amino-5-aza-spiro[2.4]heptan-5-yl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo- quinolizine-3-carboxylic acid;
8-(7-(R)-amino-5-aza-spiro[2.4]heptan-5-yl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo- quinolizine-3-carboxylic acid;
8-(trans-3-(S)-amino-4-(R)-cyclopropylpyrrolidin-1-yl)-1-cyclopropyl-7-fluoro-4H-9- methyl-4-oxo-quinolizine-3-carboxylic acid; 8-(trans-3-(R)-amino-4-(S)-cyclopropylpyrrolidin-1-yl)-1-cyclopropyl-7-fluoro-4H-9- methyl-4-oxo-quinolizine-3-carboxylic acid;
8-(trans-3-(S)-amino-4-(R)-methylpyrrolidin-1-yl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4- oxo-quinolizine-3-carboxylic acid;
8-(trans-3-(R)-amino-4-(S)-methylpyrrolidin-1-yl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4- oxo-quinolizine-3-carboxylic acid;
8-(cis-3-(S)-amino-4-(S)-cyclopropylpyrrolidin-1-yl)-1-cyclopropyl-7-fluoro-4H-9- methyl-4-oxo-quinolizine-3-carboxylic acid;
8-(cis-3-(R)-amino-4-(R)-cyclopropylpyrrolidin-1-yl)-1-cyclopropyl-7-fluoro-4H-9- methyl-4-oxo-quinolizine-3-carboxylic ac
8-(trans-3-amino-4-ethylpyrrolidin-1-yl) clopropyl-7-fluoro-4H-9-methyl-4-oxo- quinolizine-3-carboxylic acid diastereomer A;
8-(trans-3-ammo-4-ethylpyrrolidin-1-yl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo- quinolizine-3-carboxylic acid diastereomer B;
8-(cis-3-amino-4-ethylpyrrodin-1-yl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo- quinolizine-3-carboxylic acid diastereomer A;
8-(cis-3-amino-4-ethylpyrrodin-1-yl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo- quinolizine-3-carboxylic acid diastereomer B;
8-(cis-3-(S)-amino-4-(S)-methylpyrrodin-1-yl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4- oxo-quinolizine-3-carboxylic acid; and
8-(cis-3-(R)-amino-4-(R)-methylpyrrodin-1-yl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4- oxo-quinolizine-3-carboxylic acid;
and the pharmaceutically acceptable salts, esters and amides thereof.
23. A compound according to Claim 22 selected from the group consisting of: 8-(3-(aminomethyl)pyrrolidinyl)-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine- 3-carboxylic acid;
8-(3(S)-amino-1-pyrrolidinyl)-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3- carboxylic acid;
8-(3-amino-1-pyrrolidinyl)-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3- carboxylic acid;
(3R,1S)-8-(3-(1-amino)propyl)pyrrolidinyl)-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H- quinolizine-3-carboxylic acid;
8-(3-(1-aminobutyl)pyrrolidinyl)-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine- 3-carboxylic acid; (3R,1S)-8-(3-(1-anιino-2-methoxyethyl)pyrrolidinyl)-1-cyclopropyl-7-fluoro-9-methyl-4- oxo-4H-quinolizine-3-carboxylic acid;
1-cyclopropyl-7-fluoro-9-methyl-4-oxo-8-(4-amino-1-piperdinyl)-4H-quinolizine-3- carboxylic acid;
1-cyclopropyl-7-fluoro-9-methyl-4-oxo-8-(4-(aminomethyl)-1-piperdinyl)-4H-quinolizine-
3-carboxylic acid;
1-cyclopropyl-7-fluoro-9-methyl-4-oxo-8-(3-amino-1-piperdinyl)-4H-quinolizine-3- carboxylic acid;
8-(3-(S)-aminopiperidinyl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3- carboxylic acid;
1-cyclopropyl-8-(3-aza-6-amino-6-methylbicyclo[3.3.0]octan-1-yl)-7-fluoro-9-methyl-4- oxo-4H-quinolizine-3-carboxylic acid;
1-cyclopropyl-8-(6-amino-3-azabicyclo[3.3.0]octyl)-7-fluoro-9-methyl-4-oxo-4H- quinolizine-3-carboxylic acid;
8-((1R*,2S*,6R*)-2-amino-8-azabicyclo[4.3.0]nonan-8-yl))-1-cyclopropyl-7-fluoro-4H-
9-methyl-4-oxo-quinolizine-3-carboxylic acid;
8-((1R*,2R*,6R*)-2-amino-8-azabicyclo[4.3.0]nonan-8-yl))-1-cyclopropyl-7-fluoro-4H- 9-methyl-4-oxo-quinolizine-3-carboxylic acid;
8-(3-(1-aminoethyl)pyrrolidinyl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-
3-carboxylic acid;
(8-(3-(1-amino-1-methylethyl)pyrrolidinyl)-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H- quinolizine-3-carboxylic acid;
(3R,1S)-8-(3-(1-(N-methyl)amino)propyl)pyrrolidinyl)-1-cyclopropyl-7-fluoro-9-methyl-
4-oxo-4H-quinolizine-3-carboxylic acid;
8-(3-aminopiperidinyl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3- carboxylic acid;
