WO2004018428A1 - Antibacterial benzoic acid derivatives - Google Patents

Antibacterial benzoic acid derivatives Download PDF

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Publication number
WO2004018428A1
WO2004018428A1 PCT/US2003/024796 US0324796W WO2004018428A1 WO 2004018428 A1 WO2004018428 A1 WO 2004018428A1 US 0324796 W US0324796 W US 0324796W WO 2004018428 A1 WO2004018428 A1 WO 2004018428A1
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Prior art keywords
amino
carbonyl
benzoic acid
cyano
alkyl
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PCT/US2003/024796
Other languages
French (fr)
Inventor
Atli Thorarensen
Craig J. Ruble
Jed F. Fisher
Donna L. Romero
Thomas J. Beauchamp
Jill M. Northuis
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Pharmacia & Upjohn Company Llc
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Application filed by Pharmacia & Upjohn Company Llc filed Critical Pharmacia & Upjohn Company Llc
Priority to AU2003264005A priority Critical patent/AU2003264005A1/en
Publication of WO2004018428A1 publication Critical patent/WO2004018428A1/en

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    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D213/00Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/78Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/81Amides; Imides
    • C07D213/82Amides; Imides in position 3
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
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    • C07D209/00Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04Indoles; Hydrogenated indoles
    • C07D209/30Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
    • C07D209/42Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
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    • C07DHETEROCYCLIC COMPOUNDS
    • C07D231/00Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/14Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D241/00Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
    • C07D241/02Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
    • C07D241/10Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
    • C07D241/14Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D241/24Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
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    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D261/00Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings
    • C07D261/02Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings
    • C07D261/06Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members
    • C07D261/08Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
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    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D261/00Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings
    • C07D261/02Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings
    • C07D261/06Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members
    • C07D261/10Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D261/00Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings
    • C07D261/20Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings condensed with carbocyclic rings or ring systems
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    • C07D277/00Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/60Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings condensed with carbocyclic rings or ring systems
    • C07D277/62Benzothiazoles
    • C07D277/68Benzothiazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 2
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D279/00Heterocyclic compounds containing six-membered rings having one nitrogen atom and one sulfur atom as the only ring hetero atoms
    • C07D279/021,2-Thiazines; Hydrogenated 1,2-thiazines
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D333/00Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/26Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D333/38Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
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    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D401/00Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D405/00Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D409/00Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D413/00Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/04Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D413/00Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D417/00Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07D471/00Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04Ortho-condensed systems
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    • C07D487/02Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/08Bridged systems
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    • C07D495/00Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04Ortho-condensed systems

Definitions

  • the present invention relates to antibacterial agents that are useful for sterilization, sanitation, antisepsis, and disinfection.
  • Bacteria have caused degradation of natural product materials, infection in humans and other animals, and spoilage of foods.
  • Sterilization denotes the use of either physical or chemical agents to eliminate all viable bacteria from a material, while disinfection generally refers to the use of germicidal chemical agents to destroy the potential infectivity of a material. Sanitizing refers to procedures used to simply lower the bacterial content of utensils used for food. Antisepsis refers to the topical application of chemicals to a body surface to kill or inhibit pathogenic microbes. Disinfectants are widely used for skin antisepsis in preparation for surgery.
  • Bacteria are the smallest organisms that contain all the machinery required for growth and self-replication.
  • a bacterium includes a rigid cell wall surrounding the cytoplasmic membrane, which itself encloses a single naked chromosome without a nuclear membrane.
  • the cytoplasmic membrane consists primarily of a bi-layer of lipid molecules.
  • bactericidal action is loss ofthe ability ofthe organism to propagate indefinitely, when placed in a suitable environment.
  • Bactericidal action suggests microbe damage of various types, including the triggering of irreversible damage to the cytoplasmic cell membrane or irreversible impairment of the DNA (or viral RNA replication. Accordingly, sterilization is not identical with destruction of microbes. Additionally, it is understood that damage to nucleic acids (DNA or RNA) is not always irreversible, as it is known that ultraviolet light-induced damage to viral nucleic acids can be repaired by enzymatic and genetic mechanisms.
  • the invention relates to antibacterial agents that are useful for sterilization, sanitation, antisepsis, and disinfection.
  • the invention features methods of using antibacterial agents of formula I for sterilizing, sanitizing, antisepsis, or disinfecting.
  • the method includes applying the antibacterial agent to a location in need of sterilization, sanitation, antisepsis, and disinfection.
  • the antibacterial agents have the formula
  • X and Y together form an alkene, or cycloalkyl
  • R 2 is an electron withdrawing group; and R t is an optionally substituted HET.
  • halo refers to a halogen atom selected from CI, Br, I, and F.
  • alkyl refers to both straight- and branched-chain moieties. Unless otherwise specifically stated alkyl moieties include between 1 and 9 carbon atoms.
  • alkynyl refers to both straight- and branched-chain moieties containing at least one -C ⁇ C- Unless otherwise specifically stated alkynyl moieties include between 1 and 9 carbon atoms, between 1 and 6 carbon atoms
  • alkoxy refers to -O-alkyl groups.
  • cycloalkyl refers to a cyclic alkyl moiety. Unless otherwise specifically stated cycloalkyl moieties will include between 3 and 9 carbon atoms.
  • amino refers to -NH 2 .
  • aryl refers to phenyl and naphthyl.
  • hetero refers to mono- or bi-cyclic ring systems containing at least one heteroatom selected from O, S, and N. Each mono-cyclic ring may be aromatic, saturated, or partially unsaturated.
  • a bi-cyclic ring system may include a mono-cyclic ring containing at least one heteroatom fused with an cycloalkyl or aryl group.
  • a bi- cyclic ring system may also include a mono-cyclic ring containing at least one heteroatom fused with another het, mono-cyclic ring system.
  • heterox examples include, but are not limited to, pyridine, thiophene, furan, pyrazoline, pyrimidine, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 5- pyrimidinyl, 3-pyridazinyl, 4-pyridazinyl, 3-pyrazinyl, 4-oxo-2-imidazolyl, 2-imidazolyl, 4-imidazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 3-pyrazolyl, 4-pyrazolyl, 5- pyrazolyl, 2-oxazolyl, 4-oxazolyl, 4-oxo-2-oxazolyl, 5-oxazolyl, 1,2,3-oxathiazole, 1,2,3-oxadiazole, 1,2,4-oxadiazole, 1,2,5-oxadiazole, 1,3,4-oxadia
  • heteroaryl refers to a mono- or bicylic het in which at least one cyclic ring is aromatic.
  • -NQi 0 S(O)Qio, -NQ 10 SQ ⁇ o, -NO 2 , -SNQ10Q10, alkyl, substituted alkyl, het, halo, cycloalkyl, cycloalkenyi, and aryl.
  • the het, cycloalkyl, cycloalkenyi, and aryl being optionally substituted with 1-3 substitutuents selected from halo and Q15.
  • substituted cycloalkenyi refers to a cycloalkenyi moiety including 1 -
  • -NQ ⁇ oS(O)Q 10 -NQioSQio, -NO 2
  • -SNQ 10 Q ⁇ o, alkyl, substituted alkyl, het, halo, cycloalkyl, cycloalkenyi, and aryl.
  • the het, cycloalkyl, cycloalkenyi, and aryl being optionally substituted with 1-3 substitutuents selected from halo and Q 15 .
  • -NQi 0 S(O) 2 Qio, -NQ ⁇ oS(O)Q ⁇ o, -NQioSQio, -NO 2 , -SNQioQio, alkyl, substituted alkyl, het, halo, cycloalkyl, cycloalkenyi, and aryl.
  • the het, cycloalkyl, cycloalkenyi, and aryl being optionally substituted with 1-3 substitutuents selected from halo and Q 15 .
  • Each Q 1 0 is independently selected from -H, alkyl, cycloalkyl, het, cycloalkenyi, and aryl.
  • the het, cycloalkyl, cycloalkenyi, and aryl being optionally substituted with 1-3 substitutuents selected from halo and Q J3 .
  • Each Qn is independently selected from -H, halo, alkyl, aryl, cycloalkyl, and het.
  • Each Q ⁇ 4 is -H or a substituent selected from alkyl, cycloalkyl, phenyl, or naphthyl, each optionally substituted with 1-4 substituents independently selected from -F, -CI, -Br, -I, -OQ 16 , -SQ ⁇ 6 , -S(O) 2 Q ⁇ 6 , -S(O)Q ⁇ 6 , -OS(O) 2 Q ⁇ 6 , -NQ ⁇ 6 Q ⁇ 6 , -C(O)Q ⁇ 6 , -C(S)Q 16 , -C(O)OQi6, -NO 2 , -C(O)NQ ⁇ 6 Qi6, -C(S)NQ 16 Q ⁇ 6 , -CN, -NQ ⁇ 6 C(O)Q ⁇ 6 , -NQ ⁇ 6 C(S)Qi6, -NQi 6 C(O)NQi 6 Qi 6 , -NQ ⁇ 6 C(S
  • Each Qi 6 is independently selected from -H, alkyl, and cycloalkyl.
  • the alkyl and cycloalkyl optionally including 1-3 halos. Mammal denotes human and animals.
  • Each Qn is independently selected from -H, -OH, and alkyl optionally including 1-3 halos and -OH.
  • electrosenor withdrawing group refers to the ability of a substituent to withdraw electrons relative to that of hydrogen if the hydrogen atom occupied the same position on the molecule.
  • electron withdrawing group is well understood by one skilled in the art and is discussed in Advanced Organic Chemistry by J. March, John Wiley & Sons, New York, New York, (1985) and the discussion therein is incorporated herein by reference.
  • alkyl optionally substituted with 1-3 halo, -OH, NO 2 , and provided that at least one of Zn is halo, -CN, or NO 2 , and further provided that Qn is not -OH when the the electron withdrawing group is -(CO)-Q ⁇ .
  • the present invention encompasses any racemic, optically-active, polymorphic, tautomeric, or stereoisomeric form, or mixture thereof, of a compound ofthe invention, which possesses the useful properties described herein.
  • Examples of pharmaceutically acceptable salts include, but are not limited to, the following acids acetic, aspartic, benzenesulfonic, benzoic, bicarbonic, bisulfuric, bitartaric, butyric, calcium edetate, camsylic, carbonic, chlorobenzoic, citric, edetic, edisylic, estolic, esyl, esylic, formic, fumaric, gluceptic, gluconic, glutamic, glycollylarsanilic, hexamic, hexylresorcinoic, hydrabamic, hydrobromic, hydrochloric, hydroiodic, hydroxynaphthoic, isethionic, lactic, lactobionic, maleic, malic, malonic, mandelic, methanesulfonic, methylnitric, methylsulfuric, mucic, muconic, napsylic, nitric, oxalic,
  • compositions may be obtained using standard procedures well known in the art, for example by reacting a sufficiently basic compound such as an amine with a suitable acid affording a physiologically acceptable anion.
  • Alkali metal (for example, sodium, potassium or lithium) or alkaline earth metal (for example calcium) salts of carboxylic acids can also be made.
  • the antibacterial agents of this invention have useful activity against a variety of organisms.
  • the in vitro activity of compounds of this invention can be assessed by standard testing procedures such as the determination of minimum inhibitory concentration (MIC) by agar dilution as described in "Approved Standard. Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria That Grow Aerobically", 3rd. ed., published 1993 by the National Committee for Clinical Laboratory Standards, Villanova, Pennsylvania, USA.
  • the antibacterial agents described herein are useful for sterilization, sanitation, antisepsis, and disinfection.
  • the antibacterial agents can be applied to a location in need of sterilization, sanitation, antisepsis, or disinfection, by methods known to those skilled in the art.
  • the antibacterial agents may be inco ⁇ orated into a cleaning solution that is applied, such as by spraying or pouring, to an item in need of sterilization, sanitation, antisepsis, or disinfection.
  • the antibacterial agents may be used alone or in combination, e.g., agents disclosed herein with one another or agent(s) disclosed herein with other antibacterial agents.
  • the antibacterial agents may be applied in varying concentrations depending upon the bacterial susceptibility to antibacterial agent(s) being applied and the desired level of sterilization, sanitation, antisepsis, or disinfection.
  • certain antibacterial agents described herein are useful for treating microbial infections in mammals, such as by administering an effective amount ofthe antibacterial agent compound to the ⁇ iammal.
  • Examples of compounds useful as antimicrobial agents for the treatment of microbial infections mammals include, but are not limited to, 5-bromo-2-( ⁇ [3-chloro-5-(trifluoromethyl)-2-pyridinyl]carbonyl ⁇ amino)benzoic acid 2-( ⁇ [4-( ⁇ [2-(4-aminophenyl)ethyl]amino ⁇ sulfonyl)-3-methylthien-2- yljcarbonyl ⁇ amino)-5-bromobenzoic acid
  • the antibacterial agent may be inco ⁇ orated into a pharmaceutical composition.
  • compositions of this invention may be prepared by combining the compounds of this invention with a solid or liquid pharmaceutically acceptable carrier and, optionally, with pharmaceutically acceptable adjuvants and excipients employing standard and conventional techniques.
  • Solid form compositions include powders, tablets, dispersible granules, capsules, cachets and suppositories.
  • a solid carrier can be at least one substance which may also function as a diluent, flavoring agent, solubilizer, lubricant, suspending agent, binder, tablet disintegrating agent, and encapsulating agent.
  • Inert solid carriers include magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, cellulosic materials, low melting wax, cocoa butter, and the like.
  • Liquid form compositions include solutions, suspensions and emulsions.
  • solutions ofthe compounds of this invention dissolved in water and water-propylene glycol systems, optionally containing suitable conventional coloring agents, flavoring agents, stabilizers and thickening agents.
  • the pharmaceutical composition is provided employing conventional techniques in unit dosage form containing effective or appropriate amounts ofthe active component, that is, the compound according to this invention.
  • the quantity of active component that is the compound according to this invention, in the pharmaceutical composition and unit dosage form thereof may be varied or adjusted widely depending upon the particular application, the potency ofthe particular compound and the desired concentration. Generally, the quantity of active component will range between 0.5% to 90% by weight ofthe composition.
  • the compounds or pharmaceutical compositions thereof will be administered orally, parenterally and/or topically at a dosage to obtain and maintain a concentration, that is, an amount, or blood-level of active component in the animal undergoing treatment which will be antibacterially effective.
  • a concentration that is, an amount, or blood-level of active component in the animal undergoing treatment which will be antibacterially effective.
  • such antibac- terially effective amount of dosage of active component will be in the range of about 0.1 to about 100, more preferably about 3.0 to about 50 mg/kg of body weight/day. It is to be understood that the dosages may vary depending upon the requirements ofthe patient, the severity ofthe bacterial infection being treated, and the particular compound being used.
  • the initial dosage administered may be increased beyond the above upper level in order to rapidly achieve the desired blood-level or the initial dosage may be smaller than the optimum and the daily dosage may be progressively increased during the course of treatment depending on the particular situation. If desired, the daily dose may also be divided into multiple doses for administration, e.g., 2-4 four times per day.
  • the compounds according to this invention may be administered parenterally, i.e., by injection, for example, by intravenous injection or by other parenteral routes of administration.
  • compositions for parenteral administration will generally contain a pharmaceutically acceptable amount ofthe compound or a soluble salt (acid addition salt or base salt) dissolved in a pharmaceutically acceptable liquid carrier such as, for example, water-for-injection and a buffer to provide a suitably buffered isotonic solution, for example, having a pH of about 3.5-6.
  • a pharmaceutically acceptable liquid carrier such as, for example, water-for-injection
  • a buffer to provide a suitably buffered isotonic solution, for example, having a pH of about 3.5-6.
  • Suitable buffering agents include, for example, trisodium orthophosphate, sodium bicarbonate, sodium citrate, N-methylglucamine, L(+)-lysine and L(+)-arginine to name but a few representative buffering agents.
  • the compound of this invention generally will be dissolved in the carrier in an amount sufficient to provide a pharmaceutically acceptable injectable concentration in the range of about 1 mg/mL to about 400 mg/mL of solution.
  • the resulting liquid pharmaceutical composition will be administered so as to obtain the above-mentioned antibacterially effective amount of dosage.
  • the compounds according to this invention are advantageously administered orally in solid and liquid dosage forms.
  • an effective amount of Formula I is admixed in a pharmaceutically acceptable gel or cream vehicle that can be applied to the patient's skin at the area of treatment.
  • a pharmaceutically acceptable gel or cream vehicle that can be applied to the patient's skin at the area of treatment.
  • Preparation of such creams and gels is well known in the art and can include penetration enhancers.
  • the antibacterial agents of this invention have useful activity against a variety of organisms.
  • the in vitro activity of compounds of this invention can be assessed by standard testing procedures such as the determination of minimum inhibitory concentration (MIC) by agar dilution as described in "Approved Standard. Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria That Grow Aerobically", 3rd. ed., published 1993 by the National Committee for Clinical Laboratory Standards, Villanova, Pennsylvania, USA.
  • the antibacterial compounds are prodrugs ofthe compounds of formula I.
  • the expression "prodrug” denotes a derivative of a known direct acting drug, which is transformed into the active drug by an enzymatic or chemical process.
  • Prodrugs ofthe compounds of formula I are prepared by modifying functional groups present on the compound in such a way that the modifications are cleaved, either in routine manipulation or in vivo, to the parent compound.
  • Prodrugs include, but are not limited to, compounds of structure (I) wherein hydroxy, amine or sulfhydryl groups are bonded to any group that, when administered to the animal, cleaves to form the free hydroxyl, amino or sulfhydryl group, respectively.
  • prodrugs include, but are not limited to, acetate, formate and benzoate derivatives of alcohol and amine functional groups. See Notari, R. E., "Theory and Practice of Prodrug Kinetics," Methods in Enzymology, 112:309-323 (1985); Bodor, N., “Novel Approaches in Prodrug Design,” Drugs ofthe Future, 6(3): 165-182 (1981); and Bundgaard, H., “Design of Prodrugs: Bioreversible- Derivatives for Various Functional Groups and Chemical Entities,” in Design of Prodrugs (H. Bundgaard, ed.), Elsevier, N.Y. (1985).
  • the antibacterial compounds of this invention may be synthesized by various methods known to those skilled in the art. Non-limiting examples of synthetic schemes for producing the antibacterial agents are described below.
  • Ethyl 7-(benzyloxy)-lH-indole-2-carboxylate (10.22 g, 34.6 mmol) was dissolved in DMF (100 mL). NaH (60% dispersion, 2 g) was added and the reaction was stirred for 30 min at rt. Mel (25 mL) was added and solution stirred overnight. The reaction was diluted with MTBE, washed with H 2 O x5, dried (MgSO 4 ), concentrated to afford 12.16 g (114%o) Ethyl 7-(benzyloxy)-l -methyl- lH-indole-2-carboxylate as a yellow solid. The crude material was carried on as is.
  • the acid chloride was re-dissolved in CH 2 C1 2 (70 mL), added to a solution of tert-butyl-2-amino-5-cyanobenzoate (4.15 g, 19.0 mmol) in CH 2 C1 2 (70 mL) and pyridine (6 mL), and stirred at rt overnight.
  • the solution was diluted with
  • Examplel.7 The compound of Examplel.7 (150 mg, 0.334 mmol) was dissolved in CH 2 C1 2 (4 ml), TFA (3 mL), and H 2 O (3 drops) and shaken at rt for 20 min. Heptane was added to the solution and the volatiles were removed in vacuo. The crude product was purified by recrystalization from MeOH/CH 2 Cl 2 to afford 74 mg (54%) of a white solid.
  • the reaction was diluted with CH 2 C1 2 , washed with H 2 O, dried (MgSO ), concentrated, and triturated with MeOH to afford 20 mg (36 %) ofthe t-Bu ester, 36883-bdw-108.
  • the ester (20 mg, 0.0399 mmol) was dissolved in THF (10 mL) and H 2 O (1 mL) with LiOH (50 mg, 1.19 mmol) and shaken at 45°C overnight.
  • the acid was diluted with CH 2 C1 2 , washed with 2 N HCl, dried (MgSO ), concentrated, and triturated with MeOH to afford 11 mg (61 %) of a white solid.
  • Example 1.21-1.121 The following compounds were produced by making non-critical variations to the methods described above.
  • the synthesis ofthe pyridine derivative is outlined in Scheme 1.
  • the amide 1 was easily prepared by acylation of 4-chloronicotinic acid.
  • the displacement ofthe chloride with a thiol nucleophile could be achieved with thioacetate in refluxing methanol affording the desired thiol in modest yield.
  • the conversion ofthe thiol to a sulfonamide and subsequent hydrolysis afforded the desired acid.
  • the aqueous solution was diluted to 100 mL with water and the solution washed 2x with CH 2 C1 2 .
  • the aqueous layer was made acidic with concentrated HCl to afford a white precipitate, which was collected by vacuum filtration, washed with water and heptane and dissolved in a mixture of CH 2 C1 2 and THF.
  • the organic solution was dried over MgSO 4 , filtered and evaporated. The resultant product was dried at 100 °C under vacuum to afford 79g (37%) of a white solid.
  • 5-Phenoxynicotinic acid (75 mg, 0.35 mmol) was suspended in dry CH 2 C1 2 (10 mL) under N 2 and treated with DMF (15 ⁇ L) followed by oxalyl chloride (60 ⁇ L, 0.70 mmol). Gas evolved as the mixture rapidly became homogenous. After stirring for one hour at RT, the solvent and excess oxalyl chloride were evaporated and the resultant yellowish residue was taken up in dry CH 2 C1 (10 mL). Methyl 2-arnino-5- cyanobenzoate (61 mg, 0.35 mmol) was added as a solution in dry pyridine (3 mL) and the dark amber solution was stirred at RT overnight.
  • tert-Butyl-2-amino-5- cyanobenzoate (2.23 g, 10.7 mmol) was added as a solution in 5 mL dry pyridine and the dark gold solution was stirred at RT for four hours.
  • the cloudy reaction was diluted with CH 2 C1 2 (200 mL), and the organic layer was washed 2x with 1.0M HCl, and lx with brine (200 mL each). The organic layer was evaporated, and then purified on a Biotage Flash 40M (90g) silica cartridge using 5% EtOAc in CH 2 C1 2 .
  • the solvent was evaporated and the resultant product dried under vacuum at 100 °C to afford 2.89 g (71%) of white solid as the t-butyl ester.
  • the t-butyl ester (l.Og, 2.61 mmol) was dissolved dry CH 2 C1 2 (10 mL) and was treated with TFA (5.0 mL) turning the mixture yellow. After stirring 24 hours at RT, the reaction was complete by HPLC.
  • the crude product was precipitated by diluting the reaction with CH 3 OH and collected by vacuum filtration thru #42 filter paper. The product was washed with CH 3 OH, THF, and heptane. The crude product was dried on the filter paper at 100 °C under vacuum to afford 626 mg (73%) of bone white solid.
  • nalidixic acid 26, 5.8 g, 0.025 mol dissolved 250 mL of CH 2 C1 2
  • DMF 2 drops
  • oxalyl chloride 25 mL of a 2 M solution in CH 2 C1 2 , 50 mmol
  • the acid chloride was concentrated to dryness, azeotroped with toluene (2 x 25 mL), dried on a high vacuum overnight, and used in situ for the following reactions.
  • Resin-bound 5-cyano anthranilic acid (5, 0.5 g, 1.0 mmol/g loading, 500 ⁇ mol) was suspended in pyridine (100 mL) in a 250-mL serum flask equipped with an overhead stirrer. After the addition of nalidixic acid chloride (27, 5 mL of a 1 M solution in CH 2 C1 2 , 10 equiv), the flask was purged with nitrogen and stirred at room temperature for 20 h.
  • the reaction mixture was then drained and the resin washed (CH 3 CN, DMF, CH 3 CN, DMF, CH 3 CN, DMF, H 2 O, THF, H 2 O, THF, H 2 O, THF, CH 3 CN, CH 2 C1 2 , CH 3 CN, CH 2 C1 2 , CH 3 CN, CH 2 C1 2 , CH 2 C1 2 , CH 2 C1 2 , 50 mL each wash).
  • the product was then cleaved from the resin using 50% TFA/CH 2 C1 2 for 3 h to yield 28 (60 mg, 32%) in 78%) reaction purity as determined by HPLC/MS analysis.
  • nalidixic acid chloride 27, 6 mL of a 1 M solution in CH 2 C1 2 , 1.2 equiv
  • pyridine 75 mL
  • Additional nalidixic acid chloride ⁇ 0.5 equiv was added until the aniline was completely consumed as determined by HPLC analysis ofthe reaction mixture.
  • the reaction mixture was concentrated to a dark brown solid and dried on a high vacuum for 4 h.
  • Example JFF-4 Example JFF-5 PHA-729249 PHA-729247 Preparation of l-Methyl-5-phenyl-lH-pyrazole-3-carboxyUc acid ethyl ester [10199-51-6] and l-Methyl-3-phenyl-lH-pyrazole-5-carboxylic acid ethyl ester [10250-63-2].
  • Compound 4a is prepared from [10199-53-8], using the procedure given for JFF-4b: MS (ESI+) w/z 415.5.
  • Example 5.1 5-Bromo-2-[[(l-methyl-5-phenyl-lH-pyrazol-3- yl)carbonyl]amino]benzoic acid (Example JFF-4).
  • Example JFF-4 is prepared from 4a using the procedure given for Example JFF-5:
  • Example 5.2 5-Bromo-2-[[(l-methyl-3-phenyl-lJ ⁇ -pyrazol-5- yl)carbonyl]amino]benzoic acid (Example JFF-5).
  • Example JFF-6 *H NMR (CDCi,, 400 MHz) ⁇ 12.29 (IH), 8.65 (IH), 8.2 (IH), 7.61 (IH), 7.25 (IH), 7.14 (IH), 6.95 (2H), 4.27 (3H); MS (FAB) m/z 436.0105.
  • the resulting solid was filtered and washed with MeOH, giving 2.9 g (72%) ofthe desired nitro-amide.
  • the nitro-amide was reduced with 10%> Pd/C in 100 mL (THF/MeOH, 1/1) with ammonium formate (4.7 g, 75 mmol) as H 2 source. After stirring for 10 hr at room temperature the mixture was filter and the resulting solids washed with THF. Excess solvent was removed in vacuo and the residue purified by chromatography (1% MeOH in CHC1 3 ) to give 2.61 g ofthe title compound (96%).
  • Example 6.5 5-cyano-2- [( ⁇ 5- [ (methylsulfonyI)amino] -1 ,2-benzisoxazol-3- yl ⁇ carb onyl) aminojbenzoic acid tert-Butyl 2- ⁇ [(5-amino : 1 ,2-benzisoxazol-3-yl)carbonyl]amino ⁇ -5-cyanobenzoate (250 mg, 0.66 mmol) was dissolved in CHC1 3 (10 ml). Pyridine (1 mL) and methanesulfonyl chloride (116 ⁇ L, 1.5 mmol) were then added and the reaction sti ⁇ ed for 10 hrs at room temperature.
  • Product was adsorbed onto silica gel, divided into two lots, and purified on Biotage Flash 40 M siliga gel cartridges using 70% CH 2 C1 2 in heptane as eluent.
  • Product was collected as 2.46 g (70%) of white solid as the t-butyl ester.
  • the conesponding tert-butyl ester (435 mg, 1.09 mmol) was sti ⁇ ed for 15.5 hours in a mixture of CH 2 C1 2 (30 mL) and TFA (20 mL). The solvents were removed by rotary evaporation, and the residue was recrystallized from ethanol/THF.
  • Trimethylsilyl cyanide (17 5 mL, 131 mmol, Aldrich) was added by syringe to a solution of 5-bromo-2-fluorobenzaldehyde (24 7 g, 122 mmol, Lancaster) and 1,4- diazabicyclo[2 2 2]octane (1 0 g, 8 9 mmol, Aldrich) in CH 2 C1 2 (60 mL) at such a rate that the mixture maintained a moderate reflux
  • the mixture was diluted with CH 2 C1 2 (150 mL) and washed with water (3 X 150 mL) and brine (150 mL)
  • the organics were dried over Na 2 SO and evaporated leaving the silylated cyanohydrin as 35 g of golden oil
  • This material was treated with concentrated HCl (75 mL) in water (25 mL) and then heated to reflux for 2 hours The mixture was allowed to cool and then made basic with 6 0 M NaOH The mixture was
  • Hycfroxylamine hydrochloride (3.57 g, 51.4 mmol, Mallinckrodt) and sodium acetate (4.39 g, 53.5 mmol, Mallinckrodt) were added as solids to a solution of ethyl (5- bromo-2-fluoropheny ⁇ )(oxo)acetate (12.8 g, 46.4 mmol) in ethanol (30 mL).
  • ethanol 30 mL
  • the mixture was stirred at room temperature for 3 hours and then at 50 °C for 1 hour.
  • the mixture was allowed to cool and was then filtered.
  • the precipitate was washed with ethanol, and these washings were added to the filtrate.
  • the filtrate was concentrated to an oil. Water (200 mL) was added, and the product was extracted into EtOAc.
  • the resulting solid was filtered and washed with MeOH, giving 2.9 g (72%>) ofthe desired nitro-amide.
  • the nitro-amide was reduced with 10% Pd/C in 100 mL (THF/MeOH, 1/1) with ammonium formate (4.7 g, 75 mmol) as H 2 source. After stirring for 10 hr at room temperature the mixture was filter and the resulting solids washed with THF. Excess solvent was removed in vacuo and the residue purified by chromatography (1% MeOH in CHC1 3 ) to give 2.61 g ofthe title compound (96%).
  • Example 6.36a 5-cyano-2-( ⁇ [5-(dimethylamino)-l,2-benzisoxazol-3- yl] carbonyl ⁇ amino)benzoic acid
  • Example 6.36b tert-butyl 2-( ⁇ [6-(acetyloxy)-l,2-benzisoxazol-3- yl]carbonyl ⁇ amino)-5-cyanobenzoate
  • 6-Hydroxy-l,2-benzisoxazole-3-carboxylic acid (4.5 g, 25 mmol) was dissolved in 25 mL of acetic anhydride. Several drops of concentrated sulfuric acid were added and the solution sti ⁇ ed at room temperature. After 4 h the reaction was poured onto ice and then extracted with CH 2 C1 2 . The organic solution was dried over Na 2 SO and concentrated to give 6-acetoxy-l,2-benzisoxazole-3-carboxylic acid as white solid. This solid (2.8 g, 12.7 mmol) was suspended in 100 mL CH 2 C1 2 and 2.5 mL of oxalyl chloride was added followed by 10 drops of DMF.
  • Example 6.37 2-( ⁇ [6-(acetyloxy)-l,2-benzisoxazol-3-yl]carbonyl ⁇ amino)-5- cyanobenzoic acid tert-Butyl 2-( ⁇ [6-(acetyloxy)-l,2-ber ⁇ zisoxazol-3-yl]carbonyl ⁇ amino)-5-cyanobenzoate (250 mg, 0.59 mmol) was dissolved in 10 mL CH 2 C1 2 /TFA (1/1) and sti ⁇ ed for 3 h at room temperature. Solvent was removed in vacuo and the remaining solid was washed with MeOH to give 206 mg ofthe title compound.
  • Example 6.38a tert-butyl 5-cyano-2- ⁇ [(6-hydroxy-l,2-benzisoxazol-3- yl) carbonyl] arnino ⁇ benzoate
  • Example 6.38b 5-cyano-2- ⁇ [(6-hydroxy-l,2-benzisoxazol-3- yl)carbonyl]amino ⁇ benzoic acid tert-Butyl 5-cyano-2- ⁇ [(6-hydroxy-l ,2-benzisoxazol-3-yl)carbonyl]amino ⁇ benzoate (250 mg, 0.60 mmol) was dissolved in 10 mL CH 2 C1 2 /TFA (1/1) and sti ⁇ ed for 4 h at room temperature. Solvent was removed in vacuo and the remaining solid was washed with MeOH to give 213 mg of the title compound.
  • Ethyl- l,2-benzisoxazole-3-carboxylate (10 g, 52 mmol) was dissolved in 100 mL of chlorosulfonic acid and heated to 80 C. After 16 h the reaction was cooled to room temperature, poured onto ice and then extracted with EtOAc. The organic solution was dried over Na 2 SO and then concentrated to a brown oil. This oil was dissolved in 60 mL of thionyl chloride and heated to 50 C. After 6 h excess reagent was removed in vacuo and the remaining residue dissolved in 300 mL CHC1 3 . Methyl-2-amino-5- bromobenzoate was added as a solution in 100 mL CHC1 3 and 10 mL pyridine.
  • Methyl 5-bromo-2-( ⁇ [5-(chlorosulfonyl)-l,2-benzisoxazol-3-yl]carbonyl ⁇ amino)benzoate 250 mg, 0.53 mmol was suspended in 5 mL of THF.
  • Mo ⁇ holine 0.5 mL, 5.7 mmol was added and the reaction warmed to 50 C. Solvent was removed in vacuo and the resulting solid washed with MeOH. This solid was suspended in 5 mL THF and 1 mL water and 50 mg LiOH was added. After 5 h the reaction was acidified with 1 N HCl and extracted with EtOAc.

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Abstract

The invention provides antimicrobial agents and methods of using the agents for sterilization, sanitation, antisepsis, disinfection, and treatment of infections in mammals.

Description

ANTIBACTERIAL BENZOIC ACID DERIVATIVES
FIELD OF THE INVENTION The present invention relates to antibacterial agents that are useful for sterilization, sanitation, antisepsis, and disinfection.
BACKGROUND
The inappropriate growth of a variety of bacteria has been a problem for many years. Bacteria have caused degradation of natural product materials, infection in humans and other animals, and spoilage of foods.
Sterilization denotes the use of either physical or chemical agents to eliminate all viable bacteria from a material, while disinfection generally refers to the use of germicidal chemical agents to destroy the potential infectivity of a material. Sanitizing refers to procedures used to simply lower the bacterial content of utensils used for food. Antisepsis refers to the topical application of chemicals to a body surface to kill or inhibit pathogenic microbes. Disinfectants are widely used for skin antisepsis in preparation for surgery.
Bacteria are the smallest organisms that contain all the machinery required for growth and self-replication. A bacterium includes a rigid cell wall surrounding the cytoplasmic membrane, which itself encloses a single naked chromosome without a nuclear membrane. The cytoplasmic membrane consists primarily of a bi-layer of lipid molecules.
The fundamental criterion of bactericidal action is loss ofthe ability ofthe organism to propagate indefinitely, when placed in a suitable environment. Bactericidal action suggests microbe damage of various types, including the triggering of irreversible damage to the cytoplasmic cell membrane or irreversible impairment of the DNA (or viral RNA replication. Accordingly, sterilization is not identical with destruction of microbes. Additionally, it is understood that damage to nucleic acids (DNA or RNA) is not always irreversible, as it is known that ultraviolet light-induced damage to viral nucleic acids can be repaired by enzymatic and genetic mechanisms.
SUMMARY OF THE INVENTION The invention relates to antibacterial agents that are useful for sterilization, sanitation, antisepsis, and disinfection. In one aspect, the invention features methods of using antibacterial agents of formula I for sterilizing, sanitizing, antisepsis, or disinfecting. The method includes applying the antibacterial agent to a location in need of sterilization, sanitation, antisepsis, and disinfection. In general, the antibacterial agents have the formula
Figure imgf000003_0001
wherein X = NH
Y = CO, CS, -C(=N-CN) or
X and Y together form an alkene, or cycloalkyl;
Figure imgf000003_0002
R2 is an electron withdrawing group; and Rt is an optionally substituted HET.
DETAILED DESCRIPTION OF THE INVENTION The term "halo" refers to a halogen atom selected from CI, Br, I, and F. The term "alkyl" refers to both straight- and branched-chain moieties. Unless otherwise specifically stated alkyl moieties include between 1 and 9 carbon atoms. The term "alkenyl" refers to both straight- and branched-chain moieties containing at least one -C=C- Unless otherwise specifically stated alkenyl moieties include between 1 and 9 carbon atoms.
The term "alkynyl" refers to both straight- and branched-chain moieties containing at least one -C≡C- Unless otherwise specifically stated alkynyl moieties include between 1 and 9 carbon atoms, between 1 and 6 carbon atoms The term "alkoxy" refers to -O-alkyl groups.
The term "cycloalkyl" refers to a cyclic alkyl moiety. Unless otherwise specifically stated cycloalkyl moieties will include between 3 and 9 carbon atoms. The term "cycloalkenyi" refers to a cyclic alkenyl moiety. Unless otherwise specifically stated cycloalkyl moieties will include between 3 and 9 carbon atoms and at least one -C=C- group within the cyclic ring. The term "amino" refers to -NH2. The term "aryl" refers to phenyl and naphthyl.
The term "het" refers to mono- or bi-cyclic ring systems containing at least one heteroatom selected from O, S, and N. Each mono-cyclic ring may be aromatic, saturated, or partially unsaturated. A bi-cyclic ring system may include a mono-cyclic ring containing at least one heteroatom fused with an cycloalkyl or aryl group. A bi- cyclic ring system may also include a mono-cyclic ring containing at least one heteroatom fused with another het, mono-cyclic ring system.
Examples of "het" include, but are not limited to, pyridine, thiophene, furan, pyrazoline, pyrimidine, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 5- pyrimidinyl, 3-pyridazinyl, 4-pyridazinyl, 3-pyrazinyl, 4-oxo-2-imidazolyl, 2-imidazolyl, 4-imidazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 3-pyrazolyl, 4-pyrazolyl, 5- pyrazolyl, 2-oxazolyl, 4-oxazolyl, 4-oxo-2-oxazolyl, 5-oxazolyl, 1,2,3-oxathiazole, 1,2,3-oxadiazole, 1,2,4-oxadiazole, 1,2,5-oxadiazole, 1,3,4-oxadiazole, 2-thiazolyl, 4- thiazolyl, 5-thiazolyl, 3-isothiazole, 4-isothiazole, 5-isothiazole, 2-furanyl, 3-furanyl, 2- thienyl, 3-thienyl, 2-pyrrolyl, 3-pyrrolyl, 3-isopyrrolyl, 4-isopyrrolyl, 5-isopyrrolyl, 1,2,3,-oxathiazole-l-oxide, l,2,4-oxadiazol-3-yl, l,2,4-oxadiazol-5-yl, 5-oxo-l,2,4- oxadiazol-3-yl, l,2,4-thiadiazol-3-yl, l,2,4-thiadiazol-5-yl, 3-oxo-l,2,4-thiadiazol-5-yl, l,3,4-thiadiazol-5-yl, 2-oxo-l,3,4-thiadiazol-5-yl, l,2,4-triazol-3-yl, l,2,4-triazol-5-yl, l,2,3,4-tetrazol-5-yl, 5-oxazolyl, 3-isothiazolyl, 4-isothiazolyl, 5-isothiazolyl, 1,3,4,- oxadiazole, 4-oxo-2-thiazolinyl, 5-methyl-l,3,4-thiadiazol-2-yl, thiazoledione, 1,2,3,4- thiatriazole, 1 ,2,4-dithiazolone, phthalimide, quinolinyl, morpholinyl, benzoxazoyl, diazinyl, triazinyl, quinolinyl, quinoxalinyl, naphthyridinyl, azetidinyl, pyrrolidinyl, hydantoinyl, oxathiolanyl, dioxolanyl, imidazolidinyl, and azabicyclo[2.2.1]heptyl. The term "heteroaryl" refers to a mono- or bicylic het in which at least one cyclic ring is aromatic. The term "substituted alkyl" refers to an alkyl moiety including 1-4 substituents selected from halo, het, cycloalkyl, cycloalkenyi, aryl, -OQio, -SQio, -S(O)2Qιo, -S(O)Qιo, -OS(O)2Qιo, -C(=NQ10)Qιo, -C(=N-O-Q10)Q10, -S(O)2-N=S(O)(Q10)2, -S(O)2-N=S(Q10)2, -NQioQio, -C(O)Qιo, -C(S)Q10, -C(O)OQι0, -OC(O)Q10, -C(S)NQιoQιo, -N(Qιo)C(S)NQ10Q10, -C(O)NQ10Qιo, -C(S)NQιoQιo, -C(O)C(Q16)2OC(O)Qιo, -CN, =O, =S, -NQ10C(O)Q10, -NQ10C(O)NQ100, -S(O)2NQ10Qιo, -NQ10S(O)2Q10, -NQι0S(O)Q10, -NQ10SQ10, -NO2, and -SNQ100. Each ofthe het, cycloalkyl, cycloalkenyi, and aryl being optionally substituted with 1- 4 substituents independently selected from halo and Q15.
The term "substituted aryl" refers to an aryl moiety having 1-3 substituents selected from -OQ10, -SQι„, -S(O)2Qι„, -S(O)Q10, -OS(O)2Qιo, -C(=NQ10)Qιo, - C(=NOQ10)Qιo, -S(O)2-N=S(O)(Q10)2, -S(O)2-N=S(Q10)2, -NQ10Qιo, -C(O)Q10, - C(S)Q10, -C(O)OQιo, -OC(O)Q10, -C(O)NQ10Qιo, -C(S)NQ10Qιo, -C(O)C(Q16)2OC(O)Q10, -CN, -NQ10C(O)Qιo, -N(Qιo)C(S)NQ10Qιo, -N(Q10)C(S)Q10, -NQ10C(O)NQ10Qιo, -S(O)2NQιoQιo, -NQi0S(O)2Qio, -NQ10S(O)Q10, -NQ10SQι0) -NO2, -SNQ10Qιo, alkyl, substituted alkyl, alkenyl, alkynyl, het, halo, cycloalkyl, cycloalkenyi, and aryl. The het, cycloalkyl, cycloalkenyi, alkenyl, alkynyl, and aryl being optionally substituted with 1-3 substitutuents selected from halo and Q15.
The term "substituted het" refers to a het moiety including 1-4 substituents selected from -OQ10, -SQ10, -S(O)2Q10, -S(O)Q10, -OS(O)2Q10, -C(=NQι0)Qιo, -C(=NOQ10)Qιo, -S(O)2-N=S(O)(Q10)2, -S(O)2-N=S(Q10)2, -NQ10Q10, -C(O)Q10, -C(S)Q10, -C(O)OQιo, -OC(O)Qιo, -C(O)NQ10Q10, -C(S)NQ10Qιo, -C(O)C(Qi6)2OC(O)Qio, -CN, =O, =S, -NQ10C(O)Q10, -NQ10C(S)Q10,
-NQ10C(O)NQ10Qιo, -NQ10C(S)NQ10Q10, -S(O)2NQ10Qιo, -NQ10S(O)2Q10, -NQ10S(O)Qιo, -NQ10SQ10, -NO2, -SNQ10Q10, alkyl, substituted alkyl, het, halo, cycloalkyl, cycloalkenyi, and aryl. The het, cycloalkyl, cycloalkenyi, and aryl being optionally substituted with 1-3 substitutuents selected from halo and Q15. The term "substituted alkenyl" refers to a alkenyl moiety including 1-3 substituents -OQ10, -SQ10, -S(O)2Qιo, -S(O)Q10, -OS(O)2Q10, -C(=NQ10)Qιo, -C(=NOQ10)Qιo, -S(O)2-N=S(O)(Q10)2, -S(O)2-N=S(Q10)2, -NQ10Q10, -C(O)Q10, -C(S)Q10, -C(O)OQ10, -OC(O)Q10, -C(O)NQ10Q10, -C(S)NQ10Qιo, -C(O)C(Qι6)2OC(O)Q10, -CN, =O, =S, -NQ10C(S)Q10, -NQ10C(O)Q10, -NQ10C(O)NQιoQιo, -NQ10C(S)NQιoQ10, -S(O)2NQ100, -NQ10S(O)2Q10,
-NQi0S(O)Qio, -NQ10SQιo, -NO2, -SNQ10Q10, alkyl, substituted alkyl, het, halo, cycloalkyl, cycloalkenyi, and aryl. The het, cycloalkyl, cycloalkenyi, and aryl being optionally substituted with 1-3 substitutuents selected from halo and Q15. The term "substituted alkoxy" refers to an alkoxy moiety including 1-3 substituents -OQio, -SQio, -S(O)2Q10, -S(O)Qι0, -OS(O)2Qιo, -C(=NQ10)Q10, -C(=NOQ10)Qιo, -S(O)2-N=S(O)(Q10)2, -S(O)2-N=S(Q10)2, -NQ10Qιo, -C(O)Q10, -C(S)Qιo, -C(O)OQ10, -OC(O)Q10, -C(O)NQ10Q10, -C(S)NQιoQιo, -C(O)C(Q16)2OC(O)Qιo, -CN, O, =S, -NQ10C(S)Q10, -NQι0C(O)Q10, -NQ10C(O)NQ10Q10, -NQ10C(S)NQ10Q10, -S(O)2NQ10Q10, -NQι0S(O)2Q10, -NQi0S(O)Qio, -NQioSQio, -NO2, -SNQ10Qιo, alkyl, substituted alkyl, het, halo, cycloalkyl, cycloalkenyi, and aryl. The het, cycloalkyl, cycloalkenyi, and aryl being optionally substituted with 1-3 substitutuents selected from halo and Qι5. The term "substituted cycloalkenyi" refers to a cycloalkenyi moiety including 1 -
3 substituents -OQio, -SQio, -S(O)2Qιo, -S(O)Qι0, -OS(O)2Q10, -C(=NQι0)Qιo, -C(=NOQ10)Qιo, -S(O)2-N=S(O)(Q10)2, -S(O)2-N=S(Q10)2, -NQ10Q10, -C(O)Q10, -C(S)Q10, -C(O)OQ10, -OC(O)Q10, -C(O)NQ10Q10, -C(S)NQ10Q10, -C(O)C(Q16)2OC(O)Q10, -CN, =O, =S, -NQ10C(S)Q10, -NQ10C(O)Q10, -NQ10C(O)NQ100) -NQ10C(S)NQ10Q1o, -S(O)2NQ10Qιo, -NQ10S(O)2Q10,
-NQιoS(O)Q10, -NQioSQio, -NO2, -SNQ10Qιo, alkyl, substituted alkyl, het, halo, cycloalkyl, cycloalkenyi, and aryl. The het, cycloalkyl, cycloalkenyi, and aryl being optionally substituted with 1-3 substitutuents selected from halo and Q15.
The term "substituted amino" refers to an amino moiety in which one or both ofthe amino hydrogens are replaced with a group selected from -OQio, -SQio, -S(O)2Qιo, -S(O)Qιo, -OS(O)2Qιo, -C(=NQι0)Q10, -C(=NOQ10)Qιo, -S(O)2- N=S(O)(Q10)2,
-S(O)2-N=S(Qιo)2, -NQioQio, -C(O)Qιo, -C(S)Qι0, -C(O)OQκ>, -OC(O)Qιo, -C(O)NQ10Qιo, -C(S)NQιoQιo, -C(O)C(Qι6)2OC(O)Qι0, -CN, =O, =S, -NQι0C(O)Qι0, -NQi0C(S)Qio, -NQi0C(O)NQioQio, -NQι0C(S)NQι0Qιo, -S(O)2NQ10Qιo,
-NQi0S(O)2Qio, -NQιoS(O)Qιo, -NQioSQio, -NO2, -SNQioQio, alkyl, substituted alkyl, het, halo, cycloalkyl, cycloalkenyi, and aryl. The het, cycloalkyl, cycloalkenyi, and aryl being optionally substituted with 1-3 substitutuents selected from halo and Q15.
Each Q10 is independently selected from -H, alkyl, cycloalkyl, het, cycloalkenyi, and aryl. The het, cycloalkyl, cycloalkenyi, and aryl being optionally substituted with 1-3 substitutuents selected from halo and QJ3. Each Qn is independently selected from -H, halo, alkyl, aryl, cycloalkyl, and het. The alkyl, aryl, cycloalkyl, and het being optionally substituted with 1-3 substituents independently selected from halo, -NO2, -CN, =S, =O, and Qi4. Each Qι3 is independently selected from Qn, -OQπ, -SQn, -S(O)2Qn, -S(O)Qn, -OS(O)2Qn, -C(=NQιι)Qπ, -S(O)2-N=S(O)(Qn)2, -S(O)2-N=S(Qn)2, -SC(O)Q,ι, -NQiiQn, -C(O)Qn, -C(S)Qn, -C(O)OQn, -OC(O)Qn, -C(O)NQnQn, -C(S)NQnQn, -C(O)C(Qι6)2OC(O)Qι0, -CN, =O, =S, -NQnC(O)Qn, -NQnC(S)Qn, -NQιιC(O)NQnQn, -NQnC(S)NQιιQn, -S(O)2NQnQn, -NQnS(O)2Qιι, -NQπS(O)Qn, -NQπSQn, -NO2, and -SNQ„Qn. Each Qι4 is -H or a substituent selected from alkyl, cycloalkyl, phenyl, or naphthyl, each optionally substituted with 1-4 substituents independently selected from -F, -CI, -Br, -I, -OQ16, -SQι6, -S(O)26, -S(O)Qι6, -OS(O)26, -NQι66, -C(O)Qι6, -C(S)Q16, -C(O)OQi6, -NO2, -C(O)NQι6Qi6, -C(S)NQ166, -CN, -NQι6C(O)Qι6, -NQι6C(S)Qi6, -NQi6C(O)NQi6Qi6, -NQι6C(S)NQι66, -S(O)2NQ166, and -NQiδS(O)2Qi6. The alkyl, cycloalkyl, and cycloalkenyi being furher optionally substituted with =O or =S.
Each Qis is H, alkyl, cycloalkyl, heterocycloalkyl, heteroaryl, phenyl, or naphthyl, each optionally substituted with 1-4 substituents independently selected from -F, -CI, -Br, -I, -OQ16, -SQi6, -S(O)2Q16, -S(O)Qι6, -OS(O)26, -C(=NQι6)Qι6,
-S(O)2-N=S(O)(Q16)2, -S(O)2-N=S(Qι6)2, -SC(O)Qι6, -NQι66, -C(O)Qι6, -C(S)Qι6, -C(O)OQi6, -OC(O)Qi6, -C(O)NQι6Q16, -C(S)NQι66, -C(O)C(Qι6)2OC(O)Qι6, -CN, -NQi6C(O)Qi6, -NQi6C(S)Qi6, -NQι6C(O)NQι66, -NQι6C(S)NQι66, - S(O)2NQι6Q16, -NQι6S(O)2Q16, -NQι6S(O)Qι6, -NQ16SQι6, -NO2, and -SNQι6Q,6. The alkyl, cycloalkyl, and cycloalkenyi being furher optionally substituted with =O or =S.
Each Qi6 is independently selected from -H, alkyl, and cycloalkyl. The alkyl and cycloalkyl optionally including 1-3 halos. Mammal denotes human and animals. Each Qn is independently selected from -H, -OH, and alkyl optionally including 1-3 halos and -OH.
The term "electron withdrawing group" refers to the ability of a substituent to withdraw electrons relative to that of hydrogen if the hydrogen atom occupied the same position on the molecule. The term "electron withdrawing group" is well understood by one skilled in the art and is discussed in Advanced Organic Chemistry by J. March, John Wiley & Sons, New York, New York, (1985) and the discussion therein is incorporated herein by reference. Electron withdrawing groups include, but are not limited to, groups such as halo, nitro, carboxy, cyano, aryl optionally substituted, aromatic het (excluding pyridine) optionally substituted, -OC(Zn)3, -C(Zn)3, -C^ O-C^, -(CO)-Q17, -SOz-QZn -SO2-aryl, -C(NQ17)Qι7, -CH=C(Qι7)2, - C≡C-Qπ, in which each Zn and Zm is independently H, halo, -CN, -NO2 -OH, or Ci. alkyl optionally substituted with 1-3 halo, -OH, NO2, and provided that at least one of Zn is halo, -CN, or NO2, and further provided that Qn is not -OH when the the electron withdrawing group is -(CO)-Qι .
It is to be understood that the present invention encompasses any racemic, optically-active, polymorphic, tautomeric, or stereoisomeric form, or mixture thereof, of a compound ofthe invention, which possesses the useful properties described herein.
In cases where compounds are sufficiently basic or acidic to form stable nontoxic acid or base salts, use ofthe compounds as pharmaceutically acceptable salts may be appropriate. Examples of pharmaceutically acceptable salts which are within the scope ofthe present invention include organic acid addition salts formed with acids which form a physiological acceptable anion and inorganic salts. Examples of pharmaceutically acceptable salts include, but are not limited to, the following acids acetic, aspartic, benzenesulfonic, benzoic, bicarbonic, bisulfuric, bitartaric, butyric, calcium edetate, camsylic, carbonic, chlorobenzoic, citric, edetic, edisylic, estolic, esyl, esylic, formic, fumaric, gluceptic, gluconic, glutamic, glycollylarsanilic, hexamic, hexylresorcinoic, hydrabamic, hydrobromic, hydrochloric, hydroiodic, hydroxynaphthoic, isethionic, lactic, lactobionic, maleic, malic, malonic, mandelic, methanesulfonic, methylnitric, methylsulfuric, mucic, muconic, napsylic, nitric, oxalic, p-nitromethanesulfonic, pamoic, pantothenic, phosphoric, monohydrogen phosphoric, dihydrogen phosphoric, phthalic, polygalactouronic, propionic, salicylic, stearic, succinic, sulfamic, sulfanilic, sulfonic, sulfuric, tannic, tartaric, teoclic toluenesulfonic, primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, such as arginine, betaine, caffeine, choline, N, N-dibenzylethylenechamine, diethylamine, 2-diethylaminoethanol, 2-dimethylamino- ethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylarnine, trimethylarnine, tripropylamine, and the like. Pharmaceutically acceptable salts may be obtained using standard procedures well known in the art, for example by reacting a sufficiently basic compound such as an amine with a suitable acid affording a physiologically acceptable anion. Alkali metal (for example, sodium, potassium or lithium) or alkaline earth metal (for example calcium) salts of carboxylic acids can also be made. The antibacterial agents of this invention have useful activity against a variety of organisms. The in vitro activity of compounds of this invention can be assessed by standard testing procedures such as the determination of minimum inhibitory concentration (MIC) by agar dilution as described in "Approved Standard. Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria That Grow Aerobically", 3rd. ed., published 1993 by the National Committee for Clinical Laboratory Standards, Villanova, Pennsylvania, USA.
The antibacterial agents described herein are useful for sterilization, sanitation, antisepsis, and disinfection. The antibacterial agents can be applied to a location in need of sterilization, sanitation, antisepsis, or disinfection, by methods known to those skilled in the art. For instance, the antibacterial agents may be incoφorated into a cleaning solution that is applied, such as by spraying or pouring, to an item in need of sterilization, sanitation, antisepsis, or disinfection. The antibacterial agents may be used alone or in combination, e.g., agents disclosed herein with one another or agent(s) disclosed herein with other antibacterial agents. The antibacterial agents may be applied in varying concentrations depending upon the bacterial susceptibility to antibacterial agent(s) being applied and the desired level of sterilization, sanitation, antisepsis, or disinfection.
In other embodiments, certain antibacterial agents described herein are useful for treating microbial infections in mammals, such as by administering an effective amount ofthe antibacterial agent compound to the πiammal.
