EP1888597A2 - Antibacterial agents - Google Patents

Antibacterial agents

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Publication number
EP1888597A2
EP1888597A2 EP06755883A EP06755883A EP1888597A2 EP 1888597 A2 EP1888597 A2 EP 1888597A2 EP 06755883 A EP06755883 A EP 06755883A EP 06755883 A EP06755883 A EP 06755883A EP 1888597 A2 EP1888597 A2 EP 1888597A2
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EP
European Patent Office
Prior art keywords
compound
substituted
unsubstituted
mmol
formula
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.)
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EP06755883A
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German (de)
French (fr)
Inventor
Michael Robert Barbachyn
Paul Joseph Dobrowolski
Susan Elizabeth Hagen
Tycho Heinar Heimbach
Alexander Ross Hurd
Timothy Allen Johnson
Dennis Joseph Mcnamara
James Craig Ruble
Debra Ann Sherry
Lisa Marie Thomasco
Peter Laurence Toogood
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Warner Lambert Co LLC
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Warner Lambert Co LLC
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Publication of EP1888597A2 publication Critical patent/EP1888597A2/en
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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains three hetero rings
    • C07D498/20—Spiro-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
    • A61P31/04—Antibacterial agents

Definitions

  • antibacterial compounds Described herein are antibacterial compounds, their use as antibacterial agents, pharmaceutical compositions containing these compounds, and methods for their preparation.
  • Antibacterial resistance is a global clinical and public health problem that has emerged with alarming rapidity in recent years and undoubtedly will increase in the near future. Resistance is a problem in the community as well as in health care settings, where transmission of bacteria is greatly amplified. Because multiple drug resistance is a growing problem, physicians are now confronted with infections for which there is no effective therapy. The morbidity, mortality, and financial costs of such infections pose an increasing burden for health care systems worldwide. Strategies to address these issues emphasize enhanced surveillance of drug resistance, increased monitoring and improved usage of antimicrobial drugs, professional and public education, development of new drugs, and assessment of alternative therapeutic modalities.
  • R 1 is a substituted or unsubstituted thiadiazole
  • R 2 and R 3 are independently H or substituted or unsubstituted Ci. 6 alkyl
  • R 8 and R 9 are independently H, substituted or unsubstituted C 1 ⁇ alkyl or R 8 and R 9 together with the atom to which they are attached form a substituted or unsubstituted heterocyclic ring;
  • X and Y are independently H, halo, substituted or unsubstituted Ci- 6 alkyl, -OR 6 , a substituted or unsubstituted ether, or a substituted or unsubstituted amine; [0006] with the proviso that the compound is not rel-(2R,4S,4aS)-1 ,2,4,4a-Tetrahydro-2,4- dimethyl-8-[5-(methylthio)-1 , 3,4-th iadiazol-2-yl]spiro[[1 ,4]oxazino[4,3-a]quinoline-5(6H),5'(2'H)-pyrimidine]- 2 ⁇ 4',6'(1H3 ⁇ )-trione.
  • Forms of the compounds can include salts, such as pharmaceutically acceptable salts, solvates, hydrates or prodrugs of the described compounds.
  • the described compounds can also be part of a pharmaceutical composition, which can additionally include a pharmaceutically acceptable carrier, diluent or excipient.
  • Such compounds and compositions exhibit antibacterial activity and can be used accordingly.
  • X, Y or both can be a substituted or unsubstituted ether.
  • R 4 and R 5 can be H.
  • R 4 and R 5 can also independently be ethers.
  • independently X, Y or both can be a substituted or unsubstituted amine.
  • the group can independently have the formula -(CH 2 ) m NR 8 R 9 and each m, R 8 and R 9 is independent of any other m, R 8 and R 9 values at other positions.
  • the ring can be a monocyclic ring system, for example containing three to eight ring atoms, or the ring system can be a bi- or polyheterocyclic ring system.
  • one or more ring atoms, in addition to the N to which R 8 and R 9 are attached can be selected from non-carbon atoms, for example N, O or S.
  • Ri is one of the following:
  • ⁇ indicates a point of attachment
  • Rn, R 12 and Ri 3 are independently H 1 substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted aminoalkyl, an amino acid residue or a peptide residue.
  • amino acid residues include alanine, aspartic acid, glycine, glutamic acid, histidine, lysine or valine.
  • X is H, Y is H or both X and Y are H.
  • X is F, Y is F or both X and Y are F.
  • R 2 and R 3 can be methyl.
  • X can be -OH or -OR 6 , and in some instances R 6 will be methyl or ethyl.
  • X can be an ether or an amine.
  • m in R 7 is 0, for example where R 7 is -CO 2 E, -NR 8 Rg, -PO 3 (Rn) 2 ,
  • R 7 groups can be found in the exemplified compounds. In certain compounds R 7 is H or methyl. [0016] In some embodiments R 4 and R 5 are the same, for example where both are H.
  • R 4 and R 5 can be -OH, -(CH 2 ) m OH, -CH 2 OH, -CH 2 OAc, -CH 2 OCH 3 , -CH 2 O(CH 2 ) 2 OCH 3 .
  • R 4 or R 5 can also be substituted or unsubstituted -(CH 2 ) m aryl or -O(CH 2 ) m aryl, such as substituted or unsubstituted benzyl or substituted or unsubstituted -Obenzyl.
  • R 4 and R 5 can also be -CH 2 OPO 3 H 2 .
  • the heterocyclic ring when R 8 and R 9 together with the atom to which they are attached form a substituted or unsubstituted heterocyclic ring, the heterocyclic ring can have three, four, five, six, seven, eight or more ring members and include one, two, three or more heteroatoms, such as N, O or S.
  • Specific examples of such heterocyclic rings include morpholine and piperazine or a substituted piperazine.
  • R 11 , R 12 or R 13 can be an amino acid residue.
  • amino acids examples include alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine and valine.
  • Other amino acids include gamma-aminobutyric acid (GABA), carnitine, ornithine, citrulline, homocysteine, hydroxyproline, hydroxylysine, and sarcosine.
  • GABA gamma-aminobutyric acid
  • the amino acids can be in the L- or D- configuration.
  • R 11 , R 12 or R 13 can be a peptide residue, which can be C- or N-linked.
  • Peptides are amino acids linked together via peptide bonds and can be straight-chained or branched.
  • Suitable peptides can include dipeptides, tripeptides, tetrapeptides or more in which the amino acid residues making up the peptide can be the same or different.
  • (R p ) 2 together with the atoms to which they are attached form a substituted or unsubstituted heterocyclic ring.
  • oxygen atoms can be connected
  • each E or ether independently has the formula
  • each E or ether independently has the formula -[(CH 2 ) p O(CH 2 ) p ] q CH 3 where each p is independently 0, 1 , 2, 3 or 4 and each q is independently 1 , 2, 3 or 4.
  • X and Y are F
  • R 2 and R 3 are methyl
  • R 4 and R 5 are
  • R 7 can be methyl.
  • m is 1 or 2.
  • X and Y are F
  • R 2 and R 3 are methyl
  • m is 1 or 2.
  • X is H
  • Y is F
  • R 2 and R 3 are methyl
  • m is 1 or 2.
  • R can include H, such as in aldehydes, a hydrocarbon, such as in a ketone, -NR 8 R 9 , such as in an amide, -OR 6 such as in a carboxylic acid or ester, -0OCR 2 , such as in an acyl anhydride or a halo, such as in an acyl halide.
  • alkenyl group can optionally be substituted, for example where 1 , 2, 3, 4, 5, 6, 7, 8 or more hydrogen atoms are replaced by a substituent selected from the group consisting of halogen, haloalkyl, hydroxy, thiol, cyano, and -NR 8 R 9 .
  • alkyl refers to hydrocarbon chains, for example Ci. 6 chains, that do not contain heteroatoms.
  • the phrase includes straight chain alkyl groups such as methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl and the like.
  • the phrase also includes branched chain isomers of straight chain alkyl groups, including but not limited to, the following which are provided by way of example: -CH(CH 3 ) 2 , -CH(CH 3 )(CH 2 CH 3 ), -CH(CH 2 CH 3 ) 2 , -C(CHg) 3 , -C(CH 2 CH 3 ) 3 , -CH 2 CH(CH 3 ) 2 , -CH 2 CH(CH 3 )(CH 2 CH 3 ), -CH 2 CH(CH 2 CHg) 2 , -CH 2 C(CHa) 3 , -CH 2 C(CH 2 CH 3 ) 3 , -CH(CH 3 )CH(CH 3 )(CH 2 CH 3 ), -CH 2 CH 2 CH(CHg) 2 , -CH 2 CH 2 CH(CH 3 )(CH 2 CH 3 ), -CH 2 CH 2 CH(CHg) 2 , -CH 2 CH 2 CH(CH 3 )(CH 2 CH 3
  • the phrase includes primary alkyl groups, secondary alkyl groups, and tertiary alkyl groups.
  • Alkyl groups can be bonded to one or more carbon atom(s), oxygen atom(s), nitrogen atom(s), and/or sulfur atom(s) in the parent compound.
  • An alkyl group can optionally be substituted, for example where 1, 2, 3, 4, 5, 6 or more hydrogen atoms are replaced by a substituent selected from the group consisting of halogen, haloalkyl, hydroxy, thiol, cyano, and -NR 8 R 9 .
  • alkylene refers to a straight or branched chain divalent hydrocarbon radical, generally having from two to ten carbon atoms.
  • alkynyl refers to straight and branched chain hydrocarbon groups, such as those described with respect to alkyl groups as described herein, except that at least one triple bond exists between two carbon atoms. Examples include -C ⁇ C(H), -C ⁇ C(CH 3 ), -C ⁇ C(CH 2 CH 3 ), -C(H 2 )C ⁇ C(H), -C(H) 2 C ⁇ C(CH 3 ), and -C(H) 2 CsC(CH 2 CH 3 ) among others.
  • alkynyl group can optionally be substituted, for example where 1 , 2, 3, 4, 5, 6, 7, 8 or more hydrogen atoms are replaced by a substituent selected from the group consisting of halogen, haloalkyl, hydroxy, thiol, cyano, and -NR 8 R 9 .
  • a substituent selected from the group consisting of halogen, haloalkyl, hydroxy, thiol, cyano, and -NR 8 R 9 .
  • aminoalkyl refers to an alkyl group as above attached to an amino group, which can ultimately be a primary, secondary or tertiary amino group.
  • An example of an amino alkyl group is the -NR 8 Rg where one or both of R 8 and R 9 is a substituted or unsubstituted C-i.
  • R 8 and R 9 together with the atom to which they are attached form a substituted or unsubstituted heterocyclic ring.
  • Specific aminoalkyl groups include -NHCH 3 , -IM(CH 3 ).,, -NHCH 2 CH 3 , -N(CH 3 )CH 2 CH 3 ,-N(CH 2 CH 3 ) 2 , -NHCH 2 CH 2 CH 3 , -N(CH 2 CH 2 CH 3 ) 2 , and the like.
  • Additional aminoalkyl groups include:
  • aminoalkyl group can optionally be substituted with 1 , 2, 3, 4 or more non-hydrogen substituents, for example where each substituent is independently selected from the group consisting of halogen, cyano, hydroxy, Ci. 6 alkyl, C 1 ⁇ alkoxy, Cr 2 alkyl substituted with one or more halogens, Cr ⁇ alkoxy substituted with one or more halogens, -C(O)R 6 , -C(O)OR 6 , -S(O) n R 6 and -NR 8 R 9 .
  • substituents may be the same or different and may be located at any position of the ring that is chemically permissible.
  • aryl refers to cyclic or polycyclic aromatic rings, generally having from 5 to
  • the phrase includes, but is not limited to, groups such as phenyl, biphenyl, anthracenyl, naphthenyl by way of example.
  • the phrase "unsubstituted aryl” includes groups containing condensed rings such as naphthalene. Unsubstituted aryl groups can be bonded to one or more carbon atom(s), oxygen atom(s), nitrogen atom(s), and/or sulfur atom(s) in the parent compound. Substituted aryl groups include methoxyphenyl groups, such as para-methoxyphenyl.
  • Substituted aryl groups include aryl groups in which one or more aromatic carbons of the aryl group is bonded to a substituted and/or unsubstituted alkyl, alkenyl, alkynyl group or a heteroatom containing group as described herein. This includes bonding arrangements in which two carbon atoms of an aryl group are bonded to two atoms of an alkyl, alkenyl, or alkynyl group to define a fused ring system (e.g. dihydronaphthyl or tetrahydronaphthyl).
  • the phrase "substituted aryl” includes, but is not limited to tolyl, and hydroxyphenyl among others.
  • An aryl moiety can optionally be substituted with 1 , 2, 3, 4 or more non-hydrogen substituents, for example where each substituent is independently selected from the group consisting of halogen, cyano, hydroxy, Ci. 6 alkyl, C 1 ⁇ alkoxy, Cr 2 alkyl substituted with one or more halogens, Cr 2 alkoxy substituted with one or more halogens, -C(O)R 6 , -C(O)OR 6 , -S(O) n R 6 and - NR 8 R 9 .
  • substituents may be the same or different and may be located at any position of the ring that is chemically permissible.
  • cycloalkyl refers to cyclic hydrocarbon chains, generally having from 3 to 12 carbon atoms, and includes cyclic alkyl groups such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl and such rings substituted with straight and branched chain alkyl groups as described herein.
  • the phrase also includes polycyclic alkyl groups such as, but not limited to, adamantly, norbornyl, and bicyclo[2.2.2]octyl and such rings substituted with straight and branched chain alkyl groups as described herein.
  • Cycloalkyl groups can be saturated or unsaturated and can be bonded to one or more carbon atom(s), oxygen atom(s), nitrogen atom(s), and/or sulfur atom(s) in the parent compound.
  • a cycloalkyl group can be optionally substituted, for example where 1 , 2, 3, 4 or more hydrogen atoms are replaced by a substituent selected from the group consisting of halogen, cyano, hydroxy, C 1-6 alkyl, C 1 ⁇ alkoxy, C r ⁇ alkyl substituted with one or more halogens, Cr 2 alkoxy substituted with one or more halogens, -C(O)R 6 , -C(O)OR 6 , -S(O) n R 6 and -NR 8 R 9 .
  • Ethers as used herein, generically encompass monoethers, polyethers, straight chain ethers, branched ethers and cyclic ethers.
  • Straight chain ethers can have the structure -[(CH 2 ) p O(CH 2 ) p ] q CH 3 where each p is independently 0, 1 , 2, 3, 4, 5 or 6 and q is 1 , 2, 3, 4, 5 or 6.
  • Branched ethers can have the formula -[(CV 2 ) p O(CV 2 ) p ] q CH 3 where each V is independently H or another
  • Cyclic ethers can have the formula where p and q are as above and ⁇ JVW > indicates a point of attachment.
  • ether compounds there are -dimethyl ether, -methyl ethyl ether, -methoxy ethyl ether, -diethyl ether, -methyl t-butyl ether, -methyl cellosolve, - ethylene glycol dimethyl ether, -diethylene glycol dimethyl ether, -triethylene glycol dimethyl ether, -tetraethylene glycol dimethyl ether, -tetrahydrofuran, -1 ,4-dioxane, and the like.
  • halo refers to fluorine, chlorine, bromine or iodine.
  • haloalkyl refers to an alkyl group in which at least one, for example 1 , 2, 3,
  • haloalkyls include chloromethyl, difluoromethyl, trifluoromethyl, 1-fluro-2-chloro-ethyl, 5-fluoro-hexyl, 3-difluro-isopropyl, 3- chloro-isobutyl, etc.
  • heterocyclyl or “heterocyclic ring” refers to aromatic, nonaromatic, saturated and unsaturated ring compounds including monocyclic, bicyclic, and polycyclic ring compounds, including fused, bridged, or spiro systems, such as, but not limited to, quinuclidyl, containing 1 , 2, 3 or more ring members of which one or more is a heteroatom such as, but not limited to, N, O, P and S.
  • Unsubstituted heterocyclyl groups include condensed heterocyclic rings such as benzimidazolyl.
  • heterocyclyl groups include: unsaturated 3 to 8 membered rings containing 1 to 4 nitrogen atoms such as, but not limited to pyrrolyl, pyrrolinyl, imidazolyl, imidazolidinyl, pyrazolyl, pyridyl, dihydropyridyl, pyrimidyl, pyrazinyl, pyridazinyl, triazolyl (e.g. 4H-1 ,2,4-triazolyl, 1 H-1 ,2,3-triazolyl, 2H- 1 ,2,3-triazolyl etc.), tetrazolyl, (e.g.
  • saturated 3 to 8 membered rings containing 1 to 4 nitrogen atoms such as, but not limited to, pyrrolidinyl, piperidinyl, piperazinyl; condensed unsaturated heterocyclic groups containing 1 to 4 nitrogen atoms such as, but not limited to, indolyl, isoindolyl, indolinyl, indolizinyl, benzimidazolyl, quinolyl, isoquinolyl, indazolyl, benzotriazolyl; saturated 3 to 8 membered rings containing 1 to 3 oxygen atoms such as, but not limited to, tetrahydrofuran; unsaturated 3 to 8 membered rings containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms such as, but not limited to, oxazolyl, isoxazolyl, oxadiazolyl (e.g.
  • saturated 3 to 8 membered rings containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms such as, but not limited to, morpholinyl; unsaturated condensed heterocyclic groups containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms, for example, benzoxazolyl, benzoxadiazolyl, benzoxazinyl (e.g.
  • unsaturated 3 to 8 membered rings containing 1 to 3 sulfur atoms and 1 to 3 nitrogen atoms such as, but not limited to, thiazolyl, isothiazolyl, thiadiazolyl (e.g.
  • saturated 3 to 8 membered rings containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms such as, but not limited to, thiazolodinyl; saturated and unsaturated 3 to 8 membered rings containing 1 to 2 sulfur atoms such as, but not limited to, thienyl, dihydrodithiinyl, dihydrodithionyl, tetrahydrothiophene, tetrahydrothiopyran; unsaturated condensed heterocyclic rings containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms such as, but not limited to, benzothiazolyl, benzothiadiazolyl, benzothiazinyl (e.g.
  • unsaturated 3 to 8 membered rings containing an oxygen atom and 1 to 2 sulfur atoms such as; but not limited to, dihydrooxathiinyl; saturated 3 to 8 membered rings containing 1 to 2 oxygen atoms, and 1 to 2 sulfur atoms such as 1 ,4-oxathiane; unsaturated condensed rings containing 1 to 2 sulfur atoms such as benzothienyl, benzodithiinyl; and unsaturated condensed heterocyclic rings containing an oxygen atom and 1 to 2 oxygen atoms such as benzoxathiinyl.
  • Heterocyclyl group also include those described herein in which one or more S atoms in the ring is double-bonded to one or two oxygen atoms (sulfoxides and sulfones).
  • heterocyclyl groups include tetrahydrothiophene, tetrahydrothiophene oxide, and tetrahydrothiophene 1 ,1 -dioxide.
  • Heterocyclyl groups can contain 5 or 6 ring members.
  • heterocyclyl groups include morpholine, piperazine, piperidine, pyrrolidine, imidazole, pyrazole, 1 ,2,3- triazole, 1 ,2,4-triazole, tetrazole, thiomorpholine, thiomorpholine in which the S atom of the thiomorpholine is bonded to one or more O atoms, pyrrole, homopiperazine, oxazolidin-2-one, pyrrolidin-2-one, oxazoie, quinuclidine, thiazole, isoxazole, furan, and tetrahydrofuran.
  • a heterocyclyl group can be optionally substituted, for example where 1 , 2, 3, 4 or more hydrogen atoms are replaced by a substituent selected from the group consisting of halogen, cyano, hydroxy, C 1 ⁇ a'M.
  • Heterocyclyl groups include heteroaryl groups as a subgroup.
  • heteroaryl refers to a monovalent aromatic ring radical, generally having 5 to 10 ring atoms, containing 1 , 2, 3, or more heteroatoms independently selected from S, O, or N.
  • heteroaryl also includes bicyclic groups in which the heteroaryl ring is fused to a benzene ring, heterocyclic ring, a cycloalkyl ring, or another heteroaryl ring.
  • heteroaryl examples include 7-benzimidazolyl, benzo[b]thienyl, benzofuryl, benzothiazolyl, benzothiophenyl, 2-, 4-, 5-, 6-, or 7-benzoxazolyl, furanyl, furyl, imidazolyl, indolyl, indazolyl, isoquinolinyl, isothiazolyl, isoxazolyl, oxadiazolyl, oxazolyl, purinyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridinyl, pyrimidinyl, pyrrolyl, quinolinyl, tetrazolyl, thiadiazolyl, thiazolyl, thienyl, thiophenyl, triazolyl and the like.
  • Heteroaryl rings can also be optionally fused to one or more of another heterocyclic ring(s), heteroaryl ring(s), aryl ring(s), cycloalkenyl ring(s), or cycloalkyl rings.
  • a heteroaryl group can be optionally substituted, for example where 1 , 2, 3, 4 or more hydrogen atoms are replaced by a substituent selected from the group consisting of halogen, cyano, hydroxy, C 1-6 alkyl, Ci- 6 alkoxy, d- 2 alkyl substituted with one or more halogens, Cr 2 alkoxy substituted with one or more halogens, -C(O)R 6 , -C(O)OR 6 , -S(O) n R 6 and -NR 8 R 9 .
  • heterocyclyloxy refers to a group in which an oxygen atom is bound to a ring atom of a heterocyclyl group as described herein.
  • a “pharmaceutically acceptable” means suitable for use in mammals.
  • a “pharmaceutically acceptable salt” includes a salt with an inorganic base, organic base, inorganic acid, organic acid, or basic or acidic amino acid.
  • the invention includes, for example, alkali metals such as sodium or potassium; alkaline earth metals such as calcium and magnesium or aluminum; and ammonia.
  • salts of organic bases the invention includes, for example, trimethylamine, triethylamine, pyridine, picoline, ethanolamine, diethanolamine, and triethanolamine.
  • the instant invention includes, for example, hydrochloric acid, hydroboric acid, nitric acid, sulfuric acid, and phosphoric acid.
  • the instant invention includes, for example, formic acid, acetic acid, trifluoroacetic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid, and p-toluenesulfonic acid.
  • salts of basic amino acids the instant invention includes, for example, arginine, lysine and ornithine.
  • Acidic amino acids include, for example, aspartic acid and glutamic acid.
  • pharmaceutically acceptable salts are described in Berge, S. M. et al., "Pharmaceutical Salts," Journal of Pharmaceutical Science, 1977;66:1 19.
  • a "prodrug” is a compound that can be transformed in vivo into an active therapeutic compound, such as a compound described herein. Transformation of the prodrug compound can be accomplished chemically, enzymatically, or by action with other endogenous materials, e.g. amino acids, peptides and proteins. Prodrugs are discussed in T. Higuchi and V. Stella, "Pro-drugs as Novel Delivery Systems," Vol. 14 of the A.C.S.
  • prodrugs can include esters and amides of polar groups, such as carboxylate groups.
  • prodrugs can include esters and amides of polar groups, such as carboxylate groups.
  • protected with respect to hydroxyl groups, amine groups, and sulfhydryl groups refers to forms of these functionalities which are protected from undesirable reaction with a protecting group known to those skilled in the art such as those set forth in Protective Groups in Organic Synthesis, Greene, T. W.; Wilts, P. G. M., John Wiley & Sons, New York, N.Y., (3rd Edition, 1999) which can be added or removed using the procedures set forth therein.
  • Examples of protected hydroxyl groups include silyl ethers such as those obtained by reaction of a hydroxyl group with a reagent such as, but not limited to, t-butyldimethyl-chlorosilane, trimethylchlorosilane, triisopropylchlorosilane, triethylchlorosilane; substituted methyl and ethyl ethers such as, but not limited to methoxymethyl ether, methythiomethyl ether, benzyloxymethyl ether, t-butoxymethyl ether, 2-methoxyethoxym ethyl ether, tetrahydropyranyl ethers, 1 -ethoxyethyl ether, allyl ether, benzyl ether; esters such as, but not limited to, benzoylformate, formate, acetate, trichloroacetate, and trifluoracetate.
  • a reagent such as, but not limited to
  • protected amine groups include amides such as, formamide, acetamide, trifluoroacetamide, and benzamide; imides, such as phthalimide, and dithiosuccinimide; and others.
  • protected sulfhydryl groups include thioethers such as S-benzyl thioether, and S-4-picolyl thioether; substituted S-methyl derivatives such as hemithio, dithio and aminothio acetals; and others.
  • a "salt" is intended to refer to all salt forms of a compound, including salts suitable for use in industrial processes, such as the preparation of the compound, and pharmaceutically acceptable salts.
  • Substituted refers to a group in which one or more bonds to a hydrogen atom contained therein are replaced by a bond to non-hydrogen atom. In some instances the bond will also be replaced by non-carbon atoms such as, but not limited to: a halogen atom such as F, Cl, Br, and I; a nitrogen atom in groups such as amines, amides, alkylamines, dialkylamines, arylamines, alkylarylamines, diarylamines, heterocyclylamine, (alkyl)(heterocyclyl)amine, (aryl)(heterocyclyl)amine, or diheterocyclylamine groups, isonitrile, N-oxides, imides, and enamines; an oxygen atom in groups such as hydroxyl groups, alkoxy groups, aryloxy groups, ester groups, and heterocyclyloxy groups; a silicon atom in groups such as in trialkylsilyl groups,
  • Substituted alkyl groups and substituted cycloalkyl groups also include groups in which one or more bonds to one or more carbon or hydrogen atoms are replaced by a bond to a heteroatom such as oxygen in carbonyl, carboxyl, and ether groups; nitrogen in groups such as imines, oximes and hydrazones.
  • Substituted cycloalkyl, substituted aryl, substituted heterocyclyl and substituted heteroaryl also include rings and fused ring systems which can be substituted with alkyl groups as described herein.
  • Substituted arylalkyl groups can be substituted on the aryl group, on the alkyl group, or on both the aryl and aikyl groups.
  • substituents for substitution include one or more, for example one, two or three, groups independently selected from halogen, -OH, -C 1-6 alkyl, C 1 ⁇ alkoxy, trifluoromethoxy, -S(O) n C 1 . 6 alkyl, amino, haloalkyl, thiol, cyano, -OR 10 and -NR 8 R 9 , and trifluoromethyl.
  • Treating means an alleviation of symptoms associated with an infection, halt of further progression or worsening of those symptoms, or prevention or prophylaxis of the infection.
  • Treatment can also include administering the pharmaceutical formulations of the present invention in combination with other therapies.
  • the compounds and pharmaceutical formulations of the present invention can be administered before, during, or after surgical procedure and/or radiation therapy.
  • the compounds of the invention can also be administered in conjunction with other antibacterial drugs.
  • compounds described herein can be provided ex vivo or produced in vivo, for example where a prodrug of a compound is administered.
  • reference to a certain element such as hydrogen or H is meant to include all isotopes of that element.
  • an R group is defined to include hydrogen or H, it also includes deuterium and tritium.
  • compound B can be obtained from compound A by forming a thiadiazole side chain precursor from the carboxylic acid moiety.
  • the thiadiazole side chain precursor can then be cyclized to the desired thiadiazole, as described in more detail in the following reactions, and the alcohol can be deprotected to obtain compound C.
  • thiadiazole ring formation can occur directly from compound A, particularly for compounds containing sulfide and sulfone substituted 1 ,3,4-thiadiazoles, using the appropriate reagents as described below.
  • compound A can be prepared at least as follows, particularly where
  • X is H and Y is F:
  • reaction, OPro 2 is a carbonyl protecting group, such as a cyclic acetal, which can be formed by reaction of a carbonyl with 1 ,2-ethanediol or propane-1 ,3-diol in the presence of an acid catalyst. Typical halo atoms include bromine.
  • the carbonyl deprotection can be performed by acid deprotection in THF.
  • the carbonyl can be reduced, such as by using sodium borohydride in the presence of methanol.
  • the resulting alcohol can be protected utilizing art-known methods and groups, for example a trialkyl silyl ether such as t-butyldiphenyl silyl ether (TBDPS), and the halo group can be substituted by a carboxylation to give compound A.
  • TDPS t-butyldiphenyl silyl ether
  • the carboxylation can be achieved by performing a halogen metal exchange reaction followed by reacting the product with a carbonyl donor.
  • the halogen metal exchange reaction can include can include contacting the compound with a strong base, such as alkyl lithium, or a Grignard reagent in a non-protic organic solvent.
  • Compound A can also be produced according to the following synthetic scheme, particularly when both X and Y are F:
  • ring coupling can be achieved by the use of a base, such as lithium hexamethyldisilazide (LiHDMS), Et 3 N, or the like. Similar to the preceding reaction, the carbonyl can be reduced, such as by using sodium borohydride and I 2 . The resulting alcohol can be protected utilizing art- known methods and groups, for example a trialkyl silyl ether such as t-butyldiphenyl silyl ether (TBDPS), and the halo group can be displaced by a carboxylation reaction to give compound A.
  • a base such as lithium hexamethyldisilazide (LiHDMS), Et 3 N, or the like.
  • the carbonyl can be reduced, such as by using sodium borohydride and I 2 .
  • the resulting alcohol can be protected utilizing art- known methods and groups, for example a trialkyl silyl ether such as t-butyldiphenyl silyl ether (TBDPS), and
  • compound A is modified to add the thiadiazole side chain precursor by converting the starting carboxylic acid into a ketone via the Weinreb amide using Grignard chemistry.
  • a non-limiting example of this chemistry is shown in Example 2, steps 1 and 2.
  • Reaction with tosyl hydrazine to generate a hydrazone, followed by treatment with thionyl chloride produces the 1 ,2,3-thiadiazole as shown.
  • compound A where n is 1 may be obtained from compound A where n is 0 by adding a carbon to the carboxyl side chain.
  • the carboxlic acid is converted to an acid chloride using oxalyl chloride then treated with trimethylsilyl-diazomethane and methanol resulting in homologation to a methyl ester as follows:
  • the carboxyl group of compound A is converted to an amide which is converted to a thioamide.
  • the thiadiazole of compound C is then formed from the thioamide of compound B by cyclization with the appropriate reagents, as described in more detail in the examples.
  • Pro 3 represents a protecting group, for example an amine protecting group such as a tert-butoxycarbonyl (BOC) group.
  • BOC tert-butoxycarbonyl
  • the carboxyl group of compound A is converted to a protected hydrazide which is converted to a thiohydrazide similar to the thioamide conversion described herein.
  • the thiohydrazide is deprotected and cyclized to a thiadiazole, for example by using an acylating agent.
  • reaction to form Il can occur in an aqueous or organic solvent.
  • temperatures for this reaction will be about 60 to about 180 0 C, for example from about 80 to 180 0 C, 100 to 140 0 C or 140 to 180 0 C, and can occur from about 2 to about 24 hours, for example 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22 or 24 hours.
  • solvents that can be used include DMSO, methanol, isopropanol, butanol, toluene and water.
  • temperatures can range from about 80 0 C to about 120 0 C.
  • reaction times can range from about 5 to 24 h.
  • the method can also involve (b) reacting a compound of formula V with a compound of formula Vl, optionally in a non-protic organic solvent and/or in the presence of a base, to make the compound of formula III:
  • the base when present, can be an organic or inorganic base.
  • compound Vl can act as a base.
  • the reaction will take place at a temperature of about 20 to about 100 0 C, for example from about 40 to 100 0 C, 60 to 80 0 C or 80 to 100 0 C.
  • This reaction can also be performed alone to provide the compound of formula III.
  • solvents that can be used include acetonitrile and dimethylformamide.
  • Temperature ranges for the reaction can also be about 70 to 90 0 C
  • Bases that can be used in the reaction include triethylamine, diisopropylethylamine or potassium carbonate. Reaction times can range from about 2 to 24 hours, for example 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22 or 24 hours.
  • Compound V can be made by:
  • reaction Ha is hydrogen or a halogen, for example bromine. Ha can also be chlorine or iodine.
  • (c)(i) can include contacting the compound of formula VII with a strong base, such as alkyl lithium.
  • (c)(i) can include contacting the compounds of formula VII with a Grignard reagent in a non-protic organic solvent. These reactions typically occur at a temperature from about -78 to about 50 °C, for example from about -78 to about 0 0 C.
  • the carbonyl donor can include one or more of dimethylformamide, N-formylmorpholine, or para- nitrophenylformate. Examples of reaction times can be from about 1 to about 18 hours, for example 2, 4, 6, 8, 10, 12, 14, 16 or 18 hours.
  • Compound V can also be synthesized by (c) oxidizing a compound of formula VIII to make the compound of formula V:
  • X IX is a halogen, such as iodine. Accordingly, compound IX is made by reacting compounds X and Xl. This coupling reaction can also be performed with reverse polarity wherein the boron is attached to R 1 and the halogen is attached to compound X at the position indicated by B' (see structure XII below). In general, the coupling reaction can be performed under standard Suzuki cross-coupling conditions employing 0.01- 0.1 equivalents of a palladium catalyst with appropriate ligands, such as Pd(PPh 3 ) 4 or Pd(dppf) Cl 2 , in an organic solvent or solvent mixture containing organic solvents, such as toluene and an alcohol, and water.
  • a palladium catalyst with appropriate ligands, such as Pd(PPh 3 ) 4 or Pd(dppf) Cl 2
  • organic solvent or solvent mixture such as toluene and an alcohol, and water.
  • the reaction can be performed in the presence of a base such as potassium carbonate, sodium carbonate, potassium phosphate, cesium carbonate or sodium acetate for example, at temperatures, e.g. from about 20 to 120 0 C for about 2 to 24 h.
  • a base such as potassium carbonate, sodium carbonate, potassium phosphate, cesium carbonate or sodium acetate for example, at temperatures, e.g. from about 20 to 120 0 C for about 2 to 24 h.
  • This route can also be used to make compounds of formula III when a trans-morpholine compound is used in the reaction.
  • Compounds III or IX can be used to make compound of formula I or Il according to the methods described herein.
  • Compound X can be made by reacting compound XII to provide compound X:
  • Conversion of compounds XII to compound X can be performed by reaction with a borane such as for example, bis(pinacolato)diboron, under palladium catalysis employing a palladium(ll) or palladium(o) species with appropriate ligands, for example Pd(PPh 3 )4, Pd(dppf)CI 2 , Pd(PCy) 2 CI 2 , in an organic solvent such as tetrahydrofuran, methyl-tetrahydrofuran, or toluene, and in the presence of an inorganic base such as, for example, potassium acetate, potassium phosphate, sodium carbonate, cesium carbonate.
  • the reaction typically proceeds at elevated temperatures from 80 to 120 0 C over about 12 h to 5 days.
  • compound XII can be made by reacting compounds XIII and XIV:
  • the method can involve (a) reacting a compound of formula XIV with a compound of formula XIII, optionally in a non-protic organic solvent and/or in the presence of a base, to make the compound of formula XII.
  • the base can be an organic or inorganic base.
  • compound XII can act as a base.
  • the reaction will take place at a temperature of about 20 to about 100 0 C, for example from about 40 to 100 0 C, 60 to 80 0 C or 80 to 100 0 C.
  • Compound XIV can be made from compound XV as follows:
  • compound XIV can be made by:
  • reaction, Ha is hydrogen.
  • reaction, (b)(i) can include contacting the compound of formula XV with a strong base, such as alkyl lithium. These reactions typically occur at a temperature from about -78 to about 50 0 C.
  • the carbonyl donor can include one or more of dimethylformamide, N-formylmorpholine, or para-nitrophenylformate.
  • R 14 is a halogen, such as bromine or iodine, boronic acid, a boronate ester, such
  • the base when present, can be an organic or inorganic base. In some instances compound Vl can act as a base. Typically, the reaction will take place at a temperature of about 20 to about 100 0 C, for example from about 40 to 100 0 C, 60 to 80 0 C or 80 to 100 0 C. Examples of solvents that can be used include acetonitrile and dimethylformamide. Temperatures ranges for the reaction can also be about 70 to 90 0 C. Bases that can be used in the reaction include triethylamine, dirsopropylethylam ine or potassium carbonate. Reaction times can range from about 2 to 24 hours, for example 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22 or 24 hours.
  • compound XVII can be used to make compound XVII where R 14 is boronic acid or a boronate ester using the same reaction as set forth for making compound X.
  • compound XVII can also be used to make the compound of formula III by coupling compound XVII with a compound of formula RrB', where B' is
  • the compound of formula III can also be produced when Ru is boronic acid, a boronate ester, by reaction compound XVII with compound Xl (R r halo) by the method set forth for making compound IX described herein.
  • this coupling reaction can be performed under standard Suzuki cross-coupling conditions employing 0.01- 0.1 or more equivalents of a palladium catalyst with appropriate ligands, such as Pd(PPh 3 ) 4 or Pd(dppf) Cl 2 , in an organic solvent or solvent mixture containing organic solvents, such as toluene and an alcohol, and water.
  • the reaction can be performed in the presence of a base, such as potassium carbonate, sodium carbonate, potassium phosphate, cesium carbonate or sodium acetate for example, at temperatures, e.g. from about 20 to 120 0 C for about 2 to 24 h.
  • Compound III can then be used to produce compounds of Formula Il as described herein.
  • Compound XVIII can be made by:
  • Ha is hydrogen or a halogen, for example bromine. Ha can also be chlorine or iodine.
  • (c)(i) can include contacting the compound of formula VII with a strong base, such as alkyl lithium.
  • (c)(i) can include contacting the compounds of formula W
  • the carbonyl donor can include one or more of tetrahydrofuran, diethylether, dimethylformamide, N- formylmorpholine, or para-nitrophenylformate. Examples of reaction times can be from about 1 to about 18 hours, for example 2, 4, 6, 8, 10, 12, 14, 16 or 18 hours.
  • Compound XVIII can also be synthesized by (c) oxidizing a compound of formula VIII to make the compound of formula XVIII:
  • compositions that can be prepared by mixing one or more compounds described herein, or pharmaceutically acceptable salts or tautomers thereof, with pharmaceutically acceptable carriers, excipients, binders, diluents or the like, to treat or ameliorate a variety of bacterial infections.
  • a therapeutically effective dose or amount refers to that amount of one or more compounds described herein sufficient to result in amelioration of symptoms of the infection.
  • the pharmaceutical compositions of the instant invention can be manufactured by methods well known in the art such as conventional granulating, mixing, dissolving, encapsulating, lyophilizing, emulsifying or levigating processes, among others.
  • compositions can be in the form of, for example, granules, powders, tablets, capsule syrup, suppositories, injections, emulsions, elixirs, suspensions or solutions.
  • the instant compositions can be formulated for various routes of administration, for example, by oral administration, by transmucosal administration, by rectal administration, or subcutaneous administration as well as intrathecal, intravenous, intramuscular, intraperitoneal, intranasal, intraocular or intraventricular injection.
  • the compound or compounds of the instant invention can also be administered in a local rather than a systemic fashion, such as injection as a sustained release formulation.
  • the following dosage forms are given by way of example and should not be construed as limiting the instant invention.
  • powders, suspensions, granules, tablets, pills, capsules, gelcaps, and caplets are acceptable as solid dosage forms. These can be prepared, for example, by mixing one or more compounds of the instant invention, or pharmaceutically acceptable salts or tautomers thereof, with at least one additive or excipient such as a starch or other additive.
  • Suitable additives or excipients are sucrose, lactose, cellulose sugar, mannitol, maltitol, dextran, sorbitol, starch, agar, alginates, chitins, chitosans, pectins, tragacanth gum, gum arabic, gelatins, collagens, casein, albumin, synthetic or semi-synthetic polymers or glycerides, methyl cellulose, hydroxypropylmethyl- cellulose, and/or polyvinylpyrrolidone.
  • oral dosage forms can contain other ingredients to aid in administration, such as an inactive diluent, or lubricants such as magnesium stearate, or preservatives such as paraben or sorbic acid, or anti-oxidants such as ascorbic acid, tocopherol or cysteine, a disintegrating agent, binders, thickeners, buffers, sweeteners, flavoring agents or perfuming agents. Additionally, dyestuffs or pigments can be added for identification. Tablets and pills can be further treated with suitable coating materials known in the art.
  • Liquid dosage forms for oral administration can be in the form of pharmaceutically acceptable emulsions, syrups, elixirs, suspensions, slurries and solutions, which can contain an inactive diluent, such as water.
  • Pharmaceutical formulations can be prepared as liquid suspensions or solutions using a sterile liquid, such as, but not limited to, an oil, water, an alcohol, and combinations of these.
  • Pharmaceutically suitable surfactants, suspending agents, emulsifying agents can be added for oral or parenteral administration.
  • suspensions can include oils.
  • oils include peanut oil, sesame oil, cottonseed oil, corn oil, olive oil and mixtures of oils.
  • Suspension preparation can also contain esters of fatty acids such as ethyl oleate, isopropyl myristate, fatty acid glycerides and acetylated fatty acid glycerides.
  • Suspension formulations can include alcohols, such as, but not limited to, ethanol, isopropyl alcohol, hexadecyl alcohol, glycerol and propylene glycol.
  • Ethers such as but not limited to, poly(ethyleneglycol), petroleum hydrocarbons such as mineral oil and petrolatum; and water can also be used in suspension formulations.
  • the pharmaceutical formulations can be a spray or aerosol containing and appropriate solvents and optionally other compounds such as, but not limited to, stabilizers, antimicrobial agents, antioxidants, pH modifiers, surfactants, bioavailablity modifiers and combinations of these.
  • a propellant for an aerosol formulation can include compressed air, nitrogen, carbon dioxide, or a hydrocarbon based low boiling solvent.
  • the compound or compounds of the instant invention are conveniently delivered in the form of an aerosol spray presentation from a nebulizer or the like.
  • Injectable dosage forms generally include aqueous suspensions or oil suspensions which can be prepared using a suitable dispersant or wetting agent and a suspending agent. Injectable forms can be in solution phase or in the form of a suspension, which is prepared with a solvent or diluent. Acceptable solvents or vehicles include sterilized water, Ringer's solution, or an isotonic aqueous saline solution. Alternatively, sterile oils can be employed as solvents or suspending agents. Generally, the oil or fatty acid is non-volatile, including natural or synthetic oils, fatty acids, mono-, di- or tri-glycerides.
  • the pharmaceutical formulation can be a powder suitable for reconstitution with an appropriate solution as described above. Examples of these include freeze dried, rotary dried or spray dried powders, amorphous powders, granules, precipitates, or particulates.
  • the formulations can optionally contain stabilizers, pH modifiers, surfactants, bioavailability modifiers and combinations of these.
  • the compounds can be formulated for parenteral administration by injection such as by bolus injection or continuous infusion.
  • a unit dosage form for injection can be in ampoules or in multi-dose containers.
  • the pharmaceutical formulations can be in the form of a suppository, an ointment, an enema, a tablet or a cream for release of compound in the intestines, sigmoid flexure and/or rectum.
  • Rectal suppositories are prepared by mixing one or more compounds of the instant invention, or pharmaceutically acceptable salts or tautomers of the compound, with acceptable vehicles, for example, cocoa butter or polyethylene glycol, which is present in a solid phase at normal storing temperatures, and present in a liquid phase at those temperatures suitable to release a drug inside the body, such as in the rectum. Oils can also be employed in the preparation of formulations of the soft gelatin type and suppositories.
  • suspension formulations which can also contain suspending agents such as pectins, carbomers, methyl cellulose, hydroxypropyl cellulose or carboxym ethyl cellulose, as well as buffers and preservatives.
  • suspending agents such as pectins, carbomers, methyl cellulose, hydroxypropyl cellulose or carboxym ethyl cellulose, as well as buffers and preservatives.
  • the formulations of the invention can be designed for to be short-acting, fast-releasing, long-acting, and sustained-releasing.
  • the pharmaceutical formulations can also be formulated for controlled release or for slow release.
  • compositions can also comprise, for example, micelles or liposomes, or some other encapsulated form, or can be administered in an extended release form to provide a prolonged storage and/or delivery effect. Therefore, the pharmaceutical formulations can be compressed into pellets or cylinders and implanted intramuscularly or subcutaneously as depot injections or as implants such as stents. Such implants can employ known materials such as silicones and biodegradable polymers.
  • the compositions can contain, for example, from about 0.1% by weight, to about 90% or more by weight, of the active material, depending on the method of administration. Where the compositions comprise dosage units, each unit can contain, for example, from about 5 to 500 mg or more of the active ingredient.
  • the dosage as employed for adult human treatment can range, for example, from about 10 to 3000 mg per day, depending on the route and frequency of administration. [00111] Specific dosages can be adjusted depending on conditions of infection, the age, body weight, general health conditions, sex, and diet of the subject, dose intervals, administration routes, excretion rate, and combinations of drugs. Any of the above dosage forms containing effective amounts are well within the bounds of routine experimentation and therefore, well within the scope of the instant invention. Generally, the total daily dose can typically range from about 0.1 mg/kg/day to about 500 mg/kg/day in single or in divided doses. Typically, dosages for humans can range from about 10 mg to about 3000 mg per day, in a single or multiple doses.
  • a therapeutically effective dose or amount can vary depending upon the route of administration and dosage form.
  • Some compositions of the instant invention provide a formulation that exhibits a high therapeutic index.
  • the therapeutic index is the dose ratio between toxic and therapeutic effects which can be expressed as the ratio between LD 50 and ED 50 .
  • the LD 50 is the dose lethal to 50% of the population and the ED 50 is the dose therapeutically effective in 50% of the population.
  • the LD 50 and ED 50 can be determined by standard pharmaceutical procedures in animal cell cultures or experimental models.