8-(3-(1-aminocyclopropyl)pyrrolidinyl)-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H- quinolizine-3-carboxylic acid;
(3S,1R)-8-(3-(1-aminoethyl)pyrrolidinyl)-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H- quinolizine-3-carboxylic acid;
(3R,1S)-8-(3-(1-aminoethyl)pyrrolidinyl)-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H- quinolizine-3-carboxylic acid;
(3R,1R)-8-(3-(1-aminoethyl)pyrrolidinyl)-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H- quinolizine-3-carboxylic acid;
1-cyclopropyl-8-(S,S-2,8-diaza-8-bicyclo[4.3.0]nonyl)-7-fluoro-4H-9-methyl-4-oxo- quinolizine-3-carboxylic acid; 1-cyclopropyl-8-(R,R-2,8-diaza-8-bicyclo[4.3.0]nonyl)-7-fluoro-4H-9-methyl-4-oxo- quinolizine-3-carboxylic acid;
1-cyclopropyl-8-(1-amino-3-aza-bicyclo[3.1.0]hexan-3-yl)-7-fluoro-4H-9-methyl-4-oxo- quinolizine-3-carboxylic acid;
8-(3-amino-3-fluoromethyl-1-pyrrolidinyl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo- quinolizine-3-carboxylic acid;
8-(trans-3-amino-4-fluoromethylpyrrodin-1-yl)-1-cyclopropy1-7- fluoro-4H-9-methyl-4- oxo-quinolizine-3-carboxylic acid;
8-(cis-3-amino-4-fluoromethylpyrrodin-1-yl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo- quinolizine-3-carboxylic acid;
8-(3-(S)-(2-fluoroethyl)aminopyrrolidin-1-yl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo- quinolizine-3-carboxylic acid;
8-(3-(R)-(2-fluoroethyl)aminopyrrolidin-1-yl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo- quinolizine-3-carboxylic acid;
8-(3-(R)-(hydroxymethyl)pyrrolidin-1-yl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo- quinolizine-3-carboxylic acid;
8-(2-(R)-aminomethyl-pyrrolidin-1-yl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo- quinolizine-3-carboxylic acid;
8-(2-(R)-aminomethyl-pyrrolidin-1-yl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo- quinolizine-3-carboxylic acid;
(8-(3-amino-4-methyl-piperidin-1-yl)-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H- quinolizine-3-carboxylic acid;
8-(3-(7-amino-5-azaspiro[2.4]heptan-5-yl)-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H- quinolizine-3-carboxylic acid;
8-(7-(S)-amino-5-aza-spiro[2.4]heptan-5-yl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo- quinolizine-3-carboxylic acid;
8-(7-(R)-amino-5-aza-spiro[2.4]heptan-5-yl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo- quinolizine-3-carboxylic acid;
8-(trans-3-(S)-amino-4-(R)-cyclopropylpyrrolidin-1-yl)-1-cyclopropyl-7-fluoro-4H-9- methyl-4-oxo-quinolizine-3-carboxylic acid;
8-(trans-3-(R)-amino-4-(S)-cyclopropylpyrrolidin-1-yl)-1-cyclopropyl-7-fluoro-4H-9- methyl-4-oxo-quinolizine-3-carboxylic acid;
8-(trans-3-(S)-amino-4-(R)-methylpyrrolidin-1-yl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4- oxo-quinolizine-3-carboxylic acid;
8-(trans-3-(R)-amino-4-(S)-methylpyrrolidin-1-yl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4- oxo-quinolizine-3-carboxylic acid; 8-(cis-3-(S)-amino-4-(S)-cyclopropylpyrrolidin-1-yl)-1-cyclopropyl-7-fluoro-4H-9- methyl-4-oxo-quinolizine-3-carboxylic acid;
8-(cis-3-(R)-amino-4-(R)-cyclopropylpyrrolidin-1-yl)-1-cyclopropyl-7-fluoro-4H-9- methyl-4-oxo-quinolizine-3-carboxylic acid;
8-(trans-3-amino-4-ethylpyrrolidin-1-yl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo- quinolizine-3-carboxylic acid diastereomer A;
8-(trans-3-amino-4-ethylpyrrolidin-1-yl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo- quinolizine-3-carboxylic acid diastereomer B;
8-(cis-3-amino-4-ethylpyrrodin-1-yl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo- quinotizine-3-carboxytic acid diastereomer A;
8-(cis-3-amino-4-ethylpyrrodin-1-yl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo- quinolizine-3-carboxylic acid diastereomer B;
8-(cis-3-(S)-amino-4-(S)-methylpyrrodin-1-yl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4- oxo-quinolizine-3-carboxylic acid; and
8-(cis-3-(R)-amino-4-(R)-methylpyrrodin-1-yl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4- oxo-quinolizine-3-carboxylic acid;
and the pharmaceutically acceptable salts, esters and amides thereof.