Examples of compounds useful as antimicrobial agents for the treatment of microbial infections mammals, include, but are not limited to, 5-bromo-2-( {[3-chloro-5-(trifluoromethyl)-2-pyridinyl]carbonyl} amino)benzoic acid 2-( {[4-( {[2-(4-aminophenyl)ethyl]amino} sulfonyl)-3-methylthien-2- yljcarbonyl} amino)-5-bromobenzoic acid
5-bromo-2-( { [4-( { [3 -( 1 H-imidazol- 1 -yl)propyl] arnino } sulfonyl) -3 -methylthien-2- yl] carbonyl} amino)benzoic acid 5-bromo-2-({[5-({4-[3-(trifluoromethyl)phenyl]piperazin-l-yl}sulfonyl)thien-3- yl] carbonyl} amino)benzoic acid
5-bromo-2-( {[3-methyl-4-( {4-[3-(trifluoromethyl)phenyl]piperazin- 1 -yl} sulfonyl)thien-
2-yl] carbonyl} amino)benzoic acid
5-bromo-2-( {[5-methyl-4-( {4-[3-(trifluoromethyl)phenyl]piperazin- 1 -yl} sulfonyl)thien- 2-yl] carbonyl} amino)benzoic acid
2- {[(4- {[( 1 -ben2ylpiperidm-4-yl)amino]sulfonyl} -3-methylthien-2-yl)carbonyl]amino} -
5-bromobenzoic acid
2- {[(4- {[(1 -benzylpiperidin-4-yl) amino] sulfonyl} -5-methylthien-2-yl)carbonyl]amino} -
5-bromobenzoic acid 5-bromo-2-( { [5-( { [3 -(dibutylamino)propyl] arnino } sulfonyl)thien-3 - yl] carbonyl} amino)benzoic acid
5-bromo-2-({[4-({[3-(ώbutylarrmo)propyl]amino}sulfonyl)-3-methylthien-2- yl] carbonyl} amino)benzoic acid
5-bromo-2-({[4-({[3-(o butylaπmo)propyl]amino}sulfonyl)-5-methylthien-2- yl] carbonyl} amino)benzoic acid
5-chloro-2-( {[5-chloro-2-(methylsulfonyl)pyrimidin-4-yl]carbonyl} amino)benzoic acid
5-bromo-2-( { [5-chloro-2-(methylthio)pyrirnidin-4-yl] carbonyl} amino)benzoic acid
5-bromo-2-{[(5-chloro-2-mo holm-4-ylpyrimiα^-4-yl)carbonyl]amino}benzoic acid
2- {[( 1 -benzyl-5-methoxy-l H-pyrazol-3-yl) carbonyl] arnino} -5-bromobenzoic acid 2-({[5-(benzyloxy)-l-methyl-lH-pyrazol-3-yl]carbonyl}amino)-5-bromobenzoic acid
2-[( {2-[4-(acetyloxy)phenyl]- 1 ,3-dioxo-2,3-dihydro- 1 H-isoindol-5- yl} carbonyl)amino]-5-bromobenzoic acid
2-({[5-({[2-(4-ammophenyl)ethyl]am o}sulfonyl)thien-3-yl]carbonyl}amino)-5- bromobenzoic acid 5-bromo-2-[({5-[(2,3-dmydro-lH-mden-2-ylamino)sulfonyl]thien-3- yl} carbonyl) amino]benzoic acid
2-{[(5-{[(l -benzylpiperidin-4-yl) arnino] sulfonyl} thien-3 -yl) carbonyl] arnino } -5- bromobenzoic acid 5-bromo-2- { [(5- { [4-(4-chlorophenyl)piperazin- 1 -yl] sulfonyl} thien-3 - yl)carbonyl]amino}benzoic acid
5-bromo-2-( {[5-( { [4-(dimethylamino)benzyl] amino } sulfonyl)thien-3 - yl] carbonyl} arnino)benzoic acid 5-bromo-2-({[4-({[4-(dimethylammo)benzyl]amino}sulfonyl)-5-methylthien-2- yl] carbonyl} amino)benzoic acid
5-bromo-2- {[(5- {[(4-chlorophenyl)(methyl)amino]sulfonyl}thien-3- yl)carbonyl]amino}benzoic acid
5-bromo-2-( {[5-(2,3-dihydro- 1 H-indol- 1 -ylsulfonyl)thien-3- yl] carbonyl} amino)benzoic acid
5-bromo-2-[( {5-[(2,3-dihydro- 1 ,4-benzoώoxm-6-ylamino)sulfonyl]thien-3- yl} carbonyl) arnino]benzoic acid
5-bromo-2-[({4-[(2,3-α^ydro-l,4-benzodioxm-6-ylaιnino)sulfonyl]-3-methylthien-2- yl}carbonyl)amino]benzoic acid 5-bromo-2-{[(4-{[(3-chloro-4-fluorophenyl)amino]sulfonyl}-5-methylthien-2- yl)carbonyl]amino}benzoic acid
5-bromo-2- { [(3 -methyl-4- { [(4-morpholin-4-ylphenyl) amino] sulfonyl} thien-2- yl)carbonyl]amino}benzoic acid
5-bromo-2-({[4-({[4-(diethylammo)phenyl]arnino}sulfonyl)-3-methylthien-2- yl] carbonyl} amino)benzoic acid
5-bromo-2-[( {5-[(6-chloro-2,3-dihydro- 1 H-indol- 1 -yl)sulfonyl]thien-3- yl}carbonyl)amino]benzoic acid
5-bromo-2-[( {4-[(6-chloro-2,3-dihydro- 1 H-indol- 1 -yl)sulfonyl]-5-methylthien-2- yl}carbonyl)anτino]benzoic acid 2-[({5-[(5-benzyl-2,5-diazabicyclo[2.2.1]hept-2-yl)sulfonyl]thien-3- yl} carbonyl)amino]-5-bromobenzoic acid
2-[({4-[(5-benzyl-2,5-diazabicyclo[2.2.1]hept-2-yl)sulfonyl]-3-methylthien-2- yl} carbonyl)amino]-5-bromobenzoic acid
2-[({4-[(5-benzyl-2,5-diazabicyclo[2.2.1]hept-2-yl)sulfonyl]-5-methylthien-2- yl}carbonyl)amino]-5-bromobenzoic acid
5-bromo-2-(2-furoylarnino)benzoic acid
5-bromo-2-[(5-bromo-2-furoyl)arnino]benzoic acid
5-bromo-2-[(lH-pyrrol-2-ylcarbonyl)amino]benzoic acid 5-bromo-2-(3-furoylamino)benzoic acid
5-bromo-2- {[(3-methylthien-2-yl)carbonyl]amino}benzoic acid
5-bromo-2- {[(5-methylthien-2-yl)carbonyl]amino}benzoic acid
5-bromo-2-[(thien-3-ylcarbonyl)amino]benzoic acid 5-bromo-2-[(lH-mdol-3-ylcarbonyl)arnino]benzoic acid
2-[(l ,3-benzodioxol-5-ylcarbonyl)amino]-5-bromobenzoic acid
2-[( 1 -benzofuran-2-ylcarbonyl)amino]-5-bromobenzoic acid
5-bromo-2- {[(2-chloropyridin-3-yl)carbonyl]amino}benzoic acid
5-bromo-2-[(pyridm-2-ylcarbonyl)amino]benzoic acid 5-bromo-2-{[(5-butylpyrid -2-yl)carbonyl]amino}benzoic acid
5-bromo-2- {[(2-phenylquinolin-4-yl) carbonyl] amino} benzoic acid
5-bromo-2-[(qumolm-2-ylcarbonyl)amino]benzoic acid
5-bromo-2-[(qumolin-4-ylcarbonyl)arnino]benzoic acid
5-bromo-2-( {[2-(methylthio)pyridin-3-yl]carbonyl} amino)benzoic acid 5-bromo-2-[(qumoxalm-2-ylcarbonyl)amino]benzoic acid
5-bromo-2-{[(3-methyl-lH-mden-2-yl)carbonyl]amino}benzoic acid
5-bromo-2-{[(7-methoxy-l-benzofuran-2-yl)carbonyl]amino}benzoic acid
5-bromo-2- {[(5-methylpyrazm-2-yl)carbonyl]amino}benzoic acid
5-bromo-2- {[(5,6-dichloropyridm-3-yl)carbonyl]amino}benzoic acid 5-bromo-2-{[(10,10-dioxido-9-oxo-9H-thioxanthen-3-yl)carbonyl]amino}benzoic acid
5-bromo-2- {[(2,6-dimethoxypyridm-3-yl)carbonyl]amino}benzoic acid
5-bromo-2- {[(5-bromothien-2-yl)carbonyl]amino}benzoic acid
5-bromo-2-[(2,5-dimethyl-3-furoyl)amino]benzoic acid
5-bromo-2- {[(6-bromopyridm-2-yl)carbonyl]amino}benzoic acid 5-bromo-2-{[5-(4-nitrophenyl)-2-nιroyl]amino}benzoic acid
5-bromo-2- {[5-(4-chlorophenyl)-2-furoyl]amino}benzoic acid
5-bromo-2-[(2,6-dichloroisonicotinoyl)arnino]benzoic acid
5-bromo-2-( {5-[3-(trifluoromethyl)phenyl]-2-furoyl} amino)benzoic acid
5-bromo-2- {[(4- {[(3-chloro-4-fluorophenyl)amino]sulfonyl} -3-methylthien-2- yl)carbonyl]amino}benzoic acid
5-bromo-2-{[(5-methyl-4-{[(2-methyl-l,3-berizothiazol-5-yl)amino]sulfonyl}thien-2- yl)carbonyl]amino}benzoic acid 5-bromo-2-[( {4-[( {4-[(diethoxyphosphoryl)methyl]phenyl} amino)sulfonyl]-5- methylthien-2-yl} carbonyl) arnino]benzoic acid
5-bromo-2-{[(4-{[(4-chlorophenyl)aπιino]sulfonyl}-5-methylthien-2- yl)carbonyl]amino} benzoic acid 5-bromo-2-( {[5-( {[4-(o ethylammo)phenyl]amino} sulfonyl)thien-3- yl] carbonyl} arnino)benzoic acid
5-bromo-2-[({4-[(2,3-α^ydro-lH-mden-2-ylamino)sulfonyl]-3-methylthien-2- yl}carbonyl)amino]benzoic acid
5-bromo-2-[( {4-[(2,3-dihydro- 1 ,4-benzodioxm-6-ylamino)sulfonyl]-5-methylthien-2- yl}carbonyl)arnino]benzoic acid
2-( {[4-( {[2-(4-an---nophenyl)ethyl]amino} sulfonyl)-5-methylthien-2- yl]carbonyl} arnino)-5-bromobenzoic acid
5-bromo-2- {[(4- {[4-(4-chlorophenyl)piperazin- 1 -yl]sulfonyl} -5-methylthien-2- yl)carbonyl]arnino}benzoic acid 5-bromo-2-[({4-[(2,3-α^ydro-lH-mden-2-ylamino)sulfonyl]-5-methylthien-2- yl} carbonyl) amino]benzoic acid
2-{[(3-benzoylpyrichn-2-yl)carbonyl]amino}-5-bromoberizoic acid
5-bromo-2-{[(2-isobutyl-l,3-dioxo-2,3-dihydro-lH-isoindol-5- yl) carbonyl] arnino} benzoic acid 5-bromo-2-({[l,3-dioxo-2-(tetrahydrofuran-2-ylmethyl)-2,3-dihydro-lH-isoindol-5- yl]carbonyl}amino)benzoic acid
2-( {[6-(benzylthio)pyridin-3-yl] carbonyl} amino)-5-cyanobenzoic acid hydrochloride
5-bromo-2-( { [2-(methylsulfonyl)-5-moφholin-4-ylpyrimidin-4- yl] carbonyl} amino)benzoic acid 2-( {[2-(4-chlorophenyl)- 1 , 1 -dioxido-3 ,4-dihydro-2H- 1 ,2-benzothiazin-7- yl]carbonyl}arnino)-5-cyanobenzoic acid
5-cyano-2-( {[6-(methylthio)pyridin-3-yl] carbonyl} arnino)benzoic acid hydrochloride
5-cyano-2-( {[6-(ethylthio)pyridin-3-yl]carbonyl} amino)benzoic acid hydrochloride
2- {[(6-chloropyridin-3-yl)carbonyl]amino} -5-cyanobenzoic acid 5-cyano-2-{[(3-methylthien-2-yl)carbonyl]amino}benzoic acid
5-cyano-2-(3-furoylarrιino)benzoic acid
5-cyano-2-{[(3-methyl-lH-mden-2-yl)carbonyl]amino}benzoic acid
2-{[(6-bromopyridin-2-yl)carbonyl]arnino}-5-cyanobenzoic acid 5-cyano-2-[(2,5-o^ethyl-3-furoyl)amino]benzoic acid -cyano-2-[(thien-3-ylcarbonyl)amino]benzoic acid -cyano-2-[(pyridm-2-ylcarbonyl)amino]benzoic acid -cyano-2- {[(2,6-dimethoxypyriα^-3-yl)carbonyl]amino}benzoic acid -[(l,3-benzodioxol-5-ylcarbonyl)arnino]-5-cyanobenzoic acid 5-cyano-2-[(qumolm-2-ylcarbonyl)amino]benzoic acid - {[(5-bromopyriα -3-yl)carbonyl]amino} -5-cyanobenzoic acid 5-cyano-2- {[(6-methoxypyridm-3-yl)carbonyl]amino}benzoic acid 5-cyano-2-( { [5-( 1 -methyl- 1 H-pyrrol-2-yl)pyridin-3 -yl] carbonyl} amino)benzoic acid 5-cyano-2-({[5-(4-methoxyphenyl)pyriα^-3-yl]carbonyl}arnino)benzoic acid 5-cyano-2- {[(5-pvrazm-2-ylpyridm-3-yl)carbonyl]amino}benzoic acid 2-[(2,3'-bipyridin-5'-ylcarbonyl)amino]-5-cyanobenzoic acid 5-cyano-2-( {[5-(2-furyl)pyridin-3-yl]carbonyl} amino)benzoic acid 5-cyano-2-( {[5-(2-methylphenyl)pyrito-3-yl]carbonyl}amino)benzoic acid 5-cyano-2- [( { 5- [2-(trifluoromethyl)phenyl]pyridin-3 -yl} carbonyl) amino]benzoic acid 2-( {[5-(4-tert-butylphenyl)pyridin-3-yl]carbonyl} amino)-5-cyanobenzoic acid 2-({[5-(4-chlorophenyl)pyriclm-3-yl]carbonyl}amino)-5-cyanobenzoic acid 5-cyano-2-( { [6-(propylthio)pyridin-3 -yl] carbonyl} arnino)benzoic acid hydrochloride 5-cyano-2-[( 1 H-mdol-2-ylcarbonyl)amino]benzoic acid 2-[(l-benzofuran-2-ylcarbonyl)amino]-5-cyanobenzoic acid 5-cyano-2-[(pyrazm-2-ylcarbonyl)amino]benzoic acid 5-cyano-2- {[(5-phenoxypvridm-3-yl)carbonyl]ammo}benzoic acid 2-({[6-(butylthio)pyridm-3-yl]carbonyl}amino)-5-cyanobenzoic acid 2-[({6-[(5-chloro-2,3-d ydro-lH-indol-l-yl)sulfonyl]pyrid^-3-yl}carbonyl)amino]-5- cyanobenzoic acid
5-cyano-2-( { [5-(3-hydroxyprop- 1 -ynyl)pyridin-3 -yl] carbonyl} amino)benzoic acid 5-cyano-2-[( {6-[( 1 -phenylethyl)thio]pyridin-3-yl} carbonyl) amino]benzoic acid 5-cyano-2-( {[6-(isopropylthio)pyridin-3-yl]carbonyl} amino)benzoic acid 5-cyano-2-({[6-(cyclopentylthio)pyridm-3-yl]carbonyl}amino)benzoic acid 5-cyano-2- {[(2-pyridin-3-yl-l ,3-thiazol-4-yl)carbonyl]amino}benzoic acid
2-( {[2-(benzylthio)-4-ethoxypyrirnidin-5-yl]carbonyl} amino)-5-cyanobenzoic acid 2-({[5-(benzylthio)-l,3,4-thiaώazol-2-yl]carbonyl}amino)-5-cyanobenzoic acid 5-cyano-2- { [(2-phenylquinolin-4-yl)carbonyl] arnino } benzoic acid 5-cyano-2-(2-furoylamino)benzoic acid
5-cyano-2-[({4-[(2,6-dimethylmoφholin-4-yl)sulfonyl]-5-methylthien-2- yl}carbonyl)amino]benzoic acid
5-cyano-2-{[(4-{[cyclohexyl(methyl)aιrιino]sulfonyl}-5-methylthien-2- yl) carbonyl] arnino} benzoic acid
2-{[(4-{[4-(4-acetylphenyl)piperazin-l-yl]sulfonyl}-5-methylthien-2- yl)carbonyl]amino}-5-cyanobenzoic acid
5-cyano-2-({[4-({3-[(diethylamino)carbonyl]piperidin-l-yl}sulfonyl)-5-methylthien-2- yl] carbonyl} amino)benzoic acid 2-{[(4-{[allyl(cyclopentyl)arrιmo]sulfonyl}-5-methylthien-2-yl)carbonyl]anτino}-5- cyanobenzoic acid
5-cyano-2-[({4-[(c isobutylamino)sulfonyl]-5-methylthien-2- yl}carbonyl)amino]benzoic acid
5-cyano-2-[( {5-methyl-4-[(4-pyrimidin-2-ylpiperazin- 1 -yl)sulfonyl]thien-2- yl}carbonyl)amino]benzoic acid
2-{[(4-{[benzyl(2-cyanoethyl)anτmo]sulfonyl}-5-methylthien-2-yl)carbonyl]arrιino}-5- cyanobenzoic acid
2-{[(4-{[benzyl(2-hydroxyethyl)ambo]sulfonyl}-5-methylthien-2-yl)carbonyl]amino}-
5-cyanobenzoic acid 2-({[4-(azepan-l-ylsulfonyl)-5-methylthien-2-yl]carbonyl}amino)-5-cyanobenzoic acid
5-cyano-2-( {[5-methyl-4-( {4-[3-(trifluoromethyl)phenyl]piperazin- 1 -yl} sulfonyl)thien-
2-yl] carbonyl} amino)benzoic acid
5-cyano-2- { [(5-methyl-4- { [2-(pyrrolidin- 1 -ylmethyl)pyrrolidin- 1 -yl]sulfonyl} thien-2- yl)carbonyl]amino}benzoic acid 5-cyano-2-( {[5-methyl-4-(moφholin-4-ylsulfonyl)thien-2-yl]carbonyl} arnino)benzoic acid
5-cyano-2- { [(5-methyl-4- { [4-(4-nitrophenyl)piperazin- 1 -yl]sulfonyl} thien-2- yl)carbonyl]amino}benzoic acid
2- {[(4- {[butyl(ethyl)amino]sulfonyl} -5-methylthien-2-yl)carbonyl]amino} -5- cyanobenzoic acid
5-cyano-2- {[(4- {[(2-hydroxy-2-phenylethyl)(methyl)amino]sulfonyl} -5-methylthien-2- yl)carbonyl]amino}benzoic acid 5-cyano-2- {[(4- {[2-(methoxymethyl)pyrrolidin- 1 -yl]sulfonyl} -5-methylthien-2- yl)carbonyl]anτino}benzoic acid
5-cyano-2-[( {4-[(4-cyano-4-phenylpiperidin- 1 -yl)sulfonyl]-5-methylthien-2- yl}carbonyl)amino]benzoic acid 5-cyano-2-[({4-[(3,5-dimethylpiperidin-l-yl)sulfonyl]-5-methylthien-2- yl} carbonyl) amino]benzoic acid
5-cyano-2-{[(4-{[[2-(diethylarrιmo)ethyl](ethyl)amino]sulfonyl}-5-methylthien-2- yl)carbonyl]amino}benzoic acid
2- {[(4- {[benzyl(isopropyl)amino]sulfonyl} -5-methylthien-2-yl) carbonyl] amino} -5- cyanobenzoic acid
5-cyano-2-[( {5-methyl-4-[(4-phenylpiperazin- 1 -yl)sulfonyl]thien-2- yl}carbonyl)amino]benzoic acid
5-cyano-2-[( {5-methyl-4-[(2-methylpyrrolidin- 1 -yl)sulfonyl]thien-2- yl} carbonyl) amino]benzoic acid 5-cyano-2- { [(4- {[4-(4-fluorophenyl)piperazin- 1 -yl]sulfonyl} -5-methylthien-2- yl)carbonyl]amino}benzoic acid
5-cyano-2-[( {5-methyl-4-[(4-pyridin-2-ylpiperazin- 1 -yl)sulfonyι]thien-2- yl}carbonyl)amino]benzoic acid
5-cyano-2-[({5-methyl-4-[(4-methylpiperidin-l-yl)sulfonyl]thien-2- yl}carbonyl)amino]benzoic acid
5-cyano-2-[({4-[(2,3-(lmy(-ro-lH-mden-5-ylamino)sulfonyl]-5-methylthien-2- yl}carbonyl)amino]benzoic acid
5-cyano-2-{[(5-methyl-4-{[methyl(2-phenylethyl)amino]sulfonyl}thien-2- yl)carbonyl]amino}benzoic acid 2-( {[4-(azocan- 1 -ylsulfonyl)-5-methylthien-2-yl]carbonyl} amino)-5-cyanobenzoic acid
5-cyano-2- {[(4- {[(2-hydroxy- 1 -methyl-2-phenylethyl)(methyl)amino]sulfonyl} -5- methylthien-2-yl)carbonyl]amino}benzoic acid
5-cyano-2-[({5-methyl-4-[(3-methylpiperidin-l-yl)sulfonyl]thien-2- yl} carbonyl) amino]benzoic acid 5-cyano-2-{[(4-{[(3-hyαVoxy-3-phenylpropyl)(methyl)amino]sulfonyl}-5-methylthien-
2-yl)carbonyl]amino}benzoic acid
2-{[(4-{[butyl(cyanomethyl)ammo]sujfonyl}-5-methylthien-2-yl)carbonyl]amino}-5- cyanobenzoic acid 5-cyano-2-({[5-methyl-4-(pyrrolidm-l-ylsulfonyl)thien-2-yl]carbonyl}amino)benzoic acid
2-[( {4-[(4-benzylpiperazin- 1 -yl)sulfonyl]-5-methylthien-2-yl} carbonyl)amino]-5- cyanobenzoic acid 5-cyano-2-{[(4-{[(2-cyanoethyl)(methyl)amino]sulfonyl}-5-methylthien-2- yl)carbonyl]amino}benzoic acid
5-cyano-2- {[(4- {[(2-hydroxy- 1 -methyl-2-phenylethyl)(methyl)amino]sulfonyl} -5- methylthien-2-yl)carbonyl]amino}benzoic acid
5-cyano-2-[( {4-[(4-hydroxypiperidin- 1 -yl)sulfonyl]-5-methylthien-2- yl} carbonyl)amino]benzoic acid
5-cyano-2-({[5-methyl-4-(octahydroquinolin-l(2H)-ylsulfonyl)thien-2- yl] carbonyl} amino)benzoic acid
5-cyano-2-{[(5-methoxy-lH-mdol-2-yl)carbonyl]amino}benzoic acid
2-( {[5-(benzyloxy)- 1 H-indol-2-yl] carbonyl} amino)-5-cyanobenzoic acid 5-cyano-2-( {[5-(3,5-dimethylisoxazol-4-yl)pyridm-3-yl]carbonyl}amino)benzoic acid
5-cyano-2- {[(5-qumolm-3-ylpvriα^-3-yl)carbonyl]amino}benzoic acid
5-cyano-2-[({5-[4-(trMuoromethyl)phenyl]pyridm-3-yl}carbonyl)amino]benzoic acid
5-cyano-2-[({5-[3-(trifluoromethyl)phenyl]pyridm-3-yl}carbonyl)amino]benzoic acid
5-cyano-2-({[5-(2,4-dimethoxypyrimidm-5-yl)pyridm-3-yl]carbonyl}arrano)benzo acid
5-cyano-2- {[(5-phenylpyridm-3-yl)carbonyl]arnino}benzoic acid
2-( {[2-(benzylthio)-l ,3-thiazol-5-yl]carbonyl} amino)-5-cyanobenzoic acid
5-isocyano-2- {[(5-phenyl-l ,2,4-oxadiazol-3-yl)carbonyl]amino}benzoic acid
5-isocyano-2- {[(2-phenyl-l ,3 -oxazol-4-yl)carbonyl] arnino} benzoic acid 2-{[(2-tert-butyl-l,3-dioxo-2,3-dihydro-lH-isomdol-5-yl)carbonyl]amino}-5- cyanobenzoic acid
5-bromo-2-{[(2-tert-butyl-l,3-dioxo-2,3-dihydro-lH-isoindol-5- yl) carbonyl] amino} benzoic acid
5-cyano-2- {[(4- {[2-(hydroxymethyl)pyπOlidin- 1 -yl] sulfonyl} -5-methylthien-2- yl)carbonyl]arnino}benzoic acid
2- {[(4- {[4-(4-bromophenyl)-4-hydroxypiperidin- 1 -yl]sulfonyl} -5-methylthien-2- yl)carbonyl]amino}-5-cyanobenzoic acid 2-{[(4-{[butyl(2-hydroxyethyl)amino]sulfonyl}-5-methylthien-2-yl)carbonyl]arnino}-5- cyanobenzoic acid
5-cyano-2- {[(5-qumolm-8-ylpyrio -3-yl)carbonyl]arrιino}benzoic acid
5-cyano-2- {[(6-moφholin-4-ylpyridin-3-yl) carbonyl] amino} benzoic acid 5-cyano-2-( {[5-( 1 H-pyrazol-4-ylethynyl)pyridin-3-yl] carbonyl} amino)benzoic acid
5-cyano-2-[({5-[(2,4-dimethoxypyrimidin-5-yl)ethynyl]pyridin-3- yl}carbonyl)amino]benzoic acid
5-cyano-2- {[(5-ethynylpyridm-3-yl)carbonyl]amino}benzoic acid
5-cyano-2-[({4-[(2-ethylpiperidin-l-yl)sulfonyl]-5-methylthien-2- yl}carbonyl)amino]benzoic acid
5-cyano-2-[({4-[(6,7-dimethoxy-3,4-dmydroisoquinolin-2(lH)-yl)sulfonyl]-5- methylthien-2-yl} carbonyl)arnino]benzoic acid
5-cyano-2-({[4-(3,4-dmydroisoquinolin-2(lH)-ylsulfonyl)-5-methylthien-2- yl] carbonyl} amino)benzoic acid 2-({[6-(beri2ylsulfonyl)pyridm-3-yl]carbonyl}arnino)-5-cyanobenzoic acid
5-cyano-2- { [(6-piperidin- 1 -ylpyridin-3 -yl) carbonyl] arnino } benzoic acid
5-cyano-2-[({5-[(3,5-dimethylisoxazol-4-yl)ethynyl]pyridin-3- yl}carbonyl)amino]benzoic acid
5-cyano-2-( {[5-(phenylethynyl)pyridin-3-yl]carbonyl} amino)benzoic acid 5-cyano-2-[( {5-[2-( 1 ,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro- 1 H-pyrazol-4-yl)-2- oxoethyl]pyridin-3-yl}carbonyl)amino]benzoic acid
5-cyano-2- {[(5-phenylisoxazol-3-yl)carbonyl]amino}benzoic acid
5-cyano-2-( { [6-(tetrahydro-2H-pyran-4-ylthio)pyridin-3 -yl] carbonyl} arnino)benzoic acid 5-cyano-2-({[5-(ethylthio)pyridm-3-yl]carbonyl}amino)benzoic acid
2-( {[2-(benzylthio)-l ,3-thiazol-4-yl]carbonyl} amino)-5-cyanobenzoic acid
5-bromo-2- {[(5-phenylisoxazol-3-yl)carbonyl]amino}benzoic acid
2-{[(6-{[3 -(4-bromophenoxy)propyl]thio} pyridin-3 -yl)carbonyl] arnino } -5- cyanobenzoic acid 5-cyano-2-[( {6-[(cyclopropylmethyl)thio]pyridin-3-yl} carbonyl)amino]benzoic acid
5-bromo-2-( {[6-(isopropylthio)pyridin-3-yl]carbonyl} amino)benzoic acid
2-( { [5-(benzylthio)pyrazin-2-yl]carbonyl} amino)-5-cyanobenzoic acid
5-cyano-2- {[(5-methoxy-l-benzofuran-2-yl)carbonyl]amino}benzoic acid 5-cyano-2- {[(7-methoxy- 1 -benzofuran-2-yl)carbonyl]amino}benzoic acid 5-cyano-2-{[(l-methyl-lH-mdol-2-yl)carbonyl]amino}benzoic acid 5-cyano-2-( {[6-(cyclohexylthio)pyridin-3-yl]carbonyl} amino)benzoic acid 2-( {[5-(benzylthio)isoxazol-3-yl]carbonyl}amino)-5-bromobenzoic acid 5-bromo-2-( {[6-(cyclohexylthio)pyridin-3-yl]carbonyl} arnino)benzoic acid 2-( {[5-(benzylthio)isoxazol-3-yl]carbonyl} arnino)-5-cyanobenzoic acid 2-( {[5-(benzylthio)pyrazm-2-yl]carbonyl}amino)-5-bromobenzoic acid 2-( {[6-(sec-butylthio)pyridin-3-yl]carbonyl} amino)-5-cyanobenzoic acid 5-cyano-2-( {[6-(pentylthio)pyridin-3-yl]carbonyl} amino)benzoic acid 2-({[5-(benzylthio)-l,3,4-oxadiazol-2-yl]carbonyl}amino)-5-bromobenzoic acid 2-( { [6-(benzyloxy)- 1 H-indol-2-yl] carbonyl} amino)-5-cyanobenzoic acid N-[4-bromo-2-(5-oxo-4,5-dihydro-l,2,4-oxadiazol-3-yl)phenyl]-5-phenylisoxazole-3- carboxamide 2- {[(7-chloro- 1 H-mdol-2-yl)carbonyl]amino} -5-cyanobenzoic acid 5-cyano-2-{[(4-methoxy-lH-mdol-2-yl)carbonyl]amino}benzoic acid 5-bromo-2- { [( 1 -methyl- 1 H-indol-2-yl) carbonyl] arnino} benzoic acid 2- {[(6-chloro- 1 H-indol-2-yl)carbonyl]amino} -5-cyanobenzoic acid 2- {[( 1 -benzyl- 1 H-mdol-2-yl)carbonyl]amino} -5-cyanobenzoic acid 5-cyano-2- { [( 1 -ethyl- 1 H-indol-2-yl) carbonyl] arnino } benzoic acid 5-cyano-2-( { [7-(phenylsulfonyl)- 1 H-indol-2-yl] carbonyl} amino)benzoic acid 5-cyano-2- {[(5-phenyl-l ,3-oxazol-2-yl)carbonyl]amino}benzoic acid 2-({[5-(benzylthio)-l,3,4-thiadiazol-2-yl]carbonyl}amino)-5-bromobenzoic acid 5-cyano-2- {[(2-phenylfuro[2,3-c]pyridm-5-yl)carbonyl]amino}benzoic acid 5-cyano-2-( {[6-(hexylthio)pyridin-3-yl] carbonyl} amino)benzoic acid 5-cyano-2-[( {6-[(3-ethoxy-3-oxopropyl)thio]pyridin-3-yl} carbonyl)amino]benzoic acid 2-( {[6-(benzylthio)pyrazin-2-yl]carbonyl} amino)-5-cyanobenzoic acid 2-( {[6-(benzylthio)pyrazin-2-yl] carbonyl} amino)-5-bromobenzoic acid 2-({[5-(3-chlorophenyl)-l,3-thiazol-2-yl]carbonyl}amino)-5-cyanobenzoic acid 5-cyano-2-{[(5-phenyl-l,3-thiazol-2-yl)carbonyl]amino}benzoic acid 5-cyano-2-{[(4-phenyl-l,3-thiazol-2-yl)carbonyl]arnino}benzoic acid 2-[(l ,3-benzothiazol-2-ylcarbonyl)amino]-5-cyanobenzoic acid 5-cyano-2-[(thieno[2,3-b]pyridm-2-ylcarbonyl)aιnino]benzoic acid 5-cyano-2- {[(3-methylfuro[2,3-c]pyriα^-5-yl)carbonyl]amino}benzoic acid 5-bromo-2-({[5-(pentylthio)-l,3,4-oxadazol-2-yl]carbonyl}amino)benzoic acid 5-cyano-2- {[(6- {[3-(2-methoxyethoxy)propyl]thio}pyridin-3- yl)carbonyl]arnino}benzoic acid 5-chloro-2- {[(5-phenyl-l ,3-oxazol-2-yl)carbonyl]amino}benzoic acid 5-bromo-2-( {[6-(tetrahydro-2H-pyran-4-ylthio)pyridin-3-yl] carbonyl} amino)benzoic acid
5-cyano-2-( {[6-(nonylthio)pyridin-3-yl]carbonyl} amino)benzoic acid 5-cyano-2- { [(6- { [(3 , 5-dimethylisoxazol-4-yl)methyl]thio } pyridin-3 - yl) carbonyl] amino} benzoic acid 5-cyano-2-{[(5-methylisoxazol-3-yl)carbonyl]amino}benzoic acid
5-cyano-2-[({6-[(2-methoxy-2-oxoethyl)thio]pyridm-3-yl}carbonyl)amino]benzoic acid
5-bromo-2-( {[6-(hexylthio)pyridin-3-yl]carbonyl} amino)benzoic acid
5-chloro-2-( {[6-(hexylthio)pyridin-3-yl] carbonyl} amino)benzoic acid 5-bromo-2- {[(6- {[3-(2-methoxyethoxy)propyl]thio}pyridin-3- yl)carbonyl]arnino}benzoic acid
2- { [( 1 -allyl- 1 H-mdol-2-yl)carbonyl]amino} -5-cyanobenzoic acid 5-cyano-2-( {[1 -(cyclohexylmethyl)- 1 H-indol-2-yl]carbonyl} arnino)benzoic acid 5-cyano-2-( {[1 -(2-methoxyethyl)- 1 H-indol-2-yl] carbonyl} amino)benzoic acid 5-cyano-2-{[(l-pentyl-lH-mdol-2-yi)carbonyl]amino}benzoic acid 2- { [( 1 -butyl- 1 H-indol-2-yl) carbonyl] amino} -5-cyanobenzoic acid 5-cyano-2- { [( 1 -propyl- 1 H-indol-2-yl)carbonyl] amino}benzoic acid 5-chloro-2-{[(l-propyl-lH-mdol-2-yl)carbonyl]amino}benzoic acid 2- {[( 1 -butyl- 1 H-indol-2-yl)carbonyl] arnino} -5-chlorobenzoic acid 5-chloro-2-{[(l-pentyl-lH-mdol-2-yl)carbonyl]amino}benzoic acid
5-chloro-2-( { [ 1 -(2-methoxyethyl) - 1 H-indol-2-yl] carbonyl} amino)benzoic acid 5-chloro-2-( {[1 -(cyclohexylmethyl)- 1 H-indol-2-yl]carbonyl} amino)benzoic acid 2- {[(l-allyl-lH-mdol-2-yl)carbonyl]amino}-5-chlorobenzoic acid 2- { [( 1 -allyl- 1 H-indol-2-yl)carbonyl]amino} -5-bromobenzoic acid 5-bromo-2-( {[1 -(cyclohexylmethyl)- 1 H-indol-2-yl] carbonyl} arnino)benzoic acid 5-bromo-2-( {[1 -(2-methoxyethyl)- 1 H-indol-2-yl] carbonyl} amino)benzoic acid 5-bromo-2- {[( 1 -pentyl- 1 H- dol-2-yl)carbonyl]amino}benzoic acid 5-bromo-2-{[(l-butyl-lH-mdol-2-yl)carbonyl]amino}benzoic acid 5-bromo-2- { [( 1 -propyl- 1 H-indol-2-yl) carbonyl] amino } benzoic acid 2-( {[4-(benzyloxy)pyridin-2-yl]carbonyl} amino)-5-bromobenzoic acid 2- {[( 1 -benzyl- 1 H-mdol-2-yl)carbonyl]amino} -5-chlorobenzoic acid 2- {[( 1 -benzyl- 1 H-mdol-2-yl)carbonyl]amino} -5-bromobenzoic acid 5-bromo-2-{[(l-isopropyl-lH-mdol-2-yl)carbonyl]amino}benzoic acid 5-cyano-2- { [( 1 -isopropyl- 1 H-indol-2-yl) carbonyl] amino } benzoic acid 5-chloro-2-{[(l-methyl-lH-mdol-2-yl)carbonyl]arnino}benzoic acid 5-chloro-2- {[(l-isobutyl-lH-mdol-2-yl)carbonyl]amino}benzoic acid 5-bromo-2- {[(1 -isobutyl- 1 H-indol-2-yl) carbonyl] arnino} benzoic acid 5-cyano-2-{[(l-isobutyl-lH-mdol-2-yl)carbonyl]arnino}benzoic acid
5-cyano-2-({[l-(3-phenylpropyl)-lH-mdol-2-yl]carbonyl}arnino)benzoic acid 5-chloro-2-( {[1 -(3-phenylpropyl)- lH-indol-2-yl] carbonyl} amino)benzoic acid 5-bromo-2-( {[1 -(3-phenylpropyl)-l H-indol-2-yl] carbonyl} amino)benzoic acid 5-chloro-2- {[(6- {[3-(2-methoxyethoxy)propyl]thio}pyridin-3- yl)carbonyl]amino}benzoic acid
5-cyano-2- {[(4,5-dichloroisothiazol-3-yl)carbonyl]amino}benzoic acid 2- {[(4-chloro-5-phenylisothiazol-3-yl)carbonyl]amino} -5-cyanobenzoic acid 5-bromo-2-{[(4-chloro-l-oxidopyridm-2-yl)carbonyl]amino}benzoic acid 5-cyano-2- {[(3-phenylisoxazol-5-yl)carbonyl]amino}benzoic acid 5-chloro-2-[(E)-2-(5-phenylisoxazol-3-yl)ethenyl]benzoic acid 5-cyano-2-[(E)-2-(5-phenylisoxazol-3-yl)ethenyl]benzoic acid 2-( {[4-(benzyloxy)pyridin-2-yl] carbonyl} arnino)-5-cyanobenzoic acid 2-{[(6-{[(5-chloro-l,2,4-thiadiazol-3-yl)methyl]thio}pyridm-3-yl)carbonyl]amino}-5- cyanobenzoic acid 5-cyano-2-[({6-[(l,2,4-oxaώazol-3-ylmethyl)thio]pyridin-3- yl} carbonyl) amino]benzoic acid
2-({[4-(benzyloxy)-l-oxidopyridm-2-yl]carbonyl}arrιino)-5-bromobenzoic acid 2-( {[4-(benzylthio)- 1 -oxidopyridin-2-yl] carbonyl} amino)-5-bromobenzoic acid 5-cyano-2-( {[5-(4-methoxyphenyl)isoxazol-3-yl]carbonyl} amino)benzoic acid 5-cyano-2-[( {5-[4-(trifluoromethyl)phenyl]isoxazol-3-yl} carbonyl)amino]benzoic acid 2-( {[5-(2-chlorophenyl)isoxazol-3-yl]carbonyl} amino)-5-cyanobenzoic acid 5-cyano-2-( {[5-(2-fluorophenyl)isoxazol-3-yl]carbonyl} amino)benzoic acid 2- { [(6- { [4-(acetyloxy)butyl]thio } pyridin-3 -yl) carbonyl] amino } -5-cyanobenzoic acid 5-cyano-2- {[(5-methyl-2-phenyl-2H-l ,2,3-triazol-4-yl)carbonyl]amino}benzoic acid 5-cyano-2-[( {6-[(4-hydroxybutyl)thio]pyridin-3-yl} carbonyl)arnino]benzoic acid 5-chloro-2-({[7-(phenylsu]fonyl)-lH-mdol-2-yl]carbonyl}amino)benzoic acid 5-bromo-2-( {[7-(phenylsulfonyl)- 1 H-indol-2-yl] carbonyl} amino)benzoic acid 5-cyano-2-( { [ 1 -methyl-7-(phenylsulfonyl)- 1 H-indol-2-yl] carbonyl} amino)benzoic acid 5-cyano-2-({[5-(4-methoxyphenyl)-l,3-oxazol-2-yl]carbonyl}amino)benzoic acid 5-cyano-2-({[5-(2-methoxyphenyl)-l,3-oxazol-2-yl]carbonyl}amino)benzoic acid 5-bromo-2-({[5-(2-methoxyphenyl)-l,3-oxazol-2-yl]carbonyl}amino)benzoic acid 5-chloro-2-( {[5-(4-methoxyphenyl)isoxazol-3-yl] carbonyl} amino)benzoic acid 5-cyano-2-[( {5-[2-(trifluoromethyl)phenyl]isoxazol-3-yl} carbonyl)amino]benzoic acid 2-{[(5-tert-butylisoxazol-3-yl)carbonyl]amino}-5-cyanobenzoic acid 5-cyano-2- { [(3 ,5-dimethyl-4, 5'-biisoxazol-3 '-yl)carbonyl]amino} benzoic acid 5-cyano-2-{[(4-methyl-5-phenylisoxazol-3-yl)carbonyl]amino}benzoic acid 5-bromo-2-[({5-[2-(trifluoromethyl)phenyl]isoxazol-3-yl}carbonyl)amino]benzoic acid 5-chloro-2- {[(4-methyl-5-phenylisoxazol-3-yl)carbonyl]amino}benzoic acid
5-chloro-2-[( {5-[2-(trifluoromethyl)phenyl]isoxazol-3-yl} carbonyl)arnino]benzoic acid 5-bromo-2-{[(4-methyl-5-phenylisoxazol-3-yl)carbonyl]amino}benzoic acid 5-bromo-2-[( {5-[4-(trifluoromethyl)phenyl]isoxazol-3-yl} carbonyl)amino]benzoic acid 5-bromo-2-({[5-(4-{[(5-methylisoxazol-3-yl)arnino]sulfonyl}phenyl)isoxazol-3- yl] carbonyl} amino)benzoic acid
5-chloro-2- {[(5-phenylisoxazol-3-yl)carbonyl]amino}benzoic acid
5-chloro-2-[( {5-[4-(trifluoromethyl)phenyl]isoxazol-3-yl} carbonyl)amino]benzoic acid
5-bromo-2-({[5-(4-methoxyphenyl)isoxazol-3-yl]carbonyl}amino)benzoic acid
5-cyano-2-( {[5-(3-cyclohexylpropyl)isoxazol-3-yl]carbonyl} arnino)benzoic acid 5-cyano-2-( {[5-(3-phenylpropyl)isoxazol-3-yl]carbonyl} amino)benzoic acid 5-cyano-2-({[5-(2-methoxyphenyl)isoxazol-3-yl]carbonyl}amino)benzoic acid 5-bromo-2- {[(5-phenyl-l ,3-oxazol-2-yl)carbonyl]amino}benzoic acid 5-bromo-2-( {[5-(4-methoxyphenyl)-l ,3-oxazol-2-yl]carbonyl} amino)benzoic acid 2-( {[5-( 1 ,3-benzodioxol-5-yl)- 1 ,3-oxazol-2-yl]carbonyl} arnino)-5-bromobenzoic acid 5-bromo-2-( {[1 -methyl-7-(phenylsulfonyl)- 1 H-indol-2-yl]carbonyl} arnino)benzoic acid 5-chloro-2-( {[1 -methyl-7-(phenylsulfonyl)- 1 H-indol-2-yl]carbonyl} amino)benzoic acid 5-cyano-2-[(isoquinolin-3 -ylcarbonyl)arnino]benzoic acid 5-cyano-2-[({7-[(phenylacetyl)arrmo]-lH-mdol-2-yl}carbonyl)amino]benzoic acid 2-( {[7-(benzoylammo)-lH-mdol-2-yl]carbonyl}amino)-5-cyanobenzoic acid
2-{[(7-{[(acetyloxy)acetyl]an-ιmo}-lH-mdol-2-yl)carbonyl]amino}-5-cyanobenzoic acid
5-cyano-2-[( {7-[(cyclopentylcarbonyl)amino]- 1 H-indol-2-yl} carbonyl) amino]benzoic acid
2-{[(7-arnmo-lH-mdol-2-yl)carbonyl]arrιino}-5-cyanobenzoic acid
2-[(l ,2-benzisoxazol-3-ylcarbonyl)amino]-5-cyanobenzoic acid
5-cyano-2-( {[5-(4-fluorophenyl)- 1 ,3-oxazol-2-yl]carbonyl} amino)benzoic acid
5-bromo-2-( {[5-(3-cyclohexylpropyl)isoxazol-3-yl] carbonyl} amino)benzoic acid 5-bromo-2-( {[5-(3-phenylpropyl)isoxazol-3-yl]carbonyl} amino)benzoic acid 5-bromo-2-( {[5-(2-methoxyphenyl)isoxazol-3-yl]carbonyl} amino)benzoic acid 5-chloro-2-({[5-(3-cyclohexylpropyl)isoxazol-3-yl]carbonyl}amino)benzoic acid 5-chloro-2-( {[5-(3-phenylpropyl)isoxazol-3-yl]carbonyl} amino)benzoic acid 5-chloro-2-({[5-(2-methoxyphenyl)isoxazol-3-yl]carbonyl}arnino)benzoic acid 5-cyano-2-[( {6-[( 1 -methylpentyl)thio]pyridin-3 -yl} carbonyl) amino]benzoic acid 5-cyano-2-[( {6-[( 1 -ethylpropyl)thio]pyridin-3-yl} carbonyl)amino]benzoic acid 5-bromo-2-( {[5-(2-chlorophenyl)isoxazol-3-yl]carbonyl} amino)benzoic acid 5-bromo-2-({[5-(2-fluorophenyl)isoxazol-3-yl]carbonyl}amino)benzoic acid 5-bromo-2-({[5-(3-methoxyphenyl)-l,3-oxazol-2-yl]carbonyl}amino)benzoic acid 5-bromo-2-[( {5-[2-(trifluoromethyl)phenyl]- 1 ,3-oxazol-2-yl} carbonyl)amino]benzoic acid
2- { [(7- { [(6-chloropyridin-3 -yl)carbonyl] amino } - 1 H-indol-2-yl)carbonyl] amino } -5- cyanobenzoic acid 5-chloro-2-( {[5-(2-fluorophenyl)isoxazol-3-yl]carbonyl} amino)benzoic acid 5-chloro-2-({[5-(2-chlorophenyl)isoxazol-3-yl]carbonyl}amino)benzoic acid 5-cyano-2-({[5-(2-methylphenyl)isoxazol-3-yl]carbonyl}amino)benzoic acid 5-cyano-2-( {[5-(triisopropylsilyl)isoxazol-3-yl]carbonyl} amino)benzoic acid 5-cyano-2-[( {7-[(isoxazol-5-ylcarbonyl)amino]- 1 H-indol-2-yl} carbonyl)amino]benzoic acid 5-cyano-2-[( {7-[(2,4-difluorobenzoyl)amino]- 1 H-indol-2-yl} carbonyl)amino]benzoic acid
5-cyano-2-[( {7-[(fluoroacetyl)amino]- 1 H-indol-2-yl} carbonyl)arnino]benzoic acid 2-( {[7-(acetylammo)-lH-mdol-2-yl]carbonyl}amino)-5-cyanobenzoic acid 2-{[(7-{[(4-chlorophenyl)acetyl]ammo}-lH-mdol-2-yl)carbonyl]amino}-5- cyanobenzoic acid
5-cyano-2-{[(7-{[(4-methoxyphenyl)acetyl]amino}-lH-indol-2- yl)carbonyl]amino}benzoic acid 5-cyano-2-[({7-[(cyclopentylacetyl)am o]-lH-mdol-2-yl}carbonyl)arnino]benzoic acid
5-cyano-2-[({7-[(3-fluorober-zoyl)ammo]-lH-mdol-2-yl}carbonyl)amino]benzoic acid
5-cyano-2-[({7-[(3-cyanobenzoyl)ammo]-lH-mdol-2-yl}carbonyl)arrιino]berιzoic acid
5-cyano-2-[( {7-[(cyclohexylcarbonyl)amino]- 1 H-indol-2-yl} carbonyl)amino]benzoic acid
5-cyano-2-({[7-(propionylammo)-lH-mdol-2-yl]carbonyl}amino)benzoic acid
5-cyano-2-[( {7-[(5-methoxy-5-oxopentanoyl)amino]- 1 H-indol-2- yl}carbonyl)amino]benzoic acid
2-( {[7-(butyrylamino)-lH-indol-2-yl] carbonyl} amino)-5-cyanobenzoic acid 2-[({7-[(4-bromoberizoyl)am o]-lH-mdol-2-yl}carbonyl)amino]-5-cyanobenzoic acid
5-cyano-2-[({7-[(3-phenylpropanoyl)arnmo]-lH-mdol-2-yl}carbonyl)amino]benzoic acid
5-cyano-2-[( {7-[(phenoxyacetyl)amino]- 1 H-indol-2-yl} carbonyl)amino]benzoic acid
5-cyano-2-[( {7-[(3-cyclopentylpropanoyl)amino]- 1 H-indol-2- yl}carbonyl)amino]benzoic acid
5-cyano-2-[( {7-[(3-methoxy-3-oxopropanoyl)amino]- 1 H-indol-2- yl}carbonyl)amino]benzoic acid
5-cyano-2-[( {7-[(2-ethymexanoyl)amino]- 1 H-indol-2-yl} carbonyl)amino]benzoic acid
5-cyano-2-{[(7-{[(3,4-dimethoxyphenyl)acetyl]amino}-lH-indol-2- yl)carbonyl]amino}benzoic acid
5-cyano-2-[({7-[(3,5,5-trimethymexanoyl)amino]-lH-indol-2- yl}carbonyl)arnino]benzoic acid
5-cyano-2-[( {7-[(cyclopropylcarbonyl)amino]- 1 H-indol-2-yl} carbonyl)amino]benzoic acid 5-cyano-2-[({7-[(methoxyacetyl)arnmo]-lH-mdol-2-yl}carbonyl)amino]benzoic acid
5-cyano-2-[({7-[(3-methylbutanoyl)ammo]-lH-mdol-2-yl}carbonyl)amino]benzoic acid
5-cyano-2-({[7-(pentanoylarrιmo)-lH-mdol-2-yl]carbonyl}amino)benzoic acid 5-cyano-2-{[(7-{[(4,7,7-trimethyl-3-oxo-2-oxabicyclo[2.2.1]hept-l- yl) carbonyl] arnino } - 1 H-indol-2-yl) carbonyl] amino } benzoic acid
2-{[(7-{[chloro(phenyl)acetyl]ammo}-lH-mdol-2-yl)carbonyl]amino}-5-cyanobenzoic acid 2-{[(7-{[(benzyloxy)acetyl]arrimo}-lH-mdol-2-yl)carbonyl]amino}-5-cyanobenzoic acid
5-cyano-2-[({7-[(3-ethoxy-3-oxopropanoyl)arnino]-lH-indol-2- yl}carbonyl)amino]benzoic acid
2-[({7-[(l-adamantylcarbonyl)amko]-lH-mdol-2-yl}carbonyl)amino]-5-cyanobenzoic acid
5-cyano-2-( { [7-(hexanoylamino)- 1 H-indol-2-yl] carbonyl} amino)benzoic acid
5-cyano-2- { [(7- { [(2-phenylcyclopropyl) carbonyl] amino } - 1 H-indol-2- yl)carbonyl]amino}benzoic acid
5-cyano-2-[({7-[(2-phenylbutanoyl)am o]-lH-mdol-2-yl}carbonyl)amino]benzoic acid
5-cyano-2-({[7-(heptanoylammo)-lH-indol-2-yl]carbonyl}amino)benzoic acid
2- {[(7- {[(acetyloxy)(phenyl)acetyl]amino} -lH-indol-2-yl)carbonyl]amino} -5- cyanobenzoic acid
5-cyano-2-[({7-[(thien-2-ylcarbonyl)armno]-lH-mdol-2-yl}carbonyl)amino]benzoic acid
5-cyano-2-[( {7-[(2-methylbutanoyl)amino]- 1 H-indol-2-yl} carbonyl)amino]benzoic acid
5-cyano-2-[({7-[(8-methoxy-8-oxooctanoyl)amino]-lH-indol-2- yl} carbonyl) amino]benzoic acid 5-cyano-2-[( {7-[(2-ethylbutanoyl)amino]- 1 H-indol-2-yl} carbonyl)amino]benzoic acid
5-cyano-2-( {[7-(octanoylamino)- 1 H-indol-2-yl] carbonyl} amino)benzoic acid
5-cyano-2-[({7-[(cyclobutylcarbonyl)ammo]-lH-mdol-2-yl}carbonyl)amino]benzoic acid
5-cyano-2-( {[7-( 1 ,3-dioxo- 1 ,3-dihydro-2H-isoindol-2-yl)-l H-indol-2- yl] carbonyl} amino)benzoic acid
2-( {[7-( {[2-(benzylthio)- 1 ,3-thiazol-4-yl]carbonyl} arnino)- 1 H-indol-2- yl]carbonyl}amino)-5-cyanobenzoic acid 5-cyano-2- { [(7- { [3 -(moφholin-4-ylsulfonyl)benzoyl] amino } - 1 H-indol-2- yl)carbonyl]amino}benzoic acid
5-cyano-2-[({7-[(lH-mdol-2-ylcarbonyl)amino]-lH-indol-2- yl}carbonyl)amino]benzoic acid 5-cyano-2- {[(7- { [( 1 -methyl- 1 H-indol-2-yl)carbonyl] amino} - 1 H-indol-2- yl) carbonyl] amino} benzoic acid
5-cyano-2-{[(7-{[(5-phenylisoxazol-3-yl)carbonyl]amino}-lH-indol-2- yl)carbonyl]amino}benzoic acid
5-cyano-2-[({7-[(5-phenylpentanoyl)am o]-lH-mdol-2-yl}carbonyl)amino]benzoic acid
5-cyano-2-[( {7-[(4-phenylbutanoyl)amino]- 1 H-indol-2-yl} carbonyl) arnino]benzoic acid
5-cyano-2- {[(7- {[4-(4-methoxyphenyl)butanoyl] amino} - 1 H-indol-2- yl)carbonyl]amino}benzoic acid 5-cyano-2-[({6-[(l-methylbutyl)thio]pyridm-3-yl}carbonyl)amino]benzoic acid
5-cyano-2-( {[5-(3-methylthien-2-yl)isoxazol-3-yl]carbonyl} amino)benzoic acid
5-cyano-2-( {[5-(3-methoxyphenyl)-l ,3-oxazol-2-yl]carbonyl} amino)benzoic acid
2- {[(7- {[(2-chlorophenyl)acetyl]amino} -lH-indol-2-yl) carbonyl] amino} -5- cyanobenzoic acid 5-cyano-2-{[(7-{[(2,4-dichlorophenyl)acetyl]amino}-lH-indol-2- yl)carbonyl]amino}benzoic acid
5-cyano-2- { [(7- { [(3 ,4-dichlorophenyl) acetyl] amino } - 1 H-indol-2- yl)carbonyl]amino}benzoic acid
2-{[(7-{[(3-chlorophenyl)acetyl]ammo}-lH-mdol-2-yl)carbonyl]amino}-5- cyanobenzoic acid
5-cyano-2-( {[7-( {[3-(trifluoromethyl)phenyl]acetyl}amino)-lH-indol-2- yl] carbonyl} amino)benzoic acid
5-cyano-2-{[(7-{[(3-methylphenyl)acetyl]amino}-lH-indol-2- yl)carbonyl]amino} benzoic acid 2- {[(7- {[(4-tert-butylphenyl)acetyl]amino} - 1 H-mdol-2-yl)carbonyl]amino} -5- cyanobenzoic acid
5-cyano-2-{[(7-{[(3-methoxyphenyl)acetyl]amino}-lH-indol-2- yl)carbonyl]amino}benzoic acid 5-cyano-2- {[(7- {[(2-methoxyphenyl)acetyl]amino} - lH-indol-2- yl)carbonyl]arnino}benzoic acid
5-cyano-2- {[(7- {[(2-methylphenyl)acetyl]amino} -lH-indol-2- yl)carbonyl]amino}benzoic acid 5-cyano-2-({[7-({[4-(trifluoromethyl)phenyl]acetyl}amino)-lH-indol-2- yl] carbonyl} amino)benzoic acid
5-cyano-2- { [(7- { [(4-isopropylphenyl)acetyl]arnino} - 1 H-indol-2- yl)carbonyl]arnino}benzoic acid
5-cyano-2- { [(7- { [(4-methylphenyl) acetyl] amino } - 1 H-indol-2- yl)carbonyl]arnino}benzoic acid
5-cyano-2-{[(7-{[(4-fluorophenyl)acetyl]amino}-lH-indol-2- yl)carbonyl]amino}benzoic acid
2-( {[5-(butylthio)pyrazm-2-yl]carbonyl}amino)-5-cyanobenzoic acid
5-cyano-2-( {[7-( {[2-(trifluoromethyl)phenyl] acetyl} amino)- 1 H-indol-2- yl] carbonyl} arnino)benzoic acid
5-cyano-2-{[(7-{[(3-fluorophenyl)acetyl]arnino}-lH-indol-2- yl)carbonyl]arnino}benzoic acid
5-cyano-2-{[(7-{[(phenylthio)acetyl]ammo}-lH-mdol-2-yl)carbonyl]amino}benzoic acid 5-cyano-2-[({7-[(2-naphthylacetyl)ammo]-lH-mdol-2-yl}carbonyl)amino]benzoic acid
5-cyano-2-[( {7-[(l -naphthylacetyl) amino]- 1 H-indol-2-yl} carbonyl)arnino]benzoic acid
5-cyano-2- { [(7- { [(2 -naphthyloxy) acetyl] amino } - 1 H-indol-2- yl) carbonyl] arnino} benzoic acid
5-cyano-2-[( {7-[(2-propoxybenzoyl)amino]- 1 H-indol-2-yl} carbonyl)amino]benzoic acid
5-cyano-2-[({7-[(tetrahyo ofuran-3-ylcarbonyl)amino]-lH-indol-2- yl}carbonyl)amino]benzoic acid
5-cyano-2- { [(7- { [( 1 -methylcyclopropyl)carbonyl] arnino } - 1 H-indol-2- yl)carbonyl]amino}benzoic acid 5-cyano-2- {[(7- {[(4-ethoxyphenyl)acetyl]amino} -lH-indol-2- yl)carbonyl]amino}benzoic acid
2-[( {7-[( 1 -benzothien-3 -ylacetyl) amino] - 1 H-indol-2-yl} carbonyl)amino]-5- cyanobenzoic acid 2-[( {7-[( 1 , 1 '-biphenyl-4-ylcarbonyl)amino]- 1 H-indol-2-yl} carbonyl)aιrιino]-5- cyanobenzoic acid
2-[( {7-[(4-butoxybenzoyl)amino]- 1 H-indol-2-yl} carbonyl)amino]-5-cyanobenzoic acid
5-cyano-2- {[(7- {[2-(2-phenylethyl)benzoyl]amino} -1 H-indol-2- yl)carbonyl]amino}benzoic acid
2-[( {7-[( 1 , 1 '-biphenyl-2-ylcarbonyl)amino]- 1 H-indol-2-yl} carbonyl)arnino]-5- cyanobenzoic acid
5-cyano-2- { [(7- { [4-(ethylthio)benzoyl] amino } - 1 H-indol-2-yl)carbonyl] amino } benzoic acid 5-cyano-2-{[(7-{[2-(methylsulfonyl)benzoyl]amino}-lH-indol-2- yl)carbonyl]amino}benzoic acid
5-cyano-2- {[(7- {[(2,6-dichlorophenyl)acetyl]amino} - lH-indol-2- yl)carbonyl]amino}benzoic acid
2-[({7-[(l,l '-biphenyl-4-ylacetyl) amino] - 1 H-indol-2-yl} carbonyl) amino] -5- cyanobenzoic acid
2-[( {7-[( 1 ,3-benzodioxol-5-ylacetyl)amino]- lH-indol-2-yl} carbonyl)amino]-5- cyanobenzoic acid
5-cyano-2-[({7-[(3,3-α^ethylbutanoyl)aπιmo]-lH-mdol-2-yl}carbonyl)arrιino]benzoic acid 5-cyano-2-[({7-[(thien-2-ylacetyl)amώo]-lH-mdol-2-yl}carbonyl)amino]benzoic acid
5-bromo-2-({[5-(4-cyanophenyl)-l,3-oxazol-2-yl]carbonyl}arrιino)benzoic acid
5-bromo-2- {[(5-methoxypyrazm-2-yl)carbonyl]amino}benzoic acid
2-( {[5-( 1 ,3-benzodioxol-5-yl)- 1 ,3-oxazol-2-yl]carbonyl} arnino)-5-cyanobenzoic acid
5-bromo-2-( {[5-(sec-butylthio)pyrazin-2-yl]carbonyl} amino)benzoic acid 5-bromo-2-({[5-(butylthio)pyrazin-2-yl]carbonyl}amino)benzoic acid
2-({[5-(burylthio)pyrazm-2-yl]carbonyl}amino)-5-chlorobenzoic acid
5-cyano-2-[(E)-2-( 1 -methyl-1 H-indol-2-yl)ethenyl]benzoic acid
5-bromo-2- { [( 1 -methyl-3 -phenyl- 1 H-pyrazol-5-yl) carbonyl] arnino } benzoic acid
5-bromo-2- { [( 1 -methyl- 5-phenyl- 1 H-pyrazol-3 -yl)carbonyl] arnino } benzoic acid 5-bromo-2-( {[5-(4-methoxyphenyl)- 1 -methyl- 1 H-pyrazol-3- yl] carbonyl} amino)benzoic acid
5-bromo-2- { [(3 -phenyl- 1 H-pyrazol-5-yl)carbonyl] amino } benzoic acid
2-[(l ,2-benzisoxazol-3-ylcarbonyl)arnino]-5-bromobenzoic acid 5-cyano-2-[({5-[2-(trifluoromethyl)phenyl]-l,3-oxazol-2-yl}carbonyl)amino]benzoic acid
2-[( {6-[(4-aminobutyl)thio]pyridin-3-yl} carbonyl)amino]-5-cyanobenzoic acid trifluoroacetate 5-bromo-2-({[5-(pentylthio)pyrazm-2-yl]carbonyl}amino)benzoic acid
5-bromo-2-( {[5-(hexylthio)pyrazin-2-yl]carbonyl} amino)benzoic acid
2-({[5-(sec-butylthio)pyrazm-2-yl]carbonyl}amino)-5-cyanobenzoic acid
5-cyano-2-( {[5-(2-furyι)- 1 ,3-oxazol-2-yl]carbonyl} amino)benzoic acid
5-bromo-2-( { [5-(2-furyl)- 1 ,3 -oxazol-2-yl]carbonyl} amino)benzoic acid 5-bromo-2-( {[3-(2,6-difluorophenyl)- 1 -methyl- 1 H-pyrazol-5- yl] carbonyl} arnino)benzoic acid
5-cyano-2- {[(7- {[(3-methyl-5-phenylisoxazol-4-yl)carbonyl]arnino} - 1 H-indol-2- yl)carbonyl]amino}benzoic acid
5-cyano-2-( { [7-( { [2-(2-methoxyethoxy) ethoxy] acetyl} amino)- 1 H-indol-2- yl] carbonyl} amino)benzoic acid
5-cyano-2-[( {7-[(2-hydroxybenzoyl)amino]- 1 H-indol-2-yl} carbonyl) amino]benzoic acid
5-cyano-2-({[7-({[4-(trifluoromethoxy)phenyl]sulfonyl}amino)-lH-indol-2- yl] carbonyl} amino)benzoic acid 5-cyano-2-({[7-(prolylammo)-lH-mdol-2-yl]carbonyl}amino)benzoic acid
5-cyano-2-{[(7-{[(3-methylisoxazol-5-yl)acetyl]amino}-lH-indol-2- yl)carbonyl]amino}benzoic acid
5-bromo-2-({[5-(4-fluorophenyl)-l,3-oxazol-2-yl]carbonyl}amino)benzoic acid
5-cyano-2-({[5-(4-cyanophenyl)-l,3-oxazol-2-yl]carbonyl}arnino)benzoic acid 5-bromo-2-( {[5-( 1 -methyl- 1 H-pyrrol-2-yl)- 1 ,3-oxazol-2-yl]carbonyl} amino)benzoic acid
5-bromo-2-({[5-(3-cyanophenyl)-l,3-oxazol-2-yl]carbonyl}arnino)benzoic acid
5-cyano-2-( {[5-(pentylthio)pyrazin-2-yl]carbonyl} amino)benzoic acid
5-bromo-2- {[(5- {[3-(2-methoxyethoxy)propyl]thio}pyrazin-2- yl)carbonyl]amino}benzoic acid
5-chloro-2- {[(5- {[3-(2-methoxyethoxy)propyl]thio}pyrazin-2- yl)carbonyl]amino}benzoic acid 5-cyano-2-[( {5-[2-( {[4-(trifluoromethoxy)phenyl]sulfonyl} amino)phenyl]isoxazol-3- yl} carbonyl) amino]benzoic acid
5-chloro-2-[( {5-[2-( {[4-(trifluoromethoxy)phenyl] sulfonyl} amino)phenyι]isoxazol-3- yl} carbonyl) amino]benzoic acid 2-({[5-(l,3-benzodioxol-5-yl)isoxazol-3-yl]carbonyl}amino)-5-cyanobenzoic acid
2-({[5-(l,3-benzoώoxol-5-yl)isoxazol-3-yl]carbonyl}amino)-5-bromobenzoic acid
5-cyano-2- {[(5-nitro-l ,2-benzisoxazol-3-yl)carbonyl]arnino}benzoic acid
2-{[(l-acetyl-lH-mdazol-3-yl)carbonyl]amino}-5-cyanobenzoic acid
2-[(l,3-benzoxazol-2-ylcarbonyl)amino]-5-cyanobenzoic acid 2-[({7- [(benzylsulfonyl) arnino] - 1 H-indol-2-yl} carbonyl) arnino] -5-cyanobenzoic acid
5-cyano-2- {[(1 -methyl-7- {[3-(moφholin-4-ylsulfonyl)benzoyl]amino} -lH-indol-2- yl)carbonyl]amino}benzoic acid
5-cyano-2-{[(7-{[(4-fluorophenyl)acetyl]amino}-l-methyl-lH-indol-2- yl)carbonyl]amino}benzoic acid 5-cyano-2-[( {7-[(fluoroacetyl)amino]- 1 -methyl- 1 H-indol-2-yl} carbonyl)amino]benzoic acid
5-cyano-2- { [( 1 -methyl-7- { [( 1 -methyl- 1 H-mdol-2-yl)carbonyl]amino} - 1 H-indol-2- yl)carbonyl]amino}benzoic acid
5-cyano-2- {[(5- {[3-(2-methoxyethoxy)propyl]thio}pyrazin-2- yl)carbonyl]amino}benzoic acid
5-chloro-2-({[5-(pentylthio)pyrazm-2-yl]carbonyl}amino)benzoic acid
5-cyano-2-( { [5-(hexylthio)pyrazin-2-yl] carbonyl} amino)benzoic acid
5-chloro-2-( {[5-(hexylthio)pyrazin-2-yl] carbonyl} amino)benzoic acid
5-cyano-2-( {[5-( 1 -methyl- lH-pyrrol-2-yl)- 1 , 3 -oxazol-2-yl] carbonyl} amino)benzoic acid
2-( {[5-(sec-butylthio)pyrazin-2-yl]carbonyl} amino)-5-chlorobenzoic acid
5-cyano-2-({[5-(3-cyanophenyl)-l,3-oxazol-2-yl]carbonyl}amino)benzoic acid
5-bromo-2-[({2-[(3R)-3,4-dmydroxybutyl]-l,3-oxazol-4-yl}carbonyl)amino]benzoic acid 5-cyano-2-[( {5-[(phenylacetyl)amino]- 1 ,2-benzisoxazol-3-yl} carbonyl) amino]benzoic acid
2-[( {5-[(benzylsulfonyl)amino]- 1 ,2-benzisoxazol-3-yl} carbonyl)amino]-5- cyanobenzoic acid 2-( { [6-(benzyloxy)- 1 -methyl- 1 H-indol-2-yl]carbonyl} amino)-5-cyanobenzoic acid 5-cyano-2-{[(6-methoxy-l-methyl-lH-mdol-2-yl)carbonyl]arnino}benzoic acid 5-cyano-2-( {[5-(2-isopropoxyphenyl)isoxazol-3-yl]carbonyl} amino)benzoic acid 5-cyano-2-[( { 1 -methyl-7-[(moφholm-4-ylcarbonyl)amino]- 1 H-indol-2- yl}carbonyl)amino]benzoic acid
5-cyano-2-( {[1 -methyl-7-( {[(tetrahydrofuran-2-ylmethyl)amino]carbonyl} amino)- 1 H- indol-2-yl] carbonyl} amino)benzoic acid
5-cyano-2-{[(7-hydroxy-l-methyl-lH-mdol-2-yl)carbonyl]amino}benzoic acid 5-bromo-2- {[(2- {2-[(4S)-2,2-dimethyl- 1 ,3-dioxolan-4-yl]ethyl} -1 ,3-oxazol-4- yl)carbonyl]amino}benzoic acid
5-cyano-2-( {[5-(2-phenylethyl)pyrazin-2-yl]carbonyl} amino)benzoic acid
5-bromo-2-{[(5-{(E)-2-[(4S)-2,2-dimethyl-l,3-dioxolan-4-yl]ethenyl}pyrazin-2- yl)carbonyl]amino}benzoic acid
5-cyano-2-( {[5-(isopentylthio)pyrazin-2-yl]carbonyl} amino)benzoic acid 5-cyano-2-({[5-(isobutylthio)pyrazm-2-yl]carbonyl}amino)benzoic acid 5-cyano-2- {[(5-methoxypyra2--n-2-yl)carbonyl]amino}benzoic acid 2- {[(7- {[(benzylammo)carbonyl]amino} -1 -methyl- 1 H-indol-2-yl)carbonyl]amino} -5- cyanobenzoic acid 5-cyano-2-({[7-({[(2,3-dihydroxypropyl)ammo]carbonyl}arnino)-l-methyl-lH-indol- 2-yl] carbonyl} amino)benzoic acid
1 -[ {[(2- {[(2-carboxy-4-cyanophenyl) amino] carbonyl} - 1 -methyl- 1 H-indol-7- yl) amino] carbonyl} (methyl)amino]- 1 -deoxyhexitol
5-cyano-2-({[7-(2,3-dihydro-l,4-benzodioxin-2-ylmethoxy)-l-methyl-lH-indol-2- yl] carbonyl} amino)benzoic acid 5-cyano-2-{[(5-{2-[2-(2-ethoxyethoxy)ethoxy]phenyl}isoxazol-3- yl)carbonyl]amino}benzoic acid
5-cyano-2-[( {5-[2-(hexyloxy)phenyl]isoxazol-3-yl} carbonyl)arnino]benzoic acid 2-[( {5-[2-(allyloxy)phenyl]isoxazol-3-yl} carbonyl)amino]-5-cyanobenzoic acid 5-cyano-2-[( {5-[2-(2,3-dihydro- 1 ,4-benzodioxin-2-ylmethoxy)phenyl]isoxazol-3- yl}carbonyl)amino]benzoic acid
2-({[7-(benzyloxy)-lH- dol-2-yl]carbonyl}amino)-5-cyanobenzoic acid 5-cyano-2-( {[1 -methyl-7-(3-phenoxypropoxy)- 1 H-indol-2-yl] carbonyl} amino)benzoic acid 5-cyano-2-( {[5-(hydroxymethyl)isoxazol-3-yl]carbonyl} amino)benzoic acid
5-cyano-2-( {[5-(hexyloxy)pyrazin-2-yl]carbonyl} amino)benzoic acid
2-( { [5-(acetylamino)- 1 ,2-benzisoxazol-3-yl] carbonyl} amino)-5-cyanobenzoic acid
5-cyano-2-[( {5-[(methylsulfonyl)amino]-l ,2-benzisoxazol-3- yl} carbonyl) amino]benzoic acid
5-bromo-2-[({5-[2-(2,2-dimethyl-l,3-dioxolan-4-yl)ethyl]isoxazol-3- yl}carbonyl)amino]benzoic acid
2-({[5-(benzoylarrιmo)-l,2-benzisoxazol-3-yl]carbonyl}amino)-5-cyanobenzoic acid
5-cyano-2-[( {5-[(phenylsulfonyl)amino]- 1 ,2-benzisoxazol-3- yl}carbonyl)amino]benzoic acid
5-cyano-2-( {[5-(2-ethoxyphenyl)isoxazol-3-yl]carbonyl} amino)benzoic acid
5-cyano-2-[({5-[2-(tetrahydro-2H-pyran-2-ylmethoxy)phenyl]isoxazol-3- yl} carbonyl) amino]benzoic acid
5-cyano-2-( { [7-(cyclobutylmethoxy)- 1 -methyl- 1 H-indol-2-yl] carbonyl} amino)benzoic acid
5-cyano-2-[({5-[2-(3-phenoxypropoxy)phenyl]isoxazol-3-yl}carbonyl)amino]benzoic acid
5-cyano-2-( {[7-(2-furylmethoxy)- 1 -methyl- 1 H-indol-2-yl] carbonyl} amino)benzoic acid 5-cyano-2- {[(7- {[(4S)-2,2-dimethyl- 1 ,3-dioxolan-4-yι]methoxy} - 1 -methyl- 1 H-indol-
2-yl)carbonyl]amino}benzoic acid
5-cyano-2-{[(7-{[(2R)-2,3-dihydroxypropyl]oxy}-l-methyl-lH-indol-2- yl)carbonyl]amino}benzoic acid
5-cyano-2-({[5-(2-hydroxyphenyl)isoxazol-3-yl]carbonyl}amino)benzoic acid 5-cyano-2-[( {5-[2-(tetrahydrofuran-3-yloxy)phenyl]isoxazol-3- yl}carbonyl)arnino]benzoic acid
5-cyano-2-[( {5-[2-(cyclobutyloxy)phenyl]isoxazol-3-yl} carbonyl)amino]benzoic acid
5-cyano-2- [( { 5- [2-(tetrahydro-2H-pyran-4-yloxy)phenyl] isoxazol-3 - yl}carbonyl)arnino]benzoic acid 5-cyano-2-({[5-(2-{[(lS,2R)-2-methylcyclopentyl]oxy}phenyl)isoxazol-3- yl] carbonyl} amino)benzoic acid
5-cyano-2-[( {5-[2-(2-methoxy- 1 -methylethoxy)phenyl]isoxazol-3- yl}carbonyl)amino]benzoic acid 5-cyano-2-[( {5-[2-(l -methylbutoxy)phenyl]isoxazol-3-yl} carbonyl)amino]benzoic acid
5-cyano-2-[({5-[2-(cyclobutylmethoxy)phenyl]isoxazol-3-yl}carbonyl)amino]benzoic acid
5-cyano-2-( {[7-(cyclobutyloxy)- 1 -methyl- lH-indol-2-yl] carbonyl} amino)benzoic acid 5-cyano-2-( { [7-(2-methoxy- 1 -methylethoxy)- 1 -methyl- 1 H-indol-2- yl] carbonyl} amino)benzoic acid
5-cyano-2- { [(7-isopropoxy- 1 -methyl- 1 H-indol-2-yl)carbonyl] amino } benzoic acid
2-( { [7-(benzyloxy)- 1 -methyl- 1 H-indol-2-yl] carbonyl} amino)-5-cyanobenzoic acid
2- {[(6-chloro- 1 ,2-benzisoxazol-3-yl)carbonyl]amino} -5-cyanobenzoic acid 5-bromo-2-{[(6-chloro-l,2-benzisoxazol-3-yl)carbonyl]amino}benzoic acid
5-cyano-2-[( {5-[2-(cyclohex-2-en- 1 -ylmethoxy)phenyl]isoxazol-3- yl}carbonyl)amino]benzoic acid
2-({[2-(3-{[(2-carboxy-4-cyanophenyl)amino]carbonyl}isoxazol-5- yl)phenoxy] acetyl} arnino)-5-cyanobenzoic acid 5-cyano-2-[( {5-[2-(l-ethylpropoxy)phenyl]isoxazol-3-yl}carbonyl)aιrιino]benzoic acid
5-cyano-2- {[(5- {2-[2-(4-methyl- 1 ,3-thiazol-5-yl)ethoxy]phenyl} isoxazol-3- yl)carbonyl]amino}benzoic acid
5-cyano-2-[({5-[2-(l-cyclohexylethoxy)phenyl]isoxazol-3-yl}carbonyl)amino]benzoic acid 2-{[(6-sec-butoxy-l-methyl-lH-mdol-2-yl)carbonyl]arnino}-5-cyanobenzoic acid
2- { [(6-butoxy- 1 -methyl- 1 H-indol-2-yl)carbonyl] amino} -5-cyanobenzoic acid