  • the invention provides methods of treating or preventing a bacterial infection in a subject, such as a mammal, e.g., a human or non-human mammal, comprising administering an effective amount of one or more compounds described herein to the subject.
  • Suitable subjects that can be treated include domestic or wild animals, companion animals, such as dogs, cats and the like; livestock, including horses, cows and other ruminants, pigs, poultry, rabbits and the like; primates, for example monkeys, such as rhesus monkeys and cynomolgus (also known as crab-eating or long-tailed) monkeys, marmosets, tamarins, chimpanzees, macaques and the like; and rodents, such as rats, mice, gerbils, guinea pigs and the like.
  • the compound is administered in a pharmaceutically acceptable form, optionally in a pharmaceutically acceptable carrier.
  • the compounds described herein can be used for the treatment or prevention of infectious disorders caused by a variety of bacterial organisms, including infections by pathogenic bacterial species.
  • infections by pathogenic bacterial species examples include Gram positive and Gram negative aerobic and anaerobic bacteria, such as Staphylococci, e.g. S. aureus; Enterococci, e.g. E. faecalis; Streptococci, e.g. S. pyogenes and S. pneumoniae; Escherichia species, e.g. E. coli, including enterotoxigenic, enteropathogenic, enteroinvasive, enterohemorrhagic and enteroaggregative E. coli strains; Haemophilus, e.g. H.
  • influenza e.g. M. tuberculosis
  • M. avian-intracellulare M. kansasii, M. bovis
  • M. africanum M. genavense
  • M. leprae M. xenopi
  • M. simiae M. scrofulaceum
  • M. malmoense M. celatum
  • M. abscessus M. chelonae
  • M. szulgai M. gordonae, M. haemophilum, M. fortuni and M. marinum
  • Corynebacteria e.g. C.
  • Vibrio species e.g. V. cholerae
  • Campylobacter species e.g. C. jejuni
  • Helicobacter species e.g. H. pylori
  • Pseudomonas species e.g. P. aeruginosa
  • Legionella species e.g. L. pneumophila
  • Treponema species e.g. T. pallidum
  • Borrelia species e.g. B. burgdorferi
  • Listeria species e.g. L monocytogenes
  • Bacillus species e.g. B. cereus
  • Bordatella species e.g. B.
  • Clostridium species e.g. C. perfringens, C. tetani, C. difficile and C. botulinum
  • Neisseria species e.g. N. meningitidis and N. gonorrhoeae
  • Chlamydia species e.g. C. psittaci, C. pneumoniae and C. trachomatis
  • Rickettsia species e.g. R. rickettsii and R. prowazekii
  • Shigella species e.g. S. sonnei
  • Salmonella species e.g. S. typhimurium
  • Yersinia species e.g. Y. enterocolitica and Y. pseudotuberculosis
  • Klebsiella species e.g. K. pneumoniae
  • Mycoplasma e.g. M. pneumoniae.
  • Infections that can be treated with the described compounds include central nervous system infections, external ear infections, infections of the middle ear, such as acute otitis media, infections of the cranial sinuses, eye infections, infections of the oral cavity, such as infections of the teeth, gums and mucosa, upper respiratory tract infections, lower respiratory tract infections, genitourinary infections, gastrointestinal infections, gynecological infections, septicemia, bone and joint infections, skin and skin structure infections, bacterial endocarditis, burns, antibacterial prophylaxis of surgery, and antibacterial prophylaxis in immunosuppressed patients, such as patients receiving cancer chemotherapy, or organ transplant patients. These infections can be treated in hospital or community settings via various routes of administration as described herein.
  • one or more of the present compounds or compositions can be administered to an individual deemed to be at risk for developing a microbial infection.
  • Individuals at risk for developing a microbial infection include individuals who have been exposed to a particular microorganism, such as a pathogenic bacterial species; individuals having a compromised immune system, such as individuals suffering from an immunodeficiency disease or taking immunocompromising medication; and individuals having a history of repeated or chronic infection, such as children who have repeated infections of the middle ear.
  • Another embodiment provides a method of killing or preventing the growth of bacteria that includes contacting a bacteria with either a non-therapeutic amount or a therapeutically effective amount of one or more of the present compounds. Such methods can occur in vivo or in vitro.
  • In vitro contact can involve a screening assay to determine the efficacy of the one or more compounds against selected bacteria at various amounts or concentrations.
  • In vivo contact with a therapeutically effective amount of the one or more compounds can involve treatment or prophylaxis of a bacterial infection in the animal in which the contact occurs.
  • the effect of the one or more compounds on the bacteria and/or host animal can also be determined or measured.
  • ail isomers e.g. stereoisomers, diastereoisomers, epimers, geometrical isomers
  • ail isomers e.g. stereoisomers, diastereoisomers, epimers, geometrical isomers
  • the present invention also covers the individual isomers of the compounds represented by the formulas herein as mixtures with isomers thereof in which one or more chiral centers are inverted.
  • Stereoisomeric mixtures e.g. mixtures of diastereomers, can be separated into their corresponding isomers in a known manner by means of suitable separation methods.
  • Diastereomeric mixtures for example can be separated into their individual diastereomers by means of fraction crystallization, chromatography, solvent distribution, and similar procedures. This separation can take place either at the level of one of the starting compounds or in a compound of formula I itself.
  • Enantiomers can be separated through the formation of diastereomeric salts, for example by salt formation with an enantiomerically pure chiral acid, or by means of chromatography, for example by HPLC, using chiral chromatographic media.
  • the compounds described herein can exhibit the phenomenon of tautomerism. As the chemical structures sometimes only represent one of the possible tautomeric forms, it should be understood that the invention encompasses any tautomeric form of the represented structure. [00120]
  • the compounds described herein can exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like. In general, the solvated forms are considered equivalent to the unsolvated forms for the purposes of the present invention.
  • Step 1 1-[3-(fert-Butyl-diphenyl-silanyloxymethyl)-4-(2,6-dimethyl-morpholin-4-yl)-5- fluoro-phenyl]-ethanone.
  • Steps 2-4 [2-(2,6-Dimethyl-morpholin-4-yl)-3-fluoro-5-[1 ,2,3]thiadiazol-4-yl-phenyl]- methanol.
  • steps 1-4 was followed using 1-[3-(fert-butyl-diphenyl- silanyloxymethyl)-4-(2,6-dimethyl-morpholin-4-yl)-5-fluoro-phenyl]-ethanone to provide the compound (0.188 g) as a colorless oil.
  • Step 5 part 1 : 2-(2,6-Dimethyl-morpholin-4-yl)-3-fluoro-5-[1 ,2,3]thiadiazol-4-yl- benzaldehyde.
  • the procedure of Example 10, step 5 was followed except the residue following the filtration was purified by column chromatography to provide the compound (0.154 g) as an oil.
  • Step 6, part 2 Compound 1.
  • the procedure of Example 10, step 6 was followed except the reaction mixture was filtered at rt. The filter cake was washed with isopropanol (IPA) (2 x 1 mL) providing the compound (0.148 g) as a beige solid.
  • IPA isopropanol
  • Step 1 5-(fe/t-Butyl-diphenyl-silanyloxymethyi)-4-(2,6-dimethyl-morpholin-4-yl)-2,3- difluoro-N-methoxy-N-methyl-benzamide.
  • a solution of 5-(tert-Butyl-diphenyl-silanyloxymethyl)-4-(2,6- dimethyl-morpholin-4-yl)-2,3-difluoro-benzoic acid (10.0 g, 19 mmol) in CH 2 CI 2 (50 mL) at 0 °C was treated with CDI (3.76 g, 23.2 mmol).
  • Step 2 1-[5-(ferf-Butyl-diphenyl-silanyloxymethyl)-4-(2,6-dimethyl-morpholin-4-yl)-2,3- difluoro-phenyl]-ethanone.
  • Step 3 and Step 4 parts 1 and 2: [2-(2,6-Dimethyl-morpholin-4-yl)-3,4-difluoro-5-
  • the filter cake was washed with EtOH (2 x 10 ml) and dried to provide a white solid (2.0 g, 2.8 mmol).
  • the white solid (0.50 g, 0.71 mmol) was dissolved in SOCI ⁇ (5 mL) at rt and stirred for 30 min. The solution was quenched carefully with water (50 mL) and extracted with EtOAc (50 mL). The organics were dried over Na 2 SO 4 and concentrated. The residue was dissolved in HCI (10 mL of a 4M solution in dioxane) and stirred overnight. The solution was diluted with water (75 ml) and extracted with EtOAc (2 x 50 mL). The combined organics were dried over Na 2 SO 4 and concentrated.
  • Step 4, part 3 2-(2,6-Dimethyl-morpholin-4-yl)-3,4-difluoro-5-[1 ,2,3]thiadiazol-4-yl- benzaldehyde.
  • the procedure of Example 10, step 5 was followed to provide the compound (0.088 g) as a yellow oil.
  • Step 5 Compound 2.
  • the procedure of Example 10, step 6 was followed except the reaction mixture was filtered at rt.
  • the filter cake was washed with IPA (2 x 1 mL) providing the compound (0.070 g) as a beige solid, mp: >260 0 C;
  • Step 1 Performed as set forth in Step 1 of Example 2.
  • Step 2 1-[5-(tert-Butyl-diphenyl-silanyloxymethyl)-4-(2,6-dimethyl-morpholin-4-yl)-2,3- difluoro-phenyl]-propan-1-one.
  • the Grignard addition procedure of Example 2, step 2 was followed using ethylmagnesium bromide to provide the compound (1.78 g) as a colorless oil.
  • Step 3 and Step 4 parts 1 and 2: [2-(2,6-Dimethyl-morpholin-4-yl)-3,4-difluoro-5-(5- methyl-[1 ,2,3]thiadiazol-4-yl)-phenyl]-methanol.
  • steps 1-4 was followed to provide the compound (0.340 g) as a pale yellow oil.
  • Step 4, part 3 2-(2,6-Dimethyl-morpholin-4-yl)-3,4-difluoro-5-(5-methyl-[1 ,2,3]thiadiazol-
  • Step 1 Performed as set forth in Step 1 of Example 2.
  • Step 2 1-[5-(tert-Butyl-diphenyl-silanyloxymethyl)-4-(2,6-dimethyl-morpholin-4-yl)-2,3- difluoro-phenyl]-2-phenyl-ethanone.
  • the Grignard addition procedure of Example 2, step 2 was followed using benzylmagnesium bromide to provide the compound (1.92 g) as a colorless oil.
  • Step 3 and Step 4 parts 1 and 2: [2-(2,6-Dimethyl-morpholin-4-yl)-3,4-difluoro-5-(5- phenyl-[1 ,2,3]thiadiazol-4-yl)-phenyl]-methanol.
  • steps 1-4 was followed to provide the compound (0.371 g) as a beige solid.
  • Step 4, part 3 2-(2,6-Dimethyl-mo ⁇ holin-4-yl)-3,4-difluoro-5-(5-phenyl-[1 ,2,3]thiadiazol-
  • Step 5 Compound 6.
  • the procedure of Example 10, step 6 was followed except the reaction was concentrated and the residue was purified by column chromatography to provide the compound (0.296 g) as a yellow foam.
  • Step 1 [5-(fert-Butyl-diphenyl-silanyloxymethyl)-4-(2,6-dimethyl-morpholin-4-yl)-2,3- difluoro-phenyl]-acetic Acid Methyl Ester.
  • Step 2 part 1 : 2-[5-(tert-Butyl-diphenyl-silanyloxymethyl)-4-(2,6-dimethyl-morpholin-4-yl)-
  • Steps 3 and 4 [2-(2,6-Dimethyl-morpholin-4-yl)-3,4-difluoro-5-[1 ,2,3]thiadiazol-5-yl- phenyl]-methanol.
  • a solution of [5-(fert-Butyl-diphenyl-silanyloxymethyl)-4-(2,6-dimethyl-morpholin-4-yl)- 2,3-difluoro-phenyl]-acetaldehyde (0.375 g, 0.70 mmol) in CH 2 CI 2 (5 mL) at -78 0 C was treated with tosyl hydrazide (0.130 g, 0.70 mmol).
  • Step 5 part 1 : 2-(2,6-Dimethyl-morpholin-4-yl)-3,4-difluoro-5-[1 ,2,3]thiadiazol-5-yl- benzaldehyde.
  • the procedure of Example 10, step 5 was followed except the residue following the filtration was purified by column chromatography to provide the compound (0.100 g) as an oil.
  • Step 5 part 2: Compound 7.
  • Step 1 Preparation of 5-(ferf-Butyl-diphenyl-silanyloxymethyl)-4-(2,6-dimethyl-morpholin-
  • Step 2 Preparation of 5-(terf-Butyl-diphenyl-silanyloxymethyl)-4-(2,6-dimethyl-morpholin-
  • Step 4 parts 1 and 2: Preparation of 2-(2,6-Dimethylmorpholin-4-yI)-3,4-difIuoro-5-(3- methyl-1 ,2,4-thiadiazol-5-yl)benzaldehyde.
  • Step 4, part 3 Compound 8. A solution of 2-(2,6-dimethylmorpholin-4-yl)-3,4-difluoro-5-
  • Steps 1 and 2 were performed as set forth in Example 8, steps 1 and 2.
  • Step 3 4-(6-(tert-Butyl-diphenyl-silyloxymethyl)-2,3-difluoro-4-(1 ,2,4-thiadiazol-5- yl)phenyl]-2,6-dimethylmorpholine.
  • dimethyl acetamide-dimethylacetal 0.2 ml, 1.5 mmol
  • DMF-DMA dimethyl acetamide-dimethylacetal
  • Step 4 parts 1 and 2: Preparation of 2-(2,6-Dimethylmorpholin-4-yl)-3,4-difluoro-5-(1 ,2,4- thiadiazol-5-yl)benzaldehyde.
  • a solution of 4-(6-(tert-butyl-diphenyI-silyloxymethyl)-2,3-difluoro-4-(1 ,2,4- thiadiazol-5-yl)phenyl]-2,6-dimethylmorpholine (0.26 g, 0.45 mmol) in MeOH (1 ml) was treated with 4M HCI in dioxane (2 ml) and stirred at room temperature for 3 hours. TLC analysis shows no starting material.
  • Step 1 5-(terf-Butyl-diphenyl-silanyloxymethyl)-4-(2,6-dimethyl-morpholin-4-yl)-2,3- difluoro-benzoylj-hydrazinecarboxylic Acid terf-Butyl Ester.
  • Step 4 [2-(2,6-Dimethyl-morpholin-4-yl)-3,4-difluoro-5-(5-methyl-[1 ,3,4]thiadiazol-2-yl)- phenyl]-methanol.
  • a solution of 4-(2,6-Dimethyl-morpholin-4-yl)-2,3-difluoro-5-hydroxymethyl-thiobenzoic acid hydrazide hydrochloride (0.80 g, 2.2 mmol) in THF (20 mL) at rt was treated with diisopropylethylamine (1.14 mL, 6.5 mmol) followed by acetyl choride (0.23 mL, 3.26 mmol).
  • Step 6 Compound 10. A stirring slurry of 2-(2,6-Dimethyl-morpholin-4-yl)-3,4-difluoro-5-
  • Step 1 Preparation of 2-(2,6-Dimethyl-morpholin-4-yl)-3,4-difluoro-benzoic acid.
  • a stirred solution of 2,3,4-trifluorobenzoic acid (Aldrich, 890 g, 5.05 mol) in tetrahydrofuran (5 L) was cooled to - 78°C.
  • a 1 M solution of lithium bis(trimethylsilyl)amide in tetrahydrofuran (5.56 L) was added dropwise to the reaction at such a rate that the reaction temperature did not rise above -65°C. Stirring was continued at -78°C for 45 min.
  • Step 2 Preparation of 4-[6-(tert-Butyl-diphenyl-silanyloxymethyl)-2,3-difluoro-phenyl]-2,6- dimethyl-morpholine.
  • Step 3 Preparation of 5-(tert-Butyl-diphenyl-silanyloxymethyl)-4-(2,6-dimethyl-morpholin-
  • Steps 4 and 5 A solution of 5-(terf-Butyl-diphenyl-silanyloxymethyl)-4-(2,6-dimethyl- morpholin-4-y!-2,3-difluoro-benzoic acid (20.0 g, 37 mmol) in CH 2 CI 2 (100 mL) was treated with carbonyldiimidazole (7.2 g, 44 mmol). The resulting solution was stirred for 30 min, acetic hydrazide (3.3 g, 44 mmol) was added followed by diisopropylethylamine (5.7 g, 44 mmol) and the solution was stirred at rt for 5h. The reaction was poured into sat.
  • the solution was diluted with water (100 mL) and extracted with CH 2 CI 2 (3 x 100 mL). The combined organics were dried over Na 2 SO 4 and concentrated. The residue was treated with HCI (50 mL of a 4M solution in dioxane) and stirred overnight. The solution was diluted with water (150 mL) and extracted with EtOAc (2 x 200 mL). The combined organics were dried over Na 2 SO 4 .
  • Step i 2-Bromo-3,4,5-trifluorobenzaldehyde.
  • a 3-L 4-neck flask was dried by heating with a hot air gun to 94-95 °C. After cooling to room temperature, 74.48 g (1.47 mol) diisopropylamine was added and dissolved in 600 ml dry THF. The solution was cooled to -75 0 C and n-butyllithium (2.5 M in hexane, 320 ml) was added dropwise over 70 min while maintaining the temperature between -75 to - 60 °C. The mixture was allowed to warm to -10.4 0 C to 0.2 0 C for 13 min.
  • Step 2 3-Bromo-6-(2,6-cis-dimethylmorpholin-4-yl)-4,5-difluorobenzaldehyde. 2-Bromo-
  • 3,4,5-trifluorobenzaldehyde (133.15 g, 0.56 mol) was dissolved in 1000 ml dry acetonitrile. Triethylamine (118.65 ml, 0.85 mol) was added, followed by cis-2,6-dimethylmorpholine (71.64 g, 0.62 mol), and 125 ml additional acetonitrile. The mixture was refluxed for 24 hours, then cooled to room temperature, and poured into 1500 ml saturated sodium bicarbonate solution. The phases were separated and the aqueous phase extracted 2 x 500 ml ethyl acetate. The combined organic portions were washed 2 x 500 ml brine and then dried over magnesium sulfate.
  • Methyltetrahydrofuran (3300 ml) was added. The mixture was mechanically stirred as it was evacuated until bubbling stopped. The reactants were flushed with argon, then evacuated and flushed with argon again. Argon was then bubbled through the mixture for 2 h 16 min. The mixture was then evacuated until bubbling ceased, then flushed with argon, evacuated, and flushed with argon again. The mixture was heated to reflux for 4.7 days, when NMR indicated that all 3-bromo-6-(2,6-cis-dimethylmorpholin-4-yl)-4,5-difluorobenzaldehyde had been consumed.
  • Step 4 2-lodo-5-methyl-[1 ,3,4]thiadiazole (2.0 g) was slurried in CH 3 CN (30 ml) and
  • Steps 1 to 4 [2-(2,6-Dimethyl-morpholin-4-yl)-3,4-difluoro-5-(5-phenyl-[1 ,3,4]thiadiazol-2- yl)-phenyl]-methanol.
  • the procedure set forth in Example 10, steps 1 to 4 was followed using benzoyl chloride as the acylating reagent to provide the compound (0.150 g) as an orange solid.
  • Step 5 2-(2,6-Dimethyl-morpholin-4-yl)-3,4-difluoro-5-(5-phenyl-[1 ,3,4]thiadiazol-2-yl)- benzaldehyde.
  • the procedure of Example 10, step 5 was followed to provide the compound (0.120 g) as a yellow solid.
  • Steps 1 to 4 [2-(2,6-Dimethyl-morpholin-4-yl)-3,4-difluoro-5-(5-trifluoromethyl-
  • Step 5 2-(2,6-Dimethyl-morpholin-4-yl)-3,4-difluoro-5-(5-trifluoromethyl-[1 ,3,4]thiadiazol-
  • Step 5 2-(2,6-Dimethyl-morpholin-4-yI)-3,4-difluoro-5-(5-acetoxymethyl-[1 ,3,4]thiadiazol-
  • Steps 1 to 4 [2-(2,6-Dimethyl-morpholin-4-yl)-3,4-difluoro-5-([1 ,3,4]thiadiazol-2-yl)- phenylj-methanol.
  • the procedure set forth in Example 10, steps 1 to 4 was followed using formic acid as the acylating reagent except the reaction was heated to reflux for 3h to provide the compound (0.120 g) as a green oil.
  • Step 5 2-(2,6-Dimethyl-mo ⁇ holin-4-yl)-3,4-difluoro-5-([1 ,3,4]thiadiazol-2-yl)- benzaldehyde.
  • the procedure of Example 10, step 5 was followed to provide the compound (0.069 g) as a yellow oil.
  • Step 1 [2-(2,6-Dimethyl-morpholin-4-yl)-3,4-difluoro-5-(5-ethyl-[1 ,3,4]thiadiazol-2-yl)- phenylj-methanol.
  • steps 1 to 4 was followed using propionyl chloride as the acylating reagent to provide the compound (0.231 g).
  • Step 2 2-(2,6-Dimethyl-morpholin-4-yl)-3,4-difluoro-5-(5-ethyl-[1 ,3,4]thiadiazol-2-yl)- benzaldehyde.
  • the procedure of Example 10, step 5 was followed to provide the compound (0.200 g) as a yellow solid.
  • Step 3 Compound 15.
  • Step 1 parts 1 and 2: 3- ⁇ 5-[4-(2,6-Dimethyl-morpholin-4-yl)-2,3-difluoro-5-hydroxymethyl- phenyl]-[1,3,4]thiadiazoi-2-yl ⁇ -propionic Acid Methyl Ester.
  • steps 1 to 4 was followed using 3-chlorocarbonyl-propionic acid methyl ester as the acylating reagent to provide the compound (0.495 g).
  • Step 2 Compound 17.
  • the procedure of Example 10, step 6 was followed providing the compound (0.250 g).
  • Step 1 parts 1 and 2: 5-[4-(2,6-Dimethyl-morpholin-4-yl)-2,3-difluoro-5-hydroxymethyl- phenyl]-[1,3,4]thiadiazole-2-carboxylic Acid Methyl Ester.
  • steps 1 to 4 was followed using chloromethyloxalate as the acylating reagent to provide the compound (0.120 g).
  • Step 1 part 3: 5-[4-(2,6-Dimethyl-morpholin-4-yl)-2,3-difluoro-5-formyl-phenyl]-
  • Step 2 Compound 18.
  • the procedure of Example 10, step 6 was followed except the reaction mixture was filtered at rt. The filter cake was washed with IPA (2 x 1 ml_) providing the compound (0.085 g) as a yellow solid, mp: >260 0 C;
  • Step 1 [2-(2,6-Dimethyl-morpholin-4-yl)-3,4-difluoro-5-(5-(pyridin-4-yl)-t1 ,3,4]thiadiazol-2- yl)-phenyl]-methanol.
  • steps 1 to 4 was followed using isonicotinoyl chloride hydrochloride as the acylating reagent to provide the compound (0.370 g).
  • Step 2 2-(2,6-Dimethyl-morpholin-4-yl)-3,4-difluoro-5-(5-(pyridin-4-yl)-[1 ,3,4]thiadiazol-2- yl)-benzaldehyde.
  • the procedure of Example 10, step 5 was followed except for the reaction was heated to reflux for 30 min. Normal work-up provided the compound (0.095 g) as a yellow solid.
  • Step 3 Compound 19. The procedure of Example 10, step 6 was followed except the residue was crystallized from MeOH (2 mL) to provide the compound (0.090 g).
  • Step 1 [2-(2,6-Dimethyl-morpholin-4-yl)-3,4-difluoro-5-(5-cyclopropyl-[1 ,3,4]thiadiazol-2- yl)-phenyl]-methanol.
  • steps 1 to 4 was followed using cyclopropanecarbonyl chloride as the acylating reagent to provide the compound (0.315 g).
  • Step 2 2-(2,6-Dimethyl-morpholin-4-yl)-3,4-difluoro-5-(5-cyclopropyl -[1 ,3,4]thiadiazol-2- yl)-benzaldehyde.
  • the procedure of Example 10, step 5 was followed to provide the compound (0.245 g) as a yellow solid.
  • 1H NMR (400 MHz, CDCI 3 ) ⁇ 1.2 (m, 10 H), 2.4 (m, 1 H) 3.1 (m, 4 H), 3.8 (m, 2 H), 8.5 (d, J 7.6 Hz, 1 H), 10.1 (s, 1 H); MS (APCI + ) m/z 380 (MH + ).
  • Step 3 Compound 20.
  • Step 1 [2-(2,6-Dimethyl-morpholin-4-yl)-3,4-difluoro-5-(5-isoxazol-5-yl)-[1 ,3,4]thiadiazol-
  • Step 2 2-(2,6-Dimethyl-morpholin-4-yl)-3,4-difluoro-5-(5-isoxazol-5-yl-[1 ,3,4]thiadiazol-2- yl)-benzaldehyde.
  • the procedure of Example 10, step 5 was followed to provide the compound (0.150 g) as an orange solid.
  • Step 3 Compound 21.
  • the procedure of Example 10, step 6 was followed except following the IPA reflux overnight, the residue was refluxed in n-BuOH for 5 h.
  • Concentration and crystallization from MeCN (4 mL) provided the compound (0.070 g) as an orange/brown solid, mp: >260 0 C;
  • Step 1 [2-(2,6-Dimethyl-morpholin-4-yl)-3,4-difluoro-5-(5-fluoromethyl-[1 ,3,4]thiadiazol-2- yl)-phenyl]-methanol.
  • steps 1 to 4 was followed using fluoroacetyl chloride as the acylating reagent to provide the compound (0.200 g).
  • Step 2 2-(2,6-Dimethyl-mor ⁇ holin-4-yl)-3,4-difluoro-5-(5-fluoromethyl-[1 ,3,4]thiadiazol-2- yl)-benzaldehyde.
  • the procedure of Example 10, step 5 was followed to provide the compound (0.115 g) as a yellow solid.
  • Step 3 Compound 22.
  • the procedure of Example 10, step 6 was followed except the residue was crystallized from MeOH (2 mL) to provide the compound (0.038 g).
  • Step 1 [5-(5-Chloromethyl-[1 ,3,4]thiadiazol-2-yl)-2-(2,6-dimethyl-morpholin-4-yl)-3,4- difluoro-phenyrj-methanol.
  • steps 1 to 4 was followed using chloroacetyl chloride as the acylating reagent to provide the compound (1.04 g).
  • Step 2 5-(5-Chloromethyl-[1 ,3,4]thiadiazol-2-yl)-2-(2,6-dimethyl-morpholin-4-yl)-3,4- difluoro-benzaldehyde.
  • the procedure of Example 10, step 5 was followed to provide the compound (0.145 g) as a yellow oil.
  • Step 3 Compound 23.
  • the procedure of Example 10, step 6 was followed to provide the compound (0.077 g).
  • Step i [5-[5-(2-Chloro-phenyl)-[1 ,3,4]thiadiazol-2-yl]-2-(2,6-dimethyl-morpholin-4-yl)-3,4- difluoro-phenyl]-methanol.
  • steps 1 to 4 was followed using 2- chlorobenzoyl chloride as the acylating reagent to provide the compound (0.860 g).
  • Step 2 5-[5-(2-Chloro-phenyl)-[1 ,3,4]thiadiazol-2-yl]-2-(2,6-dimethyl-morpholin-4-yl)-3,4- difluoro-benzaldehyde.
  • the procedure of Example 10, step 5 was followed to provide the compound (0.690 g) as a yellow solid.
  • Step 3 Compound 24.
  • the procedure of Example 10, step 6 was followed to provide the compound (0.037 g).
  • Step 1 [5-[5-(2-Fluoro-phenyl)-[1 ,3,4]thiadiazol-2-yl]-2-(2,6-dimethyl-morpholin-4-yl)-3,4- difluoro-phenyl]-methanol.
  • steps 1 to 4 was followed using 2- fluorobenzoyl chloride as the acylating reagent to provide the compound (0.278 g).
  • Step 2 5-[5-(2-Fluoro-phenyl)-[1 ,3,4]thiadiazol-2-yl]-2-(2,6-dimethyl-morpholin-4-yl)-3,4- difluoro-benzaldehyde.
  • the procedure of Example 10, step 5 was followed to provide the compound (0.079 g) as a yellow solid.
  • Step 3 Compound 25.
  • the procedure of Example 10, step 6 was followed to provide the compound (0.036 g).
  • Step 3 (S)-[5-[5-(2,2-Dimethyl-[1 ,3]dioxolan-4-yl)-[1 ,3,4]thiadiazol-2-yl]-2-(2,6-dimethyl- morpholin-4-yl)-3,4-difluoro-phenyl]-methanol.
  • Step 4 part 1 (S)-5-[5-(2,2-Dimethyl-[1 ,3]dioxolan-4-yl)-[1 ,3,4]thiadiazol-2-yl]-2-(2,6- dimethyl-morpholin-4-yl)-3,4-difluoro-benzaldehyde.
  • step 5 was followed except for the concentrated residue following filtration was purified by column chromatography to provide the compound (0.470 g).
  • Example 10 The procedure of Example 10, step 6 was followed except the reaction was concentrated to a residue that was purified by column chromatography to provide the compound (0.525 g) as a mixture of diastereomers.
  • Step 5 Compound 27.
  • a solution of compound 26 (0.32 g, 0.58 mmol) in THF (10 ml.) was treated with 1 N HCI (10 ml_). The reaction was stirred overnight at rt, heated to reflux for 2 h and cooled to rt. The reaction was diluted with water (50 ml_) and extracted with EtOAc (50 ml). The combined organics were dried over Na 2 SO 4 and concentrated. Purification by column chromatography provided the compound (0.220 g) as a mixture of diastereomers.
  • Step 1 A suspension of rel-(2R,4S,4aS)-9,10-difluoro-2,4-dimethyl-2',4',6'-trioxo-
  • Step 2 Compound 28.
  • Steps 1 and 2 [5-Bromo-2-(2,6-dimethyl-morpholin-4-yl)-3-fluoro-phenyl]-methanol.
  • a solution of 4-(4-bromo-2-[1 ,3]dioxolan-2-yl-6-fluoro-phenyl)-2,6-dimethyl-morpholine (5.0 g, 14 mmol) in THF (100 ml_) was treated with 1M HCI (3 mL) and stirred for 5 h at rt.
  • the reaction was diluted with EtOAc (250 mL) and sat. NaHCO 3 (150 mL) was added. The organics were separated and washed with sat.
  • Step 3 4-[4-Bromo-2-(fert-butyl-diphenyl-silanyloxymethyl)-6-fluoro-phenyl]-2,6-dimethyl- morpholine.
  • Step 4 3-(ferf-Butyl-diphenyl-silanyloxymethyl)-4-(2,6-dimethyl-morpholin-4-yl)-5-fluoro- benzoic Acid.
  • Step 5 3-(t ⁇ rt-Butyl-diphenyl-siIanyloxymethyl)-4-(2,6-dimethyl-morpholin-4-yI)-5-fluoro- benzoyl]-hydrazinecarboxylic Acid terf-Butyl Ester.
  • a suspension of 3-(terf-butyl-diphenyl- silanyloxymethyl)-4-(2,6-dimethyl-morpholin-4-yl)-5-fluoro-benzoic acid (1.72 g, 3.3 mmol) in DMF (8 ml_) was treated with triethylamine (0.460 mL, 3.3 mmol) and HATU (1.5 g, 4.0 mmol).
  • Step 6 3-(terf-Butyl-diphenyl-silanyloxymethyl)-4-(2,6-dimethyl-morpholin-4-yl)-5-fluoro- thiobenzoyl]-hydrazinecarboxylic Acid terf-Butyl Ester.
  • Step 7 2-(2,6-Dimethyl-morpholin-4-yl)-3-fluoro-5-(5-methyl-[1 ,3,4]thiadiazol-2-yl)- phenyl]-methanol.
  • 3-(terf-Butyl-diphenyl-silanyloxymethyl)-4-(2,6-dimethyl-morpholin-4-yl)-5-fluoro- thiobenzoyl]-hydrazinecarboxylic acid terf-butyl ester (1.25 g, 1.92 mmol) was treated with HCI (12 mL of a 4 M solution in dioxane) and the resulting solution was stirred for 4h at rt and concentrated.
  • Step 8 2-(2,6-Dimethyl-morpholin-4-yl)-3-fluoro-5-(5-methyl-[1 ,3,4]thiadiazol-2-yl)- benzaldehyde.
  • the procedure of Example 10, step 5 was followed to provide the compound (0.180 g) as a yellow solid.
  • Step 9 Compound 35.
  • the procedure of Example 10, step 6 was followed except the residue was crystallized from MeOH (4 mL) to provide the compound (0.149 g) as a solid, mp: >260 0 C;
  • Steps 1 and 2 [2-(2,6-Dimethyl-morpholin-4-yl)-3,4-difluoro-5-(5-methylsulfanyl-
  • Step 3a 2-(2,6-Dimethyl-morpholin-4-yl)-3,4-difluoro-5-(5-methylsulfanyl-
  • Triethylamine (0.404 mL, 2.90 mmol) was added and the solution was allowed to warm to rt. The reaction was poured into water (50 mL) and extracted with EtOAc (2 x 50 mL). The combined organics were dried over Na 2 SO 4 and concentrated. Purification by column chromatography provided the compound (0.160 g) as a pale yellow solid.
  • Step 4 Compound 36.
  • Steps 1 and 2 were performed as set forth in Example 36, steps 1 and 2.
  • Step 3b 2-(2,6-Dimethyl-morpholin-4-yl)-3,4-difluoro-5-(5-methanesulfonyl-
  • Step 1 2-(2,6-Dimethyl-morpholin-4-yl)-3-fluoro-4-methoxy-5-(5-methyl-[1 ,3,4]thiadiazol-
  • Steps 1 and 2 2-(2,6-Dimethyl-morpholin-4-yl)-3-fluoro-4-hydroxy-5-(5-methyl-
  • Step 3 Compound 41.
  • the procedure of Example 10, step 6 was followed except the reaction was heated for an additional day in MeOH.
  • the reaction mixture was filtered at rt.
  • the filter cake was washed with MeOH (1 mL) providing the compound (0.050 g) as a beige solid.
  • Step i 5-Bromo-2,3,4-trifluoro-benzoic acid.
  • Steps 2 and 3 2-(5-Bromo-2,3,4-trifluoro-phenyl)-5-methyl-[1 ,3,4]thiadiazole.
  • Step 4 2,3,4-Trifluoro-5-(5-methyl-[1 ,3,4]thiadiazol-2-yl)-benzaldehyde.
  • Step 5 K 2 CO 3 was added to a vigorously stirred mixture of 2R,6R-(trans)-dimethyl- morpholine (from BASF) in acetone (100 ml). Benzyl bromide was added dropwise to the mixture resulting in an exothermic reaction. The reaction was allowed to cool and stirred 18 h at rt. A majority of the acetone was removed under vacuum and portioned with water (100 ml) and EtOAc (100 ml). The aqueous layer was extracted with EtOAc (100 ml), dried over Na 2 SO 4 and concentrated. The product was distilled under reduced pressure at 120 °C (75-80 at 0.5 torr) providing a colorless oil of 4-Benzyl-2R,6R- (trans)-dimethyl-morpholine.
  • Step 6 Compound 42.
  • Steps 1 and 2 2-Methyl-5-(2,3,4-trifluoro-phenyl)-[1 ,3,4]thiadiazole.
  • the procedure set forth in Example 10 was followed using 2,3,4-trifluoro-benzoic acid to provide the compound (20.5 g).
  • 1 H NMR (400 MHz, CDCI 3 ) ⁇ 2.8 (s, 3 H), 7.1 (m, J 9.0, 9.0, 6.9, 2.0 Hz, 1 H), 8.1 (m, 1 H); MS (APCI + ) m/z 231 (MH + ).
  • Step 3 2,3,4-Trifluoro-5-(5-methyl-[1 ,3,4]thiadiazol-2-yl)-benzaldehyde.
  • a solution of diisopropylamine (9.8 ml_, 70 mmol THF (100 mL) at -78 0 C treated with n-BuLi (44 ml_ of a 1.6 M solution in hexanes).
  • the solution was stirred for 5 min and a solution of 2-Methyl-5-(2,3,4-trifluoro- phenyl)-[1 ,3,4]thiadiazole (6.43 g, 28 mmol) in THF (100 mL) was added dropwise.
  • Compound 42 can then be made by treating 5-bromo-3,4-difluoro-2-((2R,6R)(trans)- dimethyl-morpholin-4-yl)-benzaldehyde according to the procedure set forth in 10 B, steps 3 and 4.
  • Compound 56 Compound 55 (0.3 g, 0.53 mmol) was dissolved in 50% MeOH/THF (50 ml), 5 wt% of PdBaSO 4 (0.1 g) was added and the mixture was subjected to 50 psi of hydrogen for 34 hrs The mixture was filtered to remove the catalyst and concentrated by rotoevaporation. The residue was purified by column chromatography to provide the title compound as white solids (91 mg).
  • N-(4- methoxybenzyl)urea (3.81 g, 21.1 mmol) and malonic acid (2.55 g, 24.5 mmol) were dissolved in acetic acid (8 ml) and heated at 70 0 C for 1 hr. The reaction mixture was cooled to room temperature, acetic acid (5 ml) was added and the resulting mixture was heated at 90 °C for 2 hrs. The reaction was cooled and concentrated by rotoevaporation and the resulting solids were recrystallized from ethanol to provide the title compound as white solids (3.1 g).
  • Steps 1 and 2 A flame-dried round-bottom flask was charged with Rieke magnesium
  • the reaction mixture was then cooled again to 23 0 C, poured into water and extracted with EtOAc. The organic extract was washed with brine, dried (Na 2 SO 4 ), filtered and concentrated.
  • the crude dithioester was dissolved in EtOH (15 mL) and hydrazine monohydrate was added (0.24 mL, 4.92 mmol). The resulting solution was stirred at 23 0 C for 1 h.
  • the reaction mixture was concentrated onto silica gel and purified by silica gel chromatography (Biotage, 40 g SiO 2 , 50% EtOAc/Hex to 5% MeOH/CH 2 CI 2 ) to afford 150 mg of thiohydrazide.
  • Steps 3 and 4 A mixture of thiohydrazide (63.9 mg, 0.19 mmol) and acetyl chloride (20 ⁇ L, 0.26 mmol) in dry THF (2 mL) was heated to reflux for 1 h. 1 M HCI (0.75 mL) was added and the heating was continued for 1 h. The reaction mixture was cooled to 23 0 C, diluted with CH 2 CI 2 , washed with 10% Na 2 CO 3 (2 x 10 mL). The organic extract was washed with brine, dried (Na 2 SOzO, filtered and concentrated. The residue was purified by silica gel chromatography (Biotage 12 g SiO 2 , 40% EtOAc/Hex) to afford 33.6 mg of thiadiazole aldehyde.
  • Step 5 A mixture of aldehyde (32.4 mg, 0.10 mmol) and barbituric acid in MeOH (2 mL) was heated to reflux for 18 hr. The solution was concentrated and the residue was purified by silica gel chromatography (Biotage 12 g SiO 2 , 50% EtOAc/Hex to 100% EtOAc) to afford 23.4 mg of compound 59: IR (diffuse reflectance) 2340 (w), 2048 (w), 1915 (w), 1754, 1727 (s), 1704 (s), 1610 (s), 1523, 1442, 1414, 1377, 1372, 1354 (s), 1338, 1245 cm '1 .
  • Compound 60 was prepared according to Example 59, except that methoxy acetyl chloride was used as the acetyl chloride.
  • Compound 60 IR (diffuse reflectance) 2350 (w), 2338 (w), 2052 (W), 1996 (w), 1990 (w), 1727 (s), 1710 (s), 1699 (s), 1608, 1447, 1439, 1429, 1415, 1354, 1338 cm " 1 .
  • HRMS (ESl) calcd for C 21 H 23 N 5 O 5 S +H 1 458.1498, found 458.1498.
  • Compound 62 was prepared according to Example 59, except that ethyl oxalyl chloride was used as the acetyl chloride.
  • Compound 62 IR (diffuse reflectance) 2352 (w), 2334 (w), 1957 (w), 1920 (W), 1915 (W), 1716 (s), 1607, 1414, 1396, 1393, 1351 , 1332, 1306, 1279, 1242 cm "1 .
  • HRMS (ESI) calcd for C 22 H 23 N 5 O 6 S +H 1 486.1447, found 486.1451.
  • Anal. Calcd for C 22 H 23 N 5 OeS 1 C, 54.42; H, 4.77; N, 14.42; S, 6.60. Found: C, 53.44; H, 4.84; N, 14.24; S, 6.35.
  • Compound 63 was prepared according to Example 59, except that the following acetyl chloride was produced as follows and used:
  • Compound 63 IR (diffuse reflectance) 2481 (w), 2372 (w), 2347 (w), 2281 (w), 2048 (w),
  • Step 1 To a suspension of acid (636.1 mg, 0.70 mmol) in THF (15 mL) was added
  • Step 2 A mixture of the Boc-hydrazide (620 mg, 1.27 mmol), solid Na 2 HCO 3 (373.4 mg,
  • Step 3 part 1 : A mixture of Boc-thiohydrazide in 4 N HCI/dioxane was stirred at 23 0 C for
  • Step 3, part 2 To a mixture of the thiohydrazide (52.3 mg, 0.13 mmol) in THF (2 mL) was added 3,4-difluorbenzoyl chloride (17 ⁇ L, 0.136 mmol). The reaction was stirred at 23 0 C for 1 h. Concentrated HCI (2 drops) was added and the stirring was continued for 30 min. The formed solid precipitate was filtered, rinsed with Et 2 O and dried to afford 65.8 mg of compound 65.
  • Staphylococcus aureus SA-1 (UC-76) and H. influenzae HI-3542. Incubations were at 35°C. Stock bacterial cultures were maintained on Tryptic Soy Agar containing 5% Sheep Blood (BD, Becton Dickinson Microbiology Systems, Cockeysville, Maryland), anaerobes were maintained on Anaerobic Blood Agar plates - CDC Formulation (BD), and fastidious organisms were maintained on Chocolate Agar Il Plates (BD). Specific conditions of handling are listed below.
  • WalkAway 40 SI Instrument (Dade Behring, West Sacramento, California). This device utilizes an automated incubator, reader, and computer to assess for identification purposes the biochemical reactions carried out by each organism. Using this machine, organism identification (confirmation) and an initial antibiogram was generated for each strain.
  • Standardized Organism lnocula Frozen stock cultures were used as the initial source of organisms for performing microbroth dilution MIC testing. Stock cultures were passed on their standard growth medium for at least 1 growth cycle (18 24 hours) prior to their use.
  • Test Compound (Drug) Preparation Compounds were solubilized in DMSO. Drug stock solutions were prepared on the day of testing. Drugs were weight corrected for assay content where necessary.
  • BioMek FX robot Beckman Coulter Inc., Fullerton, CA
  • 10 of the remaining 11 wells each of which contained 100 ⁇ L of the appropriate solvent/diluent.
  • Row 12 contained solvent/diluent only and served as the control.
  • 200 ⁇ L of an 8 ⁇ g/mL stock was added to duplicate rows of a 96-well plate. Serial two-fold dilutions were made as described above.
  • BioMek FX robot were either used immediately or frozen at -70°C until use.
  • NCCLS document M7-A6 ⁇ ISBN 1-56238-486-4 ⁇ , NCCLS, 940 West Valley Road, Suite 1400, Wayne, Pennsylvania 19087-1898 USA, 2003.
  • the range C 1 -C 6 includes the subranges C 2 -C 6 , C 3 -C 6 , C 3 - C 5 , C 4 -C 6 , etc., as well as Ci (methl), C 2 (ethyl), C 3 (propyl), C 4 (butyl), C 5 (pentyl) and C 6 (hexyl) individually.
  • Ci methl
  • C 3 propyl
  • C 4 butyl
  • C 5 (pentyl) and C 6 (hexyl) individually individually.
  • all language such as “up to,” “at least,” “greater than,” “less than,” “more than,” “or more” and the like include the number recited and refer to ranges which can be subsequently broken down into subranges as discussed above.

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Abstract

Described herein are antibacterial compounds of the formula (I), methods for making the compounds, pharmaceutical compositions containing the compounds and methods of treating bacterial infections utilizing the compounds and pharmaceutical compositions.

Description

ANTIBACTERIAL AGENTS
FIELD OF THE INVENTION
[0001] Described herein are antibacterial compounds, their use as antibacterial agents, pharmaceutical compositions containing these compounds, and methods for their preparation.
BACKGROUND
[0002] Antibacterial resistance is a global clinical and public health problem that has emerged with alarming rapidity in recent years and undoubtedly will increase in the near future. Resistance is a problem in the community as well as in health care settings, where transmission of bacteria is greatly amplified. Because multiple drug resistance is a growing problem, physicians are now confronted with infections for which there is no effective therapy. The morbidity, mortality, and financial costs of such infections pose an increasing burden for health care systems worldwide. Strategies to address these issues emphasize enhanced surveillance of drug resistance, increased monitoring and improved usage of antimicrobial drugs, professional and public education, development of new drugs, and assessment of alternative therapeutic modalities.
[0003] As a result, alternative and improved agents are needed for the treatment of bacterial infections, particularly for the treatment of infections caused by resistant strains of bacteria, e.g. penicillin- resistant, methicillin-resistant, ciprofloxacin-resistant, and/or vancomycin-resistant strains.
SUMMARY
[0004] One embodiment provides a compound having formula I:
or a salt, solvate, hydrate or prodrug thereof.