24. A compound according to Claim 22 selected from the group consisting of:
8-(3(S)-amino-1-pyrrolidinyl)-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3- carboxylic acid;
8-(3-amino-1-pyrrolidinyl)-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3- carboxylic acid;
(3R,1S)-8-(3-(1-amino-2-methoxyethyl)pyrrolidinyl)-1-cyclopropyl-7-fluoro-9-methyl-4- oxo-4H-quinolizine-3-carboxylic acid;
(8-(3-(1-amino-1-methylethyl)pyrrolidinyl)-1-cyclopropyl-7-fluoro- 9-methyl-4-oxo-4H- quinolizine-3-carboxylic acid;
8-(3-(1-aminocyclopropyl)pyrrolidinyl)-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H- quinolizine-3-carboxylic acid;
(3R,1S)-8-(3-(1-aminoethyl)pyrrolidinyl)-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H- quinolizine-3-carboxylic acid;
1-cyclopropyl-8-(S,S-2,8-diaza-8-bicyclo[4.3.0]nonyl)-7-fluoro-4H-9-methyl-4-oxo- quinolizine-3-carboxylic acid;
1-cyclopropyl-8-(R,R-2,8-diaza-8-bicyclo[4.3.0]nonyl)-7-fluoro-4H-9-methyl-4-oxo- quinolizine-3-carboxylic acid;
1-cyclopropyl-8-(1-amino-3-aza-bicyclo[3.1.0]hexan-3-yl)-7-fluoro-4H-9-methyl-4-oxo- quinolizine-3-carboxylic acid; 8-(3-amino-3-fluoromethyl-1-pyrrolidinyl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo- quinolizine-3-carboxylic acid;
8-(trans-3-amino-4-fluoromethylpyrrodin-1-yl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4- oxo-quinolizine-3-carboxylic acid;
8-(cis-3-amino-4-fluoromethylpyrrodin-1-yl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo- quinolizine-3-carboxylic acid;
8-(3-(S)-(2-fluoroethyl)aminopyrrolidin-1-yl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo- quinolizine-3-carboxylic acid;
8-(3-(R)-(2-fluoroethyl)aminopyrrolidin-1-yl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo- quinolizine-3-carboxylic acid;
8-(3-(R)-(hydroxymethyl)pyrrolidin-1-yl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo- quinolizine-3-carboxylic acid;
8-(2-(R)-aminomethyl-pyrrolidin-1-yl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo- quinolizine-3-carboxylic acid; and
(8-(3-amino-4-methyl-piperidin-1-yl)-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H- quinolizine-3-carboxylic acid; and
8-(3-(7-amino-5-azaspiro[2.4]heptan-5-yl)-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H- quinolizine-3-carboxylic acid;
8-(7-(S)-amino-5-aza-spiro[2.4]heptan-5-yl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo- quinolizine-3-carboxylic acid;
8-(7-(R)-amino-5-aza-spiro[2.4]heptan-5-yl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo- quinolizine-3-carboxylic acid;
8-(trans-3-(S)-amino-4-(R)-cyclopropylpyrrolidin-1-yl)-1-cyclopropyl-7-fluoro-4H-9- methyl-4-oxo-quinolizine-3-carboxylic acid;
8-(trans-3-(R)-amino-4-(S)-cyclopropylpyrrolidin-1-yl)-1-cyclopropyl-7-fluoro-4H-9- methyl-4-oxo-quinolizine-3-carboxylic acid;
8-(trans-3-(S)-amino-4-(R)-methylpyrrolidin-1-yl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4- oxo-quinolizine-3-carboxylic acid;
8-(trans-3-(R)-amino-4-(S)-methylpyrrolidin-1-yl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4- oxo-quinolizine-3-carboxylic acid;
8-(cis-3-(S)-amino-4-(S)-cyclopropylpyrrolidin-1-yl)-1-cyclopropyl-7-fluoro-4H-9- methyl-4-oxo-quinolizine-3-carboxylic acid;
8-(cis-3-(R)-amino-4-(R)-cyclopropylpyrrolidin-1-yl)-1-cyclopropyl-7-fluoro-4H-9- methyl-4-oxo-quinolizine-3-carboxylic acid;