5-cyano-2- {[(5- {[(4-fluorophenyl)sulfonyl]amino} - 1 ,2-benzisoxazol-3- yl) carbonyl] arnino} benzoic acid
5-cyano-2-[( {5-[2-(trifluoromethyl)phenyl]pyrazin-2-yl} carbonyl)arnino]benzoic acid 5-cyano-2-[( {5-[2-(2-oxobutoxy)phenyl]isoxazol-3-yl} carbonyl) amino]benzoic acid
5-cyano-2-[({5-[2-(2-oxo-2-phenylethoxy)phenyl]isoxazol-3- yl}carbonyl)amino]benzoic acid
2-( {[5-(2-bromophenyl)isoxazol-3-yl]carbonyl} amino)-5-cyanobenzoic acid
2-( {[5-( 1 , 1 '-biphenyl-2-yl)isoxazol-3-yl]carbonyl} amino)-5-cyanobeιιzoic acid 2-{[(5-arnmo-l,2-benzisoxazol-3-yl)carbonyl]amino}-5-cyanobenzoic acid
5-cyano-2-[( {5-[(4-methoxybenzyl)thio]pyrazin-2-yl} carbonyl)amino]benzoic acid
5-cyano-2-( {[5-(3-methoxyphenyl)isoxazol-3-yl]carbonyl} arnino)benzoic acid
5-cyano-2-( {[5-(2-fluorophenyl)pyrazin-2-yl]carbonyl} amino)benzoic acid 5-bromo-2-{[(5-{(E)-2-[(2S)-l,4-dioxaspiro[4.5]dec-2-yl]ethenyl}pyrazin-2- yl)carbonyl] arnino} benzoic acid
2- {[(5-bromo-l ,2-benzisoxazol-3-yl)carbonyl]amino} -5-cyanobenzoic acid
2-[( {6-[(benzylsulfonyl)amino]- 1 ,2-benzisoxazol-3-yl} carbonyl)amino]-5- cyanobenzoic acid
5-cyano-2-[( {6-[(phenylsulfonyl)arnino]- 1 ,2-benzisoxazol-3- yl}carbonyl)amino]benzoic acid
5-cyano-2-( {[7-(cyclohexylmethoxy)- 1 -methyl- lH-indol-2-yl] carbonyl} amino)benzoic acid 5-cyano-2-( { [7-(cyclopropylmethoxy) - 1 -methyl- 1 H-indol-2- yl] carbonyl} amino)benzoic acid
5-cyano-2-( { [ 1 -methyl-7-(tetrahydro-2H-pyran-2-ylmethoxy) - 1 H-indol-2- yl] carbonyl} amino)benzoic acid
5-cyano-2-( {[1 -methyl-7-(pentyloxy)- 1 H-indol-2-yl] carbonyl} amino)benzoic acid 2-({[5-(chloromethyl)isoxazol-3-yl]carbonyl}arnino)-5-cyanobenzoic acid
5-cyano-2-({[5-(moφholm-4-ylmethyl)isoxazol-3-yl]carbonyl}amino)benzoic acid
5-cyano-2-{[(5-phenyl-l,2-benzisoxazol-3-yl)carbonyl]amino}benzoic acid
5-bromo-2-{[(5-bromo-l,2-benzisoxazol-3-yl)carbonyl]amino}benzoic acid
2-{[(5-{2-[(5-chloropentyl)oxy]phenyl}isoxazol-3-yl)carbonyl]amino}-5-cyanobenzoic acid
2-( {[4,5-bis(methoxymethyl)isoxazol-3-yl]carbonyl} arnino)-5-cyanobenzoic acid
5-cyano-2-[( {5-[2-(trifluoromethyl)phenyl]- 1 ,2-benzisoxazol-3- yl}carbonyl)amino]benzoic acid
5-cyano-2-( {[5-(2-methylphenyl)pyrazm-2-yl]carbonyl}arnino)benzoic acid 5-cyano-2-( {[5-(2,3 ,4-trimethoxyphenyl)pyrazin-2-yl]carbonyl} amino)benzoic acid
5-cyano-2-( {[7-(2-methoxyethoxy)- 1 -methyl- 1 H-indol-2-yl] carbonyl} amino)benzoic acid
5-cyano-2-({[7-(2-hydroxy-3-isopropox propoxy)-l-methyl-lH-indol-2- yl] carbonyl} amino)benzoic acid 5-cyano-2-{[(6-phenyl-l,2-benzisoxazol-3-yl)carbonyl]aιτιino}benzoic acid
5-cyano-2-[( {6-[2-(trifluoromethyl)phenyl]-l ,2-benzisoxazol-3- yl} carbonyl) amino]benzoic acid
2-[( {5-[(benzylamino)methyl]isoxazol-3-yl} carbonyl)arnino]-5-cyanobenzoic acid 2-{[(5-{[bis(2-hydroxyethyl)ammo]methyl}isoxazol-3-yl)carbonyl]arnino}-5- cyanobenzoic acid
2-( {[5-(azidomethyl)isoxazol-3-yl]carbonyl} amino)-5-cyanobenzoic acid
5-cyano-2-( {[5-(nonylthio)pyrazin-2-yl]carbonyl} amino)benzoic acid 5-cyano-2-[( { 1 -methyl-7- [2-(methylthio) ethoxy]- 1 H-indol-2- yl}carbonyl)amino]benzoic acid
5-cyano-2-{[(5-phenyl-4,5-d ydroisoxazol-3-yl)carbonyl]amino}benzoic acid
5-cyano-2-[(4,5-dihydronaphtho[2, 1 -d]isoxazol-3-ylcarbonyl)amino]benzoic acid
5-cyano-2-[(pyrrolo[l ,2-c]pyrimidm-3-ylcarbonyl)amino]benzoic acid 2-[({7-[(4-azido-3-iodobenzoyl)ammo]-l-methyl-lH-mdol-2-yl}carbonyl)amino]-5- cyanobenzoic acid
2-[( {5-[(4-azido-3-iodobenzoyl)amino]- 1 ,2-benzisoxazol-3-yl} carbonyl)amino]-5- cyanobenzoic acid
2-[(E)-2-(l,2-benzisoxazol-3-yl)ethenyl]-5-cyanobenzoic acid 5-cyano-2- {[(5- {[(pyridm-4-ylmethyl)amino]methyl}isoxazol-3- yl)carboriyl]amino}benzoic acid trifluoroacetate
5-cyano-2-[( {5-[(pyridin-4-ylthio)methyl]isoxazol-3-yl} carbonyl)amino]benzoic acid
5-cyano-2-( {[6-(hexylthio)pyridazin-3-yl]carbonyl} amino)benzoic acid
5-cyano-2-({[5-(octylthio)pyrazιn-2-yl]carbonyl}amino)benzoic acid 5-cyano-2-({[5-(6-methoxypyriαlm-3-yl)pyrazm-2-yl]carbonyl}aπιino)benzoic acid
5-cyano-2- {[(5-phenylpyrazin-2-yl) carbonyl] amino} benzoic acid
5-cyano-2-[(4,5,6,7-tetrahydro- 1 ,2-benzisoxazol-3-ylcarbonyl)amino]benzoic acid
5-cyano-2-[( {5-[4-(methylsulfonyl)phenyl]pyrazin-2-yl} carbonyl) amino]benzoic acid
5-cyano-2-({[5-(3,5-dimethylisoxazol-4-yl)pyrazm-2-yl]carbonyl}amino)benzoic acid 2-[(2,l-benzisoxazol-3-ylcarbonyl)amino]-5-cyanobenzoic acid
2-( {[5-( {[ammo(irrιmo)methyl]arrιino}methyl)isoxazol-3-yl]carbonyl} amino)-5- cyanobenzoic acid
2-[(2, 1 -benzisoxazol-3-ylcarbonyl)arnino]-5-bromobenzoic acid
5-cyano-2-[({6-[(methylsulfonyl)amino]-l,2-benzisoxazol-3- yl}carbonyl)amino]benzoic acid
5-cyano-2-{[(6-{[(4-fluorophenyl)sujfonyl]amino}-l,2-benzisoxazol-3- yl) carbonyl] amino} benzoic acid
2-{[(6-ammo-l,2-benzisoxazol-3-yl)carbonyl]amino}-5-cyanobenzoic acid 5-cyano-2-( {[5-(2-fluorophenyι)- 1 ,2-benzisoxazol-3-yl]carbonyl} amino)benzoic acid 5-cyano-2-[( {6-[2-(trifluoromethyl)phenyl]pyridazin-3-yl} carbonyl)amino]benzoic acid 2- {[(2-benzyl- 1 , 1 -dioxido-3 ,4-dihydro-2H- 1 ,2-benzothiazm-5-yl)carbonyl]amino} -5- bromobenzoic acid 2- { [(2-benzyl- 1 , 1 -dioxido-3 ,4-dihydro-2H- 1 ,2-benzothiazm-5-yl)carbonyl]amino} -5- cyanobenzoic acid
5-cyano-2-[( { 1 -methyl-6-[2-(trifluoromethyl)phenyl]- lH-indol-2- yl}carbonyl)arnino]benzoic acid 5-cyano-2-({[l-methyl-6-(2,3,4-trimethoxyphenyl)-lH-indol-2- yl] carbonyl} amino)benzoic acid
5-iodo-2- {[(1 -methyl- 1 H-indol-2-yl)carbonyl] amino} benzoic acid
5-iodo-2-( {[1 -methyl-7-(phenylsulfonyl)- 1 H-indol-2-yl] carbonyl} amino)benzoic acid
5-cyano-2-( {[1 -methyl-7-(pyridin-3-ylmethoxy)- 1 H-indol-2- yl] carbonyl} amino)benzoic acid 2-({[5-(2-fluorophenyl)isoxazol-3-yl]carbonyl}amino)-5-iodobenzoic acid 5-iodo-2-({[5-(2-methylphenyl)isoxazol-3-yl]carbonyl}amino)benzoic acid 5-iodo-2- {[(5-phenylisoxazol-3-yl)carbonyl]amino}benzoic acid 4-( {[5-(2-fluorophenyl)isoxazol-3-yl]carbonyl} amino)-2l-(trifluoromethyl)- 1,1'- biphenyl-3-carboxylic acid 2-( {[5-(2- {[(2R)-3-bromo-2-methylpropyl]oxy}phenyl)isoxazol-3-yl]carbonyl} amino)- 5-cyanobenzoic acid
5-cyano-2-( {[6-(heptylthio)pyridazin-3-yl] carbonyl} amino)benzoic acid 5-cyano-2-( {[5-(heptylthio)pyrazm-2-yl]carbonyl}amino)benzoic acid 5-cyano-2-( { [6-(3 ,5-dimethylisoxazol-4-yl)- 1 -methyl- 1 H-indol-2- yl] carbonyl} amino)benzoic acid
2- {[(5-chloropyrazm-2-yl)carbonyl]amino}-5-cyanobenzoic acid
5-cyano-2-( { [ 1 -methyl-6-(2-methylphenyl)- 1 H-indol-2-yl] carbonyl} amino)benzoic acid
5-bromo-2-( {[6-(hexylthio)pyridazin-3-yl] carbonyl} amino)benzoic acid 5-cyano-2-({[6-(pentylthio)pyridazm-3-yl]carbonyl}amino)benzoic acid 2- {[(5-chloropyrazm-2-yl)carbonyl]amino}-5-iodobenzoic acid 2-( {[5-(benzylthio)pyrazin-2-yl]carbonyl} amino)-5-iodobenzoic acid 2-[({5-[(benzyloxy)carbonyl]-4,5,6,7-tetrahydroisoxazolo[4,5-c]pyridin-3- yl}carbonyl)arnino]-5-cyanobenzoic acid
2-{[(7-ammo-4,6-dibromo-l-methyl-lH-mdol-2-yl)carbonyl]aιrιino}-5-cyanobenzoic acid 5-cyano-2-( {[5-(2-fluorophenyl)isoxazol-3-yl]carbonothioyl} amino)benzoic acid
2-[( {5-[2-( 1 , 1 '-biphenyl-4-yloxy)phenyl]isoxazol-3-yl} carbonyl)amino]-5- cyanobenzoic acid
2-[( {5-[2-( 1 , 1 '-biphenyl-3-yloxy)phenyl]isoxazol-3-yl} carbonyl)amino]-5- cyanobenzoic acid 5-cyano-2-( {[5-(3,4-dihydroxybutyl)isoxazol-3-yl]carbonyl} arnino)benzoic acid
5-cyano-2-[({4,6-dibromo-l-methyl-7-[(phenylacetyl)amino]-lH-indol-2- yl} carbonyl) amino]benzoic acid
2-( {[6-(acetyloxy)-l ,2-benzisoxazol-3-yl]carbonyl} amino)-5-cyanobenzoic acid
5-cyano-2- { [(6-hydroxy- 1 ,2-benzisoxazol-3 -yl) carbonyl] amino } benzoic acid 2-[({5-[2-(l, -biphenyl-2-yloxy)phenyl]isoxazol-3-yl}carbonyl)amino]-5- cyanobenzoic acid
5-cyano-2-( {[5-(hexylthio)pvrimidin-2-yl]carbonyl} amino)benzoic acid
2-({[6-(benzyloxy)-l,2-benzisoxazol-3-yl]carbonyl}arnino)-5-cyanobenzoic acid
5-cyano-2-{[(6-methoxy-l,2-benzisoxazol-3-yl)carbonyl]amino}benzoic acid 2-[({6-[(berizylsulfonyl)oxy]-l,2-benzisoxazol-3-yl}carbonyl)amino]-5-cyanobenzoic acid
5-cyano-2-[({6-[(phenylsulfonyl)oxy]-l,2-benzisoxazol-3-yl}carbonyl)amino]benzoic acid
2- {[(7-amino-4-bromo- 1 -methyl- 1 H-mdol-2-yl) carbonyl] arnino} -5-cyanobenzoic acid 2-( {[7-(benzyloxy)-3-bromo- 1 H-indol-2-yl]carbonyl} amino)-5-cyanobenzoic acid
2-[(lH-benzinιidazol-2-ylcarbonyl)amino]-5-cyanobenzoic acid
5-bromo-2-{[(5-{2-[(2R)-l,4-dioxaspiro[4.5]dec-2-yl]-2-hydroxyethyl}pyrazin-2- yl) carbonyl] arnino} benzoic acid
2- { [(6- { [(acetyloxy) acetyl] amino } - 1 -methyl- 1 H-indol-2-yl) carbonyl] arnino } - 5- cyanobenzoic acid
2-({[5-(anilmosulfonyl)-l,2-benzisoxazol-3-yl]carbonyl}arnino)-5-cyanobenzoic acid
5-cyano-2-[( {5-[(diethylamino)sulfonyl]-l ,2-benzisoxazol-3- yl}carbonyl)amino]benzoic acid 2- {[(7-amino-6-bromo- 1 -methyl- 1 H-mdol-2-yl)carbonyl]amino} -5-cyanobenzoic acid
5-cyano-2-[( { 1 -methyl-7-[(phenylacetyl)amino]-4,6-bis[2-(trifluoromethyl)phenyl]- 1 H- mdol-2-yl}carbonyl)amino]benzoic acid
5-bromo-2-( {[6-(heptylthio)pyridazin-3-yl] carbonyl} amino)benzoic acid 5-cyano-2-[( {5-nitro-6-[4-nitro-2-(trifluoromethyl)phenyl]- 1 ,2-benzisoxazol-3- yl} carbonyl) amino]benzoic acid
2-( {[7-(benzyloxy)-3-bromo- 1 -methyl- 1 H-indol-2-yl] carbonyl} amino)-5-cyanobenzoic acid
2-[( {4-bromo- 1 -methyl-7-[(phenylacetyl)amino]- lH-indol-2-yl} carbonyl)amino]-5- cyanobenzoic acid
5-cyano-2-[( { 1 -methyl-6-[(qumolm-8-ylsulfonyl)amino]- lH-indol-2- yl}carbonyl)amino]benzoic acid
5-cyano-2-( {[5-(moφholin-4-ylsulfonyl)-l ,2-benzisoxazol-3- yl] carbonyl} amino)benzoic acid 5-cyano-2-({[6-(cyclobutyl ι ethoxy)-l-methyl-lH-mdol-2-yl]carbonyl}amino)benzoic acid
2-( { [6-(butyrylamino)- 1 -methyl- 1 H-indol-2-yl] carbonyl} amino)-5-cyanobenzoic acid
5-cyano-2-[({6-[(methoxyacetyl)amino]-l-methyl-lH-indol-2- yl}carbonyl)amino]benzoic acid 5-bromo-2-({[6-(pentylthio)pyridazm-3-yl]carbonyl}amino)benzoic acid
5-cyano-2- { [(7-methyl- 1 H-indol-2-yl) carbonyl] amino } benzoic acid
5-cyano-2- {[(6-oxo-5,6-dihydro-4H-pyrrolo[3,2, 1 -ij]quinolin-2- yl)carbonyl]amino}benzoic acid
2-[({5-(acetylammo)-6-[4-(acetylarnino)-2-(trifluoromethyl)phenyl]-l,2-benzisoxazol- 3 -yl} carbonyl) amino] -5-cyanobenzoic acid
5-cyano-2-[( {5-[(α^ethylarnino)sulfonyl]-l ,2-benzisoxazol-3- yl}carbonyl)arnino]benzoic acid
5-cyano-2-[( {5-[(methoxyacetyl)amino]- 1 ,2-benzisoxazol-3- yl} carbonyl) arnino]benzoic acid 5-cyano-2-[( {5-[(cyclobutylcarbonyl)arnino]- 1 ,2-benzisoxazol-3- yl}carbonyl)arnino]benzoic acid
5-cyano-2-( {[6-(2-furoylamino)- 1 -methyl- 1 H-indol-2-yl]carbonyl} amino)benzoic acid 5-cyano-2-({[l-methyl-6-({[methyl(phenyl)anτmo]carbonyl}amino)-lH-indol-2- yl] carbonyl} amino)benzoic acid
2-( {[6-(acetylamino)- 1 -methyl- 1 H-indol-2-yl] carbonyl} amino)-5-cyanobenzoic acid
5-cyano-2-{[(l-methyl-6-{[4-(trifluoromethoxy)benzoyl]amino}-lH-indol-2- yl)carbonyl]amino}benzoic acid
5-cyano-2-( { [6-(2-fluorophenyl)- 1 -methyl- 1 H-indol-2-yl] carbonyl} amino)benzoic acid
5-cyano-2-( { [6-(cyclopropylmethoxy) - 1 -methyl- 1 H-indol-2- yl] carbonyl} amino)benzoic acid
5-cyano-2-{[(l-methyl-lH-mdol-3-yl)carbonyl]amino}benzoic acid 2- {[(7-bromo-l-methyl-lH-mdol-2-yl)carbonyl]amino}-5-cyanobenzoic acid
5-bromo-2-{[(5-{2-[(2R)-l,4-dioxaspiro[4.5]dec-2-yl]-2-methoxyethyl}pyrazin-2- yl)carbonyl]amino}benzoic acid
5-bromo-2-[({5-[(3R)-2,3,4-trmyo^oxybutyl]pyrazin-2-yl}carbonyl)amino]benzoic acid
5-cyano-2-{[(6-methoxy-5,6-dihydro-4H-pyrrolo[3,2,l-ij]quinolin-2- yl) carbonyl] amino } benzoic acid
5-cyano-2-{[(6-hydroxy-5,6-dihydro-4H-pyrrolo[3,2,l-ij]quinolin-2- yl)carbonyl]amino}benzoic acid
5-cyano-2-{[(6-phenoxy-5,6-dihydro-4H-pyrrolo[3,2,l-ij]quinolin-2- yl)carbonyl]arnino}benzoic acid 5-cyano-2-[({l-methyl-7-[2-(trifluoromethyl)phenyl]-lH-indol-2- yl}carbonyl)amino]benzoic acid
5-cyano-2- { [( 1 -methyl-7-phenyl- 1 H-mdol-2-yl)carbonyl]arnino} benzoic acid
2-( {[7-(4-tert-butylphenyl)- 1 -methyl- 1 H-indol-2-yl] carbonyl} amino)-5-cyanobenzoic acid 5-cyano-2-( { [ 1 -methyl-7-(5-methylthien-2-yl)- 1 H-indol-2-yl] carbonyl} amino)benzoic acid
5-cyano-2-[( { 1 -methyl-6-[(methylsulfonyl) amino]- 1 H-indol-2- yl} carbonyl) amino]benzoic acid
5-bromo-2-[({5-[(3R)-2,3,4-trimethoxybutyl]pyrazm-2-yl}carbonyl)arnino]benzoic acid
5-bromo-2-[({5-[(3R)-3,4-dihydroxy-2-methoxybutyl]pyrazin-2- yl}carbonyl)amino]benzoic acid 2-[({5-[3,4-bis(methoxymethoxy)butyl]isoxazol-3-yl}carbonyl)amino]-5- bromobenzoic acid
5-cyano-2-({[6-({[(2,5-dimetfroxyphenyl)ammo]carbonyl}arrιino)-l-methyl-lH-indol-
2-yl] carbonyl} amino)benzoic acid 5-cyano-2-[( {6-[(isoxazol-5-ylcarbonyl)amino]-l -methyl- 1 H-indol-2- yl}carbonyl)amino]benzoic acid
5-cyano-2- {[( 1 -methyl-6- {[(pentylarnmo)carbonyl] amino} - lH-indol-2- yl)carbonyl]arnino}benzoic acid
5-cyano-2- [( { 1 -methyl-7- [4-(methylsulfonyl)phenyl] - 1 H-indol-2- yl}carbonyl)amino]benzoic acid
5-cyano-2-( { [7-(2-methoxyphenyl)- 1 -methyl- 1 H-indol-2-yl] carbonyl} amino)benzoic acid
5-cyano-2-( {[7-(2-fluorophenyl)- 1 -methyl- 1 H-indol-2-yl] carbonyl} amino)benzoic acid
5-cyano-2-( { [ 1 -methyl-7-(2-methylphenyl) - 1 H-indol-2-yl] carbonyl} arnino)benzoic acid
5-cyano-2-[( {6-[(pyridin-4-ylmethyl)thio]pyridazin-3-yl} carbonyl) amino]benzoic acid
5-cyano-2- {[(6-{[(3, 5-dimethylisoxazol-4-yl)sulfonyl] amino} - 1 -methyl- 1 H-indol-2- yl)carbonyl]arnino}benzoic acid
5-cyano-2-( {[5-(dmιethylamino)- 1 ,2-benzisoxazol-3-yl]carbonyl} amino)benzoic acid 5-cyano-2-({[5-(ethylammo)-l,2-benzisoxazol-3-yl]carbonyl}amino)benzoic acid
5-cyano-2-[( {5-[(cyclopropylmethyl)amino]- 1 ,2-benzisoxazol-3- yl} carbonyl) amino]benzoic acid
5-cyano-2-[( {5-[(2-methoxyethyl)amino]- 1 ,2-benzisoxazol-3- yl}carbonyl)amino]benzoic acid 5-cyano-2-[( {5-[(2-hydroxyethyl)amino]-l ,2-benzisoxazol-3- yl}carbonyl)amino]benzoic acid
5-cyano-2-[( {5-[(2,3-dihydroxypropyl)amino]- 1 ,2-benzisoxazol-3- yl}carbonyl)arnino]benzoic acid
5-bromo-2-[({5-[(3R)-2-methoxy-3,4-bis(methoxymethoxy)butyl]pyrazin-2- yl}carbonyl)amino]benzoic acid
2-[( {6-[bis(butylsulfonyl)amino]- 1 -methyl- 1 H-indol-2-yl} carbonyl)amino]-5- cyanobenzoic acid 2-[( {6-[bis(phenylsulfonyl)amino]- 1 -methyl- 1 H-indol-2-yl} carbonyl)amino]-5- cyanobenzoic acid
5-cyano-2- { [(6- {[(2-methoxyethoxy)acetyl]amino } - 1 -methyl- 1 H-indol-2- yl)carbonyl]amino}benzoic acid 5-cyano-2-[(lH-mdazol-3-ylcarbonyl)amino]benzoic acid
5-cyano-2-( {[5-(hexylthio)pyridin-2-yl]carbonyl} amino)benzoic acid
5-cyano-2- {[(6- {[(2E)-5-hydroxypent-2-enyl]thio}pyridazin-3- yl)carbonyl]amino}benzoic acid
5-cyano-2- {[(6- {[2-oxo-2-(4-oxo-3,4-dihydro-2H- 1 ,3-benzoxazin-6- yl)ethyl]thio}pyridazm-3-yl)carbonyl]amino}benzoic acid '
5-cyano-2-({[5-(2-methylphenyl)-l,2-benzisoxazol-3-yl]carbonyl}amino)benzoic acid
5-bromo-2- [({5-[(3R)-3 -hydroxy-2-methoxy-4-(methoxymethoxy)butyl]pyrazin-2- yl}carbonyl)amino]benzoic acid
5-cyano-2-( {[5-(pyrrolidin- 1 -ylsulfonyl)- 1 ,2-benzisoxazol-3- yl] carbonyl} arnino)benzoic acid
5-cyano-2-[( {5-[(dipropylamino)sulfonyl]- 1 ,2-benzisoxazol-3- yl}carbonyl)amino]benzoic acid
2-[({5-[(5-chloro-2,3-dihydro-lH-indol-l-yl)sulfonyl]-l,2-benzisoxazol-3- yl}carbonyl)amino]-5-cyanobenzoic acid 5-cyano-2-{[(l-methyl-lH-indazol-3-yl)carbonyl]arnino}benzoic acid
2-( {[5-(anilinosulfonyl)-l ,2-benzisoxazol-3-yl]carbonyl} arnino)-5-bromobenzoic acid
5-bromo-2-({[5-(moφholin-4-ylsulfonyl)-l,2-benzisoxazol-3- yl] carbonyl} amino)benzoic acid
5-bromo-2-( {[5-(hexylthio)pyridin-2-yl]carbonyl} amino)benzoic acid 5-cyano-2-[( { 1 -methyl-6-[(thien-2-ylsulfonyl)amino]- 1 H-indol-2- yl}carbonyl)amino]benzoic acid
5-cyano-2- { [( 1 -methyl-6- { [(methylamino) carbonyl] amino } - 1 H-indol-2- yl)carbonyl]amino}benzoic acid
5-cyano-2- { [(6- { [(isopropylamino) carbonyl] arnino } - 1 -methyl- 1 H-indol-2- yl)carbonyl]amino}benzoic acid
5-cyano-2-[( {5-[(methylarnino)sulfonyl]-l ,2-benzisoxazol-3- yl}carbonyl)amino]benzoic acid compound with N,N-diethylamine (1: 1) 2- {[(5- {[bis(2-hydroxyethyl) amino] sulfonyl} - 1 ,2-benzisoxazol-3-yl)carbonyl] a ino} -
5-cyanobenzoic acid
2-( { [6-(bis { [4-(acetylamino)phenyl]sulfonyl} amino)- 1 -methyl- 1 H-indol-2- yl]carbonyl}amino)-5-cyanobenzoic acid 2-[({6-[bis(thien-2-ylsulfonyl)ammo]-l-methyl-lH-mdol-2-yl}carbonyl)amino]-5- cyanobenzoic acid
5-bromo-2- [( { 5- [(dimethylamino) sulfonyl] - 1 ,2-benzisoxazol-3 - yl} carbonyl) amino]benzoic acid
5-bromo-2-[( {5-[(diethylamino)sulfonyl]- 1 ,2-benzisoxazol-3- yl} carbonyl) amino]benzoic acid
2-[{ {5-[(benzylamino)sulfonyl]- 1 ,2-benzisoxazol-3-yl} carbonyl)amino]-5- bromobenzoic acid
2-[( {5-(acetylarrιmo)-6-[4-(acetylarnino)-2-(trifluoromethyl)phenyl]- 1 ,2-benzisoxazol-
3-yl} carbonyl)amino]-5-bromobenzoic acid 2-[({5-[3-(acetylammo)phenyl]-l,2-ben-risoxazol-3-yl}carbonyl)amino]-5- cyanobenzoic acid or 5-Cyano-2-{[5-(3-acetamidophenyl)-benzisoxazole-3- carbonyl] arnino} benzoic acid
5-cyano-2-[({5-[4-(methylsulfonyl)phenyl]-l,2-benzisoxazol-3- yl} carbonyl) amino]benzoic acid 5-bromo-2-( {[5-(pyrrolidin- 1 -ylsulfonyl)- 1 ,2-benzisoxazol-3- yl] carbonyl} amino)benzoic acid
5-bromo-2-[( {5-[(methylamino)sulfonyl]- 1 ,2-benzisoxazol-3- yl}carbonyl)amino]benzoic acid
2-( {[5-(arrιinosulfonyl)-l ,2-benzisoxazol-3-yl]carbonyl} amino)-5-bromobenzoic acid 5-cyano-2-[({l-methyl-6-[(moφholm-4-ylcarbonyl)amino]-lH-indol-2- yl}carbonyl)amino]benzoic acid
5-cyano-2-[({5-[4-(moφholin-4-ylcarbonyl)phenyl]-l,2-benzisoxazol-3- yl} carbonyl)amino]benzoic acid
2-( {[5-(2-acetylphenyl)-l ,2-benzisoxazol-3-yl] carbonyl} amino)-5-cyanobenzoic acid 5-cyano-2-( {[5-(2,5-dimethoxyphenyl)- 1 ,2-benzisoxazol-3-yl]carbonyl} amino)benzoic acid
5-cyano-2-({[5-(2-phenoxyphenyl)isoxazol-3-yl]carbonyl}amino)benzoic acid 2-[( {7-[3-(acetylamino)phenyl]- 1 -methyl- 1 H-indol-2-yl} carbonyl)arnino]-5- cyanobenzoic acid
5-cyano-2-( {[6-(2-methylphenyl)-l ,2-benzisoxazol-3-yl]carbonyl} arnino)benzoic acid
5-bromo-2-[( {5-[(3S)-3,4-dihydroxybutyl]pyrazin-2-yl} carbonyl)amino]benzoic acid 5-cyano-2-({[6-(3,5-dimethylisoxazol-4-yl)-l,2-benzisoxazol-3- yl] carbonyl} amino)benzoic acid
2-[( {5-[2-(acetylamino)phenyl]- 1 ,2-benzisoxazol-3-yl} carbonyl)arnino]-5- cyanobenzoic acid
5-cyano-2-[( {7-[(ethylsulfonyl)amino]- 1 -methyl- lH-indol-2- yi}carbonyl)amino]benzoic acid
2-[( {7-[bis(methylsulfonyl)amino]- 1 -methyl- 1 H-indol-2-yl} carbonyl)amino]-5- cyanobenzoic acid
5-cyano-2- {[(1 -methyl-7- { [( 1 -methyl- 1 H-imidazol-4-yl)sulfonyl]amino} - 1 H-indol-2- yl)carbonyl]amino}benzoic acid 2- {[(7- {[(5-chloro- 1 ,3-dimethyl- lH-pyrazol-4-yl)sulfonyl]amino} - 1 -methyl- 1 H-indol-
2-yl)carbonyl]amino} -5-cyanobenzoic acid
2-[( {7-[(butylsulfonyl)amino]- 1 -methyl- lH-indol-2-yl} carbonyl)amino]-5- cyanobenzoic acid
2- {[(7- {[(3-chloropropyl)sulfonyl]amino} - 1 -methyl- 1 H-mdol-2-yl) carbonyl] arnino} -5- cyanobenzoic acid
5-cyano-2-{[(7-{[(3,5-dimethylisoxazol-4-yl)sulfonyl]amino}-l-methyl-lH-indol-2- yl)carbonyl]amino}benzoic acid
2-{[(7-{bis[(5-bromo-6-chloropyridm-3-yl)sulfonyl]amino}-l-methyl-lH-indol-2- yl)carbonyl]amino} -5-cyanobenzoic acid 5-cyano-2-[( { 1 -methyl-7- [(methylsulfonyl) amino]- 1 H-indol-2- yl}carbonyl)amino]benzoic acid
5-cyano-2-( {[(6E)-6-(methoxyimino)-5,6-dihydro-4H-pyrrolo[3,2, 1 -ij]quinolin-2- yl]carbonyl}arnino)benzoic acid
2-[({(6E)-6-[(benzyloxy)irrimo]-5,6-dmydro-4H-pyrrolo[3,2,l-ij]quinolin-2- yl}carbonyl)amino]-5-cyanobenzoic acid
5-cyano-2-( {[(6E)-6-(phenoxyimino)-5,6-dihydro-4H-pyrrolo[3,2, 1 -ij]quinolin-2- yl] carbonyl} amino)benzoic acid 5-cyano-2-[( { 1 -methyl-7-[(propylsulfonyl)amino]- 1 H-indol-2- yl} carbonyl) amino]benzoic acid
5-cyano-2- { [(7- { [(2,4-dimethyl- 1 ,3-thiazol-5-yl)sulfonyl]amino} - 1 -methyl- 1 H-indol-2- yl)carbonyl]amino}benzoic acid 5-cyano-2-({[l-methyl-7-({[(methylsulfonyl)methyl]sulfonyl}amino)-lH-indol-2- yl]carbonyl}amino)benzoic acid
2-[({7-[3-(butylanτmo)-2-hydroxypropoxy]-l-methyl-lH-mdol-2-yl}carbonyl)amino]-
5-cyanobenzoic acid hydrochloride
5-cyano-2-[( {7-[2-hydroxy-3-(2-phenoxyethoxy)propoxy]- 1 -methyl- 1 H-indol-2- yl} carbonyl) amino]benzoic acid
5-cyano-2- {[(7- {2-hydroxy-3-[(3-methylbut-2-enyl)oxy]propoxy} - 1 -methyl- 1 H-indol-
2-yl)carbonyl]arnino}benzoic acid
5-cyano-2-[({7-[3-(2,3-dihydroxypropoxy)-2-hydroxypropoxy]-l-methyl-lH-indol-2- yl}carbonyl)amino]benzoic acid 2-[({7-[3-(but-3-ynyloxy)-2-hydroxypropoxy]-l-methyl-lH-indol-2- yl} carbonyl) arnino] -5-cyanobenzoic acid
2-[({5-[acetyl(ethyl)ammo]-l,2-benzisoxazol-3-yl}carbonyl)amino]-5-cyanobenzoic acid
5-cyano-2-[( {5-[ethyl(methylsulfonyl)amino]-l ,2-benzisoxazol-3- yl}carbonyl)amino]benzoic acid
5-cyano-2- {[(5- {[(dimethylammo)sulfonyl]amino} - 1 ,2-benzisoxazol-3- yl)carbonyl]amino}benzoic acid
2-{[(6-bromo-l,2-berizisoxazol-3-yl)carbonyl]amino}-5-cyanobenzoic acid
2-[({6-[2-(acetylarnmo)phenyl]-l,2-benzisoxazol-3-yl}carbonyl)arnino]-5- cyanobenzoic acid
2-[( {6-[3-(acetylamino)phenyl]- 1 ,2-benzisoxazol-3-yl} carbonyl)amino]-5- cyanobenzoic acid
5-cyano-2-({[(6E)-6-(ethoxyimmo)-5,6-dmydro-4H-pyrrolo[3,2,l-ij]quinolin-2- yl] carbonyl} amino)benzoic acid 2-({[(6E)-6-(tert-butoxyirmno)-5,6-dmydro-4H-pyrrolo[3,2,l-ij]quinolin-2- yl]carbonyl}amino)-5-cyanobenzoic acid
5-cyano-2-( {[(6E)-6-(hydVoxyimino)-5,6-dihydro-4H-pyrrolo[3,2, 1 -ij]quinolin-2- yl] carbonyl} amino)benzoic acid 5-bromo-2- {[(1,1 -dioxido- 1 ,2-benzisothiazol-3-yl)carbonyl]amino}benzoic acid
2-[(l ,2-berιzisothiazol-3-ylcarbonyl)amino]-5-bromobenzoic acid
5-cyano-2-({[7-(2-hydroxy-3-methoxypropoxy)-l-methyl-lH-indol-2- yl] carbonyl} arnino)benzoic acid 5-cyano-2-( { [7-(3-ethoxy-2-hydroxypropoxy)- 1 -methyl- 1 H-indol-2- yl] carbonyl} amino)benzoic acid
2-({[7-(3-chloro-2-hyα oxypropoxy)-l-methyl-lH-mdol-2-yl]carbonyl}arnino)-5- cyanobenzoic acid
5-cyano-2-[( { 1 -methyl-7- [(pyridin-4-ylacetyl) amino]- 1 H-indol-2- yl}carbonyl)amino]benzoic acid trifluoroacetate
5-cyano-2-[({5-[2-(hydroxymethyl)phenyl]-l,2-benzisoxazol-3- yl}carbonyl)amino]benzoic acid
5-cyano-2-[({6-[3-(hydroxymethyl)phenyl]-l,2-benzisoxazol-3- yl}carbonyl)amino]benzoic acid 5-cyano-2-[({5-[(methylsulfonyl)ammo]-6-[4-[(methylsulfonyl)amino]-2-
(trifluoromethyl)phenyl]-l ,2-benzisoxazol-3-yl} carbonyl) amino]benzoic acid
5-bromo-2-[( {6-[(ώpropylamino)sulfonyl]-3-pyridinyl} carbonyl)amino]benzoic acid
5-bromo-2-{[(4-{[4-chloro(methyl)anilmo]sulfonyl}-2-thienyl)carbonyl]arnino}benzoic acid 5-bromo-2- {[(5- {[4-chloro(methyl)anilino]sulfonyl} -2-thienyl)carbonyl]amino}benzoic acid
5-bromo-2-[(5- {[4-chloro(methyl)anilino]sulfonyl} -2-furoyl)amino]benzoic acid
2-( {[2-(berizylsulfanyl)-lH-imidazol-4-yl]carbonyl} amino)-5-bromobenzoic acid
5-bromo-2- {[(4- {[4-chloro(methyl)anilino]sulfonyl} -5-methyl-2- thienyl) carbonyl] arnino} benzoic acid
5-bromo-2- {[(4- {[4-chloro(methyl)anilino]sulfonyl} -3-methyl-2- thienyl)carbonyl]amino}benzoic acid
5-bromo-2-{[(5-{[4-chloro(methyl)anilmo]sulfonyl}-3-thienyl)carbonyl]arnino}benzoic acid 5-bromo-2-[(2-thienylcarbonyl)amino]benzoic acid
2- {[2-(benzylsulfanyl)isonicotinoyl]amino} -5-bromobenzoic acid
5-bromo-2- {[(5- {[4-chloro(methyl)anilino]sulfonyl} -3- pyridmyl)carbonyl]amino}benzoic acid 5-bromo-2- {[(5- {[4-chloro(methyl)anilino]sulfonyl} - 1 -oxido-3- pyridmyl)carbonyl]amino}benzoic acid
2-( {[4-(benzylsulfanyl)-2-pyridinyl]carbonyl} amino)-5-bromobenzoic acid 2-( {[6-(benzylsulfanyl)-2-pyridinyl]carbonyl} amino)-5-bromobenzoic acid. The antibacterial agent may be incoφorated into a pharmaceutical composition.
The pharmaceutical compositions of this invention may be prepared by combining the compounds of this invention with a solid or liquid pharmaceutically acceptable carrier and, optionally, with pharmaceutically acceptable adjuvants and excipients employing standard and conventional techniques. Solid form compositions include powders, tablets, dispersible granules, capsules, cachets and suppositories. A solid carrier can be at least one substance which may also function as a diluent, flavoring agent, solubilizer, lubricant, suspending agent, binder, tablet disintegrating agent, and encapsulating agent. Inert solid carriers include magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, cellulosic materials, low melting wax, cocoa butter, and the like. Liquid form compositions include solutions, suspensions and emulsions. For example, there may be provided solutions ofthe compounds of this invention dissolved in water and water-propylene glycol systems, optionally containing suitable conventional coloring agents, flavoring agents, stabilizers and thickening agents. Preferably, the pharmaceutical composition is provided employing conventional techniques in unit dosage form containing effective or appropriate amounts ofthe active component, that is, the compound according to this invention.
The quantity of active component, that is the compound according to this invention, in the pharmaceutical composition and unit dosage form thereof may be varied or adjusted widely depending upon the particular application, the potency ofthe particular compound and the desired concentration. Generally, the quantity of active component will range between 0.5% to 90% by weight ofthe composition.
In therapeutic use for treating, or combatting, bacterial infections in warmblooded animals, the compounds or pharmaceutical compositions thereof will be administered orally, parenterally and/or topically at a dosage to obtain and maintain a concentration, that is, an amount, or blood-level of active component in the animal undergoing treatment which will be antibacterially effective. Generally, such antibac- terially effective amount of dosage of active component will be in the range of about 0.1 to about 100, more preferably about 3.0 to about 50 mg/kg of body weight/day. It is to be understood that the dosages may vary depending upon the requirements ofthe patient, the severity ofthe bacterial infection being treated, and the particular compound being used. Also, it is to be understood that the initial dosage administered may be increased beyond the above upper level in order to rapidly achieve the desired blood-level or the initial dosage may be smaller than the optimum and the daily dosage may be progressively increased during the course of treatment depending on the particular situation. If desired, the daily dose may also be divided into multiple doses for administration, e.g., 2-4 four times per day. • The compounds according to this invention may be administered parenterally, i.e., by injection, for example, by intravenous injection or by other parenteral routes of administration. Pharmaceutical compositions for parenteral administration will generally contain a pharmaceutically acceptable amount ofthe compound or a soluble salt (acid addition salt or base salt) dissolved in a pharmaceutically acceptable liquid carrier such as, for example, water-for-injection and a buffer to provide a suitably buffered isotonic solution, for example, having a pH of about 3.5-6. Suitable buffering agents include, for example, trisodium orthophosphate, sodium bicarbonate, sodium citrate, N-methylglucamine, L(+)-lysine and L(+)-arginine to name but a few representative buffering agents. The compound of this invention generally will be dissolved in the carrier in an amount sufficient to provide a pharmaceutically acceptable injectable concentration in the range of about 1 mg/mL to about 400 mg/mL of solution. The resulting liquid pharmaceutical composition will be administered so as to obtain the above-mentioned antibacterially effective amount of dosage. The compounds according to this invention are advantageously administered orally in solid and liquid dosage forms.
As a topical treatment an effective amount of Formula I is admixed in a pharmaceutically acceptable gel or cream vehicle that can be applied to the patient's skin at the area of treatment. Preparation of such creams and gels is well known in the art and can include penetration enhancers. The antibacterial agents of this invention have useful activity against a variety of organisms. The in vitro activity of compounds of this invention can be assessed by standard testing procedures such as the determination of minimum inhibitory concentration (MIC) by agar dilution as described in "Approved Standard. Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria That Grow Aerobically", 3rd. ed., published 1993 by the National Committee for Clinical Laboratory Standards, Villanova, Pennsylvania, USA.
In some embodiments, the antibacterial compounds are prodrugs ofthe compounds of formula I. The expression "prodrug" denotes a derivative of a known direct acting drug, which is transformed into the active drug by an enzymatic or chemical process. Prodrugs ofthe compounds of formula I are prepared by modifying functional groups present on the compound in such a way that the modifications are cleaved, either in routine manipulation or in vivo, to the parent compound. Prodrugs include, but are not limited to, compounds of structure (I) wherein hydroxy, amine or sulfhydryl groups are bonded to any group that, when administered to the animal, cleaves to form the free hydroxyl, amino or sulfhydryl group, respectively. Representative examples of prodrugs include, but are not limited to, acetate, formate and benzoate derivatives of alcohol and amine functional groups. See Notari, R. E., "Theory and Practice of Prodrug Kinetics," Methods in Enzymology, 112:309-323 (1985); Bodor, N., "Novel Approaches in Prodrug Design," Drugs ofthe Future, 6(3): 165-182 (1981); and Bundgaard, H., "Design of Prodrugs: Bioreversible- Derivatives for Various Functional Groups and Chemical Entities," in Design of Prodrugs (H. Bundgaard, ed.), Elsevier, N.Y. (1985). The antibacterial compounds of this invention may be synthesized by various methods known to those skilled in the art. Non-limiting examples of synthetic schemes for producing the antibacterial agents are described below.
EXAMPLES Without further elaboration, it is believed that one skilled in the art can, using the preceding description, practice the present invention to its fullest extent. The following detailed examples describe how to prepare the various compounds and/or perform the various processes ofthe invention and are to be construed as merely illustrative, and not limitations ofthe preceding disclosure in any way whatsoever. Those skilled in the art will promptly recognize appropriate variations from the procedures both as to reactants and as to reaction conditions and techniques. Example: 1 R, as an INDOLE or Derivative thereof:
Preparation of 7-(benzyloxy)-lH-indoIe-2-carboxylic acid
Figure imgf000049_0001
Ethyl 7-(benzyloxy)-lH-indole-2-carboxylate (645 mg, 2.18 mmol) and LiOH*H2O (480 mg, 11.4 mmol) were combined in THF (10 mL) and H2O (5 mL) and staken at 45°C overnight. When the reaction was complete, the solution was diluted with MTBE, washed with 2 N HCl and brine, dried (MgSO ), and concentrated in vacuo to afford 554 mg (95%) ofthe acid.
Figure imgf000049_0002
Preparation of
Figure imgf000049_0003
Preparation of
Figure imgf000049_0004
Ethyl 7-(benzyloxy)-lH-indole-2-carboxylate (10.22 g, 34.6 mmol) was dissolved in DMF (100 mL). NaH (60% dispersion, 2 g) was added and the reaction was stirred for 30 min at rt. Mel (25 mL) was added and solution stirred overnight. The reaction was diluted with MTBE, washed with H2O x5, dried (MgSO4), concentrated to afford 12.16 g (114%o) Ethyl 7-(benzyloxy)-l -methyl- lH-indole-2-carboxylate as a yellow solid. The crude material was carried on as is.
The yellow solid product (7.5 g, 24.2 mmoL) and LiOH»H2O (9 g, 214 mmol) were combined in THF (100 mL) and H2O (10 mL) and stirred at 45°C overnight. When hydrolysis was complete, the solution was diluted with CH2C12, washed with 2 N HCl, dried (MgSO ), and concentrated to afford 5.62 (83%) ofthe title compound as a white solid.
Analytical data
1H NMR (300 MHz, DMSO--i6) δ 12.85 (br s, 1 H), 7.54 (d, J= 6.9 Hz, 2 H), 7.43 (t, J= 7.38 Hz, 2 H), 7.36 (d, J= 7.08 Hz, 1 H), 7.22 (d, J= 6.96 Hz, 1 H), 7.17 (s, 1 H), 6.99 (t, J= 7.83 Hz, 1 H), 6.91 (d, J= 6.93 Hz, 1 H), 5.25 (s, 2 H), 4.30 (s, 3 H).
Example 1.1: tert-Butyl 2-({[7-(benzyloxy)-l-methyl-lH-indol-2- yl]carbonyl} amino)- 5-cyanobenzoate
Figure imgf000050_0001
7-(Benzyloxy)-l -methyl- lH-indole-2-carboxylic acid (5.62 g, 20.0 mmol) and 4 drops of DMF were combined in CH2C12 (150 mL). Oxalyl chloride (2.0 mL) was added and the suspension was stirred until clear, 4 hrs. The volatiles were removed in vacuo and the resulting acid chloride was placed under high- vac for 30 minutes to ensure removal ofthe oxalyl chloride. The acid chloride was re-dissolved in CH2C12 (70 mL), added to a solution of tert-butyl-2-amino-5-cyanobenzoate (4.15 g, 19.0 mmol) in CH2C12 (70 mL) and pyridine (6 mL), and stirred at rt overnight. The solution was diluted with
CH2C12, washed with 2 N HCl, dried (MgSO4), concentrated, and triturated with
MeOH to afford 7.25 g (75%) ofthe title compound as yellow solid.
Analytical data
1H NMR (300 MHz, OMSO-d6) δ 11.85 (s, 1 H), 8.63 (d, J= 8.79 Hz, 1 H), 8.34 (d, J= 2.01 Hz, 1 H), 8.08 (dd, J= 8.64, 2.07 Hz, 1 H), 7.55 (d, J= 6.96 Hz, 2 H), 7.44 (t, J= 7.53 Hz, 2 H), 7.37 (d, J= 1.10 Hz, 1 H), 7.33 (d, J= 7.35 Hz, 1 H), 7.22 (s, 1 H), 7.05 (t, J= 7.92 Hz, 1 H), 6.95 (d, J= 7.35 Hz, 1 H), 5.28 (s, 2 H), 4.29 (s, 3 H), 1.59 (s, 9 H). Example 1.2: 5-Cyano-2-{[(7-hydroxy-l-methyl-lH-indol-2- yl)carbonyl]amino}benzoic acid
Figure imgf000051_0001
The compound from Example 1.1 (152 mg, 0.316 mmol) was dissolved in CH2C12 (5 mL). T1CI4 (1.0 M in CH C12, 10 mL) was added slowly and the reaction was stirred for 20 min. The reaction was quenched with MeOH, concentrated, and triturated with
MeOH for afford 63 mg (59%) ofthe title compound as a white solid.
Analytical data
Η NMR (400 MHz, DMSO- ) δ 12.31 (s, 1 H), 9.95 (s, 1 H), 8.82 (d, J= 6.63 Hz, 1 H), 8.41 (d, J= 1.56 Hz, 1 H), 8.08 (dd, J= 6.60, 1.59 Hz, 1 H), 7.15 (s, 1 H), 7.12 (d, J= 5.52 Hz, 1 H), 6.90 (t, J= 5.79 Hz, 1 H), 6.67 (d, J= 5.64 Hz, 1 H), 4.32 (s, 3 H).
Example 1.3: 5-Cyano-2-({[l-methyl-7-(3-phenoxypropoxy)-lH-indol-2- yl]carbonyl}amino)benzoic acid
Figure imgf000051_0002
General method A: The compound of Example 1.1 (500 mg, 1.28 mmol), PPh3 (677 mg, 2.58 mmol), and 3-phenyloxy-l-propanol (388 mg, 2.55 mmol) were combined in
THF (10 mL) and cooled in an ice bath. DIAD (570 μL, 2.89 mmol) was added over 1 min. The reaction was shaken overnight on an orbital shaking block at rt. The reaction was absorbed on SiO2 and purified using silica gel chromatography (EtOAc/Hep: 1/19, 1/4) to afford 261 mg (39%) ofthe t-Bu ester, 36883-bdw-33. In some occasions a DIAD product co-eluted with the product, in which case the co- elutants were triturated with MeOH to afford the clean desired ester. The ester (255 mg, 485 mmol) and LiOH»H2O (262 mg, 624 mmol) were dissolved in THF (10 mL) and H2O (1 mL) and shaken at 45°C overnight. When the hydrolysis was complete, the reaction was diluted with CH2C12, washed with 2 N HCl, dried (MgSO4), concentrated and triturated with MeOH to afford 73 mg (32%) ofthe title compound as a white solid.
Analytical data
1HNMR (300 MHz, DMSO--i6) δ 12.40 (s, 1 H), 8.81 (d, J= 8.80 Hz, 1 H), 8.41 (d, J= 2.06 Hz, 1 H), 8.08 (dd, J= 8.78, 2.11 Hz, 1 H), 7.31-7.26 (m, 3 H), 7.18 (s, 1 H), 7.06-6.85 (m, 5 H), 4.31-4.29 (m, 5), 4.21 (t, J= 6.17 Hz, 2 H), 2.36-2.29 (m, 2 H).
Example 1.4: 2-({[7-(Benzyloxy)-lH-indol-2-yl]carbonyl}amino)-5-cyanobenzoic acid
Figure imgf000052_0001
General procedure B: The acid, 7-(benzyloxy)-lH-indole-2-carboxylic acid (146 mg, 0.546 mmol) and 2 drops of DMF were combined in CH2C12 (10 mL). Oxalyl chloride (300 μL) was added and the reaction was stirred for 4 hrs. Heptane was added and the volatiles were removed in vacuo. The resulting acid chloride was dissolved in CH2C12 (10 mL), added to a solution of tert-butyl 2-amino-5-cyanobenzoate (118 mg, 0.541 mmol) in CH2C12 (10 mL) and pyridine (1 mL), and the reaction was shaken overnight at rt. The solution was then diluted with MTBE, washed with 2 N HCl and brine, dried (MgSO ), concentrated, and triturated with MeOH to afford 142 mg (56%) of the title compound as a white solid. Analytical data
*H NMR (400 MHz, DMSO-</6) δ 12.48 (s, 1 H), 12.10 (s, 1 H), 8.84 (d, J= 8.80 Hz, 1 H), 8.42 (d, J= 2.08 Hz, 1 H), 8.10 (dd, J= 8.76, 2.09 Hz, 1 H), 7.65 (d, J= 7.00, Hz, 2 H), 7.41 (t, J= 7.64 Hz, 2 H), 7.34 (d, J= 7.36 Hz, 1 H), 7.30 (d, J= 7.96 Hz, 1 H), 7.17 (d, J= 2.16 Hz, 1 H), 7.02 (t, J= 7.88 Hz, 1 H), 6.90 (d, J= 7.44 Hz, 1 H), 5.30 (s, 2 H).
Example 1.5: 5-Cyano-2-({[7-(2,3-dihydro-l,4-beιιzodioxin-2-ylmethoxy)-l- methyl- 1 H-indol-2 -yl] carb onyl} amino)b enzoic acid
Figure imgf000053_0001
Prepared according to method A: The compound from example 1.1 (401 mg, 1.02 mmol) and 2,3-dihydro-l,4-benzodioxin-2-ylmethanol (350 mg, 2.11 mmol) afforded 237 mg (42%) ofthe t-Bu ester. The ester (234 mg, 4.34 mmol) was hydrolyzed to afford 125 mg (56%) of a white solid.
Analytical data lH NMR (400 MHz, OMSO-d6) δ 12.41 (s, 1 H), 8.81 (d, J= 8.88 Hz, 1 H), 8.41 (d, J= 2.08 Hz, 1 H), 8.08 (dd, J= 8.88, 2.04 Hz, 1 H), 7.31 (d, J= 8.08 Hz, 1 H), 7.20 (s, 1 H), 7.05 (t, J= 7.88 Hz, 1 H), 6.94-6.85 (m, 5 H), 4.74-4.68 (m, 1 H), 4.52 (dd, J= 11.60, 2.28 Hz, 1 H), 4.44 (dd, J= 10.60, 4.10 Hz, 1 H), 4.37 (dd, J= 10.36, 5.56 Hz, 1 H), 4.30 (s, 3 H), 4.23 (dd, J = 11.40, 7.04 Hz, 1 H).
Example 1.6: 5-Cyano-2-({[7-(cyclobutylmethoxy)-l-methyl-lH-indol-2- yl] carb onyl} am in o)b enzoic acid
Figure imgf000053_0002
Prepared according to method A: The compound of exampole 1.1 (384 mg, 0.981 mmol) and cyclobutane methanol (200 μL, 2.12 mmol) afforded 299 mg (66%) ofthe t-Bu ester. The ester (242 mg, 0.527 mmol) was hydrolyzed to afford 171 mg (80%) of a white solid following recrystalization with MeOH/CH2Cl2.
Analytical data
1H NMR (400 MHz, DMSO-ti6) δ 12.40 (s, 1 H), 8.81 (d, J= 8.80 Hz, 1 H), 8.41 (d, J= 2.08 Hz, 1 H), 8.08 (dd, J= 8.84, 2.12 Hz, 1 H), 7.26 (d, J= 7.48 Hz, 1 H), 7.19 (s, 1 H), 7.02 (t, J= 7.80 Hz, 1 H), 6.82 (d, J= 7.36 Hz, 1 H), 4.31 (s, 3 H), 4.08 (d, J= 6.52 Hz, 2 H), 2.90-2.83 (m, 1 H), 2.14-2.11 (m, 2 H), 1.95-1.89 (m, 4 H).
Example 1.7: 5-Cyano-2-[({7-[(2,2-dimethyl-l,3-dioxolan-4-yl)methoxy]-l- methyl-lH-indol-2-yl}carbonyl)amino]benzoic acid
Figure imgf000054_0001
Prepared according to method A: The compound of example 1.1 (709 mg, 1.81 mmol) and (R)-(-)-2,2-dimethyl-l,3-dioxolane-4-methanol (450 mg, 3.62 mmol) afforded
467 mg (51%) ofthe t-Bu ester. The ester (202 mg, 400 mmol) was hydrolyzed to afford 127 mg (71%) of a white solid following recrystalization with MeOH/CH2Cl2.
Analytical data
*H NMR (400 MHz, OMSO-d6) δ 12.40 (s, 1 H), 8.81 (d, J= 8.80 Hz, 1 H), 8.41 (d, J= 2.04 Hz, 1 H), 8.09 (dd, J= 8.80, 2.12 Hz, 1 H), 7.29 (d, J= 7.52 Hz, 1 H), 7.20 (s, 1 H), 7.03 (t, J= 7.88 Hz, 1 H), 6.86 (d, J= 7.40 Hz, 1 H), 4.54 (quintet, J= 5.80 Hz, 1 H), 4.31 (s, 3 H), 4.19-4.13 (m, 3 H), 3.89 (dd, J= 8.36, 6.04 Hz, 1 H), 1.39 (s, 3 H), 1.33 (s, 3 H). Example 1.8: 5-Cyano-2-({[7-(2,3-dihydroxypropoxy)-l-methyl-lH-indol-2- yl] carb onyl} amino)b enzoic acid
Figure imgf000055_0001
The compound of Examplel.7 (150 mg, 0.334 mmol) was dissolved in CH2C12 (4 ml), TFA (3 mL), and H2O (3 drops) and shaken at rt for 20 min. Heptane was added to the solution and the volatiles were removed in vacuo. The crude product was purified by recrystalization from MeOH/CH2Cl2 to afford 74 mg (54%) of a white solid.
Analytical data *H NMR (400 MHz, DMSO--i6) δ 12.40 (s, 1 H), 8.82 (d, J= 8.80 Hz, 1 H), 7.41 (d, J= 2.08 Hz, I H), 8.09 (dd, J= 8.72, 2.08 Hz, 1 H), 7.26 (d, J= 7.96 Hz, 1 H), 7.19 (s, 1 H), 7.03 (t, J= 7.88 Hz, 1 H), 6.82 (d, J= 7.64 Hz, 1 H), 4.33 (s, 3 H), 4.15 (dd, J= 9.76, 4.16 Hz, 1 H), 4.03 (dd, J= 9.72, 5.60 Hz, 1 H), 3.91 (quintet, J= 5.40 Hz, I H), 3.53 (d, J= 5.76 Hz, 2 H).
Example 1.9: 5-Cyano-2-({[7-(cyclobutyloxy)-l-methyl-lH-indol-2- yl] carb onyl} amino)b enzoic acid
Figure imgf000055_0002
Prepared according to method A: The compound of example 1.1 (402 mg, 1.03 mmol) cyclobutyl alcohol (161 μL, 2.06 mmol) afforded 240 mg (52%) ofthe t-Bu ester. The ester (240 mg, 0.539 mmol) was hydrolyzed to afford 154 mg (73%) of a white solid following recrystalization with MeOH/CH2Cl2.
Analytical data lH NMR (400 MHz, DMSO--i6) δ 12.35 (s, 1 H), 8.81 (d, J= 8.80 Hz, 1 H), 8.41 (d, J= 2.12 Hz, 1 H), 8.08 (dd, J= 8.80, 2.12 Hz, 1 H), 7.25 (d, J= 7.44 Hz, 1 H), 7.18 (s, 1 H), 7.00 (t, J= 7.88 Hz, 1 H), 6.66 (d, J= 7.44 Hz, 1 H), 4.84 (quintet, J= 7.08 Hz, 1 H), 4.32 (s, 3 H), 2.51-2.48 (m, 2 H), 2.19-2.12 (m, 2 H), 1.90-1.82 (m, 1 H), 1.74-1.68 (m, I H). Example 1.10: 5-Cyano-2-({[7-(2-methoxy-l-methylethoxy)-l-methyl-lH-indol- 2-yl] carb onyl} amino)b enzoic acid
Figure imgf000056_0001
Prepared according to method A: The compound of example 1.1 (428 mg, 1.09 mmol) and 2-hydroxy-l-methoxypropane (220 μL, 2.25 mmol) afforded 249 mg (49%) of the t-Bu ester. The ester (246 mg, 0.531 mmol) was hydrolyzed to afford 138 mg (63%>) of a white solid following recrystalization with MeOH/CH2Cl2.
Analytical data
*H NMR (300 MHz, DMSO-c?6) δ 12.40 (s, 1 H), 8.82 (d, J= 8.82 Hz, 1 H), 8.41 (d, J= 2.07 Hz, 1 H), 8.08 (dd, J= 8.79, 2.10 Hz, 1 H), 7.26 (d, J= 7.50 Hz, 1 H), 7.18 (s, 1 H), 7.03 (t, J= 7.86 Hz, 1 H), 6.91 (d, J= 7.56 Hz, 1 H), 4.76 (sextet, J= 4.55 Hz, 1 H), 4.29 (s, 3 H), 3.63-3.54 (m, 2 H), 3.32 (s, 3 H), 1.33 (d, J= 6.21 Hz, 3 H).
Example 1.11: 5-Cyano-2-{[(7-isopropoxy-l-methyl-lH-indol-2- yl)carbonyl]amino}benzoic acid
Figure imgf000056_0002
Prepared according to method The compound of example 1.1 (409 mg, 1.04 mmol) and isopropanol (300 μL) afforded 291 mg (65%) ofthe t-Bu ester. The ester (288mg, 0.664 mmol) was hydrolyzed to afford 158 mg (63%) of a white solid following recrystalization with MeOH CH2Cl2. Analytical data
1H NMR (300 MHz, DMSO-^) δ 12.35 (s, 1 H), 8.81 (d, J= 8.82 Hz, 1 H), 8.40 (d, J= 2.04 Hz, 1 H), 8.07 (dd, J= 8.82, 2.10 Hz, 1 H), 7.24 (d, J= 7.92 Hz, 1 H), 7.17 (s, 1 H), 7.02 (t, J= 7.89 Hz, 1 H), 6.86 (d, J= 7.62 Hz, 1 H), 4.76 (septet, J= 6.06 Hz, 1 H), 4.29 (s, 3 H), 1.37 (d, J= 6.00 Hz, 6 H).
Example 1.12: 2-({ [7-(Benzyloxy)-l-methyl-lH-indol-2-yl] carbonyl} amino)-5- cyanob enzoic acid
Figure imgf000057_0001
Prepared according to method B: 7-(benzyloxy)-l -methyl- lH-indole-2-carboxylic acid (7.80 g, 27.7 mmol) and methyl 5-cyanoanthranilate (4.80 g, 27.2 mmol) afforded 8.37 g (70%>) ofthe methyl ester. The ester (398 mg, 0.906 mmol) was hydrolyzed to afford 327 mg (85%) of a white solid.
Analytical data
1H NMR (400 MHz, DMSO--iδ) δ 12.39 (s, 1 H), 8.80 (d, J= 8.71 Hz, 1 H), 8.40 (d, J= 2.08 Hz, 1 H), 8.07 (dd, J= 8.71, 2.08 Hz, 1 H), 7.56 (d, J= 7.05 Hz, 2 H), 7.44 (t, J- 7.26 Hz, 2 H), 7.36 (t, J = 7.25 Hz, 1 H), 7.29 (d, J= 7.67 Hz, 1 H), 7.19 (s, 1 H), 7.04 (t, J= 7.67 Hz, 1 H), 6.94 (d, J= 7.47 Hz, 1 H), 5.27 (s, 2 H), 4.30 (s, 3 H).
Example 1.13: 5-Cyano-2-({[7-(cyclopropylmethoxy)-l-methyl-lH-indol-2- yl] carbonyl} amino)benzoic acid
Figure imgf000057_0002
Prepared according to method A: The compound of example 1.1 (399 mg, 1.02 mmol) and cyclopropyl alcohol (180 μL, 2.22 mmol) afforded 249 mg (55%) ofthe t-Bu ester. The ester (246 mg, 0.552 mmol) was hydrolyzed to afford 154 mg (70%) of a white solid following recrystalization with MeOH/CH2Cl2.
Analytical data JH NMR (300 MHz, DMSO- 6) δ 12.39 (s, 1 H), 8.82 (d, J- 8.86 Hz, 1 H), 7.41 (d, J= 2.07 Hz, 1 H), 8.08 (dd, J= 8.67, 2.07 Hz, 1 H), 7.26 (d, J= 7.54 Hz, 1 H), 7.18 (s, 1 H), 7.01 (t, J= 6.79 Hz, 1 H), 6.80 (d, J= 7.35 Hz, 1 H), 4.35 (s, 3 H), 3.98 (d, J- 6.79 Hz, 2 H), 1.41-1.27 (m, 1 H), 0.65-0.59 (m, 2 H), 0.43-0.37 (m, 2 H).
Example 1.14: 5-Cyano-2-({[7-(cyclohexylmethoxy)-l-methyl-lH-indol-2- yl] carbonyl} amino)benzoic acid
Figure imgf000058_0001
Prepared according to method A: The compound of example 1.1 (413 mg, 1.06 mmol) and cyclohexane methanol (150 μL) afforded 261 mg (52%) ofthe t-Bu ester. The ester (257 mg, 0.543 mmol) was hydrolyzed to afford 173 mg (75%) of a white solid following recrystalization with MeOH/CH2Cl2.
Analytical data
*H NMR (400 MHz, DMSO- ) δ 12.39 (s, 1 H), 8.81 (d, J= 8.92 Hz, 1 H), 8.41 (d, J= 2.07 Hz, I H), 8.08 (dd, J= 8.71, 2.07 Hz, 1 H), 7.26 (d, J= 7.67 Hz, 1 H), 7.18 (s, 1 H), 7.02 (t, J= 7.88 Hz, 1 H), 6.83 (d, J= 7.67 Hz, 1 H), 4.30 (s, 3 H), 4.13 (dd, J= 6.64, 6.42 Hz, 2 H), 2.06-1.95 (m, 1 H), 1.89-1.77 (m, 4 H), 1.64-1.50 (m, 4 H), 1.22-1.15 (m, 2 H).
Example 1.15: 5-Cyano-2-({[7-(2-methoxyethoxy)-l-methyl-lH-indol-2- yl] carbonyl} amino)benzoic acid
Figure imgf000059_0001
Prepared according to method A: The compound of example 1.1 (411 mg, 1.05 mmol) and 2-methoxy ethanol (170 μL, 2.16 mmol) afforded 323 mg (68%) ofthe t-Bu ester. The ester (319 mg, 0.638 mmol) was hydrolyzed to afford 228 mg (81%) of a white solid following recrystalization with MeOH/CH2Cl2.
Analytical data
1H NMR (400 MHz, DMSO--i6) δ 12.37 (s, 1 H), 8.81 (d, J= 8.71 Hz, 1 H), 8.40 (d, J= 2.28 Hz, I H), 8.07 (dd, J= 8.91, 2.07 Hz, 1 H), 7.27 (d, J= 8.08 Hz, I H), 7.18 (s, 1 H), 7.03 (t, J= 7.88 Hz, 1 H), 6.84 (d, J= 7.67 Hz, 1 H), 4.31 (s, 3 H), 4.26- 4.23 (m, 2 H), 3.79-3.76 (m, 2 H)3.36 (s, 3 H).
Example 1.16: 5-Cyano-2-({[l-methyl-7-(tetrahydro-2H-pyran-2-ylmethoxy)- lH-indol-2-yl] carbonyl} amino)benzoic acid
Figure imgf000059_0002
Prepared according to method A: The compound of example 1.1 (410 mg, 1.05 mmol) and 2-methanol tetrahydopyran (250 μL) afforded the t-Bu ester. The ester was hydrolyzed to afford 180 mg (40% 2-steps) of a white solid following recrystalization with MeOH/CH2Cl2.
Analytical data
*H NMR (400 MHz, OMSO-d6) δ 12.37 (s, 1 H), 8.80 (d, J= 8.59 Hz, 1 H), 8.39 (d, J= 2.53 Hz, 1 H), 8.06 (dd, J= 9.10, 2.02 Hz, 1 H), 7.26 (d, J= 7.57 Hz, 1 H), 7.17 (s, 1 H), 7.01 (t, J= 8.09 Hz, 1 H), 6.81 (d, J = 7.58 Hz, 1 H), 4.30 (s, 3 H), 4.06 (d, J= 5.05 Hz, 2 H), 3.96-3.92 (m, 1 H), 3.75-3.71 (m, 1 H), 3.47-3.40 (m, 1 H), 1.87- 1.84 (m, 1 H), 1.74-1.70 (m, 1 H), 1.59-1.40 (m, 4 H).
Example 1.17: 5-Cyano-2-({[l-methyl-7-(oxiran-2-ylmethoxy)-lH-indol-2- yl] carb onyl} amino)b enzoic acid
Figure imgf000060_0001
Prepared according to method A: The compound of example 1.1 (406 mg, 1.04 mmol) and glycidol (170 μL) afforded 52 mg (11%) the t-Bu ester which was hydrolyzed to afford the title compound.
Analytical data
1H MR (400 MHz, DMSO--i6) δ 11.79 (s, 1 H), 8.62 (d, J= 8.71 Hz, 1 H), 8.34 (d, J= 2.08 Hz, 1 H), 8.09 (dd, J= 8.71, 2.08 Hz, 1 H), 7.33 (d, J= 7.47 Hz, 1 H), 7.22 (s, 1 H), 7.04 (t, J= 7.88 Hz, 1 H), 6.86 (d, J- 7.88 Hz, 1 H), 4.49 (dd, J= 11.20, 2.49 Hz, 1 H), 4.30 (s, 3 H), 4.02 (dd, J= 11.20, 6.22 Hz, 1 H), 3.49-3.44 (m, 1 H), 2.79 (dd, J= 4.98, 4.35 Hz, 1 H), 2.79 (dd, J= 4.97, 2.69 Hz, 1 H), 1.58 (s, 9 H).