[0005] In the above formula, R1 is a substituted or unsubstituted thiadiazole;
R2 and R3 are independently H or substituted or unsubstituted Ci.6 alkyl;
R4 and R5 are independently H, a substituted or unsubstituted C^6 alkyl, a substituted or unsubstituted ether, substituted or unsubstituted -(CH2)maryl, substituted or unsubstituted -O(CH2)maryl, - (CH2)mNR8Rg, -(CH2)mOR6, -(CH2)mOPO3(Rp)2, -(CH2)mOC(=O)(CH2)mCH3) -(CH2)mOC(=O)(CH2)mCO2R6, -(CH2)mOC(=O)(CH2)mNR8Rg, -(CH2)mOC(=O)E or R4 and R5 together with the atoms to which they are attached form a substituted or unsubstituted heterocyclic ring; each m is independently 0, 1 , 2 or 3; E is a substituted or unsubstituted ether; each Rp is independently H, C1^ alkyl, benzyl, substituted benzyl, phenyl, substituted phenyl, or (Rp)2 together with the atoms to which they are attached form a substituted or unsubstituted heterocyclic ring; each R6 is independently H, C1^ alkyl, C1^ acyl or benzyl;
R8 and R9 are independently H, substituted or unsubstituted C1^ alkyl or R8 and R9 together with the atom to which they are attached form a substituted or unsubstituted heterocyclic ring; and
X and Y are independently H, halo, substituted or unsubstituted Ci-6 alkyl, -OR6, a substituted or unsubstituted ether, or a substituted or unsubstituted amine; [0006] with the proviso that the compound is not rel-(2R,4S,4aS)-1 ,2,4,4a-Tetrahydro-2,4- dimethyl-8-[5-(methylthio)-1 , 3,4-th iadiazol-2-yl]spiro[[1 ,4]oxazino[4,3-a]quinoline-5(6H),5'(2'H)-pyrimidine]- 2\4',6'(1H3Η)-trione.
[0007] Forms of the compounds can include salts, such as pharmaceutically acceptable salts, solvates, hydrates or prodrugs of the described compounds. The described compounds can also be part of a pharmaceutical composition, which can additionally include a pharmaceutically acceptable carrier, diluent or excipient.
[0008] Such compounds and compositions exhibit antibacterial activity and can be used accordingly.
DETAILED DESCRIPTION
[0009] Provided herein are compounds of Formula I. In a subset of the compounds of Formula I, the compounds can have the stereochemistry shown in Formula Ia below:
[0010] In some embodiments, X, Y or both can be a substituted or unsubstituted ether. In the compounds, none, one or both of R4 and R5 can be H. R4 and R5 can also independently be ethers. [0011] Alternatively, independently X, Y or both can be a substituted or unsubstituted amine.
When X or Y is a substituted or unsubstituted amine, then the group can independently have the formula -(CH2)mNR8R9 and each m, R8 and R9 is independent of any other m, R8 and R9 values at other positions. When any R8 and Rg together with the atom to which they are attached form a substituted or unsubstituted heterocyclic ring, the ring can be a monocyclic ring system, for example containing three to eight ring atoms, or the ring system can be a bi- or polyheterocyclic ring system. Additionally, one or more ring atoms, in addition to the N to which R8 and R9 are attached, can be selected from non-carbon atoms, for example N, O or S. [0012] In some compounds, Ri is one of the following:
[0013] In these embodiments, ΛΛΛΓ indicates a point of attachment;
R7 is H, halo, substituted or unsubstituted Ci.6 alkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted heterocyclyl, a substituted or unsubstituted ether, -(CH2)mOPO3(Rp)2, -(CH2)mOC(=O)(CH2)mCH3, -(CH2)mOC(=O)(CH2)mCO2R6, -(CH2)mOC(=O)(CH2)mNR8R9, -(CH2)mOC(=O)E, -(CH2)mCO2(CH2)mCH3, -(CH2)mCO2(CH2)mCO2R6, -(CH2)mCO2(CH2)mNR8R9j -(CH2)mCO2E, -(CH2)mC(=O)NR6(CH2)mCO2R6> -(CH2)mC(=O)NR8R9, -(CH2)mNR8Rg, -(CH2)mPO3(R11)2, -(CH2)mOR10, which is optionally substituted with -ORn, -(CH2)mC(=O)ORn, -(CHs)111NR11SOnRi2, -(CH2)mSOnR12, -(CH2)mSOnNR8R9, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; each m is as above, each n is independently 0, 1 or 2;
R10 is H, substituted or unsubstituted C1-6 alkyl, -PO3H2, C(=0)R13, C(=O)ORi3 or C(=O)NR8R9; and
Rn, R12 and Ri3 are independently H1 substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted aminoalkyl, an amino acid residue or a peptide residue. Examples of amino acid residues include alanine, aspartic acid, glycine, glutamic acid, histidine, lysine or valine. [0014] In certain compounds, X is H, Y is H or both X and Y are H. In other compounds X is F, Y is F or both X and Y are F. In these and other compounds, R2 and R3 can be methyl. In some compounds X can be -OH or -OR6, and in some instances R6 will be methyl or ethyl. Alternatively, X can be an ether or an amine.
[0015] In some compounds, m in R7 is 0, for example where R7 is -CO2E, -NR8Rg, -PO3(Rn)2,
-OR10, -C(=O)ORii, -C(=O)NR8R9, -NRnSOnRi2, -SOnRi2, Or -SOnNR8R9. R7 groups can be -(CH2)mCN, such as -CH2CN or -CN, -OH, -OCH3, -NH2, -NHCH3, -N(CH3)2 or -C(=O)NH2. Other examples of R7 groups can be found in the exemplified compounds. In certain compounds R7 is H or methyl. [0016] In some embodiments R4 and R5 are the same, for example where both are H. One or both of R4 and R5 can be -OH, -(CH2)mOH, -CH2OH, -CH2OAc, -CH2OCH3, -CH2O(CH2)2OCH3. R4 or R5 can also be substituted or unsubstituted -(CH2)maryl or -O(CH2)maryl, such as substituted or unsubstituted benzyl or substituted or unsubstituted -Obenzyl. One or both of R4 and R5 can also be -CH2OPO3H2. [0017] In certain compounds, when R8 and R9 together with the atom to which they are attached form a substituted or unsubstituted heterocyclic ring, the heterocyclic ring can have three, four, five, six, seven, eight or more ring members and include one, two, three or more heteroatoms, such as N, O or S. Specific examples of such heterocyclic rings include morpholine and piperazine or a substituted piperazine.
[0018] In certain embodiments, R11, R12 or R13 can be an amino acid residue. Amino acid residues are molecules that contain both amino and carboxylic acid functional groups. Some amino acids can be represented by the formula -C(=O)CH(Z)NRa, where Z alone can be a side chain of a naturally or non-naturally occurring amino acid. In cyclic amino acids, such as proline, Z in combination with Ra can be a side chain of a naturally or non-naturally occurring amino acid. When R3 is not part of the amino acid side chain, then generally R3 is H. Amino acids and peptides can be C- or N-linked. Examples of amino acids include alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine and valine. Other amino acids include gamma-aminobutyric acid (GABA), carnitine, ornithine, citrulline, homocysteine, hydroxyproline, hydroxylysine, and sarcosine. The amino acids can be in the L- or D- configuration.
[0019] Alternatively, R11, R12 or R13 can be a peptide residue, which can be C- or N-linked.
Peptides are amino acids linked together via peptide bonds and can be straight-chained or branched.
Suitable peptides can include dipeptides, tripeptides, tetrapeptides or more in which the amino acid residues making up the peptide can be the same or different.
[0020] In some embodiments, (Rp)2 together with the atoms to which they are attached form a substituted or unsubstituted heterocyclic ring. In some compounds the oxygen atoms can be connected
via an alkyl, aryl, or alkyl-aryl-alkyl bridge, such as in [0021] In some of the compounds each E or ether independently has the formula
-[(CV2)pO(CV2)p]qCH3 wherein each p is independently 0, 1 , 2, 3, 4, 5 or 6, each q is independently 1 , 2, 3, 4, 5 or 6, each V is independently H or another -[(CV2)pO(CV2)p]qCH3. Examples of these compounds include where each E or ether independently has the formula -[(CH2)pO(CH2)p]qCH3 where each p is independently 0, 1 , 2, 3 or 4 and each q is independently 1 , 2, 3 or 4.
[0022] In some specific embodiments, X and Y are F, R2 and R3 are methyl, and R4 and R5 are
H. In some of these compounds R7 can be methyl. In other embodiments, R7 is a substituted or unsubstituted ether, -(CH2)mOPO3(Rp)2, -(CH2)mOC(=O)(CH2)mCH3, -(CH2)mOC(=O)(CH2)mCO2R6, -(CH2)mOC(=O)(CH2)mNR8R9, -(CH2)mOC(=O)E, -(CH2)mCO2(CH2)mCH3, -(CH2)mCO2(CH2)mCO2R6, -(CH2)mCO2(CH2)mNR8R9) -(CH2)mCO2E, -(CH2)mC(=O)NR6(CH2)mCO2R6, -(CH2)mC(=O)NR8R9, -(CH2)mNR8R9, -(CH2)mPO3(R11)2, -(CH2)^=O)OR11, -(CH2)H1NR11SOnR12, -(CH2)mSOnR12, or -(CH2)mSOnNR8R9. In certain of these embodiments, m is 1 or 2.
[0023] In additional specific embodiments, X is H, Y is F, R2 and R3 are methyl, and R4 and R5 are H. In some of these compounds R7 can be methyl. In other embodiments, R7 is a substituted or unsubstituted ether, -(CH2)mOPO3(Rp)2, -(CH2)mOC(=O)(CH2)mCH3, -(CH2)mOC(=O)(CH2)mCO2R6, -(CH2)mOC(=O)(CH2)mNR8R9, -(CH2)mOC(=O)E, -(CH2)mCO2(CH2)mCH3, -(CH2)mCO2(CH2)mCO2R6, -(CH2)mCO2(CH2)mNR8R9, -(CH2)mCO2E, -(CH2)mC(=O)NR6(CH2)mCO2R6, -(CH2)mC(=O)NR8R9, -(CH2)mNR8R9, -(CH2)mPO3(R11)2, -(CH2)mC(=O)OR11, -(CH2UNR11SOnR12, -(CH2)mSOnR12, or -(CH2)mSOnNR8R9. In certain of these embodiments, m is 1 or 2. [0024] In further specific embodiments, X and Y are F, R2 and R3 are methyl, and R4 and R5 are a substituted or unsubstituted ether, -(CH2)mNR8R9, -(CH2)mOR6, -(CH2)mOPO3(Rp)2, -(CH2)mOC(=O)(CH2)mCH3, -(CH2)mOC(=O)(CH2)mCO2R6, -(CH2)mOC(=O)(CH2)mNR8R9, or -(CH2)mOC(=O)E. In certain of these embodiments, m is 1 or 2.
[0025] In other specific embodiments, X is H, Y is F, R2 and R3 are methyl, and R4 and R5 are a substituted or unsubstituted ether, -(CH2)mNR8R9, -(CH2)mOR6, -(CH2)mOPO3(Rp)2, -(CH2)mOC(=O)(CH2)mCH3> -(CH2)mOC(=O)(CH2)mCO2R6, -(CH2)mOC(=O)(CH2)mNR8R9, or -(CH2)mOC(=O)E. In certain of these embodiments, m is 1 or 2.
[0026] Any embodiment described herein can be combined with any other suitable embodiment described herein to provide additional embodiments. For example, where one embodiment individually or collectively describes possible groups for R1, R2, R3, R4, R5, etc., and a separate embodiment describes possible R7 groups, it is understood that these embodiments can be combined to provide an embodiment describing possible groups for Rj, R2, R3, R4, R5, etc. with the possible R7 groups, etc. With respect to the above compounds, and throughout the application and claims, the following terms have the meanings defined below.
[0027] The phrase "acyl" refers to groups having a carbon double-bonded to an oxygen atom, such as in the structure -C(=O)R. Examples of R can include H, such as in aldehydes, a hydrocarbon, such as in a ketone, -NR8R9, such as in an amide, -OR6 such as in a carboxylic acid or ester, -0OCR2, such as in an acyl anhydride or a halo, such as in an acyl halide.
[0028] The phrase "alkenyl" refers to straight and branched chain hydrocarbons, such as those described with respect to alkyl groups described herein, that include at least one double bond existing between two carbon atoms. Examples include vinyl, -CH=C(H)(CH3), -CH=C(CH3)2, -C(CH3)=C(H)2, -C(CH3)=C(H)(CH3), -C(CH2CH3)=CH2, cyclohexenyl, cyclopentenyl, cyclohexadienyl, butadienyl, pentadienyl, and hexadienyl among others. An alkenyl group can optionally be substituted, for example where 1 , 2, 3, 4, 5, 6, 7, 8 or more hydrogen atoms are replaced by a substituent selected from the group consisting of halogen, haloalkyl, hydroxy, thiol, cyano, and -NR8R9.
[0029] The phrase "alkyl" refers to hydrocarbon chains, for example Ci.6 chains, that do not contain heteroatoms. Thus, the phrase includes straight chain alkyl groups such as methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl and the like. The phrase also includes branched chain isomers of straight chain alkyl groups, including but not limited to, the following which are provided by way of example: -CH(CH3)2, -CH(CH3)(CH2CH3), -CH(CH2CH3)2, -C(CHg)3, -C(CH2CH3)3, -CH2CH(CH3)2, -CH2CH(CH3)(CH2 CH3), -CH2CH(CH2CHg)2, -CH2C(CHa)3, -CH2C(CH2CH3)3, -CH(CH3)CH(CH3)(CH2CH3), -CH2CH2CH(CHg)2, -CH2CH2CH(CH3)(CH2CH3), -CH2CH2CH(CH2CH3)2I -CH2CH2C(CH3), -CH2CH2C(CH2CHg)3, -CH(CH3)CH2CH(CHs)2, -CH(CH3)CH(CH3)CH(CHg)2, -CH(CH2CH3)CH(CHg)CH(CH3)(CH2CH3), and others. Thus, the phrase includes primary alkyl groups, secondary alkyl groups, and tertiary alkyl groups. Alkyl groups can be bonded to one or more carbon atom(s), oxygen atom(s), nitrogen atom(s), and/or sulfur atom(s) in the parent compound. An alkyl group can optionally be substituted, for example where 1, 2, 3, 4, 5, 6 or more hydrogen atoms are replaced by a substituent selected from the group consisting of halogen, haloalkyl, hydroxy, thiol, cyano, and -NR8R9. [0030] The phrase "alkylene" refers to a straight or branched chain divalent hydrocarbon radical, generally having from two to ten carbon atoms. [0031] The phrase "alkynyl" refers to straight and branched chain hydrocarbon groups, such as those described with respect to alkyl groups as described herein, except that at least one triple bond exists between two carbon atoms. Examples include -C≡C(H), -C≡C(CH3), -C≡C(CH2CH3), -C(H2)C≡C(H), -C(H)2C≡C(CH3), and -C(H)2CsC(CH2CH3) among others. An alkynyl group can optionally be substituted, for example where 1 , 2, 3, 4, 5, 6, 7, 8 or more hydrogen atoms are replaced by a substituent selected from the group consisting of halogen, haloalkyl, hydroxy, thiol, cyano, and -NR8R9. [0032] The phrase "aminoalkyl" refers to an alkyl group as above attached to an amino group, which can ultimately be a primary, secondary or tertiary amino group. An example of an amino alkyl group is the -NR8Rg where one or both of R8 and R9 is a substituted or unsubstituted C-i.6 alkyl or R8 and R9 together with the atom to which they are attached form a substituted or unsubstituted heterocyclic ring. Specific aminoalkyl groups include -NHCH3, -IM(CH3).,, -NHCH2CH3, -N(CH3)CH2CH3,-N(CH2CH3)2, -NHCH2CH2CH3, -N(CH2CH2CH3)2, and the like. Additional aminoalkyl groups include:
aminoalkyl group can optionally be substituted with 1 , 2, 3, 4 or more non-hydrogen substituents, for example where each substituent is independently selected from the group consisting of halogen, cyano, hydroxy, Ci.6 alkyl, C1^ alkoxy, Cr2 alkyl substituted with one or more halogens, Cr∑ alkoxy substituted with one or more halogens, -C(O)R6, -C(O)OR6, -S(O)nR6 and -NR8R9. These substituents may be the same or different and may be located at any position of the ring that is chemically permissible. [0033] The phrase "aryl" refers to cyclic or polycyclic aromatic rings, generally having from 5 to
12 carbon atoms. Thus the phrase includes, but is not limited to, groups such as phenyl, biphenyl, anthracenyl, naphthenyl by way of example. The phrase "unsubstituted aryl" includes groups containing condensed rings such as naphthalene. Unsubstituted aryl groups can be bonded to one or more carbon atom(s), oxygen atom(s), nitrogen atom(s), and/or sulfur atom(s) in the parent compound. Substituted aryl groups include methoxyphenyl groups, such as para-methoxyphenyl.
[0034] Substituted aryl groups include aryl groups in which one or more aromatic carbons of the aryl group is bonded to a substituted and/or unsubstituted alkyl, alkenyl, alkynyl group or a heteroatom containing group as described herein. This includes bonding arrangements in which two carbon atoms of an aryl group are bonded to two atoms of an alkyl, alkenyl, or alkynyl group to define a fused ring system (e.g. dihydronaphthyl or tetrahydronaphthyl). Thus, the phrase "substituted aryl" includes, but is not limited to tolyl, and hydroxyphenyl among others. An aryl moiety can optionally be substituted with 1 , 2, 3, 4 or more non-hydrogen substituents, for example where each substituent is independently selected from the group consisting of halogen, cyano, hydroxy, Ci.6 alkyl, C1^ alkoxy, Cr2 alkyl substituted with one or more halogens, Cr2 alkoxy substituted with one or more halogens, -C(O)R6, -C(O)OR6, -S(O)nR6 and - NR8R9. These substituents may be the same or different and may be located at any position of the ring that is chemically permissible.
[0035] The phrase "cycloalkyl" refers to cyclic hydrocarbon chains, generally having from 3 to 12 carbon atoms, and includes cyclic alkyl groups such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl and such rings substituted with straight and branched chain alkyl groups as described herein. The phrase also includes polycyclic alkyl groups such as, but not limited to, adamantly, norbornyl, and bicyclo[2.2.2]octyl and such rings substituted with straight and branched chain alkyl groups as described herein. Cycloalkyl groups can be saturated or unsaturated and can be bonded to one or more carbon atom(s), oxygen atom(s), nitrogen atom(s), and/or sulfur atom(s) in the parent compound. A cycloalkyl group can be optionally substituted, for example where 1 , 2, 3, 4 or more hydrogen atoms are replaced by a substituent selected from the group consisting of halogen, cyano, hydroxy, C1-6 alkyl, C1^ alkoxy, Cr∑ alkyl substituted with one or more halogens, Cr2 alkoxy substituted with one or more halogens, -C(O)R6, -C(O)OR6, -S(O)nR6 and -NR8R9.
[0036] Ethers, as used herein, generically encompass monoethers, polyethers, straight chain ethers, branched ethers and cyclic ethers. Straight chain ethers can have the structure -[(CH2)pO(CH2)p]qCH3 where each p is independently 0, 1 , 2, 3, 4, 5 or 6 and q is 1 , 2, 3, 4, 5 or 6. Branched ethers can have the formula -[(CV2)pO(CV2)p]qCH3 where each V is independently H or another
-[(CV2)p0(CV2)p]qCH3 group. Cyclic ethers can have the formula where p and q are as above and <JVW> indicates a point of attachment. Specifically, as ether compounds, there are -dimethyl ether, -methyl ethyl ether, -methoxy ethyl ether, -diethyl ether, -methyl t-butyl ether, -methyl cellosolve, - ethylene glycol dimethyl ether, -diethylene glycol dimethyl ether, -triethylene glycol dimethyl ether, -tetraethylene glycol dimethyl ether, -tetrahydrofuran, -1 ,4-dioxane, and the like. [0037] The phrase "halo" refers to fluorine, chlorine, bromine or iodine.
[0038] The phrase "haloalkyl" refers to an alkyl group in which at least one, for example 1 , 2, 3,
4, 5 or more, hydrogen atom(s) is/are replaced with a halogen. Examples of suitable haloalkyls include chloromethyl, difluoromethyl, trifluoromethyl, 1-fluro-2-chloro-ethyl, 5-fluoro-hexyl, 3-difluro-isopropyl, 3- chloro-isobutyl, etc.
[0039] The phrases "heterocyclyl" or "heterocyclic ring" refers to aromatic, nonaromatic, saturated and unsaturated ring compounds including monocyclic, bicyclic, and polycyclic ring compounds, including fused, bridged, or spiro systems, such as, but not limited to, quinuclidyl, containing 1 , 2, 3 or more ring members of which one or more is a heteroatom such as, but not limited to, N, O, P and S. Unsubstituted heterocyclyl groups include condensed heterocyclic rings such as benzimidazolyl. Examples of heterocyclyl groups include: unsaturated 3 to 8 membered rings containing 1 to 4 nitrogen atoms such as, but not limited to pyrrolyl, pyrrolinyl, imidazolyl, imidazolidinyl, pyrazolyl, pyridyl, dihydropyridyl, pyrimidyl, pyrazinyl, pyridazinyl, triazolyl (e.g. 4H-1 ,2,4-triazolyl, 1 H-1 ,2,3-triazolyl, 2H- 1 ,2,3-triazolyl etc.), tetrazolyl, (e.g. 1H-tetrazolyl, 2H tetrazolyl, etc.); saturated 3 to 8 membered rings containing 1 to 4 nitrogen atoms such as, but not limited to, pyrrolidinyl, piperidinyl, piperazinyl; condensed unsaturated heterocyclic groups containing 1 to 4 nitrogen atoms such as, but not limited to, indolyl, isoindolyl, indolinyl, indolizinyl, benzimidazolyl, quinolyl, isoquinolyl, indazolyl, benzotriazolyl; saturated 3 to 8 membered rings containing 1 to 3 oxygen atoms such as, but not limited to, tetrahydrofuran; unsaturated 3 to 8 membered rings containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms such as, but not limited to, oxazolyl, isoxazolyl, oxadiazolyl (e.g. 1 ,2,4-oxadiazolyl, 1 ,3,4- oxadiazolyl, 1 ,2,5-oxadiazolyl, etc.); saturated 3 to 8 membered rings containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms such as, but not limited to, morpholinyl; unsaturated condensed heterocyclic groups containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms, for example, benzoxazolyl, benzoxadiazolyl, benzoxazinyl (e.g. 2H-1 ,4-benzoxazinyl etc.); unsaturated 3 to 8 membered rings containing 1 to 3 sulfur atoms and 1 to 3 nitrogen atoms such as, but not limited to, thiazolyl, isothiazolyl, thiadiazolyl (e.g. 1 ,2,3- thiadiazolyl, 1 ,2,4-thiadiazolyl, 1 ,3,4-thiadiazolyl, 1 ,2,5-thiadiazolyl, etc.); saturated 3 to 8 membered rings containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms such as, but not limited to, thiazolodinyl; saturated and unsaturated 3 to 8 membered rings containing 1 to 2 sulfur atoms such as, but not limited to, thienyl, dihydrodithiinyl, dihydrodithionyl, tetrahydrothiophene, tetrahydrothiopyran; unsaturated condensed heterocyclic rings containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms such as, but not limited to, benzothiazolyl, benzothiadiazolyl, benzothiazinyl (e.g. 2H-1 ,4-benzothiazinyl, etc.), dihydrobenzothiazinyl (e.g. 2H-3,4-dihydrobenzothiazinyl, etc.), unsaturated 3 to 8 membered rings containing oxygen atoms such as, but not limited to furyl; unsaturated condensed heterocyclic rings containing 1 to 2 oxygen atoms such as benzodioxolyl (e.g. 1 ,3-benzodioxoyl, etc.); unsaturated 3 to 8 membered rings containing an oxygen atom and 1 to 2 sulfur atoms such as; but not limited to, dihydrooxathiinyl; saturated 3 to 8 membered rings containing 1 to 2 oxygen atoms, and 1 to 2 sulfur atoms such as 1 ,4-oxathiane; unsaturated condensed rings containing 1 to 2 sulfur atoms such as benzothienyl, benzodithiinyl; and unsaturated condensed heterocyclic rings containing an oxygen atom and 1 to 2 oxygen atoms such as benzoxathiinyl. Heterocyclyl group also include those described herein in which one or more S atoms in the ring is double-bonded to one or two oxygen atoms (sulfoxides and sulfones). For example, heterocyclyl groups include tetrahydrothiophene, tetrahydrothiophene oxide, and tetrahydrothiophene 1 ,1 -dioxide. Heterocyclyl groups can contain 5 or 6 ring members. Examples of heterocyclyl groups include morpholine, piperazine, piperidine, pyrrolidine, imidazole, pyrazole, 1 ,2,3- triazole, 1 ,2,4-triazole, tetrazole, thiomorpholine, thiomorpholine in which the S atom of the thiomorpholine is bonded to one or more O atoms, pyrrole, homopiperazine, oxazolidin-2-one, pyrrolidin-2-one, oxazoie, quinuclidine, thiazole, isoxazole, furan, and tetrahydrofuran.
[0040] A heterocyclyl group can be optionally substituted, for example where 1 , 2, 3, 4 or more hydrogen atoms are replaced by a substituent selected from the group consisting of halogen, cyano, hydroxy, C1^ a'M. C1-6 alkoxy, Cr2 alkyl substituted with one or more halogens, Cr2 alkoxy substituted with one or more halogens, -C(O)R6, -C(O)OR6, -S(O)nRe and -NR8R9.Examples of "substituted heterocyclyl" rings include 2-methylbenzimidazolyl, 5-methylbenzimidazolyl, 5-chlorobenzthiazolyl, 1-methylpiperazinyl, and 2-chloropyridyl among others. Any nitrogen atom within a heterocyclic ring can optionally be substituted with C1^ alkyl, if chemically permissible.
[0041] Heterocyclyl groups include heteroaryl groups as a subgroup. The phrase "heteroaryl" refers to a monovalent aromatic ring radical, generally having 5 to 10 ring atoms, containing 1 , 2, 3, or more heteroatoms independently selected from S, O, or N. The term heteroaryl also includes bicyclic groups in which the heteroaryl ring is fused to a benzene ring, heterocyclic ring, a cycloalkyl ring, or another heteroaryl ring. Examples of heteroaryl include 7-benzimidazolyl, benzo[b]thienyl, benzofuryl, benzothiazolyl, benzothiophenyl, 2-, 4-, 5-, 6-, or 7-benzoxazolyl, furanyl, furyl, imidazolyl, indolyl, indazolyl, isoquinolinyl, isothiazolyl, isoxazolyl, oxadiazolyl, oxazolyl, purinyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridinyl, pyrimidinyl, pyrrolyl, quinolinyl, tetrazolyl, thiadiazolyl, thiazolyl, thienyl, thiophenyl, triazolyl and the like. Heteroaryl rings can also be optionally fused to one or more of another heterocyclic ring(s), heteroaryl ring(s), aryl ring(s), cycloalkenyl ring(s), or cycloalkyl rings. A heteroaryl group can be optionally substituted, for example where 1 , 2, 3, 4 or more hydrogen atoms are replaced by a substituent selected from the group consisting of halogen, cyano, hydroxy, C1-6 alkyl, Ci-6 alkoxy, d-2 alkyl substituted with one or more halogens, Cr2 alkoxy substituted with one or more halogens, -C(O)R6, -C(O)OR6, -S(O)nR6 and -NR8R9.
[0042] The phrase "heterocyclyloxy" refers to a group in which an oxygen atom is bound to a ring atom of a heterocyclyl group as described herein.
[0043] "Pharmaceutically acceptable" means suitable for use in mammals. A "pharmaceutically acceptable salt" includes a salt with an inorganic base, organic base, inorganic acid, organic acid, or basic or acidic amino acid. As salts of inorganic bases, the invention includes, for example, alkali metals such as sodium or potassium; alkaline earth metals such as calcium and magnesium or aluminum; and ammonia. As salts of organic bases, the invention includes, for example, trimethylamine, triethylamine, pyridine, picoline, ethanolamine, diethanolamine, and triethanolamine. As salts of inorganic acids, the instant invention includes, for example, hydrochloric acid, hydroboric acid, nitric acid, sulfuric acid, and phosphoric acid. As salts of organic acids, the instant invention includes, for example, formic acid, acetic acid, trifluoroacetic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid, and p-toluenesulfonic acid. As salts of basic amino acids, the instant invention includes, for example, arginine, lysine and ornithine. Acidic amino acids include, for example, aspartic acid and glutamic acid. Examples of pharmaceutically acceptable salts are described in Berge, S. M. et al., "Pharmaceutical Salts," Journal of Pharmaceutical Science, 1977;66:1 19. [0044] A "prodrug" is a compound that can be transformed in vivo into an active therapeutic compound, such as a compound described herein. Transformation of the prodrug compound can be accomplished chemically, enzymatically, or by action with other endogenous materials, e.g. amino acids, peptides and proteins. Prodrugs are discussed in T. Higuchi and V. Stella, "Pro-drugs as Novel Delivery Systems," Vol. 14 of the A.C.S. Symposium Series, and in Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987. Examples of prodrugs can include esters and amides of polar groups, such as carboxylate groups. [0045] The term "protected" with respect to hydroxyl groups, amine groups, and sulfhydryl groups refers to forms of these functionalities which are protected from undesirable reaction with a protecting group known to those skilled in the art such as those set forth in Protective Groups in Organic Synthesis, Greene, T. W.; Wilts, P. G. M., John Wiley & Sons, New York, N.Y., (3rd Edition, 1999) which can be added or removed using the procedures set forth therein. Examples of protected hydroxyl groups include silyl ethers such as those obtained by reaction of a hydroxyl group with a reagent such as, but not limited to, t-butyldimethyl-chlorosilane, trimethylchlorosilane, triisopropylchlorosilane, triethylchlorosilane; substituted methyl and ethyl ethers such as, but not limited to methoxymethyl ether, methythiomethyl ether, benzyloxymethyl ether, t-butoxymethyl ether, 2-methoxyethoxym ethyl ether, tetrahydropyranyl ethers, 1 -ethoxyethyl ether, allyl ether, benzyl ether; esters such as, but not limited to, benzoylformate, formate, acetate, trichloroacetate, and trifluoracetate. Examples of protected amine groups include amides such as, formamide, acetamide, trifluoroacetamide, and benzamide; imides, such as phthalimide, and dithiosuccinimide; and others. Examples of protected sulfhydryl groups include thioethers such as S-benzyl thioether, and S-4-picolyl thioether; substituted S-methyl derivatives such as hemithio, dithio and aminothio acetals; and others. [0046] A "salt" is intended to refer to all salt forms of a compound, including salts suitable for use in industrial processes, such as the preparation of the compound, and pharmaceutically acceptable salts. [0047] "Substituted" refers to a group in which one or more bonds to a hydrogen atom contained therein are replaced by a bond to non-hydrogen atom. In some instances the bond will also be replaced by non-carbon atoms such as, but not limited to: a halogen atom such as F, Cl, Br, and I; a nitrogen atom in groups such as amines, amides, alkylamines, dialkylamines, arylamines, alkylarylamines, diarylamines, heterocyclylamine, (alkyl)(heterocyclyl)amine, (aryl)(heterocyclyl)amine, or diheterocyclylamine groups, isonitrile, N-oxides, imides, and enamines; an oxygen atom in groups such as hydroxyl groups, alkoxy groups, aryloxy groups, ester groups, and heterocyclyloxy groups; a silicon atom in groups such as in trialkylsilyl groups, dialkylarylsilyl groups, alkyldiarylsilyl groups, and triarylsilyl groups; a sulfur atom in groups such as thiol groups, alkyl and aryl sulfide groups, sulfone groups, sulfonyl groups, and sulfoxide groups; and other heteroatoms in various other groups. Substituted alkyl groups and substituted cycloalkyl groups also include groups in which one or more bonds to one or more carbon or hydrogen atoms are replaced by a bond to a heteroatom such as oxygen in carbonyl, carboxyl, and ether groups; nitrogen in groups such as imines, oximes and hydrazones. Substituted cycloalkyl, substituted aryl, substituted heterocyclyl and substituted heteroaryl also include rings and fused ring systems which can be substituted with alkyl groups as described herein. Substituted arylalkyl groups can be substituted on the aryl group, on the alkyl group, or on both the aryl and aikyl groups. All groups included herein, such as alkyl, alkenyl, alkylene, alkynyl, aryl, heterocyclyl, heterocyclyloxy, and the like, can be substituted. Representative examples of substituents for substitution include one or more, for example one, two or three, groups independently selected from halogen, -OH, -C1-6 alkyl, C1^ alkoxy, trifluoromethoxy, -S(O)nC1.6 alkyl, amino, haloalkyl, thiol, cyano, -OR10 and -NR8R9, and trifluoromethyl. [0048] 'Treating" means an alleviation of symptoms associated with an infection, halt of further progression or worsening of those symptoms, or prevention or prophylaxis of the infection. Treatment can also include administering the pharmaceutical formulations of the present invention in combination with other therapies. For example, the compounds and pharmaceutical formulations of the present invention can be administered before, during, or after surgical procedure and/or radiation therapy. The compounds of the invention can also be administered in conjunction with other antibacterial drugs. [0049] In some instances, compounds described herein can be provided ex vivo or produced in vivo, for example where a prodrug of a compound is administered.
[0050] Generally, reference to a certain element such as hydrogen or H is meant to include all isotopes of that element. For example, if an R group is defined to include hydrogen or H, it also includes deuterium and tritium.
[0051] General Synthesis of Compounds The described compounds can be made according to the following general synthetic scheme, in which all R, X and Y have the values described above, PrO1 is a protecting group, such as an alcohol protecting group, and Rtp is a side chain that is a precursor to a thiadiazole ring.
[0052] As can be seen in the above reaction scheme, compound B can be obtained from compound A by forming a thiadiazole side chain precursor from the carboxylic acid moiety. The thiadiazole side chain precursor can then be cyclized to the desired thiadiazole, as described in more detail in the following reactions, and the alcohol can be deprotected to obtain compound C. Alternatively, thiadiazole ring formation can occur directly from compound A, particularly for compounds containing sulfide and sulfone substituted 1 ,3,4-thiadiazoles, using the appropriate reagents as described below. The deprotected alcohol in compound C can then be oxidized to an aldehyde to give compound D from which can be obtained the compound of formula I by condensation with barbituric acid and cyclization. [0053] In the above scheme, compound A can be prepared at least as follows, particularly where
X is H and Y is F:
[0054] In the above, reaction, =OPro2 is a carbonyl protecting group, such as a cyclic acetal, which can be formed by reaction of a carbonyl with 1 ,2-ethanediol or propane-1 ,3-diol in the presence of an acid catalyst. Typical halo atoms include bromine. The carbonyl deprotection can be performed by acid deprotection in THF. The carbonyl can be reduced, such as by using sodium borohydride in the presence of methanol. The resulting alcohol can be protected utilizing art-known methods and groups, for example a trialkyl silyl ether such as t-butyldiphenyl silyl ether (TBDPS), and the halo group can be substituted by a carboxylation to give compound A. The carboxylation can be achieved by performing a halogen metal exchange reaction followed by reacting the product with a carbonyl donor. The halogen metal exchange reaction can include can include contacting the compound with a strong base, such as alkyl lithium, or a Grignard reagent in a non-protic organic solvent.
[0055] Compound A can also be produced according to the following synthetic scheme, particularly when both X and Y are F:
reduction alcohol protection
[0056] In the above scheme, ring coupling can be achieved by the use of a base, such as lithium hexamethyldisilazide (LiHDMS), Et3N, or the like. Similar to the preceding reaction, the carbonyl can be reduced, such as by using sodium borohydride and I2. The resulting alcohol can be protected utilizing art- known methods and groups, for example a trialkyl silyl ether such as t-butyldiphenyl silyl ether (TBDPS), and the halo group can be displaced by a carboxylation reaction to give compound A. [0057] General Synthesis of Compounds Containing 1 ,2,3-Thiadiazole Rings.
[0058] Compounds containing 1 ,2,3-thiadiazole rings can be prepared according to the following synthetic scheme:
[0059] In one embodiment of the above synthesis, compound A is modified to add the thiadiazole side chain precursor by converting the starting carboxylic acid into a ketone via the Weinreb amide using Grignard chemistry. A non-limiting example of this chemistry is shown in Example 2, steps 1 and 2. Reaction with tosyl hydrazine to generate a hydrazone, followed by treatment with thionyl chloride produces the 1 ,2,3-thiadiazole as shown. In the reactions, compound A where n is 1 may be obtained from compound A where n is 0 by adding a carbon to the carboxyl side chain. For example, the carboxlic acid is converted to an acid chloride using oxalyl chloride then treated with trimethylsilyl-diazomethane and methanol resulting in homologation to a methyl ester as follows:
[0060] General Synthesis of Compounds Containing 1,2,4-Thiadiazole Rings. [0061] Compounds containing 1 ,2,4-thiadiazole rings can be prepared according to the following synthetic scheme:
[0062] In the above scheme, the carboxyl group of compound A is converted to an amide which is converted to a thioamide. The thiadiazole of compound C is then formed from the thioamide of compound B by cyclization with the appropriate reagents, as described in more detail in the examples.
[0063] General Synthesis of Compounds Containing 1 ,2,5-Thiadiazole Rings.
[0064] Compounds containing 1 ,2,5-thiadiazole rings can be prepared according to the following route:
[0065] The carboxylic acid is treated with TMS-CN followed by ammonia in methanol to provide and aminonitrile which is converted to the 1 ,2,5-thiadiazole by treatment with sulfur monochloride. [0066] General Synthesis of Compounds Containing 1 ,3,4-Thiadiazole Rings.
[0067] Compounds containing 1 ,3,4-thiadiazole rings can be prepared according to the following synthetic scheme:
[0068] In the above synthesis, Pro3 represents a protecting group, for example an amine protecting group such as a tert-butoxycarbonyl (BOC) group. The carboxyl group of compound A is converted to a protected hydrazide which is converted to a thiohydrazide similar to the thioamide conversion described herein. The thiohydrazide is deprotected and cyclized to a thiadiazole, for example by using an acylating agent.
[0069] Also provided is a method for making the compounds of formula Il shown below. This method can be performed by (a) reacting a compound of formula III with a compound of formula IV at a temperature sufficient to produce a compound of formula II:
[0070] According to this method, specific groups can be defined as elsewhere herein. Reaction to form Il can occur in an aqueous or organic solvent. Typically temperatures for this reaction will be about 60 to about 180 0C, for example from about 80 to 180 0C, 100 to 140 0C or 140 to 180 0C, and can occur from about 2 to about 24 hours, for example 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22 or 24 hours. Examples of solvents that can be used include DMSO, methanol, isopropanol, butanol, toluene and water. In a specific example, temperatures can range from about 80 0C to about 120 0C. In a specific example, reaction times can range from about 5 to 24 h.
[0071] The method can also involve (b) reacting a compound of formula V with a compound of formula Vl, optionally in a non-protic organic solvent and/or in the presence of a base, to make the compound of formula III:
Vl
[0072] In this reaction, when present, the base can be an organic or inorganic base. In some instances compound Vl can act as a base. Typically, the reaction will take place at a temperature of about 20 to about 100 0C, for example from about 40 to 100 0C, 60 to 80 0C or 80 to 100 0C. This reaction can also be performed alone to provide the compound of formula III. Examples of solvents that can be used include acetonitrile and dimethylformamide. Temperature ranges for the reaction can also be about 70 to 90 0C Bases that can be used in the reaction include triethylamine, diisopropylethylamine or potassium carbonate. Reaction times can range from about 2 to 24 hours, for example 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22 or 24 hours. [0073] Compound V can be made by:
(c)(i) performing a halogen metal exchange or deprotonation reaction on a compound of formula VII, and
(c)(ii) reacting the product of (c)(i) with a carbonyl donor to make the compound of
[0074] In the above, reaction, Ha is hydrogen or a halogen, for example bromine. Ha can also be chlorine or iodine. In this reaction, (c)(i) can include contacting the compound of formula VII with a strong base, such as alkyl lithium. Alternatively, (c)(i) can include contacting the compounds of formula VII with a Grignard reagent in a non-protic organic solvent. These reactions typically occur at a temperature from about -78 to about 50 °C, for example from about -78 to about 0 0C. In (c)(ii) the carbonyl donor can include one or more of dimethylformamide, N-formylmorpholine, or para- nitrophenylformate. Examples of reaction times can be from about 1 to about 18 hours, for example 2, 4, 6, 8, 10, 12, 14, 16 or 18 hours.
[0075] Compound V can also be synthesized by (c) oxidizing a compound of formula VIII to make the compound of formula V:
VIII V
[0076] A similar oxidation is described ejsewhere herein, for example in Example 10, step 5.
[0077] One synthesis can combine several of these steps as follows:
VIII
condensation and cyclization
R3
[0078] Described compounds and intermediates can also be produced according to the following reaction:
Xl
X IX is a halogen, such as iodine. Accordingly, compound IX is made by reacting compounds X and Xl. This coupling reaction can also be performed with reverse polarity wherein the boron is attached to R1 and the halogen is attached to compound X at the position indicated by B' (see structure XII below). In general, the coupling reaction can be performed under standard Suzuki cross-coupling conditions employing 0.01- 0.1 equivalents of a palladium catalyst with appropriate ligands, such as Pd(PPh3)4 or Pd(dppf) Cl2, in an organic solvent or solvent mixture containing organic solvents, such as toluene and an alcohol, and water. The reaction can be performed in the presence of a base such as potassium carbonate, sodium carbonate, potassium phosphate, cesium carbonate or sodium acetate for example, at temperatures, e.g. from about 20 to 120 0C for about 2 to 24 h. This route can also be used to make compounds of formula III when a trans-morpholine compound is used in the reaction. Compounds III or IX can be used to make compound of formula I or Il according to the methods described herein. [0080] Compound X can be made by reacting compound XII to provide compound X:
XII
[0081] Conversion of compounds XII to compound X can be performed by reaction with a borane such as for example, bis(pinacolato)diboron, under palladium catalysis employing a palladium(ll) or palladium(o) species with appropriate ligands, for example Pd(PPh3)4, Pd(dppf)CI2, Pd(PCy)2CI2, in an organic solvent such as tetrahydrofuran, methyl-tetrahydrofuran, or toluene, and in the presence of an inorganic base such as, for example, potassium acetate, potassium phosphate, sodium carbonate, cesium carbonate. The reaction typically proceeds at elevated temperatures from 80 to 120 0C over about 12 h to 5 days. [0082] In turn, compound XII can be made by reacting compounds XIII and XIV:
XIII
XII [0083] The method can involve (a) reacting a compound of formula XIV with a compound of formula XIII, optionally in a non-protic organic solvent and/or in the presence of a base, to make the compound of formula XII. In this reaction, when present, the base can be an organic or inorganic base. In some instances compound XII can act as a base. Typically, the reaction will take place at a temperature of about 20 to about 100 0C, for example from about 40 to 100 0C, 60 to 80 0C or 80 to 100 0C.
[0084] Compound XIV can be made from compound XV as follows:
[0085] In one embodiment, compound XIV can be made by:
(b)(i) performing a deprotonation reaction on a compound of formula XV; and (b)(ii) reacting the product of (b)(i) with a carbonyl donor to make the compound of formula XIV: In the above, reaction, Ha is hydrogen. In this reaction, (b)(i) can include contacting the compound of formula XV with a strong base, such as alkyl lithium. These reactions typically occur at a temperature from about -78 to about 50 0C. In (b)(ii) the carbonyl donor can include one or more of dimethylformamide, N-formylmorpholine, or para-nitrophenylformate.
[0086] Also provided is a method of making the compound of formula XVII that includes
(a) reacting a compound of formula Vl with a compound of formula XVIII, optionally in a non-protic organic solvent and/or in the presence of a base, to make the compound of formula XVII.
Vl
In this reaction, R14 is a halogen, such as bromine or iodine, boronic acid, a boronate ester, such
as or a substituted or unsubstituted thiadiazole, as in R1.
[0087] In this reaction, when present, the base can be an organic or inorganic base. In some instances compound Vl can act as a base. Typically, the reaction will take place at a temperature of about 20 to about 100 0C, for example from about 40 to 100 0C, 60 to 80 0C or 80 to 100 0C. Examples of solvents that can be used include acetonitrile and dimethylformamide. Temperatures ranges for the reaction can also be about 70 to 90 0C. Bases that can be used in the reaction include triethylamine, dirsopropylethylam ine or potassium carbonate. Reaction times can range from about 2 to 24 hours, for example 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22 or 24 hours.
[0088] When R14 is a halogen, such as bromine, compound XVII can be used to make compound XVII where R14 is boronic acid or a boronate ester using the same reaction as set forth for making compound X.
[0089] When Ri4 is a halogen, such as iodine, compound XVII can also be used to make the compound of formula III by coupling compound XVII with a compound of formula RrB', where B' is
boronic acid or a boronate ester, such The compound of formula III can also be produced when Ru is boronic acid, a boronate ester, by reaction compound XVII with compound Xl (Rr halo) by the method set forth for making compound IX described herein.