8-(trans-3-amino-4-ethylpyrrolidin-1-yl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo- quinolizine-3-carboxylic acid diastereomer A; 8-(trans-3-amino-4-ethylpyrrolidin-1-yl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo- quinolizine-3-carboxylic acid diastereomer B;
8-(cis-3-amino-4-ethylpyrrodin-1-yl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo- quinolizine-3-carboxylic acid diastereomer A;
8-(cis-3-amino-4-ethylpyrrodin-1-yl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4-oxo- quinolizine-3-carboxylic acid diastereomer B;
8-(cis-3-(S)-amino-4-(S)-methylpyrrodin-1-yl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4- oxo-quinolizine-3-carboxylic acid; and
8-(cis-3-(R)-ammo-4-(R)-methylpyrrodin-1-yl)-1-cyclopropyl-7-fluoro-4H-9-methyl-4- oxo-quinolizine-3-carboxylic acid;
and the pharmaceutically acceptable salts, esters and amides thereof.
25. A pharmaceutical composition comprising a compound according to Claim 1 in combination with a pharmaceuticaliy acceptable carrier.
26. A pharmaceutical composition comprising a compound according to Claim 10 in combination with a pharmaceuticaliy acceptable carrier.
27. A pharmaceutical composition comprising a compound according to Claim 22 in combination with a pharmaceuticaliy acceptable carrier.
28. A pharmaceutical composition comprising a compound according to Claim 25 in combination with a pharmaceuticaliy acceptable carrier.
29. A method of treating a bacterial infection in a human or veterinary patient, comprising administering to the patient a therapeuticaliy effective amount of a compound according to Claim 1.
30. A method of treating a bacterial infection in a human or veterinary patient, comprising administering to the patient a therapeutically effective amount of a compound according to Claim 10.
31. A method of treating a bacterial infection in a human or veterinary patient, comprising administering to the patient a therapeuticaliy effective amount of a compound according to Claim 22.
32. A method of treating a bacterial infection in a human or veterinary patient, comprising administering to the patient a therapeuticaliy effective amount of a compound according to Claim 25.
33. A synthetic intermediate selected from the group consisting of:
4-t-butoxy-3-chloro-2,5,6-trifluoropyridine;
4-t-butoxy-2,3,6-trifluoropyridine;
4-t-butoxy-2,3,6-trifluoro-5-methylpyridine;
4-t-butoxy-2,5-difluoro-3-methylpyridine;
2-(4-t-butoxy-5-fluoro-3-methyl-2-pyridinyl)cyclopropaneacetonitrile;
2-(4-chloro-5-fluoro-3-methyl-2-pyridinyl)cyclopropaneacetonitrile;
2-(4-chloro-5-fluoro-3-methyl-2-pyridinyl)cyclopropaneacetic acid;
ethyl 2-(4-chloro-5-fluoro-3-methyl-2-pyridinyl)cyclopropaneacetate;
2-(4-chloro-5-fluoro-3-methyl-2-pyridinyl)cyclopropaneacetaldehyde;
2-(4-chloro-5-fluoro-3-methyl-2-pyridinyl)cyclopropaneethanol;
2-(2-(4-chloro-5-fluoro-3-methyl-2-pyridinyl)-2-cyclopropylethylidinyl)-
1,3-propanedicarboxylic acid, diethyl ester; and
8-chloro-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4h-quinolizine-3-carboxylic acid ethyl ester.
EP96919103A 1995-06-06 1996-06-05 Quinolizinone type compounds Withdrawn EP0871628A1 (en)

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US63811296A 1996-05-29 1996-05-29
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