Exmaple 1.18: 5-Cyano-2-({[7-(2-hydroxy-3-isopropoxypropoxy)-l-methyl-lH- indol-2-yl]carbonyl}amino)benzoic acid
Figure imgf000060_0002
The epoxide, 5-Cyano-2-( { [ 1 -methyl-7-(oxiran-2-ylmethoxy)- 1 H-indol-2- yl] carbonyl} amino)benzoic acid, (50 mg, 0.112 mmol), isopropanol (2 mL), and
Yb(OTf)3 (52 mg), and CH2C12 (2 mL) were combined and shaken at 45°C overnight.
The reaction was diluted with CH2C12, washed with H2O, dried (MgSO ), concentrated, and triturated with MeOH to afford 20 mg (36 %) ofthe t-Bu ester, 36883-bdw-108. The ester (20 mg, 0.0399 mmol) was dissolved in THF (10 mL) and H2O (1 mL) with LiOH (50 mg, 1.19 mmol) and shaken at 45°C overnight. The acid was diluted with CH2C12, washed with 2 N HCl, dried (MgSO ), concentrated, and triturated with MeOH to afford 11 mg (61 %) of a white solid.
Analytical data
1H NMR (400 MHz, OMSO-d6) δ 12.43 (s, 1 H), 8.82 (d, J= 8.92 Hz, 1 H), 8.41 (d, J= 2.08 Hz, 1 H), 8.09 (dd, J= 8.91, 2.07 Hz, 1 H), 7.27 (d, J= 7.47 Hz, 1 H), 7.19 (s, 1 H), 7.03 (t, J= 7.88 Hz, 1 H), 6.82 (d, J= 7.47 Hz, 1 H), 4.33 (s, 3 H), 4.12 (dd, J= 9.53, 3.94 Hz, 1 H), 4.07-3.99 (m, 2 H), 3.59 (quintet, J= 6.22 Hz, 1 H), 3.54- 3.46 (m, 2 H), 1.09 (dd, J= 6.02, 3.11 Hz, 6 H).
Example 1.19: 5-Cyano-2-({[7-(2-furylmethoxy)-l-methyl-lH-indol-2- yl] carbonyl} amino)benzoic acid
Figure imgf000061_0001
Prepared according to method A: The compound of example 1.1 (437 mg, 1.16 mmol) and 2-methanol furan (200 μL, 2.31 mmol) afforded 75 mg (14%) ofthe t-Bu ester. The ester (72 mg, 0.157 mmol) was hydrolyzed to afford 19 mg (28%) of a white solid.
Analytical data
1H NMR (400 MHz, DMSO-c?6) δ 12.35 (s, 1 H), 8.80 (d, J= 8.80 Hz, 1 H), 8.41 (d, J= 2.04 Hz, 1 H), 8.08 (dd, J= 8.80, 2.08 Hz, 1 H), 7.74 (s, 1 H), 7.32 (dd, J= 7.00, 1.84 Hz, 1 H), 7.19 (s, 1 H), 7.08-7.04 (m, 2 H), 6.65 (d, J= 3.16 Hz, 1 H), 6.50 (dd, J= 3.12, 1.88 Hz, 1 H), 5.23 (s, 2 H), 4.23 (s, 3 H). Example 1.20: 5-Cyano-2-({[l-methyl-7-(pentyloxy)-lH-indol-2- yl] carbonyl} amino)benzoic acid
Figure imgf000062_0001
Prepared according to method A: The compound of example 1.1 (215 mg, 0.549 mmol) and 1-pentanol (120 μL, 1.11 mmol) afforded 58 mg (23%) ofthe t-Bu ester. The ester (55 mg, 0.119 mmol) was hydrolyzed to afford 7.0 mg (14%) of a white solid.
Example 1.21-1.121 The following compounds were produced by making non-critical variations to the methods described above.
Figure imgf000062_0002
Figure imgf000063_0001
Figure imgf000064_0001
Figure imgf000065_0001
Figure imgf000066_0001
Figure imgf000067_0001
Figure imgf000068_0001
Figure imgf000069_0001
Figure imgf000070_0001
Figure imgf000071_0001
Figure imgf000072_0001
Figure imgf000073_0001
Figure imgf000074_0001
Figure imgf000075_0001
Figure imgf000076_0001
Figure imgf000077_0001
Figure imgf000078_0001
Figure imgf000079_0001
Example 2: R4 as Benzothiazine and Derivatives thereof
Preparation of 2-(4-Chlorophenyl)-3,4-dihydro-2H-l,2-benzothiazine-7- carboxylic acid 1,1-dioxide
Figure imgf000079_0002
Chlorosulfonic acid (25 mL, 380 mmol, Aldrich) was added to a flask containing 4-(2- chloroethyl)benzoic acid (5.00 g, 27.1 mmol, Lancaster), and the mixture was heated in an 80 °C oil bath for 4.3 hours. The mixture was then poured over ice. The precipitate was extracted into 2 X 200 mL of CH2C12 to which a small amount of THF was added to help solubility. The organics were dried over MgSO and evaporated leaving 6.82 g of brown solid. To 3.95 g of this sulfonyl chloride was added 4-chloro- N-methylaniline (3.65 g, 28.6 mmol) and toluene (60 mL). Triethylamine (2.0 mL, 14 mmol, Aldrich) was added, and the mixture was heated in a 100 °C oil bath for 4.25 hours. A solution of 3 M aqueous sodium hydroxide (25 mL) was added, and the mixture was heated for a further 15 minutes. The mixture was then added to a separatory funnel with 50 mL of water and 50 mL of MTBE. The aqueous layer was washed with an additional 100 mL of MTBE and then made acidic with concentrated HCl. Product was extracted into 2 X 150 mL of CH2C12. The combined CH2C12 was dried over MgSO and evaporated leaving 1.75 g of brown solid that was carried on without further purification. For the purposes of characterization, 340 mg ofthe product was recrystallized from hot toluene/THF. The crystals were washed with toluene and dried at 105 °C under vacuum yielding 76 mg of light brown solid.
Example 2.1 Methyl 2-({[2-(4-chlorophenyl)-l,l-dioxido-3,4-dihydro-2H-l,2- benzothiazin-7-yl] carbonyl} amino)-5-cyanobenzoate
Figure imgf000080_0001
To 2-(4-chlorophenyl)-3 ,4-dihydro-2H- 1 ,2-benzothiazine-7-carboxylic acid 1,1- dioxide (705 mg, 2.09 mmol) in CH2C12 (30 mL) was added DMF (20 μL) and oxalyl chloride (300 μL, 3.4 mmol). The mixture was stirred for 3.5 hours, and the solvent and excess oxalyl chloride were removed by rotary evaporation. The residue was dissolved in CH2C1 (15 mL), and methyl 2-amino-5-cyanobenzoate (310 mg, 1.76 mmol) in pyridine (6 mL) was added. The mixture was stirred overnight and then added to a separatory funnel with 100 mL of CH2C12. This solution was washed with 2 X 100 mL of 1 M aqueous HCl and 100 mL of brine. The CH2C12 was evaporated in the presence of silica gel, and the product was purified by chromatography using a Biotage Flash 40 M silica cartridge with CH2C12 as eluent. Yield was 372 mg of white solid.
Example 2.2 2-({[2-(4-Chlorophenyl)-l,l-dioxido-3,4-dihydro-2H-l,2- benzothiazin-7-yl] carbonyl} amino)-5-cyanobenzoic acid
Figure imgf000080_0002
To a mixture ofthe corresponding methyl ester (276 mg, 0.556 mmol) in dioxane (20 mL) was added 1 M aqueous sodium hydroxide (1.0 mL). The mixture was stirred at room temperature for 1.5 hours and then at 50 °C for 20 minutes. The reaction mixture was added to a separatory funnel with 100 mL of 1 M aqueous HCl, and the product was extracted into 100 mL of EtOAc with a small amount of THF added. The organics were washed with an additional 100 mL of 1 M aqueous HCl followed by 100 mL of water. They were then dried over MgSO and evaporated. The residue was recrystallized from hot ethanol/THF. The solids were washed with ethanol and then dried at 100 °C under vacuum yielding 116 mg of white solid.
1H NMR (400 MHz, DMSO- 6) δ 12.53 (s, 1 H), 8.78 (d, J= 8.8 Hz, 1 H), 8.40 (d, J = 2.1 Hz, 1 H), 8.32 (d, J= 1.8 Hz, 1 H), 8.18 (dd, J= 8.2, 1.9 Hz, 1 H), 8.11 (dd, J = 8.8, 2.1 Hz, 1 H), 7.75 (d, J= 8.2 Hz, 1 H), 7.46 (d, J= 8.8 Hz, 2 H), 7.28 (d, J = 8.8 Hz, 2 H), 4.23 (t, J= 6.3 Hz, 2 H), 3.29 (t, J = 6.3 Hz, 2 H).
Example 3: R4 as Pyridine or Derivatives thereof
Pyridine Synthesis
The synthesis ofthe pyridine derivative is outlined in Scheme 1. The amide 1 was easily prepared by acylation of 4-chloronicotinic acid. The displacement ofthe chloride with a thiol nucleophile could be achieved with thioacetate in refluxing methanol affording the desired thiol in modest yield. The conversion ofthe thiol to a sulfonamide and subsequent hydrolysis afforded the desired acid.
Scheme 1
Figure imgf000081_0001
Preparation of 5-Phenoxynicotinonitrile
Figure imgf000082_0001
5-Bromonicotinonitrilel (915 mg, 5 mmol) and sodium phenoxide (697 mg, 6 mmol, Aldrich) were suspended in dry DMSO (10 mL) and heated to 120 °C for 10 hours. The reaction had stalled at this point and was diluted with EtOAc (200 mL). The organic mixture was washed 2x with 1.0M HCl, lx with 1.0M NaOH, lx with water and lx with brine (175 mL each). The organic layer was dried over MgSO , filtered and evaporated. The resultant dark oil was purified on a Biotage Flash 40M (90 g) silica cartridge using 100% CH2C12. After evaporation the resultant milky oil became a solid and was dried under vacuum at 100 °C to afford 225 mg (23%) of an off-white solid. 1H NMR (400 MHz, CDC13) δ 8.60 (dd, J= 6.3, 2.2 Hz, 2 H), 7.42-7.48 (m, 3 H), 7.25-7.30 (m, 1 H), 7.05-7.09 (m, 2 H).
Preparation of 5-Phenoxynicotinic acid
Figure imgf000082_0002
5-Phenoxynicotinonitrile (196 mg, 1.0 mmol) was dissolved in EtOH (2 mL), and the solution was treated with NaOH (800 mg, 20.0 mmol) in water (10 mL). The colorless solution was refluxed for one hour then stirred at RT overnight. After evaporating the
EtOH, the aqueous solution was diluted to 100 mL with water and the solution washed 2x with CH2C12. The aqueous layer was made acidic with concentrated HCl to afford a white precipitate, which was collected by vacuum filtration, washed with water and heptane and dissolved in a mixture of CH2C12 and THF. The organic solution was dried over MgSO4, filtered and evaporated. The resultant product was dried at 100 °C under vacuum to afford 79g (37%) of a white solid. 1H NMR (400 MHz, CD3OD + CHC13) δ 8.93 (s, 1 H), 8.52 (s, 1 H), 7.96 (d, J= 1.5 Hz, 1 H), 7.40-7.46 (m, 2 H), 7.22-7.27 (m, 1 H), 7.07-7.10 (m, 2 H), 4.30 (br s, 1 H).
Example 3.1: Methyl 5-cyano-2-{ [(5-phenoxypyridin-3- yl)carbonyl] amino}benzoate
Figure imgf000083_0001
5-Phenoxynicotinic acid (75 mg, 0.35 mmol) was suspended in dry CH2C12 (10 mL) under N2 and treated with DMF (15 μL) followed by oxalyl chloride (60 μL, 0.70 mmol). Gas evolved as the mixture rapidly became homogenous. After stirring for one hour at RT, the solvent and excess oxalyl chloride were evaporated and the resultant yellowish residue was taken up in dry CH2C1 (10 mL). Methyl 2-arnino-5- cyanobenzoate (61 mg, 0.35 mmol) was added as a solution in dry pyridine (3 mL) and the dark amber solution was stirred at RT overnight. The reaction was poured into CH2C12 (100 mL) and washed 2x with 1.0M HCl and lx with brine (75 mL each). The solvents were evaporated and the crude product was purified on a Biotage Flash 40M (90 g) silica cartridge using a step gradient of CH2C12 to 5% EtOAc in CH2C12. After evaporation the resultant solid was dried under vacuum at 100 °C to afford 68 mg
(52%) of a white solid. 1H NMR (400 MHz, CDC13) δ 12.37 (s, 1 H), 9.02 (d, J= 8.9 Hz, 1 H), 8.99 (br s, 1 H), 8.61 (br, s, 1 H), 8.41 (d, J= 1.9 Hz, 1 H), 7.83-7.88 (m, 2 H), 7.45 (t, J= 7.9 Hz, 2 H), 7.25 (t, J= 7.4 Hz, 1 H), 7.12 (d, J= 7.7 Hz, 2 H), 4.01 (s, 3 H).
Example 3.2: 5-Cyano-2-{[(5-phenoxypyridin-3-yl)carbonyl]amino}benzoic acid
Figure imgf000083_0002
The corresponding methyl ester (example 3.1, 54 mg, 0.14 mmol) was dissolved in dioxane (10 mL), and the solution was treated with 1.0M LiOH (1.0 mL, 1.0 mmol) turning the solution a light yellow color. After stirring overnight at RT, the reaction was complete by HPLC and the solution was poured into EtOAc (100 mL). The organic layer was washed 2x with 1.0M HCl, 4x with water and lx with brine (75 mL each). The organic layer was dried over Na2SO4 and following evaporation of solvent the resultant white solid was re-crystallized from hot CH3OH/THF. A second crop of crystals was similarly obtained from the mother liquor. The resultant products were combined and dried at 100 °C under vacuum to afford 17 mg (33%) of straw colored crystals. (-2.5% HCl salt). lH NMR (400 MHz, OMSO-d6) δ 12.41 (s, 1 H), 8.90 (d, J= 1.2 Hz, 1 H), 8.72 (d, J= 8.7 Hz, 1 H), 8.65 (d, J= 2.7 Hz, 1 H), 8.40 (d, J= 1.9 Hz, 1 H), 8.11 (dd, J= 8.7, 1.9 Hz, 1 H), 7.79 (t, J= 2.1 Hz, 1 H), 7.48 (t, J= 7.9 Hz, 2 H), 7.27 (t, J= 7.4 Hz, 1 H), 7.18 (d, J= 7.7 Hz, 2 H).
Preparation of 5-(Ethylthio)nicotinonitrile
Figure imgf000084_0001
5-Bromonicotinonitrilel (1.83 g, 10 mmol), sodium ethanethiolate (799 mg, 9.5mmol, Aldrich) and a dash of sodium ethoxide were suspended in dry DMF (20 mL) and stirred at RT. A moderate exotherm was noted after five minutes and the reaction was judged complete after 2 hours. The reaction was poured into MTBE (200 mL), and was washed 6x with water, lx with 1.0M NaOH, lx with 1.0M HCl, and lx with brine (175 mL each). The organic layer was evaporated and the resultant oil was purified on a Biotage Flash 40M (90 g) silica cartridge using 0.75% EtOAc in CH2C12. After evaporation the resultant colorless oil became a solid and was dried under vacuum at RT to afford 848 mg (54%) of an off-white solid. 1H NMR (400 MHz, DMSO-ck) δ 8.79 (d, J= 1.9 Hz, 1 H), 8.77 (d, J= 2.3 Hz, 1 H), 8.28-8.40 (m, 1 H), 3.13 (q, J = 7.3 Hz, 2 H), 1.26 (t, J= 7.4 Hz, 3 H). Preparation of 5-(Ethylthio)nicotinic acid
Figure imgf000085_0001
5-(Ethylthio)nicotinonitrile (569 mg, 3.47 mmol) was dissolved in EtOH (10 mL), and the solution was treated with NaOH (2.77 g, 69.3 mmol) in water (20 mL). The colorless solution was refluxed for one hour during which time the solution became straw colored. After evaporating the EtOH, the aqueous solution was diluted to 175 mL with water and the solution washed 2x with CH2C12 (200 mL each). The aqueous layer was made acidic with concentrated HCl and extracted 3x with EtOAc. The combined organics were dried over MgSO4, filtered and evaporated. The resultant white solid was dried at 100 °C under vacuum to afford 561 g (88%) of white solid. lH NMR (400 MHz, OMSO-d6) δ 13.57 (s, 1 H), 8.85 (d, J= 1.9 Hz, 1 H), 8.72 (d, J = 2.3 Hz, 1 H), 8.11 (t, J= 2.2 Hz, 1 H), 3.10 (q, J= 7.3 Hz, 2 H), 1.25 (t, J= 7.3 Hz, 3 H).
Example 3.3: 5-Cyano-2-({ [ 5-(ethylthio)pyridin-3-yl] carb onyl} amino)b enzoic acid
Figure imgf000085_0002
5-(Ethylthio)nicotinic acid, (1.95 g, 10.6 mmol) was suspended in dry CH2C12 (30 mL) under N2 and treated with DMF (25 μL) followed by oxalyl chloride (1.86 mL, 21.3 mmol). Gas evolved as the mixture rapidly became homogenous. After stirring for one hour at RT, the solvent and excess oxalyl chloride were evaporated and the resultant residue was taken up in CH2C1 (30 mL). tert-Butyl-2-amino-5- cyanobenzoate (2.23 g, 10.7 mmol) was added as a solution in 5 mL dry pyridine and the dark gold solution was stirred at RT for four hours. The cloudy reaction was diluted with CH2C12 (200 mL), and the organic layer was washed 2x with 1.0M HCl, and lx with brine (200 mL each). The organic layer was evaporated, and then purified on a Biotage Flash 40M (90g) silica cartridge using 5% EtOAc in CH2C12. The solvent was evaporated and the resultant product dried under vacuum at 100 °C to afford 2.89 g (71%) of white solid as the t-butyl ester. The t-butyl ester (l.Og, 2.61 mmol) was dissolved dry CH2C12 (10 mL) and was treated with TFA (5.0 mL) turning the mixture yellow. After stirring 24 hours at RT, the reaction was complete by HPLC. The crude product was precipitated by diluting the reaction with CH3OH and collected by vacuum filtration thru #42 filter paper. The product was washed with CH3OH, THF, and heptane. The crude product was dried on the filter paper at 100 °C under vacuum to afford 626 mg (73%) of bone white solid. 1H NMR (400 MHz, DMSO--i6) δ 12.39 (s, I H), 8.89 (d, J= 2.1 Hz, 1 H), 8.76 (d, J= 8.5 Hz, 1 H), 8.76 (d, J= 2.3 Hz, 1 H), 8.41 (d, J= 2.1 Hz, 1 H), 8.18 (t, J= 2.1 Hz, 1 H), 8.12 (dd, J= 8.7, 2.1 Hz, 1 H), 3.13 (q, J= 7.4 Hz, 2 H), 1.29 (t, J= 7.3 Hz, 3 H).
Example 3.4: 5-Cyano-2-{[(6-morpholin-4-ylpyridin-3- yl)carbonyl]amino}benzoic acid
Figure imgf000086_0001
t-butyl 2-{[(6-chloropyridm-3-yl)carbonyl]amino}-5-cyanobenzoate (100 mg, 0.28 mmol), morpholine (73 mg, 0.84 mmol) and AgNO3 (51 mg, 0.28 mmol) were refluxed in Ethanol (30 ml) for 24 h. The resulting misture was filtrated through celite. The solvent was removed and the residue was loaded on silica gel to be purified by flash chromatography (DCM/MeOH= 50: 1) to afford 110 mg (95%) of advanced t- butyl ester, 105 mg of which was hydrolyzed by TFA (2 ml) in DCM (8 ml) to afford 81 mg (89%) of a yellow solid.
Analytical data lH NMR (300 MHz, DMSO-c?β) δ 12.28 (s, 1 H), 8.84 (d, J= 8.9 Hz, 1 H), 8.72 (d, J = 2.3 Hz, 1 H), 8.39 (d, J = 2.1 Hz, 1 H), 8.07 (dd, J = 2.1 , 8.9 Hz, 1 H), 8.02 (dd, J = 2.6, 9.1 Hz, I H), 7.0 (d, J= 8.9 Hz, 1 H), 3.67 (m, 8H); Example 3.5: 5-Cyano-2-{[(6-piperidin-l-ylpyridin-3-yl)carbonyl] amino}benzoic acid
Figure imgf000087_0001
t-butyl 2-{[(6-chloropyridm-3-yl)carbonyl]ammo}-5-cyanobenzoate (100 mg, 0.28 mmol) and piperidine (73 mg, 0.84 mmol) afforded 86 mg (76%) of advanced t-butyl ester, 105 mg of which was hydrolyzed by TFA (2 ml) in DCM (8 ml) to afford 62 mg (90%)) of a yellow solid.
Analytical data 1H NMR (300 MHz, DMSO-^) δ 12.23 (s, 1 H), 8.84 (d, J= 9.0 Hz, 1 H), 8.67 (d, J
= 2.4 Hz, 1 H), 8.38 (d, J= 2.0 Hz, 1 H), 8.05 (dd, J= 2.1, 8.9 Hz, 1 H), 7.95 (dd, J
= 2.5, 9.1 Hz, 1 H), 6.95 (d, J= 9.2 Hz, 1 H), 3.68 (t, J= 5.4 Hz, 4 H), 1.65 (m, 2 H),
1.55 (m, 4 H).
Example 3.6: Methyl 2-({[4-(benzyloxy)pyridin-2-yl] carbonyl} amino)-5- bromobenzoate
Figure imgf000087_0002
To sodium 4-(benzyloxy)pyridine-2-carboxylate, as described by Clark-Lewis et al. in
J. Chem. Soc. 1961, 189-201, (2.02 g, 8.04 mmol) in CH2C12 (100 mL) was added DMF (50 μL) and oxalyl chloride (1.4 mL, 16 mmol). The mixture was stirred for 1 hour, and the solvent and excess oxalyl chloride were removed by rotary evaporation.
The residue was suspended in CH2C12 (75 mL), and methyl 2-amino-5-bromobenzoate
(1.50 g, 6.52 mmol, Avocado) in pyridine (20 mL) was added. The mixture was stirred overnight and then concentrated by rotary evaporation. The residue was added to a separatory funnel with 150 mL of CH2C12, and this solution was washed with 100 mL of saturated NaHCO3, 100 mL of 4% aqueous acetic acid, 100 mL of saturated
NaHCO3) and 100 mL of brine. The CH2C12 was evaporated in the presence of silica gel, and the product was purified by chromatography using a Biotage Flash 40 M silica cartridge with a gradient from 50 % CH2C12 in heptane to 75% CH2C12 in heptane as eluent Yield was 1 52 g of white solid
Example 3.7: 2-({[4-(Benzyloxy)pyridin-2-yl] carbonyl} amino)-5-bromobenzoic acid
Figure imgf000088_0001
To a mixture ofthe methyl ester from example 3 6 (356 mg, 0 807 mmol) in dioxane
(20 mL) was added 1 M aqueous sodium hydroxide (2 0 mL) The mixture was stirred at room temperature for 4 hours and then in a 50 °C oil bath for 1 hour The reaction mixture was added to a separatory funnel with 100 mL of 1 M aqueous HCl, and the product was extracted into 100 mL of EtOAc The EtOAc was washed with an additional 100 mL of 1 M aqueous HCl followed by 100 mL of water It was then dried over MgSO and evaporated The residue was recrystallized from hot ethanol/THF The solids were washed with ethanol followed by heptane and then dried at 100 °C under vacuum yielding 249 mg of white solid !H NMR (400 MHz,
DMSO- 6) δ 13 00 (s, 1 H), 8 81 (d, J= 9 1 Hz, 1 H), 8 56 (d, J= 5 8 Hz, 1 H), 8 13
(d, J= 2 5 Hz, 1 H), 7 87 (dd, J= 9 1, 2 5 Hz, 1 H), 7 76 (d, J= 2 5 Hz, 1 H), 7 50
(d, J= 6 8 Hz, 2 H), 7 43 (t, J= 7 2 Hz, 2 H), 7 37 (t, J= 7 2 Hz, 1 H), 7 32 (dd, J =
5 7, 2 6 Hz, 1 H), 5 33 (s, 2 H)
Example 3.8: 2-({[4-(Benzyloxy)-l-oxidopyridin-2-yl]carbonyl}amino)-5- bromob enzoic acid
Figure imgf000088_0002
O" To a solution of methyl 2-({[4-(benzyloxy)pyridm-2-yl]carbonyl}amino)-5- bromobenzoate (262 mg, 0 593 mmol) in 1,2-dichloroethane (10 mL) was added solid -CPBA (225 mg, 1 30 mmol, Aldπch) The mixture was stiπed at room temperature for 3 hours, at 55 °C for 6 5 hours, and then at 75 °C for 8 5 hours An additional portion of m-CPBA (302 mg, 1 75 mmol) was added, and the mixture was heated at 75 °C for an additional 15 hours. The solution was diluted with 100 mL of CH2C12 and then washed with 100 mL of saturated NaHCO3. The CH2C12 was dried over MgSO and evaporated. The residue was dissolved in CH2C12 and loaded onto a 1" plug of silica gel. Unreacted starting material was eluted with CH2C12, and the desired N-oxide was eluted with EtOAc. Yield was 137 mg of white solid as the methyl ester. To a solution ofthe corresponding methyl ester (137 mg, 0.300 mmol) in THF (30 mL) in a 50 °C oil bath was added sodium hydroxide (0.50 mL of 1.0 M solution in water). A precipitate formed withm minutes. An additional portion of sodium hydroxide solution (1.0 mL) was added after 1 hour. Heat was removed after an additional 4.2 hours. The reaction mixture was stirred ovenight with 100 mL of 1.0 M aqueous HCl and 100 mL of CH2C12, but the solids did not dissolve. The solids were then filtered, washed with water followed by heptane, and dried at 100 °C under vacuum. Yield was 63 mg of white solid. 1H NMR (400 MHz, DMSO-D6) δ ppm 5.31 (s, 2 H) 7.40 (m, 4 H) 7.49 (m, 2 H) 7.81 (dd, J=8.98, 2.59 Hz, 1 H) 7.89 (d, J=3.65 Hz, 1 H) 8.01 (d, J=2.74 Hz, 1 H) 8.39 (d, J=7.00 Hz, 1 H) 8.54 (d, J=8.83 Hz, 1 H) 13.68 (s, 1 H) 14.73 (s, 1 H).
Example 3.9: 2-({[4-(Benzyloxy)pyridin-2-yl]carbonyl} amino)- 5-cyanobenzoic acid
Figure imgf000089_0001
To a slurry of sodium 4-(benzyloxy)pyridine-2-carboxylate (2.58 g, 10.3 mmol) in CH2C12 (100 mL) was added DMF (50 μL) followed by oxalyl chloride (1.8 mL, 21 mmol). It became a solution. Solvent and excess oxalyl chloride were removed by rotary evaporation after 1 hour. The residue was dissolved in CH2C12 (75 mL), and methyl 2-amino-5-cyanobenzoate (1.61 g, 9.14 mmol) in pyridine (15 mL) was added. The mixture was stiπed for 2 days and then added to a separatory funnel with 100 mL of CH2C12. This solution was washed with 2 X 100 of 1.0 M citric acid and 100 mL of brine. Product was adsorbed onto silica gel and purified on a Biotage Flash 40 M silica gel cartridge using a gradient from 50% CH2C12 in heptane to 100% CH2C12. Product was collected as 296 mg of white solid as the methyl ester. To a mixture of the corresponding methyl ester (134 mg, 0.346 mmol) in dioxane (10 mL) was added 1 M aqueous sodium hydroxide (1.0 mL). The mixture was stirred at room temperature for 7 hours and then added to a separatory funnel with 100 mL of 1 M aqueous HCl. The product was extracted into 100 mL of EtOAc. The EtOAc was washed with 100 mL of water. It was then dried over MgSO4 and evaporated. The residue was recrystallized from hot ethanol/THF. The solids were washed with ethanol followed by heptane and then dried at 100 °C under vacuum yielding 68 mg of white solid. 1H NMR (400 MHz, DMSO-D6) δ ppm 5.34 (s, 2 H) 7.34 (dd, J=5.85, 2.63 Hz, 1 H) 7.38 (d, J=7.31 Hz, 1 H) 7.43 (t, J=7.16 Hz, 2 H) 7.50 (d, J=7.02 Hz, 2 H) 7.78 (d, J=2.63 Hz, 1 H) 8.11 (dd, J=8.77, 2.05 Hz, 1 H) 8.41 (d, J=2.05 Hz, 1 H) 8.57 (d, J=5.55 Hz, 1 H) 9.00 (d, J=8.77 Hz, 1 H) 13.29 (s, 1 H) 14.16 (s, 1 H)
Example 4: R4 as Nalidixic Acid or Derivative Thereof
Preparation of of Nalidixic Acid Chloride (27)
Figure imgf000090_0001
To a solution nalidixic acid (26, 5.8 g, 0.025 mol dissolved 250 mL of CH2C12) was added DMF (2 drops) and oxalyl chloride (25 mL of a 2 M solution in CH2C12, 50 mmol) under a nitrogen atmosphere. After stirring for 20 h, the acid chloride was concentrated to dryness, azeotroped with toluene (2 x 25 mL), dried on a high vacuum overnight, and used in situ for the following reactions.
Example 4.1: Solid Phase Synthesis of 5-Cyano-2-[(l-ethyl-7-methyl-4-oxo-l,4- dihydro-[l,8]naphthyridine-3-carbonyl)-amino]benzoic Acid (28)
Figure imgf000090_0002
Resin-bound 5-cyano anthranilic acid (5, 0.5 g, 1.0 mmol/g loading, 500 μmol) was suspended in pyridine (100 mL) in a 250-mL serum flask equipped with an overhead stirrer. After the addition of nalidixic acid chloride (27, 5 mL of a 1 M solution in CH2C12, 10 equiv), the flask was purged with nitrogen and stirred at room temperature for 20 h. The reaction mixture was then drained and the resin washed (CH3CN, DMF, CH3CN, DMF, CH3CN, DMF, H2O, THF, H2O, THF, H2O, THF, CH3CN, CH2C12, CH3CN, CH2C12, CH3CN, CH2C12, CH2C12, CH2C12, 50 mL each wash). The product was then cleaved from the resin using 50% TFA/CH2C12 for 3 h to yield 28 (60 mg, 32%) in 78%) reaction purity as determined by HPLC/MS analysis.
Example 4.2: Solution Phase Synthesis of 5-Cyano-2-[(l-ethyl-7-methyl-4-oxo- l,4-dihydro-[l,8]naphthyridine-3-carbonyl)-amino]benzoic Acid (28)
Figure imgf000091_0001
To a 250-mL round bottom flask containing t-butyl-2-amino-5-cyano-benzoate8 (29, 100 mg, 459 μmol, PHA-561053, lot 34629-tjb-145) was added nalidixic acid chloride (27, 6 mL of a 1 M solution in CH2C12, 1.2 equiv) and pyridine (75 mL). Additional nalidixic acid chloride (~0.5 equiv) was added until the aniline was completely consumed as determined by HPLC analysis ofthe reaction mixture. The reaction mixture was concentrated to a dark brown solid and dried on a high vacuum for 4 h. The solid was dissolved in CH2C12 (250 mL) and extracted with 2 N NaOH (3 x 250 mL). The combined organic layers were dried over MgSO and concentrated to yield a brown solid. The crude product was dissolved in CH2C12 (100 mL) and stirred with a 50% TFA/CH2C12 solution (50 mL) for 24 h. The reaction mixture was then concentrated and the crude solid triturated with CH2C1 (5 mL) to yield 67.3 mg (39%>) ofthe corresponding amide (28) in 96% purity: 1H NMR (DMSO-d6) δ 13.20 (s, IH), 9.11 (s, IH), 8.82 (d, J= 8.84 IH), 8.27 (d, J = 2.08, IH), 8.01 (dd, J = 2.08, 8.82, IH), 7.51 (d, J = 8.17, IH), 4.61 (q, J = 6.87), 2.68 (s, 3H), 1.43 (t, J = 7.03). Example 5: R4 as Pyrazole or Derivatives Thereof Pyrazole Synthesis
JFF Scheme 4
Figure imgf000092_0001
JFF-4A JFF-4B
Example JFF-4 Example JFF-5 PHA-729249 PHA-729247 Preparation of l-Methyl-5-phenyl-lH-pyrazole-3-carboxyUc acid ethyl ester [10199-51-6] and l-Methyl-3-phenyl-lH-pyrazole-5-carboxylic acid ethyl ester [10250-63-2]. To a mixture of [98-86-2] (50 mL, 0.42 mol) and NaH (60% oil dispersion, 17.5 g, 0.44 mol) in EtOH (1 L) is added diethyloxalate (36.5 mL, 0.42 mol). The reaction mixture is stirred overnight at rt. It is concentrated to give 85 g (92%) of a yellow powder. To a solution of this powder (3.15 g, 14.3 mmol) in a mixture of EtOH (50 mL) and aqueous 3 M HCl (5 mL) is added methylhydrazine (0.76 mL, 14.3 mmol). The reaction mixture is stirred overnight. It is concentrated, and the residue is purified by silica chromatography to give the two pyrazole products. [10199-51-6]: Rf = 0.8 (4: 1 hexanes/EtOAc); 1H NMR (CDC13, 400 MHz) δ 7.84 (2H), 7.45 (2H), 7.35 (IH), 4.42 (2H), 4.28 (3H), 1.45 (3H); MS (ESI+) m/z 231.2. [10250-63-2]: Rf = 0.3 (4: 1 hexanes/EtOAc); 1H NMR (CDC13, 400 MHz) δ 7.4 (5H), 6.90 (IH), 4.62 (2H), 4.00 (3H), 1.44 (3H); MS (ESI+) m/z 231.4.
Preparation of l-Methyl-5-phenyl-lH-pyrazole-3-carboxylic acid [10199-53-8],
Using 1.2 g of [10199-51-6], and the procedure described for the preparation of [10250-64-3], acid [10199-53-8] is isolated as a powder: MS (ESI-) m/z 185.2.
Preparation of l-Methyl-3-phenyl-l//-pyrazole-5-carboxylic acid [10250-64-3].
A mixture of ester [10250-63-2] (1.7 g, 7.4 mmol) and aqueous 1 M KOH (10 mmol) in EtOH (20 mL) is stirred for 6 h. The reaction mixture is concentrated, and the residue is partitioned between cold aqueous 1 M HCl and EtOAc. The EtOAc solution is separated. The aqueous solution is further extracted with EtOAc. The combined
EtOAc extracts are dried and concentrated to give [10250-64-3] as a powder: MS
(ESI-) m/z 185.5.
Preparation of 5-Bromo-2-[ [(l-methyl-S-phenyl-lH-pyrazol-S- yl)carb onyl] amino] benzoic acid methyl ester (JFF-4b).
To a suspension of acid [10250-64-3] (150 mg, 0.74 mmol) in CH2C12 is added oxalyl chloride (65 μL, 0.74 mmol) and DMF (1 drop). The reaction mixture is stirred at rt for 90 min. It is concentrated to give an oil. The oil is dissolved in CH2C12 (5 mL), and methyl 5-bromoanthranilate (17 mg, 0.74 mmol), NEt3 (207 μL, 1.48mmol), and
DMAP (10 mg, 0.074 mol) are added. The reaction mixture is stirred at rt for 72h. It is quenched with aqueous 1 M HCl (10 mL). The aqueous mixture is extracted with
EtOAc. The EtOAc extracts are dried and concentrated to give an oil. The oil is dissolved in CH2C12, and 4b is precipitated as a solid by the addition of hexanes: MS
(ESI+) m/z 415.3.
Preparation of 5-Bromo-2-[ [(l-methyl-5-phenyl-l -r-pyrazol-3- yl)carbonyl]amino]benzoic acid methyl ester (JFF-4a).
Compound 4a is prepared from [10199-53-8], using the procedure given for JFF-4b: MS (ESI+) w/z 415.5.
Example 5.1: 5-Bromo-2-[[(l-methyl-5-phenyl-lH-pyrazol-3- yl)carbonyl]amino]benzoic acid (Example JFF-4).
Example JFF-4 is prepared from 4a using the procedure given for Example JFF-5:
MS (ESI+) m/z 399.2.
Example 5.2: 5-Bromo-2-[[(l-methyl-3-phenyl-lJΪ-pyrazol-5- yl)carbonyl]amino]benzoic acid (Example JFF-5).
To a solution of ester JFF-4b (75 mg, 0.18 mmol) in 2: 1 MeOH/CH2Cl2 (3 mL) is added aqueous 1 M KOH (200 μL). The reaction mixture is stirred for 4 h. It is concentrated. The residue is partitioned between aqueous 1 M HCl and EtOAc. The
EtOAc solution is separated, and the aqueous solution is extracted further with EtOAc. The combined EtOAc extracts are dried and concentrated to give Example JFF-5 as a solid: MS (ESI-) m/z 399.2.
JFF Scheme 5
Figure imgf000095_0001
JFF-5D
Figure imgf000095_0002
Example JFF-6 PHA-731935 Preparation of (±)-4-(2,6-Difluorophenyl)-4-hydroxybut-2-ynoic acid ethyl ester (JFF-5a).
A solution of LDA (2.0 M, 17.5 mL) is added to a solution of ethyl propiolate (3.6 mL, 0.035 mol) in THF (0.3 L) at -78 °C. The reaction mixture is stirred for 30 min, at which time [437-81-0] (3.8 mL, 0.035 mol) is added. The reaction mixture is stirred at -78 °C for 30 min, and then is warmed to rt. It is poured into aqueous 5% CuSO4 (0.2 L). The aqueous mixture is extracted with EtOAc (2 x 0.1 L). The combined EtOAc extracts are dried and concentrated to give an oil, that is purified by silica flash chromatography (9: 1 hexanes:EtOAc to give 5A: TLC Rf= 0.2 (9: 1 hexanes/EtOAc); ^ NMR CDCk, 400 MHz) δ 7.4 (IH), 7.0 (2H), 5.91 (IH), 4.3 (2H), 2.81 (IH), 1.35 (3H).
Preparation of 4-(2,6-Difluorophenyl)-4-oxobut-2-ynoic acid ethyl ester (JFF- 5B).
To a solution of 5A (4.2 g, 17.5 mmol) in acetone (0.2 L) at 0 °C is added dropwise Jones' reagent (2.7 M Cr, 0.54 equiv). The reaction mixture separates into two layers. When the reaction is determined as complete by TLC (30 min), the reaction mixture is diluted with Et2O and brine. The Et2O extract is dried and concentrated to give an oil, that is purified by silica chromatography (4: 1 hexanes: EtOAc) to give 5B.
Preparation of 3-(2,6-Difluorophenyl)-l-methyl-lH-pyrazole-5-carboxylic acid ethyl ester (JFF-5C, CuH^NzOz).
A mixture of methylhydrazine (228 μL, 4.28 mmol) and 5B (680 mg, 2.86 mmol) in
EtOH (30 mL) is refluxed for 4 h. The reaction mixture is evaporated, and the residue is purified by silica chromatography (2: 1 hexanes: EtOAc) to give 5C: 1H NMR
(CDC13, 400 MHz) δ 7.3 (IH), 7.2 (IH), 7.0 (2H), 4.4 (2H), 4.3 (3H), 1.4 (3H); MS (FAB) m/z 267.0949; Anal.C 58.64, H 4.56, N 10.06.
Preparation of 3-(2,6-Difluorophenyl)-l-methyl-l/ -pyrazole-5-carboxylic acid (JFF-5D)
A mixture of ester 5C (200 mg, 0.75 mmol) and aqueous 1 M KOH (2 mL) in EtOH (3 mL) is stirred for 2 h at rt. The reaction mixture is concentrated, and the residue is partitioned between aqueous 1 M HCl and EtOAc. The EtOAc solution is separated, and the aqueous solution is further extracted with EtOAc. The combined EtOAc extracts are dried and concentrated to give 5D: 1H NMR (CD3OD, 400 MHz) δ 7.43 (IH), 7.10 (3H), 4.24 (3H).
5-Bromo-2-[[[3-(2,6-difluorophenyl)-l-methyl-ljH-pyrazol-5-yl] carbonyl] amino] - benzoic acid (Example JFF-6, dgHnBrF∑NjOs).
To a suspension of acid 5D (100 mg, 0.42 mmol) in CH2C12 (5 mL) is added oxalyl chloride (73 μL, 0.84 mmol). After 2 h the reaction mixture is concentrated, and the residue is dissolved in CH2C12 (5 mL). Methyl 5-bromoanthranilate (145 mg, 0.63 mmol), Et3N (176 μL, 1.26 mmol), and DMAP (10 mg, 0.084 mmol) are added. The reaction mixture is stirred at it for 24 h. It is poured into aqueous 1 M HCl (10 mL). The aqueous mixture is extracted with EtOAc. The EtOAc solution is dried and concentrated. The residue is purified by silica chromatography (4: 1 hexanes/EtOAc) to give 5E, the methyl ester : 'H NM (CDC13, 400 MHz) δ 11.97 (IH), 8.78 (IH), 8.26 (IH), 7.73 (IH), 7.35 (IH), 7.23 (IH), 7.06 (2H), 4.38 (3H), 4.02 (3H); MS (ESI+) m/z 451.3. A mixture of 5E (50 mg) and aqueous 1 M KOH (2 mL) in 2: 1 MeOH/CH2Cl2 (3 mL) is stirred at rt for 2 h. The reaction mixture is concentrated, and the residue is partitioned between aqueous 1 M HCl and EtOAc. The EtOAc solution is separated, and the aqueous solution is further extracted with EtOAc. The combined EtOAc extracts are dried and concentrated to give Example JFF-6: *H NMR (CDCi,, 400 MHz) δ 12.29 (IH), 8.65 (IH), 8.2 (IH), 7.61 (IH), 7.25 (IH), 7.14 (IH), 6.95 (2H), 4.27 (3H); MS (FAB) m/z 436.0105.
Example 6: R4 as Benzisoxazolyl of Derivatives Thereof
Benzisoxazolyl Synthesis
1. CHCI3/ 1 pyridine 2.hydrolyssii:s
Figure imgf000097_0001
Figure imgf000097_0002
Preparation of 2-[(l,2-benzisoxazol-3-ylcarbonyl)amino]-5-cyanobenzoic acid
Figure imgf000098_0001
1 ,2-benzisoxazole-3-carboxylic acid (200 mg, 1.23 mmol) was suspended in CH2C12 (10 mL) and (COCl)2 added (725 mg, 0.5 mL, 5.7 mmol). A catalytic amount of DMF was then added and the mixture stirred for 4 hrs. The solvent was then removed in vacuo to give the acid chloride as an oil. The oil was dissolved in CHC13 (10 mL). tert-butyl 2-amino-5-cyanobenzoate (270 mg, 1.23 mmol) was added dropwise as a solution in THF/ pyridine (5 mL/1 mL). The solution was stiπed at room temperature for an additional 12 hrs then poured into 1 M HCl (20 mL) and extracted with EtOAc (3 x 20 mL). The combined organic solutions were dried over Na2SO and concentrated in vacuo. The resulting residue was purified by chromatography (1% MeOH in CHC1 ) to give 100 mg ofthe desired amide (22%). This amide was dissolved in 10 mL CH2C12/TFA (1/1) and stirred for 10 hrs at room temperature. The solvent was then removed in vacuo and the resulting solid was washed with MeOH, providing 80 mg ofthe title compound (95%). IH NMR (400 MHz, DMSO) 7.59 (t, IH), 7.81 (t, IH), 7.96 (d, IH), 8.16 (dd, IH), 8.24 (d, IH), 8.90 (d, IH), 12.92 (s, IH).
Example 6.1: 2-[(l,2-benzisoxazol-3-ylcarbonyl)amino]-5-bromobenzoic acid
Figure imgf000098_0002
1 ,2-benzisoxazole-3-carboxylic acid (815 mg, 5.0 mmol) was suspended in dichloroethane (DCE) (10 mL). Oxalyl chloride (0.545 mL, 6.25 mmol) was added followed by a catalytic amount of DMF. The reaction was stiπed at room temperature for 5 hrs. The solvent was removed in vacuo, and the resulting oil was redissolved in DCE (10 mL). Methyl 2-amino-5-bromobenzoate was added dropwise as a solution in
THF/pyridine (5 mL/2 mL). The mixture was stiπed for 48 hrs. The resulting solid was filtered and washed with MeOH, giving 925 mg (50%) ofthe desired amide. The ester was treated with LiOH in 1 : 1 : 1 THF/MeOH H2O for 12 hrs followed by acidification to give 608 mg (68%) ofthe title compound. IH NMR (400 MHz,
DMSO) 7.58 (t, IH), 7.78 (t, IH), 7.92 (dd, IH), 7.95 (d, IH), 8.16 (d, IH), 8.24 (d,
IH), 8.71 (d, IH), 12.60 (s, IH).
Figure imgf000099_0001
acid chloride or sulfonyl chloride
CHCI3/pyridine
Figure imgf000099_0002
Figure imgf000099_0003
Preparation of tert-butyl 2-{[(5-amino-l,2-benzisoxazol-3-yl)carbonyl]amino}-5- cyanobenzoate
Figure imgf000099_0004
5-Nitro-l,2-benzisoxazole-3 -carboxylic (2.08 g, 10 mmol) was suspended in CH2C12 (50 mL). Oxalyl chloride (1.1 mL, 12.5 mmol) was added followed by a catalytic amount of DMF. The reaction was stiπed at room temperature for 5 hrs. The solvent was removed in vacuo, and the resulting residue was redissolved in CHC13 (50 mL). tert-Butyl 2-amino-5-cyanobenzoate was added dropwise as a solution in THF/pyridine (40 mL/10 mL). The mixture was stiπed for 12 hrs at room temperature. The resulting solid was filtered and washed with MeOH, giving 2.9 g (72%) ofthe desired nitro-amide. The nitro-amide was reduced with 10%> Pd/C in 100 mL (THF/MeOH, 1/1) with ammonium formate (4.7 g, 75 mmol) as H2 source. After stirring for 10 hr at room temperature the mixture was filter and the resulting solids washed with THF. Excess solvent was removed in vacuo and the residue purified by chromatography (1% MeOH in CHC13) to give 2.61 g ofthe title compound (96%). IH NMR (400 MHz, CDC13) 1.69 (s, 9H), 3.90 (bs, 2H), 7.04 (dd, IH), 7.49 (m, 2H), 7.84 (dd, IH), 8.37 (d, IH), 9.06 (d, IH), 12.76 (s, IH).
Example 6.2: 2-({[5-(acetylamino)-l,2-benzisoxazol-3-yl] carb onyl) amino)-5- cyanob enzoic acid
Figure imgf000100_0001
tert-Butyl 2-{[(5-ammo-l,2-benzisoxazol-3-yl)carbonyl]arnino}-5-cyanobenzoate (250 mg, 0.66 mmol) was dissolved in CHC13 (10 ml). Pyridine (1 mL) and acetyl chloride ( 57 μL, 0.8 mmol) were then added and the reaction stiπed for 10 hrs at room temperature. The resulting mixture was absorbed onto silica and purified by chromatography (2% MeOH in CHC13) to give 203 mg (73%) ofthe desired acetamide. This amide was dissolved in 10 mL CH2Cl2/TFA (1/1) and stirred for 10 hrs at room temperature. Solvent was removed in vacuo and the remaining solid was recrystalized from THF/MeOH to give 170 mg (96%) ofthe title compound. IH NMR (400 MHz, DMSO) 2.10 (s, 3H), 7.86 (m, 2H), 8.16 (dd, IH), 8.45 (d, IH), 8.63 (d, IH), 8.91 (d, IH), 10.32 (s, IH), 12.86 (s, IH).
Example 6.3: 2-({[5-(benzoylamino)-l,2-benzisoxazol-3-yl]carbonyl}amino)-5- cyanob enzoic acid
Figure imgf000100_0002
tert-Butyl 2- {[(5-amino- 1 ,2-benzisoxazol-3-yl)carbonyl]amino} -5-cyanobenzoate (250 mg, 0.66 mmol) was dissolved in CHC13 (10 ml). Pyridine (1 mL) and benzoyl chloride (175 μL, 1.5 mmol) were then added and the reaction stiπed for 10 hrs at room temperature. The resulting mixture was absorbed onto silica and purified by chromatography (2% MeOH in CHC13) to give 214 mg (67%) ofthe desired phenylamide. This amide was dissolved in 10 mL CH2C12/TFA (1/1) and stiπed for 10 hrs at room temperature. Solvent was removed in vacuo and the remaining solid was recrystalized from THF/MeOH to give 168 mg (88%) ofthe title compound. IH NMR (400 MHz, DMSO) 7.60 (m, 3H), 7.95 (d, IH), 8.02 (m, 2H), 8.12 (dd, IH), 8.17 (dd, IH) 8.45 (d, IH), 8.81 (d, IH), 8.92 (d, IH), 10.62 (s, IH), 12.92 (s, IH).
Example 6.4: 5-cyano-2-[({5-[(phenylacetyl)amino]-l,2-benzisoxazol-3- yl}carbonyl)amino]benzoic acid
Figure imgf000101_0001
tert-Butyl 2- {[(5-arnino-l ,2-benzisoxazol-3-yl)carbonyl]amino} -5-cyanobenzoate (250 mg, 0.66 mmol) was dissolved in CHC13 (10 ml). Pyridine (1 mL) and phenylacetyl chloride (200 μL, 1.5 mmol) were then added and the reaction stiπed for 10 hrs at' room temperature. The resulting mixture was absorbed onto silica and purified by chromatography (2% MeOH in CHC13) to give 151 mg (46%) ofthe desired phenylacetamide. This amide was dissolved in 10 mL CH2C12/TFA (1/1) and stiπed for 10 hrs at room temperature. Solvent was removed in vacuo and the remaining solid was recrystalized from THF/MeOH to give 92 mg (68%) ofthe title compound. IH NMR (400 MHz, DMSO) 3.70 (s, 2H), 7.30 (m, 5H), 7.89 (m, 2H), 8.16 (dd, IH), 8.44 (d, IH) 8.63 (s, IH), 8.89 (d, IH), 10.57 (s, IH), 12.89 (s, IH).
Example 6.5 : 5-cyano-2- [({5- [ (methylsulfonyI)amino] -1 ,2-benzisoxazol-3- yl} carb onyl) aminojbenzoic acid
Figure imgf000102_0001
tert-Butyl 2- {[(5-amino: 1 ,2-benzisoxazol-3-yl)carbonyl]amino} -5-cyanobenzoate (250 mg, 0.66 mmol) was dissolved in CHC13 (10 ml). Pyridine (1 mL) and methanesulfonyl chloride (116 μL, 1.5 mmol) were then added and the reaction stiπed for 10 hrs at room temperature. The resulting mixture was absorbed onto silica and purified by chromatography (2% MeOH in CHC13) to give 234 mg (73%) ofthe desired methanesulfonamide. This amide was dissolved in 10 mL CH2C1 /TFA (1/1) and stiπed for 10 hrs at room temperature. Solvent was removed in vacuo and the remaining solid was recrystalized from THF/MeOH to give 194 mg (95%) ofthe title compound. IH NMR (400 MHz, DMSO) 3.02 (s, 3H), 7.62 (dd, IH), 7.95 (d, IH), 8.08 (d, IH), 8.16 (dd, IH), 8.45 (d, IH), 8.63 (d, IH), 8.91 (d, IH), 10.09 (s, IH), 12.87 (s, IH). MS (CI) m/z (rel. intensity) 418 (M+NH4, 100), 260 (7), 241 (9), 230 (10), 180 (33), 152 (19), 136 (87), 118 (64), 88 (19), 74 (43). Anal. Calcd for Cn Hι2 N4 O6 S: C, 51.00; H, 3.02; N, 13.99; S, 8.01. Found: C, 49.27; H, 3.19; N, 13.38.
Example 6.6: 5-cyano-2-[({5-[(phenylsulfonyl)amino]-l,2-benzisoxazol-3- yl}carbonyl)amino]benzoic acid
Figure imgf000102_0002
tert-Butyl 2- {[(5-amino- 1 ,2-benzisoxazol-3-yl)carbonyl]amino} -5-cyanobenzoate (250 mg, 0.66 mmol) was dissolved in CHC13 (10 ml). Pyridine (1 mL) and benzenesulfonyl chloride (191 μL, 1.5 mmol) were then added and the reaction stirred for 10 hrs at room temperature. The resulting mixture was absorbed onto silica and purified by chromatography (2% MeOH in CHC13) to give 242 mg (67%) ofthe desired phenylamide. This amide was dissolved in 10 mL CH2C12/TFA (1/1) and stiπed for 10 hrs at room temperature. Solvent was removed in vacuo and the remaining solid was recrystalized from THF/MeOH to give 201 mg (93%) ofthe title compound. IH
NMR (400 MHz, DMSO) 7.55 (m, 4H), 7.76 (m, 2H), 7.85 (d, IH), 7.95 (d, IH),
8.16 (dd, IH) 8.43 (d, IH), 8.88 (d, IH), 10.65 (s, IH), 12.85 (s, IH).
Example 6.7: 2-[({5-[(benzylsulfonyl)amino]-l,2-benzisoxazol-3- yl}carbonyl)amino]-5-cyanobenzoic acid
Figure imgf000103_0001
tert-Butyl 2- {[(5-ammo-l,2-benzisoxazol-3- Oyl)carbon (250 mg, 0.66 mmol) was dissolved in CHC13 (10 ml). Pyridine (1 mL) and α- toluenesulfonyl chloride (200 μL, 1.5 mmol) were then added and the reaction stiπed for 10 hrs at room temperature. The resulting mixture was absorbed onto silica and purified by chromatography (2% MeOH in CHC13) to give 169 mg (48%) ofthe desired phenylacetamide. This amide was dissolved in 10 mL CH2C12/TFA (1/1) and stirred for 10 hrs at room temperature. Solvent was removed in vacuo and the remaining solid was recrystalized from THF/MeOH to give 102 mg (68%) ofthe title compound. IH NMR (400 MHz, DMSO) 4.52 (s, 2H), 7.30 (m, 5H), 7.55 (dd, IH), 7.92 (d, IH), 8.07 (d, IH), 8.16 (dd, IH), 8.45 (d, IH), 8.93 (d, IH), 10.21 (s, IH), 12.94 (s, IH).
Example 6.8: 2-{[(6-Chloro-l,2-benzisoxazol-3-yl)carbonyl]amino}-5- cyanobenzoic acid
Figure imgf000103_0002
A solution of concentrated sulfuric acid (15 mL) and water (5 mL) was added to a flask containing ethyl 6-chloro-l ,2-benzisoxazole-3-carboxylate, as described in Chem.
Pharm. Bull. 1998, 46, 84-96, (1.99 g, 8.82 mmol), and the resulting mixture was stiπed in an 80 °C oil bath for 1 hour. A thick precipitate had formed which prevented stirring, so another 20 mL ofthe acid solution was added, and the mixture was stiπed for an additional 2 hours at 80 °C. The reaction mixture was then added to water. The resulting precipitate was washed with water and then dried briefly on a frit with a flow of air. It was then suspended in CH2C12 (60 mL) and treated with DMF (20 μL) and oxalyl chloride (1.4 mL, 16 mmol). An additional portion of oxalyl chloride (0.4 mL) was added after 35 minutes. After a further 40 minutes, the solvent and excess oxalyl chloride were removed by rotary evaporation. The residue was dissolved in CH2C12 (50 mL) and treated with tert-butyl 2-amino-5-cyanobenzoate (1.50 g, 6.87 mmol) and pyridine (15 mL). The mixture was stiπed overnight and then added to a separatory funnel with CH2C12 (150 mL). This solution was washed with 1.0 M HCl (2 X 100 mL) and brine (100 mL). Product was adsorbed onto silica gel, divided into two lots, and purified on Biotage Flash 40 M siliga gel cartridges using 70% CH2C12 in heptane as eluent. Product was collected as 2.46 g (70%) of white solid as the t-butyl ester. The conesponding tert-butyl ester (435 mg, 1.09 mmol) was stiπed for 15.5 hours in a mixture of CH2C12 (30 mL) and TFA (20 mL). The solvents were removed by rotary evaporation, and the residue was recrystallized from ethanol/THF. The solids were washed with ethanol followed by heptane and then dried at 100 °C under vacuum yielding 250 mg of white solid. 1H NMR (400 MHz, DMSO-D6) δ ppm 7.64 (dd, J=8.50, 1.66 Hz, 1 H) 8.16 (dd, J=8.71, 2.07 Hz, 1 H) 8.20 (d, J=8.71 Hz, 1 H) 8.22 (d, J=1.66 Hz, 1 H) 8.44 (d, J=2.07 Hz, 1 H) 8.87 (d, J=8.92 Hz, 1 H) 12.91 (s, I H).
Example 6.9: 5-Bromo-2-{[(6-chloro-l,2-benzisoxazol-3- yl)carbonyl]amino}benzoic acid
Figure imgf000104_0001
A solution of concentrated sulfuric acid (15 mL) and water (5 mL) was added to a flask containing ethyl 6-chloro-l, 2-benzisoxazole-3-carboxylate (680 mg, 3.01 mmol), and the resulting mixture was stiπed in an 80 °C oil bath for 3.3 hours. The reaction mixture was then added to water (50 mL) The resulting precipitate was washed with water and then dried briefly on a frit with a flow of air It was then suspended in CH2C12 (40 mL) and treated with DMF (20 μL) and oxalyl chloride (0 50 mL, 5 7 mmol) Solvent and excess oxalyl chloride were removed by rotary evaporation after 50 minutes The residue was dissolved in CH2C12 (30 mL) and treated with tert-butyl 2-amino-5-bromobenzoate (528 mg, 1 94 mmol) and pyridine (10 mL) The mixture was stiπed overnight and then added to a separatory funnel with CH2C12 (150 mL) This solution was washed with 1 0 M HCl (2 X 100 mL) and brine ( 100 mL) Product was adsorbed onto silica gel and purified on a Biotage Flash 40 M siliga gel cartridge using 40%) CH2C12 in heptane as eluent Product was collected as 690 mg (51%) of white solid as the t-butyl ester The conesponding tert-butyl ester (497 mg, 1 10 mmol) was stiπed for 6 hours in a mixture of CH2C12 (15 mL) and TFA (15 mL) Solvents were removed by rotary evaporation, and the residue was recrystallized from THF The solids were washed with THF followed by heptane and then dried at 100 °C under vacuum yielding 286 mg of white solid 1H NMR (400 MHz, DMSO-D6) δ ppm 7 63 (dd, J=8 50, 1 66 Hz, 1 H) 7 91 (dd, J=9 02, 2 59 Hz, 1 H) 8 15 (d, J=2 49 Hz, 1 H) 8 20 (m, J=8 91 Hz, 2 H) 8 67 (d, J=8 91 Hz, 1 H) 12 60 (s, 1 H)
Preparation of (5-Bromo-2-fluorophenyl)(hydroxy)acetic acid
Figure imgf000105_0001
Trimethylsilyl cyanide (17 5 mL, 131 mmol, Aldrich) was added by syringe to a solution of 5-bromo-2-fluorobenzaldehyde (24 7 g, 122 mmol, Lancaster) and 1,4- diazabicyclo[2 2 2]octane (1 0 g, 8 9 mmol, Aldrich) in CH2C12 (60 mL) at such a rate that the mixture maintained a moderate reflux After 20 minutes of stirring, the mixture was diluted with CH2C12 (150 mL) and washed with water (3 X 150 mL) and brine (150 mL) The organics were dried over Na2SO and evaporated leaving the silylated cyanohydrin as 35 g of golden oil This material was treated with concentrated HCl (75 mL) in water (25 mL) and then heated to reflux for 2 hours The mixture was allowed to cool and then made basic with 6 0 M NaOH The mixture was diluted with water (300 mL) and washed with CH2C12 (2 X 250 mL) It was then made acidic with concentrated HCl, and the product was extracted into CH2C12 (2 X 250 mL). The organics were dried over Na2SO and evaporated leaving the product as 21.5 g (71%) of white solid. lH NMR (400 MHz, DMSO-D6) δ ppm 5.22 (s, 1 H) 6.18 (br s, 1 H) 7.21 (dd, J=9.74, 8.91 Hz, 1 H) 7.55 (ddd, J=8.71, 4.56, 2.70 Hz, 1 H) 7.62 (dd, J=6.32, 2.59 Hz, 1 H) 12.92 (br s, 1 H).
Preparation of Ethyl (5-bromo-2-fluorophenyl)(hydroxy)acetate
Figure imgf000106_0001
Sulfuric acid (1.0 mL) was added to a solution of 5-bromo-2- fluorophenyl)(hydroxy)acetic acid (20.0 g, 80.3 mmol) in ethanol (150 mL), and the solution was heated at reflux for 22 hours. The ethanol was removed by rotary evaporation, and the residue was dissolved in EtOAc. This solution was washed with saturated NaHCO3 (2 X 200 mL) and brine (200 mL) and then dried over Na2SO4. Evaporation yielded the product as 20.6 g (93 %) of golden oil. H NMR (400 MHz,
19F Decoupled, CHLOROFORM-D) δ ppm 1.24 (t, J=7.15 Hz, 3 H) 3.55 (d, J=4.98
Hz, 1 H) 4.25 (m, 2 H) 5.35 (d, J=4.56 Hz, 1 H) 6.97 (d, J=8.92 Hz, 1 H) 7.43 (dd,
J=8.71, 2.49 Hz, 1 H) 7.53 (d, J=2.49 Hz, 1 H).
Preparation of Ethyl (5-bromo-2-fluorophenyl)(oxo)acetate
O
Br Acetic anhydride (8.0 mL, 85 mmol, Mallinckrodt) was added dropwise to a solution of ethyl (5-bromo-2-fluorophenyl)(hydroxy)acetate (19.1 g, 68.7 mmol) in DMSO (30 mL) with stirring in a 90 °C oil bath. The heat was removed after 3 hours. Water (10 mL) was added, and the mixture was stiπed for 30 minutes before being added to a separatory funnel with EtOAc (100 mL). This mixture was washed with brine (3 X
100 mL) and then dried over MgSO . Solvent was removed by rotary evaporation, and the residue was purified by chromatography on a Biotage Flash 75 L silica cartridge using 50 %> CH2C12 in heptane as eluent. Yield was 14.0 g (74%) of white solid. 1H NMR (400 MHz, 19F Decoupled, CHLOROFORM-D) δ ppm 1.40 (t, J=7.15 Hz, 3 H) 4.44 (q, J=7.26 Hz, 2 H) 7.08 (d, J=8.91 Hz, 1 H) 7.73 (dd, J=8.81, 2.59 Hz, 1 H) 8.03 (d, J=2.70 Hz, 1 H).
Preparation of Ethyl (5-bromo-2-fluorophenyl)(hydroxyimino)ethanoate
Figure imgf000107_0001
Hycfroxylamine hydrochloride (3.57 g, 51.4 mmol, Mallinckrodt) and sodium acetate (4.39 g, 53.5 mmol, Mallinckrodt) were added as solids to a solution of ethyl (5- bromo-2-fluorophenyι)(oxo)acetate (12.8 g, 46.4 mmol) in ethanol (30 mL). The mixture was stirred at room temperature for 3 hours and then at 50 °C for 1 hour. The mixture was allowed to cool and was then filtered. The precipitate was washed with ethanol, and these washings were added to the filtrate. The filtrate was concentrated to an oil. Water (200 mL) was added, and the product was extracted into EtOAc. The EtOAc was washed with an additional portion of water (100 mL) and then dried over MgSO4. Evaporation left the product as 13.6 g (101 %) of oil that was used without further purification. NMR and HPLC indicated a mixture of isomers. lH NMR (Major Isomer, 400 MHz, 19F Decoupled, DMSO-D6) δ ppm 1.24 (t, J=6.95 Hz, 3 H) 4.24 (q, J=7.05 Hz, 2 H) 7.29 (d, J=8.91 Hz, 1 H) 7.61 (d, J=2.49 Hz, 1 H) 7.68 (dd, J=8.81, 2.59 Hz, 1 H) 12.98 (s, 1 H).
Preparation of Ethyl 5-bromo-l,2-benzisoxazole-3-carboxylate
Figure imgf000107_0002
A mixture of ethyl (5-bromo-2-fluorophenyl)(hydroxyimino)ethanoate (2.15 g, 7.41 mmol) and potassium carbonate (1.13 g, 8.18 mmol, Mallinckrodt) in DMSO (10 mL) was heated in a 100 °C oil bath for 50 minutes. The mixture was diluted with MTBE (100 mL) and washed with water (2 X 100 mL). The organics were evaporated in the presence of silica gel, and the product was purified by chromatography using a Biotage Flash 40 M silica cartridge with 50 % CH2C12 in heptane as eluent. Yield was 1.44 g (72%) of white solid. 1H NMR (400 MHz, DMSO-D6) δ ppm 1.40 (t, J=7.15 Hz, 3 H) 4.50 (q, J=7.12 Hz, 2 H) 7.94 (m, 2 H) 8.19 (m, 1 H).
Example 6.10: 2-{[(5-Bromo-l,2-benzisoxazol-3-yl)carbonyl]amino}-5- cyanobenzoic acid
Figure imgf000108_0001
A solution of sulfuric acid (37.5 mL) in water (12.5 mL) was added to a flask containing ethyl 5-bromo-l,2-benzisoxazole-3-carboxylate (1.26 g, 4.67 mmol), and the mixture was heated in an 80 °C oil bath for 3.75 hours. The mixture was then added to 150 mL of water. The precipitate was collected, washed with water, and briefly air dried. The resulting white solid (711 mg) was sluried in CH2C12 (30 mL) and treated with DMF (20 μL) and oxalyl chloride (1.0 mL, 12 mmol). The solvent and excess oxalyl chloride were removed by rotary evaporation after 1.7 hours. The residue was dissolved in CH2C12 (20 mL) and treated with tert-butyl 2-amino-5- cyanobenzoate (547 mg, 2.51 mmol) and pyridine (8 mL). The mixture was stiπed overnight and then added to a separatory funnel with 100 mL of EtOAc. A few mL of THF were added to improve solubility. This mixture was washed with 1.0 M HCl (2 X 100 mL) and brine (100 mL). Product was adsorbed onto silica gel and purified on a Biotage Flash 40 M siliga gel cartridge using a gradient from 50% CH2C12 to 75 % CH2C12 in heptane as eluent. Product was collected as 647 mg (31%>) of white solid as the t-butyl ester. tert-Butyl 2-{[(5-bromo-l,2-berizisoxazol-3-yl)carbonyl]amino}-5- cyanobenzoate (435 mg, 0.984 mmol) was stiπed for 23 hours in a mixture of CH2C12 (10 mL) and TFA (10 mL). The solvents were removed by rotary evaporation, and the residue was recrystallized from THF/heptane. Yield was 89 mg of white solid. The mother liquor was concentrated, and the residue was recrystallized from EtOH/THF yielding an additional 162 mg of white solid. Total yield was 251 mg (66%). 1H NMR {OMSO-d6) δ 12.90 (s, 1 H), 8.86 (d, J= 8.9 Hz, 1 H), 8.43 (d, J= 2.1 Hz, 1 H), 8.31-8.32 (m, 1 H), 8.16 (dd, J= 8.8, 2.2 Hz, 1 H), 7.93-7.98 (m, 2 H). Example 6.11: 2-[(2,l-Benzisoxazol-3-ylcarbonyl)amino]-5-cyanobenzoic acid
Figure imgf000109_0001
To a slurry of 2,1 -benzisoxaz -carboxylic acid, as described in J Chem. Soc. (C) 1970, 2660-2661, (1.01 g, 6.19 mmol) in CH2C12 (50 mL) was added DMF (20 μL) and oxalyl chloride (2.0 mL, 23 mmol). Solvent and excess oxalyl chloride were removed by rotary evaporation after 2.5 hours of stirring. The residue was dissolved in CH2C12 (30 mL), and tert-butyl 2-amino-5-cyanobenzoate (1.07 g, 4.90 mmol) in pyridine (20 mL) was added. After 3.5 hours, the mixture was diluted with CH2C12 (100 mL) and washed with 1 M HCl (2 X 100 mL) followed by brine (100 mL). The product was adsorbed onto silica gel and purified on a Biotage Flash 40 M silica cartridge using a gradient from 60% to 75% CH2C12 in heptane as eluent. Product was isolated as 1.16 g of white solid as the t-butyl ester. To a solution ofthe conesponding tert-butyl ester (809 mg, 2.23 mmol) in CH2C12 (25 mL) was added TFA (15 mL). The solvents were removed by rotary evaporation after 23 hours. Methanol was added and then removed by rotary evaporation to remove residual TFA. The residue was then recrystallized from 50 mL of 4: 1 ethanol THF. The collected solids were washed with methanol, CH2C12, and heptane and then dried at 100 °C under vacuum yielding 258 mg of pale yellow solid. 1H NMR (400 MHz, DMSO-D6) δ ppm 7.39 (dd, J=8.81, 6.32 Hz, 1 H) 7.57 (dd, J=9.12, 6.43 Hz, 1 H) 7.85 (d, J=9.12 Hz, 1 H) 8.03 (d, J=8.71 Hz, 1 H) 8.15 (dd, J=8.71, 2.07 Hz, 1 H) 8.44 (d, J=2.28 Hz, 1 H) 8.86 (d, J=8.71 Hz, 1 H) 12.95 (s, 1 H).