[0090] In general, this coupling reaction can be performed under standard Suzuki cross-coupling conditions employing 0.01- 0.1 or more equivalents of a palladium catalyst with appropriate ligands, such as Pd(PPh3)4 or Pd(dppf) Cl2, in an organic solvent or solvent mixture containing organic solvents, such as toluene and an alcohol, and water. The reaction can be performed in the presence of a base, such as potassium carbonate, sodium carbonate, potassium phosphate, cesium carbonate or sodium acetate for example, at temperatures, e.g. from about 20 to 120 0C for about 2 to 24 h. Compound III can then be used to produce compounds of Formula Il as described herein. [0091] Compound XVIII can be made by:
(b)(i) performing a halogen metal exchange or deprotonation reaction on a compound of formula XIX, and
(c)(ii) reacting the product of (c)(i) with a carbonyl donor to make the compound of formula XVII:
[0092] In the above, reaction, Ha is hydrogen or a halogen, for example bromine. Ha can also be chlorine or iodine. In this reaction, (c)(i) can include contacting the compound of formula VII with a strong base, such as alkyl lithium. Alternatively, (c)(i) can include contacting the compounds of formula W
VII with a Grignard reagent in a non-protic organic solvent. These reactions typically occur at a temperature from about -78 to about 50 0C, for example from about -78 to about 0 0C. In (c)(ii) the carbonyl donor can include one or more of tetrahydrofuran, diethylether, dimethylformamide, N- formylmorpholine, or para-nitrophenylformate. Examples of reaction times can be from about 1 to about 18 hours, for example 2, 4, 6, 8, 10, 12, 14, 16 or 18 hours.
[0093] Compound XVIII can also be synthesized by (c) oxidizing a compound of formula VIII to make the compound of formula XVIII:
[0094] A similar oxidation is described elsewhere herein, for example in Example 10, step 5. [0095] Below is an example of a synthesis for 1,2,5-thiadiazoles: H
H2
R = OMe, Me, NHMe, H R = OMe, Me, NHMe, H
[0096] The compounds described herein can also be synthesized by appropriately modifying the protocols set forth in WO 2004/031195.
[0097] Certain compounds described herein are also useful as intermediates for preparing other described compounds and such intermediates are included within the scope of the present invention. [0098] Specific compounds are described throughout with particular reference to the Examples and the following table:
[0099] Also provided are compositions that can be prepared by mixing one or more compounds described herein, or pharmaceutically acceptable salts or tautomers thereof, with pharmaceutically acceptable carriers, excipients, binders, diluents or the like, to treat or ameliorate a variety of bacterial infections. A therapeutically effective dose or amount refers to that amount of one or more compounds described herein sufficient to result in amelioration of symptoms of the infection. The pharmaceutical compositions of the instant invention can be manufactured by methods well known in the art such as conventional granulating, mixing, dissolving, encapsulating, lyophilizing, emulsifying or levigating processes, among others. The compositions can be in the form of, for example, granules, powders, tablets, capsule syrup, suppositories, injections, emulsions, elixirs, suspensions or solutions. The instant compositions can be formulated for various routes of administration, for example, by oral administration, by transmucosal administration, by rectal administration, or subcutaneous administration as well as intrathecal, intravenous, intramuscular, intraperitoneal, intranasal, intraocular or intraventricular injection. The compound or compounds of the instant invention can also be administered in a local rather than a systemic fashion, such as injection as a sustained release formulation. The following dosage forms are given by way of example and should not be construed as limiting the instant invention. [00100] For oral, buccal, and sublingual administration, powders, suspensions, granules, tablets, pills, capsules, gelcaps, and caplets are acceptable as solid dosage forms. These can be prepared, for example, by mixing one or more compounds of the instant invention, or pharmaceutically acceptable salts or tautomers thereof, with at least one additive or excipient such as a starch or other additive. Suitable additives or excipients are sucrose, lactose, cellulose sugar, mannitol, maltitol, dextran, sorbitol, starch, agar, alginates, chitins, chitosans, pectins, tragacanth gum, gum arabic, gelatins, collagens, casein, albumin, synthetic or semi-synthetic polymers or glycerides, methyl cellulose, hydroxypropylmethyl- cellulose, and/or polyvinylpyrrolidone. Optionally, oral dosage forms can contain other ingredients to aid in administration, such as an inactive diluent, or lubricants such as magnesium stearate, or preservatives such as paraben or sorbic acid, or anti-oxidants such as ascorbic acid, tocopherol or cysteine, a disintegrating agent, binders, thickeners, buffers, sweeteners, flavoring agents or perfuming agents. Additionally, dyestuffs or pigments can be added for identification. Tablets and pills can be further treated with suitable coating materials known in the art. [00101] Liquid dosage forms for oral administration can be in the form of pharmaceutically acceptable emulsions, syrups, elixirs, suspensions, slurries and solutions, which can contain an inactive diluent, such as water. Pharmaceutical formulations can be prepared as liquid suspensions or solutions using a sterile liquid, such as, but not limited to, an oil, water, an alcohol, and combinations of these. Pharmaceutically suitable surfactants, suspending agents, emulsifying agents, can be added for oral or parenteral administration.
[00102] As noted above, suspensions can include oils. Such oils include peanut oil, sesame oil, cottonseed oil, corn oil, olive oil and mixtures of oils. Suspension preparation can also contain esters of fatty acids such as ethyl oleate, isopropyl myristate, fatty acid glycerides and acetylated fatty acid glycerides. Suspension formulations can include alcohols, such as, but not limited to, ethanol, isopropyl alcohol, hexadecyl alcohol, glycerol and propylene glycol. Ethers, such as but not limited to, poly(ethyleneglycol), petroleum hydrocarbons such as mineral oil and petrolatum; and water can also be used in suspension formulations.
[00103] For nasal administration, the pharmaceutical formulations can be a spray or aerosol containing and appropriate solvents and optionally other compounds such as, but not limited to, stabilizers, antimicrobial agents, antioxidants, pH modifiers, surfactants, bioavailablity modifiers and combinations of these. A propellant for an aerosol formulation can include compressed air, nitrogen, carbon dioxide, or a hydrocarbon based low boiling solvent. The compound or compounds of the instant invention are conveniently delivered in the form of an aerosol spray presentation from a nebulizer or the like.
[00104] Injectable dosage forms generally include aqueous suspensions or oil suspensions which can be prepared using a suitable dispersant or wetting agent and a suspending agent. Injectable forms can be in solution phase or in the form of a suspension, which is prepared with a solvent or diluent. Acceptable solvents or vehicles include sterilized water, Ringer's solution, or an isotonic aqueous saline solution. Alternatively, sterile oils can be employed as solvents or suspending agents. Generally, the oil or fatty acid is non-volatile, including natural or synthetic oils, fatty acids, mono-, di- or tri-glycerides. [00105] For injection, the pharmaceutical formulation can be a powder suitable for reconstitution with an appropriate solution as described above. Examples of these include freeze dried, rotary dried or spray dried powders, amorphous powders, granules, precipitates, or particulates. For injection, the formulations can optionally contain stabilizers, pH modifiers, surfactants, bioavailability modifiers and combinations of these. The compounds can be formulated for parenteral administration by injection such as by bolus injection or continuous infusion. A unit dosage form for injection can be in ampoules or in multi-dose containers.
[00106] For rectal administration, the pharmaceutical formulations can be in the form of a suppository, an ointment, an enema, a tablet or a cream for release of compound in the intestines, sigmoid flexure and/or rectum. Rectal suppositories are prepared by mixing one or more compounds of the instant invention, or pharmaceutically acceptable salts or tautomers of the compound, with acceptable vehicles, for example, cocoa butter or polyethylene glycol, which is present in a solid phase at normal storing temperatures, and present in a liquid phase at those temperatures suitable to release a drug inside the body, such as in the rectum. Oils can also be employed in the preparation of formulations of the soft gelatin type and suppositories. Water, saline, aqueous dextrose and related sugar solutions, and glycerols can be employed in the preparation of suspension formulations which can also contain suspending agents such as pectins, carbomers, methyl cellulose, hydroxypropyl cellulose or carboxym ethyl cellulose, as well as buffers and preservatives.
[00107] Besides those representative dosage forms described above, pharmaceutically acceptable excipients and carries are generally known to those skilled in the art and are thus included in the instant invention. Such excipients and carriers are described, for example, in "Remingtons Pharmaceutical Sciences" Mack Pub. Co., New Jersey (1991).
[00108] The formulations of the invention can be designed for to be short-acting, fast-releasing, long-acting, and sustained-releasing. Thus, the pharmaceutical formulations can also be formulated for controlled release or for slow release.
[00109] The instant compositions can also comprise, for example, micelles or liposomes, or some other encapsulated form, or can be administered in an extended release form to provide a prolonged storage and/or delivery effect. Therefore, the pharmaceutical formulations can be compressed into pellets or cylinders and implanted intramuscularly or subcutaneously as depot injections or as implants such as stents. Such implants can employ known materials such as silicones and biodegradable polymers. [00110] The compositions can contain, for example, from about 0.1% by weight, to about 90% or more by weight, of the active material, depending on the method of administration. Where the compositions comprise dosage units, each unit can contain, for example, from about 5 to 500 mg or more of the active ingredient. The dosage as employed for adult human treatment can range, for example, from about 10 to 3000 mg per day, depending on the route and frequency of administration. [00111] Specific dosages can be adjusted depending on conditions of infection, the age, body weight, general health conditions, sex, and diet of the subject, dose intervals, administration routes, excretion rate, and combinations of drugs. Any of the above dosage forms containing effective amounts are well within the bounds of routine experimentation and therefore, well within the scope of the instant invention. Generally, the total daily dose can typically range from about 0.1 mg/kg/day to about 500 mg/kg/day in single or in divided doses. Typically, dosages for humans can range from about 10 mg to about 3000 mg per day, in a single or multiple doses.
[00112] A therapeutically effective dose or amount can vary depending upon the route of administration and dosage form. Some compositions of the instant invention provide a formulation that exhibits a high therapeutic index. The therapeutic index is the dose ratio between toxic and therapeutic effects which can be expressed as the ratio between LD50 and ED50. The LD50 is the dose lethal to 50% of the population and the ED50 is the dose therapeutically effective in 50% of the population. The LD50 and ED50 can be determined by standard pharmaceutical procedures in animal cell cultures or experimental models.
[00113] In one embodiment, the invention provides methods of treating or preventing a bacterial infection in a subject, such as a mammal, e.g., a human or non-human mammal, comprising administering an effective amount of one or more compounds described herein to the subject. Suitable subjects that can be treated include domestic or wild animals, companion animals, such as dogs, cats and the like; livestock, including horses, cows and other ruminants, pigs, poultry, rabbits and the like; primates, for example monkeys, such as rhesus monkeys and cynomolgus (also known as crab-eating or long-tailed) monkeys, marmosets, tamarins, chimpanzees, macaques and the like; and rodents, such as rats, mice, gerbils, guinea pigs and the like. In one embodiment, the compound is administered in a pharmaceutically acceptable form, optionally in a pharmaceutically acceptable carrier. The compounds described herein can be used for the treatment or prevention of infectious disorders caused by a variety of bacterial organisms, including infections by pathogenic bacterial species. Examples include Gram positive and Gram negative aerobic and anaerobic bacteria, such as Staphylococci, e.g. S. aureus; Enterococci, e.g. E. faecalis; Streptococci, e.g. S. pyogenes and S. pneumoniae; Escherichia species, e.g. E. coli, including enterotoxigenic, enteropathogenic, enteroinvasive, enterohemorrhagic and enteroaggregative E. coli strains; Haemophilus, e.g. H. influenza; Moraxella, e.g. M. catarrhalis. Other examples include Mycobacteria, e.g. M. tuberculosis, M. avian-intracellulare, M. kansasii, M. bovis, M. africanum, M. genavense, M. leprae, M. xenopi, M. simiae, M. scrofulaceum, M. malmoense, M. celatum, M. abscessus, M. chelonae, M. szulgai, M. gordonae, M. haemophilum, M. fortuni and M. marinum; Corynebacteria, e.g. C. diphtheriae; Vibrio species, e.g. V. cholerae; Campylobacter species, e.g. C. jejuni; Helicobacter species, e.g. H. pylori; Pseudomonas species, e.g. P. aeruginosa; Legionella species, e.g. L. pneumophila; Treponema species, e.g. T. pallidum; Borrelia species, e.g. B. burgdorferi; Listeria species, e.g. L monocytogenes; Bacillus species, e.g. B. cereus; Bordatella species, e.g. B. pertussis; Clostridium species, e.g. C. perfringens, C. tetani, C. difficile and C. botulinum; Neisseria species, e.g. N. meningitidis and N. gonorrhoeae; Chlamydia species, e.g. C. psittaci, C. pneumoniae and C. trachomatis; Rickettsia species, e.g. R. rickettsii and R. prowazekii; Shigella species, e.g. S. sonnei; Salmonella species, e.g. S. typhimurium; Yersinia species, e.g. Y. enterocolitica and Y. pseudotuberculosis; Klebsiella species, e.g. K. pneumoniae; and Mycoplasma, e.g. M. pneumoniae.
[00114] Infections that can be treated with the described compounds include central nervous system infections, external ear infections, infections of the middle ear, such as acute otitis media, infections of the cranial sinuses, eye infections, infections of the oral cavity, such as infections of the teeth, gums and mucosa, upper respiratory tract infections, lower respiratory tract infections, genitourinary infections, gastrointestinal infections, gynecological infections, septicemia, bone and joint infections, skin and skin structure infections, bacterial endocarditis, burns, antibacterial prophylaxis of surgery, and antibacterial prophylaxis in immunosuppressed patients, such as patients receiving cancer chemotherapy, or organ transplant patients. These infections can be treated in hospital or community settings via various routes of administration as described herein.
[00115] The compounds or compositions described herein can also be used prophylactically.
Accordingly, one or more of the present compounds or compositions can be administered to an individual deemed to be at risk for developing a microbial infection. Individuals at risk for developing a microbial infection include individuals who have been exposed to a particular microorganism, such as a pathogenic bacterial species; individuals having a compromised immune system, such as individuals suffering from an immunodeficiency disease or taking immunocompromising medication; and individuals having a history of repeated or chronic infection, such as children who have repeated infections of the middle ear. [00116] Another embodiment provides a method of killing or preventing the growth of bacteria that includes contacting a bacteria with either a non-therapeutic amount or a therapeutically effective amount of one or more of the present compounds. Such methods can occur in vivo or in vitro. In vitro contact can involve a screening assay to determine the efficacy of the one or more compounds against selected bacteria at various amounts or concentrations. In vivo contact with a therapeutically effective amount of the one or more compounds can involve treatment or prophylaxis of a bacterial infection in the animal in which the contact occurs. The effect of the one or more compounds on the bacteria and/or host animal can also be determined or measured.
[00117] Included within the scope of the invention are ail isomers (e.g. stereoisomers, diastereoisomers, epimers, geometrical isomers) of the compounds described herein as well as any wholly or partially equilibrated mixtures thereof (e.g. racemic or optically active mixtures). The present invention also covers the individual isomers of the compounds represented by the formulas herein as mixtures with isomers thereof in which one or more chiral centers are inverted. [00118] Stereoisomeric mixtures, e.g. mixtures of diastereomers, can be separated into their corresponding isomers in a known manner by means of suitable separation methods. Diastereomeric mixtures for example can be separated into their individual diastereomers by means of fraction crystallization, chromatography, solvent distribution, and similar procedures. This separation can take place either at the level of one of the starting compounds or in a compound of formula I itself. Enantiomers can be separated through the formation of diastereomeric salts, for example by salt formation with an enantiomerically pure chiral acid, or by means of chromatography, for example by HPLC, using chiral chromatographic media.
[00119] It is understood that the compounds described herein can exhibit the phenomenon of tautomerism. As the chemical structures sometimes only represent one of the possible tautomeric forms, it should be understood that the invention encompasses any tautomeric form of the represented structure. [00120] In addition, the compounds described herein can exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like. In general, the solvated forms are considered equivalent to the unsolvated forms for the purposes of the present invention.
EXAMPLE 1
[00121] Step 1 : 1-[3-(fert-Butyl-diphenyl-silanyloxymethyl)-4-(2,6-dimethyl-morpholin-4-yl)-5- fluoro-phenyl]-ethanone. A solution of 4-[4-Bromo-2-(terf-butyl-diphenyl-silanyloxymethyl)-6-fluoro- phenyl]-2,6-dimethyl-morpholine (3.0 g, 5.4 mmol) in THF (50 mL) was cooled to -78 0C. TMEDA (0.81 mL, 5.4 mmol) was added followed by t-BuLi (7.9 mL of a 1.7 M solution in pentane). The solution was stirred 45 min at -78 ° and N-methoxy-N-methyl-acetamide (1.72 mL, 16.2 mmol) was added. The reaction was allowed to warm to rt and stirred overnight. The solution was poured into sat. aq. NH4CI (100 mL) and extracted with EtOAc (2 x 100 mL). The combined organics were dried over Na2SO4 and concentrated. Purification by column chromatography provided the compound (1.10 g) as a colorless oil. 1 H NMR (400 MHz, CDCl3) δ 1.1 (m, 15 H), 2.6 (m, 4 H), 2.8 (m, 2 H), 3.5 (m, 2 H), 4.8 (s, 1 H), 7.4 (m, 7 H), 7.5 (d, J=12.9 Hz, 1 H), 7.7 (m, 4 H); MS (APCI+) m/z 520 (MH+).
[00122] Steps 2-4: [2-(2,6-Dimethyl-morpholin-4-yl)-3-fluoro-5-[1 ,2,3]thiadiazol-4-yl-phenyl]- methanol. The procedure set forth in Example 10, steps 1-4 was followed using 1-[3-(fert-butyl-diphenyl- silanyloxymethyl)-4-(2,6-dimethyl-morpholin-4-yl)-5-fluoro-phenyl]-ethanone to provide the compound (0.188 g) as a colorless oil. 1 H NMR (400 MHz, CDCI3) δ 1.2 (d, J=6.3 Hz, 6 H), 2.9 (m, 2 H), 3.0 (m, 2 H), 3.8 (m, 2 H), 4.8 (d, J=14.7 Hz, 2 H), 7.7 (d, J=1.2 Hz, 1 H), 7.7 (m, 1 H), 8.6 (s, 1 H); MS (APCI+) m/z 324 (MH+).
[00123] Step 5, part 1 : 2-(2,6-Dimethyl-morpholin-4-yl)-3-fluoro-5-[1 ,2,3]thiadiazol-4-yl- benzaldehyde. The procedure of Example 10, step 5 was followed except the residue following the filtration was purified by column chromatography to provide the compound (0.154 g) as an oil. 1 H NMR (400 MHz, CDCI3) δ 1.2 (d, J=6.7 Hz, 6 H), 3.0 (d, J=11.0 Hz, 2 H), 3.1 (m, 2 H), 3.9 (m, 2 H), 8.1 (m, 2 H), 8.7 (s, 1 H), 10.5 (m, 1 H); MS (APCI+) m/z 322 (MH+).
[00124] Step 6, part 2: Compound 1. The procedure of Example 10, step 6 was followed except the reaction mixture was filtered at rt. The filter cake was washed with isopropanol (IPA) (2 x 1 mL) providing the compound (0.148 g) as a beige solid.1 H NMR (400 MHz, DMSO- d6) δ 0.9 (d, J=6.3 Hz, 3 H), 1.1 (d, J=6.3 Hz, 3 H), 3.0 (m, 2 H), 3.5 (d, J=14.2 Hz, 1 H), 3.6 (ddd, J=15.0, 6.3, 6.1 Hz, 1 H), 3.7 (m, 1 H), 3.8 (d, J=8.5 Hz, 1 H), 4.1 (dd, J=13.1 , 2.1 Hz, 1 H), 7.6 (s, 1 H), 7.7 (dd, J=14.9, 1.7 Hz, 1 H), 9.3 (s, 1 H), 11.5 (s, 1 H), 11.8 (s, 1 H); MS (APCI+) m/z 432 (MH+). Anal, calcd for C19H18FN5O4S: C, 52.89; H, 4.21 ; N, 16.23. Found: C, 53.06; H, 3.87; N, 15.83.
SYNTHETIC SCHEME FOR EXAMPLES 2-6
EXAMPLE 2
[00125] Step 1 : 5-(fe/t-Butyl-diphenyl-silanyloxymethyi)-4-(2,6-dimethyl-morpholin-4-yl)-2,3- difluoro-N-methoxy-N-methyl-benzamide. A solution of 5-(tert-Butyl-diphenyl-silanyloxymethyl)-4-(2,6- dimethyl-morpholin-4-yl)-2,3-difluoro-benzoic acid (10.0 g, 19 mmol) in CH2CI2 (50 mL) at 0 °C was treated with CDI (3.76 g, 23.2 mmol). The solution was stirred for 10 min and Λ/,O-dimethyl- hydroxylamine hydrochloride (2.25 g, 23.2 mmol) was added followed by DIPEA (4.03 mL, 23.2 mmol). The resulting solution was allowed to warm to rt and stirred overnight. CH2CI2 (40 mL) was added and the combined organics were washed with 0.5 N HCI (100 mL), saturated aqueous NaHCO (100 mL) and dried over Na2SO4. Concentration and purification by column chromatography provided the compound (9.90 g) as a colorless oil. 1 H NMR (400 MHz, CDCI3) δ 1.0 (s, 9 H), 1.1 (d, J=6.3 Hz, 6 H) 2.6 (d, J=10.3 Hz, 2 H), 2.8 (m, 2 H), 3.3 (s, 3 H), 3.4 (m, 2 H), 3.6 (s, 3 H), 4.7 (s, 2 H), 7.4 (m, 7 H), 7.6 (m, 4 H); MS (APCI+) m/z 583 (MH+).
[00126] Step 2: 1-[5-(ferf-Butyl-diphenyl-silanyloxymethyl)-4-(2,6-dimethyl-morpholin-4-yl)-2,3- difluoro-phenyl]-ethanone. A solution of 5-(terf-Butyl-diphenyl-silanyloxymethyl)-4-(2,6-dimethyl- morpholin-4-yl)-2,3-difluoro-N-methoxy-N-methyl-benzamide (2.5 g, 4.3 mmol) in THF (20 mL) at rt was treated with methylmagnesium bromide (7.1 mL of a 3.0 M solution in diethyl ether). The reaction was stirred for 15 min, quenched carefully with water (20 mL) and diluted with sat. NH4CI (50 mL). The aqueous was extracted with EtOAc (2 x 50 mL) and the combined organics were dried over Na2SO4 and concentrated to provide the compound (2.28 g) as a colorless oil. 1H NMR (400 MHz, CDCI3) δ 1.1 (m, 15 H), 2.6 (d, J=4.4 Hz, 2 H), 2.7 (d, J=10.7 Hz, 2 H), 2.8 (m, 2 H), 3.5 (m, 2 H), 4.7 (s, 2 H), 7.4 (m, 7 H), 7.6 (m, 3 H), 7.8 (dd, J=7.8, 1.7 Hz, 1 H); MS (APCI+) m/z 538 (MH+).
[00127] Step 3 and Step 4, parts 1 and 2: [2-(2,6-Dimethyl-morpholin-4-yl)-3,4-difluoro-5-
[1 ,2,3]thiadiazol-4-yl-phenyl]-methanol. A solution of 1-[5-(te/?-Butyl-diphenyl-silanyloxymethyl)-4-(2,6- dimethyl-morpholin-4-yl)-2,3-difluoro-phenyl]-ethanone (2.25 g, 4.18 mmol) in EtOH (25 mL) was treated with tosylhydrazide (0.857 g, 4.6 mmol) followed by 1 drop of acetic acid. The solution was heated to reflux for 1.5 h resulting in a thick suspension. The suspension was cooled to rt and filtered. The filter cake was washed with EtOH (2 x 10 ml) and dried to provide a white solid (2.0 g, 2.8 mmol). The white solid (0.50 g, 0.71 mmol) was dissolved in SOCI≥ (5 mL) at rt and stirred for 30 min. The solution was quenched carefully with water (50 mL) and extracted with EtOAc (50 mL). The organics were dried over Na2SO4 and concentrated. The residue was dissolved in HCI (10 mL of a 4M solution in dioxane) and stirred overnight. The solution was diluted with water (75 ml) and extracted with EtOAc (2 x 50 mL). The combined organics were dried over Na2SO4 and concentrated. Purification of the residue by column chromatography provided the compound (0.100 g) as a colorless oil. 1 H NMR (400 MHz, DMSO- d6) δ 1.1 (d, J=6.3 Hz, 6 H), 2.7 (m, 2 H), 3.0 (d, J=10.7 Hz, 2 H), 3.7 (m, 2 H), 4.6 (s, 2 H), 8.1 (d, J=7.3 Hz, 1 H), 9.4 (d, J=2.2 Hz, 1 H); MS (APCI+) m/z 342 (MH+).
[00128] Step 4, part 3: 2-(2,6-Dimethyl-morpholin-4-yl)-3,4-difluoro-5-[1 ,2,3]thiadiazol-4-yl- benzaldehyde. The procedure of Example 10, step 5 was followed to provide the compound (0.088 g) as a yellow oil. 1 H NMR (400 MHz, CDCI3) δ 1.2 (d, J=6.3 Hz, 6 H), 3.1 (d, J=6.3 Hz, 4 H)1 3.9 (m, 2 H), 8.7 (m, 1 H), 8.9 (s, 1 H), 10.3 (s, 1 H); MS (APCI+) m/z340 (MH+).
[00129] Step 5: Compound 2. The procedure of Example 10, step 6 was followed except the reaction mixture was filtered at rt. The filter cake was washed with IPA (2 x 1 mL) providing the compound (0.070 g) as a beige solid, mp: >260 0C; 1 H NMR (400 MHz, DMSO- d6) δ 0.9 (d, J=6.3 Hz, 3 H), 1.1 (d, J=6.1 Hz, 3 H), 2.9 (d, J=14.9 Hz, 1 H), 3.0 (m, 1 H), 3.6 (m, 2 H)1 3.7 (m, 1 H),3.8 (d, J=8.8 Hz, 1 H), 4.0 (m, 1 H), 7.7 (d, J=7.3 Hz, 1 H), 9.2 (d, J=2.0 Hz, 1 H), 11.5 (s, 1 H), 11.8 (s, 1 H); MS (APCI+) m/z 450 (MH+). Anal, calcd for C19Hi7F2N5O4S: C, 50.78; H, 3.81 ; N, 15.58. Found: C, 50.76; H, 3.65; N, 15.22.
EXAMPLES 3 AND 4
[00130] The enantiomers, compounds 3 and 4, were separated by chiral SFC (Chiracel OJ-H, 30
% MeOH, 4 ml_/min). More retained enantiomer: [αD] = -230.0 ° c=5.0, MeOH.
EXAMPLE 5
[00131] Step 1 : Performed as set forth in Step 1 of Example 2.
[00132] Step 2: 1-[5-(tert-Butyl-diphenyl-silanyloxymethyl)-4-(2,6-dimethyl-morpholin-4-yl)-2,3- difluoro-phenyl]-propan-1-one. The Grignard addition procedure of Example 2, step 2 was followed using ethylmagnesium bromide to provide the compound (1.78 g) as a colorless oil. 1 H NMR (400 MHz, CDCI3) δ 1.1 (m, 15 H), 1.2 (m, 3 H), 2.7 (d, JM2.0 Hz, 2 H), 2.8 (m, 1 H), 3.0 (m, 1 H), 3.4 (d, J=7.3 Hz, 2 H), 4.7 (s, 2 H), 7.4 (m, 6 H), 7.6 (dd, J=6.6, 1.5 Hz, 4 H), 7.9 (d, J=7.8 Hz, 1 H); MS (APCI+) m/z 552 (MH+). [00133] Step 3 and Step 4, parts 1 and 2: [2-(2,6-Dimethyl-morpholin-4-yl)-3,4-difluoro-5-(5- methyl-[1 ,2,3]thiadiazol-4-yl)-phenyl]-methanol. The procedure set forth in Example 10, steps 1-4 was followed to provide the compound (0.340 g) as a pale yellow oil. 1 H NMR (400 MHz, DMSO- d6) δ 1.1 (d, J=6.3 Hz, 6 H), 2.6 (d, J=1.2 Hz, 3 H), 2.8 (m, 2 H), 3.0 (d, J=10.7 Hz, 2 H), 3.7 (m, 2 H), 4.6 (s, 2 H), 5.3 (s, 1 H), 7.5 (d, J=6.6 Hz, 1 H); MS (APCI+) m/z 356 (MH+).
[00134] Step 4, part 3: 2-(2,6-Dimethyl-morpholin-4-yl)-3,4-difluoro-5-(5-methyl-[1 ,2,3]thiadiazol-
4-yl)-benzaldehyde. The procedure of Example 10, step 5 was followed to provide the compound (0.280 g) as a yellow solid. 1 H NMR (400 MHz, CDCI3) 5 1.2 (d, J=6.3 Hz, 6 H), 2.6 (d, J=2.2 Hz, 3 H), 3.1 (m, 4 H), 3.9 (m, 2 H), 7.9 (dd, J=7.6, 2.2 Hz, 1 H), 10.3 (s, 1 H); MS (APCI+) m/z 354 (MH+). [00135] Step 5: Compound 5. The procedure of Example 10, step 6 was followed except the reaction mixture was filtered at rt. The filter cake was washed with IPA (2 x 1 mL) providing the compound (0.250 g) as a beige solid, mp: >260 0C; 1 H NMR (400 MHz, DMSO- dβ) δ 0.9 (d, J=6.3 Hz, 3 H), 1.1 (d, J=6.3 Hz, 3 H), 2.5 (s, 3 H), 2.9 (d, JM 4.7 Hz, 1 H), 3.0 (m, 1 H), 3.5 (d, JM4.7 Hz, 1 H), 3.6 (ddd, J=15.0, 6.3, 6.2 Hz, 1 H), 3.8 (ddd, J=10.0, 6.2, 1.8 Hz, 1 H), 3.8 (d, J=8.8 Hz, 1 H), 4.1 (dd, J=13.7, 2.0 Hz, 1 H), 7.0 (d, J=7.3 Hz, 1 H), 11.5 (s, 1 H), 11.8 (s, 1 H); MS (APCl+) m/z 464 (MH+). Anal, calcd for C20H19F2N5O4S: C, 51.83; H, 4.13; N, 15.11. Found: C, 51.95; H, 4.26; N, 14.72.
EXAMPLE 6
[00136] Step 1 : Performed as set forth in Step 1 of Example 2.
[00137] Step 2: 1-[5-(tert-Butyl-diphenyl-silanyloxymethyl)-4-(2,6-dimethyl-morpholin-4-yl)-2,3- difluoro-phenyl]-2-phenyl-ethanone. The Grignard addition procedure of Example 2, step 2 was followed using benzylmagnesium bromide to provide the compound (1.92 g) as a colorless oil. 1H NMR (400 MHz, CDCI3) δ 1.1 (m, 15 H), 2.7 (d, JM 2.0 Hz, 2 H), 2.8 (m, 2 H), 3.4 (m, 2 H), 4.2 (d, J=2.2 Hz, 2 H), 4.6 (s, 2 H), 7.3 (m, 3 H), 7.3 (m, 5 H), 7.4 (m, 2 H), 7.6 (ddd, J=6.4, 1.6, 1.5 Hz, 5 H), 7.9 (dd, J=7.7, 2.1 Hz, 1 H); MS (APCI+) m/2614 (MH+).
[00138] Step 3 and Step 4, parts 1 and 2: [2-(2,6-Dimethyl-morpholin-4-yl)-3,4-difluoro-5-(5- phenyl-[1 ,2,3]thiadiazol-4-yl)-phenyl]-methanol. The procedure set forth in Example 10, steps 1-4 was followed to provide the compound (0.371 g) as a beige solid. 1 H NMR (400 MHz, DMSO- d6) δ 1.1 (d, J=6.3 Hz, 6 H), 2.7 (m, 2 H), 3.0 (d, JM 0.7 Hz, 2 H), 3.7 (m, 2 H), 4.6 (s, 2 H), 5.3 (s, 1 H), 7.4 (m, 2 H), 7.4 (m, 3 H), 7.5 (d, J=7.3 Hz, 1 H); MS (APCI+) m/z418 (MH+).
[00139] Step 4, part 3: 2-(2,6-Dimethyl-moφholin-4-yl)-3,4-difluoro-5-(5-phenyl-[1 ,2,3]thiadiazol-
4-yl)-benzaldehyde. The procedure of Example 10, step 5 was followed to provide the compound (0.300 g) as a yellow solid. 1 H NMR (400 MHz, CDCI3) δ 1.2 (d, J=6.3 Hz, 6 H), 3.1 (m, 4 H), 3.9 (dq, J=12.5, 6.2 Hz, 2 H), 7.3 (m, 2 H), 7.4 (m, 3 H), 7.9 (dd, J=7.4, 2.1 Hz, 1 H), 10.2 (s, 1 H); MS (APCI+) m/z416 (MH+).
[00140] Step 5: Compound 6. The procedure of Example 10, step 6 was followed except the reaction was concentrated and the residue was purified by column chromatography to provide the compound (0.296 g) as a yellow foam. 1 H NMR (400 MHz, DMSO- dβ) δ 0.9 (d, J=6.3 Hz, 3 H), 1.1 (d, J=6.3 Hz, 3 H), 2.9 (d, JM 4.7 Hz, 1 H), 3.0 (m, 1 H), 3.5 (m, 1 H), 3.6 (m, 1 H), 3.7 (m, 1 H), 3.8 (d, J=8.8 Hz, 1 H), 4.0 (m, 1 H), 7.0 (d, J=6.8 Hz, 1 H), 7.3 (m, 2 H), 7.4 (m, 3 H), 11.5 (s, 1 H), 11.8 (s, 1 H); MS (APCI+) m/z 526(MH+). Anal, calcd for C20H19F2N5O4S-O^C4H8O2: C, 56.96; H, 4.36; N, 12.45. Found: C, 57.16; H, 4.32; N, 12.06.
EXAMPLE 7
[00141] Step 1 : [5-(fert-Butyl-diphenyl-silanyloxymethyl)-4-(2,6-dimethyl-morpholin-4-yl)-2,3- difluoro-phenyl]-acetic Acid Methyl Ester. A solution of 5-(fert-Butyl-diphenyl-silanyloxymethyl)-4-(2,6- dimethyl-morpholin-4-yl)-2,3-difluoro-benzoic acid (1.0 g, 1.9 mmol) in CH2CI2 (5 ml_) was treated with 1 drop DMF followed by oxalyl chloride (0.323 ml_, 3.7 mmol). The solution was stirred for 15 min at rt and concentrated. The residue was redissolved in MeCN (5 ml_) and TMS-diazomethane 1.85 ml_ of a 2 M solution) was added. The orange solution was stirred for 1h and poured into EtOAc (50 mL). The organics were washed with 10 % citric acid (50 mL), sat. NaHCO3 (50 mL), brine (50 mL) and dried over Na2SO4. The solution was concentrated and the residue was redissolved in MeOH (20 mL). A slurry of silver acetate (0.077 g, 0.463 mmol) in triethylamine (1 mL) was added while sonicating the MeOH solution.. The black solution was allowed to sonicate 5 min. The solution was concentrated and redissolved in EtOAc (50 mL). The organics were washed with sat NaHCO3 (50 mL), 10 % citric acid (50 mL), brine (50 mL) and dried over Na2 SO4. Concentration and purification by column chromatography provided the compound (0.670 g) as a pale yellow oil. 1 H NMR (400 MHz, CDCI3) δ 1.1 (m, 15 H), 2.6 (dd, J=11.8, 1.9 Hz, 2 H), 2.8 (m, 2 H), 3.5 (m, 2 H), 3.7 (d, J=1.0 Hz, 2 H), 3.7 (s, 3 H), 4.7 (s, 2 H), 7.2 (dd, J=7.7, 1.7 Hz, 1 H), 7.4 (m, 6 H), 7.6 (m, 4 H); MS (APCI+) m/z 568 (MH+).
[00142] Step 2, part 1 : 2-[5-(tert-Butyl-diphenyl-silanyloxymethyl)-4-(2,6-dimethyl-morpholin-4-yl)-
2,3-difluoro-phenyl]-ethanol. A solution of [5-(fert-butyl-diphenyl-silanyloxymethyl)-4-(2,6-dimethyl- morpholin-4-yl)-2,3-difluoro-phenyl]-acetic acid methyl ester (4.5 g, 7.9 mmol) in THF (50 ml.) at 0 0C was treated with LAH (7.9 ml_ of a 1M solution in THF). The reaction was allowed to warm to rt over 30 min and carefully quenched with sat. Na2SO4. The mixture was diluted with EtOAc (100 mL), dried over solid Na2SO4 and filtered. Concentration provided the compound (4.0 g) as a colorless oil. 1 H NMR (400 MHz, CDCI3) δ 1.1 (m, 15 H), 2.6 (d, JM 1.9 Hz, 2 H), 2.8 (m, 2 H), 2.9 (t, J=6.5 Hz, 2 H), 3.5 (m, 2 H), 3.8 (t, J=6.6 Hz, 2 H), 4.7 (s, 2 H), 7.1 (d, J=7.4 Hz, 1 H), 7.4 (m, 6 H), 7.7 (m, 4 H); MS (APCI+) m/z 540 (MH+). [00143] Step 2, part 2: [5-(terf-Butyl-diphenyl-silanyloxymethyl)-4-(2,6-dimethyl-morpholin-4-yI)-
2,3-difluoro-phenyl]-acetaldehyde. A solution of 2-[5-(te/t-butyl-diphenyl-silanyloxymethyl)-4-(2,6- dimethyl-morpholin-4-yl)-2,3-difluoro-phenyl]-ethanol (0.650 g, 1.20 mmol) in CH2CI2 (10 mL) at rt was treated with Dess-Martin periodinane (0.562 g, 1.32 mmol). The reaction was allowed to stir for 20 h and diluted with CH2CI2 (25 mL). The organics were washed with sat. NaHCO3. (25 mL), dried over Na2SO4 and concentrated. The residue was triturated with 1 :2 EtOAc/hexanes and filtered. The filtrates were concentrated to a residue that was purified by column chromatography to provide the compound (0.40 g) as a colorless oil. 1 H NMR (400 MHz, CDCI3) δ 1.1 (m, 15 H), 2.6 (d, J=12.1 Hz, 2 H), 2.8 (t, J=10.9 Hz, 2 H), 3.4 (dd, J=7.9, 6.3 Hz, 2 H), 3.7 (d, J=1.2 Hz, 2 H), 4.7 (s, 2 H), 7.1 (d, J=7.4 Hz, 1 H), 7.4 (m, 6 H), 7.6 (m, 4 H), 9.7 (m, 1 H); MS (APCI+) m/z 538Step 5, part 1 : (MH+).
[00144] Steps 3 and 4: [2-(2,6-Dimethyl-morpholin-4-yl)-3,4-difluoro-5-[1 ,2,3]thiadiazol-5-yl- phenyl]-methanol. A solution of [5-(fert-Butyl-diphenyl-silanyloxymethyl)-4-(2,6-dimethyl-morpholin-4-yl)- 2,3-difluoro-phenyl]-acetaldehyde (0.375 g, 0.70 mmol) in CH2CI2 (5 mL) at -78 0C was treated with tosyl hydrazide (0.130 g, 0.70 mmol). The reaction was allowed to warm to rt and concentrated. The residue was redissolve in SOCI2 (4 mL) and stirred for 5 min. The solution was carefully poured into water and extracted with EtOAc (30 mL). The organics were concentrated and redissolved in HCI (10 mL of a 4M solution in dioxane). The solution was stirred overnight at rt, diluted with water (30 mL) and extracted with EtOAc (2 x 25 mL). The organics were dried over Na2SO4 and concentrated to a residue that was purified by column chromatography to provide the compound (0.140 g) as a yellow oil. 1 H NMR (400 MHz, CDCI3) δ 1.2 (d, J=6.3 Hz, 6 H), 2.9 (d, J=2.1 Hz, 2 H), 3.0 (m, 2 H), 3.8 (m, 2 H), 4.8 (s, 2 H), 7.4 (dd, J=7.4, 2.1 Hz, 1 H), 9.0 (s, 1 H); MS (APCI+) m/z 342 (MH+).
[00145] Step 5, part 1 : 2-(2,6-Dimethyl-morpholin-4-yl)-3,4-difluoro-5-[1 ,2,3]thiadiazol-5-yl- benzaldehyde. The procedure of Example 10, step 5 was followed except the residue following the filtration was purified by column chromatography to provide the compound (0.100 g) as an oil. 1 H NMR (400 MHz, CDCI3) δ 1.2 (d, J=6.3 Hz, 6 H), 3.1 (d, J=6.4 Hz, 4 H), 3.8 (m, 2 H), 7.9 (m, 1 H), 9.1 (s, 1 H), 10.2 (d, J=2.0 Hz, 1 H); MS (APCI+) m/z 340 (MH+).
[00146] Step 5, part 2: Compound 7. The procedure of Example 10, step 6 was followed to provide the compound (0.085 g) as a brown solid.1H NMR (400 MHz, DMSO- d6) δ 0.9 (d, J=6.4 Hz, 3 H), 1.1 (d, J=6.1 Hz, 3 H), 2.9 (d, J=14.5 Hz, 1 H), 3.0 (s, 1 H), 3.4 (d, J=14.5 Hz, 1 H), 3.6 (dd, J=8.7, 6.3 Hz, 1 H), 3.7 (s, 1 H), 3.9 (d, J=8.8 Hz, 1 H), 4.0 (d, J=13.7 Hz, 1 H), 7.4 (d, J=7.2 Hz, 1 H), 9.2 (s, 1 H), 11.5 (s, 1 H)1 11.9 (s, 1 H); MS (APCI+) m/z 450 (MH+). Anal, calcd for
C19H17F2N5O4SCeI C2H3NO-IC3H8O-CI S H2O: C1 51.01 ; H1 4.16; N1 16.26. Found: C, 50.67; H, 3.82; N1 16.21.
EXAMPLE 8
I) DMF-DMA Step 3 2) pyr/EtOH
H2NOSO3H
acid
[00147] Step 1: Preparation of 5-(ferf-Butyl-diphenyl-silanyloxymethyl)-4-(2,6-dimethyl-morpholin-
4-yl)-2,3-difluorobenzamide. A solution of 5-(tert-Butyl-diphenyl-silanyloxymethyl)-4-(2,6-dimethyl- morpholin-4-yl)-2,3-difluoro-benzoic acid (4.0 g, 7.4 mmol) in THF (13 mL) was treated with CDI (1.4 g, 8.9 mmol). The solution was stirred for one hour and confirmed to be complete by the TLC of a quenched aliquot into NaOMe in MeOH. Ammonium hydroxide (10 mL, 74 mmol) was added and the resulting solution stirred at room temperature overnight. The reaction was quenched with saturated aqueous NaHCO3 and extracted with EtOAc (2x). The combined organic layers were washed with brine, dried through Na2SO4 and concentrated by rotoevaporation to provide the title compound (4.06 g) as a solid. 1 H NMR (400 MHz, CDCI3) d ppm 1.04 (d, J=5.6 Hz, 15 H)1 2.7 (d, J=11.5 Hz1 2 H), 2.8 (m, 2 H), 3.4 (dd, J=7.4, 6.5 Hz1 2 H)1 4.6 (s, 2 H)1 5.9 (s, 1 H)1 6.5 (s, 1 H), 7.4 (m, 6 H)1 7.6 (dd, J=6.6, 1.2 Hz1 4 H)1 8.0 (d, J=8.3 Hz1 1 H); MS (APCI+) m/z 539 (MH+).
[00148] Step 2: Preparation of 5-(terf-Butyl-diphenyl-silanyloxymethyl)-4-(2,6-dimethyl-morpholin-
4-yl)-2,3-difluorobenzenecarbothioamide. A solution of 5-(tert-butyl-diphenyl-silanyloxymethyl)-4-(2,6- dimethyl-morpholin-4-yl)-2,3-difluorobenzamide (3.0 g, 5.6 mmol) in toluene (50 mL) was treated with NaHCO3 (1.4 g, 17 mmol) and Lawesson's reagent (2.7 g, 6.7 mmol). The mixture was heated at reflux for 1.5 hrs., cooled to room temperature, filtered to remove solids and rinsed with toluene. The filtrate was concentrated by rotoevaporation to give crude solids. Purification of the residue by column chromatography provided the title compound (0.89 g) and the 8-nitrile by-product (1.95 g) as solids. 1 H NMR (400 MHz, CDCI3) of the title compound - d ppm 1.04 (m, 15 H)1 2.69 (d, J=10.50 Hz1 2 H)1 2.78 (m, 2 H), 3.45 (m, 2 H), 4.64 (s, 2 H)1 7.37 (m, 6 H)1 7.60 (m, 1 H)1 7.64 (m, 4 H), 7.81 (m, 1 H)1 8.35 (dd, J=9.03, 1.22 Hz, 1 H); 13C NMR (101 MHz1 CDCI3) d ppm 18.84, 19.43, 27.04, 32.07, 56.84, 56.88, 61.78, 72.47, 76.88, 77.20, 77.52, 127.91 , 127.96, 128.40, 128.43, 130.02, 133.34, 135.81 , 216.70; MS (APCI+) m/z 555 (MH+). [00149] Step 3: 4-(6-(tert-Buty!-diphenyl-silyloxymethyl)-2,3-difluoro-4-(3-methyI-1 ,2,4-thiadiazol-
5-yl)phenyl]-2,6-dimethylmorpholine. 5-(fert-butyl-diphenyl-silanyloxymethyl)-4-(2,6-dimethyl-morpholin-4- yl)-2,3-difluorobenzenecarbothioamide (0.4 g, 0.72 mmol) was dissolved in dimethylacetamide- dimethylacetal (0.8 ml_, 5.5 mmol) and stirred at room temperature for one hour. An aliquot of the reaction mixture had an OAMS (+) = 624, good for the dimethylamine intermediate. The reaction was concentrated using high vacuum on the rotoevaporator. The colored residue was dissolved in EtOH (1.8 ml). Pyridine (0.12 ml) and hydroxylamine sulfonic acid (90 mg) were added and the resulting mixture was stirred at room temperature overnight. The reaction was quenched with saturated aqueous NaHCO3 and extracted with EtOAc (2x). The combined organic layers were washed with brine, dried through Na2SO4 and concentrated by rotoevaporation. Purification of the residue by column chromatography provided the compound (0.35 g) as a solid. 1H NMR (400 MHz, CDCI3) δ ppm 1.07 (m, 15 H) 2.71 (m, 5 H) 2.81 (m, 2 H) 3.46 (dd, J=7.69, 6.47 Hz, 2 H) 4.72 (s, 2 H) 7.38 (m, 6 H) 7.65 (m, 4 H) 8.23 (d, J=7.08 Hz, 1 H); 13C NMR (101 MHz, CDCI3) δ ppm 14.30, 18.86, 19.01 , 19.48, 22.88, 27.05, 29.21 , 32.07, 56.94, 56.97, 61.84, 72.49, 76.88, 77.20, 77.52, 122.13, 127.95, 127.98, 130.03, 133.40, 135.81 , 147.26, 172.89; MS (APCI+) m/z 594 (MH+).
[00150] Step 4, parts 1 and 2: Preparation of 2-(2,6-Dimethylmorpholin-4-yI)-3,4-difIuoro-5-(3- methyl-1 ,2,4-thiadiazol-5-yl)benzaldehyde. A solution of 4-(6-(tert-butyl-diphenyl-silyloxymethyl)-2,3- difluoro-4-(3-methyl-1 ,2,4-thiadiazoi-5-yl)phenyl]-2,6-dimethylmorpholine (0.35 g, 0.59 mmol) in MeOH (1 ml) was treated with 4M HCI in dioxane (2 ml) and stirred at room temperature for 3 hours. TLC analysis shows no starting material. The reaction was quenched with saturated aqueous NaHCO3 solution and extracted with EtOAc (2x). The combined organic layers were washed with brine, dried through Na2SO4 and concentrated by rotoevaporation. A solution of the resulting product in CH2CI2 (5 ml) and CH3CN (5 ml) was treated with NMO (0.11 g, 0.88 mmol), 4 angstrom powdered molecular sieves (0.32 g) and TPAP (21 mg, 0.06 mmol). The mixture was stirred for 30 min at room temperature. TLC analysis of the reaction shows no starting material remaining. The reaction mixture was filtered through a pad of SiO2, rinsed with 50% EtOAc/heptane and concentrated by rotoevaporation. Purification of the residue by column chromatography provided the compound (0.15 g) as a solid. 1H NMR (400 MHz, CDCI3) δ ppm 1.18 (d, J=6.10 Hz, 6 H) 2.70 (s, 3 H) 3.10 (m, 4 H) 3.84 (m, 2 H) 8.48 (dd, J=7.69, 2.07 Hz, 1 H) 10.13 (s, 1 H); 13C NMR (101 MHz, CDCI3) δ ppm 18.80, 18.94, 58.59, 58.64, 72.33, 76.88, 77.19, 77.40, 77.51 , 126.28, 126.32, 126.35, 173.00, 188.43, 188.46; MS (APCI+) m/z 354 (MH+).
[00151] Step 4, part 3: Compound 8. A solution of 2-(2,6-dimethylmorpholin-4-yl)-3,4-difluoro-5-
(3-methyl-1 ,2,4-thiadiazol-5-yl)benzaldehyde (0.15 g, 0.42 mmol) in MeOH (5 ml) was treated with barbituric acid (57 mg, 0.45 mmol) and subjected to microwaves for 20 minutes. The reaction was concentrated by rotoevaporation and purified by column chromatography to provide the title compound with diastereomer determined by NMR. A solution of this product in MeOH (4 ml) was resubjected to microwaves for 20 minutes. The reaction was concentrated to give the title compound as a solid (106 mg). 1H NMR (400 MHz, DMSO-d6) d ppm 0.84 (m, 3 H) 1.06 (m, 3 H) 2.58 (m, 3 H) 2.83 (d, J=14.64 Hz, 1 H) 2.99 (m, 1 H) 3.58 (m, 2 H) 3.72 (m, 1 H) 3.86 (t, J=8.05 Hz, 1 H) 4.06 (dd, J=13.55, 1.59 Hz, 1 H) 7.59 (d, J=7.32 Hz, 1 H) 11.63 (m, 2 H); 13C NMR (101 MHz, CDCI3) d ppm 18.28, 18.52, 18.73, 22.80, 27.00, 39.35, 48.78, 48.99, 49.21 , 49.43, 49.45, 49.64, 49.85, 50.06, 53.21 , 56.46, 56.57, 64.61 , 65.05, 65.93, 67.54, 72.35, 72.85, 76.84, 76.93, 77.16, 77.24, 77.45, 77.56, 108.08, 108.19, 121.03, 137.66, 149.23, 167.23, 170.60, 171.55; MS (APCI+) m/z 464 (MH+). Anal. Calcd for C20H19F2N5O4S 0.2 C4H10O 0.03 C7H16: C, 52.43; H, 4.50; N, 14.55. Found: C, 52.68; H, 4.20; N, 14.25.
EXAMPLE 9
I) DMA-DMA Step 3 2) pyr/EtOH
H2NOSO3H
acid
[00152] Steps 1 and 2 were performed as set forth in Example 8, steps 1 and 2.
[00153] Step 3: 4-(6-(tert-Butyl-diphenyl-silyloxymethyl)-2,3-difluoro-4-(1 ,2,4-thiadiazol-5- yl)phenyl]-2,6-dimethylmorpholine. The same procedure as above was followed except dimethyl acetamide-dimethylacetal (0.2 ml, 1.5 mmol) was added instead of DMF-DMA and provided the compound (0.344 g) as a solid. 1H NMR (400 MHz, CDCI3) δ ppm 1.06 (m, 15 H) 2.75 (m, 4 H) 3.40 (m, 2 H) 4.71 (s, 2 H) 7.40 (m, 6 H) 7.62 (m, 4 H) 8.29 (dd, J=7.44, 2.07 Hz, 1 H) 8.74 (m, 1 H); 13C NMR (101 MHz, CDCI3) δ ppm 18.77, 18.86, 19.41 , 19.45, 22.88, 27.01 , 27.05, 32.07, 56.91 , 56.94, 61.82, 72.47, 76.88, 77.19, 77.51 , 121.94, 127.96, 128.06, 130.06, 130.26, 132.94, 133.33, 135.69, 135.78, 162.30; MS (APCI+) m/z 580 (MH+).
[00154] Step 4, parts 1 and 2: Preparation of 2-(2,6-Dimethylmorpholin-4-yl)-3,4-difluoro-5-(1 ,2,4- thiadiazol-5-yl)benzaldehyde. A solution of 4-(6-(tert-butyl-diphenyI-silyloxymethyl)-2,3-difluoro-4-(1 ,2,4- thiadiazol-5-yl)phenyl]-2,6-dimethylmorpholine (0.26 g, 0.45 mmol) in MeOH (1 ml) was treated with 4M HCI in dioxane (2 ml) and stirred at room temperature for 3 hours. TLC analysis shows no starting material. The reaction was quenched with saturated aqueous NaHCO3 solution and extracted with EtOAc (2x). The combined organic layers were washed with brine, dried through Na2SO4 and concentrated by rotoevaporation. A solution of the resulting product in CH2CI2 (4 ml) and CH3CN (4 ml) was treated with NMO (81 mg, 0.67 mmol), 4 angstrom powdered molecular sieves (0.24 g) and TPAP (16 mg, 0.04 mmol). The mixture was stirred for 30 min at room temperature. TLC analysis of the reaction shows no starting material remaining. The reaction mixture was filtered through a pad of SiO2, rinsed with 50% EtOAc/heptane and concentrated by rotoevaporation. Purification of the residue by column chromatography provided the compound (0.11 g) as a solid. 1H NMR (400 MHz, CDCI3) δ ppm 1.19 (d, J=6.10 Hz, 6 H) 3.11 (m, 4 H) 3.84 (m, 2 H) 8.51 (d, J=7.57 Hz, 1 H) 8.72 (d, J=1.95 Hz, 1 H) 10.13 (s, 1 H); 13C NMR (101 MHz, CDCI3) δ ppm 18.79, 58.61 , 58.65, 72.32, 76.88, 77.20, 77.51 , 126.34, 126.37, 126.41 , 162.27, 188.32; MS (APCI+) m/z 340 (MH+). [00155] Step 4, part 3: Compound 9. A solution of 2-(2,6-dimethylmorpholin-4-yl)-3,4-difluoro-5-
(1 ,2,4-thiadiazol-5-yl)benzaIdehyde (0.11 g, 0.32 mmol) in IPA (10 ml) was treated with barbituric acid (44 mg, 0.34 mmol) and refluxed overnight. The reaction was concentrated by rotoevaporation and purified by column chromatography to provide the compound as a solid (89 mg). 1H NMR (400 MHz, DMSO-d6) d ppm 0.88 (m, 3 H) 1.08 (d, J=6.10 Hz, 3 H) 2.85 (d, J=14.64 Hz, 1 H) 3.05 (m, 1 H) 3.60 (m, 2 H) 3.73 (m, 1 H) 3.87 (d, J=8.79 Hz, 1 H) 4.07 (dd, J=13.67, 1.95 Hz, 1 H) 7.62 (d, J=7.08 Hz, 1 H) 8.84 (m, 1 H) 11.59 (m, 2 H); 13C NMR (101 MHz, DMSO-c/6) d ppm 18.75, 19.02, 38.10, 39.54, 39.75, 39.96, 40.17, 40.37, 40.59, 40.79, 52.76, 64.71 , 72.28, 72.95, 107.48, 150.09, 163.15, 168.26, 171.45; MS (APCI+) m/z 450 (MH+). Anal. Calcd for C19H17F2N5O4S 0.2 C4H10O 0.27 CH2Cl2: C, 49.00; H, 3.74; N, 14.83. Found: C, 49.11 ; H, 3.60; N, 14.86.
SYNTHETIC SCHEME FOR EXAMPLES 10-14
EXAMPLE 10
[00156] Step 1. 5-(terf-Butyl-diphenyl-silanyloxymethyl)-4-(2,6-dimethyl-morpholin-4-yl)-2,3- difluoro-benzoylj-hydrazinecarboxylic Acid terf-Butyl Ester. A suspension of 5-(tert-Butyl-diphenyl- silanyloxymethyl)-4-(2,6-dimethyl-morpholin-4-yl)-2,3-difluoro-benzoic acid (5.0 g, 9.2 mmol) in DMF (15 mL) was treated with triethylamine (1.55 mL, 11.12 mmol) and HATU (4.2 g, 11.0 mmol). The resulting solution was stirred for 15 min, terf-Butyl carbazate (1.0 g, 9.0 mmol) was added the solution was stirred overnight. The reaction was poured into water (200 mL) and the aqueous was extracted with EtOAc (3x100 ml). The combined organics were dried over Na2SO4 and concentrated. Purification of the residue by column chromatography provided the compound (4.20 g) as an oil. 1H NMR (400 MHz, DMSO-c/6) δ 0.9 (d, J=6.1 Hz, 6 H), 1.0 (s, 9 H), 1.3 (s, 3 H), 1.4 (s, 6 H), 2.6 (d, JM 0.0 Hz, 2 H), 2.7 (m, 2 H), 3.3 (s, 2 H), 4.7 (s, 2 H), 7.4 (m, 6 H), 7.6 (m, 5 H); MS (APCI+) m/z 654 (MH+). [00157] Step 2. δ-Ctørt-Butyl-diphenyl-silanyloxymethylJ-ΦCa.θ-climethyl-morpholin-ΦyO-a.S- dif!uoro-thiobenzoyl]-hydrazinecarboxylic Acid ferf-Butyl Ester. A suspension of 5-(ferf-butyl-diphenyl- silanyloxymethyl)-4-(2,6-dimethyl-morpholin-4-yl)-2,3-difluoro-benzoyl]-hydrazineGarboxylic acid ferf-butyl ester (0.5 g, 0.76 mmo!), sodium bicarbonate (0.19g, 2.29 mmol), and Lawesson's reagent (0.371 g, 0.92 mmol) in toluene (8 mL) was heated to reflux for 1.5 h and cooled the rt. The suspension was filtered and the filtrates were concentrated. Purification of the residue by column chromatography provided the compound (0.47 g) as a green oil. 1 H NMR (400 MHz, DMSO- Cf6) δ 0.9 (m, 6 H), 1.0 (m, 9H), 1.4 (s, 9 H), 2.6 (m, 3 H), 3.3 (s, 3 H), 4.7 (s, 2 H), 7.4 (m, 6 H), 7.6 (m, 5 H); MS (APCI+) m/z670 (MH+). [00158] Step 3. 4-(2,6-Dimethyl-morpholin-4-yl)-2,3-difluoro-5-hydroxymethyl-thiobenzoic Acid
Hydrazide Hydrochloride. 5-(fert-Butyl-diphenyl-silanyloxymethyl)-4-(2,6-dimethyl-morpholin-4-yl)-2,3- difluoro-thiobenzoyl]-hydrazinecarboxylic acid ferf-butyl ester (10.0 g, 15 mmol) was treated with HCI (80 mL of a 4 M solution in dioxane) and the resulting solution was stirred for 4h at rt resulting in a yellow precipitate. Hexane (40 mL) was added dropwise and the slurry was filtered and the solids dried under vacuum to afforded the compound (3.8 g) as a pale yellow solid. 1 H NMR (400 MHz, DMSO- Of6) δ 1.0 (d, J=6.3 Hz, 6 H), 2.7 (m, 2 H), 2.9 (d, J=10.5 Hz, 2 H), 3.6 (m, 2 H), 4.5 (s, 2 H), 7.4 (d, J=7.3 Hz, 1 H); MS (APCI+) m/z 332 (MH+).
[00159] Step 4. [2-(2,6-Dimethyl-morpholin-4-yl)-3,4-difluoro-5-(5-methyl-[1 ,3,4]thiadiazol-2-yl)- phenyl]-methanol. A solution of 4-(2,6-Dimethyl-morpholin-4-yl)-2,3-difluoro-5-hydroxymethyl-thiobenzoic acid hydrazide hydrochloride (0.80 g, 2.2 mmol) in THF (20 mL) at rt was treated with diisopropylethylamine (1.14 mL, 6.5 mmol) followed by acetyl choride (0.23 mL, 3.26 mmol). The reaction was stirred for 1 h and cone. HCI (3 mL) was added. The reaction was stirred for an additional 30 min and diluted with water (50 mL). The aqueous was extracted with EtOAc (50 mL) and the combined organics were dried over Na2SO4. Concentration and purification of the residue by column chromatography provided the compound (0.59 g) as a white foam. 1 H NMR (400 MHz, DMSO- Of6) δ 1.1 (d, J=6.3 Hz, 6 H), 2.7 (m, 2 H), 2.8 (s, 3 H), 3.0 (d, JM 1.0 Hz, 2 H), 3.7 (dd, J=13.8, 6.5 Hz, 2 H), 4.6 (d, J=5.6 Hz, 2 H), 5.4 (t, J=5.6 Hz, 1 H), 8.1 (d, J=7.6 Hz, 1 H); MS (APCI+) m/z 356 (MH+). [00160] Step 5. 2-(2,6-Dimethyl-morpholin-4-yl)-3,4-difluoro-5-(5-methyl-[1 ,3,4]thiadiazol-2-yl)- benzaldehyde. A mixture of [2-(2,6-Dimethyl-morpholin-4-yl)-3,4-difluoro-5-(5-methyl-[1 ,3,4]thiadiazol-2- yl)-phenyl]-methanol (0.140 g, 0.39 mmol), NMO (0.069 g, 0.59 mmol) and powered sieves (0.25 g) in 1 :1 MeCN/CH2CI2 (5 mL) was added TPAP (0.014 g, 0.039 mmol). The dark solution was stirred for 15 min and loaded on to a pad of silica. The silica pad was washed with EtOAc (3 x 25 mL) and the filtrate was concentrated to provide the compound (0.120) as a yellow solid. 1 H NMR (400 MHz, CDCI3) δ 1.2 (d, J=6.3 Hz, 6 H), 2.8 (s, 3 H), 3.1 (m, 4 H), 3.9 (m, 2 H), 8.5 (m, 1 H), 10.2 (s, 1 H); MS (APCI+) m/z 354 (MH+).
[00161] Step 6. Compound 10. A stirring slurry of 2-(2,6-Dimethyl-morpholin-4-yl)-3,4-difluoro-5-
(5-methyl-[1 ,3,4]thiadiazol-2-yl)-benzaldehyde (0.111 g, 0.314 mmol) in IPA (10 mL) was treated with barbituric acid (0.050 g, 0.314 mmol). The reaction was heated to 80 °C overnight and cooled to rt. The solution was concentrated to a residue that was crystallized from MeCN (2 mL) to provide the compound (0.085 g) as a pale yellow solid, mp: >260 0C; 1 H NMR (400 MHz, DMSO- d6) δ 0.9 (d, J=6.1 Hz, 3 H), 1.1 (d, J=6.1 Hz, 3 H), 2.7 (s, 3 H), 2.9 (d, J=14.4 Hz, 1 H), 3.0 (s, 1 H), 3.6 (d, J=14.7 Hz, 2 H), 3.7 (s, 1 H), 3.9 (d, J=8.8 Hz, 1 H), 4.1 (d, J=12.0 Hz, 1 H), 7.6 (d, J=6.8 Hz, 1 H), 11.5 (s, 1 H), 11.8 (s, 1 H); MS (APCI+) m/z 464 (MH+). Anal, calcd for C20H19F2N5O4S: C, 51.83; H, 4.13; N, 15.11. Found: C, 51.47; H, 4.01 ; N, 14.95. The enantiomers were separated by chiral SFC (Whelko, 15 % MeOH, 4 mL/min). Less retained enantiomer: [αD] = -267.0 ° c=5.0, MeOH.
EXAMPLE 1O A
[00162] Step 1 : Preparation of 2-(2,6-Dimethyl-morpholin-4-yl)-3,4-difluoro-benzoic acid. A stirred solution of 2,3,4-trifluorobenzoic acid (Aldrich, 890 g, 5.05 mol) in tetrahydrofuran (5 L) was cooled to - 78°C. A 1 M solution of lithium bis(trimethylsilyl)amide in tetrahydrofuran (5.56 L) was added dropwise to the reaction at such a rate that the reaction temperature did not rise above -65°C. Stirring was continued at -78°C for 45 min. In a second flask, cis-2,6-dimethylmorpholine (623 mL, 5.05 mol) was stirred in tetrahydrofuran (2.5 L) and cooled to -780C. A 1 M solution of lithium bis(trimethylsilyl)amide in tetrahydrofuran (5.56 L, 5.56 mol) was added dropwise to the reaction at such a rate that the reaction temperature did not rise above -65°C. Stirring was continued at -78°C for 45 min. The contents of the second flask were cannulated directly into the first flask and stirring was continued at -78°C for 1 hr. The reaction was allowed to warm to room temperature overnight. The solvent was removed by evaporation and the residue poured into 2 N hydrochloric acid (10 L), and extracted three times with ethyl acetate (3x4 L). The combined organic extracts were washed with brine (3 L), dried over sodium sulfate and evaporated to give 1270 g of 2-(2,6-Dimethyl-morpholin-4-yl)-3,4-difluoro-benzoic acid as a tan solid. [00163] Step 2: Preparation of 4-[6-(tert-Butyl-diphenyl-silanyloxymethyl)-2,3-difluoro-phenyl]-2,6- dimethyl-morpholine. In a 12 L, 4-neck flask under N2, A solution of 2-(2,6-Dimethyl-morpholin-4-yl)-3,4- difluoro-benzoic acid (274 g, 1.24 mol) in tetrahydrofuran (1.6 L) was cooled to O0C, and anhydrous sodium borohydride (170 g, 4.5 mol) was added portionwise to reduce foaming. Iodine (465 g, 1.83 mol) was dissolved in tetrahydrofuran (3.5L) and added slowly to the solution to prevent the reaction temperature from rising above 1O0C. The solution was refluxed for 18 hours after the iodine addition was complete. The reaction was cooled and methanol (1.5L) was added dropwise to prevent the reaction temperature from rising above 3O0C. The solvent was then removed from the reaction in vacuo. The residue was stirred in 2N sodium hydroxide (6L) for 2 hours. The aqueous phase was extracted with ethyl acetate (3x, 2L). The organic phases were combined, dried over sodium sulfate, and the solvent was removed in vacuo (temperature less than 4O0C). This gave 302g of the product alcohol as a thick colorless oil. Two batches of the alcohol were combined (500 g, 2.08 mol) and dissolved in dichloromethane (5L). Imidazole (145g, 2.18 mol) was added and the reaction mixture was cooled to 0°C. t-Butyl chlorodiphenylsilane (537 ml, 2.10 mol) was added dropwise to the reaction so that the temperature never rose above 100C. The reaction was allowed to stir at room temperature for 72 hours. Additional dichloromethane (2L) was added and the reaction was poured into 1 N HCI (4L). The layers were separated, and the organic phase was washed with saturated sodium bicarbonate (2L). The organic phase was dried over sodium sulfate and the solvent removed in vacuo. The material was combined with a previous batch and dry loaded onto silica gel, and chromatographed using 0-5% ethyl acetate in heptane to give 1.46 kg of 4-[6-(tert-Butyl-diphenyl-silanyloxymethyl)-2,3-difluoro-phenyl]-2,6-dimethyl- morpholine as a white solid.
[00164] Step 3: Preparation of 5-(tert-Butyl-diphenyl-silanyloxymethyl)-4-(2,6-dimethyl-morpholin-
4-yl)-2,3-difluoro-benzoic acid. A solution of 4-[6-(tert-Butyl-diphenyl-silanyloxymethyl)-2,3-difluoro- phenyl]-2,6-dimethyl-morpholine (231.5g, 0.46 mol) in tetrahydrofuran (2.6L) was cooled to -78°C. 1.4M sec-Butyl lithium (400 ml, 0.56 mol) was added dropwise so that the temperature remained below -7O0C. After the addition was complete the reaction was stirred for an additional 30 minutes at -78°C (D2O quench of an aliquot showed complete deprotonation of starting material). Carbon dioxide gas was bubbled through the orange solution for 30 minutes and the temperature rose to -55°C before it began to fall again. After the CO2 addition was complete the reaction was warmed to room temperature and water (500 ml) was slowly added to the reaction. Most of the solvent was removed in vacuo and additional water (1 L) was added. The solution was acidified to pH~2 with 2N HCI, and the aqueous phase was extracted with ethyl acetate (3x, 1 L) (make sure all solids dissolve). The organic phases were dried over sodium sulfate, and the solvent removed in vacuo. Heptane (1 L) was added to the oil, and the solution was allowed to sit for 18 hours. The solid was filtered off and washed with additional heptane to give 199.5g of 5-(tert-Butyl-diphenyl-silanyloxymethyl)-4-(2,6-dimethyl-morpholin-4-yl)-2,3-difluoro-benzoic acid as a white solid.
[00165] Steps 4 and 5: A solution of 5-(terf-Butyl-diphenyl-silanyloxymethyl)-4-(2,6-dimethyl- morpholin-4-y!)-2,3-difluoro-benzoic acid (20.0 g, 37 mmol) in CH2CI2 (100 mL) was treated with carbonyldiimidazole (7.2 g, 44 mmol). The resulting solution was stirred for 30 min, acetic hydrazide (3.3 g, 44 mmol) was added followed by diisopropylethylamine (5.7 g, 44 mmol) and the solution was stirred at rt for 5h. The reaction was poured into sat. NH4CI (200 mL) and the aqueous was extracted with CH2CI2 (100 ml). The combined organics were dried over Na2SO4 and concentrated. The residue was combined with phosphorous pentasulfide (8.23g, 18.5 mmol) and hexamethyldisiloxane (13.2 mL, 62.0 mmol) in toluene (150 mL). The mixture was heated to reflux for 1.5 h and cooled to rt. The solution was diluted with acetone (150 mL). 5.3 M K2Cθ3 (18.2 mL ) was carefully added and the solution was stirred for 20 min and concentrated. The solution was diluted with water (100 mL) and extracted with CH2CI2 (3 x 100 mL). The combined organics were dried over Na2SO4 and concentrated. The residue was treated with HCI (50 mL of a 4M solution in dioxane) and stirred overnight. The solution was diluted with water (150 mL) and extracted with EtOAc (2 x 200 mL). The combined organics were dried over Na2SO4. Concentration and purification of the residue by column chromatography provided [2-(2,6-Dimethyl- morpholin-4-yl)-3,4-difluoro-5-(5-methyl-[1 ,3,4]thiadiazol-2-yl)-phenyl]-methanol (7.77 g) as a white foam. 1 H NMR (400 MHz, DMSO- dβ) δ 1.1 (d, J=6.3 Hz, 6 H), 2.7 (m, 2 H)1 2.8 (s, 3 H), 3.0 (d, Jt=I LO Hz, 2 H), 3.7 (dd, J=13.8, 6.5 Hz, 2 H), 4.6 (d, J=5.6 Hz, 2 H), 5.4 (t, J=5.6 Hz, 1 H), 8.1 (d, J=7.6 Hz, 1 H); MS (APCI+) m/z 356 (MH+).
[00166] Steps 6 and 7:Compound 10 was obtained by processing the [2-(2,6-Dimethyl-morpholin-
4-yl)-3,4-difluoro-5-(5-methyl-[1 ,3,4]thiadiazol-2-yl)-phenyl]-methanol according to steps 5 and 6, respectively in Example 10 above.
EXAMPLE 10 B
[00167] Alternate synthesis for 2-(2,6-Dimethyl-morpholin-4-yl)-3,4-difluoro-5-(5-methyl-
[1 ,3,4]thiadiazo!-2-yl)-benzaldehyde.
Step 2
[00168] Step i : 2-Bromo-3,4,5-trifluorobenzaldehyde. A 3-L 4-neck flask was dried by heating with a hot air gun to 94-95 °C. After cooling to room temperature, 74.48 g (1.47 mol) diisopropylamine was added and dissolved in 600 ml dry THF. The solution was cooled to -75 0C and n-butyllithium (2.5 M in hexane, 320 ml) was added dropwise over 70 min while maintaining the temperature between -75 to - 60 °C. The mixture was allowed to warm to -10.4 0C to 0.2 0C for 13 min. The reaction was cooled to - 73.7 CC and then 140 g (0.665 mol) 1-bromo-2,3,4-trifluorobenzene dissolved in 860 ml THF was added dropwise over 2 h while maintaining the temperature between -73.7 0C to -66 0C. The reaction was allowed to stir 5 h between -76.3 0C to -71.7 0C. DMF (146 ml) was added over 40 min at -70.2 to -64.8 °C. The cooling bath was removed and the reaction allowed to warm to 13 0C overnight. The reaction was cooled to -25.6 0C before adding dropwise a solution of 259 ml concentrated hydrochloric acid in 538 ml distilled water. The addition was complete in 30 min with the temperature getting no higher than -9 0C. The layers were separated and the aqueous portion extracted 3 x 400 ml ethyl acetate. The combined organic portions were washed successively with 500 ml saturated NaHCO3 solution and 500 ml brine. After drying over sodium sulfate, the mixture was filtered and rotary evaporated to give 148.4 g brown liquid. The liquid was vacuum distilled and the product collected at 47.9 - 51.3 0C (1.6 Torr), giving 110.17 g with 91% purity (HPLC). This was taken up in heptane and chilled in the freezer to yield 80.23 g (43%) of white to light yellow crystals. This was combined with a subsequent crop and material from an earlier pilot reaction to give 106.21 g. This was vacuum dried to remove heptane, yielding 104.95 g with 98.8 % purity, mp 36.8-38 0C. HPLC analysis done on a Chromolith Performance, RP-18e, 100-4.6 mm. Mobil Phase: A= Methanol, B= 0.1 N TEAA (pH =7). Gradient from 50% to 90% methanol over 5 min. Detector at 254 nm. Retention time: 1.79 minutes.
[00169] Step 2: 3-Bromo-6-(2,6-cis-dimethylmorpholin-4-yl)-4,5-difluorobenzaldehyde. 2-Bromo-
3,4,5-trifluorobenzaldehyde (133.15 g, 0.56 mol) was dissolved in 1000 ml dry acetonitrile. Triethylamine (118.65 ml, 0.85 mol) was added, followed by cis-2,6-dimethylmorpholine (71.64 g, 0.62 mol), and 125 ml additional acetonitrile. The mixture was refluxed for 24 hours, then cooled to room temperature, and poured into 1500 ml saturated sodium bicarbonate solution. The phases were separated and the aqueous phase extracted 2 x 500 ml ethyl acetate. The combined organic portions were washed 2 x 500 ml brine and then dried over magnesium sulfate. After filtering and rotary evaporation, 199.7 g of oil was recovered. This was diluted to -300 ml with heptane to induce crystallization and placed in the freezer overnight. The resulting yellow crystals were filtered to yield 111.7 g, 99.8 % purity (HPLC). Mp 88.1- 92.0 0C. HPLC analysis done on a Chromolith Performance column, RP-18e, 100-4.6 mm; Mobile phase: A=MeOH, B= 0.1 N TEAA (pH=7); Gradient: 60% A to 100% A over 5 minutes; wavelength: 254 nm; Retention time: 1.94 minutes.
[00170] Step 3: 2-(2,6-Dimethyl-morpholin-4-yl)-3,4-difluoro-5-(4,4,5,5-tetramethyl-
[1 ,3,2]dioxaborolan-2-yl)-benzaldehyde. Potassium acetate (179.7 g, 1.83 mol), Pd(PCy3^CI2 (Aldrich, 32.0 g, 0.043 mol), bis-(pinacolato)diboron (149.7 g, 0.59 mol), and 3-Bromo-6-(2,6-cis- dimethylmorpholin-4-yl)-4,5-difluorobenzaldehyde (147.0 g, 0.538 mol) were placed in a 5L 4-neck flask. The solids were evacuated and flushed with argon six times. Methyltetrahydrofuran (3300 ml) was added. The mixture was mechanically stirred as it was evacuated until bubbling stopped. The reactants were flushed with argon, then evacuated and flushed with argon again. Argon was then bubbled through the mixture for 2 h 16 min. The mixture was then evacuated until bubbling ceased, then flushed with argon, evacuated, and flushed with argon again. The mixture was heated to reflux for 4.7 days, when NMR indicated that all 3-bromo-6-(2,6-cis-dimethylmorpholin-4-yl)-4,5-difluorobenzaldehyde had been consumed. The mixture was cooled to room temperature, filtered, and rinsed with ethyl acetate. The filtrate was rotary evaporated to give a sticky solid which was taken up in ethyl acetate and filtered. This yielded 101.9 g of crystals, which NMR showed to still be contaminated with residual catalyst. The crystals were mixed with -800 ml warm ethyl acetate and filtered to remove the catalyst. Rotary evaporation yielded 94.4 g of product with satisfactory NMR. The initial ethyl acetate filtrate was concentrated, then heptane was added to induce crystallization, and the resulting mixture placed in the freezer. This was filtered to yield 45.45 g of additional product. This was taken up with -400 ml warm ethyl acetate, filtered to remove a white impurity, and then rotary evaporated. The residue was treated with hot heptane to yield fine particles and then filtered to collect additional clean product. Total product collected was 121 g , mp 142.9-143.8 0C. Anal, calcd.: 59.86% C, 6.87% H, 3.67% N; Found: 59.81% C, 7.03% H, 3.66% N.
[00171] Step 4: 2-lodo-5-methyl-[1 ,3,4]thiadiazole (2.0 g) was slurried in CH3CN (30 ml) and
CH2CI2 (1.68 ml) was added. The slurry was cooled to 0 0C and added iAmONO (3.5 ml), was added, the mixture was llowed to warm to RT and noted white solids still present. DMF was added (10 ml) and stirring was continued overnight at RT. Saturated NaHSO3 was added and the mixture was extracted with EtOAc (2X) and CH2CI2 (2 x). The combined organic layers were washed with brine, dried through Na2SO4 and concentrated by rotoevaporation to give, after some high vac, crude product with DMF. Mtbe was added and solids precipitated. The mixture was cooled at 0 °C for about 2 hrs, filtered and rinsed with cold mtbe to give brown solids. The solids were dried at 40 0C overnight in a vacuum oven to give 23 - 1.7 g. The crude product was dissolved in CH2CI2 and applied to a 20 g plug of SiO2. The product was eluted with 20% EtOAc/CH2CI2 and fractions were collected that contained product. Fractions 2-6 were concentrated by rotoevaporation and high vacuum to give product - 0.629 g. The mixed cuts were concentrated by rotoevaporation and applied to a 40 g lsco column. The product was eiuted with 20% EtOAc/CH2CI2 taking 25 ml cuts. Fractions 18-24 were concentrated by rotoevaporation and high vacuum to give 2-lodo-5-methyl-[1 ,3,4]thiadiazole - 0.631 g, 16%, 32% total yield. [00172] 2-(2,6-Dimethyl-morpholin-4-yl)-3,4-difluoro-5-(5-methyl-[1 ,3,4]thiadiazol-2-yl)- benzaldehyde. 2-(2,6-Dimethyl-morpholin-4-yl)-3,4-difluoro-5-(4,4,5,5-tetramethyl-[1 ,3,2]dioxaborolan-2- yl)-benzaldehyde and cesium carbonate were suspended in a mixture of toluene (8 ml_), n-BuOH (8 ml_), and H2O (2 ml_). This mixture was stirred and then purged with Nitrogen. Pd(PPh3)4 was added and the reaction mixture was heated at 80 0C for 1hr 15min. MS indicated that the reaction was almost complete and that only a very minor amount of the starting materials remained. The reaction was heated for an additional hour. The reaction mixture was partitioned between H2O and ethyl acetate and the aqueous layer was extracted twice with ethyl acetate. The combined extracts were dried over w/ MgSO4, filtered and concentrated. The crude product was purified by column chromatography eluting with 5-50% ethyl acetate in hexanes. Compound 10 can then be obtained by treating the title compound as set forth in Example 10, step 6.
EXAMPLE 11
[00173] Steps 1 to 4: [2-(2,6-Dimethyl-morpholin-4-yl)-3,4-difluoro-5-(5-phenyl-[1 ,3,4]thiadiazol-2- yl)-phenyl]-methanol. The procedure set forth in Example 10, steps 1 to 4 was followed using benzoyl chloride as the acylating reagent to provide the compound (0.150 g) as an orange solid. 1 H NMR (400 MHz, CDCI3) δ 1.2 (d, J=6.3 Hz, 6 H), 3.0 (m, 4 H), 3.8 (m, 2 H), 4.8 (s, 2 H), 7.5 (dd, J=5.1 , 1.7 Hz, 3 H), 8.0 (m, 2 H), 8.1 (dd, J=7.2, 1.8 Hz, 1 H); MS (APCI+) m/z418 (MH+).
[00174] Step 5: 2-(2,6-Dimethyl-morpholin-4-yl)-3,4-difluoro-5-(5-phenyl-[1 ,3,4]thiadiazol-2-yl)- benzaldehyde. The procedure of Example 10, step 5 was followed to provide the compound (0.120 g) as a yellow solid. 1 H NMR (400 MHz, CDCI3) δ 1.2 (d, J=6.3 Hz, 6 H), 3.1 (m, 4 H), 3.9 (ddd, J=9.2, 6.3, 2.8 Hz, 2 H), 7.5 (m, 3 H), 8.0 (s, 2 H), 8.6 (dd, J=7.7, 2.1 Hz, 1 H), 10.2 (s, 1 H); MS (APCI+) m/z416 (MH+). [00175] Step 6: Compound 11. The procedure of Example 10, step 6 was followed to provide the compound (0.055 g) as a solid, mp: >260 0C; 1 H NMR (400 MHz, DMSO- d6) δ 0.9 (d, J=6.3 Hz, 3 H), 1.1 (d, J=6.1 Hz, 3 H), 2.9 (s, 1 H), 3.1 (s, 1 H), 3.6 (dd, J=8.2, 5.7 Hz, 2 H), 3.7 (s, 1 H), 3.9 (d, J=8.8 Hz, 1 H), 4.1 (s, 1 H), 7.6 (m, 3 H), 7.7 (d, J=6.8 Hz, 1 H), 8.0 (m, 2 H), 11.5 (s, 1 H), 11.9 (s, 1 H); MS (APCI+) m/z 526 (MH+). Anal, calcd for C25H21F2N5O4S -1.5H2O : C, 54.34; H, 4.38; N, 12.67. Found: C, 54.0; H, 4.24; N, 12.63.
EXAMPLE 12
[00176] Steps 1 to 4: [2-(2,6-Dimethyl-morpholin-4-yl)-3,4-difluoro-5-(5-trifluoromethyl-
[1 ,3,4]thiadiazol-2-yl)-phenyl]-methanol. The procedure set forth in Example 10, steps 1 to 4 was followed using trifluoroacetic anhydride as the acylating reagent. In this case combined organic extracts were also washed with 10% NaOH, dried over Na2SO4 and concentrated to a residue that was filtered through silica with EtOAc and concentrated. The residue was carried on directly on to the next step without further characterization. MS (APCI+) /τ?/z410 (MH+).
[00177] Step 5: 2-(2,6-Dimethyl-morpholin-4-yl)-3,4-difluoro-5-(5-trifluoromethyl-[1 ,3,4]thiadiazol-
2-yl)-benzaldehyde. The procedure of Example 10, step 5 was followed to provide the compound (0.115 g). 1 H NMR (400 MHz, CDCI3) δ 1.2 (d, J=6.3 Hz, 6 H), 3.1 (m, 4 H), 3.9 (m, 2 H), 8.6 (dd, J=7.6, 1.7 Hz, 1 H), 10.1 (s, 1 H); MS (APCI+) m/z 408 (MH+).
[00178] Step 6: Compound 12. The procedure of Example 10, step 6 was followed except the residue was purified by column chromatography and crystallized from MeOH (2 mL) to provide the compound (0.085 g) as a solid, mp: 219-224 °C; 1 H NMR (400 MHz, DMSO- d6) δ 0.9 (d, J=6.3 Hz, 3 H), 1.1 (d, J=6.3 Hz, 3 H), 2.9 (d, J=4.9 Hz, 1 H), 3.1 (m, 1 H) 3.6 (dd, J=8.5, 6.6 Hz, 1 H), 3.7 (d, J=14.2 Hz, 1 H), 3.9 (d, J=8.8 Hz, 1 H), 4.1 (m, 2 H), 7.7 (d, J=7.1 Hz, 1 H), 11.6 (s, 1 H)5 11.9 (s, 1 H); MS (APCI+) m/z 518 (MH+). Anal, calcd for C20H16F5N5O4S»1.5H2O : C, 44.19; H, 3.50; N, 12.88. Found: C, 43.80; H, 3.24; N, 13.38.
EXAMPLE 13
[00179] Steps 1 to 4: [2-(2,6-Dimethyl-morpholin-4-yl)-3,4-difluoro-5-(5-acetoxymethyl-
[1 ,3,4]thiadiazol-2-yl)-phenyl]-methanol. The procedure set forth in Example 10, steps 1 to 4 was followed using acetoxyacetyl chloride as the acylating reagent to provide the compound (0.635 g) as a brown oil. 1 H NMR (400 MHz, CDCI3) δ 1.2 (d, J=6.3 Hz, 6 H), 2.2 (s, 3 H), 3.0 (m, 4 H), 3.8 (m, 2 H), 4.8 (s, 2 H), 5.5 (s, 2 H), 8.1 (d, J=7.1 Hz, 1 H); MS (APCI+) m/z414 (MH+).
[00180] Step 5: 2-(2,6-Dimethyl-morpholin-4-yI)-3,4-difluoro-5-(5-acetoxymethyl-[1 ,3,4]thiadiazol-
2-yl)-benzaldehyde. The procedure of Example 10, step 5 was followed to provide the compound (0.482 g) as a green oil. 1 H NMR (400 MHz, CDCI3) δ 1.2 (d, J=6.3 Hz, 6 H), 2.2 (s, 3 H) 3.1 (m, 4 H), 3.9 (m, 2 H), 5.5 (s, 2 H), 8.5 (d, J=7.6 Hz, 1 H), 10.2 (s, 1 H); MS (APCI+) m/z 412 (MH+). [00181] Step 6: Compound 13. The procedure of Example 10, step 6 was followed except the reaction mixture was filtered at rt. The filter cake was washed with IPA (2 x 1 mL) providing the compound (0.125 g) as a beige solid, mp: >260 0C; 1 H NMR (400 MHz, DMSO- d6) δ 0.9 (d, J=6.3 Hz, 3 H), 1.1 (d, J=6.1 Hz, 3 H), 2.1 (s, 3 H), 2.9 (d, J=14.4 Hz, 1 H), 3.1 (m, 1 H), 3.6 (m, 2 H), 3.7 (s, 1 H), 3.9 (d, J=8.8 Hz, 1 H), 4.1 (dd, J=13.7, 1.7 Hz, 1 H), 5.5 (s, 2 H), 7.6 (d, J=7.1 Hz, 1 H), 11.5 (s, 1 H), 11.9 (s, 1 H); MS (APCI+) m/z 522 (MH+). Anal, calcd for C22H21F2N5O6S: C, 50.67; H, 4.06; N1 13.43. Found: C, 50.59; H, 3.93; N, 13.18. EXAMPLE 14
[00182] Steps 1 to 4: [2-(2,6-Dimethyl-morpholin-4-yl)-3,4-difluoro-5-([1 ,3,4]thiadiazol-2-yl)- phenylj-methanol. The procedure set forth in Example 10, steps 1 to 4 was followed using formic acid as the acylating reagent except the reaction was heated to reflux for 3h to provide the compound (0.120 g) as a green oil. 1 H NMR (400 MHz, CDCI3) δ 1.2 (d, J=4.4 Hz, 6 H), 3.0 (m, 4 H), 3.8 (m, 2 H), 4.8 (s, 2 H), 8.1 (s, 1 H), 9.3 (s, 1 H); MS (APCI+) m/z342 (MH+).
[00183] Step 5: 2-(2,6-Dimethyl-moφholin-4-yl)-3,4-difluoro-5-([1 ,3,4]thiadiazol-2-yl)- benzaldehyde. The procedure of Example 10, step 5 was followed to provide the compound (0.069 g) as a yellow oil. 1 H NMR (400 MHz, CDCI3) δ 1.2 (d, J=6.1 Hz, 6 H), 3.1 (m, 4 H), 3.8 (ddd, J=9.3, 6.2, 3.1 Hz, 2 H), 8.5 (m, 1 H), 9.2 (s, 1 H), 10.1 (s, 1 H); MS (APCI+) m/z340 (MH+).
[00184] Step 6: Compound 14. The procedure of Example 10, step 6 was followed except the reaction mixture was filtered at rt. The filter cake was washed with IPA (2 x 1 ml_) providing the compound (0.044 g) as a beige solid, mp: >260 0C; 1 H NMR (400 MHz, DMSO- d6) δ 0.9 (d, J=6.3 Hz, 3 H), 1.1 (d, J=6.3 Hz, 3 H), 2.9 (d, J=14.7 Hz, 1 H), 3.1 (m, 1 H), 3.6 (m, 2 H), 3.7 (m, 1 H), 3.9 (d, J=8.5 Hz, 1 H), 4.1 (d, J=11.7 Hz, 1 H), 7.7 (d, J=7.1 Hz, 1 H), 9.6 (s, 1 H), 11.5 (s, 1 H), 11.9 (s, 1 H); MS (APCI+) m/z 450 (MH+). Anal, calcd for C19H17F2N5O4S-O.^ C3H8O: C, 50.92; H, 3.96; N, 15.34. Found: C, 50.87; H, 3.47; N, 14.95.
EXAMPLE 15
[00185] Step 1 : [2-(2,6-Dimethyl-morpholin-4-yl)-3,4-difluoro-5-(5-ethyl-[1 ,3,4]thiadiazol-2-yl)- phenylj-methanol. The procedure set forth in Example 10, steps 1 to 4 was followed using propionyl chloride as the acylating reagent to provide the compound (0.231 g). 1 H NMR (400 MHz, CDCI3) δ 1.2 (d, J=6.3 Hz, 6 H), 1.5 (td, J=7.6, 1.6 Hz, 3 H), 3.0 (m, 4 H), 3.2 (m, 2 H), 3.8 (ddd, J=8.8, 4.3, 4.0 Hz, 2 H),
4.8 (s, 2 H), 8.1 (d, J=6.8 Hz, 1 H); MS (APCI+) m/z 370 (MH+).
[00186] Step 2: 2-(2,6-Dimethyl-morpholin-4-yl)-3,4-difluoro-5-(5-ethyl-[1 ,3,4]thiadiazol-2-yl)- benzaldehyde. The procedure of Example 10, step 5 was followed to provide the compound (0.200 g) as a yellow solid. 1 H NMR (400 MHz, CDCI3) δ 1.2 (d, J=6.3 Hz, 6 H), 1.5 (t, J=7.6 Hz, 3 H), 3.1 (m, 4 H), 3.2 (q, J=7.6 Hz, 2 H), 3.9 (ddd, J=9.1 , 6.2, 3.3 Hz, 2 H), 8.5 (dd, J=7.7, 2.1 Hz, 1 H), 10.2 (s, 1 H); MS (APCI+) m/z 368 (MH+).