Synthesis of 5- and 6- substituted l,2-benzisoxazole-3-carboxylic acids
(COCI)2 CHCI3/ pyridine - hydrolysis
Figure imgf000109_0002
CHzCyDMF
Figure imgf000109_0003
2
Figure imgf000109_0004
Figure imgf000110_0001
Such as described by in JACS 1975 97 7305.
Example 6.13 2-[(l,2-benzisoxazol-3-ylcarbonyl)amino]-5-cyanobenzoic acid
l,2-benzisoxazole-3-carboxylic acid (200 mg, 1.23 mmol) was suspended in CH2C12 (10 mL) and (COCl)2 added (725 mg, 0.5 mL, 5.7 mmol). A catalytic amount of DMF was then added and the mixture stiπed for 4 hrs. The solvent was then removed in vacuo to give the acid chloride as an oil. The oil was dissolved in CHC13 (10 mL). tert-butyl 2-amino-5-cyanobenzoate (270 mg, 1.23 mmol) was added dropwise as a solution in THF/ pyridine (5 mL/1 mL). The solution was stiπed at room temperature for an additional 12 hrs then poured into 1 M HCl (20 mL) and extracted with EtOAc (3 x 20 mL). The combined organic solutions were dried over Na2SO4 and concentrated in vacuo. The resulting residue was purified by chromatography (1% MeOH in CHC13) to give 100 mg ofthe desired amide (22%). This amide was dissolved in 10 mL CH2C12/TFA (1/1) and stiπed for 10 hrs at room temperature. The solvent was then removed in vacuo and the resulting solid was washed with MeOH, providing 80 mg ofthe title compound (95%).
H NMR (400 MHz, DMSO) 7.59 (t, IH), 7.81 (t, IH), 7.96 (d, IH), 8.16 (dd, IH), 8.24 (d, IH), 8.90 (d, IH), 12.92 (s, IH)
MS (El ) m/z (rel. intensity) 307 (M+, 0), 171 (81), 119 (59), 115 (46), 91 (99), 90 (30), 78 (31), 65 (26), 64 (59), 62 (46), 61 (68). HRMS (FAB) calcd for C16H9N3O4+H 308.0671, found 308.0665.
Example 6.14: 2-[(l,2-benzisoxazol-3-ylcarbonyl)amino]-5-bromobenzoic acid
Figure imgf000110_0002
l,2-benzisoxazole-3-carboxylic acid (815 mg, 5.0 mmol) was suspended in dichloroethane (DCE) (10 mL). Oxalyl chloride (0.545 mL, 6.25 mmol) was added followed by a catalytic amount of DMF. The reaction was stiπed at room temperature for 5 hrs. The solvent was removed in vacuo, and the resulting oil was redissolved in DCE (10 mL). Methyl 2-amino-5-bromobenzoate was added dropwise as a solution in THF/pyridine (5 mL/2 mL). The mixture was stiπed for 48 hrs. The resulting solid was filtered and washed with MeOH, giving 925 mg (50%) ofthe desired amide. The ester was treated with LiOH in 1 : 1 : 1 THF/MeOH/H2O for 12 hrs followed by acidification to give 608 mg (68%) ofthe title compound.
H NMR (400 MHz, DMSO) 7.58 (t, IH), 7.78 (t, IH), 7.92 (dd, IH), 7.95 (d, IH), 8.16 (d, IH), 8.24 (d, IH), 8.71 (d, IH), 12.60 (s, IH)
Scheme 8
Figure imgf000111_0001
acid chloride or sulfonyl chloride
CHCI3/pyridιne
Figure imgf000111_0002
Figure imgf000111_0003
Example 6.16: tert-butyl 2-{[(5-ammo-l,2-benzisoxazol-3-yl)carbonyl]amino}-5- cyanobenzoate
Figure imgf000111_0004
5-Nitro-l,2-benzisoxazole-3-carboxylic (2.08 g, 10 mmol) was suspended in CH2C12 (50 mL). Oxalyl chloride (1.1 mL, 12.5 mmol) was added followed by a catalytic amount of DMF. The reaction was stiπed at room temperature for 5 hrs. The solvent was removed in vacuo, and the resulting residue was redissolved in CHC13 (50 mL). tert-Butyl 2-amino-5-cyanobenzoate was added dropwise as a solution in THF/pyridine (40 mL/10 mL). The mixture was stiπed for 12 hrs at room temperature. The resulting solid was filtered and washed with MeOH, giving 2.9 g (72%>) ofthe desired nitro-amide. The nitro-amide was reduced with 10% Pd/C in 100 mL (THF/MeOH, 1/1) with ammonium formate (4.7 g, 75 mmol) as H2 source. After stirring for 10 hr at room temperature the mixture was filter and the resulting solids washed with THF. Excess solvent was removed in vacuo and the residue purified by chromatography (1% MeOH in CHC13) to give 2.61 g ofthe title compound (96%).
H NMR (400 MHz, CDC13) 1.69 (s, 9H), 3.90 (bs, 2H), 7.04 (dd, IH), 7.49 (m, 2H), 7.84 (dd, IH), 8.37 (d, IH), 9.06 (d, IH), 12.76 (s, IH)
Example 6.17: 2-( {[5-(acetylamino)-l ,2-benzisoxazol-3-yl] carbonyl} amino)-5- cyanobenzoic acid
Figure imgf000112_0001
tert-Butyl 2- {[(5-amino- 1 ,2-benzisoxazol-3-yl)carbonyl]amino} -5-cyanobenzoate (250 mg, 0.66 mmol) was dissolved in CHC1 (10 ml). Pyridine (1 mL) and acetyl chloride ( 57 μL, 0.8 mmol) were then added and the reaction stiπed for 10 hrs at room temperature. The resulting mixture was absorbed onto silica and purified by chromatography {2% MeOH in CHC13) to give 203 mg (73%) ofthe desired acetamide. This amide was dissolved in 10 mL CH2C12/TFA (1/1) and stiπed for 10 hrs at room temperature. Solvent was removed in vacuo and the remaining solid was recrystalized from THF/MeOH to give 170 mg (96%>) ofthe title compound.
H NMR (400 MHz, DMSO) 2.10 (s, 3H), 7.86 (m, 2H), 8.16 (dd, IH), 8.45 (d, IH), 8.63 (d, IH), 8.91 (d, IH), 10.32 (s, IH), 12.86 (s, IH) Example 6.18: 2-({[5-(benzoylamino)-l,2-benzisoxazol-3-yl]carbonyl}amino)-5- cyanobenzoic acid
Figure imgf000113_0001
The title compound, 168 mg, was synthesized as above from tert-butyl 2-{[(5-amino- l,2-berιzisoxazol-3-yl)carbonyl]arnino}-5-cyanobenzoate (250 mg, 0.66 mmol) and benzoyl chloride (175 μL, 1.5 mmol). H NMR (400 MHz, DMSO) 7.60 (m, 3H), 7.95 (d, IH), 8.02 (m, 2H), 8.12 (dd, IH), 8.17 (dd, IH) 8.45 (d, IH), 8.81 (d, IH), 8.92 (d, IH), 10.62 (s, IH), 12.92 (s, IH).
Example 6.19: 5-cyano-2-[( { 5- [(phenylacetyl) arnino] -1 ,2-benzisoxazol-3- yl}carbonyl)amino]benzoic acid
Figure imgf000113_0002
Synthesized as above from tert-butyl 2- { [(5-amino- 1 ,2-benzisoxazol-3 - yl)carbonyl]amino}-5-cyanobenzoate (250 mg, 0.66 mmol) and phenylacetyl chloride (200 μL, 1.5 mmol) to give 92 mg ofthe title compound. H NMR (400 MHz, DMSO) 3.70 (s, 2H), 7.30 (m, 5H), 7.89 (m, 2H), 8.16 (dd, IH), 8.44 (d, IH) 8.63 (s, IH), 8.89 (d, IH), 10.57 (s, IH), 12.89 (s, IH).
Example 6.20: 5-cyano-2-[( {5-[(methylsulfonyl)amino]- 1 ,2-benzisoxazol-3- yl} carbonyl) amino]benzoic acid
Figure imgf000114_0001
Synthesized as above from tert-butyl 2-{[(5-arnino-l,2-benzisoxazol-3- yl)carbonyl]amino}-5-cyanobenzoate (250 mg, 0.66 mmol) and methanesulfonyl chloride (116 μL, 1.5 mmol) to give 194 mg ofthe title compound. H NMR (400 MHz, DMSO) 3.02 (s, 3H), 7.62 (dd, IH), 7.95 (d, IH), 8.08 (d, IH), 8.16 (dd, IH), 8.45 (d, IH), 8.63 (d, IH), 8.91 (d, IH), 10.09 (s, IH), 12.87 (s, IH).
Example 6.21: 5-cyano-2-[({5-[(phenylsulfonyl)amino]-l,2-benzisoxazol-3- yl} carbonyl) amino]benzoic acid
Figure imgf000114_0002
Synthesized as above from tert-butyl 2-{[(5-amino-l,2-benzisoxazol-3- yl)carbonyl]amino}-5-cyanobenzoate (250 mg, 0.66 mmol) and benzenesulfonyl chloride (191 μL, 1.5 mmol) to give 201 mg ofthe title compound. H NMR (400 MHz, DMSO) 7.55 (m, 4H), 7.76 (m, 2H), 7.85 (d, IH), 7.95 (d, IH), 8.16 (dd, IH) 8.43 (d, IH), 8.88 (d, IH), 10.65 (s, IH), 12.85 (s, IH).
Example 6.22: 2-[({5-[(benzylsulfonyl)amino]-l,2-benzisoxazol-3- yl}carbonyl)amino]-5-cyanobenzoic acid
Figure imgf000115_0001
Synthesized as above from tert-butyl 2-{[(5-amino-l,2-benzisoxazol-3- yl)carbonyl]amino}-5-cyanobenzoate (250 mg, 0.66 mmol) and α-toluenesulfonyl chloride (200 μL, 1.5 mmol) to give 102 mg ofthe title compound. H NMR (400 MHz, DMSO) 4.52 (s, 2H), 7.30 (m, 5H), 7.55 (dd, IH), 7.92 (d, IH), 8.07 (d, IH), 8.16 (dd, IH), 8.45 (d, IH), 8.93 (d, IH), 10.21 (s, IH), 12.94 (s, IH).
Example 6.23: 5-cyano-2-{[(5-{[(4-fluorophenyl)sulfonyl]arnino}-l,2-benzisoxazol- 3-yl)carbonyl]arnino}benzoic acid
Figure imgf000115_0002
Synthesized as above from tert-butyl 2- {[(5-amino- l,2-benzisoxazol-3- yl)carbonyl]amino}-5-cyanobenzoate (250 mg, 0.66 mmol) and 4- fluorobenzenesulfonyl chloride (200 mg, 1.0 mmol) to give 205 mg ofthe title compound. H NMR (400 MHz, DMSO) 7.40 (m, 2H), 7.49 (dd, IH), 7.80 (m, 2H), 7.87 (d, IH), 7.94 (d, IH), 8.16 (dd, IH), 8.44 (d, IH), 8.88 (d, IH), 10.66 (s, IH), 12.91 (s, IH).
Example 6.24: 5-cyano-2-[({5-[(methoxyacetyl)amino]-l,2-benzisoxazol-3- yl}carbonyl)amino]benzoic acid
Figure imgf000116_0001
Synthesized as above from tert-butyl 2-{[(5-amino-l,2-benzisoxazol-3- yl)carbonyl]amino} -5-cyanobenzoate (150 mg, 0.44 mmol) and methoxyacetyl chloride (40 μL, 0.44 mmol) to give 106 mg ofthe title compound. H NMR (400 MHz, DMSO) 3.41 (s, 3H), 4.07 (s, 2H), 7.90 (d, IH), 7.96 (dd, IH), 8.17 (dd, IH), 8.45 (d, IH), 8.72 (d, IH), 8.91 (d, IH), 10.19 (s, IH), 12.89 (s, IH)
Example 6.25: 5-cyano-2-[( {5-[(cyclobutylcarbonyl)amino]-l ,2-benzisoxazol-3- yl} carbonyl) amino]benzoic acid
Figure imgf000116_0002
Synthesized as above from tert-butyl 2-{[(5-amino-l,2-benzisoxazol-3- yl)carbonyl]amino}-5-cyanobenzoate (150 mg, 0.44 mmol) and cyclobutylcarbonyl chloride (50 μL, 0.44 mmol) to give 112 mg ofthe title compound. H NMR (400
MHz, DMSO) 1.85 (m, IH), 1.95 (m, IH), 2.14 (m, 2H), 2.26 (m, 2H), 3.27 (m, IH), 7.88 (d, IH), 8.17 (dd, IH), 8.45 (d, IH), 8.66 (d, IH), 8.90 (d, IH), 10.11 (s, IH), 12.89 (s, IH).
Example 6.26: 5-cyano-2-[({6-[(methylsulfonyl)amino]-l,2-benzisoxazol-3- yl} carbonyl) amino]benzoic acid
Figure imgf000117_0001
Synthesized as above from tert-butyl 2-{[(6-amino-l,2-benzisoxazol-3- yl)carbonyl]amino}-5-cyanobenzoate (250 mg, 0.66 mmol) and methanesulfonyl chloride (100 μL, 1.28 mmol) to give 220 mg ofthe title compound.
H NMR (400 MHz, DMSO) 3.19 (s, 3H), 7.35 (dd, IH), 7.65 (d, IH), 8.14 (d, IH), 8.16 (d, IH), 8.45 (d, IH), 8.89 (d, IH), 10.59 (s, IH), 12.87 (s, IH)
Example 6.27: 5-cy-mo-2-[({6-[(phenylsulfonyl)amino]-l,2-benzisoxazol-3- yl} carbonyl) amino]benzoic acid
Figure imgf000117_0002
Synthesized as above from tert-butyl 2-{[(6-amino-l,2-benzisoxazol-3- yl) carbonyl] arnino} -5-cyanobenzoate (250 mg, 0.66 mmol) and benzenesulfonyl chloride (150 μL, 1.17 mmol) to give 252 mg ofthe title compound. H NMR (400 MHz, DMSO) 7.29 (dd, IH), 7.55 (m, 4H), 7.88 (m, 2H), 8.05 (d, IH), 8.15 (dd, IH), 8.43 (d, IH), 11.14 (s, IH), 12.79 (s, IH).
Example 6.28 : 5-cyano-2- { [(6- { [(4-fluorophenyl)sulfonyl]amino } - 1 ,2-benzisoxazol- 3-yl)carbonyl]amino}benzoic acid
Figure imgf000118_0001
Synthesized as above from tert-butyl 2-{[(6-amino-l,2-benzisoxazol-3- yl)carbonyl]amino} -5-cyanobenzoate (250 mg, 0.66 mmol) and 4- fluorobenzenesulfonyl chloride (200 mg, 1.0 mmol) to give 256 mg ofthe title compound. H NMR (400 MHz, DMSO) 7.29 (dd, IH), 7.42 (m, 2H), 7.57 (d, IH), 7.94 (m, 2H), 8.07 (d, IH), 8.16 (dd, IH), 8.43 (d, IH), 8.85 (d, IH), 11.15 (s, IH), 12.80 (s, lH).
Example 6.29: 2-[({6-[(benzylsulfonyl)amino]-l,2-benzisoxazol-3- yl}carbonyl)amino]-5-cyanobenzoic acid
Figure imgf000118_0002
Synthesized as above from tert-butyl 2-{[(6-amino-l,2-benzisoxazol-3- yl)carbonyl]a ino} -5-cyanobenzoate (250 mg, 0.66 mmol) and α-toluenesulfonyl chloride (200 μL, 1.5 mmol) to give 140 mg ofthe title compound. H NMR (400 MHz, DMSO) 5.17 (s, 2H), 7.00 (d, IH) 7.50 (m, 5H), 7.78 (d, IH), 8.16 (dd, IH), 8.43 (d, IH), 8.87 (d, IH), 10.21 (s, IH), 12.78 (s, IH). Example 6.30: 2- {[(6-amino- 1 ,2-benzisoxazol-3-yl)carbonyl]amino} -5-cyanobenzoic acid
Figure imgf000119_0001
Synthesized as above from tert-butyl 2- {[(6-amino- l,2-benzisoxazol-3- yl)carbonyl]amino}-5-cyanobenzoate (250 mg, 0.66 mmol) to give 165 mg ofthe title compound. H NMR (400 MHz, DMSO) 6.73 (d, IH), 6.80 (IH, dd), 7.78 (d, IH), 8.14 (dd, IH), 8.43 (d, IH), 8.87 (d, IH), 12.70 (s, IH).
Example 6.31: 5-cyano-2-({[5-(ethylamino)-l,2-benzisoxazol-3- yl] carbonyl} amino)benzoic acid
Figure imgf000119_0002
General Procedure:
Figure imgf000119_0003
tert-Butyl 2-{[(5-ammo-l,2-benzisoxazol-3-yl)carbonyl]amino}-5-cyanobenzoate (150 mg, 0.44 mmol) was suspended in 5 mL of THF/MeOH (1/1). To the suspension was added acetaldehyde (22 μL, 0.4 mmol), sodium cyanoborohydride (NaCNBH3) (25 mg, 0.4 mmol) and 0.1 mL of acetic acid (AcOH). The reaction was monitored by HPLC and was diluted with 50 mL of CH2C12 when complete. The organic solution was washed with brine, dried over Na2SO and concentrated to a yellow solid. This solid was dissolved in 10 mL CH2C12/TFA (1/1) and stiπed for 10 hrs at room temperature. Solvent was removed in vacuo and the remaining solid was washed with
MeOH to give 60 mg ofthe title compound. H NMR (400 MHz, DMSO) 1.23 (t,
3H), 3.08 (q, 2H), 7.06 (d, IH), 7.13 (dd, IH), 7.65 (d, IH), 8.13 (dd, IH), 8.42 (d,
IH), 8.90 (d, IH), 12.79 (s, IH)
Example 6.32: 5-cyano-2-[( {5-[(cyclopropylmethyl)amino]-l ,2-benzisoxazol-3- yl} carbonyl) amino]benzoic acid
Figure imgf000120_0001
Synthesized as above from tert-butyl 2- { [(5-amino- l,2-benzisoxazol-3- yl)carbonyl]amino}-5-cyanobenzoate (150 mg, 0.44 mmol) and cyclopropyl carboxaldehyde (33 μL, 0.45 mmol) to give 58 mg ofthe title compound. H NMR
(400 MHz, DMSO) 0.27 (m, 2H), 0.52 (m, 2H), 1.09 (m, IH), 2.96 (d, 2H), 7.14 (s, IH), 7.22 (d, IH), 7.68 (d, IH), 8.15 (dd, IH), 8.44 (d, IH), 8.91 (d, IH), 12.80 (s,
IH).
Example 6.33: 5-cyano-2-[({5-[(2-methoxyethyl)amino]-l,2-benzisoxazol-3- yl}carbonyl)amino]benzoic acid
Figure imgf000120_0002
Synthesized as above from tert-butyl 2-{[(5-amino-l,2-benzisoxazol-3- yl)carbonyl]amino} -5-cyanobenzoate (150 mg, 0.44 mmol) and methoxyacetaldehyde (40 mg, 0.45 mmol) to give 75 mg ofthe title compound. H NMR (400 MHz, DMSO) 3.25 (t, 2H), 3.31 (s, 3H), 3.56 (t, 2H), 7.10 (d, IH), 7.20 (dd, IH), 7.66 (d, IH), 8.15 (dd, IH), 8.44 (d, IH), 8.92 (d, IH), 12.79 (s, IH). Example 6.34: 5-cyano-2-[( {5-[(2-hydroxyethyl)amino]- 1 ,2-benzisoxazol-3- yl}carbonyl)amino]benzoic acid
Figure imgf000121_0001
Synthesized as above from tert-butyl 2-{[(5-amino-l,2-benzisoxazol-3- yl)carbonyl]amino}-5-cyanobenzoate (150 mg, 0.44 mmol) and tert- butyldimethylsiloxyacetaldehyde (85 μL, 0.45 mmol) to give 111 mg ofthe title compound. H NMR (400 MHz, DMSO) 3.15 (t, 2H), 3.63 (t, 2H), 7.09 (d, IH), 7.18 (dd, IH), 7.65 (d, IH), 8.15 (dd, IH), 8.43 (d, IH), 8.91 (d, IH), 12.79 (s, IH).
Example 6.35: 5-cyano-2-[( {5-[(2,3-dihy<_troxypropyl)amino]-l ,2-benzisoxazol-3- yl} carbonyl) amino]benzoic acid
Figure imgf000121_0002
Synthesized as above from tert-butyl 2-{[(5-amino-l,2-benzisoxazol-3- yl)carbonyl]amino}-5-cyanobenzoate (150 mg, 0.44 mmol) and glyceraldehyde dimer (40 mg, 0.21 mmol) to give 91 mg ofthe title compound. H NMR (400 MHz, DMSO) 2.96 (dd, IH), 3.22 (dd, IH), 3.42 (m, 3H), 3.70 (m, IH), 7.09 (d, IH), 7.21 (dd, IH), 7.65 (d, IH), 8.15 (dd, IH), 8.43 (d, IH), 8.92 (d, IH), 12.81 (s, IH).
Example 6.36a: 5-cyano-2-({[5-(dimethylamino)-l,2-benzisoxazol-3- yl] carbonyl} amino)benzoic acid
Figure imgf000122_0001
Synthesized as above from tert-butyl 2- {[(5-amino- 1, 2-benzisoxazol-3- yl) carbonyl] arnino} -5-cyanobenzoate (150 mg, 0.44 mmol), formaldehyde (0.5 mL, 6.25 mmol) and NaCNBH3 (95 mg, 1.5 mmol) to give 85 mg ofthe title compound. H NMR (400 MHz, DMSO) 2.99 (s, 6H), 7.24 (d, IH), 7.35 (dd, IH), 7.77 (d, IH), 8.15 (dd, IH), 8.43 (d, IH), 8.91 (d, IH), 12.84 (s, IH).
Example 6.36b: tert-butyl 2-({[6-(acetyloxy)-l,2-benzisoxazol-3- yl]carbonyl} amino)-5-cyanobenzoate
Figure imgf000122_0002
6-Hydroxy-l,2-benzisoxazole-3-carboxylic acid (4.5 g, 25 mmol) was dissolved in 25 mL of acetic anhydride. Several drops of concentrated sulfuric acid were added and the solution stiπed at room temperature. After 4 h the reaction was poured onto ice and then extracted with CH2C12. The organic solution was dried over Na2SO and concentrated to give 6-acetoxy-l,2-benzisoxazole-3-carboxylic acid as white solid. This solid (2.8 g, 12.7 mmol) was suspended in 100 mL CH2C12 and 2.5 mL of oxalyl chloride was added followed by 10 drops of DMF. The reaction was stiπed at room temperature for 3 h. The solution was concentrated to an off white solid and then redisolved in lOO mL CHCk. To this solution was added tert-butyl 2-amino-5- cyanobenzoate as a solution in THF/pyridine (40 mL/10 mL). After stirring for 12 h at room temperature the solution was concentrated to a pink solid. The solid was dissolved in EtOAc and washed with IN HCl. The organic solution was dried over Na2SO and then concentrated to a white solid which was washed with MeOH to give 2.55 g ofthe title compound. H NMR (300 MHz, CDC13) 1.69 (s, 9H), 2.40 (s, 3H), 7.25 (dd, IH), 7.53 (d, IH), 7.86 (dd, IH), 8.30 (d, IH), 8.38 (d, IH), 9.05 (d, IH), 12.84 (s, IH).
Example 6.37: 2-({[6-(acetyloxy)-l,2-benzisoxazol-3-yl]carbonyl}amino)-5- cyanobenzoic acid tert-Butyl 2-({[6-(acetyloxy)-l,2-berιzisoxazol-3-yl]carbonyl}amino)-5-cyanobenzoate (250 mg, 0.59 mmol) was dissolved in 10 mL CH2C12/TFA (1/1) and stiπed for 3 h at room temperature. Solvent was removed in vacuo and the remaining solid was washed with MeOH to give 206 mg ofthe title compound. H NMR (400 MHz, DMSO) 2.35 (s, 3H), 7.39 (dd, IH), 7.85 (d, IH), 8.16 (dd, IH), 8.22 (d, IH), 8.44 (d, IH), 8.89 (d, IH), 12.87 (s, IH)
Example 6.38a: tert-butyl 5-cyano-2-{[(6-hydroxy-l,2-benzisoxazol-3- yl) carbonyl] arnino } benzoate
Figure imgf000123_0001
tert-Butyl 2-({[6-(acetyloxy)-l,2-beιιzisoxazol-3-yl]carbonyl}amino)-5-cyanobenzoate (1.93 g, 4.58 mmol) was suspended in 100 mL THF/MeOH (1/1). A solution of K2CO3 in 50 mL of H2O and stiπed for 3 h at room temperature. 50 mL of 1 N HCl was added and the resulting precipitate was filtered and dried overnight at 50 C in a vacuum oven to give 1.61 g ofthe title compound. H NMR (400 MHz, DMSO) 1.60 (s, 9H), 7.04 (dd, IH), 7.14 (d, IH), 7.97 (d, IH), 8.16 (dd, IH), 8.39 (d, IH), 8.77 (d, IH), 10.73 (s, IH), 12.32 (s, IH).
Example 6.38b: 5-cyano-2-{[(6-hydroxy-l,2-benzisoxazol-3- yl)carbonyl]amino}benzoic acid tert-Butyl 5-cyano-2-{[(6-hydroxy-l ,2-benzisoxazol-3-yl)carbonyl]amino}benzoate (250 mg, 0.60 mmol) was dissolved in 10 mL CH2C12/TFA (1/1) and stiπed for 4 h at room temperature. Solvent was removed in vacuo and the remaining solid was washed with MeOH to give 213 mg of the title compound. H NMR (400 MHz, DMSO) 7.03 (dd, IH), 7.13 (d, IH), 7.99 (d, IH), 8.16 (dd, IH), 8.44 (d, IH), 8.89 (d, IH), 10.73 (s, IH), 12.87 (s, IH)
Example 6.39: 2-({[6-(benzyloxy)-l,2-benzisoxazol-3-yl]ca bonyl}amino)-5- cyanobenzoic acid
Figure imgf000124_0001
Figure imgf000124_0002
tert-Butyl 5-cyano-2-{[(6-hyαVoxy-l,2-berizisoxazol-3-yl)carbonyl]amino}benzoate (250 mg, 0.66 mmol) was dissolved in 10 mL of THF. To this solution was added benzyl alcohol (155 μL, 1.5 mmol), triphenyl phosphine (393 mg, 1.5 mmol) and diethylazodicarboxylate (236 μL, 1.5 mmol). After stirring at room temperature for 12 h the reaction was diluted with 50 mL of CH2C12 and filterd through SiO2. The organic solution was concentrated to a oil and redisolved in 10 mL CH2C12/TFA (1/1) and stiπed for 4 h at room temperature. Solvent was removed in vacuo and the remaining solid was washed with MeOH to give 35 mg ofthe title compound. H NMR (400 MHz, DMSO) 5.27 (s, 2H), 7.24 (dd, IH), 7.37 (m, IH), 7.43 (m, 2H), 7.51 (m, 2H), 7.61 (d, IH), 8.06 (d, IH), 8.15 (dd, IH), 8.44 (d, IH), 8.89 (d, IH), 12.84 (s, IH).
Example 6.40: 5-cyano-2-{[(6-methoxy-l,2-benzisoxazol-3- yl)carbonyl] arnino} benzoic acid
Figure imgf000125_0001
Synthesized as above from tert-butyl 5-cyano-2-{[(6-hydroxy-l,2-benzisoxazol-3- yl)carbonyl]amino}benzoate (250 mg, 0.66 mmol) and MeOH (60 μL, 1.5 mmol) to give 154 mg ofthe title compound. H NMR (400 MHz, DMSO) 3.91 (s, 3H), 7.17 (dd, IH), 7.51 (d, IH), 8.04 (d, IH), 8.15 (dd, IH), 8.44 (d, IH), 8.89 (d, IH), 12.81 (s, IH).
Example 6.41 : 2-[( {6- [(benzylsulfonyl) oxy]- 1 ,2-benzisoxazol-3-yl} carbonyl) amino] - 5-cyanobenzoic acid
ridine
Figure imgf000125_0002
Figure imgf000125_0003
Figure imgf000125_0004
tert-Butyl 5-cyano-2-{[(6-hydroxy-l,2-berizisoxazol-3-yl)carbonyl]amino}benzoate (250 mg, 0.66 mmol) was dissolved in CHC13 (10 ml). Pyridine (1 mL) and α- toluenesulfonyl chloride (400 mg, 2.1 mmol) were then added and the reaction stiπed for 12 h at 50 C. The solvent was removed in vacuo and the resulting solid washed with MeOH. This solid was dissolved in 10 mL CH2C12/TFA (1/1) and stiπed for 10 hrs at room temperature. Solvent was removed in vacuo and the remaining solid was washed with MeOH to give 240 mg ofthe title compound. H NMR (400 MHz, DMSO) 5.14 (s, 2H), 7.45 (m, 3H), 7.54 (m, 2H), 7.92 (d, IH), 8.17 (dd, IH), 8.27 (d, IH), 8.45 (d, IH), 8.89 (d, IH), 12.91 (s, IH).
Example 6.42: 5-cyano-2-[({6-[(phenylsulfonyl)oxy]-l,2-benzisoxazol-3- yl}carbonyl)amino]benzoic acid
Figure imgf000126_0001
Synthesized as above from tert-butyl 5-cyano-2-{[(6-hydroxy-l,2-benzisoxazol-3- yl)carbonyι]amino}benzoate (250 mg, 0.66 mmol) and benzenesulfonyl chloride (400 μL, 3.1 mmol) to give 235 mg ofthe title compound. H NMR (400 MHz, DMSO) 7.24 (dd, IH), 7.70 (t, 2H), 7.80 (d, IH), 7.86 (t, IH), 7.92 (m, 2H), 8.17 (dd, IH), 8.19 (d, IH), 8.45 (d, IH), 8.85 (d, IH), 12.86 (s, IH).
Example 6.43: Methyl 5-bromo-2-({[5-(chlorosulfonyl)-l,2-benzisoxazol-3- yl] carbonyl} amino)benzoate
CHCI3, pyridine
Figure imgf000126_0002
Figure imgf000126_0003
Figure imgf000126_0004
Ethyl- l,2-benzisoxazole-3-carboxylate (10 g, 52 mmol) was dissolved in 100 mL of chlorosulfonic acid and heated to 80 C. After 16 h the reaction was cooled to room temperature, poured onto ice and then extracted with EtOAc. The organic solution was dried over Na2SO and then concentrated to a brown oil. This oil was dissolved in 60 mL of thionyl chloride and heated to 50 C. After 6 h excess reagent was removed in vacuo and the remaining residue dissolved in 300 mL CHC13. Methyl-2-amino-5- bromobenzoate was added as a solution in 100 mL CHC13 and 10 mL pyridine. After stirring overnight at room temperature the resulting precipitate was filtered providing 3.96 g ofthe title compound. H NMR (400 MHz, CDC13) 3.80 (s, 3H), 7.77 (dd, IH), 7.92 (d, IH), 8.27 (d, IH), 8.32 (dd, IH), 8.82 (d, IH), 9.12 (d, IH), 12.63 (s, IH)
Example 6.44: 5-bromo-2-( {[5-(mo holin-4-ylsulfonyl)- 1 ,2-benzisoxazol-3- yl] carbonyl} arnino)benzoic acid
Figure imgf000127_0001
Methyl 5-bromo-2-({[5-(chlorosulfonyl)-l,2-benzisoxazol-3-yl]carbonyl} amino)benzoate (250 mg, 0.53 mmol) was suspended in 5 mL of THF. Moφholine (0.5 mL, 5.7 mmol) was added and the reaction warmed to 50 C. Solvent was removed in vacuo and the resulting solid washed with MeOH. This solid was suspended in 5 mL THF and 1 mL water and 50 mg LiOH was added. After 5 h the reaction was acidified with 1 N HCl and extracted with EtOAc. The organic solution was dried over Na2SO and concentrated to a white solid which was suspended in MeOH and filtered giving 140 mg ofthe title compound. H NMR (400 MHz, DMSO) 2.94 (m, 4H), 3.65 (m, 4H), 7.93 (dd, IH), 8.11 (dd, IH), 8.16 (d, IH), 8.23 (d, IH), 8.54 (d, IH), 8.69 (d, IH), 12.68 (s, IH).
Example 6.45: 2-( {[5-(anilinosulfonyl)- 1 ,2-benzisoxazol-3-yl]carbonyl} amino)-5- bromobenzoic acid
Figure imgf000127_0002
Synthesized as above from methyl 5-bromo-2-({[5-(chlorosulfonyl)-l,2-benzisoxazol- 3 -yl] carbonyl} amino)benzoate (250 mg, 0.53 mmol) and aniline (0.5 mL, 5.3 mmol) to give 99 mg ofthe title compound. H NMR (400 MHz, DMSO) 7.04 (t, IH), 7.11 (d, 2H), 7.23 (2H), 7.93 (dd, IH), 8.07 (dd, IH), 8.12 (d, IH), 8.16 (d, IH), 8.64 (d, IH), 8.67 (d, IH), 10.52 (s, IH), 12.68 (s, IH).
Example 6.46: 2-({[5-(dimethylaminosulfonyl)-l,2-benzisoxazol-3- yl]carbonyl} amino)-5-bromobenzoic acid
Figure imgf000128_0001
Synthesized as above from methyl 5-bromo-2-({[5-(chlorosulfonyl)-l,2-benzisoxazol- 3 -yl] carbonyl} amino)benzoate (250 mg, 0.53 mmol) and dimethylamine (1.0 mL, 2.0 mmol) to give 130 mg ofthe title compound. H NMR (400 MHz, DMSO) 2.67 (s, 6H) 7.93 (dd, IH), 8.13 (dd, IH), 8.16 (d, IH), 8.21 (d, IH), 8.54 (d, IH), 8.69 (d, IH), 12.67 (s, IH).
Example 6.47: 2-({[5-(diethylammosulfonyl)-l,2-benzisoxazol-3-yl]carbonyl}arnino)- 5-bromobenzoic acid
Figure imgf000128_0002
Synthesized as above from methyl 5-bromo-2-({[5-(chlorosulfonyl)-l,2-benzisoxazol- 3 -yl] carbonyl} amino)benzoate (250 mg, 0.53 mmol) and diethylamine (0.2 mL, 1.94 mmol) to give 150 mg ofthe title compound. H NMR (400 MHz, DMSO) 1.07 (t, 3H), 3.22 (q, 2H), 7.93 (dd, IH), 8.16 (m, 3H), 8.58 (t, IH), 8.69 (d, IH), 12.66 (s, IH). Example 6.48: 2-({[5-(benzylammosulfonyl)-l,2-berizisoxazol-3-yl]carbonyl}amino)- 5-bromobenzoic acid
Figure imgf000129_0001
Synthesized as above from methyl 5-bromo-2-({[5-(chlorosulfonyl)-l,2-benzisoxazol- 3 -yl] carbonyl} amino)benzoate (250 mg, 0.53 mmol) and benzylamine (0.2 mL,1.83 mmol) to give 131 mg ofthe title compound. H NMR (400 MHz, DMSO) 4.04 (d, 2H), 7.19 (m, 5H), 7.93 (dd, IH), 8.11 (d, IH), 8.17 (d, IH), 8.46 (t, IH), 8.58 (t, IH), 8.69 (d, IH), 12.66 (s, IH).
Example 6.49: 2-({[5-(ammosulfonyl)-l,2-berιzisoxazol-3-yl]carbonyl}amino)-5- bromobenzoic acid
Figure imgf000129_0002
Synthesized as above from methyl 5-bromo-2-({[5-(chlorosulfonyl)-l,2-benzisoxazol- 3 -yl] carbonyl} amino)benzoate (250 mg, 0.53 mmol) and ammonia (4.0 mL, 2.0 mmol) to give 220 mg ofthe title compound. H NMR (400 MHz, DMSO) 7.63 (s, 2H), 7.93 (dd, IH), 8.16 (m, 3H), 8.69 (dd, IH), 12.67 (s, IH).
Example 6.50: 2-( {[5-(methylaminosulfonyl)- 1 ,2-benzisoxazol-3-yl]carbonyl} arnino)- 5-bromobenzoic acid
Figure imgf000130_0001
Synthesized as above from methyl 5-bromo-2-({[5-(chlorosulfonyl)-l,2-benzisoxazol- 3 -yl] carbonyl} arnino)benzoate (250 mg, 0.53 mmol) and methylamine (5.0 mL, 10 mmol) to give 300 mg ofthe title compound. H NMR (400 MHz, DMSO) 2.45 (d, 3H), 7.75 (q, IH), 7.93 (dd, IH), 8.16 (m, 3H), 8.64 (d, IH), 8.69 (d, IH), 12.65 (s, IH).
Example 6.51: 2-({[5-(pyπolidin-l-ylsulfonyl)-l,2-benzisoxazol-3- yl]carbonyl}amino)-5-bromobenzoic acid
Figure imgf000130_0002
Synthesized as above from methyl 5-bromo-2-({[5-(chlorosulfonyl)-l,2-benzisoxazol- 3 -yl] carbonyl} amino)benzoate (250 mg, 0.53 mmol) and pyπolodine (.125 mL, 1.5 mmol) to give 260 mg ofthe title compound. H NMR (400 MHz, DMSO) 1.67 (m, 4H) 3.20 (m, 4H), 7.93 (dd, IH), 8.13 (dd, IH), 8.16 (d, IH), 8.19 (m, 2H), 8.58 (t, IH), 8.69 (d, IH), 12.67 (s, IH).
Example 6.52: 5-Cyano-2-({[6-(2-methylphenyl)-l,2-benzisoxazol-3- yl] carbonyl} amino)benzoic acid
Figure imgf000131_0001
Preparation Pa: Ethyl 6-(2-methylphenyl)benzoisoxazole-3-carboxylate.
Figure imgf000131_0002
A mixture of ethyl 6-bromobenzoisoxazole-3-carboxylate (550 mg, 1.39 mmol), o- tolylboronic acid (377 mg, 1.5 eq), Pd(PPh3)4 (171 mg, 0.08 eq), toluene (10 mL), ethanol (1.5 mL), and 1 M Na2CO3 (1.5 mL) is stiπed at reflux for 3.5 h. The reaction mixture is diluted with CH2C12 (0.1 L) and H2O (0.1 mL). The CH2C12 solution is dried (Na2SO ), filtered, and evaporated. The residue is purified by silica chromatography (heptane/EtOAc) to give Preparation Pa: 1H NMR (300 MHz, CDC13) δ 8.14 (IH), 7.61 (2H), 7.42 (IH), 7.35-7.2 (IH), 4.59 (2H), 2.28 (3H), 1.51 (3H).
A mixture of Preparation Pa (440 mg, 1.6 mmol) and 5-cyanoanthranilic acid (260 mg, 1.6 mmol) and 3 equiv of NaH (192 mg of 60%> NaH in mineral oil) in DMF (3 mL) at rt under N2 is stiπed overnight. The reaction mixture is added dropwise to 0.1 L of aq 1 N HCl. The precipitated solid is collected and washed with water, heptane and iPrOH. It is recrystallized from EtOH to give a white solid: 1H NMR (300 MHz, DMSO-de) δ8.94 (IH), 8.45 (IH), 8.28 (IH), 8.18 (IH), 7.91 (IH), 7.56 (IH), 7.40- 7.25 (4H) 2.24 (3H); MS (ESI-) m/z 396.22; Anal. C 69.19, H 3.85, N 10.64.
Example 6.53: 5-Cyano-2-({[6-(3,5-dimethylisoxazol-4-yl)-l,2-benzisoxazol-3- yl] carbonyl} amino)b enzoic acid
Figure imgf000132_0001
This example, prepared from ethyl 6-(3,5-dimethyl)-3-isoxazolecarboxylate and 1,1- dimethyl 5-cyanoanthranilate as described for Example 6.53, is isolated as a solid: 1H NMR (300 MHz, DMSO-de) δ 8.94 (IH), 8.42 (IH), 8.32 (IH), 8.20 (IH), 8.05 (IH), 7.63 (IH), 2.30 (6H); MS (ESI-) m/z 401.14; H2O 4.19% (0.98 equiv); Anal. C 59.89, H 3.86, N 13.27.
Example 6.54: 5-Cyano-2-[({5-[4-(morpholin-4-ylcarbonyl)phenyl]-l,2- benzisoxazol-3-yl}carbonyl)amino]benzoic acid
Figure imgf000132_0002
Preparation Pb:
Figure imgf000132_0003
1,1-Dimethylethyl 2-[(6-bromobenzoisoxazole-3-carbonyl)amino]-5-cy nobenzoate.
To a mixture of ethyl 6-bromobenzisoxazole-3-carboxylate (2.0 g, 7.4 mmol) and t- butyl 5-cyanoanthranilate (1.62 g, 7.4 mmol) in toluene (27 mL) is added NaH (1.5 g of a 60%) mineral oil dispersion, 3.8 mmol) under N2. The reaction mixture is stiπed overnight at rt. This mixture is diluted with aq 1 N HCl, extracted with EtOAc (0.2 L). The EtOAc solution is dried and concentrated to give Preparation Pb as a solid: 1H NMR (300 MHz, CDC13) δ 12.8 (IH), 9.05 (IH), 8.38 (IH), 8.18 (IH), 7.92 (IH), 7.82 (IH), 7.61 (IH), 1.69 (9H).
Preparation Pc:
1,1-Dimethylethyl 2-[(5-bromobenzoisoxazole-3-carbonyl)amino]-5-cyanobenzoate.
This Preparation is made from ethyl 5-bromobenzisoxazole-3-carboxylate and t-butyl 5- cyanoanthranilate by the procedure given for Preparation Pb.
Preparation Pd:
Figure imgf000133_0001
1,1-Dimethylethyl 5-cyano-2-({5-[4-(morpholin-4- carbonyl)phenyl]benzo[</]isoxazole-3-carbonyl}amino]benzoate. A mixture of Preparation Pc (615 mg, 1.39 mmol), 4-(moφholin-4-ylcarbonyl)phenylboronic acid (536 mg, 1.5 equiv), Pd(PPh3)4 (118 mg, 0.08 equiv), toluene (15 mL), EtOH (2 mL), and 1 M aq Na2CO3 (2 mL) is stiπed at reflux for 2.75 h. The reaction mixture is diluted with CH2C12. The reaction mixture is filtered through Celite. The CH2C12 solution is dried (Na2SO4), filtered, and evaporated. The residue is triturated with hot MeOH (50 mL). After cooling to rt a solid is collected by filtration. The solid is washed with MeOH and heptane, and dried to give Preparation Pd as an off-white solid: 1H NMR (300 MHz, DMSO-de) δ 8.85 (IH), 8.43 (IH), 8.39 (IH), 8.11 (IH), 8.09 (IH), 8.02 (IH), 7.81 (2H), 7.57 (2H), 3.8-3.4 (8H), 1.65 (9H).
This Example, made by TFA deprotection of Preparation Pd is isolated as a solid: 1H NMR (300 MHz, DMSO-ds) δ 12.97 (IH), 8.94 (IH), 8.41 (IH), 8.10 (6H), 7.80 (IH), 7.53 (IH), 3.7 (8H); MS (CI) m/z (rel intensity) 497; Anal. C 65.33, H 4.04, N 11.28.
Example 6.55: 2-({[5-(2-Acetylphenyl)-l,2-benzisoxazol-3-yl]carbonyl}amino)-5- cyanobenzoic acid
Preparation Pe:
Figure imgf000134_0002
1,1-Dimethylethyl 2-{[5-(2-acetylphenyl)benzo[<f|isoxazole-3-carbonyl]amino}-5- cyano-benzoate. This Preparation, made from Preparation Pc and 2- acetylphenylboronic acid by the procedure given for Preparation Pd, is isolated as a solid: 1H NMR (300 MHz, CDC13) δl2.86 (IH), 9.04 (IH), 8.49 (IH), 8.39 (IH), 7.82 (IH), 7.72 (IH), 7.67 (IH), 7.4-7.6 (4H), 2.19 (3H), 1.69 (9H).
This Example, made by TFA deprotection of Preparation Pe is isolated as solid: 1H NMR (300 MHz, DMSO-d*) δ 12.85 (IH), 8.95 (IH), 8.41 (IH), 8.15 (IH), 8.07 (IH), 7.99 (IH), 7.6 (5H), 2.25 (3H); MS (ESI-) m/z 424.25 (calcd [M-H]- 424.09); Anal. C 67.68, H 3.57, N 9.81.
Example 6.56: 5-Cyano-2-({[5-(2,5-dimethoxyphenyl)-l,2-benzisoxazol-3- yl] carb onyl} amino)b enzoic acid
Figure imgf000135_0001
Preparation Pf:
Figure imgf000135_0002
1,1-Dimethylethyl 5-cyano-2-{[5-(2,5-dimethoxyphenyl)benzo[</]isoxazole-3- carbonyl]-amino}benzoate. This Preparation, made from Preparation Pc and 2,5- dimethoxyphenylboronic acid by the procedure given for Preparation Pd, is isolated as a solid: lH NMR (300 MHz, CDC13) δ 12.83 (IH), 9.04 (IH), 8.51 (IH), 8.45 (IH), 7.8-7.9 (2H), 7.70 (IH), 6.85-7.0 (3H), 3.78 (3H), 3.82 (3H), 1.69 (9H).
This Example, made by TFA deprotection of Preparation Pf is isolated as solid: lH NMR (300 MHz, DMSO-dβ) 612.93 (IH), 8.92 (IH), 8.43 (IH), 8.35 (IH), 8.10 (IH), 7.95 (IH), 7.86 (IH), 7.10 (IH), 6.94 (IH), 3.75 (3H), 3.70 (3H); MS (ESI-) m/z 442.24; Anal. C 64.93, H 3.90, N 9.52.
Example 6.57: 5-Cyano-2-({[5-(2-methylphenyl)-l,2-benzisoxazol-3- yl] carb onyl} amino)b enzoic acid Preparation Pg:
Figure imgf000135_0003
1,1-Dimethylethyl 5-cyano-2-{[5-(2-methylphenyl)benzoisoxazol-3- yl] carbonyl] amino}-benzoate. This Preparation, made from Preparation Pc and 2- methylphenylboronic acid by the procedure given for Preparation Pd, is isolated as a solid: 1H NMR (300 MHz, CDC13) δl2.80 (IH), 9.03 (IH), 8.36 (IH), 8.24 (IH), 7.81 (IH), 7.72 (IH), 7.61 (IH), 7.2-7.35 (4H), 2.28 (3H), 1.66 (9H).
This Example, made by TFA deprotection of Preparation Pg is isolated as solid: MS (ESI-) m/z 396.23; MS (FAB+) m/z 397.1070; H2O 1.98% (0.45 equiv); Anal. C 68.96, H 3.86, N 10.52.
Example 6.58: 5-Cyano-2-[({5-[4-(methylsulfonyl)phenyl]-l,2-benzisoxazol-3- yl}carbonyl)amino]benzoic acid
Figure imgf000136_0001
Preparation Ph:
Figure imgf000136_0002
1,1-Dimethylethyl 5-cyano-2-{[5-(4-methylsulfonyl)phenyl]benzoisoxazol-3-yl}- carbonyl]-amino}benzoate. This Preparation, made from Preparation Pc and 4- methylsulfonyl-phenylboronic acid by the procedure given for Preparation Pd, is isolated as a solid: 1H NMR (300 MHz, DMSO-de) δ 8.82 (IH), 8.48 (IH), 8.40 (IH), 8.25-7.9 {IH), 3.32 (3H), 1.62 (9H).
This Example, made by TFA deprotection of Preparation Ph is isolated as solid: lH NMR (300 MHz, DMSO-ds) δl3.00 (IH), 8.92 (IH), 8.51 (IH), 8.45 (IH), 8.0-8.23 (7H), 3.32 (3H); MS (ESI-) m/z 460.24; MS (FAB+) m/z 461.0700; H2O 1.12% (0.31 equiv); Anal. C 58.74, H 3.56, N 8.96.
Example 6.59: 2-[({6-[3-(Acetylamino)phenyl]-l,2-benzisoxazol-3- yl}carbonyl)amino]-5-cyanobenzoic acid
Figure imgf000137_0001
Preparation Pi:
Figure imgf000137_0002
1,1-Dimethylethyl 2-{[6-(2-acetylaminophenyl)benzoisoxazol-3-yl]carbonyl]- amino}-5-cyanobenzoate. This Preparation, made from Preparation Pb and 2- acetylamino-phenylboronic acid by the procedure given for Preparation Pd, is isolated as a solid: 1H NMR (300 MHz, CDC13) δl2.82 (IH), 9.05 (IH), 8.35-8.4 (2H), 8.18 (IH), 7.84 (IH), 7.70 (IH), 7.55-7.40 (2H), 7.35-7.20 (2H), 7.05 (IH), 2.06 (3H), 1.70 (9H).
This Example, made by TFA deprotection of Preparation Pi is isolated as solid: 1H NMR (300 MHz, DMSO-de) δ 9.25 (IH), 8.82 (IH), 8.31 (IH), 8.15 (IH), 8.00 (IH), 7.80 (IH), 7.5-7.2 (4H), 1.75 (3H); MS (ESI-) m/z 439.10.
Example 6.60: 2-{[6-(3-Acetylaminophenyl)benzoisoxazole-3-carbonyl]amino}-5- cyano-benzoic acid.
Figure imgf000138_0001
Preparation Pj:
Figure imgf000138_0002
1 , 1 -Dimethylethyl 2- { [ 6-(3-acetylaminophenyl)b enzo [</] isoxazole-3-carb onyl] - amino}-5-cyanobenzoate. This Preparation, made from Preparation Pb and 3- acetamido-phenylboronic acid by the procedure given for Preparation Pd, is isolated as a solid: 1H NMR (300 MHz, CDC13) δ 12.9 (IH), 9.10 (IH), 8.38 (IH), 8.32 (2H), 7.95 (IH), 7.9-7.8 (2H), 7.72 (IH), 7.5-7.4 (3H), 2.25 (3H), 1.72 (9H).
This Example, made by TFA deprotection of Preparation Pj is isolated as solid: lH NMR (300 MHz, DMSO-de) δ 9.95 (IH), 8.78 (IH), 8.31 (IH), 8.15 (IH), 8.05 (2H), 7.90 (IH), 7.70 (IH), 7.54 (IH), 7.4-7.3 (2H), 1.93 (3H); MS (ESI-) m/z 439.09.
Example 6.61: 2-[({5-[2-(Acetylamino)phenyl]-l,2-benzisoxazol-3- yl}carbonyl)amino]-5-cyanobenzoic acid
Figure imgf000138_0003
Preparation Pk:
1 , 1 -Dimethylethyl 2-[( {5-[2-(acetylamino)phenyl]- 1 ,2-benzisoxazol-3- yl}carbonyl)amino]-5-cyanobenzoate. This Preparation, made from Preparation Pc and 2-acetylaminophenylboronic acid by the procedure as given for Preparation Pd, is isolated as a solid.
This Example, made by TFA deprotection of Preparation Pk is isolated as solid: lH NMR (300 MHz, DMSO-dδ) δl2.89 (IH), 9.36 (IH), 8.87 (IH), 8.41 (IH), 8.15 (IH), 8.11 (IH), 7.97 (IH), 7.72 (IH), 7.5-7.25 (4H), 1.9 (3H).
Example 6.62: 2-[({5-[3-(Acetylamino)phenyl]-l,2-benzisoxazol-3- yl}carbonyl)amino]-5-cyanobenzoic acid
Figure imgf000139_0001
Preparation PI:
1 , 1 -Dimethylethyl 2-[( {5-[3-(acetylamino)phenyl]- 1 ,2-benzisoxazol-3- yl}carbonyl)amino]-5-cyanobenzoate. This Preparation, made from Preparation Pc and 3-acetylaminophenylboronic acid by the procedure given for Preparation Pd, is isolated as a solid.
This Example, made by TFA deprotection of Preparation PI is isolated as solid: 1H NMR (300 MHz, DMSO-d*) δl2.95 (IH), 10.12 (IH), 8.91 (IH), 8.49 (IH), 8.39 (IH), 8.19 (IH), 8.1-7.9 (2H), 7.67 (IH), 7.72 (IH), 7.5-7.4 (2H), 2.08 (3H).
Example 6.63: Benzyl 5-cyano-2-({[5-(pyrrolidin-l-ylsulfonyl)-l,2-benzisoxazol- 3-yl] carbonyl} amino)benzoate
Figure imgf000140_0001
Preparation of 5-(ChlorosulfonyI)-l,2-benzisoxazole-3-carboxylic acid
Figure imgf000140_0002
Ethyl l,2-benzisoxazole-3-carboxylate (586 mg, 3.1 mmol) was dissolved in chlorosulfonic acid (10 mL, Aldrich) under N2 and heated to 80 °C for 15 hours. The dark brown solution was carefully poured into a flask with crushed ice. The resultant tan precipitate was collected by vacuum filtration and washed thoroughly with water. Air-drying yielded 382 mg (49%) of a tan solid. 1H NMR (400 MHz, DMSO-ci6) δ ppm 7.83 (d, J=8.71 Hz, 1 H) 7.96 (dd, J=8.71, 1.66 Hz, 1 H) 8.32 (d, J=1.66 Hz, 1 H) 14.23 (s, 1 H); 13C NMR (100 MHz, DMSO-c?6) δ ppm 109.61, 118.89, 119.99, 129.17, 145.98, 151.49, 160.70, 163.42.
Preparation of terf-Butyl 2-({[5-(chlorosulfonyl)-l,2-benzisoxazol-3- yl]carbonyl}amino)-5-cyanobenzoate
Figure imgf000140_0003
5-(Chlorosulfonyl)-l,2-benzisoxazole-3-carboxylic acid (346 mg, 1.32 mmol) was dissolved in dry CH2C12 (10 mL) under N2 and treated with DMF (50 μL) followed by oxalyl chloride (0.231 mL, 2.64 mmol). Gas was evolved, and the mixture was stirred for 1 hour. The solvent and excess oxalyl chloride were evaporated, and the residue was combined with tert-butyl 2-amino-5-cyanobenzoate (218 mg, 1.00 mmol) in 15 mL of dry CH2C12. The solution was refluxed for 30 minutes and then diluted to 100 mL with CH2C12. The organic solution was washed with 1.0 M HCl, with water, and with brine (75 mL each). The organic layer was dried over Na2SO , filtered, and evaporated. The crude product was purified on a Biotage Flash 40M+ silica cartridge using 95%> CH2C12 in heptane. Evaporation of solvent from the product fractions followed by drying under high vacuum afforded 162 mg (35%) of an off-white solid. 1H NMR (400 MHz, CDC13) δ ppm 1.68 (s, 9 H) 7.88 (dd, J=8.81, 1.97 Hz, 1 H) 7.94 (d, J=9.12 Hz, 1 H) 8.34 (dd, J=9.02, 1.97 Hz, 1 H) 8.38 (d, J=1.87 Hz, 1 H) 9.03 (d, J=8.91 Hz, 1 H) 9.10 (d, J=1.87 Hz, 1 H) 12.98 (s, 1 H); 13C NMR (100 MHz, CDC13) δ ppm 28.13, 84.80, 107.30, 111.88, 117.90, 118.09, 120.49, 121.24, 125.27, 129.02, 135.70, 137.15, 141.75, 143.39, 152.76, 156.86, 165.75, 166.19.
Preparation of Benzyl 2-({[5-(chlorosulfonyl)-l,2-benzisoxazol-3- yl]carbonyl}amino)-5-cyanobenzoate
Figure imgf000141_0001
5-(Chlorosulfonyl)-l,2-benzisoxazole-3-carboxylic acid (1.25 g, 4.78 mmol) was dissolved in dry CH2C12 (15 mL) under N2 and treated with DMF (50 μL) followed by oxalyl chloride (0.83 mL, 9.56 mmol). Gas was evolved, and the mixture was stiπed for 1 hour. The solvent and excess oxalyl chloride were evaporated, and the residue was combined with benzyl 2-amino-5-cyanobenzoate (1.13 g, 4.48 mmol) in 15 mL of dry CH2C12. The solution was refluxed for 20 minutes and then stiπed at room temperature overnight. The reaction mixture was diluted with CH2C12 and filtered through a plug of silica. Evaporation ofthe solvent followed by drying under high vacuum afforded 1.87 g (84%) of a pale yellow solid. 1H NMR (400 MHz, CDC13) δ ppm 5.49 (s, 2 H) 7.46 (m, 5 H) 7.91 (dd, J=8.81, 1.97 Hz, 1 H) 7.95 (d, J=8.91 Hz, 1 H) 8.34 (dd, J=9.02, 1.97 Hz, 1 H) 8.47 (d, J=1.87 Hz, 1 H) 9.06 (d, J=8.71 Hz, 1 H) 9.10 (d, J=1.45 Hz, 1 H) 12.90 (s, 1 H). 13C NMR (100 MHz, OMSO-d6) δ ppm 67.47, 106.41, 109.81, 117.61, 117.88, 118.47, 119.99, 121.46, 128.31, 128.38, 128.55, 129.60, 135.14, 135.22, 138.02, 142.73, 146.32, 152.22, 157.54, 163.71, 165.72.
Benzyl 2-({[5-(chlorosulfonyl)-l,2-benzisoxazol-3-yl]carbonyl}amino)-5- cyanobenzoate (410 mg, 0.83 mmol) was dissolved in dry CH2C12 (10 mL) and treated with pyπolidine (0.145 mL, 1.74 mmol, Aldrich) resulting in a cream colored precipitate. After 15 minutes, the reaction mixture was diluted to 200 mL with CH2C12 and washed 2x with 1.0 M HCl and lx with brine (175 mL each). The golden organic solution was dried over Na2SO and filtered. Evaporation ofthe solvent followed by drying under high vacuum afforded 432 mg (98%) of white solid. 1H NMR (400 MHz, DMSO- d6) δ ppm 2.50 (m, 4 H) 3.20 (m, 4 H) 5.45 (s, 2 H) 7.38 (m, 3 H) 7.52 (d, J=6.63 Hz, 2 H) 8.21 (m, 3 H) 8.49 (d, J=1.87 Hz, 1 H) 8.56 (s, 1 H) 8.76 (d, J=8.92 Hz, 1 H) 12.43 (s, 1 H). 13C NMR (100 MHz, DMSO- 6 CDC13) δ ppm 24.64, 47.51, 67.52, 106.62, 110.76, 115.93, 117.09, 119.54, 120.75, 123.48, 128.00, 128.23, 128.28, 129.20, 134.02, 134.27, 134.87, 137.21, 142.96, 151.81, 156.69, 165.01, 165.56. IR (diffuse reflectance) 2498 (w), 2470 (w), 2395 (w), 2351 (w), 2230, 1709 (s), 1583 (s), 1519 (s), 1348 (s), 1316, 1294, 1268 (s), 1236 (s),
1199, 741, cm-1. Anal. Calc. for C27H22N4O6S: C, 61.12; H, 4.18; N, 10.56; S, 6.04. Found: C, 61.00; H, 4.31; N, 10.54.
Example 6.64: 5-Cyano-2-({[5-(pyrrolidin-l-ylsulfonyl)-l,2-benzisoxazol-3- yl] carbonyl} amino)benzoic acid
Figure imgf000142_0001
To a mixture of benzyl 5-cyano-2-({[5-(pyπolidin-l-ylsulfonyl)-l,2-benzisoxazol-3- yl] carbonyl} amino)benzoate (336 mg, 0.63 mmol) and 10% palladium on carbon (84 mg, Aldrich) was added dry, inhibitor-free THF (15 mL). The mixture was placed under 1 ATM of H2, and the reaction was stiπed vigorously for 15 minutes. The reaction was filtered through powdered cellulose to remove the catalyst, and the solvent was evaporated. The crude product was re-crystallized from hot EtOH/THF and dried under high vacuum to afford 189 mg (68%) of white, crystalline solid. 1H NMR (400 MHz, DMSO- d6) δ ppm 1.67 (m, 4 H) 3.21 (m, 4 H) 8.17 (dd, J=8.71, 2.07 Hz, 1 H) 8.20 (m, 2 H) 8.44 (d, J=2.07 Hz, 1 H) 8.57 (s, 1 H) 8.88 (d, J=8.91 Hz, 1 H) 12.95 (s, 1 H).
Example 6.65: 5-Cyano-2-[({5-[(dipropylamino)sulfonyl]-l,2-benzisoxazol-3- yl}carbonyl)amino]benzoic acid
Figure imgf000143_0001
tert-Butyl 5-cyano-2-[( {5-[(dipropylamino)sulfonyl]- 1 ,2-benzisoxazol-3- yl}carbonyl)amino]benzoate (249 mg, 0.47 mmol) was dissolved in CH2C12 (10 mL) and treated with TFA (10 mL, Aldrich). After 3 hours, the solvent and excess TFA were evaporated, and the product was dried under vacuum at 100 °C overnight to afford 182 mg (quantitative) of off-white solid. 1H NMR (400 MHz, DMSO- d6) δ ppm 0.82 (t, J=7.36 Hz, 6 H) 1.50 (septet, J=7.41 Hz, 4 H) 3.09 (t, J=7.46 Hz, 4 H) 8.18 (m, 3 H) 8.44 (d, J=2.07 Hz, 1 H) 8.57 (s, 1 H) 8.89 (d, J=8.71 Hz, 1 H) 12.96 (s, 1 H).
Example 6.66: 2-({[5-(Anilinosulfonyl)-l,2-benzisoxazol-3-yl]carbonyl}amino)-5-cyanobenzoic acid
Figure imgf000144_0001
Preparation of tert-Butyl 2-({[5-(anilinosulfonyl)-l,2-benzisoxazol-3- yl] carbonyl} amino)-5-cyanobenzoate
Figure imgf000144_0002
Prepared from aniline and tert-butyl 2-( {[5-(chlorosulfonyl)- 1 ,2-benzisoxazol-3- yl]carbonyl}amino)-5-cyanobenzoate in 49%> yield according to the general procedure except that CH2C12 was replaced by pyridine as the solvent. 1H NMR (400 MHz, OMSO-d6) δ ppm 1.59 (s, 9 H) 7.04 (t, J=7.26 Hz, 1 H) 7.11 (d, J=7.46 Hz, 2 H) 7.23 (t, J=7.88 Hz, 2 H) 8.09 (dd, J=8.91, 1.66 Hz, 1 H) 8.14 (d, J=9.12 Hz, 1 H) 8.17 (dd, J=8.91, 1.87 Hz, 1 H) 8.40 (d, J=2.07 Hz, 1 H) 8.62 (d, J=1.24 Hz, 1 H) 8.73 (d, J=8.71 Hz, 1 H) 10.53 (s, 1 H) 12.42 (s, 1 H); 13C NMR (100 MHz, DMSO-^) δ ppm 27.64, 83.97, 106.50, 111.84, 117.92, 119.22, 119.59, 120.50, 121.49, 123.14, 124.56, 129.30, 135.31, 137.17, 137.21, 137.50, 142.32, 152.36, 156.99, 164.84, 165.18; IR (diffuse reflectance) 2351 (w), 2309 (w), 2227, 2176 (w), 2113 (w), 1698, 1599, 1519 (s), 1498, 1330, 1295, 1276, 1259, 1161 (s), 1150 (s), cm"1; HRMS (FAB) Calc. for C26H22N4O6S+H 519.1338, found 519.1323.