[00187] Step 3: Compound 15. The procedure of Example 10, step 6 was followed providing the compound (0.145 g) as a solid, mp: >260 0C; 1 H NMR (400 MHz, DMSO- d6) δ 0.9 (d, J=6.3 Hz, 3 H), 1.1 (d, J=6.1 Hz, 3 H), 1.3 (t, J=7.6 Hz, 3 H), 2.9 (d, J=14.9 Hz, 1 H), 3.1 (m, 3 H), 3.6 (m, 2 H), 3.8 (s, 1 H),
3.9 (d, J=8.8 Hz, 1 H), 4.1 (d, J=11.7 Hz, 1 H), 7.6 (d, J=7.1 Hz, 1 H), 11.5 (s, 1 H), 11.8 (s, 1 H); MS (APCI+) m/z 478 (MH+). Anal, calcd for C21H21F2N5O4S: C, 52.82; H, 4.43; N, 14.67. Found: C, 52.89; H, 4.28; N, 14.61.
EXAMPLE 16
[00188] Compound 16. rel-(2R,4S,4aS)- 9,10-difluoro-8-(5-acetoxymethyl-[1 ,3,4]thiadiazoi-2-yl)-
1 ,2,4,4a-tetrahydro-2,4-dimethylspiro[[1 ,4]oxazino[4,3-a]quinoline-5(6H),5'(2'/V)-pyrim idine]- 2'4'6'(1Η,3'/^-trione (0.070 g, 0.13 mmol)was slurried with ammonia (4 mL of a 2.0 M solution in MeOH) for 6h becoming a solution after 1h. The solution was diluted with EtOAc (50 mL) and washed with 1 N HCI (30 mL). The organics were dried over Na2SO4 and concentrated to an oil. Purification of the residue by column chromatography provided an oil that crystallized upon the addition of CHCI3. Concentration provided the compound (0.058). 1H NMR (400 MHz, DMSO- Cf6) δ 0.9 (d, J=6.1 Hz, 3 H), 1.1 (d, J=6.1 Hz, 3 H), 2.9 (m, 1 H), 3.0 (m, 1 H), 3.6 (d, J=2.2 Hz, 2 H), 3.7 (m, 1 H), 3.8 (dd, J=8.7, 3.8 Hz, 1 H), 4.0 (m, 1 H), 4.8 (d, J=5.4 Hz, 2 H), 6.2 (m, 1 H),7.6 (m, 1 H), 11.5 (s, 1 H), 11.8 (s, 1 H); MS (APCI+) m/z480 (MH+). Anal, calcd for C20H19F2N5O5S«0.5 CHC)3 «0.2 C3H8O2: C, 45.48; H, 3.85; N, 12.69. Found: C, 45.74; H, 3.65; N, 12.30. [00189]
SYNTHETIC SCHEME FOR EXAMPLES 17 AND 18
Step i Step 2
O
R =
R = Ethyl
"VA
EXAMPLE 17
[00190] Step 1 , parts 1 and 2: 3-{5-[4-(2,6-Dimethyl-morpholin-4-yl)-2,3-difluoro-5-hydroxymethyl- phenyl]-[1,3,4]thiadiazoi-2-yl}-propionic Acid Methyl Ester. The procedure set forth in Example 10, steps 1 to 4 was followed using 3-chlorocarbonyl-propionic acid methyl ester as the acylating reagent to provide the compound (0.495 g). 1 H NMR (400 MHz, DMSO- dβ) δ 1.1 (d, J=6.3 Hz, 6 H), 2.7 (m, 2 H), 2.9 (t, J=7.1 Hz, 2 H), 3.0 (d, J=11.0 Hz, 2 H), 3.4 (t, J=7.0 Hz, 2 H), 3.6 (s, 3 H), 3.7 (m, 2 H), 4.6 (d, J=4.9 Hz, 2 H), 5.4 (t, J=5.5 Hz, 1 H), 8.1 (d, J=7.1 Hz, 1 H); MS (APCI+) m/z428 (MH+). [00191] Step 1 , part 3: 3-{5-[4-(2,6-Dimethyl-morpholin-4-yl)-2,3-difluoro-5-formyl-phenyl]-
[1 ,3,4]thiadiazol-2-yl}-propionic Acid Methyl Ester. The procedure of Example 10, step 5 was followed except the residue from the filtrates was purified by column chromatograph to provide the compound (0.237 g) as a yellow solid. 1H NMR (400 MHz, CDCI3) δ 1.2 (d, J=6.3 Hz, 6 H), 2.9 (td, J=7.0, 4.0 Hz, 2 H), 3.1 (m, 4 H), 3.5 (td, J=7.1 , 3.9 Hz, 2 H), 3.7 (s, 3 H), 3.9 (dd, J=6.0, 3.1 Hz, 2 H), 8.5 (m, 1 H), 10.2 (d, J=3.7 Hz, 1 H); MS (APCI+) m/z426 (MH+).
[00192] Step 2: Compound 17. The procedure of Example 10, step 6 was followed providing the compound (0.250 g). 1H NMR (400 MHz, DMSO- d6) δ 0.9 (d, .7=6.3 Hz, 3 H), 1.1 (d, J=6.1 Hz, 3 H), 2.9 (m, 3 H), 3.1 (m, 1 H), 3.3 (t, J=7.0 Hz, 2 H), 3.6 (s, 3 H), 3.6 (m, 2 H), 3.7 (m, 1 H), 3.9 (d, J=8.8 Hz, 1 H), 4.1 (d, JM2.0 Hz, 1 H), 7.6 (d, J=7.1 Hz, 1 H), 11.5 (s, 1 H), 11.8 (s, 1 H); MS (APCI+) m/z536 (MH+). Anal, calcd for C23H23F2N5O6S^ H2O: C, 48.33; H, 4.76; N, 12.25. Found: C, 47.96; H, 4.53; N, 12.10.
EXAMPLE 18
[00193] Step 1 , parts 1 and 2: 5-[4-(2,6-Dimethyl-morpholin-4-yl)-2,3-difluoro-5-hydroxymethyl- phenyl]-[1,3,4]thiadiazole-2-carboxylic Acid Methyl Ester. The procedure set forth in Example 10, steps 1 to 4 was followed using chloromethyloxalate as the acylating reagent to provide the compound (0.120 g). 1H NMR (400 MHz1 DMSO- d6) δ 1.0 (d, ^6.1 Hz, 6 H), 2.7 (t, J=9.9 Hz, 2 H), 3.0 (d, JM 1.7 Hz, 2 H), 3.7 (d, J=7.1 Hz, 2 H), 4.0 (s, 3 H), 4.5 (d, J=5.6 Hz, 2 H), 5.4 (t, J=5.5 Hz, 1 H), 8.2 (d, J=7.3 Hz, 1 H); MS (APCI+) m/z 400 (MH+).
[00194] Step 1 , part 3: 5-[4-(2,6-Dimethyl-morpholin-4-yl)-2,3-difluoro-5-formyl-phenyl]-
[1 ,3,4]thiadiazole-2-carboxylic Acid Methyl Ester. The procedure of Example 10, step 5 was followed to provide the compound (0.095 g) as a yellow solid. 1 H NMR (400 MHz, CDCI3) δ 1.2 (d, J=6.1 Hz, 6 H), 3.1 (m, 4 H), 3.8 (m, 2 H), 4.0 (s, 3 H), 8.6 (dd, J=7.6, 2.2 Hz, 1 H), 10.1 (s, 1 H); MS (APCI+) m/z398 (MH+).
[00195] Step 2: Compound 18. The procedure of Example 10, step 6 was followed except the reaction mixture was filtered at rt. The filter cake was washed with IPA (2 x 1 ml_) providing the compound (0.085 g) as a yellow solid, mp: >260 0C; 1 H NMR (400 MHz, DMSO- d6) δ 0.9 (d, J=6.3 Hz, 3 H), 1.1 (d, J=6.1 Hz, 3 H), 2.9 (d, J=14.7 Hz, 1 H), 3.1 (m, 1 H), 3.6 (dd, J=8.8, 6.3 Hz, 1 H), 3.7 (m, 2 H), 3.9 (m, 4 H), 4.1 (m, 1 H), 7.7 (d, J=7.3 Hz, 1 H), 11.5 (s, 1 H), 11.9 (s, 1 H); MS (APCI+) m/z 508 (MH+). Anal, calcd for C2IH19F2N5O6SO-S C3H8O*0.35 H2O: C, 49.69; H, 4.39; N, 12.88. Found: C, 49.31 ; H, 4.01 ; N, 12.74.
SYNTHETIC SCHEME FOR EXAMPLES 19 - 21
EXAMPLE 19
[00196] Step 1 : [2-(2,6-Dimethyl-morpholin-4-yl)-3,4-difluoro-5-(5-(pyridin-4-yl)-t1 ,3,4]thiadiazol-2- yl)-phenyl]-methanol. The procedure set forth in Example 10, steps 1 to 4 was followed using isonicotinoyl chloride hydrochloride as the acylating reagent to provide the compound (0.370 g). 1 H NMR (400 MHz, DMSO- Qf6) δ 1.1 (d, J=6.3 Hz, 6 H), 2.8 (m, 2 H), 3.0 (d, J=11.5 Hz, 2 H), 3.7 (m, 2 H), 4.6 (d, J=5.1 Hz, 2 H), 5.5 (t, J=5.3 Hz, 1 H), 8.0 (d, J=5.9 Hz, 2 H), 8.2 (d, J=7.3 Hz, 1 H), 8.8 (d, J=5.9 Hz, 2 H); MS (APCI+) m/z 419 (MH+).
[00197] Step 2: 2-(2,6-Dimethyl-morpholin-4-yl)-3,4-difluoro-5-(5-(pyridin-4-yl)-[1 ,3,4]thiadiazol-2- yl)-benzaldehyde. The procedure of Example 10, step 5 was followed except for the reaction was heated to reflux for 30 min. Normal work-up provided the compound (0.095 g) as a yellow solid. 1 H NMR (400 MHz, DMSO- d6) δ 1.1 (d, J=6.3 Hz, 6 H), 3.0 (m, 2 H), 3.3 (m, 2 H), 3.8 (m, 2 H), 8.0 (dd, J=4.8, 1.6 Hz, 2 H), 8.41 (m, 1 H), 8.8 (d, J=6.1 Hz, 2 H), 10.1 (s, 1 H); MS (APCI+) m/z 417 (MH+). [00198] Step 3: Compound 19. The procedure of Example 10, step 6 was followed except the residue was crystallized from MeOH (2 mL) to provide the compound (0.090 g). 1 H NMR (400 MHz, DMSO- Qf6) δ 0.9 (d, J=6.3 Hz, 3 H), 1.1 (d, J=6.1 Hz, 3 H), 2.9 (d, J=14.4 Hz, 1 H), 3.1 (m, 1 H), 3.6 (m, 1
H), 3.7 (m, 2 H), 3.9 (d, J=8.8 Hz, 1 H), 4.1 (m, 1 H). 7.7 (d, J=7.1 Hz, 1 H), 8.0 (m, 2 H), 8.7 (m, 2 H), 11.5 (s, 1 H), 11.9 (s, 1 H); MS (APCI+) m/z 527 (MH+). Anal, calcd for C24H20F2N6O4S-O-IO C3H8O0.87 H2O: C, 53.24; H, 4.14; N, 15.33. Found: C, 52.99; H, 4.24; N, 15.16.
EXAMPLE 20
[00199] Step 1 : [2-(2,6-Dimethyl-morpholin-4-yl)-3,4-difluoro-5-(5-cyclopropyl-[1 ,3,4]thiadiazol-2- yl)-phenyl]-methanol. The procedure set forth in Example 10, steps 1 to 4 was followed using cyclopropanecarbonyl chloride as the acylating reagent to provide the compound (0.315 g). 1 H NMR (400 MHz, DMSO- dβ) δ 1.1 (d, J=6.3 Hz, 6 H), 1.1 (m, 2 H)1 1.2 (m, 2 H), 2.6 (tt, J=8.3, 4.9 Hz, 2 H), 2.7 (m, 2 H), 3.0 (d, J=11.0 Hz, 2 H), 3.7 (m, 2 H), 4.5 (d, J=5.4 Hz, 2 H), 5.4 (m, 1 H), 8.0 (m, 1 H); MS (APCI+) m/z 382 (MH+).
[00200] Step 2: 2-(2,6-Dimethyl-morpholin-4-yl)-3,4-difluoro-5-(5-cyclopropyl -[1 ,3,4]thiadiazol-2- yl)-benzaldehyde. The procedure of Example 10, step 5 was followed to provide the compound (0.245 g) as a yellow solid. 1H NMR (400 MHz, CDCI3) δ 1.2 (m, 10 H), 2.4 (m, 1 H) 3.1 (m, 4 H), 3.8 (m, 2 H), 8.5 (d, J=7.6 Hz, 1 H), 10.1 (s, 1 H); MS (APCI+) m/z 380 (MH+).
[00201] Step 3: Compound 20. The procedure of Example 10, step 6 was followed providing the compound (0.145 g) as a solid, mp: >260 °C; 1 H NMR (400 MHz, DMSO- d6) δ 0.9 (d, J=6.3 Hz, 3 H), 1.0 (m, 2 H), 1.1 (d, J=6.1 Hz, 3 H), 1.2 (m, 2 H), 2.5 (m, 1 H), 2.9 (d, JM4.4 Hz, 1 H), 3.0 (m, 1 H), 3.6 (m, 2 H), 3.7 (m, 2 H), 3.9 (d, J=8.8 Hz, 1 H), 4.0 (dd, J=13.6, 1.6 Hz, 1 H), 7.5 (d, J=7.3 Hz, 1 H), 11.5 (s, 1 H), 11.8 (s, 1 H); MS (APCI+) m/z 490 (MH+). Anal, calcd for C22H21 F2N5O4S-0.4 C3H8O-CI 9 H2O: C, 53.90; H, 4.79; N, 13.55. Found: C, 53.99; H, 4.78; N, 13.16.
EXAMPLE 21
[00202] Step 1 : [2-(2,6-Dimethyl-morpholin-4-yl)-3,4-difluoro-5-(5-isoxazol-5-yl)-[1 ,3,4]thiadiazol-
2-yl)-phenyl]-methanol. The procedure set forth in Example 10, steps 1 to 4 was followed using isoxazole-5-carbonyl chloride as the acylating reagent to provide the compound (0.299 g). 1 H NMR (400 MHz, DMSO- dβ) δ 1.1 (d, J=6.3 Hz, 6 H), 2.8 (m, 2 H), 3.0 (d, JM 1.2 Hz, 2 H), 3.7 (m, 2 H), 4.6 (d, J=3.9 Hz, 2 H), 5.5 (m, 1 H), 7.5 (d, J=2.0 Hz, 1 H), 8.2 (d, J=7.6 Hz, 1 H), 8.9 (d, J=2.0 Hz, 1 H); MS (APCI+) m/z 409 (MH+).
[00203] Step 2: 2-(2,6-Dimethyl-morpholin-4-yl)-3,4-difluoro-5-(5-isoxazol-5-yl-[1 ,3,4]thiadiazol-2- yl)-benzaldehyde. The procedure of Example 10, step 5 was followed to provide the compound (0.150 g) as an orange solid. 1 H NMR (400 MHz, DMSO- d6) δ 1.1 (d, Jfc-6.1 Hz, 6 H), 3.0 (t, J=ICO Hz, 2 H), 3.3 (m, 2 H), 3.8 (m, 2 H), 7.5 (t, J=2.2 Hz, 1 H), 8.4 (dd, J=7.7, 1.8 Hz, 1 H), 8.9 (t, JM .7 Hz, 1 H), 10.1 (s, 1 H); MS (APCI+) m/z 407 (MH+).
[00204] Step 3: Compound 21. The procedure of Example 10, step 6 was followed except following the IPA reflux overnight, the residue was refluxed in n-BuOH for 5 h. Concentration and crystallization from MeCN (4 mL) provided the compound (0.070 g) as an orange/brown solid, mp: >260 0C; 1 H NMR (400 MHz, DMSO- de) δ 0.9 (d, J=6.1 Hz, 3 H), 1.1 (d, J=6.1 Hz, 3 H), 2.9 (d, JM 4.4 Hz, 1 H), 3.1 (m, 1 H), 3.6 (m, 2 H), 3.7 (m, 1 H), 3.9 (d, J=8.8 Hz, 1 H), 4.1 (d, JM 3.4 Hz, 1 H), 7.4 (d, J=2.0 Hz, 1 H), 7.7 (d, J=6.8 Hz, 1 H), 8.9 (d, J=2.0 Hz, 1 H), 11.5 (s, 1 H), 11.9 (s, 1 H); MS (APCI+) m/z 517 (MH+). Anal, calcd for C22H18F2N6O5S-CgI H2O: C, 49.59; H, 3.75; N, 15.77. Found: C, 49.20; H, 3.36; N, 15.41. EXAMPLE 22
[00205] Step 1 : [2-(2,6-Dimethyl-morpholin-4-yl)-3,4-difluoro-5-(5-fluoromethyl-[1 ,3,4]thiadiazol-2- yl)-phenyl]-methanol. The procedure set forth in Example 10, steps 1 to 4 was followed using fluoroacetyl chloride as the acylating reagent to provide the compound (0.200 g). 1 H NMR (400 MHz, CDCI3) δ 1.2 (d, J=6.3 Hz, 6 H), 3.0 (m, 4 H), 3.8 (m, 2 H), 4.8 (s, 2 H), 5.8 (s, 1 H), 5.9 (s, 1 H), 8.1 (dd, J=7.2, 2.1 Hz, 1 H); MS (APCI+) m/z 374 (MH+).
[00206] Step 2: 2-(2,6-Dimethyl-morρholin-4-yl)-3,4-difluoro-5-(5-fluoromethyl-[1 ,3,4]thiadiazol-2- yl)-benzaldehyde. The procedure of Example 10, step 5 was followed to provide the compound (0.115 g) as a yellow solid. 1 H NMR (400 MHz, CDCI3) 51.2 (d, J=6.3 Hz, 6 H), 3.1 (m, 4 H), 3.9 (td, J=6.2, 3.2 Hz, 2 H), 5.8 (s, 1 H), 5.9 (s, 1 H), 8.6 (dd, J=7.6, 2.0 Hz, 1 H), 10.2 (s, 1 H); MS (APCI+) m/z 372 (MH+). [00207] Step 3: Compound 22. The procedure of Example 10, step 6 was followed except the residue was crystallized from MeOH (2 mL) to provide the compound (0.038 g). 1 H NMR (400 MHz, DMSO- c/6) δ 0.9 (d, J=6.3 Hz, 6 H), 1.1 (d, J=6.1 Hz, 6 H), 2.9 (d, J=14.2 Hz, 1 H), 3.1 (s, 1 H), 3.6 (m, 2 H), 3.7 (m, 1 H), 3.9 (d, J=8.5 Hz, 1 H), 4.1 (m, 1 H), 5.8 (s, 1 H), 5.9 (s, 1 H), 7.7 (d, J=6.8 Hz, 1 H), 11.5 (s, 3 H), 11.8 (s, 3 H); MS (APCI+) m/z 482 (MH+). Anal, calcd for C20H18F3N5O4S«0.07 CH3OH: C, 49.84; H, 3.81 ; N, 14.48. Found: C, 49.44; H, 3.48; N, 14.28.
EXAMPLE 23
[00208] Step 1 : [5-(5-Chloromethyl-[1 ,3,4]thiadiazol-2-yl)-2-(2,6-dimethyl-morpholin-4-yl)-3,4- difluoro-phenyrj-methanol. The procedure set forth in Example 10, steps 1 to 4 was followed using chloroacetyl chloride as the acylating reagent to provide the compound (1.04 g). 1 H NMR (400 MHz, DMSO- de) δ 1.1 (d, J=6.3 Hz, 6 H), 2.7 (m, 2 H), 3.0 (m, 2 H), 3.7 (m, 2 H), 4.6 (d, J=5.6 Hz, 2 H), 5.3 (s, 2 H), 5.4 (t, J=5.6 Hz, 1 H), 8.1 (d, J=6.8 Hz, 1 H); MS (APCI+) m/z 390 (MH+). [00209] Step 2: 5-(5-Chloromethyl-[1 ,3,4]thiadiazol-2-yl)-2-(2,6-dimethyl-morpholin-4-yl)-3,4- difluoro-benzaldehyde. The procedure of Example 10, step 5 was followed to provide the compound (0.145 g) as a yellow oil. 1 H NMR (400 MHz, DMSO- d6) δ 1.1 (d, J=6.1 Hz, 6 H), 2.9 (m, 2 H), 3.3 (m, 2 H), 3.8 (m, 2 H), 5.3 (s, 2 H), 8.3 (dd, J=7.8, 1.7 Hz, 1 H), 10.1 (s, 1 H); MS (APCI+) m/z 388 (MH+). [00210] Step 3: Compound 23. The procedure of Example 10, step 6 was followed to provide the compound (0.077 g). 1 H NMR (400 MHz, DMSO- d6) δ 0.9 (d, J=6.4 Hz, 3 H), 1.1 (d, J=6.1 Hz, 3 H), 2.9 (d, J=14.7 Hz, 1 H), 3.1 (m, 1 H), 3.6 (m, 2 H), 3.7 (s, 1 H), 3.9 (d, Λ=8.8 Hz, 1 H), 4.1 (s, 1 H), 5.3 (s, 2 H), 7.6 (m, 1 H), 11.5 (s, 1 H), 11.8 (s, 1 H); MS (APCI+) m/z 498 (MH+). Anal, calcd for C20H18F2N5O4SChCSO H2O: C, 47.73; H, 3.72; N, 13.91. Found: C, 47.34; H, 3.56; N, 13.75.
EXAMPLE 24
[00211] Step i : [5-[5-(2-Chloro-phenyl)-[1 ,3,4]thiadiazol-2-yl]-2-(2,6-dimethyl-morpholin-4-yl)-3,4- difluoro-phenyl]-methanol. The procedure set forth in Example 10, steps 1 to 4 was followed using 2- chlorobenzoyl chloride as the acylating reagent to provide the compound (0.860 g). 1 H NMR (400 MHz, CDCI3) δ 1.2 (d, J=6.3 Hz, 6 H), 3.2 (m, 4 H), 3.8 (ddd, J=8.9, 6.1 , 2.8 Hz, 2 H), 4.6 (s, 2 H), 7.5 (ddd, J=4.7, 2.3, 2.1 Hz, 2 H), 7.6 (m, 1 H), 8.4 (m, 1 H), 8.5 (dd, J=7.6, 2.0 Hz, 1 H); MS (APCI+) m/z 452 (MH+).
[00212] Step 2: 5-[5-(2-Chloro-phenyl)-[1 ,3,4]thiadiazol-2-yl]-2-(2,6-dimethyl-morpholin-4-yl)-3,4- difluoro-benzaldehyde. The procedure of Example 10, step 5 was followed to provide the compound (0.690 g) as a yellow solid. 1 H NMR (400 MHz, CDCI3) δ 1.2 (d, .7=6.3 Hz, 6 H), 3.1 (m, 4 H), 3.9 (ddd, J=8.9, 6.1 , 2.8 Hz, 2 H), 7.4 (ddd, J=4.7, 2.3, 2.1 Hz, 2 H), 7.6 (m, 1 H), 8.4 (m, 1 H), 8.6 (dd, J=7.6, 2.0 Hz, 1 H), 10.2 (s, 1 H); MS (APCI+) m/z450 (MH+).
[00213] Step 3: Compound 24. The procedure of Example 10, step 6 was followed to provide the compound (0.037 g). 1H NMR (400 MHz, DMSO- dβ) δ 0.9 (d, J=6.3 Hz, 3 H), 1.1 (d, J=6.1 Hz, 3 H), 2.9 (m, 1 H), 3.1 (m, 1 H), 3.6 (dd, J=8.2, 5.7 Hz, 2 H), 3.7 (m, 1 H), 3.9 (d, J=8.8 Hz, 1 H), 4.1 (s, 1 H), 7.6 (m, 2 H), 7.7 (d, J=6.8 Hz, 1 H), 8.2 (m, 2 H), 11.5 (s, 1 H), 11.9 (s, 1 H); MS (APCI+) m/z559 (MH"). Anal, calcd for C25H20F2N5O4SCI: C, 53.62; H, 3.60; N, 12.51. Found: C, 53.34; H, 3.41 ; N, 12.36.
EXAMPLE 25
[00214] Step 1 : [5-[5-(2-Fluoro-phenyl)-[1 ,3,4]thiadiazol-2-yl]-2-(2,6-dimethyl-morpholin-4-yl)-3,4- difluoro-phenyl]-methanol. The procedure set forth in Example 10, steps 1 to 4 was followed using 2- fluorobenzoyl chloride as the acylating reagent to provide the compound (0.278 g). 1 H NMR (400 MHz, DMSO- d6)) δ 1.1 (d, J=6.3 Hz, 6 H), 2.7 (m, 4 H), 3.0 (m, 2 H), 3.7 (m, 2 H), 4.6 (s, 2 H), 7.5 (m, 2 H), 7.8 (m, 1 H), 8.2 (m, 1 H), 8.4 (m, 1 H); MS (APCI+) m/z436 (MH+).
[00215] Step 2: 5-[5-(2-Fluoro-phenyl)-[1 ,3,4]thiadiazol-2-yl]-2-(2,6-dimethyl-morpholin-4-yl)-3,4- difluoro-benzaldehyde. The procedure of Example 10, step 5 was followed to provide the compound (0.079 g) as a yellow solid. 1 H NMR (400 MHz, CDCI3) δ 1.2 (d, J=6.3 Hz, 6 H), 3.1 (m, 4 H), 3.9 (ddd, J=8.9, 6.1 , 2.8 Hz, 2 H), 7.3 (m, 3 H), 8.4 (m, 1 H), 8.6 (dd, J=7.6, 1 H), 10.1 (s, 1 H); MS (APCI+) m/z434 (MH+).
[00216] Step 3: Compound 25. The procedure of Example 10, step 6 was followed to provide the compound (0.036 g). 1 H NMR (400 MHz, DMSO- dβ) δ 0.9 (d, J=6.3 Hz, 3 H), 1.1 (d, J=6.1 Hz, 3 H), 2.9 (m, 1 H), 3.1 (m, 1 H), 3.6 (dd, J=8.2, 5.7 Hz, 2 H), 3.7 (m, 1 H), 3.9 (d, J=8.8 Hz, 1 H), 4.1 (s, 1 H), 7.4 (m, 2 H), 7.6 (m, 2 H), 8.3 (m, 1 H), 11.5 (s, 1 H), 11.8 (s, 1 H); MS (APCI+) m/z 543 (MH").
EXAMPLE 26
[00217] Steps 1 and 2: (S)-2,2-Dimethyl-[1 ,3]dioxolane-4-carbonyl chloride. A solution of (S)-2,2-
Dimethyl-[1 ,3]dioxolane-4-carboxylic acid (0.97 g, 6.6 mmol) in EtOH (20 mL) was treated with KOH (0.372 g, 6.6 mmol) The solution was concentrated to a white solid that was suspended in ether (15 mL). The suspension was treated with 2 drops of DMF followed by oxalyl chloride (3.0 mL, 34.5 mmol). The slurry was stirred for 2 h and filtered. The filtrates were concentrated to provide the compound (0.55 g) as an orange oil that was used without further purification. 1 H NMR (400 MHz, CDCI3) δ 1.4 (s, 3 H), 1.5 (s, 3 H), 4.3 (m, 2 H), 4.8 (t, J=5.6 Hz, 1 H). [00218] Step 3: (S)-[5-[5-(2,2-Dimethyl-[1 ,3]dioxolan-4-yl)-[1 ,3,4]thiadiazol-2-yl]-2-(2,6-dimethyl- morpholin-4-yl)-3,4-difluoro-phenyl]-methanol. The procedure set forth in Example 10, steps 1 to 4 was followed using (S)-2,2-Dimethyl-[1 ,3]dioxolane-4-carbonyl chloride as the acylating reagent to provide the compound (0.700 g). 1 H NMR (400 MHz, CDCI3) δ 1.2 (d, J=6.1 Hz, 6 H), 1.5 (s, 3 H), 1.6 (s, 3 H), 3.0 (m, 4 H), 3.8 (m, 2 H), 4.2 (dd, J=8.8, 5.1 Hz, 1 H), 4.5 (dd, J=8.8, 6.8 Hz, 1 H), 4.7 (s, 2 H), 5.6 (dd, J=6.6, 5.1 Hz, 1 H), 8.0 (dd, J=7.1 , 2.0 Hz, 1 H); MS (APCI+) m/z 442 (MH+).
[00219] Step 4, part 1 : (S)-5-[5-(2,2-Dimethyl-[1 ,3]dioxolan-4-yl)-[1 ,3,4]thiadiazol-2-yl]-2-(2,6- dimethyl-morpholin-4-yl)-3,4-difluoro-benzaldehyde. The procedure of Example 10, step 5 was followed except for the concentrated residue following filtration was purified by column chromatography to provide the compound (0.470 g). 1 H NMR (400 MHz, CDCI3) δ 1.2 (d, J=6.1 Hz, 6 H), 1.5 (s, 3 H), 1.6 (d, J=7.6 Hz, 3 H), 3.1 (m, 4 H), 3.9 (m, 2 H), 4.2 (ddd, J=8.8, 5.1 , 1.0 Hz, 1 H), 4.5 (ddd, J=8.9, 6.7, 1.2 Hz, 1 H), 5.6 (t, J=5.9 Hz, 1 H), 8.5 (dd, J=7.6, 1.0 Hz, 1 H), 10.2 (s, 1 H); MS (APCI+) m/z 440 (MH+). [00220] Step 4, part 2: Compound 26. The procedure of Example 10, step 6 was followed except the reaction was concentrated to a residue that was purified by column chromatography to provide the compound (0.525 g) as a mixture of diastereomers. 1 H NMR (400 MHz, DMSO- d6) δ 0.9 (d, J=6.1 Hz, 3 H), 1.1 (d, J=6.1 Hz, 3 H), 1.4 (s, 3 H), 1.4 (s, 3 H), 2.9 (d, J=14.7 Hz, 1 H), 3.1 (m, 1 H), 3.6 (m, 2 H), 3.7 (s, 1 H), 3.9 (d, J=8.5 Hz, 1 H), 4.1 (m, 2 H), 4.4 (dd, J=8.8, 6.8 Hz, 1 H), 5.6 (m, 1 H), 7.6 (m, 1 H), 11.5 (s, 1 H), 11.8 (s, 1 H); MS (APCI+) m/z 550 (MH+). Anal, calcd for C24H25F2N5O6S^O.10C6H14-0.35H2O4: C, 52.34; H, 4.84; N, 12.41. Found: C, 52.20; H, 4.65; N, 12.05.
EXAMPLE 27
[00221] Step 5: Compound 27. A solution of compound 26 (0.32 g, 0.58 mmol) in THF (10 ml.) was treated with 1 N HCI (10 ml_). The reaction was stirred overnight at rt, heated to reflux for 2 h and cooled to rt. The reaction was diluted with water (50 ml_) and extracted with EtOAc (50 ml). The combined organics were dried over Na2SO4 and concentrated. Purification by column chromatography provided the compound (0.220 g) as a mixture of diastereomers. 1 H NMR (400 MHz, DMSO- d6) δ 0.9 (d, J=6.3 Hz, 3 H), 1.1 (d, J=6.3 Hz, 3 H), 2.9 (d, J=14.7 Hz, 1 H), 3.0 (d, J=10.5 Hz, 1 H), 3.6 (m, 3 H), 3.7 (dt, J=10.7, 5.3 Hz, 2 H), 3.9 (d, J=8.5 Hz, 1 H), 4.0 (m, 1 H), 5.0 (q, J=4.4 Hz, 1 H), 5.1 (t, J=6.0 Hz, 1 H), 6.4 (dd, J=6.1, 5.1 Hz, 1 H), 7.6 (s, 1 H), 11.5 (s, 1 H), 11.8 (s, 1 H); MS (APCI+) m/z 510 (MH+). Anal, calcd for C2IH2IF2N5O6S* 0.18C4H8O2 «0.5H2O4: C, 48.56; H, 4.40; N, 13.04. Found: C, 48.22; H, 4.32; N, 12.76.
EXAMPLE 28
[00222] Ethyl 3-(2-{[rel-(4R,4aS,5S)-9,10-difluoro-2,4-dimethyl-2',4',6'-trioxo-1 , 1 ',2,3',4,4',4a,6'- octahydro-2'H,6H-spiro[1 ,4-oxazino[4,3-a]quinoline-5,5'-pyrimidin]-8-yl]carbonyl}hydrazino)-3- oxopropanoate.
[00223] Step 1 : A suspension of rel-(2R,4S,4aS)-9,10-difluoro-2,4-dimethyl-2',4',6'-trioxo-
1 ,1 ',2!3',4,4',4a,6'-octahydro-2'H,6H7spiro[1 ,4-oxazino[4,3-a]quinoline-5,5'-pyrimidine]-8-carboxylic acid (20.0 g, 48.9 mmol), HATU (19.0 g, 49 mmol) and triethylamine (7.5 mL) in DMF (90 mL) was stirred at rt for 15 min. The resulting solution was treated with ethyl-3-hydrazino-3-oxopropionate (7.1 g, 49 mmol) and stirred overnight. The reaction was poured into sat. NaHCO3 (450 mL) and the resulting slurry was stirred for 30 min and filtered. The filter cake was washed with water (2 x 25 mL). The filter cake was collected in a flask and concentrated from THF (2 x 300 mL). The solid was dried overnight under vacuum to provide the compound (17.8 g) as a beige solid. 1H NMR (400 MHz, DMSO- Cf6) δ 0.9 (d, J=6.3 Hz, 3 H), 1.1 (d, J=6.3 Hz, 3 H), 1.2 (m, 3 H), 2.8 (d, J=14.8 Hz, 1 H), 3.0 (m, 1 H), 3.5 (d, J=14.8 Hz, 1 H), 3.6 (m, 1 H), 3.7 (m, 1 H), 3.8 (d, J=8.6 Hz, 1 H), 4.0 (m, 3 H), 7.1 (d, J=7.0 Hz, 1 H), 10.0 (s, 1 H), 10.2 (S1 1 H), 11.6 (s, 2 H); MS (APCI+) m/z 538 (MH+).
[00224] Step 2: Compound 28. A suspension of ethyl 3-(2-{[rel-(4R,4aS,5S)-9,10-difluoro-2,4- dimethyl^'^'.e'-trioxo-i .i'^.S'^^'^a.θ'-octahydro-Z'H.eH-spiroti^-oxazino^.S-alquinoline-δ.δ'- pyrimidin]-8-yl]carbonyl}hydrazino)-3-oxopropanoate (17.75 g, 33.3 mmol) and Lawesson's reagent (13.4 g g, 33 mmol) in THF (150 mL) and CH2CI2 (150 mL) were heated with an oil bath at 75 0C for 2h distilling off solvent. The resulting solution was concentrated and the residue was purified by column chromatography to provide the compound (7.5 g) as a white solid. 1 H NMR (400 MHz, DMSO- d6) δ 0.9 (d, J=6.2 Hz, 3 H), 1.1 (d, J=6.2 Hz, 3 H), 1.2 (q, J=6.8 Hz, 3 H), 2.9 (s, 1 H), 3.0 (s, 1 H), 3.6 (m, 2 H), 3.7 (s, 1 H), 3.9 (d, J=8.8 Hz, 1 H), 4.1 (m, 1 H), 4.1 (q, J=7.2 Hz, 2 H), 4.3 (s, 2 H), 7.6 (d, J=6.8 Hz, 1 H), 11.5 (s, 1 H) 11.8 (s, 1 H); MS (APCI+) m/z 536 (MH+). Anal, calcd for C23H23F2N5O6S-CSO H2O-0.40 C2H3N: C, 51.29; H, 4.48; N, 13.57. Found: C, 50.94; H, 4.37; N, 13.45.
EXAMPLE 29
[00225] Compound 29. EthyHδ-Krel^R^S^aSΪ-Θ.IO-difluoro^-dimethyl-^'^β'-trioxo-
1 ,1',2,3',4,4',4a,6'-octahydro-2'H,6H-spiro[1,4-oxazino[4,3-a]quinoline-5,5'-pyrimidin]-8-yl]-1 ,3,4-thiadiazol- 2-yl}acetate (1.0 g, 1.87 mmol) was dissolved in 0.5 M NaOH (14.5 mL) and stirred for 5 min. 1 M HC! (9 mL) was added and the resulting precipitate was filtered and redissolved in THF ( 100 mL) and dried over Na2SO4. Concentration provided the compound (0.745 g) as a white solid that slowly decarboxylates upon standing at rt. 1 H NMR (400 MHz, DMSO- d6) δ 0.9 (d, J=6.4 Hz, 2 H), 1.1 (d, J=6.0 Hz, 2 H), 2.9 (d, J=14.2 Hz, 1 H), 3.0 (m, 1 H), 3.6 (m, 2 H), 3.7 (s, 1 H), 3.9 (d, J=8.8 Hz, 1 H), 4.1 (s, 1 H), 4.2 (s, 2 H), 7.6 (d, J=6.8 Hz, 1 H), 11.5 (s, 1 H), 11.8 (s, 1 H); MS (APCI+) m/z 464 (M-CO2Et).
EXAMPLE 30
[00226] Compound 30. A solution of compound 29 (0.700 g, 1.38 mmol) in DMF (5 mL) was treated with triethylamine (0.461 mL, 3.31 mmol) followed by HATU (0.525 g, 1.38 mmol). The reaction was stirred for 5 min and glycine methyl ester hydrochloride (0.210 g, 1.7 mmol) was added. The reaction was stirred over the 60 h and diluted with sat NaHCO3 (50 mL). The aqueous was extracted with 2:1 EtOAcA-HF (2 x 100 mL). The combined organics were dried over Na2SO4 and concentrated. Purification of the residue by column chromatography provided the compound (0.300 g) as a pale yellow solid. 1 H NMR (400 MHz, DMSO- d6) δ 1 H NMR 0.9 (d, J=6.0 Hz, 3 H), 1.1 (d, J=6.0 Hz, 3 H), 2.9 (m, 1 H), 3.1 (m, 2 H), 3.6 (m, 4 H), 3.7 (s, 1 H), 3.9 (m, 1 H), 4.1 (m, 2 H), 4.2 (s, 2 H), 7.6 (s, 1 H), 8.8 (s, 1 H), 11.5 (s, 1 H), 11.8 (s, 1 H); MS (APCI+) m/z 579 (MH+). EXAMPLE 31
[00227] Compound 31. Compound 30 (0.300 g, 0.518 mmol) was dissolved in 0.5N NaOH ( 4 mL) and stirred at rt for 5 min. The solution was acidified with 1 N HCI (2.5 ml.) and the resulting precipitate was filtered and dried to provide the compound (0.260 g) as a solid. 1 H NMR (400 MHz, DMSO- d6) δ 0.9 (d, J=6.4 Hz, 3 H), 1.1 (d, J=6.0 Hz, 3 H), 2.9 (m, 1 H), 3.0 (m, 1 H), 3.6 (m, 2 H), 3.7 (s,
1 H), 3.8 (m, 3 H), 4.1 (m, 1 H), 4.1 (s, 2 H), 7.6 (d, J=6.6 Hz, 1 H), 8.7 (d, J=6.0 Hz, 1 H), 11.5 (s, 1 H), 11.8 (s, 1 H), 12.6 (s, 1 H); MS (APCI+) m/z565 (MH+). Anal, calcd for C23H22F2N6O7S-LOI H2O: C, 47.41 ; H, 4.15; N, 14.42. Found: C, 47.01 ; H, 4.00; N, 14.05.
EXAMPLE 32
[00228] Compound 32. A solution of compound 18 (0.125 g, 0.246 mmol) in N1N- dimethylaminoethanol (5.0 mL) was stirred overnight at room temperature. The suspension that developed was diluted with hexane and filtered. The solids were dried in vacuo to give the compound (81 mg) as a yellow powder. 1 H NMR (400 MHz, DMSO-D6) d ppm 0.86 (d, J=6.05 Hz, 3 H) 1.08 (d, J=6.25 Hz, 3 H) 2.17 (s, 6 H) 2.25 (s, 1 H) 2.59 (t, J=5.76 Hz, 2 H) 2.84 (d, 1 H) 3.05 (t, 1 H) 3.60 (m, 1 H) 3.71 (m,1 H) 3.88 (d, J=8.59 Hz, 1 H) 4.07 (d, 1 H) 4.42 (t, J=5.86 Hz, 2 H) 7.71 (d, J=7.22 Hz, 1 H) 1.43 (br s,
2 H). Analysis. Calculated for C24H26F2N6O6S1 ■ 0.9 H2O: C, 49.63; H, 4.82; N, 14.4 Found: C, 49.60; H, 4.63; N, 14.23
EXAMPLE 33
[00229] Compound 33. A solution of compound 29 (1.6 g, 3.2 mmol) in THF (15 mL) was treated with triethylamine (0.483 mL, 3.47 mmol) followed by HATU (1.32 g, 3.47 mmol). The reaction was stirred for 30 min resulting in formation of yellow slurry and 2-morpholin-4-yl-ethanol (0.424 mL, 3.47 mmol) I was added. The mixture was stirred for 2 h and concentrated. The residue was partitioned with sat NaHCO3 (50 mL) and EtOAc (50 mL). The aqueous was extracted with EtOAc (50 mL). The combined organics were dried over Na2SO4 and concentrated. Purification of the residue by reverse phase column chromatography provided an oil that crystallized from MeCN to provide the compound (0.420 g) as a pale yellow solid, mp: 164-180 0C; 1H NMR (400 MHz, DMSO- d6) δ 0.9 (d, J=6.2 Hz, 3 H), 1.1 (d, J=6.2 Hz, 3 H), 2.3 (m, 4 H), 2.5 (m, 2 H), 2.9 (m, 1 H), 3.0 (s, 1 H), 3.5 (m, 3 H), 3.5 (s, 1 H), 3.6 (m, 2 H), 3.7 (s, 1 H), 3.9 (d, J=8.8 Hz, 1 H), 4.1 (d, J=13.7 Hz, 1 H), 4.2 (t, J=5.7 Hz, 2 H), 4.3 (s, 2 H), 7.6 (d, J=7.0 Hz, 1 H); MS (APCI+) m/z621 (MH+). Anal, calcd for C27H30F2N6O7S»0.04 H2O: C, 52.19; H, 4.88; N, 13.53. Found: C, 51.8; H, 4.77; N, 13.18.
EXAMPLE 34
[00230] Compound 34. The procedure set forth in Example 10 was followed was followed using
3-morpholin-4-yl-propan-1-ol to provide the compound (0.270 g) as a pale yellow solid, mp: 190-200 0C; 1 H NMR (400 MHz, DMSO- d6) δ 0.9 (d, J=6.3 Hz, 3 H), 1.1 (d, J=6.1 Hz, 3 H), 1.7 (m, 2 H), 2.3 (t, J=6.7 Hz, 6 H), 2.9 (d, JM4.7 Hz, 1 H), 3.1 (m, 1 H), 3.5 (m, 3 H), 3.6 (m, 3 H), 3.7 (s, 1 H), 3.9 (d, J=8.8 Hz, 1 H), 4.1 (m, 3 H), 4.3 (s, 2 H), 7.6 (d, J=6.8 Hz, 1 H); MS (APCI+) m/z 635 (MH+). Anal, calcd for C28H32F2N6O7S'0.66 C2H3N: C, 53.22; H, 5.18; N, 14.10. Found: C, 53.01 ; H, 5.17; N, 14.11. EXAMPLE 35
[00231] Steps 1 and 2: [5-Bromo-2-(2,6-dimethyl-morpholin-4-yl)-3-fluoro-phenyl]-methanol. A solution of 4-(4-bromo-2-[1 ,3]dioxolan-2-yl-6-fluoro-phenyl)-2,6-dimethyl-morpholine (5.0 g, 14 mmol) in THF (100 ml_) was treated with 1M HCI (3 mL) and stirred for 5 h at rt. The reaction was diluted with EtOAc (250 mL) and sat. NaHCO3 (150 mL) was added. The organics were separated and washed with sat. NaHCO3 (150 mL), brine (150 mL) and dried over Na2SO4. Concentration provided a yellow oil that was dissolved in MeOH (150 mL) and treated with NaBH4 (0.503 g, 13.3 mmol). The colorless solution was stirred for 10 min, concentrated and diluted with water (100 mL). The aqueous was extracted with EtOAc (2 x 150 mL) and the combined organics were dried over Na2SO4 and concentrated. Purification of the residue by column chromatography provided the compound (2.96 g) as a colorless oil. 1H NMR (400 MHz, CDCI3) δ 1.2 (d, J=6.3 Hz, 6 H), 2.8 (d, JM .5 Hz, 2 H), 2.9 (m, 2 H), 3.7 (m, J=8.1 , 4.0, 4.0, 2.0 Hz, 2 H), 4.3 (s, 1 H), 4.7 (s, 2 H), 7.1 (d, J=2.2 Hz, 1 H), 7.2 (s, 1 H); MS (APCI+) m/z 320 (MH+). [00232] Step 3: 4-[4-Bromo-2-(fert-butyl-diphenyl-silanyloxymethyl)-6-fluoro-phenyl]-2,6-dimethyl- morpholine. A solution of [5-bromo-2-(2,6-dimethyl-morpholin-4-yl)-3-fluoro-phenyl]-methanol (2.96 g, 9.3 mmol) in CH2CI2 (40 mL) was treated with DIPEA (1.71 mL, 9.8 mmol), TBDPSCI (2.54 mL, 9.8 mmol) and imidizole (0.665 g, 9.8 mmol). The solution was stirred for 4 h at rt and diluted with CH2CI2 (60 mL). The organic was washed with 1 N HCI (60 mL), water (60 mL) and dried over Na2SO4. Concentration provided the compound (5.17 g) as an oil that was used without further purification. 1 H NMR (400 MHz, CDCI3) δ 1.1 (m, 15 H), 2.4 (d, J=2.0 Hz, 2 H), 2.7 (m, 2 H), 3.4 (m, 2 H), 4.7 (s, 2 H), 7.1 (dd, JM 1.4, 2.3 Hz, 1 H), 7.4 (m, 7 H), 7.7 (dt, J=6.3, 1.6 Hz, 4 H); MS (APCI+) m/z 559 (MH+).
[00233] Step 4: 3-(ferf-Butyl-diphenyl-silanyloxymethyl)-4-(2,6-dimethyl-morpholin-4-yl)-5-fluoro- benzoic Acid. A solution of 4-[4-bromo-2-(terf-butyl-diphenyl-silanyloxymethyl)-6-fluoro-phenyl]-2,6- dimethyl-morpholine (5.0 g, 9.0 mmol) in THF (50 mL) at -78 0C was treated with f-BuLi (13.3 mL of a 1.7 M solution in pentane). The solution was stirred for 30 min at -78 0C and CO2 gas was bubbled through the solution for 2 min at -78 0C continuing while allowing the solution to warm to rt. The solution was carefully quenched with 1 N HCI (50 mL) and extracted with EtOAc (150 mL). The combined organics were dried over Na2SO4 and concentrated. Purification of the residue by column chromatography provided the compound (1.75 g) as a white foam. 1H NMR (400 MHz, CDCI3) δ 1.1 (m, 15 H), 2.6 (d, Jt=11.5 Hz, 2 H), 2.8 (t, J=10.9 Hz, 2 H), 3.5 (m, 2 H), 4.8 (s, 2 H), 7.4 (m, 7 H), 7.7 (dd, J=6.5, 1.3 Hz, 5 H); MS (APCI+) m/z 522 (MH+).
[00234] Step 5: 3-(tørt-Butyl-diphenyl-siIanyloxymethyl)-4-(2,6-dimethyl-morpholin-4-yI)-5-fluoro- benzoyl]-hydrazinecarboxylic Acid terf-Butyl Ester. A suspension of 3-(terf-butyl-diphenyl- silanyloxymethyl)-4-(2,6-dimethyl-morpholin-4-yl)-5-fluoro-benzoic acid (1.72 g, 3.3 mmol) in DMF (8 ml_) was treated with triethylamine (0.460 mL, 3.3 mmol) and HATU (1.5 g, 4.0 mmol). The resulting solution was stirred for 15 min, terf-Butyl carbazate (0.435 g, 3.3 mmol) was added the solution was stirred overnight. The reaction was poured into water (50 mL) and the aqueous was extracted with EtOAc (3x50 ml). The combined organics were dried over Na2SO4 and concentrated. Purification of the residue by column chromatography provided the compound (1.53 g) as a foam. 1 H NMR (400 MHz, DMSO-ofe) δ 0.9 (d, J=6.1 Hz, 6 H), 1.0 (s,, 9 H), 1.4 (m, 9 H), 2.6 (d, J=5.1 Hz, 4 H), 3.2 (m, 2 H), 4.8 (s, 2 H), 7.4 (m, 7 H), 7.6 (dd, J=7.6, 6.1 Hz, 5 H); MS (APCI+) m/z 636 (MH+).
[00235] Step 6: 3-(terf-Butyl-diphenyl-silanyloxymethyl)-4-(2,6-dimethyl-morpholin-4-yl)-5-fluoro- thiobenzoyl]-hydrazinecarboxylic Acid terf-Butyl Ester. A suspension of 3-(terf-butyl-diphenyl- silanyloxymethyI)-4-(2,6-dimethyl-morpholin-4-yl)-5-fluoro-benzoyl]-hydrazinecarboxylic acid terf-butyl ester (1.53 g, 2.41 mmol), sodium bicarbonate (0.61 g, 7.22 mmol), and Lawesson's reagent (1.26 g, 3.13 mmol) in toluene (25 mL) was heated to reflux for 1.5 h and cooled the rt. The suspension was filtered and the filtrates were concentrated. Purification of the residue by column chromatography provided the compound (1.45 g) as a green oil. 1 H NMR (400 MHz, DMSO- d6) δ 0.9 (dd, J=6.1 , 3.9 Hz, 6 H), 1.0 (d, J=2.0 Hz, 9 H), 1.2 (s, 9 H), 2.6 (d, J=4.2 Hz, 4 H), 3.3 (dd, JM 1.5, 6.3 Hz, 2 H), 4.8 (d, J=14.4 Hz, 2 H) 7.4 (m, 7 H) 7.6 (m, 5 H); MS (APCI+) m/z 652 (MH+).
[00236] Step 7: 2-(2,6-Dimethyl-morpholin-4-yl)-3-fluoro-5-(5-methyl-[1 ,3,4]thiadiazol-2-yl)- phenyl]-methanol. 3-(terf-Butyl-diphenyl-silanyloxymethyl)-4-(2,6-dimethyl-morpholin-4-yl)-5-fluoro- thiobenzoyl]-hydrazinecarboxylic acid terf-butyl ester (1.25 g, 1.92 mmol) was treated with HCI (12 mL of a 4 M solution in dioxane) and the resulting solution was stirred for 4h at rt and concentrated. The residue was dissolved in THF (10 mL) at rt and treated with diisopropylethylamine (0.83 mL, 4.8 mmol) followed by acetyl choride (0.136 mL, 1.91 mmol). The reaction was stirred for 15 min and 1 mL cone. HCI was added. The reaction was stirred for an additional 15 min and diluted with water (50 mL). The aqueous was extracted with EtOAc (50 mL) and the combined organics were washed with sat. NaHCO3 (50 mL), brine (50 mL) and dried over Na2SO4. Concentration and purification of the residue by column chromatography provided the compound (0.210 g) as an oil. 1 H NMR (400 MHz, DMSO- d6) δ 1.0 (d, J=6.3 Hz, 6 H), 2.7 (m, 5H), 2.8 (d, J=10.3 Hz, 2 H), 3.6 (m, 2 H), 4.6 (d, J=4.9 Hz, 2 H), 5.3 (t, J=5.4 Hz, 1 H), 7.6 (dd, J=12.8, 2.1 Hz, 1 H), 7.8 (d, JM .5 Hz, 1 H); MS (APCI+) m/z 338 (MH+). [00237] Step 8: 2-(2,6-Dimethyl-morpholin-4-yl)-3-fluoro-5-(5-methyl-[1 ,3,4]thiadiazol-2-yl)- benzaldehyde. The procedure of Example 10, step 5 was followed to provide the compound (0.180 g) as a yellow solid. 1 H NMR (400 MHz, CDCI3) δ 1.2 (d, J=6.3 Hz, 6 H), 2.8 (s, 3 H), 3.1 (m, 4 H), 3.8 (ddd, J=8.7, 6.0, 3.2 Hz, 2 H), 7.9 (d, J=2.2 Hz, 1 H), 8.0 (dd, J=12.9, 2.0 Hz, 1 H), 10.3 (s, 1 H); MS (APCI+) /77/2336 (MH+).
[00238] Step 9: Compound 35. The procedure of Example 10, step 6 was followed except the residue was crystallized from MeOH (4 mL) to provide the compound (0.149 g) as a solid, mp: >260 0C; 1 H NMR (400 MHz, DMSO- dβ) δ 0.9 (d, J=6.3 Hz, 3 H), 1.1 (d, J=6.1 Hz, 3 H), 2.7 (s, 3 H), 2.9 (m, 2 H), 3.6 (m, 2 H), 3.7 (s, 1 H), 3.9 (d, J=8.5 Hz, 1 H), 4.1 (d, J=12.0 Hz, 1 H), 7.3 (s, 1 H), 7.5 (dd, J=14.5, 1.3 Hz, 1 H), 11.5 (s, 1 H), 11.8 (s, 1 H); MS (APCI+) /n/z 446 (MH+). Anal, calcd for C20H2oFN504S«0.71 H2O: C, 52.42; H, 4.71 ; N, 15.28. Found: C, 52.02; H, 4.75; N, 15.02.
SYNTHETIC SCHEME FOR EXAMPLES 36 AND 37
EXAMPLE 36
[00239] Steps 1 and 2: [2-(2,6-Dimethyl-morpholin-4-yl)-3,4-difluoro-5-(5-methylsulfanyl-
[1 ,3,4]thiadiazol-2-yl)-phenyl]-methanol. A suspension of 5-(fe/t-Butyl-diphenyl-silanyloxymethyl)-4-(2,6- dimethyl-morpholin-4-yl)-2,3-difluoro-benzoic acid (3.0 g, 6.0 mmol), HATU (2.53 g, 6.7 mmol) and triethylamine (0.929 mL, 6.7 mmol) in DMF (14 mL) was stirred at rt for 15 min. The resulting solution was treated with hydrazinecarbodithioic acid methyl ester (0.679 g, 5.55 mmol) and stirred overnight. The reaction was poured into water (200 mL) and the resulting precipitate was filtered, redissolved in EtOAc (100 mL). The organics were dried over Na2SO4 and concentrated to an orange oil that was dissolved in HCI (10 mL of a 4 M solution in dioxane). The solution was stirred at rt for 30 min, heated to reflux for 1 h, cooled to rt and concentrated. Purification of the residue by column chromatography provided the compound (0.95 g) as a white solid. 1 H NMR (400 MHz, CDCI3) δ 1.2 (d, J=6.3 Hz, 6 H), 2.8 (s, 3 H), 3.0 (m, J=11.8, 11.8, 11.5, 2.7 Hz, 4 H), 3.8 (m, 2 H) 4.8 (s, 2 H), 8.0 (dd, J=7.2, 1.6 Hz, 1 H); MS (APCI+) m/z 388 (MH+).
[00240] Step 3a: 2-(2,6-Dimethyl-morpholin-4-yl)-3,4-difluoro-5-(5-methylsulfanyl-
[1 ,3,4]thiadiazol-2-yl)-benzaldehyde. A solution of oxalyl chloride (0.253 mL, 2.90 mmol) in CH2CI2 (15 mL) was cooled to -78 0C and treated with dimethylsulfoxide (0.247 mL, 3.50 mmol). After 15 min the solution was treated with [2-(2,6-Dimethyl-morpholin-4-yl)-3,4-difluoro-5-(5-methylsulfanyl- [1 ,3,4]thiadiazol-2-yl)-phenyl]-methanol (0.450 g, 1.16 mmol) and the reaction was stirred for an additional 30 min. Triethylamine (0.404 mL, 2.90 mmol) was added and the solution was allowed to warm to rt. The reaction was poured into water (50 mL) and extracted with EtOAc (2 x 50 mL). The combined organics were dried over Na2SO4 and concentrated. Purification by column chromatography provided the compound (0.160 g) as a pale yellow solid. 1 H NMR (400 MHz1 CDCI3) δ 1.2 (d, J=6.3 Hz1 6 H)1 2.9 (d, J=1.0 Hz, 3 H), 3.1 (m, 4 H), 3.9 (ddd, J=9.2, 6.1, 3.3 Hz, 2 H), 8.5 (m, 1 H), 10.2 (s, 1 H); MS (APCI+) m/z 386 (MH+).
[00241] Step 4: Compound 36. The procedure of Example 10, step 6 was followed to provide the compound (0.265 g) as a solid, mp: 219-220 0C; 1 H NMR (400 MHz1 DMSO- d6) δ 0.9 (d, J=6.3 Hz1 3 H)1 1.1 (d, J=6.3 Hz1 3 H)1 2.8 (s, 3 H)1 2.9 (d, J=14.4 Hz1 1 H)1 3.1 (d, J=12.7 Hz1 1 H)1 3.6 (m, 2 H)1 3.7 (m, J=6.1 , 6.1 , 6.1 , 6.1 , 4.2 Hz, 1 H)1 3.9 (d, J=8.5 Hz, 1 H), 4.0 (m, 1 H), 7.5 (d, J=7.1 Hz, 1 H), 11.5 (s, 1 H), 11.8 (s, 1 H); MS (APCI+) m/z 496 (MH+). Anal, calcd for C20H19F2N5O4S2 «0.8C3H8O»0.05 H2O: C, 49.47; H, 4.57; N, 12.90. Found: C, 49.09; H, 4.42; N, 12.53.
EXAMPLE 37
[00242] Steps 1 and 2 were performed as set forth in Example 36, steps 1 and 2.
[00243] Step 3b: 2-(2,6-Dimethyl-morpholin-4-yl)-3,4-difluoro-5-(5-methanesulfonyl-
[1 ,3,4]thiadiazol-2-yl)-benzaldehyde. The procedure of Example 10, step 5 was followed except the reaction was stirred for 2h and the residue following the filtration was purified by column chromatography to provide the compound (0.040 g) as an oil. 1 H NMR (400 MHz, CDCI3) δ 1.2 (d, J=6.3 Hz, 6 H), 3.2 (m, 4 H), 3.5 (s, 3 H), 3.9 (m, 2 H)1 8.6 (d, J=2.2 Hz, 1 H), 10.1 (s, 1 H); MS (APCI+) m/z 418 (MH+). [00244] Step 4: Compound 37. The procedure of Example 10, step 6 was followed to provide the compound (0.016 g) as a solid, mp: 210-230 0C; 1 H NMR (400 MHz, DMSO- d6) δ 0.9 (d, J=6.3 Hz, 3 H), 1.1 (d, J=6.1 Hz, 3 H), 2.9 (d, J=14.9 Hz1 1 H)1 3.1 (m, 1 H), 3.6 (m, 4 H)1 3.7 (m, 2 H)1 3.9 (d, J=8.8 Hz, 1 H), 4.1 (m, 1 H), 7.7 (d, J=6.8 Hz1 1 H), 11.6 (s, 1 H)1 11.9 (s, 1 H); MS (APCI+) m/z 528 (MH+).
EXAMPLE 38
[00245] Compound 38. A solution of compound 36 (0.156 g, 0.315 mmol) in 2:1 CH2CI2/Me0H
(15 mL) was treated with 2-Benzenesulfonyl-3-phenyl-oxaziridine (0.091 g, 0.346 mmol). The solution was stirred overnight at rt. The resulting red solution was concentrated and the residue was purified by column chromatography to provide the compound (0.130 g) as a yellow solid. 1 H NMR (400 MHz, DMSO- d6) δ 0.9 (dd, J=14.9, 6.8 Hz1 3 H)1 1.1 (d, J=6.1 Hz1 3 H)1 2.9 (d, J=14.4 Hz1 1 H), 3.0 (m, 1 H), 3.1 (s, 3 H), 3.6 (m, 2 H)1 3.7 (s, 1 H)1 3.9 (d, J=8.8 Hz, 1 H), 4.1 (m, 1 H), 7.7 (d, J=5.6 Hz, 1 H), 11.5 (s, 1 H), 11.9 (s, 1 H); MS (APCI+) m/z512 (MH+). Anal, calcd for C20H19F2N5O5S2 '0.13C4H8O2-O^ H2O: C, 46.72; H, 3.92; N, 13.28. Found: C, 46.39; H1 3.77; N1 13.00. EXAMPLE 39
[00246] Steps l and 2: Compound 39. A suspension of rel-(2R,4S,4aS)-10-fluoro-2,4-dimethyl-
2',4',6'-trioxo-1 ,1'!2,3',4,4',4a,6'-octahydro-2'H,6H-spiro[1 ,4-oxazino[4,3-a]quinoline-5,5'-pyrimidine]-8- carboxylic acid (0.75 g, 1.9 mmol), HATU (0.87 g, 2.3 mmol) and triethylamine (0.32 ml_, 2.3 mmol) in DMF (5 mL) was stirred at rt for 15 min. The resulting solution was treated with hydrazinecarbodithioic acid methyl ester (0.245 g, 2.01 mmol) and stirred overnight. The reaction was poured into water (50 mL) and the resulting precipitate was filtered, redissolved in THF (50 mL). The organics were dried over Na2SO4 and concentrated to a residue that was dissolved in HCI (5 mL of a 4 M solution in dioxane). The solution was heated to 80 0C for 30 min, cooled to rt and concentrated. The residue was partitioned with EtOAc (50 mL) and sat. NaHCO3 (50 mL). The aqueous was extracted with EtOAc (50 mL) and the combined organics were dried over Na2SO4 and concentrated. Purification go the residue by column chromatography and crystallization of the residue from MeOH provided compound (0.365 g) as a white solid, mp: >260 0C; 1 H NMR (400 MHz, DMSO- dβ) δ 0.9 (d, J=6.1 Hz, 3 H)1 1.1 (d, J=6.1 Hz, 3 H), 2.7 (s, 3 H), 2.9 (d, J=14.7 Hz, 1 H)1 3.0 (m, 1 H), 3.6 (m, 2 H), 3.7 (m, 1 H), 3.8 (d, J=8.5 Hz, 1 H), 4.0 (m, 1 H), 7.3 (d, J=1.5 Hz, 1 H), 7.5 (dd, J=14.5, 1.8 Hz, 1 H), 11.5 (s, 1 H), 11.8 (s, 1 H); MS (APCI+) m/z 478 (MH+). Anal, calcd for C20H20FN5O4S2-O^O H2O: C, 49.93; H, 4.27; N, 14.56. Found: C, 49.54; H, 4.06; N, 14.42.
SYNTHETIC SCHEME FOR EXAMPLES 40 AND 41 (C-9 SUBSTITUTED THIADIAZOLES)
Ex.4O
Step 3
LiCI, DMF
Step 2
EXAMPLE 40
[00247] Step 1 : 2-(2,6-Dimethyl-morpholin-4-yl)-3-fluoro-4-methoxy-5-(5-methyl-[1 ,3,4]thiadiazol-
2-yl)-benzaldehyde. A solution of 2-(2,6-Dimethyl-morpholin-4-yl)-3,4-difluoro-5-(5-methyl- [1 ,3,4]thiadiazol-2-yl)-benzaldehyde, which can be made according to Example 10, (0.250 g, 0.707 mmol) in MeOH (10 mL) was treated with NaOMe (0.150 g, 1.42 mmol). The reaction was heated to reflux for 5h and cooled to rt. The solution was poured into water (50 mL) and extracted with EtOAc (2 x 50 mL). The combined organics were dried over Na2SO4 and concentrated. Purification of the residue by column chromatography provided the compound (0.200 g) as a yellow solid. 1 H NMR (400 MHz, CDCI3) δ 1.2 (d, J=6.4 Hz, 6 H), 2.8 (s, 3 H), 3.1 (dd, J=QA , 2.0 Hz, 4 H), 3.9 (m, J=6.2, 6.2, 6.2, 6.2, 6.0 Hz, 2 H), 4.1 (d, J=3.1 Hz, 3 H), 8.6 (d, JM .8 Hz, 1 H), 10.2 (s, 1 H); MS (APCI+) m/z366 (MH+). [00248] Step 3: Compound 40. The procedure of Example 10, step 6 was followed except the reaction mixture was filtered at rt. The filter cake was washed with IPA (2 x 1 mL) providing the compound (0.081 g) as a beige solid.i H NMR (400 MHz, DMSO- d6) δ 0.9 (d, J=6.3 Hz, 3 H), 1.1 (d, J=6.1 Hz, 3 H), 2.7 (s, 3 H), 2.9 (s, 1 H), 3.0 (s, 1 H), 3.5 (s, 1 H), 3.6 (d, J=6.3 Hz, 1 H), 3.7 (s, 1 H), 3.8 (d, J=8.8 Hz, 1 H), 3.9 (s, 3 H), 4.0 (s, 1 H), 7.6 (s, 1 H), 11.4 (s, 1 H), 11.8 (s, 1 H); MS (APCI+) m/z476 (MH+). Anal, calcd for C21H22FN5O5S'0.87H2O: C, 51.35; H, 4.87; N, 14.26. Found: C, 50.96; H, 4.57; N, 14.07.
EXAMPLE 41
[00249] Steps 1 and 2: 2-(2,6-Dimethyl-morpholin-4-yl)-3-fluoro-4-hydroxy-5-(5-methyl-
[1 ,3,4]thiadiazol-2-yl)-benzaldehyde. A solution of 2-(2,6-dimethyl-morpholin-4-yl)-3-fluoro-4-methoxy-5- (5-methyl-[1 ,3,4]thiadiazol-2-yl)-benzaldehyde (0.090 g, 0.246 mmol) in DMF (2 mL) was treated with LiCI (0.0.031 g, 0.740 mmol). The reaction was heated to reflux under N2 for 2h and cooled to rt. The solution was poured into water (25 mL) and acidified with 10% HCI (10 mL). The aqueous was extracted with EtOAc (2 x 25 mL). The combined organics were dried over Na2SO4 and concentrated. Purification of the residue by column chromatography provided the compound (0.0.070 g) as a yellow solid. 1 H NMR (400 MHz, CDCI3) δ 1.2 (d, J=6.1 Hz, 6 H), 2.8 (s, 3 H), 3.1 (m, 4 H), 3.8 (m, 2 H), 7.8 (d, JM .7 Hz, 2 H), 10.2 (s, 2 H), 12.3 (s, 1 H); MS (APCI+) m/z352 (MH+).
[00250] Step 3: Compound 41. The procedure of Example 10, step 6 was followed except the reaction was heated for an additional day in MeOH. The reaction mixture was filtered at rt. The filter cake was washed with MeOH (1 mL) providing the compound (0.050 g) as a beige solid.1 H NMR (400 MHz, DMSO- d6) δ 0.9 (d, J=6.3 Hz, 3 H), 1.1 (d, J=6.3 Hz, 3 H), 2.7 (s, 3 H), 2.8 (d, JM 4.4 Hz, 1 H), 3.0 (m, 1 H), 3.5 (d, Jt=I 4.4 Hz, 1 H), 3.6 (m, 1 H), 3.7 (s, 1 H), 3.8 (d, J=8.5 Hz, 1 H), 4.0 (m, 1 H), 7.5 (s, 1 H), 10.9 (s, 1 H), 11.4 (s, 1 H), 11.8 (s, 1 H); MS (APCI+) m/z 462 (MH+). Anal, calcd for C20H20FN5O5SO.21 H2O: C, 51.63; H, 4.42; N, 15.05. Found: C, 51.24; H, 4.35; N, 14.87. EXAMPLE 42 A
[00251] Step i : 5-Bromo-2,3,4-trifluoro-benzoic acid. A solution of diisopropylamine (4.15 ml_,
29.6 mmol) in THF (50 ml_) at -78 °C was treated with n-BuLi (18.5 mL of a 1.6 M solution in hexanes). The solution was stirred for 5 min and 1-bromo-2,3,4-trifluoro-benzene (5.0 g, 24.0 mmol) was added. The orange solution was stirred for 1.25 h at -78 0C. CO2 gas was bubble through the solution while allowing to warm to rt. The reaction was carefully quenched with 1 N HCI (100 mL). The aqueous was extracted with EtOAc (3 x 50 ml) and the combined organics were dried over Na2SO4 and concentrated. The residue was triturated with hexanes (15 mL) and filtered to provide the compound (4.45 g) as a solid. 1 H NMR (400 MHz, DMSO- Gf6) δ 7.9 (td, J=7.2, 2.3 Hz, 1 H), 13.9 (s, 1 H).
[00252] Steps 2 and 3: 2-(5-Bromo-2,3,4-trifluoro-phenyl)-5-methyl-[1 ,3,4]thiadiazole. A slurry of
5-bromo-2,3,4-trifluoro-benzoic acid (4.45 g, 17.45 mmol) in CH2CI2 (40 ml) was treated with oxalyl chloride (4.56 mL, 52.4 mmol) dropwise. The slurry was stirred for 1.5 h and concentrated to an oil. The acid chloride was diluted with CH2CI2 (20 mL ) and added dropwise to a solution of acetic hydrazide (1.94 g, 26.2 mmol) and triethylamine (3.65 mL, 26.2 mmol) in CH2CI2 (20 mL). The slurry was stirred for 1 h and concentrated. The residue was dissolved in THF (25 mL). Water (25 mL) was added and the aqueous was extracted with EtOAc (3x25 mL). The combined organics were concentrated. Toluene (50 mL) was added and the slurry was concentrated to a white solid. The solid was combined with phosphorous pentasulfide (5.30 g, 11.9 mmol) and hexamethyldisiloxane (6.05 mL, 28.5 mmol) in toluene (75 mL). The mixture was heated to reflux overnight and cooled to rt and filtered. The filtrates were concentrated to 40 mL and diluted with acetone (4OmL). 5.3 M K2CO3 (11.62 mL ) was carefully added and the solution was stirred for 20 min and concentrated to 40 mL. The solution was diluted with water (40 mL) and extracted with EtOAc (3 x 50 mL). The combined organics were dried over Na2SO4 and concentrated. Purification of the residue by column chromatography provided a solid that was triturated with MeOH (30 mL) and filtered to provide the compound (3.60 g). 1 H NMR (400 MHz, DMSO- d6) δ 2.8 (s, 3 H), 8.3 (td, J=7.0, 2.7 Hz, 1 H); MS (APCI+) /n/z 310 (MH+).
[00253] Step 4: 2,3,4-Trifluoro-5-(5-methyl-[1 ,3,4]thiadiazol-2-yl)-benzaldehyde. A solution of 2-
(5-Bromo-2,3,4-trifluoro-phenyl)-5-methyl-[1 ,3,4]thiadiazole (2.0 g, 6.5 mmol) in THF (50 mL) at 0 0C was treated with isopropylmagnesium chloride (3.88 mL of a 2 M solution in THF). The red solution was stirred 30 min at 0 0C and DMF was added. The solution was stirred an additional 1 h at 0 0C and treated with HCI (10 mL of a 4M solution in dioxane). The solution was poured into sat NH4CI (50 mL) and extracted with EtOAc (3 x 50 mL). The combined organics were dried over Na2SO4 and concentrated to provide the compound (1.65 g) as a tan solid. 1 H NMR (400 MHz, DMSO- dβ) δ 2.8 (s, 3 H), 8.5 (td, J=IA, 2A Hz, 1 H), 10.2 (s, 1 H); MS (APCI+) m/z259 (MH+).
[00254] Step 5: K2CO3 was added to a vigorously stirred mixture of 2R,6R-(trans)-dimethyl- morpholine (from BASF) in acetone (100 ml). Benzyl bromide was added dropwise to the mixture resulting in an exothermic reaction. The reaction was allowed to cool and stirred 18 h at rt. A majority of the acetone was removed under vacuum and portioned with water (100 ml) and EtOAc (100 ml). The aqueous layer was extracted with EtOAc (100 ml), dried over Na2SO4 and concentrated. The product was distilled under reduced pressure at 120 °C (75-80 at 0.5 torr) providing a colorless oil of 4-Benzyl-2R,6R- (trans)-dimethyl-morpholine.
[00255] 2-((2R,6R-Dimethyl-morpholin-4-yl)-3,4-difluoro-5-(5-methyl-[1 ,3,4]thiadiazol-2-yl)- benzaldehyde. A mixture of 4-Benzyl-2R,6R-(trans)-dimethyl-morpholine (2.4 g, 11.7 mmol) and 10 % Pd/C (0.50 g) in MeOH was hydrogenated at 50 psi for 20 h. The reaction was filtered through celite and the solution was treated with HCI (15 ml_ of a 1 M solution in diethyl ether) and concentrated to a thick oil (1.70 g). A portion of the oil (0.825 g) in MeCN (12 ml_) was treated with diisopropylethylamine (2.85 mL, 16.36 mL) and 2,3,4-Trifluoro-5-(5-methyl-[1 ,3,4]thiadiazol-2-yl)-benzaldehyde (1.28 g, 5.0 mmol). The solution was heated to reflux for 1.5 h and concentrated. Purification of the residue by column chromatography provided the compound (0.620 g) as a yellow solid. 1 H NMR (400 MHz, CDCI3) δ 1.3 (d, J=5.5 Hz, 6 H), 2.8 (s, 3 H), 3.0 (dd, J=12.2, 5.8 Hz, 2 H) 3.4 (m, 2 H), 4.2 (m, 2 H), 8.5 (d, J=2.0 Hz, 1 H), 10.2 (s, 2 H); MS (APCI+) m/z354 (MH+). [αD] = -47.2 ° c=5.0, MeOH.
[00256] Step 6: Compound 42. A stirring slurry of 2-(2R,6R-Dimethyl-morpholin-4-yl)-3,4- difluoro-5-(5-methyl-[1 ,3,4]thiadiazol-2-yl)-benzaldehyde (0.500 g, 1.42 mmol) in n-BuOH (15 mL) was treated with barbituric acid (0.0.181 g, 1.42 mmol). The reaction was heated to 120 °C for 19 h, cooled to rt and concentrated. The residue was purified by column chromatography and concentrated to an oil that crystallized by addition of MeCN to provide the compound (0.480 g) as a pale yellow solid. Spectral data of the single enantiomer was consistent with the racemic form. [αD] = -244.0 ° c=5.0, MeOH.
EXAMPLE 42 B 0C
Step i
[00257] Steps 1 and 2: 2-Methyl-5-(2,3,4-trifluoro-phenyl)-[1 ,3,4]thiadiazole. The procedure set forth in Example 10 was followed using 2,3,4-trifluoro-benzoic acid to provide the compound (20.5 g). 1 H NMR (400 MHz, CDCI3) δ 2.8 (s, 3 H), 7.1 (m, J=9.0, 9.0, 6.9, 2.0 Hz, 1 H), 8.1 (m, 1 H); MS (APCI+) m/z 231 (MH+).
[00258] Step 3: 2,3,4-Trifluoro-5-(5-methyl-[1 ,3,4]thiadiazol-2-yl)-benzaldehyde. A solution of diisopropylamine (9.8 ml_, 70 mmol THF (100 mL) at -78 0C treated with n-BuLi (44 ml_ of a 1.6 M solution in hexanes). The solution was stirred for 5 min and a solution of 2-Methyl-5-(2,3,4-trifluoro- phenyl)-[1 ,3,4]thiadiazole (6.43 g, 28 mmol) in THF (100 mL) was added dropwise. The dark solution was stirred at -78 °C for 30 min. DMF (4.32 mL, 56 mmol) was added and the solution was stirred at -78°C for 15 min. The solution was quenched dropwise at -78°C with 1 N HCI (20 mL) and warmed to rt. The reaction was diluted with 1 N HCI (250 mL) and extracted with EtOAc (2x 250 mL). The combined organics were dried over Na2SO4 and concentrated. Purification of the residue by column chromatography provide the compound (1.57 g) as a pale yellow solid. 1 H NMR (400 MHz, DMSO- d6) δ 2.8 (s, 3 H), 8.5 (td, J=7.4, 2.4 Hz, 1 H), 10.2 (s, 1 H); MS (APCI+) m/z 259 (MH+). [00259] Compound 42 can then be made by treating 2,3,4-Trifluoro-5-(5-methyl-[1 ,3,4]thiadiazol-
2-yl)-benzaldehyde according to the procedure set forth in 42 A, steps 5 and 6.
EXAMPLE 42 C
[00260] Compound 42. The enantiomers of compound 10 were separated by chiral SFC (Whelko,
15 % MeOH, 4 mL/min). Less retained enantiomer: [αD] = -267.0 ° c=5.0, MeOH.
EXAMPLE 42 D
[00261] 5-bromo-3,4-difluoro-2-((2R,6R)(trans)-dimethyl-morpholin-4-yl)-benzaldehyde. A mixture of 4-benzyl-2R,6R-dimethyl-morpholine (24 g, 117 mmol) and 10 % Pd/C (5.6 g) in MeOH (800 mL) was hydrogenated at 50 psi for 20 h. The reaction was filtered through celite and the solution was treated with HCI (150 mL of a 1 M solution in diethyl ether) and concentrated to a thick oil. A solution of 5-bromo-2,3,4- trifluorobenzaldehyde (25.35 g, 106 mmol), triethylamine (36.8 mL, 265 mmol) and the morpholine HCI salt in dry acetonitrile (230 mL) was heated to reflux for 24 h, cooled to 23 °C and poured into a saturated solution of sodium bicarbonate. The phases were separated and the aqueous wash was further extracted with EtOAc. The combined organic extracts were washed with brine, dried (MgSO4) and concentrated. The residue was treated with heptane and the resulting slurry was filtered. The filtered solid was dried to afford a 20.0 g of the product aldehyde as a yellow solid. The filtrate was concentrated and the resulting slurry was filtered again to provide an additional 7.19 g of product aldehyde. 1 H NMR (400 MHz, CDCI3) d 1.26 (d, J=6.4 Hz, 6 H), 2.91 (dd, J=11.6, 5.6 Hz, 2 H) 3.29 (d, J=11.6 Hz, 2 H), 4.14 (m, 2 H), 7.78 (dd, J=7.2, 2.28 Hz, 1 H), 10.3 (s, 1 H); MS (APCI+) m/z = 334, 336 (MH+).
[00262] Compound 42 can then be made by treating 5-bromo-3,4-difluoro-2-((2R,6R)(trans)- dimethyl-morpholin-4-yl)-benzaldehyde according to the procedure set forth in 10 B, steps 3 and 4.
EXAMPLE 43
[00263] Compound 43. The enantiomers of compound 10 were separated by chiral SFC (Whelko,
15 % MeOH, 4 mL/min). Less retained enantiomer: [αD] = -267.0 ° c=5.0, MeOH. EXAMPLE 44
[00264] Compound 44. Compound 10 (0.4 g, 0.86 mmol) was dissolved in dry DMF (4 ml.) and triethylamine (360 μl_, 2.59 mmol) was added followed by bromomethyl acetate (286 μl_, 1.90 mmol). The resulting solution was stirred at rt for 1 h then diluted with EtOAc and washed twice with water then once with brine. The organic layer was dried over MgSO4. Concentration of the filtrate and purification of the residue by column chromatography (50-70% EtOAc in hexanes) gave the compound (0.29 g) as a white solid, mp: 178 0C; 1 H NMR (400 MHz, DMSO-Cf6) δ 0.87 (d, J=6 Hz, 3 H), 1.10 (d, J=Q Hz, 3 H), 1.87 (s, 3 H), 2.02 (s, 3 H), 2.72 (s, 3 H), 3.00 (br d, JM 4 Hz, 1 H), 3.09 (dd, JM2, 12 Hz, 1 H), 3.60-3.64 (m, 2 H), 3.70-3.80 (m, 1 H), 3.96 (d, J=9 Hz, 1 H), 4.06 (dd, J=14, 2 Hz, 1 H), 5.59 (q, J=10 Hz, 2 H), 5.81 (q, J=10 Hz, 2 H), 7.53 (d, J=7 Hz, 1 H): MS (APCI+) m/z 608 (MH+). Anal. Calcd for C26H27F2N5O8S1 + 0.1 EtOAc: C, 51.24; H, 4.43; N, 10.97. Found: C, 51.44; H, 4.55; N, 11.36.
EXAMPLE 45
[00265] (2S,4R,4aR)-9,10-difluoro-1 \3'-bis[(2-methoxyethoxy)methyl]-2,4-dimethyl-8-(5-methyl-
1 ,3,4-thiadiazol-2-yl)-1 ,2,4,4a-tetrahydro-2'H,6H-spiro[1 ,4-oxazino[4,3-a]quinoline-5,5'-pyrimidine]- 2',4',6'(1'H,3'H)-trione. Compound 10 (0.4 g, 0.86 mmol) was dissolved in dry DMF (4 mL) and triethylamine (360 μL, 2.59 mmol) was added followed by methoxyethoxym ethyl chloride (118 mg, 0.95 mmol). A white precipitate was observed to form. The mixture was stirred at rt overnight them diluted with EtOAc and washed twice with water then once with brine and dried over MgSO4. Concentration of the filtrate and purification of the residue by column chromatography (100% EtOAc) gave the compound (173 mg) as a white solid, mp: 128 0C; 1 H NMR (400 MHz, CD3CN) δ 0.93 (d, J=12 Hz, 3 H), 1.16 (d, JM 2 Hz, 3 H), 2.72 (s, 3 H), 2.99 (d, J=6 Hz, 1 H), 3.09 (dd, J=10, 10 Hz, 1 H), 3.20 (s, 3 H), 3.29 (s, 3 H), 3.30-3.40 (m, 4 H), 3.49-3.52 (m, 4 H), 3.72-3.75 (m, 2 H), 3.81-3.86 (m, 1 H), 4.04 (d, J=9 Hz, 1 H), 4.13 (dd, JM 4, 2 Hz, 1 H), 5.11 (d, J=I O Hz, 1 H), 5.22 (d, J=10 Hz, 1 H), 5.35 (d, Jt=I O Hz, 1 H), 5.43 (d, JMO Hz, 1 H), 7.50 (d, J=7 Hz, 1 H): MS (APCI+) m/z 640 (MH+). Anal. Calcd for C28H35F2N5O8S1: C, 52.58; H, 5.52; N, 10.95. Found: C, 52.32; H, 5.41 ; N, 11.03.
EXAMPLE 46
[00266] Compound 46. Compound 10 (0.4 g, 0.86 mmol) was dissolved in dry DMF (4 mL) and triethylamine (360 μL, 2.59 mmol) was added followed by bromomethyl methyl ether (118 mg, 0.95 mmol). A white precipitate formed. The mixture was stirred at rt and turned orange. After 1.5 days, the mixture was diluted with EtOAc and washed twice with water then once with brine and dried over MgSO4. Concentration of the filtrate and purification of the residue by column chromatography (50% EtOAc in hexanes) gave the compound (173 mg) as a white solid. 1 H NMR (400 MHz, CD3CN) δ 0.95 (d, J=16 Hz, 3 H), 1.17 (d, JM 6 Hz, 3 H), 2.74 (s, 3 H), 3.07 (d, JM 1 Hz, 1 H), 3.09-3.03 (m, 1 H), 3.24 (s, 3 H), 3.37 (dd, JM5, 2 Hz, 1 H), 3.41 (s, 3 H), 3.72-3.79 (m, 1 H), 3.85-3.89 (m, 1 H), 4.17 (dd, JM 4, 2 Hz, 1 H), 5.04 (d, JMO Hz, 1 H), 5.18 (d, JMO Hz, 1 H), 5.28 (d, JMO Hz, 1 H), 5.37 (d, JMO Hz, 1 H), 7.56 (d, J=7 Hz, 1 H): MS (APCI+) m/z 552 (MH+). Anal. Calcd for C24H27F2N5O6S1: C, 52.26; H, 4.93; N, 12.70. Found: C, 52.04; H, 4.90; N, 12.31.
EXAMPLE 47
[00267] Compound 48 (0.300 g, 0.573 mmol) was dissolved in THF (6 mL), cooled to 00C, and treated with succinimide (0.172 g, 1.72 mmol), followed by triethylamine (0.240 mL, 1.72 mmol). The resulting suspension was stirred at room temperature overnight. The reaction was diluted with water and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate and concentrated to give a white foam. Chromatography over silica gel using 10%MeOH/DCM/0.5%AcOH gave the product as a white solid (0.165g). 1 H NMR (400 MHz, CDCI3) d 0.93 (d, J= 6.3 Hz, 3 H), 1.22 (d, J=6.1 Hz, 3 H),
2.7 (m, 8 H), 2.78 (s, 3 H), 3.05 (d, J=14.7 Hz, 1 H), 3.14 (t, J=12.0 Hz, 1 H), 3.26 (d, J= 14.8 Hz, 1 H), 3.8(m, 1 H), 3.9 (m, 1 H), 4.2 (m, 2 H), 5.67 (d, J=9.6 Hz, 1 H), 5.89 (d, J=9.6 Hz, 1 H), 5.92 (d, J=10.0 Hz, 1 H), 6.16 (d, J=9.6 Hz, 1 H), 7.82 (d, J=6.4 Hz, 1 H); MS (APCI+) m/z 724 ( MH+); Anal. Calcd for C30H31F2N5O12S1-LO H2O: C, 48.58; H, 4.48; N, 9.44; Found: C, 48.64; H, 4.07; N, 9.17.
EXAMPLE 48
[00268] Compound 48. A solution of [rel-(2R,4S,4aS)-9,10-difluoro-2,4-dimethyl-8-(5-methyl-
1 ,3,4-thiadiazol-2-yl)-2',4',6'-trioxo-1 ,2,4,4a-tetrahydro-2'H,6H-spiro[1 ,4-oxazino[4,3-a]quinoline-5,5'- pyrimidine]-1',3'(4'H,6'H)-diyl]bis(methylene) diacetate (1.60 g, 2.63 mmol) in MeOH (40 ml.) was treated with HCI (40 ml_ of a 1 M solution in diethylether). The yellow solution was stirred for 40 min resulting in a precipitate. The solid was filtered and the filtrates were concentrated to a solid. The two solids were combined to provide the compound (1.25 g). mp: 190 "C dec; 1 H NMR (400 MHz, DMSO- d6) δ 0.9 (d, J=6.4 Hz, 3 H); 1.1 (d, J=6.3 Hz, 3 H); 2.7 (s, 3H); 3.0 (d, J=14.8 Hz, 1 H); 3.1 (m, 1 H); 3.5 (m, 1 H); 3.6 (dd, J=8.7, 6.5 Hz, 1 H); 3.8 (s, 1 H); 3.9 (d, J=8.8 Hz, 1 H); 4.1 (dd, J=13.7, 2.0 Hz, 1 H); 5.0 (d, J=9.8 Hz, 1 H); 5.1 (m, 1 H); 5.2 (m, 2 H); 7.5 (m, 1 H); Anal. Calcd for C22H23F2N5O6S»2.0 H2O: C, 47.22; H, 4.86; N, 12.52. Found: C, 47.05; H, 4.25; N, 12.30.
EXAMPLE 49
[00269] Compound 49. A solution of compound 51 (0.290 g, 0.278 mmol) in THF (50 mL) was treated with 10 % Pd/C (0.10 g). The mixture was hydrogenated at 50 psi for 12 h, filtered and concentrated to provide the compound (0.165 g) as a yellow foam. 1H NMR (400 MHz, DMSO- dβ) δ 0.9 (d, J=6.1 Hz, 3 H); 1.1 (d, J=5.7 Hz, 3 H); 2.7 (s, 3 H); 3.0 (m, 1 H); 3.1 (m, 1 H); 3.6 (d, J=14.5 Hz, 1 H); 3.6 (m, 1 H); 3.8 (m, 1 H); 4.0 (d, J=8.6 Hz, 1 H); 4.1 (s, 1 H); 5.4 (m, 2 H); 5.6 (m, 2H); 7.5 (s, 1 H); MS (ESI+) m/z 684 (MH+).
EXAMPLE 50
[00270] Compound 50. A solution of (rel-2R,4S,4aS)-9,10-difluoro-1',3'-bis(hydroxymethyl)-2,4- dimethyl-8-(5-methyl-1 ,3,4-thiadiazol-2-yl)-1 ,2,4,4a-tetrahydro-2'H,6H-spiro[1 ,4-oxazino[4,3-a]quinoline- δ.δ'-pyrimidinel^'.e'OHS'HHrione (1.30 g, 2.50 mmol) in CH2CI2 (40 mL) was treated with SOCI2 (10 mL). The reaction was stirred for 30 min becoming an orange solution. The solution was carefully quenched with water (40 mL) and stirred 5 min. The organic was separated and the aqueous was extracted with CH2CI2 (40 mL). The combined organics were washed with saturated NaHCO3 (50 mL) and dried over Na2SO4. Concentration provided the compound (1.21 g) as a beige foam. 1 H NMR (400 MHz, DMSO- d6) δ 0.9 (d, J=6.1 Hz, 3 H); 1.1 (d, J=6.1 Hz, 3 H); 2.7 (s, 3 H); 3.1 (m, 2 H); 3.6 (m, 1 H);
3.8 (s, 2 H); 4.0 (d, J=8.8 Hz, 1 H); 4.1 (s, 1 H); 5.5 (m, 2 H); 5.7 (t, J=4.5 Hz, 2 H); 7.5 (m, 1 H); MS (APCI+) m/z 560 (MH+).
EXAMPLE 51
[00271] Compound 51. A mixture of silver dibenzylphosphate (2.33 g, 6.05 mmol) in toluene (15 mL) was distilled to a volume of 5 mL removing excess water. The slurry was cooled to 60 °C and compound 50 (1.50 g, 2.70 mmol) was added. The slurry was heated to 70 0C for 4h, cooled to rt, and diluted with EtOAc (40 mL) and filtered. The filtrates were concentrated to a residue that was purified by column chromatography (30-60 % acetone in hexane) to provide the compound (1.30 g) as a yellow foam. 1H NMR (400 MHz1 DMSO- dβ) δ 0.8 (d, J=6.3 Hz, 3 H); 1.1 (d, J=6.3 Hz, 3 H); 2.7 (s, 3 H); 3.0 (d, J=14.5 Hz, 1 H); 3.1 (s, 1 H); 3.5 (d, JM 4.5 Hz, 1 H); 3.6 (dd, J=8.6, 6.4 Hz, 1 H); 3.7 (m, 1 H); 4.0 (d, J=8.8 Hz, 1 H); 4.1 (m, 1 H); 4.9 (m, 4 H); 5.0 (dd, J=8.0, 2.3 Hz, 4 H); 5.5 (t, J=9.2 Hz, 1 H); 5.6 (t, J=9.8 Hz, 1 H); 5.7 (t, J=9.7 Hz, 1 H); 5.8 (m, 1 H); 7.2 (m, 4 H); 7.3 (m, 16 H); 7.5 (d, J=7.4 Hz, 1 H).