Prepared from the t-butyl ester in 40% yield according to general procedure. 1H NMR (400 MHz, DMSO- ) δ ppm 7.04 (t, J=7.26 Hz, 1 H) 7.12 (d, J=7.46 Hz, 2 H) 7.24 (t, J=7.88 Hz, 2 H) 8.08 (dd, J=8.91, 1.66 Hz, 1 H) 8.12 (t, J=9.23 Hz, 1 H) 8.17 (dd, J=8.92, 2.07 Hz, 1 H) 8.44 (d, J=2.07 Hz, 1 H) 8.63 (d, J=1.04 Hz, 1 H) 8.86 (d, J=8.91 Hz, 1 H) 10.53 (s, 1 H) 12.93 (s, 1 H). Example 6.67: 5-Cyano-2- [({5- [(diethylamino)sulfonyl] -1 ,2-benzisoxazol-3- yl}carbonyl)amino]benzoic acid
Figure imgf000145_0001
Preparation of Benzyl 5-cyano-2-[({5-[(diethylamino)sulfonyl]-l,2-benzisoxazol- 3-yl}carbonyl)amino]benzoate
Figure imgf000145_0002
Prepared from diethylamine and benzyl 2-({[5-(chlorosulfonyl)-l,2-benzisoxazol-3- yl]carbonyl}amino)-5-cyanobenzoate in 44%> yield according to the general procedure. 1H NMR (400 MHz, DMSO-^) δ ppm 1.07 (t, J=7.05 Hz, 6 H) 3.23 (q, J=7.19 Hz, 4 H) 5.44 (s, 2 H) 7.35 (m, 3 H) 7.51 (d, J=1.24 Hz, 1 H) 7.53 (d, J=1.66 Hz, 1 H) 8.19 (d, J=1.04 Hz, 2 H) 8.22 (d, J=2.07 Hz, 1 H) 8.49 (d, J=2.07 Hz, 1 H) 8.56 (s, 1 H) 8.75 (d, J=8.71 Hz, 1 H) 12.42 (s, 1 H); 13C NMR (100 MHz, DMSO-tk) δ ppm 14.12, 41.94, 67.46, 106.72, 112.02, 117.78, 118.00, 119.63, 121.66, 122.79, 128.26, 128.34, 128.49, 129.47, 135.14, 137.54, 137.94, 142.37, 152.37, 157.07, 164.83, 165.69; IR (diffuse reflectance) 2394 (w), 2351 (w), 2328 (w), 2271 (w), 2232, 1705 (s), 1590 (s), 1525 (s), 1346 (s), 1330, 1315, 1297 (s), 1272 (s), 1199 (s), 1153 (s), cm"1; HRMS (ESI) Calc. for C^H^H sS+H 533.1495, found 533.1492. Anal. Calc. for C27 H24 N4 O6 S: C, 60.89; H, 4.54; N, 10.52; S, 6.02. Found: C, 60.92; H, 4.67; N, 10.43. The benzyl ester was converted to the acid according to the general procedure. lH NMR (400 MHz, DMSO- 6) δ ppm 1.08 (t, J=7.15 Hz, 6 H) 3.23 (q, J=7.05 Hz, 4 H) 8.18 (m, 3 H) 8.44 (d, J=2.07 Hz, 1 H) 8.58 (s, 1 H) 8.88 (d, J=8.71 Hz, 1 H) 12.95
(s, 1 H). >
Example 6.68: 5-Cyano-2-({[5-(morpholin-4-ylsulfonyl)-l,2-benzisoxazol-3- yl] carb onyl} amino)b enzoic acid
Figure imgf000146_0001
Preparation of tert-Butyl 5-cyano-2-({[5-(morpholin-4-ylsulfonyl)-l,2- benzisoxazol-3-yl]carbonyl}amino)benzoate
Figure imgf000146_0002
Prepared from moφholine and tert-butyl 2-({[5-(chlorosulfonyl)-l,2-benzisoxazol-3- yl]carbonyl}amino)-5-cyanobenzoate in 90% yield according to the general procedure. 1H NMR (400 MHz, CDC13) δ ppm 1.67 (s, 9 H) 3.06 (m, 4 H) 3.76 (m, 4 H) 7.85 5 (dd, J=8.91, 2.07 Hz, 2 H) 8.04 (dd, J=8.92, 1.87 Hz, 1 H) 8.36 (d, J=1.87 Hz, 1 H) 8.77 (d, J=1.04 Hz, 1 H) 9.01 (d, J=8.91 Hz, 1 H) 12.93 (s, 1 H).
The t-butyl ester was converted to the acid according to the general procedure. 1H NMR (400 MHz, DMSO- d6) δ ppm 2.95 (m, 4 H) 3.65 (m, 4 H) 8.11 (dd, J=8.92, 0 1.87 Hz, 1 H) 8.17 (dd, J=8.81, 1.97 Hz, 1 H) 8.23 (d, J=8.71 Hz, 1 H) 8.45 (d, J=2.07 Hz, 1 H) 8.53 (d, J=1.24 Hz, 1 H) 8.88 (d, J=8.71 Hz, 1 H) 12.96 (s, 1 H). Example 6.69: 5-Cyano-2-[({5-[(dimethylamino)sulfonyl]-l,2-benzisoxazol-3- yl}carbonyl)amino]benzoic acid
Figure imgf000147_0001
Preparation oftert-Butyl 5-cvano-2-[((5-[(dimethvIammo)suIfonyll-l,2- benzisoxazol-3-vI.carbonvDaminolbenzoate
Figure imgf000147_0002
Prepared from dimethylamine and tert-butyl 2-({[5-(chlorosulfonyl)-l,2-benzisoxazol- 3-yl]carbonyl}amino)-5-cyanobenzoate in 76%> yield according to the general procedure except that CH2C12 was replaced by THF as the solvent. 1H NMR (400 MHz, CDC13) δ ppm 1.68 (s, 9 H) 2.79 (s, 6 H) 7.85 (dd, J=8.81, 0.73 Hz, 1 H) 7.86 (dd, J=8.81, 1.97 Hz, 1 H) 8.09 (dd, J=8.81, 1.76 Hz, 1 H) 8.37 (d, J=2.07 Hz, 1 H) 8.80 (d, J=1.24 Hz, 1 H) 9.03 (d, J=8.91 Hz, 1 H) 12.92 (s, 1 H).
The t-butyl ester was converted to the acid according to the general procedure. 1H NMR (400 MHz, DMSO- tf) δ ppm 2.68 (s, 6 H) 8.14 (dd, J=8.91, 1.66 Hz, 1 H) 8.17 (dd, J=8.92, 2.07 Hz, 1 H) 8.22 (d, J=8.71 Hz, 1 H) 8.45 (d, J=2.07 Hz, 1 H) 8.54 (d, J=1.24 Hz, 1 H) 8.88 (d, J=8.71 Hz, 1 H) 12.94 (s, 1 H). Example 6.70:
Figure imgf000148_0001
ϊ:ert-Butyl 5-cyano-2-[({5-[(dipropylamino)sulfonyl]-l,2-benzisoxazol-3- yl}carbonyl)amino]benzoate Prepared from dipropylamine and tert-butyl 2-({[5-(chlorosulfonyl)-l,2-benzisoxazol- 3-yl]carbonyl}amino)-5-cyanobenzoate according to the general procedure. 1H NMR (400 MHz, DMSO- d6) δ ppm 0.82 (t, J=7.36 Hz, 6 H) 1.50 (septet, J=7.26 Hz, 4 H) 1.61 (s, 9 H) 3.09 (t, J=7.46 Hz, 4 H) 8.19 (m, 3 H) 8.40 (d, J=2.07 Hz, 1 H) 8.56 (s, 1 H) 8.73 (d, J=8.71 Hz, 1 H) 12.44 (s, 1 H); 13C NMR (100 MHz, DMSO-d6) δ ppm 10.98, 21.61, 27.64, 49.65, 83.94, 106.56, 111.99, 117.91, 119.40, 119.65, 121.62, 122.83, 129.55, 135.27, 137.30, 137.47, 142.24, 152.48, 157.07, 164.80, 165.18; IR (diffuse reflectance) 2403 (w), 2292 (w), 2232, 2182 (w), 1926 (w), 1705, 1585, 1520 (s), 1350, 1330, 1295, 1278, 1155 (s), 820, 610, cm"1; Anal. Calc. for C26 H30 N4 O6 S: C, 59.30; H, 5.74; N, 10.64; S, 6.09. Found: C, 59.21; H, 5.78; N, 10.52.
Example 6.71: 2-[({5-[(5-Chloro-2,3-dihydro-lH-indol-l-yl)sulfonyl]-l,2- benzisoxazol-3-yl}carbonyl)amino]-5-cyanobenzoic acid
Figure imgf000148_0002
Preparation of
Figure imgf000149_0001
tgrt-Butyl 2-f(f5-[(5-chloro-2.3-d vdro-lH-indol-l-vπsulfonyll-1.2-benzisoxazol- 3-yllcarbonvDaminol-5-cvanobenzoate Prepared from 5-chloroindoline and tert-butyl 2-( { [5-(chlorosulfonyl)- 1 ,2- benzisoxazol-3-yl]carbonyl}amino)-5-cyanobenzoate in 45%> yield according to the general procedure. 1H NMR (DMSO-rfβ) δ ppm 1.60 (s, 9 H) 2.92 (t, J=8.40 Hz, 2 H) 3.99 (t, J=8.50 Hz, 2 H) 7.24 (d, J=1.87 Hz, 1 H) 7.29 (dd, J=8.50, 2.28 Hz, 1 H) 7.53 (d, J=8.50 Hz, 1 H) 8.16 (br s, 2 H) 8.17 (dd, J=8.71, 2.07 Hz, 1 H) 8.40 (d, J=2.07 Hz, 1 H) 8.60 (br s, 1 H) 8.73 (d, J=8.71 Hz, 1 H) 12.42 (s, 1 H).
The t-butyl ester was converted to the acid according to the general procedure. 1H NMR {OMSO-d6) δ ppm 2.92 (t, J=8.40 Hz, 2 H) 3.99 (t, J=8.40 Hz, 2 H) 7.24 (s, 1 H) 7.30 (dd, J=8.60, 2.18 Hz, 1 H) 7.54 (d, J=8.71 Hz, 1 H) 8.15 (br d, 2 H) 8.17 (dd, J=8.91, 2.07 Hz, 1 H) 8.44 (d, J=2.07 Hz, 1 H) 8.61 (s, 1 H) 8.87 (d, J=8.71 Hz, 1 H) 12.95 (s, 1 H)
Example 6.72: N,N-Diethylammonium 5-cyano-2-[({5-[(methylamino)sulfonyl]- l,2-benzisoxazol-3-yl}carbonyl)amino]benzoate
Figure imgf000149_0002
Preparation of
Figure imgf000150_0001
tgrt-Butyl 5-cvano-2-K(5-lfmethylamino)sulfonyll-l,2-benzisoxazol-3- yllcarbonvflaminolbenzoate Prepared from methylamine and tert-butyl 2-({[5- (chlorosulfonyl)-l,2-benzisoxazol-3-yl]carbonyl}amino)-5-cyanobenzoate in 99% yield according to the general procedure except that CH2C12 was replaced by THF as the solvent. Product was used without purification due to very poor solubility in organic solvents. 1H NMR (DMSO- 6) δ ppm 1.60 (s, 9 H) 2.44 (d, J=4.98 Hz, 3 H) 7.75 (q, J=4.98 Hz, 1 H) 8.16 (m, 3 H) 8.41 (d, J=2.07 Hz, 1 H) 8.61 (d, J=1.04 Hz, 1 H) 8.76 (d, J=8.92 Hz, 1 H) 12.46 (s, 1 H).
tert-Butyl 5-cyano-2-[( {5-[(methylamino)sulfonyl]-l ,2-benzisoxazol-3- yl}carbonyl)amino]benzoate (225 mg, 0.49 mmol) was dissolved in CH2C12 (10 mL) and treated with TFA (10 mL, Aldrich). A pinkish precipitate formed. After stirring overnight, the solvent and excess TFA were evaporated, and the residue was triturated in CH3OH. The product was impure but would not dissolve for purification, so it was heated at 80 °C in a sealed tube with a mixture of diethylamine and THF to form the salt. The solvent was evaporated, and the crude salt was re-crystallized from a hot mixture of EtOH and 1,2-DCE. The crystals were washed with CH3OH followed by heptane and then dried several days under vacuum at 100 °C to afford 64 mg (28%) of tan solid. 1H NMR (DMSO--i_τ) δ ppm 1.18 (t, J=7.26 Hz, 6 H) 2.45 (d, J=4.98 Hz, 3 H) 2.94 (br s, 4 H) 7.73 (q, J=4.77 Hz, 1 H) 7.92 (dd, J=8.50, 2.07 Hz, 1 H) 8.12 (dd, J=8.91, 1.87 Hz, 1 H) 8.17 (d, J=8.91 Hz, 1 H) 8.37 (d, J=2.07 Hz, 1 H) 8.43 (br s, 2 H) 8.65 (d, J=1.66 Hz, 1 H) 8.81 (d, J=8.71 Hz, 1 H).
Example 6.73: 2-{[(5-{[Bis(2-hydroxyethyl)amino]sulfonyl}-l,2-benzisoxazol-3- yl)carbonyl] amino}-5-cyanobenzoic acid
Figure imgf000151_0001
Preparation of
Figure imgf000151_0002
Benzyl 2-{[(5-{[bis(2-hydroxyethyl)amino]sulfonyl}-l,2-benzisoxazol-3- yl)carbonyl]amino}-5-cyanobenzoate Prepared from diethanolamine and benzyl 2- ({[5-(chlorosulfonyl)-l,2-benzisoxazol-3-yl]carbonyl}amino)-5-cyanobenzoate in 49% yield according to the general procedure except that triethylamine (1.1 eq) was added. 1H NMR (400 MHz, OMSO-d6) δ ppm 3.24 (t, J=6.32 Hz, 4 H) 3.53 (br s, 4 H) 4.84 (s, 2 H) 5.45 (s, 2 H) 7.36 (m, 3 H) 7.52 (d, J=6.63 Hz, 2 H) 8.20 (m, 3 H) 8.49 (d, J=2.07 Hz, 1 H) 8.58 (s, 1 H) 8.76 (d, J=8.92 Hz, 1 H) 12.43 (s, 1 H).
The benzyl ester was converted to the acid according to the general procedure.
1H NMR (400 MHz, DMSO- d6) δ ppm 3.24 (t, J=6.32 Hz, 4 H) 3.54 (t, J=6.22 Hz, 4
H) 4.86 (s, 2 H) 8.18 (m, 3 H) 8.45 (d, J=2.07 Hz, 1 H) 8.61 (s, 1 H) 8.89 (d, J=8.91 Hz, I H) 13.16 (s, 1 H); 13C NMR (100 MHz, DMSO- ή) δ ppm 50.82, 59.63, 106.11, 111.85, 118.00, 118.32, 119.61, 120.69, 123.16, 129.65, 135.51, 137.00, 137.54, 143.14, 152.61, 157.07, 164.88, 168.01; IR (diffuse reflectance) 2250, 2250, 2227 (w), 2198 (w), 1965 (w), 1915 (w), 1704, 1591, 1520 (s), 1339, 1297, 1179, 1150 (s), 987, 731, cm"1; Anal. Calc. for C20 His N4 O8 S: C, 50.63; H, 3.82; N, 11.81; S, 6.76. Found: C, 50.50; H, 3.76; N, 11.75. Example 6.74 : 5-Cyano-2- [({5-nitro-6- [4-nitro-2-(trifluoromethyl)phenyl] -1 ,2- benzisoxazol-3-yl} carb onyl)amino] b enzoic acid
Figure imgf000152_0001
Preparation of
Figure imgf000152_0002
Ethyl (4-bromo-2-fluorophenyl)(hydroxy)acetate Trimethylsilyl cyanide (15.1 mL, 113 mmol, Aldrich) was added to a solution of DABCO (0.40 g, 3.6 mmol, Fluka) and 4-bromo-2-fluorobenzaldehyde (23.1 g, 114 mmol, Fluka) in CH2C12 (350 mL) with cooling in an ice bath. The reaction mixture was stiπed at 0 °C for 30 minutes and then at room temperature for 2 hours. The mixture was washed with water (2 X 200 mL) and brine (200 mL), dried over Na2SO , and evaporated leaving the silylated cyanohydrin as 34.4 g of cloudy oil. This material was treated with water (25 mL) and concentrated HCl (75 mL) and then heated at reflux for 1.7 hours. The mixture was diluted with water (300 mL) and made basic with 6 M NaOH. This solution was washed with CH2C12 (2 X 250 mL) and then acidified with concentrated HCl. The carboxylic acid was extracted into CH2C12 (2 X 250 mL). The CH2C12 was dried over Na2SO and evaporated yielding 21.3 g of white solid. This carboxylic acid (20.1 g) was dissolved in DMF (300 mL). Cesium carbonate (27.7 g, 85.0 mmol, Aldrich) and iodoethane (6.25 mL, 78.1 mmol, Aldrich) were added, and the reaction was stiπed at room temperature for 3 hours and then at 60 °C for 2.5 hours. The mixture was diluted with MTBE (1 L) and washed with water (500 mL), saturated NaHCO3 (500 mL), water (2 X 500 mL), and brine (500 mL). The organics were dried over Na2SO , filtered through a 1" plug of silica gel, and evaporated yielding the ethyl ester as 19.8 g of off-white solid. 1H NMR (400 MHz, DMSO-- 19F decoupled) δ ppm 1.13 (t, J=7.15 Hz, 3 H) 4.10 (m, 2 H) 5.29 (d, J=5.60 Hz, 1 H) 6.32 (d, J=5.60 Hz, 1 H) 7.44 (m, 2 H) 7.56 (d, J=1.45 Hz, 1 H).
Preparation of
Figure imgf000153_0001
Ethyl (4-bromo-2-fluorophenyl)(oxo)acetate Acetic anhydride (10 mL, 110 mmol) was added dropwise to a solution of ethyl (4-bromo-2-fluorophenyl)(hydroxy)acetate (18.5 g, 66.8 mmol) in DMSO (50 mL) at 100 °C. Heat was removed after 2.3 hours. The mixture was diluted with MTBE (250 mL) and washed with brine (3 X 250 mL). The organics were filtered through a 1" plug of silica gel and evaporated leaving a golden oil. This material was purified on a Biotage Flash 75M silica gel cartridge using 50% CH2C12 in heptane as eluent. Yield was 17.0 g of golden oil. 1H NMR (400 MHz, DMSO-- 19F decoupled) δ ppm 1.31 (t, J=7.05 Hz, 3 H) 4.39 (q, J=7.19 Hz, 2 H) 7.69 (dd, J=8.29, 1.66 Hz, 1 H) 7.85 (d, J=8.29 Hz, 1 H) 7.89 (d, J=1.66 Hz, I H).
Preparation of
Figure imgf000153_0002
Ethyl (4-bromo-2-fluorophenyl)(hydroxyimino)ethanoate Hydroxylamine hydrochloride (4.77 g, 68.6 mmol, Mallinckrodt) and sodium acetate (6.11 g, 74.5 mmol) were added to a solution of ethyl (4-bromo-2-fluorophenyl)(oxo)acetate (15.8 g, 57.5 mmol) in ethanol (45 mL), and the mixture was stiπed at room temperature overnight. After removal ofthe ethanol by rotary evaporation, the residue was dissolved in ethyl acetate (250 mL). This solution was washed with water (250 mL), brine (250 mL), and saturated NaHCO3 (2 X 250 mL). The organics were dried over Na2SO and evaporated yielding 15.9 g of white solid (mixture of 2 oxime isomers). 1H NMR (400 MHz, DMSO-- 19F decoupled, major isomer) δ ppm 1.24 (t, J=7.26 Hz, 3 H) 4.23 (q, J=7.12 Hz, 2 H) 7.36 (d, J=8.29 Hz, 1 H) 7.50 (dd, J=8.19, 1.76 Hz, 1 H) 7.66 (d, J=1.66 Hz, 1 H) 12.93 (s, 1 H).
Preparation of
Figure imgf000154_0001
Ethyl 6-bromo-l,2-benzisoxazole-3-carboxylate Potassium carbonate (10.5 g, 76.0 mmol) was added to a solution of ethyl (4-bromo-2- fluorophenyl)(hydroxyimino)ethanoate (15.4 g, 53.0 mmol, mixture of isomers) in DMSO (50 mL) at 75 °C. Heat was removed after 5 hours, and the mixture was diluted with water (300 mL). Product was extracted into CH2C12 (2 X 250 mL). The combined CH2C12 was washed with water (250 mL) and brine (250 mL). The organics were filtered through a 1" plug of silica gel and evaporated leaving a white solid. This material was purified on a Biotage Flash 75 M silica gel cartridge using 50% CH2C12 in heptane as eluent. Yield was 11.2 g of white solid.
1H NMR (400 MHz, DMSO-^) δ ppm 1.40 (t, J=7.15 Hz, 3 H) 4.49 (q, J=7.05 Hz, 2 H) 7.73 (dd, J=8.50, 1.45 Hz, 1 H) 8.00 (d, J=8.50 Hz, 1 H) 8.33 (d, J=1.66 Hz, 1 H).
Preparation of
Figure imgf000154_0002
Ethyl 6-[2-(trifluoromethyl)phenyl]-l,2-benzisoxazole-3-carboxylate Toluene (40 mL) was added to a flask containing ethyl 6-bromo-l,2-benzisoxazole-3-carboxylate
(3.15 g, 11.7 mmol), tetrakis(triphenylphosphine)palladium(0) (835 mg, 0.723 mmol,
Strem), cesium carbonate (4.12 g, 12.6 mmol, Aldrich), and 2- (trifluoromethyl)phenylboronic acid (2.38 g, 12.5 mmol, Aldrich) under argon. This mixture was heated in a 100 °C oil bath for 35 hours. The mixture was diluted with
EtOAc (250 mL) and washed with 4: 1 waterbrine (250 mL) followed by brine (250 mL). The organics were filtered through a 1" plug of silica gel and evaporated.
Product was split in two, adsorbed onto silica gel, and purified on Biotage Flash 40 M+ silica cartridges using 20%> EtOAc in heptane. Yield was 2.08 g of orange solid. 1H NMR (400 MHz, DMSO-</6) δ ppm 1.42 (t, J=7.15 Hz, 3 H) 4.51 (q, J=7.05 Hz, 2 H) 7.52 (d, J=7.46 Hz, 1 H) 7.51 (d, J=8.09 Hz, 1 H) 7.71 (t, J=7.57 Hz, 1 H) 7.79 (t, J=7.36 Hz, 1 H) 7.91 (d, J=7.67 Hz, 1 H) 7.93 (s, 1 H) 8.14 (d, J=8.09 Hz, 1 H).
Preparation of
Figure imgf000155_0001
Ethyl 5-nitro-6-[4-nitro-2-(trifluoromethyl)phenyl]-l,2-benzisoxazole-3- carboxylate Nitric acid (5.0 mL, Mallinckrodt, 69%>) was added dropwise to a suspension of ethyl 6-[2-(trifluoromethyl)phenyl]- 1 ,2-benzisoxazole-3-carboxylate (2.80 g, 8.61 mmol) in sulfuric acid (20 mL, Mallinckrodt, 96%) with stirring in an ice bath. The mixture was allowed to warm slowly to room temperature overnight. The mixture was poured over ice, and the product was extracted into CH2C12 (2 X 100 mL). The product precipitated from the CH2C12, so EtOAc (200 mL) was added. The organics were washed with saturated NaHCO3, filtered through a plug of silica gel, and evaporated. Product was purified on a Biotage Flash 40 M+ cartridge using 25% EtOAc in heptane. Yield was 2.37 g of white solid that was used without further purification despite only being approximately 80%> pure.
1H NMR (400 MHz, OMSO-d6) δ ppm 1.44 (t, J=7.05 Hz, 3 H) 4.56 (q, J=7.12 Hz, 2 H) 7.92 (d, J=8.29 Hz, 1 H) 8.31 (s, 1 H) 8.63 (d, J=2.28 Hz, 1 H) 8.66 (dd, J=8.29, 2.28, 1 H) 8.92 (s, 1 H).
Preparation of
Figure imgf000155_0002
tert-Butyl 5-cyano-2-[({5-nitro-6-[4-nitro-2-(trifluoromethyl)phenyl]-l,2- benzisoxazol-3-yl}carbonyl)amino]benzoate Sulfuric acid (25 mL, 80% in water) was added to a flask containing ethyl 5-nitro-6-[4-nitro-2-(trifluoromethyl)phenyl]-l,2- benzisoxazole-3-carboxylate (2.33 g, 5.48 mmol), and the mixture was stiπed in a 75 °C oil bath for 2 hours. (Additional heating or higher temperatures can cause extensive hydrolysis ofthe trifluoromethyl group). The mixture was poured over ice and extracted with CH2C12 (2 X 100 mL). The CH2C12 was dried over Na2SO4 and evaporated. The residue was suspended in CH2C12 (50 mL) and treated with DMF (50 μL) followed by oxalyl chloride (6 mL). An additional 1 mL portion of oxalyl chloride was added after 14.5 hours, but no bubbles were observed, so the solvent and excess oxalyl chloride were removed by rotary evaporation. Heptane (50 mL) was added and then removed by rotary evaporation to remove the residual oxalyl chloride. The residue was dissolved in CH2C12 (30 mL) and treated with t-butyl 2-amino-5- cyanobenzoate (1.18 g, 5.41 mmol) in pyridine (15 mL). After 2 hours, the reaction was diluted with CH2C12 (100 mL) and THF (20 mL). The mixture was washed with 1 M HCl (100 mL). There solids were filtered away, washed with heptane, and dried under vacuum yielding 1.15 g of white solid that was used without further purification. 1H NMR (400 MHz, DMSO-c 6) δ ppm 1.62 (s, 9 H) 7.94 (d, J=8.50 Hz, 1 H) 8.21 (dd, J=8.71, 2.07 Hz, 1 H) 8.35 (s, 1 H) 8.44 (d, J=1.87 Hz, 1 H) 8.64 (d, J=2.28 Hz, 1 H) 8.66 (dd, J=8.48, 2.28 Hz, 1 H) 8.77 (d, J=8.71 Hz, 1 H) 9.04 (s, 1 H) 12.49 (s, I H).
5-Cyano-2-[({5-nitro-6-[4-nitro-2-(trifluoromethyl)phenyl]-l,2-benzisoxazol-3- yl}carbonyl)amino]benzoic acid
Trifluoroacetic acid (15 mL) was added to a slurry ofthe conesponding t-butyl ester (366 mg, 0.613 mmol) in CH2C12 (20 mL). The resulting solution was stiπed for 5.5 hours. The solvents were removed by rotary evaporation. Methanol was added and then removed by rotary evaporation. The residue was recrystallized from hot ethanol (10 mL) with a few drops of THF added. The crystals were washed with methanol followed by heptane and then dried at 100 °C yielding 177 mg of off-white solid. 1H NMR (400 MHz, DMSO--iβ) δ ppm 7.93 (d, J=8.29 Hz, 1 H) 8.20 (dd, J=8.71, 2.07 Hz, 1 H) 8.34 (s, 1 H) 8.47 (d, J=2.07 Hz, 1 H) 8.64 (d, J=2.07 Hz, 1 H) 8.66 (dd, J=8.29, 2.07 Hz, 1 H) 8.89 (d, J=8.71 Hz, 1 H) 9.05 (s, 1 H) 13.04 (s, 1 H).
Example 6.75: 2-[({5-(Acetylamino)-6-[4-(acetylamino)-2-
(trifluoromethyl)phenyl]-l,2-benzisoxazol-3-yl}carbonyl)amino]-5-cyanobenzoic acid
Figure imgf000157_0001
Preparation of
Figure imgf000157_0002
i'ert-Butyl 2-[({5-(acetylamino)-6-[4-(acetylamino)-2-(trifluoromethyl)phenyl]-l,2- benzisoxazol-3-yl}carbonyl)amino] -5-cyanobenzoate Tin (II) chloride dihydrate (5.25 g, 23.3 mmol, Aldrich) was added to a suspension of tert-butyl 5-cyano-2-[({5- nitro-6-[4-nitro-2-(trifluoromethyl)phenyl]- 1 ,2-benzisoxazol-3- yl}carbonyl)amino]benzoate (1.08 g, 1.81 mmol) in a mixture of DMF (40 mL) and THF (40 mL). The mixture was stiπed for 7 days and then diluted with MTBE (250 mL). It was washed with 1 M NaOH (3 X 100 mL) and brine (100 mL). The organics were filtered through a plug of silica and evaporated yielding 826 mg of orange solid. This material was dissolved in CH2C12 (25 mL) and treated with triethylamine (560 μL, 4.03 mmol, Aldrich) followed by acetyl chloride (250 μL, 3.52 mmol, Aldrich). The mixture was stiπed for 15 hours and then treated with an additional portion of acetyl chloride (100 μL). After an additional 30 minutes, the mixture was filtered through a plug of silica. Product was adsorbed onto silica and purified on a Biotage Flash 40 Mousing a gradient from 60% to 80% EtOAc in CH2C12. Yield was 455 mg of white solid.
1H NMR (400 MHz, DMSO- 6) δ ppm 1.62 (s, 9 H) 1.87 (s, 3 H) 2.12 (s, 3 H) 7.30 (d, J=8.50 Hz, I H) 7.80 (s, 1 H) 7.84 (dd, J=8.50, 1.66 Hz, 1 H) 8.17 (dd, J=8.71, 2.07 Hz, 1 H) 8.21 (d, J=1.87 Hz, 1 H) 8.41 (d, J=2.07 Hz, 1 H) 8.45 (s, 1 H) 8.80 (d, J=8.71 Hz, 1 H) 9.01 (s, 1 H) 10.41 (s, 1 H) 12.42 (s, 1 H).
Trifluoroacetic acid (10 mL) was added to a slurry ofthe conesponding t-butyl ester in CH2C12 (15 mL), and the resulting solution was stiπed overnight. Solvents were removed by rotary evaporation, and the product was triturated with methanol. Product was washed with heptane and dried at 100 °C under vacuum yielding 298 mg of tan solid. 1H NMR (400 MHz, OMSO-d6) δ ppm 1.88 (s, 3 H) 2.12 (s, 3 H) 7.30 (d, J=8.29 Hz, 1 H) 7.79 (s, 1 H) 7.84 (dd, J=8.60, 1.14 Hz, 1 H) 8.18 (dd, J=8.71, 1.87 Hz, 1 H) 8.21 (d, J=1.66 Hz, 1 H) 8.46 (m, 2 H) 8.91 (d, J=8.71 Hz, 1 H) 9.02 (s, 1 H) 10.41 (s, 1 H) 12.92 (s, 1 H).
Example 7.76: 2-[({5-(Acetylamino)-6-[4-(acetylamino)-2- (trifluoromethyl)phenyl]-l,2-benzisoxazol-3-yl}carbonyl)amino]-5-bromobenzoic acid
Figure imgf000158_0001
Preparation of
Figure imgf000158_0002
tert-Butyl 5-bromo-2- [({5-nitro-6- [4-nitro-2-(trifluoromethyl)phenyl] -1 ,2- benzisoxazol-3-yl}carbonyl)amino]benzoate Sulfuric acid (25 mL, 80% in water) was added to ethyl 6-[2-(trifluoromethyl)phenyl]-l,2-benzisoxazole-3-carboxylate (2.04 g, 6.27 mmol), and the mixture was stiπed in a 75 °C oil bath for 2.25 hours while monitoring the reaction to avoid hydrolysis ofthe trifluoromethyl group. The mixture was poured over ice, and the product was extracted into EtOAc (2 X 75 mL). The organics were dried over Na2SO and evaporated leaving a brown solid. This material was suspended in H2SO (20 mL, 96%) and treated with nitric acid (5 mL, 69%) with stirring in an ice bath. The mixture was allowed to warm to room temperature overnight and was then poured over ice. Product was extracted into EtOAc (2 X 100 mL). The organics were dried over Na2SO4 and evaporated. Toluene (2 X 100 mL) was added and then evaporated to help rid the material of acetic acid. The resulting orange solid (2.52 g) was suspended in CH2C12 (50 mL) and treated with DMF (20 μL) followed by oxalyl chloride (6 mL). An additional portion of oxalyl chloride (1 mL) was added after 1 hour, and the mixture was stiπed for an additional 1 hour. Solvent and excess oxalyl chloride were removed by rotary evaporation. The residue was dissolved in CH2C12 (30 mL) and treated with t-butyl 2- amino-5-bromobenzoate (1.44 g, 5.29 mmol) in pyridine (10 mL). The mixture was stiπed for 70 minutes and then added to a separatory funnel with CH2C12 (100 mL). The organics were washed with 1 M HCl (2 X 100 mL) and brine (100 mL). Product was adsorbed onto silica and purified on a Biotage Flash 40 M+ silica cartridge using a gradient from 60% to 80% CH2C12 in heptane yielding 1.61 g of white solid. This material was further purified by recrystamzation from hot toluene (approximately 75 mL). Yield was 830 mg of white solid that could not be completely freed from residual toluene, even after extended heating at 100 °C under vacuum. lH NMR (400 MHz, DMSO- 6) δ ppm 1.60 (s, 9 H) 7.95 (m, 2 H) 8.09 (d, J=2.49 Hz, 1 H) 8.33 (s, 1 H) 8.52 (d, J=8.91 Hz, 1 H) 8.63 (d, J=2.07 Hz, 1 H) 8.66 (dd, J=8.28, 2.28 Hz 1 H) 9.03 (s, 1 H) 12.20 (s, 1 H). Preparation of
Figure imgf000160_0001
tert-Butyl 2-[({5-(acetylamino)-6-[4-(acetylamino)-2-(trifluoromethyl)phenyl]-l,2- benzisoxazol-3-yl}carbonyl)amino]-5-bromobenzoate Tin (II) chloride dihydrate (4.05 g, 17.9 mmol, Aldrich) was added to a mixture of tert-butyl 5-bromo-2-[({5- nitro-6-[4-nitro-2-(trifluoromethyl)phenyl]-l,2-benzisoxazol-3- yl}carbonyl)amino]benzoate (715 mg, 1.10 mmol) in a mixture of THF (40 mL) and DMF (40 mL). The mixture was stiπed for 6 days and then diluted with MTBE (250 mL). The organics were washed with 1 M NaOH (3 X 100 mL) and brine (100 mL). It was then filtered through a plug of silica and evaporated. The resulting orange solid was dissolved in CH2C12 (25 mL) and treated with triethylamine (560 μL) and acetyl chloride (250 μL). After 5 hours, the mixture was filtered through a plug of silica gel. Product was then adsorbed onto silica gel and purified on a Biotage Flash 40 M+ using a gradient from 50% EtOAc to 75% EtOAc in CH2C12. Yield was 161 mg of light yellow solid. lH NMR (400 MHz, DMSO--i6) δ ppm 1.59 (s, 9 H) 1.87 (s, 3 H) 2.12 (s, 3 H) 7.29 (d, J=8.50 Hz, 1 H) 7.78 (s, 1 H) 7.84 (dd, J=8.40, 1.76 Hz, 1 H) 7.92 (dd, J=8.91, 2.49 Hz, 1 H) 8.08 (d, J=2.49 Hz, 1 H) 8.21 (d, J=1.87 Hz, 1 H) 8.43 (s, 1 H) 8.56 (d, J=8.91 Hz, 1 H) 9.01 (s, 1 H) 10.40 (s, 1 H) 12.11 (s, 1 H).
A slurry ofthe t-butyl ester (137 mg, 0.203 mmol) in CH2C12 (12 mL) was treated with TFA (8 mL), and the resulting solution was stiπed overnight. Solvents were removed by rotary evaporation, and the product was triturated with methanol. The acid product was washed with heptane and dried at 100 °C under vacuum yielding 49 mg of tan solid. 1H NMR (400 MHz, DMSO-J6) δ ppm 1.87 (s, 3 H) 2.12 (s, 3 H) 7.29 (d,
J=8.50 Hz, 1 H) 7.78 (s, 1 H) 7.84 (dd, J=8.19, 1.35 Hz, 1 H) 7.93 (dd, J=9.02, 2.38 Hz, 1 H) 8.17 (d, J=2.49 Hz, 1 H) 8.21 (d, J=1.45 Hz, 1 H) 8.45 (s, 1 H) 8.71 (d, J=9.12 Hz, 1 H) 9.01 (s, 1 H) 10.40 (s, 1 H) 12.63 (s, 1 H).
Example 6.77: 5-Cyano-2-[({6-[2-(trifluoromethyl)phenyl]-l,2-benzisoxazol-3- yl}carbonyl)amino]benzoic acid
Figure imgf000161_0001
Preparation of
Figure imgf000161_0002
fgrt-Butyl 5-cyano-2-[({6-[2-(trifluoromethyl)phenyl]-l,2-benzisoxazol-3- yl}carbonyl)amino]benzoate Sulfuric acid (40 mL, 75%> in water) was added to a flask containing ethyl 6-[2-(trifluoromethyl)phenyl]-l,2-benzisoxazole-3-carboxylate (1.12 g, 3.35 mmol), and the mixture was stiπed in a 60-80°C oil bath for 80-110 minutes. The mixture was diluted to 120 mL with water, and the resulting precipitate was collected and air dried yielding 862 mg of yellow solid. This material was suspended in CH2C12 ( 100 mL) and treated with DMF (30 μL) followed by oxalyl chloride (2 mL). Solvent and excess oxalyl chloride were removed by rotary evaporation after 1 hour. The residue was dissolved in CH2C12 (75 mL) and treated with t-butyl 2-amino-5-cyanobenzoate (552 mg, 2.53 mmol) in pyridine (20 mL). The mixture was stiπed for 16.5 hours and then diluted with CH2C12 (100 mL). It was washed with 1 M HCl (2 X 150 mL) followed by brine (150 mL) . Product was adsorbed onto silica gel and purified on a Biotage Flash 40 M+ silica cartridge using a gradient from 50% to 75% CH2C12 in heptane. Yield was 446 mg of white solid. 1H NMR (400 MHz, DMSO--i6) δ ppm 1.62 (s, 9 H) 7.53 (d, J=8.29 Hz, 2 H) 7.71 (t, J=7.57 Hz, 1 H) 7.80 (t, J=7.36 Hz, 1 H) 7.92 (d, J=7.67 Hz, 1 H) 7.97 (s, 1 H) 8.18 (dd, J=8.71, 2.07 Hz, 1 H) 8.26 (d, J=8.09 Hz, 1 H) 8.41 (d, J=2.07 Hz, 1 H) 8.80 (d, J=8.71 Hz, 1 H) 12.43 (s, 1 H).
A solution ofthe conesponding t-butyl ester (371 mg, 0.731 mmol) in CH2C12(15 mL) was treated with TFA (10 mL) and stiπed for 3 hours. Solvents were removed by rotary evaporation. To remove residual TFA, the residue was suspended in CH2C12, and the solvent was removed by rotary evaporation. This was repeated with methanol and with heptane. The acid product was then triturated with methanol, washed with heptane, and dried at 100 °C under vacuum yielding 310 mg of white solid. 1H NMR (400 MHz, DMSO--i6) δ ppm 7.53 (d, J=8.09 Hz, 2 H) 7.71 (t, J=7.57 Hz, 1 H) 7.80 (t, J=7.36 Hz, 1 H) 7.92 (d, J=7.46 Hz, 1 H) 7.96 (s, 1 H) 8.18 (dd, J=8.71, 2.07 Hz, 1 H) 8.27 (d, J=8.09 Hz, 1 H) 8.46 (d, J=2.07 Hz, 1 H) 8.92 (d, J=8.91 Hz, 1 H) 12.92 (s, 1 H).
Example 6.78: Other examples of R» as optionally substituted benzisoxazole
Figure imgf000162_0001
Compound No., Structure Compound Name
2-[({5-[3-(acetylamino)phenyl]-1,2- benzisoxazol-3-yl}carbonyl)amino]-5- cyanobenzoic acid
2-[({5-[4-(acetylamino)phenyl]-1,2- benzisoxazol-3-yl}carbonyl)amino]-5- cyanobenzoic acid
2-[({5-[4-(acetylamino)-2-
(trifluoromet yl)phenyl]-1,2-benzisoxazol-3- yl}carbonyl)amino]-5-cyanobenzoic acid
Figure imgf000163_0001
Compound No., Structure Compound Name
2-[({5-[4-[acetyl(methyl)amino]-2-
(trifluoromethyl)phenyl]-1,2-benzisoxazol-3- yl}carbonyl)amino]-5-cyanobenzoic acid
2-[({5-[4-(acetylamino)-2-methylphenyl]-1,2- benzisoxazol-3-yl}carbonyl)amino]-5- cyanobenzoic acid
2-[({5-[2-(acetylamino)phenyl]-6-cyano-1,2- benzisoxazol-3-yl}carbonyl)amino]-5- cyanobenzoic acid
Figure imgf000164_0001
Compound No., Structure Compound Name
2-[({5-[3-(acetylamino)phenyl]-6-cyano-1,2- benzisoxazol-3-yl}carbonyl)amiπo]-5- cyanobenzoic acid
2-[({5-[4-(acetylamino)phenyl]-6-cyano-1,2- benzisoxazol-3-yl}carbonyl)amino]-5- cyanobenzoic acid
2-[({5-[4-[acetyl(methyl)amino]-2- (trifluoromethyl)phenyl]-6-cyano-1,2- benzisoxazol-3-yl}carbonyl)amino]-5- cyanobenzoic acid
Figure imgf000165_0001
Compound No., Structure Compound Name
2-[({5-[4-(acetylamino)-2-methylphenyl]-6- cyano-1 ,2-benzisoxazol-3- yl}carbonyl)amino]-5-cyanobenzoic acid
2-[({5-[5-(acetylamino)-2-methoxyphenyl]-6- cyano-1 ,2-benzisoxazol-3- yl}carbonyl)amino]-5-cyanobenzoic acid
2-({[5-[2-(acetylamino)phenyl]-6-
(trifluoromethyl)-1,2-benzisoxazol-3- yl]carbonyl}amino)-5-cyanobenzoic acid
Figure imgf000166_0001
Compound No., Structure Compound Name
5-cyano-2-({[5-(2-methoxyphenyl)-6- (trifluoromethyl)-1,2-benzisoxazol-3- yl]carbonyl}amino)benzoic acid
2-({[5-{4-[acetyl(methyl)amino]phenyl}-6-
(trifluoromethyl)-1,2-benzisoxazol-3- yl]carbonyl}amino)-5-cyanobenzoic acid
2-[({6-acetyl-5-[2-(acetylamino)pheπyl]-1,2- benzisoxazol-3-yl}carbonyl)amino]-5- cyanobenzoic acid
Figure imgf000167_0001
Compound No., Structure Compound Name
2-[({6-acetyl-5-[3-(acetylamino)p enyl]-1,2- benzisoxazol-3-yl}carbonyl)amino]-5- cyanobenzoic acid
2-[({6-acetyl-5-[4-(acetylamino)phenyl]-1,2- benzisoxazol-3-yl}carbonyl)amiπo]-5- cyanobenzoic acid
2-[({6-acetyl-5-[2-(trifluoromethyl)phenyl]- 1,2-benzisoxazol-3-yl}carbonyl)amino]-5- cyanobenzoic acid
Figure imgf000168_0001
Compound No., Structure Compound Name
2-[({6-acetyl-5-[4-(acetylamino)-2-
(trifluoromethyl)phenyl]-1,2-benzisoxazol-3- yl}carbonyl)amino]-5-cyanobenzoic acid
2-[({6-acetyl-5-[4-[acetyl(methyl)amino]-2-
(trifluoromethyl)phenyl]-1,2-benzisoxazol-3- yl}carbonyl)amino]-5-cyanobenzoic acid
2-[({6-acetyl-5-[4- [(methoxycarbonyl)amino]-2- (trifluoromet yl)phenyl]-1,2-benzisoxazol-3- yl}carbonyl)amino]-5-cyanobenzoic acid
Figure imgf000169_0001
Compound No., Structure Compound Name
2-({[6-acetyl-5-(2-methylphenyl)-1,2- benzisoxazol-3-yl]carbonyl}amino)-5- cyanobenzoic acid
2-[({6-acetyl-5-[4-(acetylamino)-2- methylphenyl]-1,2-benzisoxazol-3- yl}carbonyl)amino]-5-cyanobenzoic acid
2-{[(6-acetyl-5-{4-
[(methoxycarboπyl)amino]-2-methylphenyl}- 1,2-benzisoxazol-3-yl)carbonyl]amiπo}-5- cyanobenzoic acid
Figure imgf000170_0001
Compound No., Structure Compound Name
2-({[6-acetyl-5-(2-methoxyphenyl)-1,2- benzisoxazol-3-yl]carbonyl}amino)-5- cyanobenzoic acid
2-[({6-acetyl-5-[5-(acetylamino)-2- methoxyphenyl]-1,2-benzisoxazol-3- yl}carbonyl)amino]-5-cyanobenzoic acid
2-{[(6-acetyl-5-{2-methoxy-5- [(methoxycarbonyl)amino]phenyl}-1,2- benzisoxazol-3-yl)carbonyl]amino}-5- cyanobenzoic acid
Figure imgf000171_0001
Compound No., Structure Compound Name
2-{[(6-acetyl-5-{2-methoxy-5- [(methoxycarbonyl)(methyl)amino]phenyl}- 1 ,2-benzisoxazol-3-yl)carbonyl]amino}-5- cyanobenzoic acid
2-[({5-[2-(acetylamino)phenyl]-6-propionyl- 1,2-benzisoxazol-3-yl}carbonyl)amino]-5- cyanobenzoic acid
2-[({5-[4-[acetyl(methyl)amino]-2- (trifluoromethyl)phenyl]-6-propionyl-1,2- beπzisoxazol-3-yl}carbonyl)amino]-5- cyanobenzoic acid
Figure imgf000172_0001
Compound No., Structure Compound Name
2-({[6-(acetylamino)-5-phenyl-1,2- benzisoxazol-3-yl]carbonyl}amino)-5- cyanobenzoic acid
2-[({6-(acetylamino)-5-[2-
(acetylamino)phenyl]-1,2-benzisoxazol-3- yl}carbonyl)amino]-5-cyanobenzoic acid
2-[({6-(acetylamino)-5-[3-
(acetylamino)phenyl]-1,2-benzisoxazol-3- yl}carbonyl)amino]-5-cyanobenzoic acid
Figure imgf000173_0001
Compound No., Structure Compound Name
2-[({6-(acetylamino)-5-[4-
(acetylamino)phenyl]-1,2-benzisoxazol-3- yl}carbonyl)amino]-5-cyanobenzoic acid
2-[({6-(acetylamino)-5-[2-
(trifluoromethyl)phenyl]-1,2-benzisoxazol-3- yl}carbonyl)amino]-5-cyanobeπzoic acid
2-[({6-(acetylamino)-5-[4-(acetylamino)-2-
(trifluoromethyl)phenyl]-1,2-benzisoxazol-3- yl}carbonyl)amino]-5-cyanobenzoic acid
Figure imgf000174_0001
Compound No., Structure Compound Name
2-[({6-(acetylamino)-5-[4- [acetyl(methyl)amino]-2- (trifluoromet yl)phenyl]-1,2-benzisoxazol-3- yl}carbonyl)amino]-5-cyanobenzoic acid
2-[({6-(acetylamino)-5-[4- [(methoxycarbonyl)(methyl)amino]-2- (trifluoromethyl)phenyl]-1,2-benzisoxazol-3- yl}carbonyl)amino]-5-cyanobenzoic acid
2-[({6-(acetylamino)-5-[4- [(methoxycarbonyl)amino]-2- (trifluoromethyl)phenyl]-1,2-benzisoxazol-3- yl}carbonyl)amino]-5-cyanobenzoic acid
Figure imgf000175_0001
Compound No., Structure Compound Name
2-({[6-(acetylamino)-5-(2-methylphenyl)-1,2- benzisoxazol-3-yl]carbonyl}amino)-5- cyanobenzoic acid
2-[({6-(acetylamino)-5-[4-(acetylamino)-2- methylphenyl]-1,2-benzisoxazol-3- yl}carbonyl)amino]-5-cyanobenzoic acid
2-{[(6-(acetylamino)-5-{4- [acetyl(methyl)amino]-2-methylphenyl}-1,2- benzisoxazol-3-yl)carbonyl]amino}-5- cyanobenzoic acid
Figure imgf000176_0001
Compound No., Structure Compound Name
2-{[(6-(acetylamino)-5-{4- [(methoxycarbonyl)amino]-2-methylphenyl}- 1,2-benzisoxazol-3-yl)carbonyl]amino}-5- cyanobenzoic acid
2-({[6-(acetylamino)-5-(2-methoxyphenyl)- 1 ,2-benzisoxazol-3-yl]carbonyl}amino)-5- cyanobenzoic acid
2-{[(6-(acetylamino)-5-{4- [acetyl(methyl)amino]pheπyl}-1,2- benzisoxazol-3-yl)carbonyl]amino}-5- cyanobenzoic acid
Figure imgf000177_0001
Compound No., Structure Compound Name
2-{[(6-(acetylamino)-5-{4- [(methoxycarbonyl)(methyl)amino]phenyl}- 1,2-benzisoxazol-3-yl)carbonyl]amino}-5- cyanobenzoic acid
2-{[(6-(acetylamino)-5-{4- [(methoxycarbonyl)amino]phenyl}-1,2- benzisoxazol-3-yl)carbonyl]amino}-5- cyanobeπzoic acid
2-[({6-(acetylamino)-5-[5-(acetylamino)-2- methoxyphenyl]-1,2-benzisoxazol-3- yl}carbonyl)amino]-5-cyanobenzoic acid
Figure imgf000178_0001
Compound No., Structure Compound Name
2-{[(6-(acetylamino)-5-{2-methoxy-5- [(methoxycarbonyl)amino]phenyl}-1,2- benzisoxazol-3-yl)carbonyl]amino}-5- cyanobenzoic acid
2-({[6-(acetylamino)-5-pyridin-2-yl-1,2- benzisoxazol-3-yl]carbonyl}amino)-5- cyanobenzoic acid
2-({[6-(acetylamino)-5-pyridin-3-yl-1,2- benzisoxazol-3-yl]carbonyl}amino)-5- cyanobenzoic acid
Figure imgf000179_0001
Compound No., Structure Compound Name
2-({[6-(acetylamino)-5-pyridin-4-yl-1,2- benzisoxazol-3-yl]carbonyl}amino)-5- cyanobenzoic acid
2-({[6-(acetylamino)-5-pyrazin-2-yl-1,2- benzisoxazol-3-yl]carbonyl}amino)-5- cyanobenzoic acid
2-({[6-(acetylamino)-5-pyridazin-3-yl-1,2- benzisoxazol-3-yl]carbonyl}amino)-5- cyanobenzoic acid
2-({[6-(acetylamino)-5-pyridazin-4-yl-1,2- benzisoxazol-3-yl]carbonyl}amino)-5- cyanobenzoic acid
Figure imgf000180_0001
Compound No., Structure Compound Name
5-cyano-2-({[5-p enyl-6-(propionylamino)- 1 ,2-benzisoxazol-3- yl]carbonyl}amino)benzoic acid
2-({[5-[2-(acetylamino)phenyl]-6-
(propionylamino)-1,2-benzisoxazol-3- yl]carbonyl}amino)-5-cyanobenzoic acid
2-({[5-[3-(acetylamino)phenyl]-6-
(propionylamino)-1,2-benzisoxazol-3- yl]carbonyl}amino)-5-cyanobenzoic acid
Figure imgf000181_0001
Compound No., Structure Compound Name
2-({[5-[4-(acetylamino)phenyl]-6-
(propionylamino)-1,2-benzisoxazol-3- yl]carbonyl}amino)-5-cyanobenzoic acid
5-cyano-2-[({6-(propionylamino)-5-[2- (trifluoromethyl)phenyl]-1,2-benzisoxazol-3- yl}carbonyl)amino]benzoic acid
2-({[5-[4-(acetylamino)-2- (trifluoromethyl)phenyl]-6-(propionylamino)- 1,2-benzisoxazol-3-yl]carbonyl}amino)-5- cyanobenzoic acid
Figure imgf000182_0001
Compound No., Structure Compound Name
2-({[5-[4-[acetyl(methyl)amino]-2- (trifluoromethyl)phenyl]-6-(propionylamino)- 1,2-benzisoxazol-3-yl]carbonyl}amino)-5- cyanobenzoic acid
5-cyano-2-({[5-[4- [(methoxycarbonyl)amino]-2- (trifluoromethyl)phenyl]-6-(propionylamino)- 1 ,2-benzisoxazol-3- yl]carbonyl}amino)benzoic acid
5-cyano-2-({[5-(2-methylphenyl)-6- (propionylamino)-1,2-benzisoxazol-3- yl]carbonyl}amino)benzoic acid
Figure imgf000183_0001
Compound No., Structure Compound Name
2-({[5-[4-(acetylamino)-2-methylphenyl]-6-
(propionylamino)-1,2-benzisoxazol-3- yl]carbonyl}amino)-5-cyanobenzoic acid
5-cyano-2-({[5-{4-
[(methoxycarbonyl)amino]-2-methylphenyl}- 6-(propionylamino)-1,2-benzisoxazol-3- yl]carbonyl}amino)benzoic acid
5-cyano-2-({[5-(2-methoxyphenyl)-6- (propionylamino)-1,2-benzisoxazol-3- yl]carbonyl}amino)benzoic acid
Figure imgf000184_0001
Compound No., Structure Compound Name
5-cyano-2-({[5-{4-
[(methoxycarbonyl)(methyl)amino]phenyl}-6- (propionylamino)-1 ,2-benzisoxazol-3- yl]carbonyl}amino)benzoic acid
5-cyano-2-({[5-{4-
[(methoxycarbonyl)amino]phenyl}-6- (propionylamino)-1 ,2-benzisoxazol-3- yl]carbonyl}amino)benzoic acid
5-cyano-2-({[5-{2-methoxy-5- [(methoxycarbonyl)amino]phenyl}-6- (propionylamino)-1 ,2-benzisoxazol-3- yl]carbonyl}amino)benzoic acid
Figure imgf000185_0001
Compound No., Structure Compound Name
5-cyano-2-({[6-(propionylamino)-5-pyridin-2- yl-1 ,2-benzisoxazol-3- yl]carbonyl}amino)benzoic acid
5-cyano-2-({[6-(propionylamino)-5-pyridin-3- yl-1 ,2-benzisoxazol-3- yl]carbonyl}amino)benzoic acid
5-cyano-2-({[6-(propionylamino)-5-pyridin-4- yl-1 ,2-benzisoxazol-3- yl]carbonyl}amiπo)benzoic acid
5-cyano-2-({[6-(propionylamino)-5- pyridazin-3-yl-1,2-benzisoxazol-3- yl]carbonyl}amino)benzoic acid
Figure imgf000186_0001
Compound No., Structure Compound Name
5-cyano-2-({[6-(propionylamino)-5- pyridazin-4-yl-1,2-benzisoxazol-3- yl]carbonyl}amino)benzoic acid
2-({[5-[2-(acetylamino)phenyl]-6-
(butyryiamino)-1,2-benzisoxazol-3- yl]carbonyl}amino)-5-cyanobenzoic acid
2-[({6-(butyrylamino)-5-[2-
(trifluoromethyl)phenyl]-1,2-benzisoxazol-3- yl}carbonyl)amino]-5-cyanobenzoic acid
Figure imgf000187_0001
Compound No., Structure Compound Name
2-({[5-[4-(acetylamino)-2- (trifluoromethyl)phenyl]-6-(butyrylamino)- 1,2-benzisoxazol-3-yl]carbonyl}amino)-5- cyanobenzoic acid
2-({[6-(butyrylamino)-5-(2-methylphenyl)- 1 ,2-benzisoxazol-3-yl]carbonyl}amino)-5- cyanobenzoic acid
2-({[5-[4-(acetylamino)-2-methylphenyl]-6-
(butyrylamino)-1,2-benzisoxazol-3- yl]carbonyl}amino)-5-cyanobenzoic acid
Figure imgf000188_0001
Compound No., Structure Compound Name
2-[({6-[acetyl(methyl)amino]-1,2- benzisoxazol-3-yl}carbonyl)amino]-5- cyanobenzoic acid
2-[({6-[acetyl(met yl)amino]-5-phenyl-1,2- benzisoxazol-3-yl}carbonyl)amino]-5- cyanobenzoic acid
2-[({5-[2-(acetylamino)phenyl]-6-
[acetyl(methyl)amino]-1,2-benzisoxazol-3- yl}carbonyl)amino]-5-cyanobenzoic acid
Figure imgf000189_0001
Compound No., Structure Compound Name
2-[({5-[4-(acetylamino)phenyl]-6-
[acetyl(methyl)amino]-1,2-benzisoxazol-3- yl}carbonyl)amino]-5-cyanobenzoic acid
2-[({6-[acetyl(methyl)amino]-5-[2- (trifluoromethyl)phenyl]-1,2-benzisoxazol-3- yl}carbonyl)amino]-5-cyanobenzoic acid
2-[({5-[4-(acetylamino)-2- (trifluoromethyl)phenyl]-6- [acetyl(methyl)amino]-1,2-benzisoxazol-3- yl}carbonyl)amino]-5-cyanobenzoic acid
Figure imgf000190_0001
Compound No., Structure Compound Name
2-[({6-[acetyl(methyl)amino]-5-[4- [acetyl(methyl)amino]-2- (trifluoromethyl)phenyl]-1,2-benzisoxazol-3- yl}carbonyl)amino]-5-cyanobeπzoic acid
2-[({6-[acetyl(methyl)amino]-5-[4- [(methoxycarbonyl)(met yl)amino]-2- (trifluoromethyl)phenyl]-1,2-benzisoxazol-3- yl}carbonyl)amino]-5-cyaπobenzoic acid
2-[({6-[acetyl(methyl)amino]-5-[4- [(methoxycarbonyl)amino]-2- (trifluoromethyl)phenyl]-1,2-benzisoxazol-3- yl}carbonyl)amino]-5-cyanobenzoic acid
Figure imgf000191_0001
Compound No., Structure Compound Name
2-({[6-[acetyl(methyl)amino]-5-(2- methylphenyl)-1,2-benzisoxazol-3- yl]carbonyl}amino)-5-cyanobenzoic acid
2-[({5-[4-(acetylamiπo)-2-methylphenyl]-6- [acetyl(methyl)amino]-1,2-benzisoxazol-3- yl}carbonyl)amino]-5-cyanobenzoic acid
2-{[(6-[acetyl(methyl)amino]-5-{4- [acetyl(methyl)amino]phenyl}-1,2- benzisoxazol-3-yl)carbonyl]amino}-5- cyanobenzoic acid
Figure imgf000192_0001
Compound No., Structure Compound Name
5-cyano-2-[({6-[methyl(propionyl)amino]-5- [2-(trifluoromethyl)phenyl]-1,2-benzisoxazol- 3-yl}carbonyl)amino]benzoic acid
2-[({5-[4-(acetylamino)-2- (trifluoromethyl)phenyl]-6- [methyl(propionyl)amino]-1,2-benzisoxazol- 3-yl}carbonyl)amino]-5-cyanobenzoic acid
2-[({5-[4-[acetyl(methyl)amino]-2- (trifluoromet yl)phenyl]-6- [methyl(propionyl)amino]-1,2-benzisoxazol- 3-yl}carbonyl)amino]-5-cyanobenzoic acid
Figure imgf000193_0001
Compound No., Structure Compound Name
2-[({5-[4-(acetylamino)-2-methylphenyl]-6-
[methyl(propionyl)amino]-1,2-benzisoxazol-
3-yl}carbonyl)amino]-5-cyanobenzoic acid
2-[({5-[4-(acetylamino)-2- (trifluoromethyl)phenyl]-6- [butyryl(methyl)amino]-1,2-benzisoxazol-3- yl}carbonyl)amino]-5-cyanobenzoic acid
5-cyano-2-[({6-[(methoxycarbonyl)amino]-5- phenyl-1 ,2-benzisoxazol-3- yl}carbonyl)amino]benzoic acid
Figure imgf000194_0001
Compound No., Structure Compound Name
2-[({5-[2-(acetylamino)phenyl]-6- [(met oxycarbonyl)amino]-1,2-benzisoxazol- 3-yl}carbonyl)amino]-5-cyanoberιzoic acid
2-[({5-[3-(acetylamino)phenyl]-6-
[(methoxycarbonyl)amino]-1,2-benzisoxazol-
3-yl}carbonyl)amino]-5-cyanobenzoic acid
2-[({5-[4-(acetylamino)phenyl]-6-
[(methoxycarbonyl)amino]-1,2-benzisoxazol-
3-yl}carbonyl)amino]-5-cyanobenzoic acid
Figure imgf000195_0001
Compound No., Structure Compound Name
5-cyano-2-[({6-[(methoxycarbonyl)amino]-5- [2-(trifluoromethyl)phenyl]-1 ,2-benzisoxazol- 3-yl}carbonyl)amino]benzoic acid
2-[({5-[4-(acetylamino)-2- (trifluoromethyl)phenyl]-6- [(methoxycarbonyl)amino]-1,2-benzisoxazol- 3-yl}carbonyl)amino]-5-cyanobenzoic acid
2-[({5-[4-[acetyl(methyl)amino]-2- (trifluoromethyl)phenyl]-6- [(methoxycarbonyl)amino]-1,2-benzisoxazol- 3-yl}carbonyl)amino]-5-cyanobenzoic acid
Figure imgf000196_0001
Compound No., Structure Compound Name
5-cyano-2-[({6-[(methoxycarbonyl)amino]-5- [4-[(methoxycarbonyl)(methyl)amino]-2- (trifluoromethyl)phenyl]-1,2-benzisoxazol-3- yl}carbonyl)amino]benzoic acid
5-cyano-2-[({6-[(methoxycarbonyl)amino]-5- [4-[(methoxycarbonyl)amino]-2- (trifluoromethyl)phenyl]-1,2-benzisoxazol-3- yl}carbonyl)amino]benzoic acid
5-cyano-2-({[6-[(methoxycarbonyl)amino]-5- (2-methylphenyl)-1,2-benzisoxazol-3- yl]carbonyl}amino)benzoic acid
Figure imgf000197_0001
Compound No., Structure Compound Name
2-[({5-[4-(acetylamino)-2-methylphenyl]-6-
[(methoxycarbonyl)amino]-1,2-benzisoxazol-
3-yl}carbonyl)amino]-5-cyanobenzoic acid
5-cyano-2-{[(6-[(methoxycarbonyl)amino]-5- {4-[(methoxycarbonyl)(methyl)amino]-2- methylphenyl}-1,2-benzisoxazol-3- yl)carbonyl]amino}benzoic acid
5-cyano-2-{[(6-[(methoxycarbonyl)amino]-5- {4-[(methoxycarbonyl)amino]-2- methylphenyl}-1,2-benzisoxazol-3- yl)carbonyl]amino}benzoic acid
Figure imgf000198_0001
Figure imgf000199_0001
Figure imgf000200_0001
Compound No., Structure Compound Name
5-cyano-2-[({6-[(methoxycarbonyl)amino]-5- pyridin-2-yl-1,2-benzisoxazol-3- yl}carbonyl)amino]benzoic acid
5-cyano-2-[({6-[(methoxycarbonyl)amino]-5- pyridin-3-yl-1,2-benzisoxazol-3- yl}carboπyl)amino]benzoic acid
5-cyano-2-[({6-[(methoxycarbonyl)amino]-5- pyridin-4-yl-1,2-benzisoxazol-3- yl}carbonyl)amino]benzoic acid
5-cyano-2-[({6-[(methoxycarbonyl)amino]-5- pyrazin-2-yl-1,2-benzisoxazol-3- yl}carbonyl)amino]benzoic acid
Figure imgf000201_0001
Figure imgf000202_0001
Compound No., Structure Compound Name
5-cyano-2-[({6-
[(methoxycarbonyl)(methyl)amino]-5-phenyl- 1 ,2-benzisoxazol-3- yl}carbonyl)amino]benzoic acid
2-[({5-[2-(acetylamino)phenyl]-6- [(methoxycarbonyl)(methyl)amino]-1 ,2- benzisoxazol-3-yl}carbonyl)amino]-5- cyanobenzoic acid
2-[({5-[4-(acetylamino)phenyl]-6- [(methoxycarbonyl)(methyl)amino]-1 ,2- benzisoxazol-3-yl}carbonyl)amino]-5- cyanobenzoic acid
Figure imgf000203_0001
Compound No., Structure Compound Name
5-cyano-2-[({6-
[(methoxycarbonyl)(methyl)amino]-5-[2- (trifluoromethyl)phenyl]-1,2-benzisoxazol-3- yl}carbonyl)amino]benzoic acid
2-[({5-[4-(acetylamino)-2- (trifluoromethyl)phenyl]-6- [(methoxycarbonyl)(methyl)amino]-1,2- benzisoxazol-3-yl}carbonyl)amino]-5- cyanobenzoic acid
2-[({5-[4-[acetyl(methyl)amino]-2- (trifluoromethyl)phenyl]-6- [(methoxycarbonyl)(methyl)amino]-1,2- benzisoxazol-3-yl}carbonyl)amino]-5- cyanobenzoic acid
Figure imgf000204_0001
Figure imgf000205_0001
Figure imgf000206_0001
Figure imgf000207_0001
Compound No., Structure Compound Name
5-cyano-2-[({6-
[(methoxycarbonyl)(methyl)amino]-5-pyridin- 3-yl-1 ,2-benzisoxazol-3- yl}carbonyl)amino]benzoic acid
5-cyano-2-[({6-
[(methoxycarbonyl)(methyl)amino]-5-pyridin- 4-yl-1 ,2-benzisoxazol-3- yl}carbonyl)amino]benzoic acid
5-cyano-2-[({6-
[(methoxycarbonyl)(methyl)amino]-5- pyridazin-4-yl-1,2-benzisoxazol-3- yl}carbonyl)amino]benzoic acid
Figure imgf000208_0001
Compound No., Structure Compound Name
2-[({5-[2-(acetylamino)phenyl]-6-methoxy- 1,2-benzisoxazol-3-yl}carbonyl)amino]-5- cyanobenzoic acid
5-cyano-2-[({6-methoxy-5-[2- (trifluoromethyl)phenyl]-1 ,2-benzisoxazol-3- yl}carbonyl)amino]benzoic acid
2-[({5-[4-(acetylamino)-2- (trifluoromethyl)phenyl]-6-methoxy-1,2- benzisoxazol-3-yl}carbonyl)amino]-5- cyanobenzoic acid
Figure imgf000209_0001
Compound No., Structure Compound Name
2-[({5-[4-[acetyl(methyl)amino]-2- (trifluoromethyl)phenyl]-6-methoxy-1,2- benzisoxazol-3-yl}carbonyl)amino]-5- cyanobenzoic acid
5-cyano-2-({[6-methoxy-5-(2-methylphenyl)- 1 ,2-beπzisoxazol-3- yl]carbonyl}amino)benzoic acid
2-[({5-[4-(acetylamino)-2-methylphenyl]-6- methoxy-1 ,2-benzisoxazol-3- yl}carbonyl)amino]-5-cyanobenzoic acid
Figure imgf000210_0001
Compound No., Structure Compound Name
2-{[(5-{4-[acetyl(methyl)amino]-2- methylphenyl}-6-methoxy-1,2-benzisoxazol-
3-yl)carbonyl]amino}-5-cyanobenzoic acid
5-cyano-2-{[(6-methoxy-5-{4- [(methoxycarbonyl)(methyl)amino]-2- methylphenyl}-1,2-benzisoxazol-3- yl)carbonyl]amino}benzoic acid
5-cyano-2-{[(6-methoxy-5-{4- [(methoxycarbonyl)amino]-2-methylphenyl}- 1 ,2-benzisoxazol-3- yl)carbonyl]amino}benzoic acid
Figure imgf000211_0001
Figure imgf000212_0001
Figure imgf000213_0001
,2-
,2-
,2-
Figure imgf000214_0001
Compound No., Structure Compound Name
5-cyano-2-{[(6-methoxy-5-pyridazin-3-yl- 1 ,2-benzisoxazol-3- yl)carbonyl]amino}benzoic acid
5-cyano-2-{[(6-methoxy-5-pyridazin-4-yl- 1 ,2-benzisoxazol-3- yl)carbonyl]amino}benzoic acid
2-[({5-[4-(acetylamino)-2- (trifluoromethyl)phenyl]-6-methyl-1,2- benzisoxazol-3-yl}carbonyl)amino]-5- cyanobenzoic acid
Figure imgf000215_0001
Compound No., Structure Compound Name
2-{[(5-{5-[acetyl(methyl)amino]-2- methoxyphenyl}-6-methyl-1,2-benzisoxazol-
3-yl)carbonyl]amino}-5-cyanobenzoic acid
2-[({5-[4-(acetylamino)-2- (trifluoromet yl)phenyl]-6-isopropyl-1,2- benzisoxazol-3-yl}carbonyl)amino]-5- cyanobenzoic acid
2-[({5-[4-(acetylamino)-2- (trifluoromethyl)phenyl]-6-isopropoxy-1,2- benzisoxazoI-3-yl}carbonyl)amino]-5- cyanobenzoic acid
Figure imgf000216_0001
Compound No., Structure Compound Name
2-({[5-[2-(acetylamino)phenyl]-6-
(aminocarbonyl)-1,2-benzisoxazol-3- yl]carbonyl}amino)-5-cyanobenzoic acid
2-[({6-(aminocarbonyl)-5-[2-
(trifluoromethyl)phenyl]-1,2-benzisoxazol-3- yl}carbonyl)amino]-5-cyanobenzoic acid
2-({[5-[4-(acetylamino)-2- (trifluoromethyl)phenyl]-6-(aminocarbonyl)- 1,2-benzisoxazol-3-yl]carbonyl}amino)-5- cyanobenzoic acid
Figure imgf000217_0001
Compound No., Structure Compound Name
2-({[5-[4-[acetyl(methyl)amino]-2- (trifluoromet yl)phenyl]-6-(aminocarbonyl)- 1,2-benzisoxazol-3-yl]carbonyl}amino)-5- cyanobenzoic acid
2-[({6-(aminocarbonyl)-5-[4- [(methoxycarbonyl)amino]-2- (trifluoromethyl)phenyl]-1,2-benzisoxazol-3- yl}carbonyl)amino]-5-cyanobenzoic acid
2-({[5-[4-(acetylamino)-2-methylphenyl]-6-
(aminocarbonyl)-1,2-benzisoxazol-3- yl]carbonyl}amino)-5-cyanobenzoic acid
Figure imgf000218_0001
Compound No., Structure Compound Name
2-[({5-[2-(acetylamino)phenyl]-6-
[(methylamino)carbonyl]-1,2-benzisoxazol-3- yl}carbonyl)amino]-5-cyanobenzoic acid
5-cyano-2-[({6-[(methylamino)carbonyl]-5- [2-(trifluoromethyl)phenyl]-1,2-benzisoxazol- 3-yl}carbonyl)amino]benzoic acid
2-[({5-[4-(acetylamino)-2- (trifluoromethyl)phenyl]-6- [(methylamino)carbonyl]-1,2-benzisoxazol-3- yl}carbonyl)amino]-5-cyanobenzoic acid
Figure imgf000219_0001
Compound No., Structure Compound Name
2-[({5-[4-[acetyl(methyl)amino]-2- (trifluoromethyl)phenyl]-6- [(methylamino)carbonyl]-1,2-benzisoxazol-3- yl}carbonyl)amino]-5-cyanobenzoic acid
5-cyano-2-[({5-[4- [(methoxycarbonyl)amino]-2- (trifluoromethyl)phenyl]-6- [(methylamino)carbonyl]-1,2-benzisoxazol-3- yI}carbonyl)amino]benzoic acid
5-cyano-2-[({6-[(dimethylamino)carbonyl]-5- [2-(trifluoromethyl)phenyl]-1,2-benzisoxazol- 3-yl}carbonyl)amino]benzoic acid
Figure imgf000220_0001
Compound No., Structure Compound Name
2-[({5-[4-(acetylamino)-2- (trifluoromethyl)phenyl]-6- [(dimethylamino)carbonyl]-1 ,2-benzisoxazol- 3-yl}carbonyl)amino]-5-cyanobenzoic acid
5-cyano-2-[({6-[(ethylamino)carbonyl]-5-[2- (trifluoromethyl)phenyl]-1,2-benzisoxazol-3- yl}carbonyl)amino]benzoic acid
2-[({5-[4-(acetylamino)-2- (trifluoromethyl)phenyl]-6- [(ethylamino)carbonyl]-1,2-benzisoxazol-3- yl}carbonyl)amino]-5-cyanobenzoic acid
Figure imgf000221_0001
Compound No., Structure Compound Name
2-[({5-[4-[acetyl(methyl)amino]-2- (trifluoromethyl)phenyl]-6- [(ethylamino)carbonyl]-1,2-benzisoxazol-3- yl}carbonyl)amino]-5-cyanobenzoic acid
2-[({5-[4-(acetylamino)-2-methylphenyl]-6- [(ethylamino)carbonyl]-1,2-benzisoxazol-3- yl}carbonyl)amino]-5-cyanobenzoic acid
5-cyano-2-[({6-
{[ethyl(methyl)amino]carbonyl}-5-[2- (trifluoromethyl)phenyl]-1,2-benzisoxazol-3- yl}carbonyl)amino]benzoic acid
Figure imgf000222_0001
Compound No., Structure Compound Name
2-{[(5-[4-[acetyl(methyl)amino]-2- (trifluoromethyl)phenyl]-6- {[ethyl(methyl)amino]carbonyl}-1,2- benzisoxazol-3-yl)carbonyl]amino}-5- cyanobenzoic acid
2-({[6-(aminosulfonyl)-1,2-benzisoxazol-3- yl]carbonyl}amino)-5-cyanobenzoic acid
2-({[6-(aminosulfonyl)-5-phenyl-1,2- benzisoxazol-3-yl]carbonyl}amino)-5- cyanobenzoic acid
Figure imgf000223_0001
Compound No., Structure Compound Name
2-({[6-(aminosulfonyl)-5-(2-methylphenyl)- 1 ,2-benzisoxazol-3-yl]carbonyl}amino)-5- cyanobenzoic acid
2-({[6-(amiπosulfonyl)-5-(2-methoxyphenyl)- 1 ,2-benzisoxazol-3-yl]carbonyl}amino)-5- cyanobenzoic acid
2-({[6-(aminosulfonyl)-5-pyridin-3-yl-1,2- benzisoxazol-3-yl]carbonyl}amino)-5- cyanobenzoic acid
2-({[6-(aminosulfonyl)-5-pyridin-4-yl-1 ,2- benzisoxazol-3-yl]carbonyl}amino)-5- cyanobenzoic acid
Figure imgf000224_0001
Figure imgf000225_0001
Figure imgf000226_0001
Figure imgf000227_0001
Compound No., Structure Compound Name
5-cyano-2-[({5-[(methoxycarbonyl)amino]-6- phenyl-1 ,2-benzisoxazol-3- yl}carbonyl)amino]benzoic acid
2-({[5-(aminosulfoπyl)-6-phenyl-1 ,2- benzisoxazol-3-yl]carbonyl}amino)-5- cyanobenzoic acid
5-cyano-2-[({5-[(methylamino)sulfonyl]-6- phenyl-1 ,2-benzisoxazol-3- yl}carbonyl)amino]benzoic acid
Figure imgf000228_0001
Compound No., Structure Compound Name
5-cyano-2-[({5-[(ethylamino)sulfonyl]-6- phenyl-1 ,2-benzisoxazol-3- yl}carbonyl)amino]benzoic acid
2-[({6-[2-(acetylamino)phenyl]-5-cyano-1 ,2- benzisoxazol-3-yl}carbonyl)amino]-5- cyanobenzoic acid
2-({[6-[2-(acetylamino)phenyl]-5-
(trifluoromethyl)-1,2-benzisoxazol-3- yl]carbonyl}amino)-5-cyanobenzoic acid
Figure imgf000229_0001
Compound No., Structure Compound Name
2-[({5-acetyl-6-[2-(acetylamino)phenyl]-1, benzisoxazol-3-yl}carbonyl)amino]-5- cyanobenzoic acid
2-[({5-(acetylamino)-6-[2-
(acetylamino)phenyl]-1,2-benzisoxazol-3- yl}carbonyl)amino]-5-cyaπobenzoic acid
2-({[6-[2-(acetylamino)phenyl]-5-
(propionylamiπo)-1,2-benzisoxazol-3- yl]carbonyl}amino)-5-cyanobenzoic acid
Figure imgf000230_0001
Compound No., Structure Compound Name
2-({[6-[2-(acetylamino)phenyl]-5-
(butyrylamino)-1,2-benzisoxazol-3- yl]carbonyl}amino)-5-cyanobenzoic acid
2-[({6-[2-(acetylamino)phenyl]-5-
[acetyl(methyl)amino]-1,2-beπzisoxazol-3- yl}carbonyl)amino]-5-cyanobenzoic acid
2-[({6-[2-(acetylamino)phenyl]-5-
[methyl(propionyl)amino]-1,2-benzisoxazol-
3-yl}carbonyl)amino]-5-cyanobenzoic acid
Figure imgf000231_0001
Compound No., Structure Compound Name
2-[({6-[2-(acetylamino)phenyl]-5-
[(methoxycarbonyl)amino]-1,2-benzisoxazol-
3-yl}carbonyl)amino]-5-cyanobenzoic acid
2-[({6-[2-(acetylamino)phenyl]-5-methoxy- 1,2-benzisoxazol-3-yl}carbonyl)amino]-5- cyanobenzoic acid
2-({[6-[2-(acetylamino)phenyl]-5-
(aminocarbonyl)-1,2-benzisoxazol-3- yl]carbonyl}amino)-5-cyanobenzoic acid
Figure imgf000232_0001
Compound No., Structure Compound Name
2-[({6-[2-(acetylamino)phenyl]-5-
[(methylamino)carbonyl]-1 ,2-benzisoxazol-3- yl}carbonyl)amino]-5-cyanobenzoic acid
2-({[6-[2-(acetylamino)phenyl]-5- (aminosulfonyl)-1,2-benzisoxazol-3- yl]carbonyl}amino)-5-cyanobenzoic acid
2-[({6-[2-(acetylamino)phenyl]-5- [(methylamino)sulfonyl]-1 ,2-benzisoxazol-3- yl}carbonyl)amino]-5-cyanobenzoic acid
Figure imgf000233_0001
Compound No., Structure Compound Name
2-[({5-acetyl-6-[3-(acetylamino)phenyl]-1 ,2- benzisoxazol-3-yl}carbonyl)amino]-5- cyanobenzoic acid
2-[({5-(acetylamino)-6-[3-
(acetylamino)phenyl]-1,2-benzisoxazol-3- yl}carbonyl)amino]-5-cyanobenzoic acid
2-({[6-[3-(acetylamino)phenyl]-5-
(propionylamino)-1 ,2-benzisoxazol-3- yl]carbonyl}amino)-5-cyanobenzoic acid
Figure imgf000234_0001
Compound No., Structure Compound Name
2-({[6-[3-(acetylamino)phenyl]-5-
(aminosulfoπyl)-1,2-benzisoxazol-3- yl]carbonyl}amino)-5-cyanobenzoic acid
2-[({6-[3-(acetylamino)phenyl]-5-
[(methylamino)sulfonyl]-1,2-beπzisoxazol-3- yl}carbonyl)amino]-5-cyanobenzoic acid
2-({[6-[4-(acetylamino)phenyl]-5-
(trifluoromethyl)-1,2-benzisoxazol-3- yl]carbonyl}amino)-5-cyanobenzoic acid
Figure imgf000235_0001
Compound No., Structure Compound Name
2-[({5-acetyl-6-[4-(acetylamino)phenyl]-1,2- benzisoxazol-3-yl}carbonyl)amino]-5- cyanobenzoic acid
2-[({5-(acetylamino)-6-[4-
(acetylamino)phenyl]-1,2-benzisoxazol-3- yl}carbonyl)amino]-5-cyanobenzoic acid
2-({[6-[4-(acetylamino)phenyl]-5-
(propionylamino)-1,2-benzisoxazol-3- yl]carbonyl}amino)-5-cyanobenzoic acid
Figure imgf000236_0001
Compound No., Structure Compound Name
2-[({6-[4-(acetylamino)phenyl]-5-
[acetyl(methyl)amino]-1 ,2-benzisoxazol-3- yl}carbonyl)amino]-5-cyanobenzoic acid
2-[({6-[4-(acetylamino)phenyl]-5-
[(methoxycarbonyl)amino]-1,2-benzisoxazol-
3-yl}carbonyl)amino]-5-cyanobenzoic acid
2-[({6-[4-(acetylamino)phenyl]-5-methoxy- 1,2-benzisoxazol-3-yl}carbonyl)amino]-5- cyanobenzoic acid
Figure imgf000237_0001
Compound No., Structure Compound Name
2-({[6-[4-(acetylamino)phenyl]-5-
(aminosulfonyl)-1 ,2-benzisoxazol-3- yl]carbonyl}amino)-5-cyanobenzoic acid
2-[({6-[4-(acetylamino)p enyl]-5-
[(methylamino)sulfonyl]-1 ,2-benzisoxazol-3- yl}carbonyl)amino]-5-cyanobenzoic acid
5-cyano-2-[({5-cyano-6-[2- (trifluoromethyl)phenyl]-1 ,2-benzisoxazol-3- yl}carbonyl)amino]benzoic acid
Figure imgf000238_0001
Compound No., Structure Compound Name
5-cyano-2-[({5-(trifluoromethyl)-6-[2- (trifluoromethyl)phenyl]-1 ,2-benzisoxazol-3- yl}carbonyl)amino]benzoic acid
2-[({5-acetyl-6-[2-(trifluoromethyl)phenyl]- 1 ,2-benzisoxazol-3-yl}carbonyl)amino]-5- cyanobeπzoic acid
2-[({5-(acetylamino)-6-[2-
(trifluoromethyl)phenyl]-1 ,2-benzisoxazol-3- yl}carbonyl)amino]-5-cyanobenzoic acid
Figure imgf000239_0001
Compound No., Structure Compound Name
5-cyano-2-[({5-(propionylamino)-6-[2- (trifluoromethyl)phenyl]-1,2-benzisoxazol-3- yl}carbonyl)amino]benzoic acid
2-[({5-(butyrylamino)-6-[2-
(trifluoromethyl)phenyl]-1,2-benzisoxazol-3- yl}carbonyl)amino]-5-cyanobenzoic acid
2-[({5-[acetyl(methyl)amino]-6-[2-
(trifluoromethyl)pheπyl]-1 ,2-benzisoxazol-3- yl}carbonyl)amino]-5-cyanobenzoic acid
Figure imgf000240_0001
Compound No., Structure Compound Name
5-cyano-2-[({5-[methyl(propionyl)amino]-6- [2-(trifluoromethyl)phenyl]-1,2-benzisoxazol- 3-yl}carbonyl)amino]benzoic acid
2-[({5-[butyryl(methyl)amino]-6-[2-
(trifluoromethyl)phenyl]-1,2-benzisoxazol-3- yl}carbonyl)amino]-5-cyanobenzoic acid
5-cyano-2-[({5-[(methoxycarbonyl)amino]-6- [2-(trifluoromethyl)phenyl]-1,2-benzisoxazol- 3-yl}carbonyl)amino]benzoic acid
Figure imgf000241_0001
Compound No., Structure Compound Name
5-cyano-2-[({5-
[(methoxycarbonyl)(methyl)amino]-6-[2- (trifluoromethyl)phenyl]-1,2-benzisoxazol-3- yl}carbonyl)amino]benzoic acid
5-cyano-2-[({5-methoxy-6-[2- (trifluoromethyl)phenyl]-1,2-benzisoxazol-3- yl}carbonyl)amino]benzoic acid
2-[({5-(aminocarbonyl)-6-[2- (trifluoromethyl)phenyl]-1,2-benzisoxazol-3- yl}carbonyl)amino]-5-cyanobenzoic acid
Figure imgf000242_0001
Compound No., Structure Compound Name
5-cyano-2-[({5-[(methylamino)carbonyl]-6- [2-(trifluoromethyl)phenyl]-1 ,2-benzisoxazol- 3-yl}carbonyl)amino]benzoic acid
5-cyano-2-[({5-[(dimethylamino)carbonyl]-6- [2-(trifluoromethyl)phenyl]-1,2-benzisoxazol- 3-yl}carbonyl)amino]benzoic acid
5-cyano-2-[({5-[(ethylamino)carbonyl]-6-[2- (trifluoromethyl)phenyl]-1 ,2-benzisoxazol-3- yl}carbonyl)amino]benzoic acid
Figure imgf000243_0001
Compound No., Structure Compound Name
2-[({6-[4-(acetylamino)-2-
(trifluoromethyl)phenyl]-1 ,2-benzisoxazol-3- yl}carbonyl)amino]-5-cyanobenzoic acid
2-[({5-acetyl-6-[4-(acetylamino)-2-
(trifluoromethyl)phenyl]-1 ,2-benzisoxazol-3- yl}carbonyl)amino]-5-cyanobenzoic acid
2-[({6-[4-(acetylamino)-2- (trifluoromethyl)phenyl]-5-propionyl-1 ,2- benzisoxazol-3-yl}carbonyl)amino]-5- cyanobenzoic acid
Figure imgf000244_0001
Compound No., Structure Compound Name
2-({[6-[4-(acetylamino)-2- (trifluoromethyl)phenyl]-5-(propionylamino)- 1 ,2-benzisoxazol-3-yl]carbonyl}amino)-5- cyanobenzoic acid
2-({[6-[4-(acetylamino)-2- (trifluoromethyl)phenyl]-5-(butyrylamino)- 1 ,2-benzisoxazol-3-yl]carbonyl}amino)-5- cyanobenzoic acid
2-({[6-[4-(acetylamino)-2- (trifluoromethyl)phenyl]-5-(pentanoylamino)- 1 ,2-benzisoxazol-3-yl]carbonyl}amino)-5- cyanobenzoic acid
Figure imgf000245_0001
Compound No., Structure Compound Name
2-[({6-[4-(acetylamino)-2- (trifluoromethyl)phenyl]-5- [acetyl(methyl)amino]-1,2-benzisoxazol-3- yl}carbonyl)amino]-5-cyanobenzoic acid
2-[({6-[4-(acetylamino)-2- (trifluoromethyl)phenyl]-5- [methyl(propionyl)amino]-1,2-benzisoxazol- 3-yl}carbonyl)amino]-5-cyarιobenzoic acid
2-[({6-[4-(acetylamino)-2- (trifluoromethyl)phenyl]-5- [butyryl(methyl)amino]-1,2-benzisoxazol-3- yl}carbonyl)amino]-5-cyanobenzoic acid
Figure imgf000246_0001
Compound No., Structure Compound Name
2-[({6-[4-(acetylamino)-2- (trifluoromethyl)phenyl]-5- [(methoxycarbonyl)amino]-1,2-benzisoxazol- 3-yl}carbonyl)amino]-5-cyanobenzoic acid
2-[({6-[4-(acetylamino)-2- (trifluoromethyl)phenyl]-5- [(methoxycarbonyl)(methyl)amino]-1,2- benzisoxazol-3-yl}carbonyl)amino]-5- cyanobenzoic acid
2-[({6-[4-(acetylamino)-2- (trifluoromethyl)phenyl]-5-methoxy-1,2- benzisoxazol-3-yl}carbonyl)amino]-5- cyanobenzoic acid
Figure imgf000247_0001
Compound No., Structure Compound Name
2-[({6-[4-(acetylamino)-2- (trifluoromethyl)phenyl]-5-methyl-1 ,2- benzisoxazol-3-yl}carbonyl)amino]-5- cyanobenzoic acid
2-[({6-[4-(acetylamino)-2- (trifluoromethyl)phenyl]-5-isopropyl-1 ,2- benzisoxazol-3-yl}carbonyl)amino]-5- cyanobenzoic acid
2-({[6-[4-(acetylamino)-2- (trifluoromethyl)phenyl]-5-(methylthio)-1 ,2- benzisoxazol-3-yl]carbonyl}amino)-5- cyanobenzoic acid
Figure imgf000248_0001
Compound No., Structure Compound Name
2-({[6-[4-(acetylamino)-2- (trifluoromethyl)phenyl]-5-(aminocarbonyl)- 1,2-benzisoxazol-3-yl]carbonyl}amino)-5- cyanobenzoic acid
2-[({6-[4-(acetylamino)-2- (trifluoromethyl)phenyl]-5- [(methylamino)carbonyl]-1,2-benzisoxazol-3- yl}carbonyl)amino]-5-cyanobenzoic acid
2-[({6-[4-(acetylamino)-2- (trifluoromethyl)phenyl]-5- [(dimethylamino)carbonyl]-1,2-benzisoxazol- 3-yl}carbonyl)amino]-5-cyanobenzoic acid
Figure imgf000249_0001
Compound No., Structure Compound Name
2-[({6-[4-(acetylamino)-2- (trifluoromethyl)phenyl]-5- [(ethylamino)carbonyl]-1,2-benzisoxazol-3- yl}carbonyl)amino]-5-cyanobenzoic acid
2-[({5-acetyl-6-[4-[acetyl(methyl)amino]-2-
(trifluoromethyl)pheπyl]-1 ,2-benzisoxazol-3- yl}carbonyl)amino]-5-cyanobenzoic acid
2-[({6-[4-[acetyl(methyl)amino]-2- (trifluoromethyl)phenyl]-5-propionyl-1,2- benzisoxazol-3-yl}carbonyl)amino]-5- cyanobenzoic acid
Figure imgf000250_0001
Compound No., Structure Compound Name
2-[({5-(acetylamino)-6-[4- [acetyl(methyl)amino]-2- (trifluoromethyl)phenyl]-1,2-benzisoxazol-3- yl}carbonyl)amiπo]-5-cyanobenzoic acid
2-({[6-[4-[acetyl(methyl)amino]-2- (trifluoromethyl)phenyl]-5-(propionylamino)- 1 ,2-benzisoxazol-3-yl]carbonyl}amino)-5- cyanobenzoic acid
2-({[6-[4-[acetyl(methyl)amino]-2- (trifluoromethyl)phenyl]-5-(butyrylamino)- 1 ,2-benzisoxazol-3-yl]carbonyl}amino)-5- cyanobenzoic acid
Figure imgf000251_0001
Compound No., Structure Compound Name
2-[({5-[acetyl(methyl)amino]-6-[4- [acetyl(methyl)amino]-2- (trifluoromethyl)phenyl]-1,2-benzisoxazol-3- yl}carbonyl)amino]-5-cyanobenzoic acid
2-[({6-[4-[acetyl(methyl)amino]-2- (trifluoromethyl)phenyl]-5- [methyl(propionyl)amino]-1,2-benzisoxazol- 3-yl}carbonyl)amino]-5-cyanobenzoic acid
2-[({6-[4-[acetyl(methyl)amino]-2- (trifluoromethyl)phenyl]-5- [(methoxycarbonyl)amino]-1 ,2-benzisoxazol- 3-yl}carbonyl)amino]-5-cyanobenzoic acid
Figure imgf000252_0001
Compound No., Structure Compound Name
2-[({6-[4-[acetyl(methyl)amino]-2- (trifluoromethyl)phenyl]-5- [(methoxycarbonyl)(methyl)amino]-1 ,2- benzisoxazol-3-yl}carbonyl)amino]-5- cyanobenzoic acid
2-[({6-[4-[acetyl (methyl)am i no]-2- (trifluoromethyl)phenyl]-5-methoxy-1,2- benzisoxazol-3-yl}carbonyl)amino]-5- cyanobenzoic acid
2-({[6-[4-[acetyl(methyl)amino]-2- (trifluoromethyl)phenyl]-5-(aminocarbonyl)- 1,2-benzisoxazol-3-yl]carbonyl}amino)-5- cyanobenzoic acid
Figure imgf000253_0001
Compound No., Structure Compound Name
2-[({6-[4-[acetyl(methyl)amino]-2- (trifluoromethyl)phenyl]-5- [(methylamino)carbonyl]-1,2-benzisoxazol-3- yl}carbonyl)amino]-5-cyanobenzoic acid
2-{[(6-[4-[acetyl(methyl)amino]-2- (trifluoromethyl)phenyl]-5- {[ethyl(methyl)amino]carbonyl}-1,2- benzisoxazol-3-yl)carbonyl]amino}-5- cyanobenzoic acid
2-[({5-(acetylamino)-6-[4- [(methoxycarbonyl)(methyl)amino]-2- (trifluoromethyl)phenyl]-1,2-benzisoxazol-3- yl}carbonyl)amino]-5-cyanobenzoic acid
Figure imgf000254_0001
Compound No., Structure Compound Name
2-[({5-[acetyl(methyl)amino]-6-[4- [(methoxycarbonyl)(methyl)amino]-2- (trifluoromethyl)phenyl]-1,2-benzisoxazol-3- yl}carbonyl)amino]-5-cyanobenzoic acid
5-cyano-2-[({5-[(methoxycarbonyl)amino]-6- [4-[(methoxycarbonyl)(methyl)amino]-2- (trifluoromethyl)phenyl]-1,2-benzisoxazol-3- yl}carbonyl)amino]benzoic acid
5-cyano-2-[({5-cyano-6-[4- [(methoxycarbonyl)amino]-2- (trifluoromethyl)phenyl]-1 ,2-benzisoxazol-3- yl}carbonyl)amino]benzoic acid
Figure imgf000255_0001
Compound No., Structure Compound Name
2-[({5-acetyl-6-[4-
[(m ethoxycarbony l)am i no]-2-
(trifluoromethyl)phenyl]-1,2-benzisoxazol-3- yl}carbonyl)amino]-5-cyanobenzoic acid
2-[({5-(acetylamino)-6-[4- [(methoxycarbonyl)amino]-2- (trifluoromethyl)phenyl]-1,2-benzisoxazol-3- yl}carbonyl)amiπo]-5-cyanobenzoic acid
5-cyano-2-({[6-[4- [(methoxycarbonyl)amino]-2- (trifluoromethyl)phenyl]-5-(propionylamino)- 1,2-benzisoxazol-3- yl]carbonyl}amino)benzoic acid
Figure imgf000256_0001
Compound No., Structure Compound Name
2-[({5-(butyryiamino)-6-[4- [(methoxycarbonyl)amino]-2- (trifluoromethyl)phenyl]-1,2-benzisoxazol-3- yl}carbonyl)amino]-5-cyanobenzoic acid
2-[({5-[acetyl(methyl)amino]-6-[4- [(methoxycarbonyl)amino]-2- (trifluoromethyl)phenyl]-1,2-berιzisoxazol-3- yl}carbonyl)amino]-5-cyanobenzoic acid
5-cyano-2-[({5-[(methoxycarbonyl)amino]-6- [4-[(methoxycarbonyl)amino]-2- (trifluoromethyl)phenyl]-1,2-benzisoxazol-3- yl}carbonyl)amino]benzoic acid
Figure imgf000257_0001
Figure imgf000258_0001
Compound No., Structure Compound Name
5-cyano-2-[({6-[4- [(methoxycarbonyl)amino]-2- (trifluoromethyl)phenyl]-5- [(methylamino)carbonyl]-1,2-benzisoxazol-3- yl}carbonyl)amino]benzoic acid
2-({[5-(acetylamino)-6-(2-methylphenyl)-1,2- benzisoxazol-3-yl]carbonyl}amino)-5- cyanobenzoic acid
5-cyano-2-({[6-(2-methylphenyl)-5- (propionylamino)-1,2-benzisoxazol-3- yl]carbonyl}amino)benzoic acid
Figure imgf000259_0001
Compound No., Structure Compound Name
2-({[5-[acetyl(methyl)amino]-6-(2- methylphenyl)-1,2-benzisoxazόl-3- yl]carbonyl}amino)-5-cyanobenzoic acid
5-cyano-2-({[5-[(methoxycarbonyl)amino]-6- (2-methylphenyl)-1,2-benzisoxazol-3- yl]carbonyl}amino)benzoic acid
2-({[5-(aminosulfonyl)-6-(2-methylphenyl)- 1,2-benzisoxazol-3-yl]carbonyl}amino)-5- cyanobenzoic acid
Figure imgf000260_0001
Compound No., Structure Compound Name
5-cyano-2-({[5-[(methylamino)sulfonyl]-6-(2- methylphenyl)-1 ,2-benzisoxazol-3- yl]carbonyl}amino)benzoic acid
5-cyano-2-({[5-[(ethylamino)sulfonyl]-6-(2- methylphenyl)-1,2-benzisoxazol-3- yl]carbonyl}amino)benzoic acid
2-({[6-[4-(acetylamino)-2-methylphenyl]-5- (trifluoromethyl)-1,2-benzisoxazol-3- yl]carbonyl}amino)-5-cyanobenzoic acid
Figure imgf000261_0001
Compound No., Structure Compound Name
2-[({5-acetyl-6-[4-(acetylamino)-2- methylphenyl]-1,2-benzisoxazol-3- yl}carbonyl)amino]-5-cyanobenzoic acid
2-[({5-(acetylamino)-6-[4-(acetylamino)-2- methylphenyl]-1 ,2-benzisoxazol-3- yl}carbonyl)amino]-5-cyanobenzoic acid
2-({[6-[4-(acetylamino)-2-methylphenyl]-5-
(propionylamiπo)-1,2-benzisoxazol-3- yl]carbonyl}amino)-5-cyanobenzoic acid
Figure imgf000262_0001
Compound No., Structure Compound Name
2-[({6-[4-(acetylamino)-2-methylphenyl]-5- [acetyl(methyl)amino]-1,2-benzisoxazol-3- yl}carbonyl)amino]-5-cyanobenzoic acid
2-[({6-[4-(acetylamino)-2-methylphenyl]-5-
[methyl(propionyl)amino]-1,2-benzisoxazol-
3-yl}carbonyl)amino]-5-cyanobenzoic acid
2-[({6-[4-(acetylamino)-2-methylphenyl]-5-
[(methoxycarbonyI)amino]-1,2-benzisoxazol-
3-yl}carbonyl)amino]-5-cyanobenzoic acid
Figure imgf000263_0001
Compound No., Structure Compound Name
2-[({6-[4-(acetylamino)-2-methylphenyl]-5- ethoxy-1 ,2-benzisoxazol-3- yl}carbonyl)amino]-5-cyanobenzoic acid
2-({[6-[4-(acetylamino)-2-methylphenyl]-5-
(aminocarbonyl)-1,2-benzisoxazol-3- yl]carbonyl}amino)-5-cyanobenzoic acid
2-[({6-[4-(acetylamino)-2-methylphenyl]-5-
[(methylamino)carbonyl]-1,2-benzisoxazol-3- yl}carbonyl)amino]-5-cyanobenzoic acid
Figure imgf000264_0001
Compound No., Structure Compound Name
2-[({6-[4-(acetylamino)-2-methylphenyl]-5- [(ethylamino)carbonyl]-1,2-benzisoxazol-3- yl}carbonyl)amino]-5-cyanobenzoic acid
2-({[6-[4-(acetylamino)-2-methylphenyl]-5-
(aminosulfonyl)-1,2-benzisoxazol-3- yl]carbonyl}amino)-5-cyanobenzoic acid
2-{[(5-(acetylamino)-6-{4- [acetyl(methyl)amino]-2-methylphenyl}-1.2- benzisoxazol-3-yl)carbonyl]amino}-5- cyanobenzoic acid
Figure imgf000265_0001
Compound No., Structure Compound Name
2-({[6-{4-[acetyl(methyl)amino]-2- methylphenyl}-5-(propionylamino)-1,2- benzisoxazol-3-yl]carbonyl}amino)-5- cyanobenzoic acid
2-{[(5-[acetyl(methyl)amino]-6-{4- [acetyl(methyl)amino]-2-methylphenyl}-1.2- benzisoxazol-3-yl)carbonyl]amino}-5- cyanobenzoic acid
2-{[(5-(acetylamino)-6-{4- [(methoxycarbonyl)amino]-2-methylphenyl}- 1,2-benzisoxazol-3-yl)carbonyl]amino}-5- cyanobenzoic acid
Figure imgf000266_0001
Compound No., Structure Compound Name
5-cyano-2-{[(5-[(methoxycarbonyl)amino]-6- {4-[(methoxycarbonyl)amino]-2- methylphenyl}-1,2-benzisoxazol-3- yl)carbonyl]amino}benzoic acid
5-cyano-2-{[(5-methoxy-6-{4- [(methoxycarbonyl)amino]-2-methylphenyl}- 1 ,2-benzisoxazol-3- yl)carbonyl]amino}benzoic acid
2-({[5-(acetylamino)-6-(2-methoxyphenyl)- 1,2-benzisoxazol-3-yl]carbonyl}amino)-5- cyanobenzoic acid
Figure imgf000267_0001
Compound No., Structure Compound Name
5-cyano-2-({[6-(2-methoxyphenyl)-5- (propionylamino)-1,2-benzisoxazol-3- yl]carbonyl}amino)benzoic acid
2-({[5-[acetyl(methyl)amino]-6-(2- methoxyphenyl)-1,2-benzisoxazol-3- yl]carbonyl}amino)-5-cyanobenzoic acid
2-({[5-(aminosulfonyl)-6-(2-methoxyphenyl)- 1 ,2-benzisoxazol-3-yl]carbonyl}amino)-5- cyanobenzoic acid
Figure imgf000268_0001
Compound No., Structure Compound Name
5-cyano-2-[({6-(2-methoxyphenyl)-5- [(methylamino)sulfonyl]-1,2-benzisoxazol-3- yl}carbonyl)amino]benzoic acid
5-cyano-2-({[5-[(ethylamino)sulfonyl]-6-(2- methoxyphenyl)-1,2-benzisoxazol-3- yl]carbonyl}amino)benzoic acid
2-({[6-{4-[acetyl(methyl)amino]phenyl}-5-
(trifluoromethyl)-1,2-benzisoxazol-3- yl]carbonyl}amino)-5-cyanobenzoic acid
Figure imgf000269_0001
Compound No., Structure Compound Name
2-{[(5-acetyl-6-{4- [acetyl(methyl)amino]pheπyl}-1,2- benzisoxazol-3-yl)carbonyl]amino}-5- cyanobenzoic acid
2-{[(5-(acetylamino)-6-{4- [acetyl(methyl)amino]phenyl}-1,2- benzisoxazol-3-yl)carbonyl]amino}-5- cyanobenzoic acid
2-{[(6-{4-[acetyl(methyl)amino]phenyl}-5- methoxy-1 ,2-benzisoxazol-3- yl)carbonyl]amino}-5-cyanobenzoic acid
Figure imgf000270_0001
Compound No., Structure Compound Name
2-{[(5-(acetylamino)-6-{4- [(methoxycarbonyl)amino]phenyl}-1,2- benzisoxazol-3-yl)carbonyl]amino}-5- cyanobenzoic acid
2-{[(5-(aminosulfonyl)-6-{4- [(methoxycarbonyl)amino]phenyl}-1,2- benzisoxazol-3-yl)carbonyl]amino}-5- cyanobenzoic acid
2-[({5-(acetylamino)-6-[5-(acetylamino)-2- methoxyphenyl]-1,2-benzisoxazol-3- yl}carbonyl)amino]-5-cyanobenzoic acid
Figure imgf000271_0001
Compound No., Structure Compound Name
2-[({6-[5-(acetylamino)-2-methoxyphenyl]-5- [(methoxycarbonyl)amino]-1,2-benzisoxazol- 3-yl}carbonyl)amino]-5-cyanobenzoic acid
2-[({6-[5-(acetylamino)-2-methoxyphenyl]-5- methyl-1 ,2-benzisoxazol-3- yl}carbonyl)amino]-5-cyanobenzoic acid
2-({[6-{5-[acetyl(methyl)amino]-2- methoxyphenyl}-5-(trifluoromethyl)-1,2- benzisoxazol-3-yl]carbonyl}amino)-5- cyanobenzoic acid
Figure imgf000272_0001
Compound No., Structure Compound Name
2-{[(5-(acetylamino)-6-{2-methoxy-5- [(methoxycarbonyl)amino]phenyl}-1 ,2- benzisoxazol-3-yl)carbonyl]amino}-5- cyanobenzoic acid
2-({[5-(acetylamino)-6-pyridin-2-yl-1 ,2- benzisoxazol-3-yl]carbonyl}amino)-5- cyanobenzoic acid
2-({[5-(aminosulfonyl)-6-pyridin-3-yl-1 ,2- benzisoxazol-3-yl]carbonyl}amino)-5- cyanobenzoic acid
Figure imgf000273_0001
Compound No., Structure Compound Name
5-cyano-2-[({5-[(methylamino)sulfonyl]-6- pyridin-3-yl-1 ,2-benzisoxazol-3- yl}carbonyl)amino]benzoic acid
5-cyano-2-[({5-[(ethylamino)sulfonyl]-6- pyridin-3-yl-1 ,2-benzisoxazol-3- yl}carbonyl)amino]benzoic acid
2-({[5-(acetylamino)-6-pyridin-4-yl-1 ,2- benzisoxazol-3-yl]carbonyl}amino)-5- cyanobenzoic acid
Figure imgf000274_0001
Compound No., Structure Compound Name
2-({[5-(aminosulfonyl)-6-pyridin-4-yl-1 ,2- benzisoxazol-3-yl]carbonyl}amino)-5- cyanobenzoic acid
5-cyano-2-[({5-[(methylamino)sulfonyl]-6- pyridin-4-yl-1,2-benzisoxazol-3- yl}carbonyl)amino]benzoic acid
5-cyano-2-[({5-[(ethylamino)sulfonyl]-6- pyridin-4-yl-1 ,2-benzisoxazol-3- yl}carbonyl)amino]benzoic acid
Figure imgf000275_0001
Compound No., Structure Compound Name
2-({[5-(acetylamino)-6-pyrazin-2-yl-1,2- benzisoxazol-3-yl]carbonyl}amino)-5- cyanobenzoic acid
2-({[5-(acetylamino)-6-pyridazin-3-yl-1 ,2- benzisoxazol-3-yl]carbonyl}amino)-5- cyanobenzoic acid
2-({[5-(acetylamino)-6-pyridazin-4-yl-1 ,2- benzisoxazol-3-yl]carbonyl}amino)-5- cyanobenzoic acid
Figure imgf000276_0001
Compound No., Structure Compound Name
2-({[5-(amiπosulfonyl)-6-pyridazin-4-yl-1 ,2- benzisoxazol-3-yl]carbonyl}amino)-5- cyanobenzoic acid
5-cyano-2-[({5-[(methylamino)sulfonyl]-6- pyridazin-4-yl-1 ,2-benzisoxazol-3- yl}carbonyl)amino]benzoic acid
Figure imgf000277_0001
Compounds ofthe invention may also be prepared via a direct coupling shown below.
Figure imgf000277_0002
A 50 mL 3-neck round bottom flask was equipped with a J-Kem thermocouple, septum, stir bar and a nitrogen inlet. The flask was heated with a heat gun under nitrogen, cooled to room temperature and tert-butyl 2-aιrιino-5-cyanobenzoate was charged. A 100 mL 3-neck round bottom flask was equipped with a J-Kem thermocouple, septum, stir bar and a nitrogen inlet. The flask was heated with a heat gun under nitrogen, cooled to room temperature and ethyl 5-bromo-l,2-benzisoxazole- 3-carboxylate was charged. Anhydrous DMF was added to the flask containing tert- butyl 2-amino-5-cyanobenzoate yielding an orange solution. This solution was cooled with an ice water bath to less than 5 °C and KOtBu was added in 5 portions keeping the temperature below 5 °C. The KOtBu additions resulted in a darkening ofthe solution.
Initial T KOtBu added Final T
1st addition 1.4 °C about 250 mg 2.6 °C
2nd addition 2.5 °C about 800 mg 4.4 °C
3rd addition 2.1 °C about 800 mg 4.3 °C
4th addition 2.0 °C about 800 mg 3.7 °C
5th addition — about 100 mg 3.7 °C
After the KOtBu addition was complete, the solution was allowed to warm to > 20 °C, and the solution was held at >20 °C for 1 hour before re-cooling with and ice water bath to < 5 °C. Anhydrous DMF was added to ethyl 5-bromo-l,2-benzisoxazole-3- carboxylate to yield a pale yellow solution, which was cooled to < 5 °C with an ice water bath. Keeping both solutions < 5 °C, the tert-butyl 2-amino-5-cyanobenzoate solution was transfeπed via cannula over 5 to 10 minutes to the ester solution and a mild exotherm was noted (T^x 4.5 °C). After the addition was complete, the flask was rinsed with DMF, and the mixture was stiπed at < 5 °C. The reaction was assayed by HPLC after 1 hour, and it showed 87%> conversion to the desired product (1.8% starting material). The reaction was called complete at this point and workup was conducted by quenching the reaction into IN HCl and CH2C12. The CH2C12 layer was removed, and the aqueous was back extracted with CH2C12. The combined organics were washed two times with water and dried over MgSO . The crude organic was filtered and concentrated on the roto vap at 40 °C to an orange semisolid, which after 1 hour at room temperature on high vacuum weighed 20.97 g, 200 wt%. The assay by lH NMR showed a significant amount of DMF in the crude. The sample was purified by adding MeOH and heating the slurry between 50 and 55 °C for 30 minutes followed by cooling to < 5 °C. The slurry was held at this temperature for 1 hour before isolating the product via filtration using a medium frit. The white product cake was rinsed with MeOH, precooled to <5 °C, and dried to constant weight of 8.02 g on high vacuum, 76.4% yield (98.4 area% by HPLC).
Example 7: R4 as Isoxazol and Derivatives Thereof
Example 7.1: Methyl 5-cyano-2-[(E)-2-(5-phenylisoxazol-3-yl)ethenyl]benzoate
Figure imgf000279_0001
Methyl 2- {[bromo(triphenyl)phosphoranyl]methyl} -5-cyanobenzoate ( 1.7 g mg, 3.46 mmol) in DMSO (20 mL) followed by the addition of NaH (140 mg, 3.4 mmol). Gas evolution was observed, the reaction was heated to 60 °C for 2h, then cooled to rt and
5-phenylisoxazole-3-carbaldehyde (500 mg, 2.8 mmol) was added and the reaction was stiπed at rt for 2 h. The mixture was diluted with MTBE, washed with H2O, brine, dried (MgSO ), filtered and concentrated in vacuo. The residue was purified by silica gel plug (DCM) to afford 996 mg of a Z/E mixture. The solid was dissolved in toluene (40 mL) followed by the addition of thiophenol (32 μL, 0.28 mmol) and AIBN (14 mg,
0.08 mmol). The reaction was heated at reflux for 12 h, then concentrated in vacuo.
The residue was recrystallized from MeOH to afford 686 mg (72%) of the title compound.
Analytical data
1H NMR (300 MHz, CDC13) δ 8.32 (s, 1 H), 8.20 (d, J= 16.4 Hz, 1 H), 7.87-7.68 (m, 4 H), 7.52-7.50 (m, 3 H), 7.26 (d, J= 16.4 Hz, 1 H), 5.68 (s, 1 H), 4.00 (s, 3 H).
Example 7.2: 5-Cyano-2-[(E)-2-(5-phenylisoxazol-3-yl)ethenyl]benzoic acid
Figure imgf000279_0002
The compound of example 7.1 (250 mg, 0.75 mmol) was dissolved in THF (10 mL) and 6N NaOH (5 mL) was added, the resulting mixture was stiπed for 16h at rt, then diluted with MTBE, washed with IN HCl, H2O, brine, dried (MgSO4) filtered and concentrated in vacuo. The residue was recrystallized from MeOH to afford 177 mg
(74%») ofthe title compound. Analytical data
1H NMR (400 MHz, OMSO-d6) δ 13.80 (s, 1 H), 8.27 (d, J= 1.6 Hz, 1 H), 8.14-8.04 (m, 3 H), 7.93 (dd, 7= 1.7, 8.0 Hz, 2 H), 7.59-7.51 (m, 3 H), 7.44 (s, 1 H), 7.36 (d, J = 16.4 Hz, I H).
Example 7.3: Methyl 5-chloro-2-[(E)-2-(5-phenylisoxazol-3-yl)ethenyl]benzoate
Figure imgf000280_0001
Methyl 2- {[bromo(triphenyl)phosphoranyl]methyl}-5-chlorobenzoate (3.6 g mg, 6.7 mmol) in DMSO (40 mL) followed by the addition of NaH (270 mg, 6.7 mmol). Gas evolution was observed, the reaction was heated to 60 °C for 2h, then cooled to rt and 5-phenylisoxazole-3-carbaldehyde (838 mg, 4.8 mmol) was added and the reaction was stiπed at rt for 2 h. The mixture was diluted with MTBE, washed with H2O, brine, dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by silica gel plug (DCM) to afford 996 mg of a Z/E mixture. The solid was dissolved in toluene (40 mL) followed by the addition of thiophenol ( 100 μL) and AIBN ( 14 mg) . The reaction was heated at reflux for 12 h, then concentrated in vacuo. The residue was recrystallized from MeOH to afford 1.07 g (69%) ofthe title compound.
Analytical data 1H NMR (400 MHz, DMSO- 6) δ 8.01-7.92 (m, 4 H), 7.88 (d, J= 2.3 Hz, 1 H), 7.72 (dd, J= 2.2, 8.4 Hz, 1 H), 7.59-7.53 (m, 3 H), 7.43 (s, 1 H), 7.25 (d, J= 16.4 Hz, 1 H), 3.91 (s, 3 H).
Example 7.4: 5-Chloro-2-[(E)-2-(5-phenyUsoxazol-3-yl)ethenyl]benzoic acid
Figure imgf000280_0002
The compound of example 7.3 (312 mg, 0.92 mmol) was dissolved in THF (20 mL) and 6N NaOH (5 mL) was added, the resulting mixture was stiπed for 18h at rt, then diluted with MTBE, washed with IN HCl, H2O, brine, dried (MgSO4) filtered and concentrated in vacuo. The residue was recrystallized from MeOH to afford 264 mg (88%) ofthe title compound. Analytical data
1H NMR (400 MHz, DMSO- d6) δ 13.50 (s, 1 H), 8.04 (d, J= 16.4 Hz, 1 H), 8.02- 7.88 (m, 4 H), 7.70-7.67 (m, 1 H), 7.58-7.52 (m, 3 H), 7.40 (s, 1 H), 7.20 (d, J= 16.4 Hz, 1 H).
Preparation of 5-(2-Fluorophenyl)isoxazole-3-carboxylic acid
Figure imgf000281_0001
General method A: l-ethynyl-2-fluorobenzene (1 g, 8.33 mmol) and dimethyl 2- nitromalonate (1.34 g, 7.58 mmol) were dissolved in mesitylene (10 ml). The solution was heated at 150°C for about 12 h. Mesitylene was removed in vacuo and the residue was recrystallized from ethanol. 1.22 g (73%) of methyl 5-(2-fluorophenyl)isoxazole- 3-carboxylate was yielded as a light brown solid, which was hydrolyzed in MeOH (10 ml) and water (5 ml) by LiOH*H2O (0.7 g, 16.6 mmol) to afford 0.8 g (70%) ofthe title compound as a light brown solid.
Analytical data lH NMR (400 MHz, OMSO-d6) 5 8.01 (dt, J= 1.7, 7.7 Hz, 1 H), 7.84 (m, 1 H), 7.49
(m, 1 H), 7.43 (dt, J= 1.3, 7.7 Hz, 1 H), 7.16 (d, J= 3.1 Hz, 1 H)
Example 7.5: 5-Cyano-2-({[5-(2-fluorophenyl)isoxazol-3- yl] carbonyl} amino)benzoic acid
Figure imgf000281_0002
General method B: 5-(2-fluorophenyl)isoxazole-3-carboxylic acid (300 mg, 1.46 mmol), DCM (10 ml) and oxyl chloride (0.5 ml) were place in a flask, followed by the addition of on drop of DMF. The solution was stiπed at room temperature for about 50 min. Then the solvent was removed and the residue was pumped high vacuum for 5 min. The residue was dissolved in DCM (5 ml). Tert-butyl-2-amino-5-cyano benzoate (289 mg, 1.32 mmol) was added and followed by the addition of pyridine (0.4 ml). The resulting solution was stiπed overnight, then diluted with MTBE (200 ml) and washed with IN HCl, IN NaOH, brine, dried (MgSO ), filtered, and concentrated in vacuo. The residue was recrystallized from MeOH to afford 320 mg (59%) of t-butyl ester as a white solid, 300 mg of which was hydrolyzed by TFA (2 ml) in DCM (8 ml) to afford 225 mg (87%) of a white solid.
General method C: 5-(2-fluorophenyι)isoxazole-3-carboxylic acid (4000 mg, 19.4 mmol) was dissolved in thionyl chloride (40 ml) and the resulting mixture was heated at refluxing temperature overnight. Toluene (30 ml) was added and the solution was concentrated in vacuo. The residue was re-dissolved in DCM (40 ml) followed by the addition of tert-butyl-2-amino-5-cyano benzoate (3530 mg, 16.2 mmol) and pyridine (5.2 ml) and the mixture was stiπed overnight. The resulting solution was diluted with MTBE (200 ml), washed with IN HCl , IN NaOH, brine and dried (MgSO4). The solution was concentrated in vacuo and the residue was washed with MeOH to afford 5800 mg (88%>) of t-butyl ester as a white solid, which was hydrolyzed by TFA (6 ml) in DCM ( 10 ml) to afford 5000 mg ( 100%) of a white solid.
Analytical data
1H NMR (300 MHz, CDC13) δ 12.75 (s, J= Hz, 1 H), 8.84 (d, J= 8.9 Hz, 1 H), 8.43 (d, J= 1.9 Hz, 1 H), 8.14 (dd, J= 1.9, 8.7 Hz, 1 H), 8.05 (t, J= 7.7 Hz, 1 H), 7.65 (m, 1 H), 7.47 (m, 2 H), 7.32 (d, J= 2.8 Hz, 1 H)
Example 7.6: 5-Bromo-2-({[5-(2-fluorophenyl)isoxazol-3- yl] carb onyl} amino)b enzoic acid
Figure imgf000283_0001
Prepared according to the General method C: 5-(2-fluorophenyl)isoxazole (300 mg, 1.46 mmol) and tert-butyl-2-amino-5-bromobenzoate (329 mg, 1.21 mmol) afforded 360 mg (54%) of t-butyl ester as a white solid, which was hydrolyzed by TFA (2 ml) in DCM (8 ml) to afford 330 mg (100%) of a white solid.
Analytical data
1H NMR (400 MHz, OMSO-d6) δ 12.44 (s, 1 H), 8.64 (d, J= 9.0 Hz, 1 H), 8.13 (d, J = 2.5 Hz, 1 H), 8.04 (dt, J= 1.3, 7.7 Hz, 1 H), 7.89 (dd, J= 2.5, 9.0 Hz, 1 H), 7.64 (m, 1 H), 7.16 (m, 2 H), 7.27 (d, J= 2.8 Hz, 1 H)
Example 7.7: 5-Chloro-2-({[5-(2-fluorophenyl)isoxazol-3- yl] carb onyl} amino)b enzoic acid
Figure imgf000283_0002
Prepared according to the General method C making non-critical variations.
Analytical data
1H NMR (300 MHz, OMSO-d6) δ 8.69 (d, J= 9.1 Hz, 1 H), 8.04 (dt, J= 1.7, 7.7 Hz, 1 H), 8.00 (d, J= 2.8 Hz, 1 H), 7.78 (dd, J= 2.6, 8.9 Hz, 1 H), 7.65 (m, 1 H), 7.46 (m, 2 H), 7.29 (d, J= 2.8 Hz, 1 H). Preparation of l-Ethynyl-2-methylbenzene
Figure imgf000284_0001
General procedure D: l-iodo-2-methylbenzene (2000 mg, 9.2 mmol), Cul (699 mg, 3.7mmol), and dichlorobis(triphenylphosphine) palladium(0) (644 mg, 0.92 mmol) were place in a 100 ml one-necked flask. The system was evacuated and filled with argon several times. THF (30 ml) and triethylamine (30 ml) were added, followed by the addition of ethynyl(trimethyl)silane (9.0 g, 92 mmol). The mixture was stiπed at refluxing temperature overnight. Then the resulting mixture was diluted with MTBE (200 ml) and washed with IN HCl, IN NaOH, and dried (MgSO4). The solution was concentrated and the residue was purified by flash chromatography
(Heptane/EtOAc=l 000/0, 1000/10) to afford 2.2 g of crude trimethyl[(2- methylphenyl)ethynyl] silane as a brown oil. The TMS group was removed by KF (2.0 g, 35 mmol) in MeOH (10 ml) to afford a 310 mg (29% in 2 steps) of l-ethynyl-2- methylbenzene as brown oil.
Preparation of 5-(2-Methylphenyl)isoxazole-3-carboxylic acid
Figure imgf000284_0002
Prepared according to the general method A: l-ethynyl-2-methylbenzene (310 mg, 2.67 mmol) and dimethyl 2-nitromalonate (430 mg, 2.43 mmol) to afford 200 mg (38%) of methyl 5-(2-methylphenyl)isoxazole-3-carboxylate as a yellow oil, which was hydrolyzed in MeOH (10 ml) and water (5 ml) by LiOH*H2O (116 mg, 2.76 mmol) to afford 150 mg (80%>) of a light yellow solid.
Example 7.8: 5-Cyano-2-({[5-(2-methylphenyl)isoxazol-3- yl] carb onyl} am ino)b enzoic acid
Figure imgf000285_0001
Prepared according to the General method C making non-critical variations with 5-(2- methylphenyl)isoxazole-3-carboxylic acid (140 mg, .7 mmol) and tert-butyl-2-amino- 5-cyano benzoate (125 mg, 0.6mmol).
Analytical data
1H NMR (300 MHz, OMSO-d6) δ 12.78 (s, 1 H), 8.86 (d, J= 8.9 Hz, 1 H), 8.44 (d, J = 2.1 Hz, 1 H), 8.15 (dd, 7= 2.1, 8.7 Hz, 1 H), 7.82 (d, J= 7.7 Hz, 1 H), 7.45 (m, 3 H), 7.34 (s, 1 H), 2.53 (s, 3 H).
Example 7.9: 5-Chloro-2-{[(5-phenylisoxazol-3-yl)carbonyl]amino}benzoic acid
Figure imgf000285_0002
Prepared according to the General method C making non-critical variations.
Analytical data
1H NMR (300 MHz, OMSO-d6) δ 12.43 (s, 1 H), 8.73 (d, J= 9.0 Hz, 1 H), 8.02 (d, J = 2.6 Hz, 2 H), 7.99 (dd, J= 2.1, 5.5 Hz, 1 H), 7.78 (dd, J= 2.8, 9.0 Hz, 1 H), 7.68 (m, 4 H). Example 7.10: 5-Cyano-2-{[(5-methyhsoxazol-3-yl)carbonyl]amino}benzoic acid
Figure imgf000286_0001
Prepared according to the general method B: 5-methylisoxazole-3-carbonyl chloride (300 mg, 2.1 mmol) and tert-butyl-2-amino-5-cyano benzoate (409 mg, 1.9 mmol) afforded 98 mg (16%) of a white solid, 90 mg of which was hydrolyzed by TFA (2 ml) in DCM (8 ml) to afford 52 mg (74%) ofthe title compound as a white solid.
Analytical data
1H NMR (300 MHz, DMSO- 6) δ 12.64 (s, 1 H), 8.82 (d, J= 8.9 Hz, 1 H), 8.42 (d, J = 1.9 Hz, I H), 8.13 (dd, J= 2.1, 8.9 Hz, I H), 6.76 (s, 1 H), 2.52 (s, 3 H).
Preparation of 5-[4-(Trifluoromethyl)phenyl]isoxazole-3-carboxylic acid
Figure imgf000286_0002
Prepared according to the general method A: l-ethynyl-2-trifluoromethylbenzene (3.2 g, 18.8 mmol) and dimethyl 2-nitromalonate (3.03 g, 17.0 mmol) to afford 1.9 g (43%>) of methyl 5-(2-trifluoromethylphenyl)isoxazole-3-carboxylate as a yellow solid, which was hydrolyzed in MeOH (40 ml) and water (20 ml) by LiOH«H2O (883 mg, 21 mmol) to afford 1.8 g (100%) of a white solid.
Analytical data
1H NMR (400 MHz, OMSO-d6) δ 14.17 (s, 1 H), 8.19 (d, J= 8.3 Hz, 2 H), 7.94 (d, J = 8.5 Hz, 2 H), 7.64 (s, 1 H). Example 7.11 : 5-Cyano-2- [({5- [4-(trifluoromethyl)phenyl] isoxazol-3- yl}carbonyl)amino]benzoic acid
Figure imgf000287_0001
Prepared according to the General method B: 5-[4-(trifluoromethyl_phenyl]isoxazole- 3 -carboxylic acid (256 mg, .1 mmol) and tert-butyl-2-amino-5-cyano benzoate (196 mg, 0.9 mmol) afforded 190 mg (46%) of t-butyl ester as a white solid, which was hydrolyzed by TFA (2 ml) in DCM (8 ml) to afford 160 mg (96%) of a white solid.
Analytical data 1H NMR (300 MHz, DMSO- 6) δ 12.79 (s, 1 H), 8.86 (d, J= 8.9 Hz, 1 H), 8.44 (d, J = 2.1 Hz, 1 H), 8.23 (d, J= 8.1 Hz, 2 H), 8.15 (dd, J= 2.1, 8.7 Hz, 1 H), 7.97 (d, J = 8.3 Hz, 2 H), 7.83 (s, 1 H).
Example 7.12 : 5-Bromo-2- [ ({5- [4-(trifluoromethyl)phenyl] isoxazol-3- yl}carbonyl)amino]benzoic acid
Figure imgf000287_0002
Prepared according to the General method C making non-critical variations. Analytical data
1H NMR (400 MHz, DMSO--i6) δ 12.47 (s, 1 H), 8.65 (d, J= 8.9 Hz, 1 H), 8.23 (d, J = 8.1 Hz, 2 H), 8.14 (d, J= 2.5 Hz, 1 H), 7.95 (d, J= 8.3 Hz, 2 H), 7.90 (dd, J= 2.5, 8.9 Hz, 1 H), 7.79 (s, 1 H).
Example 7.13 : 5-Chloro-2- [({5- [4-(trifluoromethyl)phenyl] isoxazol-3- yl}carbonyl)amino]benzoic acid
Figure imgf000288_0001
Prepared according to the General method C making non-critical variations.
Analytical data
1H NMR (400 MHz, DMSO--i6) δ 12.47 (s, 1 H), 8.72 (d, J= 8.9 Hz, 1 H), 8.23 (d, J = 8.1 Hz, 2 H), 8.01 (d, J= 2.7 Hz, 1 H), 7.96 (d, J= 8.5 Hz, 2 H), 7.79 (s, 1 H), 7.78 (dd, J= 2.7, 8.9 Hz, 1 H).
Preparation of 4-Ethynyl-3,5-dimethylisoxazole [36306-jl-69]
Figure imgf000288_0002
General procedure D: 4-iodo-3,5-dimethylisoxazole (2230 mg, 10 mmol), Cul (720 mg, 3.8 mmol), and dichlorobis(triphenylphosphine) palladium(O) (310 mg, 0.47 mmol) were place in a 100 ml one-necked flask. The system was evacuated and filled with argon several times. THF (30 ml) and triethylamine (30 ml) were added, followed by the addition of ethynyl(trimethyl)silane 11 ml, 150 mmol. The mixture was stiπed at refluxing temperature overnight. Then the resulting mixture was diluted with MTBE (200 ml) and washed with IN HCl, IN NaOH, and dried (MgSO4). The solution was concentrated and the residue was purified by flash chromatography (Heptane/EtOAc=l 000/0, 1000/10) to afford 1.7 g of trimethyl[(2- methylphenyl)ethynyl] silane as a brown oil. The TMS group was removed by KF (1.5 g, 26 mmol) in MeOH (10 ml) to afford a 690 mg (57% in 2 steps) of 4-Ethynyl-3,5- dimethylisoxazole as brown solid.
Analytical data
1H NMR (300 MHz, CDC13) δ 3.21 (s, 1 H), 2.47 (s, 3 H), 2.31 (s, 3 H);
Preparation of 3,5-Dimethyl-4,5'-biisoxazole-3,-carboxylic acid
Figure imgf000289_0001
Prepared according to the general method A: 4-Ethynyl-3,5-dimethylisoxazole (690 mg, 5.7 mmol) and dimethyl 2-nitromalonate (918 mg8.2 mmol) to afford 770 mg (67%) of methyl ester as a brown solid, which was hydrolyzed in MeOH (40 ml) and water (20 ml) by LiOH«H2O (437 mg, 10.4 mmol) to afford 730 mg (100%) of a white solid.
Analytical data
1H NMR (300 MHz, DMSO- 6) δ 7.08 (s, 1 H), 2.65 (s, 3 H), 2.42 (s, 3 H).
Example 7.14: 5-Cyano-2-{[(3,5-dimethyl-4,5,-biisoxazol-3'- yl)carbonyl]amino}benzoic acid
Figure imgf000289_0002
Prepared according to the General method C: 3,5-dimethyl-4,5'-biisoxazole-3'- carboxylic acid (350 mg, 1.68 mmol) and tert-butyl-2-amino-5-cyano benzoate (306 mg, 1.4 mmol) afforded 380 mg (55%>) of t-butyl ester as a white solid, 375 mg of which was hydrolyzed by TFA (2 ml) in DCM (8 ml) to afford 290 mg (90%) of a white solid.
Analytical data
1H NMR (400 MHz, DMSO--i«) δ 12.74 (s, 1 H), 8.84 (d, J= 8.9 Hz, 1 H), 8.43 (d, J = 2.1 Hz, 1 H), 8.15 (dd, 7= 2.1, 8.9 Hz, 1 H), 7.25 (s, 1 H), 2.69 (s, 3 H), 2.46 (s, 3 H).
Preparation of 5-(4-Methoxyphenyl)isoxazole-3-carboxylic acid
Figure imgf000290_0001
Prepared according to the general method A: l-ethynyl-4-methoxybenzene (1000 mg, 7.6 mmol) and dimethyl 2-nitromalonate (1220 mg, 6.9 mmol) to afford 1100 mg (68%) of methyl ester as a brown solid, which was hydrolyzed in MeOH (40 ml) and water (20 ml) by LiOH»H2O (594 mg, 14.2 mmol) to afford 1000 mg (97%) of a brown solid.
Analytical data
1H NMR (300 MHz, CD3OD) δ 7.73 (m, 2 H), 6.98 (m, 2 H), 6.81 (s, 1 H), 3.85 (s, 3 H).
Example 7.15: 5-Cyano-2-({[5-(4-methoxyphenyl)isoxazol-3- yl]carbonyl}amino)benzoic acid
Figure imgf000291_0001
Prepared according to the General method B: 5-(4-methoxyphenyι)isozazole-3- carboxylic acid (300 mg, 1.37 mmol) and tert-butyl-2-amino-5-cyano benzoate (271 mg, 1.25 mmol) afforded 240 mg (46%>) of t-butyl ester as a white solid, which was hydrolyzed by TFA (2 ml) in DCM (8 ml) to afford 200 mg (96%) of a white solid.
Analytical data
1H NMR (300 MHz, OMSO-d6) δ 12.70 (s, 1 H), 8.85 (d, 7= 8.9 Hz, 1 H), 8.42 (d, 7 = 1.9 Hz, I H), 8.14 (dd, 7= 1.9, 8.7 Hz, 1 H), 7.94 (d, 7= 8.9 Hz, 2 H), 7.45 (s, 1 H), 7.13 (d, 7= 8.9 Hz, 2 H), 3.85 (s, 3 H).
Example 7.16: 5-Bromo-2-({[5-(4-methoxyphenyl)isoxazol-3- yl] carbonyl} amino)benzoic acid
Figure imgf000291_0002
Prepared according to the General method C: 5-(4-methoxyphenyl)isoxazole-3- carboxylic (300 mg, 1.37 mmol) and tert-butyl-2-amino-5-bromo benzoate (309 mg, 1.14 mmol) afforded 450 mg (69%) of t-butyl ester as a white solid, 440mg of which was hydrolyzed by TFA (2 ml) in DCM (8 ml) to afford 330 mg (85%) of a white solid.
Analytical data 1H NMR (400 MHz, OMSO-d6) δ 12.39 (s, 1 H), 8.66 (d, 7= 8.9 Hz, 1 H), 8.14 (d, 7 = 2.5 Hz, 1 H), 7.92 (m, 3 H), 7.42 (s, 1 H), 7.12 (d, 7= 8.9 Hz, 2 H), 3.85 (s, 3 H).
Example 7.17: 5-Chloro-2-({[5-(4-methoxyphenyl)isoxazol-3- yl] carb onyl} amino)b enzoic acid
Figure imgf000292_0001
Prepared according to the General method C: making non-critical variations.
Analytical data
1H NMR (400 MHz, DMSO--f6) δ 12.41 (s, 1 H), 8.72 (d, 7= 8.9 Hz, 1 H), 8.02 (d, 7 = 2.7 Hz, 1 H), 7.94 (d, 7= 8.7 Hz, 2 H), 7.78 (dd, 7= 2.7, 8.9 Hz, 1 H), 7.43 (s, 1 H), 7.12 (d, 7= 8.9 Hz, 2 H), 3.85 (s, 3 H).
Preparation of 5-(2-Chlorophenyl)isoxazole-3-carboxylic acid
Figure imgf000293_0001
Prepared according to the general method A: l-ethynyl-2-chlorobenzene (2000 mg, 14.6 mmol) and dimethyl 2-nitromalonate (2356 mg, 13.2 mmol) to afford 1850 mg (59%) of methyl ester as a orange solid, which was hydrolyzed in MeOH (40 ml) and water (20 ml) by LiOH»H2O (980 mg, 23.4 mmol) to afford 1500 mg (86%) of a orange solid.
Analytical data 1H NMR (400 MHz, DMSO-^) δ 7.97 (m, 1 H), 7.71 (m, 1 H), 7.58 (m, 2 H), 7.34 (s, 1 H).
Example 7.18: 2-( { [ 5-(2-Chlorophenyl)isoxazol-3-yl] carb onyl} amino)-5- cyanobenzoic acid
Figure imgf000293_0002
Prepared according to the General method B: making non-critical variations. Analytical data
1H NMR (300 MHz, OMSO-d6) δ 12.75 (s, 1 H), 8.84 (d, 7= 8.9 Hz, 1 H), 8.43 (d, 7 = 1.9 Hz, I H), 8.15 (dd, 7= 1.7, 8.9 Hz, 1 H), 8.01 (dd, 7= 1.7, 6.8 Hz, 1 H), 7.73 (d, 7= 7.4 Hz, 1 H), 7.60 (m , 2 H), 7.50 (s, 1 H).
Example 7.19: 5-Bromo-2-({[5-(2-chlorophenyϊ)isoxazol-3- yl] carbonyl} amino)benzoic acid
Figure imgf000294_0001
Prepared according to the General method C: making non-critical variations.
Analytical data
1H NMR (300 MHz, DMSO-e?6) δ 12.46 (s, 1 H), 8.64 (d, 7= 8.9 Hz, 1 H), 8.14 (d, 7 = 2.5 Hz, 1 H), 8.00 (m, 1 H), 7.90 (dd, 7= 2.5, 9.1 Hz, 1 H), 7.73 (m, 1 H), 7.60 (m, 2 H), 7.46 (s, 1 H).
Example 7.20: 5-Chloro-2-({[5-(2-chlorophenyl)isoxazol-3- yl] carbonyl} amino)benzoic acid
Figure imgf000294_0002
Prepared according to the General method C: making non-critical variations. Analytical data
1H NMR (300 MHz, DMSO-rf6) δ 12.40 (s, 1 H), 8.70 (d, 7= 9.1 Hz, 1 H), 8.00 (m, 2
H), 7.63 (dd, 7= 2.6, 9.0 Hz, 1 H), 7.72 (m, 1 H), 7.60 (m, 2 H), 7.47 (s, 1 H).