EXAMPLE 52
[00272] Compound 52. Compound 10 (0.300 g, 0.647 mmol) was suspended in dry acetonitrile (5 mL) and treated with formaldehyde (37% aqueous solution, 0.145 mL, 1.94 mmol) and morpholine (0.169 mL, 1.94 mmol). The suspension was heated under reflux overnight. The resulting solution was cooled and filtered to give a white solid. Recrystallization from boiling acetonitrile gave the product as a white solid (0.21Og). 1 H NMR (400 MHz, CDCI3) δ 1.02 (d, J= 6.3 Hz, 3 H), 1.21 (d, J=6.3 Hz, 3 H), 2.5 (m, 4H), 2.7 (m, 4 H), 2.78 (s, 3 H), 3.00 (d, J=14.3 Hz, 1 H), 3.1 (m, 2 H), 3.55 (m, 4 H), 3.64 (m, 4 H), 3.8 (m, 1 H), 3.9 (m, 1 H), 4.13 (d, 8.8 Hz, 1 H), 4.18 (dd, JM 3.5, 2.0 Hz, 1 H), 4.66 (d, J=12.9 Hz, 1 H), 4.84 (d, J=12.9 Hz, 1 H), 4.90 (d, J=12.9 Hz, 1 H), 5.03 (d, J=12.9 Hz, 1 H), 7.60 (d, J=6.8 Hz, 1 H); MS (APCI+) m/z 662 (3%, MH+); Anal. Calcd for C3OH37F2N7O6S1-LOH2O-O-SCH3CN: C, 53.26; H, 5.86; N, 15.33; Found: C, 53.11 ; H, 5.36; N, 15.45.
EXAMPLE 53
[00273] Compound 53. Compound 10 (0.300 g, 0.647 mmol) was suspended in dry acetonitrile (4 mL) and treated with formaldehyde (37% aqueous solution, 0.145 mL, 1.94 mmol) and N- methylpiperazine (0.215 mL, 1.94 mmol). The suspension was heated under reflux overnight. The resulting solution was cooled and filtered to give the product as a white solid (0.283g). 1 H NMR (400 MHz, CDCI3) δ 1.00 (d, J=6.4 Hz, 3 H), 1.21 (d, J=6.3 Hz, 3 H), 2.20 (s, 3 H), 2.24 (s, 3 H), 2.3 (m, 4 H), 2.4 (m, 4 H), 2.55 (m, 4 H), 2.75 (m, 4 H), 2.78 (s, 3 H), 3.1 (m, 3 H), 3.8 (m, 1 H), 3.9 (m, 1 H), 4.13 (d, 8.6 Hz, 1 H), 4.18 (dd, JM 3.7, 2.1 Hz, 1 H), 4.70 (d, J=13.1 Hz, 1 H), 4.86 (d, JM 2.9 Hz, 1 H), 4.91 (d, J=12.9 Hz, 1 H), 5.03 (d, J=12.9 Hz, 1 H), 7.64 (d, J=6.8 Hz, 1 H); MS (APCI+) m/z 688.0 (2%, MH+); Anal. Calcd for C32H43F2N9O4S1-LOH2O: C, 54.45; H, 6.43; N, 17.86; Found: C, 54.08; H, 6.18; N, 17.52.
EXAMPLE 54
[00274] Preparation of Benzylpyrimidine-2,4,6(1 H,3H,5H)-trione. A mixture of benzyl urea (10.0 g, 66.6 mmol) and malonic acid (8.04 g, 77.2 mmol) in acetic acid (25 ml) was stirred at 700C for 1 hr. Acetic anhydride (15 ml) was added drop wise to the reaction over 10 min and the reaction was heated at 90°C for 2 hrs. Upon concentration by rotoevaporation, the resulting solids were triturated with ethanol (100 ml). The white solids were collected by filtration, washed with EtOH (2 x 25 ml) and dried in a vacuum oven at 60 0C overnight to provide the title compound (10.5 g). 1H NMR (400 MHz, DMSO-d6) d ppm 3.64 (s, 2 H) 4.85 (m, 2 H) 7.22 (m, 5 H) 11.36 (s, 1 H); 13C NMR (101 MHz, DMSO-d6) d ppm 39.54, 43.68, 127.57, 127.68, 127.84, 127.97, 128.85, 129.02, 137.56, 139.82, 152.36, 167.11 , 167.58; MS (APCI-) m/z 218 (M-H-).
[00275] Compound 54. A slurry of 2-[(2R,6S)-2,6-dimethylmorpholin-4-yl]-3,4-difluoro-5-(5- methyl-1 ,3,4-thiadiazol-2-yl)benzaldehyde (1.0 g, 2.8 mmol) and benzylpyrimidine-2,4,6(1 H,3H,5H)-trione (0.65 g, 2.97 mmol) in isopropyl alcohol (30 ml) was refluxed overnight. Upon cooling to 0 °C, white solids were collected by filtration, rinsed with cold isopropyl alcohol and the resulting solids were dried in a vacuum oven at 85 0C overnight to provide the title compound (1.16 g). 1H NMR (400 MHz, DMSO-d6) d ppm 0.69 (d, J=6.25 Hz, 3 H) 1.06 (d, J=6.25 Hz, 3 H) 2.71 (m, 3 H) 2.84 (d, J=14.64 Hz, 1 H) 3.01 (s, 1 H) 3.58 (dd, J=8.49, 6.54 Hz, 1 H) 3.66 (d, J=14.45 Hz, 2 H) 3.87 (d, J=8.79 Hz, 1 H) 4.01 (s, 1 H) 4.94 (s, 2 H) 7.25 (m, 5 H) 7.59 (d, J=7.42 Hz, 1 H) 11.83 (s, 1 H); Anal. Calcd for C27H25F2N5O4S: C, 58.58; H, 4.55; N, 12.65. Found: C1 58.68; H, 4.30; N, 12.62; HPLC shows the major isomer at 17.5 min (89.6%) and the minor isomer at 16.9 min (10.4%).
EXAMPLE 55
[00276] Preparation of N-(benzyloxy)urea. Benzyl-hydroxylamine (10.0 g, 62.7 mmol) was heated at 70 0C until dissolved. Potassium isocyanate (5.6 g, 68.9 mmol) was added to the solution and the slurry was cooled to room temperature and stirred for 2 hrs. The white solids were collected, rinsed with water and dried in a vacuum oven at 40 °C for about 2 hrs. The solids were recrystallized from EtOH to provide the title compound (7.0 g). 1H NMR (400 MHz, DMSO-d6) d ppm 4.66 (s, 2 H) 6.28 (s, 2 H) 7.32 (m, 5 H) 8.95 (s, 1 H); 13C NMR (101 MHz, DMSO-D6) d ppm 77.89, 128.60, 128.83, 129.33, 137.24, 161.42.
[00277] Preparation of 1-(Benzyloxy)pyrimidine-2,4,6(1 H,3H,5H)-trione. N-(benzyloxy)urea (3.5 g, 21.1 mmol) and malonic acid (2.54 g, 24.4 mmol) were heated at 70 °C in acetic acid (8 ml) for 1 hr. The reaction mixture was cooled to room temperature, acetic anhydride (5 ml) was added and the resulting mixture was heated at 90 0C for 2 hrs. The reaction was cooled to room temperature and concentrated by rotoevaporation. The residue was taken up in EtOH and concentrated again. The resulting solids were crystallized from EtOH to provide the title compound as white solids (3.36 g). 1H NMR (400 MHz, DMSO-d6) d ppm 3.68 (s, 2 H) 4.91 (s, 2 H) 7.36 (m, 3 H) 7.46 (dd, J=7.42, 1.95 Hz, 2 H) 11.44 (s, 1 H); 13C NMR (101 MHz, DMSO-d6) d ppm 41.75, 78.18, 124.18, 129.03, 129.49, 130.00, 149.33, 164, 167.
[00278] Compound 55. A slurry of 2-[(2R,6S)-2,6-dimethylmorpholin-4-yl]-3,4-difluoro-5-(5- methyl-1 ,3,4-thiadiazol-2-yl)benzaldehyde (0.4 g, 1.1 mmol) and 1-(benzy!oxy)pyrimidine- 2,4,6(1 H,3H,5H)-trione (0.28 g, 1.2 mmol) in isopropyl alcohol (12 ml) was refluxed overnight. The reaction was concentrated by rotoevaporation and the residue was purified by column chromatography to provide the title compound (0.50 g) as a white solid. 1H NMR (400 MHz, DMSO-d6) d ppm 0.82 (m, 3 H) 1.07 (m, 3 H) 2.71 (m, 3 H) 2.89 (t, J=14.25 Hz, 1 H) 3.02 (s, 1 H) 3.50 (m, 1 H) 3.71 (m, 2 H) 3.83 (m, 1 H) 4.04 (dd, J=13.57, 2.25 Hz, 1 H) 4.83 (d, J=9.96 Hz, 1 H) 4.94 (m, 1 H) 7.32 (m, 5 H) 7.51 (m, 1 H) 12.23 (s, 1 H).
EXAMPLE 56
[00279] Compound 56. Compound 55 (0.3 g, 0.53 mmol) was dissolved in 50% MeOH/THF (50 ml), 5 wt% of PdBaSO4 (0.1 g) was added and the mixture was subjected to 50 psi of hydrogen for 34 hrs The mixture was filtered to remove the catalyst and concentrated by rotoevaporation. The residue was purified by column chromatography to provide the title compound as white solids (91 mg). 1H NMR (400 MHz, DMSO-d6) d ppm 0.85 (dd, J=5.76, 2.83 Hz, 3 H), 1.07 (d, J=6.05 Hz, 3 H), 2.91 (s, 1 H), 3.03 (s, 1 H), 3.26 (s, 3 H), 3.61 (d, J=14.64 Hz, 2 H), 3.71 (m, 1 H) 3.84 (m, 1 H), 4.02 (s, 1 H), 7.53 (d, J=8.59 Hz, 1 H), 10.67 (m, 1 H), 11.94 (d, J=108.95 Hz, 1 H); 19F NMR (376 MHz, DMSO-d6) d ppm -155.52, - 155.47, -155.41 , -155.36, -138.88, -138.86, -138.83; Anal. Calcd for C20H19F2N5O5S-CSyH2O: C, 49.41 ; H, 4.09; N, 14.40. Found: C, 49.74; H, 4.13; N, 14.06.
EXAMPLE 57
[00280] Preparation of N-(4-methoxybenzyl)urea. 4-Methoxy-benzylamine (9.46 ml, 72.9 mmol) was dissolved in water (60 ml) and concentrated HCI (6.1 ml) was added. The mixture was heated to 70 CC and potassium nitrite (6.5 g, 80.0 mmol) was added. The solution was heated for 1 hr and white solids precipitated. The mixture was cooled to room temperature and the solids were collected by filtration and rinsed with water. The solids were recrystallized from ethanol to provide the title compound as white solids (9.98 g). 1H NMR (400 MHz, DMSO-d6) d ppm 3.67 (s, 3 H) 4.04 (d, J=6.05 Hz, 2 H) 5.42 (s, 2 H) 6.25 (t, J=5.86 Hz, 1 H) 6.81 (m, 2 H) 7.11 (m, 2 H); 13C NMR (101 MHz, DMSO-d6) d ppm 42.92, 55.69, 114.25, 128.97, 133.45, 158.69, 159.24; MS (APCI+) m/z 181 (MH+). [00281] Preparation of 1-(4-methoxybenzyl)pyrimidine-2,4,6(1 H,3H,5H)-trione. N-(4- methoxybenzyl)urea (3.81 g, 21.1 mmol) and malonic acid (2.55 g, 24.5 mmol) were dissolved in acetic acid (8 ml) and heated at 70 0C for 1 hr. The reaction mixture was cooled to room temperature, acetic acid (5 ml) was added and the resulting mixture was heated at 90 °C for 2 hrs. The reaction was cooled and concentrated by rotoevaporation and the resulting solids were recrystallized from ethanol to provide the title compound as white solids (3.1 g). 1H NMR (400 MHz, DMSO-d6) d ppm 3.61 (s, 2 H) 3.66 (s, 3 H) 4.74 (s, 2 H) 6.80 (d, J=8.59 Hz, 2 H) 7.19 (d, J=8.40 Hz, 2 H) 11.32 (s, 1 H); MS (APCI-) m/z 247 (M-). [00282] Compound 57. A slurry of 2-[(2R,6S)-2,6-dimethylmorpholin-4-yl]-3,4-difluoro-5-(5- methyl-1 ,3,4-thiadiazol-2-yl)benzaldehyde (0.68 g, 1.9 mmol) and 1-(4-methoxybenzyl)pyrimidine- 2,4,6(1 H,3H,5H)-trione (0.5 g, 2.90 mmol) in isopropanol (20 ml) were refluxed for 18 hrs. The mixture was cooled at 0 0C for 3-4 hours and the solids were filtered, rinsed with cold isopropanol and dried in a vacuum oven at 85 0C overnight to provide the title compound (0.48 g). 1H NMR (400 MHz, DMSO-d6) d ppm 0.98 (m, 6 H) 2.72 (s, 3 H) 2.91 (d, J=14.84 Hz, 1 H) 3.03 (m, 1 H) 3.55 (dd, J=8.59, 6.64 Hz, 2 H) 3.59 (s, 3 H) 3.72 (m, 1 H) 3.87 (m, 1 H) 4.03 (d, J=11.72 Hz, 1 H) 4.65 (m, 2 H) 6.74 (m, 2 H) 7.00 (m, 2 H) 7.44 (d, J=7.42 Hz, 1 H) 12.09 (s, 1 H).
EXAMPLE 58
[00283] Compound 58. Compound 57 (0.47 g, 0.81 mmol) was dissolved in DMF (1.1 ml) and triethylamine (0.22 ml, 1.6 mmol) and bromomethylacetate (0.16 m, 1.6 mmol) were added. The mixture was stirred at room temperature overnight and concentrated by rotoevaporation and purified by column chromatography to provide the title compound (0.35 g). 1H NMR (400 MHz, CDCI3-d) d ppm 0.84 (m, 3 H) 1.18 (t, J=6.35 Hz, 3 H) 2.04 (m, 3 H) 2.78 (m, 3 H) 2.87 (d, J=14.64 Hz, 1 H) 3.07 (d, J=14.25 Hz, 2 H) 3.73 (m, 4 H) 3.89 (m, 1 H) 4.06 (d, J=8.79 Hz, 1 H) 4.16 (dd, J=13.47, 1.95 Hz, 1 H) 4.77 (d, J=13.86 Hz, 1 H) 4.92 (m, 1 H) 5.86 (d, J=9.37 Hz, 1 H) 5.95 (m, 1 H) 6.75 (m, 2 H) 7.11 (d, J=8.40 Hz, 2 H) 7.46 (d, J=6.64 Hz, 1 H); MS (APCI+) m/z 656 (M+).
EXAMPLE 59
[00284] Compound 59. Compound 58 (0.35 g, 0.53 mmol) was slurried in MeOH (6 ml) and 1 molar hydrochloric acid (6 ml) was added and stirred overnight. The homogeneous solution was concentrated by rotoevaporation to provide the title compound (0.36 g). 1H NMR (400 MHz, DMSO-d6) d ppm 0.71 - 0.85 (m, 3 H) 1.07 (dd, J=6.15, 4.00 Hz, 3 H) 2.65 - 2.75 (m, 3 H) 2.94 (d, J=14.64 Hz, 1 H) 3.00 - 3.10 (m, 1 H) 3.41 (d, J=14.64 Hz, 1 H) 3.48 - 3.58 (m, 1 H) 3.58 - 3.62 (m, 3 H) 3.64 - 3.78 (m, 2 H) 3.82 - 3.98 (m, 1 H) 3.98 - 4.13 (m, 1 H) 4.56 - 4.83 (m, 1 H) 4.86 - 5.10 (m, 2 H) 5.12 - 5.28 (m, 1 H) 6.64 - 6.93 (in, 2 H) 6.95 - 7.30 (m, 2 H) 7.35 - 7.57 (m, 1 H)
EXAMPLE 60
[00285] Compound 60. Compound 59 (0.32 g, 0.53 mmol) was dissolved in methylene chloride (8 ml) and thionyl chloride (2 ml) was added. The reaction mixture was stirred for 30 min at room temperature. Water (40 ml) was added and the mixture was stirred for 5 minutes. The product was extracted with methylene chloride (3 x), the organic layers were combined, washed with brine, dried through sodium sulfate and concentrated by rotoevaporation to provide the title compound as solids (0.34 g). 1H NMR (400 MHz, CDCI3) d ppm 0.83 (m, 3 H) 1.20 (m, 3 H) 2.77 (m, 3 H) 2.85 (d, J=14.25 Hz, 1 H) 3.08 (m, 2 H) 3.71 (m, 4 H) 3.87 (m, 1 H) 4.11 (m, 2 H) 4.85 (d, J=13.86 Hz, 1 H), 5.07 (m, 1 H) 5.47 (m, 1 H) 5.67 (m, 1 H) 6.77 (m, 2 H) 7.20 (m, 2 H) 7.48 (m, 1 H).
EXAMPLE 61
[00286] Compound 61. Compound 60 (0.33 g, 0.52 mmol) was slurried with dibenzyl hydrogen phosphate (0.18 g, 0.65 mmol) and silver carbonate 90 mg, 0.33 mmol) in toluene (5 ml) and the mixture was heated at 70 0C for 3 hrs. More dibenzyl hydrogen phosphate (90 mg, 0.32 mmol) and silver carbonate 45 mg, 0.16 mmol) were added with continued heating for another hr. The reaction was quenched with saturated sodium bicarbonate and extracted with EtOAc (2 x). The combined organic layers were washed with brine, dried through sodium sulfate and concentrated by rotoevaporation. The crude product was purified by column chromatography to provide the title compound as a solid (0.46 g). 1H NMR (400 MHz, CDCI3) d ppm 0.66 - 0.91 (m, 3 H) 1.08 - 1.34 (m, 3 H) 2.61 - 2.81 (m, 3 H) 2.81 - 2.91 (m, 1 H) 2.91 - 2.99 (m, 1 H) 2.99 - 3.12 (m, 1 H) 3.57 - 3.67 (m, 1 H) 3.67 - 3.78 (m, 3 H) 3.77 - 3.93 (m, 1 H) 3.99 - 4.07 (m, 1 H) 4.10 - 4.19 (m, 1 H) 4.80 - 4.94 (m, 3 H) 4.94 - 5.08 (m, 3 H) 5.55 - 5.69 (m, 1 H) 5.69 - 5.91 (m, 1 H) 6.60 - 6.88 (m, 2 H) 7.02 - 7.50 (m, 13 H).
EXAMPLE 62
[00287] Steps 1 and 2: A flame-dried round-bottom flask was charged with Rieke magnesium
(1.9 ml_, 1.89 mmol, 1.0 M in THF). To the stirred dark suspension was added, dropwise over 7 min, a solution of arylnitrile (562.4 mg, 1.64 mmol) in (2 mL) of dry THF. The reaction was stirred at 23 0C for 15 min, then carbon disulfide was added (98 μl_, 1.64 mmol). The reddish-brown solution was heated to 40 0C for 45 h. After cooling to 23 0C, methyl iodide (0.11 mL, 1.83 mmol) was added and the reaction mixture was heated to 40 0C for 1 h. The reaction mixture was then cooled again to 23 0C, poured into water and extracted with EtOAc. The organic extract was washed with brine, dried (Na2SO4), filtered and concentrated. The crude dithioester was dissolved in EtOH (15 mL) and hydrazine monohydrate was added (0.24 mL, 4.92 mmol). The resulting solution was stirred at 23 0C for 1 h. The reaction mixture was concentrated onto silica gel and purified by silica gel chromatography (Biotage, 40 g SiO2, 50% EtOAc/Hex to 5% MeOH/CH2CI2) to afford 150 mg of thiohydrazide.
[00288] Steps 3 and 4: A mixture of thiohydrazide (63.9 mg, 0.19 mmol) and acetyl chloride (20 μL, 0.26 mmol) in dry THF (2 mL) was heated to reflux for 1 h. 1 M HCI (0.75 mL) was added and the heating was continued for 1 h. The reaction mixture was cooled to 23 0C, diluted with CH2CI2, washed with 10% Na2CO3 (2 x 10 mL). The organic extract was washed with brine, dried (Na2SOzO, filtered and concentrated. The residue was purified by silica gel chromatography (Biotage 12 g SiO2, 40% EtOAc/Hex) to afford 33.6 mg of thiadiazole aldehyde.
[00289] Step 5: A mixture of aldehyde (32.4 mg, 0.10 mmol) and barbituric acid in MeOH (2 mL) was heated to reflux for 18 hr. The solution was concentrated and the residue was purified by silica gel chromatography (Biotage 12 g SiO2, 50% EtOAc/Hex to 100% EtOAc) to afford 23.4 mg of compound 59: IR (diffuse reflectance) 2340 (w), 2048 (w), 1915 (w), 1754, 1727 (s), 1704 (s), 1610 (s), 1523, 1442, 1414, 1377, 1372, 1354 (s), 1338, 1245 cm'1. HRMS (ESI) calcd for C20H2IN5O4S +H1 428.1392, found 428.1400. Anal. Calcd for C20H21N5O4S: C, 56.19; H, 4.95; N, 16.38; S, 7.50. Found: C1 54.42; H, 5.15; N, 15.10.
EXAMPLE 63
[00290] Compound 60 was prepared according to Example 59, except that methoxy acetyl chloride was used as the acetyl chloride. Compound 60: IR (diffuse reflectance) 2350 (w), 2338 (w), 2052 (W), 1996 (w), 1990 (w), 1727 (s), 1710 (s), 1699 (s), 1608, 1447, 1439, 1429, 1415, 1354, 1338 cm" 1. HRMS (ESl) calcd for C21H23N5O5S +H1 458.1498, found 458.1498. % Water (KF titration): 1.40. Anal. Calcd for C21H23N5O5S: C, 55.13; H, 5.07; N, 15.31 ; S, 7.01. Found: C, 53.84; H, 5.57; N, 14.00; S, 6.69.
EXAMPLE 64
[00291] To a stirred solution of thiohydrazide (93.1 mg, 0.28 mmol) in THF (3 mL) was added
FMOC-GLY-CL (113.3 mg, 0.36 mmol). The resulting solution was heated to reflux for 1 h. 1 M HCI (0.5 ml.) was added and heating was continued for an additional hr. The reaction mixture was cool and diluted with EtOAc. The solution was washed with 10% aqueous Na2CO3. The aqueous phase was further extracted with EtOAc (1 x 20 ml_). The combined organic extracts were dried (Na2O4), filtered and concentrated to afford 140 mg of the thiadiazole.
[00292] A suspension of the thiadiazole (137 .7 mg, 0.25 mmol) and barbituric acid (31.8 mg, 0.25 mmol) in MeOH (2 mL) was heated to reflux for 18 h. The cooled solution was concentrated and purified by silica gel chromatography (Biotage 4Og SiO2, 2% MeOH/CH2CI2) to afford 98.4 mg, of barbituric acid derivative.
[00293] A mixture of the barbituric acid derivative (96.0 mg, 0.14 mrnol) in piperadine (0.5 mL) was stirred at 23 0C for 30 min. The mixture was then triturated with ether, and the solid was collected by filtration. The solid was purified by silica gel chromatography (Biotage, 12 g SiO2, 7% MeOH/CH2CL2) to afford 48.3 mg of compound 61. IR (diffuse reflectance) 3102 (b), 3085 (b), 3068 (b), 3060 (b), 3047 (b), 3036 (b), 3027 (b), 2957 (s), 2923 (s), 2853 (s), 2381 (b), 2367, 2354, 2038 (b), 2005 Cm-1. HRMS (ESI) calcd for C20H22N6O4S +H1 443.1501 , found 443.1510. Anal. Calcd for C20H22N6O4S1: C, 54.29; H, 5.01 ; N, 18.99; S, 7.25. Found: C, 52.14; H, 5.71 ; N, 16.39.
EXAMPLE 65
[00294] Compound 62 was prepared according to Example 59, except that ethyl oxalyl chloride was used as the acetyl chloride. Compound 62: IR (diffuse reflectance) 2352 (w), 2334 (w), 1957 (w), 1920 (W), 1915 (W), 1716 (s), 1607, 1414, 1396, 1393, 1351 , 1332, 1306, 1279, 1242 cm"1. HRMS (ESI) calcd for C22H23N5O6S +H1 486.1447, found 486.1451. % Water (KF titration): 1.72. Anal. Calcd for C22H23N5OeS1: C, 54.42; H, 4.77; N, 14.42; S, 6.60. Found: C, 53.44; H, 4.84; N, 14.24; S, 6.35.
EXAMPLE 66
[00295] Compound 63 was prepared according to Example 59, except that the following acetyl chloride was produced as follows and used:
[00296] Compound 63: IR (diffuse reflectance) 2481 (w), 2372 (w), 2347 (w), 2281 (w), 2048 (w),
1756 (s), 1732 (s), 1703 (s), 1609, 1438, 1408, 1379, 1375, 1355, 1245 cm'1. HRMS (ESI) calcd for C21H23N5O4S2 +H1 474.1270, found 474.1293. Anal. Calcd for C21H23N5O4S2: C, 53.26; H, 4.90; N, 14.79; S, 13.54. Found: C, 52.58; H, 4.91 ; N, 13.34; S, 12.48.
EXAMPLE 67
[00297] A mixture of nitrile (142.6 mg, 0.40 mmol) and the thiosemicarbazide (40.3 mg, 0.44 mmol) in TFA (0.150 mL) was heated to 60 0C for 30 min. The reaction mixture was cooled to 23 0C and poured into 1 N NH4OH (10 mL). The suspension was extracted with 10% MeOH/CH2CI2 (5 x 15 mL) and the combined organic extracts were dried (MgSO4) filtered and concentrated. The residue was purified by silica gel chromatography (Biotage 12 g SiO2, 7% MeOH/CH2CI2) to produce compound 64. IR (diffuse reflectance) 3321 , 2351 (w), 2338 (w), 1921 (w), 1916 (w), 1727 (s), 1710 (s), 1698 (s), 1609, 1466, 1458, 1451 , 1353, 1344, 1338 cm"1. % Water (KF titration): 5.92. Anal. Calcd for C19H20N6O4S: C, 53.26; H, 4.70; N, 19.61; S, 7.48. Found: C, 50.62; H, 5.43; N, 17.15. MP >240 0C
EXAMPLE 68
[00298] Step 1 : To a suspension of acid (636.1 mg, 0.70 mmol) in THF (15 mL) was added
HOBT (252.7 mg, 1.87 mmol), EDC-HCI (719.1 mg, 3.75 mmol) and t-Butylcarbazate (292.0 mg, 2.21 mmol). The reaction was stirred at 23 0C for 12 h, then was partitioned between CH2CI2 (100 mL) and water (35 mL). The phases were separated. The aqueous phase was further extracted with CH2CI2 (1 x 50 mL). The combined organic phases were dried (Na2SO4) filtered and concentrated. The residue was purified by silica gel chromatography (Biotage 40 g SiO2, 2 to 5% MeOH/CH2CI2) to afford 621.1 mg of Boc hydrazide.
[00299] Step 2: A mixture of the Boc-hydrazide (620 mg, 1.27 mmol), solid Na2HCO3 (373.4 mg,
4.45 mmol, and Lawesson's ragent (386.2 mg, 0.95 mmol) in THF (20 mL) was heated to reflux for 24 h. The reaction mixture was cooled to 23 0C, filtered and the filtrate was concentrated. The residue was purified by silica gel chromatography (Biotage 40 g SiO2, 2.5% MeOH/CH2CI2) to afford 359.6 mg of thiohydrazide.
[00300] Step 3, part 1 : A mixture of Boc-thiohydrazide in 4 N HCI/dioxane was stirred at 23 0C for
1.5 h. The reaction mixture was concentrated and the residue was dissolved in THF (5 mL). Disopropylethyl amine (0.25 mL, 1.46 mmol) was added. The resulting mixture was stirred at 23 0C for 15 min and then concentrated to afford the crude thiohydrazide.
[00301] Step 3, part 2: To a mixture of the thiohydrazide (52.3 mg, 0.13 mmol) in THF (2 mL) was added 3,4-difluorbenzoyl chloride (17 μL, 0.136 mmol). The reaction was stirred at 23 0C for 1 h. Concentrated HCI (2 drops) was added and the stirring was continued for 30 min. The formed solid precipitate was filtered, rinsed with Et2O and dried to afford 65.8 mg of compound 65. IR (diffuse reflectance) 2485 (w), 2351 (w), 2337 (w), 2228 (w), 2117 (w), 1758, 1727 (s), 1710 (s), 1608 (s), 1523, 1433 (s), 1397, 1353, 1337, 1282 cm'1. % Water (KF titration): 1.92. Anal. CaIcCI fOr C25H21F2N5O4S: C, 57.14; H, 4.03; N, 13.33; S, 6.10; F, 7.23. Found: C, 55.75; H, 4.15; N1 12.43.
EXAMPLE 69
[00302] In this example, the in vitro antibacterial activity of selected compounds was determined against S. aureus and H. influenzae. Except for clarifying or modifying statements, MIC testing followed procedures recommended by the NCCLS1'2 or followed the descriptions cited below. [00303] Bacterial Cultures At least the following organisms are included in the screen:
Staphylococcus aureus SA-1 (UC-76) and H. influenzae HI-3542. Incubations were at 35°C. Stock bacterial cultures were maintained on Tryptic Soy Agar containing 5% Sheep Blood (BD, Becton Dickinson Microbiology Systems, Cockeysville, Maryland), anaerobes were maintained on Anaerobic Blood Agar plates - CDC Formulation (BD), and fastidious organisms were maintained on Chocolate Agar Il Plates (BD). Specific conditions of handling are listed below.
[00304] Permanent Stock Culture Collection Stock cultures are stored as frozen suspensions at
-70°C. Most cultures are routinely suspended in 10% skim milk (BD) prior to snap freezing in dry ice/ethanol and then placed in a -700C freezer. Haemophilus were suspended in inactivated horse serum (Colorado Serum Company, Denver, Colorado) containing 7.5% glucose prior to snap freezing. [00305] Maintenance of Stock Cultures Most cultures were maintained on Tryptic Soy Agar containing 5% Sheep Blood at room temperature (2O0C). Each culture was recovered from frozen and transferred an additional time before MIC testing. Fresh plates were inoculated the day before testing, incubated overnight, and checked to confirm purity and identity.
[00306] Haemophilus was maintained on Chocolate Agar Il Plates at room temperature in a candle jar providing a 3 5% CO2 atmosphere.
[00307] Confirming Identity of Cultures Culture identifications were confirmed by standard microbiological methods3. Cultures were streaked onto appropriate agar plates for visualization of purity, expected colony morphology, and hemolytic patterns. Gram stains were also utilized. [00308] The identities of recent isolates used in this test were confirmed using a MicroScan
WalkAway 40 SI Instrument (Dade Behring, West Sacramento, California). This device utilizes an automated incubator, reader, and computer to assess for identification purposes the biochemical reactions carried out by each organism. Using this machine, organism identification (confirmation) and an initial antibiogram was generated for each strain.
[00309] Standardized Organism lnocula Frozen stock cultures were used as the initial source of organisms for performing microbroth dilution MIC testing. Stock cultures were passed on their standard growth medium for at least 1 growth cycle (18 24 hours) prior to their use.
[00310] Most bacteria, unless otherwise noted, were prepared directly from agar plates in 1O mL aliquots of the appropriate broth medium. Bacterial cultures were adjusted to the opacity of a 0.5 McFarland Standard (optical density value of 0.28-0.33 on a Perkin-Elmer Lambda EZ150 Spectrophotometer Wellesley, Massachusetts, set at a wavelength of 600nm).). The adjusted cultures were diluted 400 fold (0.25 mL inoculum + 100 mL broth) in growth media to produce a starting suspension of approximately 5 x 1O5 colony forming units (CFU)/mL. Unless otherwise noted, bacterial strains were tested in cation adjusted Mueller Hinton Broth (CAMHB). [00311] Haemophilus influenzae strains were grown on Chocolate Agar Il Plates and tested in
Haemophilus Test Medium (Remel, Lenexa, Kansas).
[00312] Test Compound ("Drug") Preparation Compounds were solubilized in DMSO. Drug stock solutions were prepared on the day of testing. Drugs were weight corrected for assay content where necessary.
[00313] Drug Dilution Tray Preparation Microbroth dilution stock plates were prepared in two dilution series, 64 to 0.06 μg drug/mL and 0.25 to 0.00025 μg drug/mL. For the high concentration series,
200 μL of stock solution (2 mg/mL) was added to duplicate rows of a 96-well microtiter plate. This was used as the first well in the dilution series. Serial two-fold decremental dilutions were made using a
BioMek FX robot (Beckman Coulter Inc., Fullerton, CA) with 10 of the remaining 11 wells, each of which contained 100 μL of the appropriate solvent/diluent. Row 12 contained solvent/diluent only and served as the control. For tube one of the low concentration series, 200 μL of an 8 μg/mL stock was added to duplicate rows of a 96-well plate. Serial two-fold dilutions were made as described above.
[00314] Daughter plates were spotted (3.2 μL/well) from the stock plates listed above using the
BioMek FX robot and were either used immediately or frozen at -70°C until use.
[00315] Plate Inoculation Aerobic organisms were inoculated (100 μL volumes) into the thawed plates using the BioMek FX robot. The inoculated plates were placed in stacks of no more than 5 and covered with an empty plate. These plates were incubated 16 to 24 hours in ambient atmosphere according to CLSI guidelines2.
[00316] Reading the Test After inoculation and incubation, the degree of bacterial growth was estimated visually with the aid of a Test Reading Mirror (Dynex Technologies 220 16) in a darkened room with a single light shining directly through the top of the microbroth tray. The MIC was the lowest concentration of drug that prevented macroscopically visible growth under the conditions of the test.
Testing was performed in duplicate. When the MIC values in duplicate tests varied by 1 well (2 fold), the lower values were reported. If the MICs varied by 2 dilutions, the middle value was reported. Greater than this 4 fold variance called for the test to be repeated, after which a similar determination was applied to all values.
REFERENCES:
[00317] 1. National Committee for Clinical Laboratory Standards. Performance Standards for
Antimicrobial Susceptibility Testing; Fourteenth Informational Supplement. NCCLS document M100-S14 {ISBN 1 -56238-516-X}, NCCLS, 940 West Valley Road, Suite 1400, Wayne, Pennsylvania 19087-1898 USA, 2004.
[00318] 2. National Committee for Clinical Laboratory Standards. Methods for Dilution
Antimicrobial Tests for Bacteria That Grow Aerobically; Approved Standard-Sixth Edition. NCCLS document M7-A6 {ISBN 1-56238-486-4}, NCCLS, 940 West Valley Road, Suite 1400, Wayne, Pennsylvania 19087-1898 USA, 2003.
[00319] 3. Murray PR, Baron EJ, Jorgensen JH, Pfaller MA, Yolken RH. Manual of Clinical
Microbiology, Eighth Edition. ASM Press {ISBN 1-55581-255-4}, American Society for Microbiology, 1752 N Street NW, Washington, DC 20036-2904 USA, 2003. [00320] Using this protocol, the following results were generated:
* - MICs for Compounds 48-52 were determined using a different protocol than set forth herein. [00321] Relative stereochemistry for racemic compounds was assigned based on the R or S designation of the active enantiomer.
[00322] As used herein, reference to "a" or "an" means "one or more." Throughout, the plural and singular should be treated as interchangeable, other than the indication of number. [00323] As will be understood by one skilled in the art, for any and all purposes, particularly in terms of providing a written description, all ranges disclosed herein also encompass any and all possible subranges and combinations of subranges thereof as well as the individual values making up the range, particularly integer values. Any listed range can be easily recognized as sufficiently describing and enabling the same range being broken down into at least equal halves, thirds, quarters, fifths, tenths, etc. As a non-limiting example, each range discussed herein can be readily broken down into a lower third, middle third and upper third, etc. For example, the range C1-C6, includes the subranges C2-C6, C3-C6, C3- C5, C4-C6, etc., as well as Ci (methl), C2 (ethyl), C3 (propyl), C4 (butyl), C5 (pentyl) and C6 (hexyl) individually. As will also be understood by one skilled in the art, all language such as "up to," "at least," "greater than," "less than," "more than," "or more" and the like include the number recited and refer to ranges which can be subsequently broken down into subranges as discussed above. In the same manner, all ratios disclosed herein also include all subratios falling within the broader ratio. [00324] One skilled in the art will also readily recognize that where members are grouped together in a common manner, such as in a Markush group, the present invention encompasses not only the entire group listed as a whole, but each member of the group individually and all possible subgroups of the main group. Additionally, for all purposes, the present invention encompasses not only the main group, but also the main group absent one or more of the group members. The present invention also envisages the explicit exclusion of one or more of any of the group members in the claimed invention. [00325] As will be understood by the skilled artisan, all numbers, including those expressing quantities of ingredients, properties such as molecular weight, reaction conditions, and so forth, are approximations and understood as being modified in all instances by the term "about." These values can vary depending upon the desired properties sought to be obtained by those skilled in the art utilizing the present teachings of the present invention. It is also understood that such values inherently contain variability necessarily resulting from the standard deviations found in their respective testing measurements.
[00326] All references disclosed herein are specifically incorporated herein by reference thereto.
[00327] While specific embodiments have been illustrated and described, it should be understood that these embodiments do not limit the scope of the invention and that changes and modifications can be made in accordance with ordinary skill in the art without departing from the invention in its broader aspects as defined in the following claims. Reference to a "step" in the application is used for convenience purposes only and does not categorize, define or limit the invention as set forth herein.

Claims

CLAIMSWhat is claimed is:
1. A compound of formula I:
or a salt, solvate, hydrate or prodrug thereof, wherein: Ri is a substituted or unsubstituted thiadiazole; R2 and R3 are independently H or substituted or unsubstituted C1-6 alkyl; R4 and R5 are independently H, a substituted or unsubstituted Ct-6 alkyl, a substituted or unsubstituted ether, substituted or unsubstituted -(CH2)maryl, substituted or unsubstituted benzyl, -O(CH2)maryl, -Obenzyl, -(CH2)mNR8R9, -(CH2)mOR6, -(CH2)mOPO3(Rp)2, -(CH2)mOC(=O)(CH2)mCH3, -(CH2)mOC(=O)(CH2)mCO2R6, -(CH2)mOC(=O)(CH2)mNR8R9, -(CH2)mOC(=O)E, or R4 and R5 together with the atoms to which they are attached form a substituted or unsubstituted heterocyclic ring; each m is independently 0, 1 , 2 or 3; E is a substituted or unsubstituted ether; each Rp is independently H, C1^ alkyl, benzyl, substituted benzyl, phenyl, substituted phenyl, or (Rp)2 together with the atoms to which they are attached form a substituted or unsubstituted heterocyclic ring; each R6 is independently H, Ci-6 alkyl, C1^ acyl or benzyl; R8 and Rg are independently H, substituted or unsubstituted C1-6 alkyl or R8 and R9 together with the atom to which they are attached form a substituted or unsubstituted heterocyclic ring; and X and Y are independently H, halo, substituted or unsubstituted C1-6 alkyl, -OR6, a substituted or unsubstituted ether, or a substituted or unsubstituted amine; with the proviso that the compound is not rel-(2R,4S,4aS)-1 ,2,4,4a-Tetrahydro- 2,4-dimethyl-8-[5-(methylthio)-1 ,3,4-thiadiazol-2-yl]spiro[[1 ,4]oxazino[4,3-a]quinoline- 5(6H),5'(2'H)-pyrimidine]-2',4',6'(1 'H,3'H)-trione.
2. The compound of claim 1 wherein R1 is: or
VΛΛ/VP indicates a point of attachment;
R7 is H, halo, substituted or unsubstituted C1-6 alky!, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted heterocyclyl, a substituted or unsubstituted ether, - (CH2)mOPθ3(Rp)2, -(CH2)mOC(=O)(CH2)mCH3, -(CH2)mOC(=O)(CH2)mCO2R6, -(CH2)mOC(=O)(CH2)mNR8R9, -(CH2)mOC(=O)E, -(CH2)mCO2(CH2)mCH3, -(CH2)mCO2(CH2)mCO2R6, -(CH2)mCO2(CH2)mNR8R9, -(CH2)mCO2E, -(CH2)mC(=O)NR6(CH2)mCO2R6, -(CH2)mC(=O)NR8R9, -(CH2)mNR8R9, -(CH2)HiPO3(Rn)2, -(CH2)mOR10, which is optionally substituted with -OR11, -(CH2)mC(=O)OR11, -(CH2)H1NR11SOnR12, -(CH2)mSOnR12, -(CH2)mSOnNR8R9) substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; each n is independently is 0, 1 or 2;
R10 is H, substituted or unsubstituted C1^ alkyl, -PO3H2, C(=0)R13, C(=0)0R13 or C(=O)NR8R9; and
R11, R12 and R13 are independently H, substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted aminoalkyl, substituted or unsubstituted benzyl, substituted or unsubstituted phenyl, an amino acid residue or a peptide residue.
3. The compound of any one of claims 1-2 wherein X is H or F, Y is H or F or both X and Y are H or F.
4. The compound of any one of claims 1-3 wherein R2 and R3 are methyl.
5. The compound of any one of claims 1-4 wherein R-i is
6. The compound of claim 5 wherein R1 is
7. The compound of any one of claims 1-6 wherein R7 is H or methyl.
8. The compound of any one of claims 1-7 having formula Ia:
9. The compound of any one of claims 1-8 wherein each E or ether independently has the formula -[(CV2)pO(CV2)p]qCH3 wherein each p is independently 0, 1 , 2, 3, 4, 5 or 6, each q is independently 1 , 2, 3, 4, 5 or 6, each V is independently H or another -[(CV2)p0(CV2)p]qCH3.
10. The compound of claim 9, wherein each E or ether independently has the formula -[(CH2)pO(CH2)p]qCH3 where each p is independently 0, 1 , 2, 3 or 4 and each q is independently 1 , 2, 3 or 4. 11. The compound of claim 1 having a structure of compound 1-9,
11 -41 , 42-48 or 50-65 of Table 1 , an enantiomer thereof or a salt, solvate, or hydrate thereof.
12. rel-(2R,4S,4aS)-9,10-Difluoro-2>4-dimethyl-8-(5-methyl-1 ,3,4-thiadiazol-2-yl)- 1 ,2,4,4a-tetrahydro-2'H,6H-spiro[1 Aoxazinoμ.S-alquinoline-δ.δ'-pyrimidinel-^'.δXI Η,3'H)- trione or a pharmaceutically acceptable salt thereof.
13. [(rel-2R,4S,4aS)-9,10-Difluoro-2,4-dimethyl-8-(5-methyl-1 ,3,4-thiadiazol-2-yl)- 2',4l,6'-trioxo-1 ,2,4,4a-tetrahydro-2lH,6H-spiro[1 ,4-oxazino[4,3-a]quinoline-5,5'-pyrimidine]- 1 ',3'(4'H,6'H)-diyl]bis(methylene) diphosphate or a pharmaceutically acceptable salt thereof.
14. A pharmaceutical composition comprising a compound of any one of claims 1-13 and a pharmaceutically acceptable carrier, diluent or excipient.
15. A bacteriostatic and/or bactericidal method comprising: (a) contacting a bacteria with a compound of any of claims 1-13 or a composition of claim 14.
16. The method of claim 15 wherein (a) occurs in vitro or in vivo.
17. A method of treating a bacterial infection in a mammal comprising administering an effective amount a compound of any of claims 1-13 or a composition of claim 14 to the mammal.
18. The method of claim 17 comprising preventing a bacterial infection in a mammal by administering an effective amount a compound of any of claims 1-13 or a composition of claim 14 to the mammal.
19. A method of making a compound of any one of claims 1-13 having formula Il comprising: (a) reacting a compound of formula III with a compound of formula IV at a temperature sufficient to produce a compound of formula II: I" Il
20. The method of claim 19 wherein (a) occurs in an aqueous or organic solvent.
21. The method of claim 19 or 20 wherein temperature of (a) is about 60 to about 180 0C.
22. The method of any one of claims 19-21 wherein (a) is performed for about 2 to about 24 hours.
23. The method of any one of claims 19-22 further comprising: (b) reacting a compound of formula V with a compound of formula Vl to make the compound of formula III,
Vl
24. The method of claim 23 wherein (b) occurs in the presence of a non-protic organic solvent and/or in the presence of a base.
25. The method of claim 24 wherein the base is an organic base or an inorganic base.
26. The method of any one of claims 23-25 wherein the temperature of (b) is about 20 to about 100 0C.
27. The method of any one of claims 23-26 further comprising: (c)(i) performing a halogen metal exchange or deprotonation reaction on a compound of formula VII; and (c)(ϋ) reacting the product of (c)(i) with a carbonyl donor to make the compound of formula V, wherein Ha is hydrogen or a halogen.
28. The method of claim 27 wherein (c)(i) comprises contacting the compound of formula VII with a strong base.
29. The method of claim 28 wherein the strong base comprises alkyl lithium.
30. The method of claim 27 wherein (c)(i) comprises contacting the compounds of formula VII with a Grignard reagent in a non-protic organic solvent.
31. The method of any one of claims 27-30 wherein the temperature of (c)(i) is about -78 to about 50 0C.
32. The method of any one of claims 27-31 wherein the carbonyl donor comprises one or more of dimethylformamide, N-formylmorpholine, or para-nitrophenylformate.
33. The method of any one of claims 23-26 further comprising:
(c) oxidizing a compound of formula VIII to make the compound of formula V,
34. A method of making the compound of formula XVII comprising (a) reacting a compound of formula XVIII with a compound of formula Vl to make the compound of formula XVII,
Vl wherein R14 is a halogen, boronic acid, a boronate ester or a substituted or unsubstituted thiadiazole; and
R2 and R3 are independently H or substituted or unsubstituted C1^ alkyl.
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