Preparation of l-Ethynyl-2-(trifluoromethyl)benzene
Figure imgf000295_0001
General procedure D: l-iodo-2-(trifluoromethyl)benzene (2720 mg, 10 mmol), Cul (720 mg, 3.8 mmol), and dichlorobis(triphenylphosphine) palladium(0) (310 mg, 0.47 mmol) were place in a 100 ml one-necked flask. The system was evacuated and filled with argon several times. THF (30 ml) and triethylamine (30 ml) were added, followed by the addition of ethynyl(trimethyl)silane 11 ml, 150 mmol. The mixture was stiπed at refluxing temperature overnight. Then the resulting mixture was diluted with MTBE (200 ml) and washed with IN HCl, IN NaOH, and dried (MgSO4). The solution was concentrated and the residue was purified by flash chromatography (Heptane/EtOAc= 1000/0, 1000/10) to afford 2.6 g of trimethyl[(2- methylphenyl)ethynyl] silane as a brown oil. The TMS group was removed by KF (1.9 g, 32 mmol) in MeOH (30 ml) to afford a 1.6 g (94% in 2 steps) of l-Ethynyl-2- (trifluoromethyl)benzene as a brown oil.
Analytical data
1H NMR (300 MHz, CDC13) δ 7.56 (t, J= 6.8 Hz, 2 H), 7.40 (t, 7= 7.3 Hz, 1 H), 7.34 (t, 7= 7.7 Hz, 1 H), 3.27 (s, 1 H);
Preparation of 5-[2-(Trifluoromethyl)phenyl]isoxazole-3-carboxylic acid
Figure imgf000295_0002
Prepared according to the general method A: l-Ethynyl-2-(trifluoromethyl)benzene (1600mg, 9.4 mmol) and dimethyl 2-nitromalonate (1514 mg, 8.56 mmol) to afford 1340 mg (52%) of methyl ester as a brown solid, which was hydrolyzed in MeOH (40 ml) and water (20 ml) by LiOH»H2O (623mg, 14.8 mmol) to afford 1180 mg (93%) of a brown solid.
Analytical data 1H NMR (300 MHz, DMSO-G?6) δ 12.41 (s, 1 H), 7.99 (d, 7= 7.4 Hz, 1 H), 7.85 (m, 3 H), 7.18 (s, I H).
Example 7.21 : 5-Cyano-2- [({5- [2-(trifluoromethyl)phenyl] isoxazol-3- yl}carbonyl)amino]benzoic acid
Figure imgf000296_0001
Prepared according to the General method C: 5-[2-(trifluoromethyl)phenyl]isoxazole-
3-carboxylic acid (300 mg, 1.17 mmol) and tert-butyl-2-arnino-5-cyanobenzoate (212 mg, 1.0 mmol) afforded 420 mg (79%>) of t-butyl ester as a white solid, 355 mg of which was hydrolyzed by TFA (2 ml) in DCM (8 ml) to afford 250 mg (80%) of a white solid.
Analytical data
1H NMR (400 MHz, OMSO-d6) δ 12.78 (s, 1 H), 8.83 (d, 7= 8.7 Hz, 1 H), 8.44 (d, 7 = 2.1 Hz, I H), 8.16 (dd, 7= 2.1, 8.7 Hz, 1 H), 8.02 (d, 7= 7.7 Hz, 1 H), 7.91 (m, 3 H), 7.38 (s, 1 H)
Example 7.22: 5-Bromo-2-[({5-[2-(trifluoromethyl)phenyl]isoxazol-3- yl}carbonyl)amino]benzoic acid
Figure imgf000297_0001
Prepared according to the General method C: making non-critical variations.
Analytical data 1H NMR (400 MHz, DMSO-ci6) δ 12.47 (s, 1 H), 8.64 (d, 7= 8.9 Hz, 1 H), 8.15 (d, 7 = 2.5 Hz, 1 H), 8.02 (d, 7= 7.7 Hz, 1 H), 7.90 (m, 3 H), 7.34 (s, 1 H).
Example 7.23: 5-Chloro-2-[({5-[2-(trifluoromethyl)phenyl]isoxazol-3- yl}carbonyl)amino]benzoic acid
Figure imgf000297_0002
Prepared according to the General method C: making non-critical variations.
Analytical data
1H NMR (400 MHz, DMSO- .) δ 12.47 (s, 1 H), 8.70 (d, 7= 9.1 Hz, 1 H), 8.02 (dd, 7= 5.2, 2.7 Hz, 2 H), 7.91 (m, 4 H), 7.35 (s, 1 H).
Preparation of 4-Methyl-5-phenylisoxazole-3-carboxylic acid
Figure imgf000298_0001
Prepared according to the general method A: prop-1-ynylbenzene (2000mg, 17.2 mmol) and dimethyl 2-nitromalonate (2770 mg, 15.7 mmol) to afford 930 mg (25%) of methyl ester as a brown solid, which was hydrolyzed in MeOH (20 ml) and water (10 ml) by LiOH«H2O (540mg, 12.9 mmol) to afford 910 mg (10%) of a brown solid.
Analytical data
1H NMR (400 MHz, DMSO-rf6) δ 7.76 (dd, 7= 1.7, 8.3 Hz, 2 H), 7.59 (m, 3 H), 2.36
(s, 3 H);
Example 7.24: 5-Cyano-2-{[(4-methyl-5-phenylisoxazol-3- yl)carbonyl]amino}benzoic acid
Figure imgf000298_0002
Prepared according to the General method C: 4-methyl-5-phenylisoxazole-3-carboxylic acid (300 mg, 1.48 mmol) and tert-butyl-2-amino-5-cyano benzoate (268 mg, 1.2 mmol) afforded 360 mg (60%) of t-butyl ester as a white solid, 355 mg of which was hydrolyzed by TFA (2 ml) in DCM (8 ml) to afford 290 mg (95%) of a white solid.
Analytical data 1H NMR (400 MHz, DMSO-ck) δ 12.68 (s, 1 H), 8.86 (d, 7= 8.7 Hz, 1 H), 8.43 (d, 7 = 2.1 Hz, 1 H), 8.13 (dd, 7= 2.1, 8.9 Hz, 1 H), 7.80 (dd, 7= 1.7, 8.3 Hz, 2 H), 7.61 (m, 3 H), 2.45 (s, 3 H). Example 7.25: 5-Bromo-2-{[(4-methyl-5-phenylisoxazol-3- yl)carbonyl]amino}benzoic acid
Figure imgf000299_0001
Prepared according to the General method C: making non-critical variations.
Analytical data
JH NMR (300 MHz, DMSO--i6) δ 12.37 (s, 1 H), 8.67 (d, 7= 8.9 Hz, 1 H), 8.14 (d, 7
= 2.5 Hz, 1 H), 7.89 (dd, 7= 2.6, 9.1 Hz, 1 H), 7.81 (m, 2 H), 7.60 (m, 3 H), 2.44 (s,
3 H);
Example 7.26: 5-Chloro-2-{[(4-methyl-5-phenylisoxazol-3- yl)carbonyl]amino}benzoic acid
Figure imgf000299_0002
Prepared according to the General method C: making non-critical variations.
Analytical data
1H NMR (400 MHz, OMSO-d6) δ 12.36 (s, 1 H), 8.72 (d, 7= 8.9 Hz, 1 H), 8.01 (d, 7
= 2.7 Hz, 1 H), 7.79 (m, 3 H), 7.60 (m, 3 H), 2.44 (s, 3 H). Preparation of l-Ethynyl-2-methoxybenzene
Figure imgf000300_0001
General procedure D: l-iodo-2-methyoxylbenzene (2000 mg, 8.6 mmol), Cul (651 mg, 3.4 mmol), and dichlorobis(triphenylphosphine) palladium(O) (600 mg, 0.86 mmol) were place in a 100 ml one-necked flask. The system was evacuated and filled with argon several times. THF (30 ml) and triethylamine (30 ml) were added, followed by the addition of ethynyl(trimethyl)silane (8.38 g, 86 mmol). The mixture was stiπed at refluxing temperature overnight. Then the resulting mixture was diluted with MTBE (200 ml) and washed with IN HCl, IN NaOH, and dried (MgSO4). The solution was concentrated and the residue was purified by flash chromatography (Heptane/EtOAc=1000/0, 1000/10) to afford 2.1 g of trimethyl[(2- methoxylphenyl)ethynyl]silane as a brown oil. The TMS group was removed by KF (0.94 g, 16 mmol) in MeOH (10 ml) to afford 1.5 g of crude l-Ethynyl-2- methoxylbenzene as brown oil.
Preparation of 5-(2-Methoxyphenyl)isoxazole-3-carboxylic acid
Figure imgf000300_0002
Prepared according to the general method A: l-Ethynyl-2-methoxylbenzene (1500mg, 11.4 mmol) and dimethyl 2-nitromalonate (1830 mg, 10.3 mmol) to afford 1100 mg (42%)) of methyl ester as a brown solid, which was hydrolyzed in MeOH (20 ml) and water (10 ml) by LiOH»H2O (600mg, 14.2 mmol) to afford 850 mg (82%) of a brown solid.
Analytical data 1H NMR (300 MHz, OMSO-d6) δ 7.91 (dd, 7= 1.7, 7.7 Hz, 1 H), 7.55 (m, 1 H), 7.26 (d, 7= 7.9 Hz, I H), 7.14 (t, 7= 7.7 Hz, l H), 7.10 (s, 1 H), 3.98 (s, 3 H). Example 7.27: 5-Cyano-2-({[5-(2-methoxyphenyl)isoxazol-3- yl]carbonyl}amino)benzoic acid
Figure imgf000301_0001
Prepared according to the General method C: 5-(2-methoxyphenyl)isoxazole-3- carboxylic acid (300 mg, 1.37 mmol) and tert-butyl-2-amino-5-cyano benzoate (249 mg, 1.14 mmol) afforded 140 mg (24%>) of t-butyl ester as a brown solid, 130 mg of which was hydrolyzed by TFA (2 ml) in DCM (8 ml) to afford 90 mg (80%) of a white solid.
Analytical data
1H NMR (400 MHz, DMSO--i6) δ 12.71 (s, 1 H), 8.84 (d, 7= 8.7 Hz, 1 H), 8.12 (d, 7 = 2.1 Hz, 1 H), 8.14 (dd, J= 2.1, 8.7 Hz, 1 H), 7.94 (dd, 7= 1.5, 7.8 Hz, 1 H), 7.57 (m, 1 H), 7.28 (d, 7= 8.3 Hz, 1 H), 7.24 (s, 1 H), 7.16 (t, 7= 8.1 Hz, 1 H), 4.00 (s, 3 H).
Example 7.28: 5-Bromo-2-({[5-(2-methoxyphenyϊ)isoxazol-3- yl] carb onyl} amino)b enzoic acid
Figure imgf000301_0002
Prepared according to the General method C: making non-critical variations.
Analytical data
1H NMR (300 MHz, DMSO- 6) δ 12.42 (s, 1 H), 8.66 (d, 7= 9.0 Hz, 1 H), 8.14 (d, 7 = 2.5 Hz, 1 H), 7.95 (dd, 7= 1.5, 7.7 Hz, 1 H), 7.90 (dd, 7= 2.4, 8.9 Hz, 1 H), 7.67 (m, 1 H), 7.28 (d, 7= 8.3 Hz, 1 H), 7.22 (s, 1 H), 7.16 (t, 7= 7.7 Hz, 1 H), 4.00 (s, 3 H). Example 7.29: 5-Chloro-2-({[5-(2-methoxyphenyl)isoxazol-3- yl] carb onyl} amino)b enzoic acid
Figure imgf000302_0001
Prepared according to the General method C: making non-critical variations.
Analytical data
1H NMR (400 MHz, OMSO-d6) δ 12.43 (s, 1 H), 8.72 (d, 7= 8.9 Hz, 1 H), 8.02 (d, 7 = 2.7 Hz, 1 H), 7.95 (dd, 7= 1.7, 7.7 Hz, 1 H), 7.79 (dd, 7= 2.7, 8.9 Hz, 1 H), 7.67 (m, l H), 7.28 (d, 7= 8.3 Hz, 1 H), 7.23 (s, 1 H), 7.16 (t, 7= 7.3 Hz, 1 H), 4.00 (s, 3 H).
Preparation of 2-Ethynyl-3-methylthiophene
Figure imgf000302_0002
General procedure D: 2-bromo-3-methylthiophene (2000 mg, 11.3 mmol), Cul (861 mg, 4.5 mmol), and dichlorobis(triphenylphosphine) palladium(0) (793 mg, 1.1 mmol) were place in a 100 ml one-necked flask. The system was evacuated and filled with argon several times. THF (30 ml) and triethylamine (30 ml) were added, followed by the addition of ethynyl(trimethyl)silane (11 g, 113 mmol). The mixture was stiπed at refluxing temperature overnight. Then the resulting mixture was diluted with MTBE (200 ml) and washed with IN HCl, IN NaOH, and dried (MgSO4). The solution was concentrated and the residue was purified by flash chromatography (Heptane/EtOAc= 1000/0, 1000/10) to afford 4.4 g brown oil. The TMS group was removed by KF (3.9 g, 68 mmol) in MeOH (10 ml) to afford 0.7 g (25% in two steps) of crude 2-Ethynyl-3-methylthiophene as brown oil. Preparation of 5-(3-methylthien-2-yl)isoxazole-3-carboxylic acid
Figure imgf000303_0001
Prepared according to the general method A: 2-ethynyl-3-methylthiophene (700mg, 5.7 mmol) and dimethyl 2-nitromalonate (923 mg, 5.2 mmol) to afford 120 mg (9%) of methyl ester as a brown solid, which was hydrolyzed in MeOH (10 ml) and water (5 ml) by LiOH«H2O (68mg, 1.6 mmol) to afford 80 mg (71%) of a brown solid.
Analytical data
1H NMR (400 MHz, OMSO-d6) δ 7.18 (d, 7= 5.0 Hz, 1 H), 6.75 (d, 7= 5.2 Hz, 1 H), 6.57 (s, 1 H), 2.27 (s, 3 H).
Example 7.30: 5-Cyano-2-({[5-(3-methylthien-2-yl)isoxazol-3- yl]carbonyl}amino)benzoic acid
Figure imgf000303_0002
Prepared according to the General method C: 5-(3-methyl-thien-2-yl)isoxazole-3- carboxylic acid (80 mg, 0.38 mmol) and tert butyl-2-amino-5-cyano benzoate (76 mg, 0.35 mmol) afforded 100 mg (64%) of t-butyl ester as a brown solid, which was hydrolyzed by TFA (2 ml) in DCM (8 ml) to afford 60 mg (70%) of a gray solid.
Analytical data lH NMR (400 MHz, DMSO--iβ) δ 12.73 (s, 1 H), 8.84 (d, 7= 8.7 Hz, 1 H), 8.43 (d, 7 = 2.1 Hz, 1 H), 8.15 (dd, 7= 2.1, 8.9 Hz, 1 H), 7.81 (d, 7= 5.0 Hz, 1 H), 7.16 (m, 2 H), 2.48 (s, 3 H). Example 7.31: 2-{[(5-t-Butylisoxazol-3-yl)carbonyl]amino}-5-cyanobenzoic acid
Figure imgf000304_0001
Prepared according to the General method C: 5-(t-butyl)isoxazole-3-carboxylic acid (280 mg, 1.66 mmol) and tert-butyl-2-amino-5-cyano benzoate (301 mg, 1.38 mmol) afforded 301 mg (49%>) of t-butyl ester as a white solid, which was hydrolyzed by TFA (2 ml) in DCM (8 ml) to afford 180 mg (71%) of a white solid.
Analytical data lH NMR (400 MHz, OMS -d6) δ 12.64 (s, 1 H), 8.82 (d, 7= 8.92 Hz, 1 H), 8.42 (d, 7= 2.1 Hz, 1 H), 8.12 (dd, 7= 2.1, 8.7 Hz, 1 H), 6.78 (s, 1 H), 1.36 (s, 9 H).
Preparation of 5-(3-Cyclohexylpropyl)isoxazole-3-carboxylic acid
Figure imgf000304_0002
Prepared according to the general method A: pent-4-ynylcyclohexane (2000mg, 13.3 mmol) and dimethyl 2-nitromalonate (2145 mg, 12.1 mmol) to afford 1600 mg (48%>) of methyl ester as a brown solid, which was hydrolyzed in MeOH (20 ml) and water (10ml) by LiOH»H2O (800mg, 19.1 mmol) to afford l lOOmg (72%) of a brown solid.
Analytical data lH NMR (400 MHz, DMSO--i6) δ 13.87 (s, 1 H), 6.60 (s, 1 H), 2.78 (t, 7= 7.5 Hz, 2 H), 1.65 (m, 7 H), 1.18 (m, 6 H), 0.85 (m, 2 H). Example 7.32: 5-Cyano-2-({[5-(3-cyclohexylpropyl)isoxazol-3- yl] carb onyl} amino)b enzoic acid
Figure imgf000305_0001
Prepared according to the General method C: 5-(3-cyclohexylpropyl)isoxazole-3- carboxylic acid (300 mg, 1.27 mmol) and tert butyl-2-amino-5-cyano benzoate (230 mg, 1.05 mmol) afforded 500 mg (90%>) of t-butyl ester as a brown solid, which was hydrolyzed by TFA (2 ml) in DCM (8 ml) to afford 150 mg (34%) of a brown solid.
Analytical data 1H NMR (400 MHz, OMSO-dβ) δ 12.62 (s, 1 H), 8.82 (d, 7= 8.9 Hz, 1 H), 8.41 (d, 7 = 2.1 Hz, 1 H), 8.12 (dd, 7= 2.1, 8.9 Hz, 1 H), 6.78 (s, 1 H), 2.83 (t, 7= 7.5 Hz, 2 H), 1.67 (m, 7 H), 1.18 (m, 6 H), 0.85 (m, 2 H).
Example 7.33: 5-Bromo-2-({[5-(3-cyclohexylpropyl)isoxazol-3- yl]carbonyl}amino)benzoic acid
Figure imgf000305_0002
Prepared according to the General method C: making non-critical variations.
Analytical data lH NMR (400 MHz, OMSO-d6) δ 12.32 (s, 1 H), 8.62 (d, 7= 8.9 Hz, 1 H), 8.13 (d, 7 = 2.5 Hz, 1 H), 7.88 (dd, 7= 2.5, 8.9 Hz, 1 H), 6.75 (s, 1 H), 2.83 (t, 7= 7.5 Hz, 2 H), 1.66 (m, 7 H), 1.18 (m, 6 H), 0.85 (m, 2 H). Example 7.34: 5-Chloro-2-({[5-(3-cyclohexylpropyl)isoxazol-3- yl] carb onyl} amino)b enzoic acid
Figure imgf000306_0001
Prepared according to the General method C: making non-critical variations.
Analytical data
:H NMR (400 MHz, OMSO-dβ) δ 12.31 (s, 1 H), 8.68 (d, 7= 8.9 Hz, 1 H), 8.00 (d, 7 = 2.7 Hz, I H), 7.76 (dd, 7= 2.5, 8.9 Hz, 1 H), 6.75 (s, 1 H), 2.83 (t, 7= 7.5 Hz, 2 H), 1.65 (m, 7 H), 1.18 (m, 6 H), 0.85 (m, 2 H).
Preparation of 5-(3-Phenylpropyl)isoxazole-3-carboxylic acid
Figure imgf000306_0002
Prepared according to the general method A: pent-4-ynylbenzene (3000mg, 20.8 mmol) and dimethyl 2-nitromalonate (3347 mg, 18.9 mmol) to afford 3800 mg (82%.) of methyl ester as a brown solid, which was hydrolyzed in MeOH (20 ml) and water (10ml) by LiOH»H2O (1540mg, 36.7 mmol) to afford 2600mg (92%) of a brown solid.
Analytical data XH NMR (300 MHz, DMSO-^) δ 13.98 (s, 1 H), 7.26 (m, 5 H), 6.64 (s, 1 H), 2.81 (t, 7= 7.7 Hz, 2 H), 2.64 (t, 7= 7.3 Hz, 2 H), 1.98 (pent, 7= 7.5 Hz, 2 H).
Example 7.35: 5-Cyano-2-({[5-(3-phenylpropyl)isoxazol-3- yl] carb onyl} amino)b enzoic acid
Figure imgf000306_0003
Prepared according to the General method C: 5-(3-phenylpropyl)isoxazole-3- carboxylic acid (300 mg, 1.30 mmol) and tert-butyl-2-amino-5-benzoate (236 mg, 1.08 mmol) afforded 320 mg (57%) of t-butyl ester as a white solid, 310mg of which was hydrolyzed by TFA (2 ml) in DCM (8 ml) to afford 170 mg (63%) of a white solid.
Analytical data
1H NMR (400 MHz, OMSO-d6) δ 12.71 (s, 1 H), 8.84 (d, J= 8.7 Hz, 1 H), 8.12 (d, 7
= 2.1 Hz, 1 H), 8.14 (dd, 7= 2.1, 8.7 Hz, 1 H), 7.94 (dd, 7= 1.5, 7.8 Hz, 1 H), 7.57
(m, I H), 7.28 (d, 7= 8.3 Hz, I H), 7.24 (s, 1 H), 7.16 (t, 7= 8.1 Hz, 1 H), 4.00 (s, 3
H).
Example 7.36: 5-Bromo-2-({[5-(3-phenylpropyl)isoxazol-3- yl] carb onyl} amino)b enzoic acid
Figure imgf000307_0001
Prepared according to the General method C: making non-critical variations.
Analytical data
1H NMR (300 MHz, DMSO-^) δ 12.32 (s, 1 H), 8.63 (d, 7= 9.0 Hz, 1 H), 8.13 (d, 7 = 2.5 Hz, 1 H), 7.88 (dd, 7= 2.5, 8.9 Hz, 1 H), 7.25 (m, 5 H), 6.79 (s, 1 H), 2.87 (t, 7 = 7.3 Hz, 2 H), 2.66 (t, 7= 7.9 Hz, 2 H), 2.00 (pent, 7= 7.5 Hz, 2 H).
Example 7.37: 5-Chloro-2-({[5-(3-phenylpropyl)isoxazol-3- yl]carbonyl}amino)benzoic acid
Figure imgf000307_0002
Prepared according to the General method C: making non-critical variations. Analytical data
1H NMR (400 MHz, DMSO-tf6) δ 12.31 (s, 1 H), 8.68 (d, 7 = 9.1 Hz, 1 H), 8.00 (d, 7 = 2.7 Hz, 1 H), 7.77 (dd, 7= 2.7, 9.1 Hz, 1 H), 7.26 (m, 5 H), 6.80 (s, 1 H), 2.86 (t, 7 = 7.5 Hz, 2 H), 2.66 (t, 7= 7.9 Hz, 2 H), 2.00 (pent, 7= 7.7 Hz, 2 H).
Preparation of N-(2-ethynylphenyl)-4-(trifluoromethoxy)benzenesulfonamide
Figure imgf000308_0001
2- [(trimethylsilyl)ethynyl] aniline (2000 mg, 10.6 mmol) and 4- (trifluoromethoxy)benzenesulfonyl chloride (2500 mg, 9.6 mmol) were dissolved in DCM ( 10 ml). Pyridine (0.4 ml) was added. And the n the solution was stiπed at room temperature over night. The resulting solution was stiπed overnight, then diluted with MTBE (200 ml) and washed with IN HCl, IN NaOH, brine, dried (MgSO4), filtered, and concentrated in vacuo. The residue was recrystallized from MeOH to afford 3340 mg (76%) of 4-(trifluoromethoxy)-N-{2- [(trimethylsilyl)ethynyl]phenyl}benzenesulfonamide as a white solid, which was de- protected by KF (1410 mg, 24.3 mmol) in MeOH (20 ml) to afford 2440 mg (99%) of N-(2-ethynylphenyl)-4-(trifluoromethoxy)berιzenesulfonamide as a yellow solid.
Analytical data 1H NMR (400 MHz, CDC13) δ 7.67 (m, 2 H), 7.45 (d, 7= 8.3 Hz, 1 H), 7.19 (m, 2 H), 7.08 (m, 2 H), 6.92 (dt, 7= 1.2, 7.7 Hz, 1 H), 3.18 (s, 1 H); Example 7.38: 5-[2-({[4(Trifluoromethoxy)phenyl]sulfonyl}amino)phenyl]- isoxazole-3-carboxylic acid
Figure imgf000309_0001
Prepared according to the general method A: N-(2-ethynylphenyl)-4- (trifluoromethoxy)benzenesulfonamide (2440mg, 7.16 mmol) and dimethyl 2- nitromalonate (1150 mg, 6.5mmol) to afford 1800 mg ( 57%) of methyl ester as a yellow solid, which was hydrolyzed in MeOH (10 ml) and water (5ml) by LiOH«H2O (513 mg, 12.22 mmol) to afford 1500mg (86%) of a brown solid.
Analytical data
1H NMR (400 MHz, OMSO-d6) δ 10.26 (s, 1 H), 7.82 (dd, 7= 1.5, 7.1 Hz, 1 H), 7.74 (d, 7= 8.7 Hz, 2 H), 7.49 (m, 4 H), 7.14 (s, 1 H), 7.08 (d, 7= 7.3 Hz, 1 H).
Example 7.39: 5-Cyano-2-[({5-[2-({[4-(trifluoromethoxy)phenyl]sulfonyl} amino)phenyl]isoxazol-3-yl}carbonyl)amino]benzoic acid
Figure imgf000309_0002
Prepared according to the General method C: 5-[2-({[4(Trifluoromethoxy)phenyl]- sulfonyl}amino)phenyl]isoxazole-3-carboxylic acid (300 mg, 0.7 mmol) and tert-butyl- 2-amino-5-cyano benzoate (127mg, 0.58 mmol) afforded 62 mg (17%>) of t-butyl ester as a white solid, 3 lOmg of which was hydrolyzed by TFA (2 ml) in DCM (8 ml) to afford 36 mg (40%) of a yellow solid. Analytical data
1H NMR (300 MHz, DMSO-tf6) δ 12.76 (s, 1 H), 10.32 (s, 1 H), 8.87 (d, 7= 8.7 Hz, 1 H), 8.45 (d, 7= 2.1 Hz, 1 H), 8.17 (2.1, 7= 8.7 Hz, 1 H), 7.86 (m, 1 H), 7.72 (m, 2 H), 7.50 (m, 4 H), 7.31 (s, 1 H), 7.12 (m, 1 H).
Example 7.40: 5-Chloro-2-[({5-[2-({[4-(trifluoromethoxy)phenyl] sulfonyl} amino)phenyl]isoxazol-3-yl}carbonyl)amino]benzoic acid
Figure imgf000310_0001
Prepared according to the General method C: making non-critical variations.
Analytical data lH NMR (300 MHz, OMSO-d6) δ 12.40 (s, 1 H), 10.32 (s, 1 H), 8.73 (d, 7= 9.0 Hz, 1 H), 8.04 (d, 7= 2.6 Hz, 1 H), 7.86 (dd, 7= 1.7, 6.8 Hz, 1 H), 7.80 (dd, 7= 2.6, 9.0 Hz, 1 H), 7.72 (d, 7= 8.9 Hz, 2 H), 7.50 (m, 4 H), 7.28 (s, 1 H), 7.11 (dd, 7= 1.7, 7.2 Hz, 1 H).
Preparation of 5-Ethynyl-l,3-benzodioxole
Figure imgf000310_0002
Prepared according to the general method D: 5-iodo-l,3-benzodioxole (5 g, 20.3 mmol) and ethynyl(trimethyl)silane (2.6 g, 26.42 mmol) afforded 4.4 g (99%) of (1,3- benzodioxol-5-ylethynyl)(trimethyl)silane as a yellow oil, which was de-protected by KF(3.5 g, 60.6 mmol) to afford 3.2 g ( 100%) yellow oil.
Analytical data 1H NMR (300 MHz, CDC13) δ 7.05 (dd, 7= 1.5, 7.9 Hz, 1 H), 6.95 (d, 7= 1.5 Hz, 1 H), 6.77 (d, 7= 8.1 Hz, 1 H), 6.00 (s, 2 H), 2.99 (s, 1 H), Preparation of 5-(l,3-Benzodioxol-5-yl)isoxazole-3-carboxylic acid
Figure imgf000311_0001
Prepared according to the general method A: 5-ethynyl-l,3-benzodioxole (3200mg, 21.9 mmol) and dimethyl 2-nitromalonate (3527 mg, 19.9 mmol) to afford 3600 mg (72%>) of methyl ester as a brown solid, 2000 mg of which was hydrolyzed in MeOH (10 ml) and water (5ml) by LiOH»H2O (1020 mg, 24.3 mmol) to afford 1500mg (80%)) of a white solid.
Analytical data lH NMR (300 MHz, DMSO-ck) δ 7.52 (d, 7= 1.3 Hz, 1 H), 7.49 (d, 7= 8.1 Hz, 1 H), 7.80 (s, 1 H), 7.09 (d, 7= 8.1 Hz, 1 H), 6.13 (s, 2 H);
Example 7.41 : 2-({[5-(l,3-Benzodioxol-5-yl)isoxazol-3-yl]carbonyl}amino)-5- cyanob enzoic acid
Prepared according to the General method C: 5-(l,3-Benzodioxol-5-yl)isoxazole-3- carboxylic acid (300 mg, 1.28 mmol) and tert-butyl-2-amino-5-cyano-benzoate (233 mg, 1.07 mmol) afforded 220 mg (47%>) of t-butyl ester as a white solid, 310mg of which was hydrolyzed by TFA (2 ml) in DCM (8 ml) to afford 120 mg (63%>) of a brown solid. Analytical data
1H NMR (300 MHz, DMSO--i6) δ 12.68 (s, 1 H), 8.84 (d, 7= 8.7 Hz, 1 H), 8.42 (d, 7 = 1.9 Hz, 1 H), 8.13 (dd, 7= 2.1, 8.7 Hz, 1 H), 7.67 (d, 7= 1.5 Hz, 1 H), 7.63 (dd, 7 = 1.7, 8.1 Hz, 1 H), 7.48 (s, 1 H), 7.11 (d, 7= 8.10 Hz, 1 H), 6.15 (s, 2 H).
Example 7.42: 2-({[5-(l,3-Benzodioxol-5-yl)isoxazol-3-yl]carbonyl}amino)-5- bromob enzoic acid
Figure imgf000312_0001
Prepared according to the General method C: making non-critical variations.
Analytical data
1H NMR (300 MHz, DMSO-^) δ 12.38 (s, 1 H), 8.65 (d, 7= 9.1 Hz, 1 H), 8.14 (d, 7
= 2.5 Hz, 1 H), 7.89 (dd, 7= 2.6, 9.0 Hz, 1 H), 7.67 (d, 7= 1.7 Hz, 1 H), 7.63 (dd, 7
= 1.7, 8.1 Hz, 1 H), 7.45 (s, 1 H), 7.11 (d, 7= 8.1 Hz, 1 H), 6.15 (s, 2 H).
Preparation of 5-(4-{[(5-Methylisoxazol-3-yl)amino]sulfonyl}phenyl)isoxazole-3- carboxylic acid
Figure imgf000312_0002
Prepared according to the general method A: 4-ethynyl-N-(5-methyl-3- isoxazoyl)benzenesulfonamide (lOOOmg, 3.8 mmol) and dimethyl 2-nitromalonate (613 mg, 3.47 mmol) to afford 1200 mg (53%>) of methyl ester as a brown solid, which was hydrolyzed in MeOH (20 ml) and water (10 ml) by LiOH«H2O (416 mg, 9.9 mmol) to afford 940mg (82%) of a brown solid. Analytical data
1H NMR (300 MHz, OMSO-dβ) δ 11.64 (s, 1 H), 8.19 (d, 7= 8.5 Hz, 2 H), 8.01 (d, 7
= 8.5 Hz, 2 H), 7.61 (s, 1 H), 6.18 (s, 1 H), 2.30 (s, 3 H).
Example 7.43: 5-Bromo-2-({[5-(4-{[(5-methylisoxazol-3- yl)amino] sulfonyl} phenyl)isoxazol-3-yl] carb onyl} amino)b enzoic acid
Figure imgf000313_0001
Prepared according to the General method C: 5-(4-{[(5-Methylisoxazol-3- yl)arnino]sulfonyl}phenyl)isoxazole-3-carboxylic acid (300 mg, 0.86 mmol) and tert- butyl-2-amino-5-bromo benzoate (194mg, 0.72 mmol) afforded 60 mg (12 %) of t- butyl ester as a brown solid, which was hydrolyzed by TFA (2 ml) in DCM (8 ml) to afford 30 mg ( 55%>) of a brown solid.
Analytical data JH NMR (400 MHz, DMSO-c?6) δ 12.47 (s, I H), 11.66 (s, 1 H), 8.65 (d, 7= 8.9 Hz, 1 H), 8.24 (d, 7= 8.7 Hz, 2 H), 8.15 (d, 7= 2.7 Hz, 1 H), 8.03 (d, 7= 8.7 Hz, 2 H), 7.91 (dd, 7= 2.5, 9.1 Hz, 1 H), 7.76 (s, 1 H), 2.31 (s, 3 H). Preparation of 5-(3-Methoxyphenyl)isoxazole-3-carboxylic acid
Figure imgf000314_0001
Prepared according to the general method A: l-ethynyl-3-methoxybenzene (5000 mg, 37.9 mmol) and diethyl 2-nitromalonate (7060 mg, 34.4 mmol) to afford 4100 mg (48%) of ethyl ester as a brown solid, 1000 mg of which was hydrolyzed in MeOH (20 ml) and water (10ml) by LiOH»H2O (1000 mg, 23.8 mmol) to afford 860mg (92%) of a brown solid.
Analytical data 1H NMR (400 MHz, DMSO- 6) δ 7.50 (m, 4 H), 7.12 (ddd, 7= 1.0, 2.5, 8.1 Hz, 1 H), 3.85 (s, 3 H).
Example 7.45: 5-Cyano-2-({[5-(3-methoxyphenyl)isoxazol-3- yl]carbonyl}amino)benzoic acid
Figure imgf000314_0002
Prepared according to the General method C: 5-(3-methoxyphenyl)isoxazole-3- carboxylic acid (340 mg, 1.55 mmol) and tert butyl-2-amino-5-cyano benzoate (372mg, 1.71 mmol) afforded 510 mg (87%) of t-butyl ester as a white solid, 500 mg of which was hydrolyzed by TFA (2 ml) in DCM (8 ml) to afford 320 mg (100%) of a white solid. Analytical data
1H NMR (400 MHz, DMSO--i6) δ 12.73 (s, 1 H), 8.85 (d, 7= 8.7 Hz, 1 H), 8.42 (d, 7 = 1.3 Hz, 1 H), 8.14 (dd, 7= 1.5, 8.7 Hz, 1 H), 7.66 (s, 1 H), 7.65 (m, 2 H), 7.49 (t, 7 = 7.9 Hz, 1 H), 7.13 (d, 7= 7.9 Hz, 1 H), 3.86 (s, 3 H).
Preparation of 5-(2-Bromophenyl)isoxazole-3-carboxylic acid
Figure imgf000315_0001
Prepared according to the general method A: l-bromo-2-ethynylbenzene (2000 mg, 11.0 mmol) and diethyl 2-nitromalonate (2050 mg, 10.0 mmol) to afford 2800 mg (96%) of ethyl ester as a brown oil, which was hydrolyzed in MeOH (20 ml) and water (10ml) by LiOH»H2O (1000 mg, 23.8 mmol) to afford 1700mg (93%) of a white solid.
Analytical data
1H NMR (400 MHz, DMSO-^) δ 7.87 (dd, 7= 1.5, 8.3 Hz, 2 H), 7.59 (dt, 7= 1.5, 7.5 Hz, 1 H), 7.51 (m, 1 H), 7.34 (s, 1 H).
Example 7.46: 2-({[5-(2-Bromophenyl)isoxazol-3-yl]carbonyl}amino)-5- cyanobenzoic acid
Figure imgf000315_0002
Prepared according to the General method C: 5-(2-bromophenyl)isoxazole-3- carboxylic acid (1900 mg, 7.1 mmol) and tert-butyl-2-amino-5-cyano benzoate (1700mg, 7.8 mmol) afforded 690 mg (20%) of t-butyl ester which was hydrolyzed by TFA (2 ml) in DCM (8 ml) to afford 38 mg (87%) of a white solid. Analytical data
1H NMR (300 MHz, DMSO--/6) δ 12.81 (s, 1 H), 8.85 (d, 7= 8.7 Hz, 1 H), 8.44 (d, 7 = 2.1 Hz, 1 H), 8.16 (dd, 7= 2.1, 8.9 Hz, 1 H), 7.91 (m, 2 H), 7.63 (dt, 7= 1.3, 7.5 Hz, 1 H), 7.65 (dd, 7= 1.7, 7.5 Hz, 1 H), 7.61 (s, 1 H).
Example 7.47: 2-({[5-(l,l'-Biphenyl-2-yl)isoxazol-3-yl]carbonyl}amino)-5- cyanob enzoic acid
Figure imgf000316_0001
5-(2-bromophenyl)isoxazole-3-carboxylic acid (300 mg, 0.64 mmol), sodium carbonate (259 mg, 2.44 mmol), benzyl boronic acid (86mg, 0.71 mmol) and tetrakis(triphenylphosphine) palladium(0) (37 mg, 0.032 mmol) were placed in a 100 ml one-necked flask. The system was evacuated and filled with argon several times. Then THF (50 ml) and distilled water (5 ml) were added. The mixture was stiπed at refluxing temperature overnight. Then the resulting solution was loaded directly on silica gel and purified by silica gel chromatography (EtOAc/Heptane=l/l 0) to afford 210 mg (70%)) ofthe advanced t-butyl ester as a white solid, which was hydrolyzed by TFA (2 ml) in DCM (8 ml) to afford 140 mg (76%) of a white solid.
Analytical data 1H NMR (300 MHz, OMSO-dβ) δ 12.61 (s, 1 H), 8.76 (d, 7= 8.9 Hz, 1 H), 8.40 (d, 7 = 2.1 Hz, 1 H), 8.11 (dd, 7= 2.1, 8.9 Hz, 1 H), 7.91 (dd, 7= 1.1, 7.4 Hz, 1 H), 7.64 (m, 2 H), 7.49 (dd, 7= 1.5, 7.5 Hz, 1 H), 7.44 (m, 1 H), 7.43 (d, 7= 2.1 Hz, 2 H), 7.29 (m, 2 H), 6.45 (s, 1 H). Preparation of l-Ethynyl-2-[(4-methoxybenzyl)oxy]benzene
Figure imgf000317_0001
2-ethynylphenol (75 g, 341 mmol), Nal (90 g, 682 mmol) and K2CO3 (63 g, 682 mmol) were place in a 1 L flask. Acetonitrile (500 ml) was added, followed by the addition of 4-methoxy benzyl chloride (50 g, 319 mmol). The mixture was stiπed at room temperature for about 12h. After filtration, the solution was washed with IN NaOH, IN HCl, and dried (MgSO4). The solution was concentrated to yield 101 g (87%) of 1- iodo-2-[(4-methoxybenzyl)oxy]benzene as a yellow solid. l-iodo-2-[(4-methoxybenzyl)oxy]benzene (61 g, 180 mmol), Cul (6.85 g, 35.9 mmol), and dichlorobis(triphenylphosphine) palladium(0) ( 12.6 g, 18.0 mmol) were placed in a 1000 ml one-necked flask. The system was evacuated and filled with argon several times. THF (250 ml) and diethylamine (250 ml) were added, followed by the addition of ethynyl(trimethyl)silane (22.8 g, 233 mmol. The mixture was stiπed at refluxing temperature overnight. Then the resulting mixture was diluted with MTBE (1000 ml) and washed with IN HCl, IN NaOH, and dried (MgSO4). The solution was concentrated and the residue was purified by flash chromatography (Heptane/EtOAc=1000/0, 1000/10) to afford 42 g (76%) of crude ({2-[(4- methoxybenzyl)oxy]phenyl}ethynyl)(trimethyl)silane as a yellow oil. The TMS group was removed by KF (12.0 g, 203 mmol) in MeOH (100 ml) to afford a 28 g (87%) of l-Ethynyl-2-[(4-methoxybenzyl)oxy]benzene as a yellow solid.
Analytical data
1H NMR (300 MHz, CDC13) δ 7.50 (dd, 7= 1.9, 7.9 Hz, 1 H), 7.42 (d, 7= 8.7 Hz, 2
H), 7.29 (m, 1 H), 6.93 (m, 5 H), 5.15 (s, 2 H), 3.83 (s, 3 H), 3.32 (s, 1 H).
Preparation of Ethyl 5-(2-hydroxyphenyl)isoxazole-3-carboxylate
Figure imgf000318_0001
l-Ethynyl-2-[(4-methoxybenzyl)oxy]benzene (28 g, 118 mmol) and diethyl 2- nitromalonate (22.3 g, 107 mmol) were dissolved in mesitylene (20 ml). The solution was heated at 150°C for about 12 h. Mesitylene was removed in vacuo and the residue was recrystallized from ethanol. 36 g (87%) of ethyl 5-{2-[(4- methoxybenzyl)oxy]phenyl}isoxazole-3-carboxylate was yielded as a light brown solid, 16 g of which was hydrolyzed in DCM (50 ml) TFA (6 mmol) to afford 10.6 g (100%) of a white solid.
Analytical data
1H NMR (400 MHz, OMSO-d6) δ 10.81 (s, 1 H), 8.83 (dd, 7= 1.7, 7.9 Hz, 1 H), 7.88 (m, 1 H), 7.14 (s, 1 H), 7.07 (dd, 7= 0.8, 8.3 Hz, 1 H), 6.99 (m, 1 H), 4.40 (tetra, 7 = 7.1 Hz, 2 H), 1.35 (t, 7= 7.3 Hz, 3 H).
Preparation of 5-(2-Isopropoxyphenyl)isoxazole-3-carboxylic acid
Figure imgf000318_0002
General method A: Ethyl 5-(2-hydroxyphenyl)isoxazole-3-carboxylate (300 mg, 1.3 mmol) and triphenylphosphine (337 mg, 1.3 mmol) were dissolved in THF (5 ml). Propan-2-ol (77 mg, 1.3 mmol) was added, followed by the addition of DEAD (224 mg, 1.3 mmol). The mixture was shaken over night. The resulting solution was loaded on silica gel and purified by flashing chromatography ((Heptane/EtOAc=1000/10, 1000/20) to afford 300 mg (51%) of ethyl 5-(2-isopropoxyphenyl)isoxazole-3- carboxylate as a white solid, which was hydrolyzed in MeOH (10 ml) and water (5 ml) by LiOH»H2O (137 mg, 3.3 mmol) to afford 270 mg (100%) of 5-(2- Isopropoxyphenyl)isoxazole-3-carboxylic acid as a white solid. Analytical data
1H NMR (300 MHz, OMSO-d6) δ 14.05 (s, 1 H), 7.91 (dd, 7= 1.5, 7.9 Hz, 1 H), 7.51 (m, 1 H), 7.26 (d, 7= 8.3 Hz, 1 H), 7.11 (d, 7= 7.5 Hz, 1 H), 7.08 (s, 1 H), 4.86 (hept, 7= 6.0 Hz, 1 H), 1.37 (d, 7= 6.0 Hz, 6 H).
Example 7.48: 5-Cyano-2-({[5-(2-isopropoxyphenyl)isoxazol-3- yl] carbonyl} amino)benzoic acid
Figure imgf000319_0001
General method B: 5-(2-Isopropoxyphenyl)isoxazole-3-carboxylic acid (270 mg, 1.1 mmol) was dissolved in thionyl chloride (20 ml) and the resulting mixture was heated at refluxing temperature overnight. Toluene (30 ml) was added and the solution was concentrated in vacuo. The residue was re-dissolved in DCM (40 ml) followed by the addition of tert-butyl-2-amino-5-cyano benzoate (218 mg, 1.0 mmol) and pyridine (0.4 ml) and the mixture was stiπed overnight. The resulting solution was diluted with MTBE (200 ml), washed with IN HCl , IN NaOH, brine and dried (MgSO4). The solution was concentrated in vacuo and the residue was washed with MeOH to afford 170 mg (38%) of t-butyl ester as a light yellow solid, which was hydrolyzed by TFA (2 ml) in DCM (10 ml) to afford 90 mg (60%) of a white solid.
Analytical data
1H NMR (400 MHz, DMSO-e?6) δ 12.75 (s, 1 H), 8.85 (d, 7= 8.9 Hz, 1 H), 8.43 (d, 7 = 2.1 Hz, 1 H), 8.14 (dd, 7= 2.1, 8.9 Hz, 1 H), 7.95 (dd, 7= 1.7, 7.9 Hz, 1 H), 7.64 (m, 1 H), 7.30 (d, 7= 8.5 Hz, 1 H), 7.22 (s, 1 H), 7.13 (m, 1 H), 4.89 (hept, 7= 6.0 Hz, 1 H), 1.40 (d, 7= 6.0 Hz, 6 H). Preparation of 5-{2-[2-(2-Ethoxyethoxy)ethoxy]phenyl}isoxazole-3-carboxylic acid
Figure imgf000320_0001
Prepared according to General method A: ethyl-5-(2-hydroxyphenyl)isoxazole-3- carboxylate (500 mg, 2.15 mmol) and 2-(2-ethoxyethoxy)ethanol (288 mg, 2.15 mmol) afforded 410 mg (55%) of ethyl 5-{2-[2-(2-ethoxyethoxy)ethoxy]phenyl}isoxazole-3- carboxylate as a white solid, which was hydrolyzed in MeOH (10 ml) and water (5 ml) by LiOH»H2O (148mg, 3.5 mmol) to afford 360 mg (95%) of 5-{2-[2-(2- ethoxyethoxy)ethoxy]phenyl}isoxazole-3-carboxylic acid as a yellow solid.
Analytical data
IH NMR (300 MHz, DMSO-d6) δ 8.02 (dd, J = 1.7, 7.8 Hz, 1 H), 7.44 (m, 1 H), 7.37 (s, 1 H), 7.11 (dt, J = 0.9, 7.7 Hz, 1 H), 7.04 (d, J = 8.5 Hz, 1 H), 4.32 (m, 2 H), 3.99 (m, 2 H), 3.80 (m, 2 H), 3.73 (m, 2 H), 3.58 (m, 2 H), 1.22 (t, J = 7.0 Hz, 3 H).
Example 7.49: 5-Cyano-2-{[(5-{2-[2-(2-ethoxyethoxy)ethoxy]phenyl}isoxazol-3- yl)carbonyl]amino}benzoic acid
Figure imgf000320_0002
Prepared according to General method B: 5-{2-[2-(2- ethoxyethoxy)ethoxy]phenyl}isoxazole-3-carboxylic acid (360 mg, 1.1 mmol) and tert- butyl-2-amino-5-cyano benzoate (284 mg, 1.3 mmol) afforded 170 mg (29%) of t- butyl ester as a white solid, which was hydrolyzed by TFA (2 ml) in DCM (10 ml) to afford 120 mg (79%) of a white solid. Analytical data
1H NMR (400 MHz, DMSO--iδ) δ 12.77 (s, 1 H), 8.85 (d, 7= 8.9 Hz, 1 H), 8.43 (d, 7 = 2.1 Hz, I H), 8.14 (dd, 7= 2.1, 8.7 Hz, 1 H), 7.95 (dd, 7= 1.7, 7.7 Hz, 1 H), 7.55 (m, 1 H), 7.27 (d, 7= 8.3 Hz, 1 H), 7.22 (s, 1 H), 7.15 (t, 7= 7.9 Hz, 1 H), 4.20 (t, 7 = 6.4 Hz, 2 H), 1.85 (pent, 7= 6.2 Hz, 2 H), 1.60 (pent, 7= 7.0 Hz, 2 H), 1.35 (m, 4 H), 0.88 (t, 7= 7.0 Hz, 3 H).
Preparation of 5-[2-(2,3-Dihydro-l,4-benzodioxin-2-ylmethoxy)phenyl]isoxazole- 3-carboxylic acid
Figure imgf000321_0001
Prepared according to General method A: ethyl-5-(2-hydroxyphenyl)isoxazole-3- carboxylic acid (500 mg, 2.15 mmol) and 2,3-dihydro-l,4-benzodioxin-2-ylmethanol (348 mg, 2.15 mmol) afforded 550 mg (68%) of ethyl 5-[2-(2,3-dihydro-l,4- benzodioxin-2-ylmethoxy)phenyl]isoxazole-3-carboxylate as a yellow solid, which was hydrolyzed in MeOH (10 ml) and water (5 ml) by LiOH«H2O (148mg, 3.5 mmol) to afford 470 mg (92%) of 5-[2-(2,3-dihydro-l,4-benzodioxin-2- ylmethoxy)phenyl]isoxazole-3 -carboxylic acid as a white solid.
Analytical data
1H NMR (400 MHz, DMSO--iβ) δ 14.05 (s, 1 H), 7.94 (dd, 7= 1.7, 7.9 Hz, 1 H), 7.55 (m, 1 H), 7.36 (s, 1 H), 7.32 (d, 7= 8.1 Hz, 1 H), 7.18 (m, 1 H), 7.01 (m, 1 H), 6.92 (m, 1 H), 6.86 (m, 2 H), 4.74 (m, 1 H), 4.67 (dd, 7= 3.5, 10.6 Hz, 1 H), 4.46 (dd, 7= 2.5, 11.6 Hz, I H), 4.33 (dd, 7= 7.5, 10.6 Hz, 1 H), 4.18 (dd, 7= 6.9, 11.6 Hz, 1 H). Example 7.50: 5-Cyano-2-[({5-[2-(2,3-dihydro-l,4-benzodioxin-2- ylmethoxy)phenyl] isoxazol-3-yl} carb onyl)amino] b enzoic acid
Figure imgf000322_0001
Prepared according to General method B: 5-[2-(2,3-dihydro-l,4-benzodioxin-2- ylmethoxy)phenyl]isoxazole-3 -carboxylic acid (470 mg, 1.4 mmol) and tert-butyl-2- amino-5-cyano benzoate (267 mg, 1.2 mmol) afforded 360 mg (54%>) of t-butyl ester as a white solid, which was hydrolyzed by TFA (2 ml) in DCM (10 ml) to afford 290 mg (89%) of a white solid.
Analytical data
1H NMR (300 MHz, OMSO-dβ) δ 12.74 (s, 1 H), 8.85 (d, 7= 8.9 Hz, 1 H), 8.43 (d, 7 = 2.1 Hz, 1 H), 8.13 (dd, 7= 2.1, 8.9 Hz, 1 H), 7.98 (dd, 7= 1.7, 7.9 Hz, 1 H), 7.57 (m, 1 H), 7.48 (s, 1 H), 7.34 (d, 7= 8.3 Hz, 1 H), 7.20 (t, 7= 7.7 Hz, 1 H), 7.04 (m, 1 H), 6.90 (m, 3 H), 4.76 (m, 1 H), 4.59 (dd, 7= 3.8, 10.7 Hz, 1 H), 4.47 (dd, 7= 2.3, 11.5 Hz, 1 H), 4.35 (dd, 7= 7.4, 10.6 Hz, 1 H), 4.20 (dd, 7= 6.6, 11.3 Hz, 1 H).
Preparation of 5-[2-(Hexyloxy)phenyl]isoxazole-3-carboxylic acid
Figure imgf000322_0002
General method C: ethyl-5-(2-hydroxylphenyl)isoxazole-3 -carboxylic acid (500 mg, 1.3 mmol), K2CO (455 mg, 4.29 mmol) and n-lodohexane were place in acetonitrile (20 ml). The mixture was stiπed over night. The resulting solution was loaded on silica gel and purified by flashing chromatography ((Heptane/EtOAc=l 000/10, 1000/20) to afford 590 mg (87%>) of ethyl 5-[2-(hexyloxy)phenyl]isoxazole-3-carboxylate as a yellow solid, which was hydrolyzed in MeOH (10 ml) and water (5 ml) by LiOH*H2O (137 mg, 3.3 mmol) to afford 528 mg (98%) of 5-[2-(hexyloxy)phenyl]isoxazole-3- carboxylic acid as a yellow solid.
Analytical data
1H NMR (400 MHz, DMSO--i6) δ 7.91 (dd, 7= 1.7, 7.9 Hz, 1 H), 7.52 (m, 1 H), 7.24
(d, 7= 8.1 Hz, I H), 7.12 (m, 1 H), 7.08 (s, 1 H), 4.17 (t, 7= 6.2 Hz, 2 H), 1.82 (m, 2
H), 1.48 (m, 2 H), 1.32 (m, 4 H), 0.87 (t, 7= 7.1 Hz, 3 H).
Example 7.51: 5-Cyano-2-[({5-[2-(hexyloxy)phenyl]isoxazol-3- yl}carbonyl)amino]benzoic acid
Figure imgf000323_0001
Prepared according to General method B: 5-[2-(hexyloxy)phenyl]isoxazole-3- carboxylic acid (528 mg, 1.8 mmol) and tert-butyl-2-arnino-5-cyano benzoate (362 mg, 1.7 mmol) afforded 430 mg (53%) of t-butyl ester as a white solid, which was hydrolyzed by TFA (2 ml) in DCM (10 ml) to afford 290 mg (76%) of a white solid.
Analytical data
1H NMR (400 MHz, DMSO--i6) δ 12.77 (s, 1 H), 8.85 (d, 7= 8.9 Hz, 1 H), 8.43 (d, 7 = 2.1 Hz, 1 H), 8.14 (dd, 7= 2.1, 8.7 Hz, I H), 7.95 (dd, 7= 1.7, 7.7 Hz, 1 H), 7.55 (m, 1 H), 7.27 (d, 7= 8.3 Hz, 1 H), 7.22 (s, 1 H), 7.15 (t, 7= 7.9 Hz, 1 H), 4.20 (t, 7 = 6.4 Hz, 2 H), 1.85 (pent, 7= 6.2 Hz, 2 H), 1.60 (pent, 7= 7.0 Hz, 2 H), 1.35 (m, 4 H), 0.88 (t, 7= 7.0 Hz, 3 H).
Preparation of 5-[2-(Allyloxy)phenyl]isoxazole-3-carboxylic acid
Figure imgf000323_0002
Prepared according to General method C: ethyl-5-(2-hydroxyphenyl)isoxazole-3- carboxylic acid (500 mg, 1.3 mmol) and allyl bromide (286 mg, 2.4 mmol) afforded 540 mg (92%) of 5-[2-(allyloxy)phenyl]isoxazole-3-carboxylic acid as a yellow solid, which was hydrolyzed in MeOH (10 ml) and water (5 ml) by LiOH*H2O (137 mg, 3.3 mmol) to afford 480 mg (99%>) of 5-[2-(allyloxy)phenyl]isoxazole-3-carboxylic acid as a yellow solid.
Analytical data lH NMR (400 MHz, OMSO-dβ) δ 14.12 (s, 1 H), 7.92 (dd, 7= 1.7, 7.7 Hz, 1 H), 7.53 (m, 1 H), 7.26 (d, 7= 8.1 Hz, 1 H), 7.14 (m, 1 H), 7.10 (s, 1 H), 6.15 (m, 1 H), 5.48 (dd, 7= 1.7, 17.2 Hz, 1 H), 5.35 (dd, 7= 1.7, 10.6 Hz, 1 H), 4.90 (dt, 7= 1.2, 5.4 Hz, 2 H)
Example 7.52 : 2- [({5- [2-(AUyloxy)phenyl]isoxazol-3-yl} carbonyl)amino] -5- cyanob enzoic acid
Figure imgf000324_0001
Prepared according to General method B: 5-[2-(allyloxy)phenyl]isoxazole-3-carboxylic acid (480 mg, 2.0 mmol) and tert-butyl-2-amino-5-cyano benzoate (388 mg, 1.8 mmol) afforded 330 mg (42%>) of t-butyl ester as a white solid, 100 mg of which was hydrolyzed by TFA (2 ml) in DCM (10 ml) to afford 60 mg (69%) of a white solid.
Analytical data
1H NMR (400 MHz, DMSO--?6) δ 12.76 (s, 1 H), 8.85 (d, 7= 8.7 Hz, 1 H), 8.33 (d, 7 = 1.9 Hz, 1 H), 8.14 (dd, 7= 2.1, 8.7 Hz, 1 H), 7.96 (dd, 7= 1.7, 7.9 Hz, 1 H), 7.65 (m, 1 H), 7.29 (d, 7= 8.5 Hz, 1 H), 7.25 (s, 1 H), 7.17 (t, 7= 7.7 Hz, 1 H), 6.17 (m, 1 H), 5.48 (dd, 7= 1.5, 17.2 Hz, 1 H), 5.37 (dd, 7= 1.5, 10.6 Hz, 1 H), 4.82 (d , 7= 5.5 Hz, 2 H). Preparation of 5-(2-Ethoxyphenyl)isoxazole-3-carboxylic acid
Figure imgf000325_0001
Prepared according to General method A: ethyl-5-(2-hydroxyphenyl)isoxazole-3- carboxylic acid (500 mg, 2.15 mmol) and tetrahydro-2H-pyran-2-ylmethanol (249 mg, 2.15 mmol) afforded 110 mg (25%>) of ethyl 5-(2-ethoxyphenyl)isoxazole-3- carboxylate as a white solid, which (plus another 110 mg from 36831-J1-34) was hydrolyzed in MeOH (10 ml) and water (5 ml) by LiOH»H2O (148mg, 3.5 mmol) to afford 200 mg (100%) of 5-(2-ethoxyphenyl)isoxazole-3-carboxylic acid as a white solid.
Analytical data
1H NMR (300 MHz, DMSO- 6) δ 7.92 (dd, 7= 1.7, 7.9 Hz, 1 H), 7.52 (m, 1 H), 7.24 (d, 7= 8.3 Hz, 1 H), 7.12 (t, 7= 7.7 Hz, 1 H), 7.08 (s, 1 H), 4.24 (tetra, 7= 7.0 Hz, 2 H), 1.45 (t, 7= 7.0 Hz, 3 H).
Example 7.53: 5-Cyano-2-({[5-(2-ethoxyphenyl)isoxazol-3- yl] carbonyl} amino)benzoic acid
Figure imgf000325_0002
Prepared according to General method B: 5-(2-ethoxyphenyl)isoxazole-3-carboxylic acid (200 mg, 0.86 mmol) and tert-butyl-2-amino-5-cyano benzoate (170 mg, 0.78 mmol) afforded 130 mg (38%>) of t-butyl ester as a white solid, which was hydrolyzed by TFA (2 ml) in DCM (10 ml) to afford 98 mg (87%) of a white solid. Analytical data
1H NMR (300 MHz, OMSO-dβ) δ 12.77 (s, 1 H), 8.85 (d, 7= 8.9 Hz, 1 H), 8.43 (d, 7 = 1.9 Hz, 1 H), 8.14 (dd, 7= 2.1, 8.9 Hz, 1 H), 7.96 (dd, 7= 1.5, 7.9 Hz, 1 H), 7.55 (m, 1 H), 7.26 (d, 7= 8.3 Hz, 1 H), 7.23 (s, 1 H), 7.15 (t, 7= 7.7 Hz, 1 H), 4.27 (tetra, 7= 7.0 Hz, 2 H), 1.48 (t, 7= 7.0 Hz, 3 H).
Preparation of 5-[2-(tetrahydro-2H-pyran-2-ylmethoxy)phenyl]isoxazole-3- carboxylic acid
Figure imgf000326_0001
General method D: ethyl-5-(2-hydroxyphenyl)isoxazole-3-carboxylic acid (500 mg,
2.15 mmol) and triphenylphosphine (562 mg, 2.15 mmol) were dissolved in THF (5 ml). tetrahydro-2H-pyran-2-ylmethanol (249 mg, 2.15 mmol) was added, followed by the addition of Di-tert-butylazocarboxylate (DIAD) (495 mg, 2.15 mmol). The mixture was shaken over night. The resulting solution was loaded on silica gel and purified by flashing chromatography ((Heptane/EtOAc=1000/10, 1000/20) to afford 380 mg (54%) of ethyl 5-[2-(tetrahydro-2H-pyran-2-ylmethoxy)phenyl]isoxazole-3- carboxylate as a yellow solid, which was hydrolyzed in MeOH (10 ml) and water (5 ml) by LiOH»H2O (137 mg, 3.3 mmol) to afford 360 mg (100%) of 5-[2-(tetrahydro- 2H-pyran-2-ylmethoxy)phenyl]isoxazole-3 -carboxylic acid as a yellow oil.
Analytical data
1H NMR (300 MHz, DMSO--iή) δ 8.02 (dd, 7= 1.5, 7.7 Hz, 1 H), 7.53 (s, 1 H), 7.44 (m, 1 H), 7.10 (t, 7= 7.7 Hz, 1 H), 7.02 (d, 7= 8.5 Hz, 1 H), 4.14 (m, 3 H), 3.86 (m, 1 H), 3.61 (m, 1 H), 1.97 (m, 1 H), 1.65 (m, 5 H). Example 7.54: 5-Cyano-2-[({5-[2-(tetrahydro-2H-pyran-2- ylmethoxy)phenyl]isoxazol-3-yl}carbonyl)amino]benzoic acid
Figure imgf000327_0001
Prepared according to General method B: 5-[2-(tetrahydro-2H-pyran-2- ylmethoxy)phenyl]isoxazole-3-carboxylic acid (360 mg, 1.2 mmol) and tert-butyl-2- amino-5-cyano benzoate (235 mg, 1.1 mmol) afforded 270 mg (50%) of t-butyl ester as a white solid, which was hydrolyzed by TFA (2 ml) in DCM (10 ml) to afford 200 mg (83%o) of a white solid.
Analytical data lH NMR (400 MHz, OMSO-dβ) δ 12.75 (s, 1 H), 8.87 (d, 7= 8.9 Hz, 1 H), 8.43 (d, 7 = 2.1 Hz, 1 H), 8.14 (dd, 7= 2.1, 8.7 Hz, 1 H), 7.96 (dd, 7= 1.7, 7.9 Hz, 1 H), 7.65 (s, I H), 7.54 (m, 1 H), 7.25 (d, 7= 8.3 Hz, 1 H), 7.16 (m, 1 H), 4.21 (dd, 7= 3.1, 10.2 Hz, I H), 4.11 (dd, 7= 6.0, 10.2 Hz, 1 H), 4.03 (d, 7= 11.0 Hz, 1 H), 3.76 (m, 1 H), 3.50 (m, 1 H), 1.86 (m, 1 H), 1.66 (d, 7= 11.2 Hz, 1 H), 1.67 (m, 4 H).
Preparation of 5-[2-(3-Phenoxypropoxy)phenyl]isoxazole-3-carboxylic acid
Figure imgf000327_0002
Prepared according to General method D: ethyl-5-(2-hydroxyphenyl)isoxazole-3- carboxylic acid (500 mg, 2.15 mmol) and 3-phenoxypropan-l-ol (327 mg, 2.15 mmol) afforded 660 mg (88%) of ethyl 5-[2-(3-phenoxypropoxy)phenyl]isoxazole-3- carboxylate as a yellow solid, which was hydrolyzed in MeOH (10 ml) and water (5 ml) by LiOH*H2O (300 mg, 7.1 mmol) to afford 540 mg (88%) of 5-[2-(3- phenoxypropoxy)phenyl]isoxazole-3-carboxylic acid as a yellow solid. Analytical data lH NMR (300 MHz, CD3OD) δ 7.94 (dd, 7= 1.9, 8.3 Hz, 1 H), 7.43 (m, 1 H), 7.24 (m, 2 H), 7.15 (s, 1 H), 7.08 (d, 7= 7.9 Hz, 2 H), 6.91 (m, 3 H), 4.35 (t, 7= 6.2 Hz, 2 H), 4.19 (t, 7= 5.8 Hz, 2 H), 3.88 (pent, 7= 6.0 Hz, 2 H).
Example 7.55: 5-Cyano-2-[({5-[2-(3-phenoxypropoxy)phenyl]isoxazol-3- yl}carbonyl)amino]benzoic acid
Figure imgf000328_0001
Prepared according to General method B: 5-[2-(3-phenoxypropoxy)phenyl]isoxazole- 3-carboxylic acid (540 mg, 1.7 mmol) and tert-butyl-2-amino-5-cyano benzoate (331 mg, 1.5 mmol) afforded 500 mg (63%) of t-butyl ester as a yellow solid, which was hydrolyzed by TFA (2 ml) in DCM (10 ml) to afford 410 mg (89%) of a white solid.
Analytical data
XH NMR (300 MHz, DMSO--i6) δ 12.73 (s, 1 H), 8.85 (d, 7= 8.9 Hz, 1 H), 8.43 (d, 7 = 2.1 Hz, 1 H), 8.14 (dd, 7= 2.1, 8.9 Hz, 1 H), 7.95 (dd, 7= 1.5, 7.9 Hz, 1 H), 7.55 (m, 1 H), 7.32 (d, 7= 8.9 Hz, 1 H), 7.26 (m, 7= 3 Hz, H), 7.16 (t, 7= 7.5 Hz, 1 H), 6.94 (m, 3 H), 4.38 (t, 7= 6.0 Hz, 2 H), 4.20 (t, 7= 6.2 Hz, 2 H), 2.82 (pent, 7= 6.2 Hz, 2 H).
Preparation of 5-(2-{[(lS)-l-phenylethyl]oxy}phenyl)isoxazole-3-carboxylic acid
Figure imgf000329_0001
Prepared according to General method D: ethyl-5-(2-hydroxyphenyl)isoxazole-3- carboxylage acid (500 mg, 2.15 mmol) and 1 (lS)-l-phenylethanol (262 mg, 2.15 mmol) afforded 440 mg (57%) of ethyl 5-(2-{[(lS)-l- phenylethyl]oxy}phenyl)isoxazole-3-carboxylate as a green oil, which was hydrolyzed in MeOH (10 ml) and water (5 ml) by LiOH»H2O (200 mg, 4.8mmol) to afford 380 mg (100%) of 5-(2-{[(lS)-l-phenylethyl]oxy}phenyl)isoxazole-3-carboxylic acid as a yellow solid.
Analytical data
1H NMR (300 MHz, DMSO--i6) δ 7.90 (dd, 7= 1.5, 7.7 Hz, 1 H), 7.37 (m, 5 H), 7.28 (m, 1 H), 7.23 (s, 1 H), 7.06 (m, 2 H), 5.78 (tetra, 7= 6.4 Hz, 1 H), 1.68 (d, 7= 6.2 Hz, 3 H);
Example 7.56: 5-Cyano-2-({[5-(2-hydroxyphenyl)isoxazol-3- yl] carb onyl} amino)b enzoic acid
Figure imgf000329_0002
Prepared according to General method B: 5-(2-{[(lS)-l- phenylethyl]oxy}phenyl)isoxazole-3-carboxylic acid (380 mg, 1.2 mmol) and tert- butyl-2-amino-5-cyano benzoate (244 mg, 1.1 mmol) afforded 45 mg (8%) of tert- butyl 5-cyano-2-( {[5-(2-{[(lS)-l-phenylethyl]oxy} phenyl)isoxazol-3- yl]carbonyl}amino)benzoate as a white solid, which was hydrolyzed by TFA (2 ml) in DCM (10 ml) to afford 18 mg (58%) of a white solid.
Analytical data 'H NMR (400 MHz, OMSO-d6) δ 12.70 (s, 1 H), 10.87 (s, 1 H), 8.86 (d, 7= 8.7 Hz, 1 H), 8.44 (d, 7= 2.1 Hz, 1 H), 8.15 (dd, 7= 2.1, 8.9 Hz, 1 H), 7.87 (dd, 7= 1.7, 7.9 Hz, 1 H), 7.89 (m, 1 H), 7.26 (s, 1 H), 7.09 (d, 7= 7.7 Hz, 1 H), 7.01 (t, 7= 7.0 Hz, 1 H).
Preparation of 5-[2-(Cyclobutyloxy)phenyl]isoxazole-3-carboxylic acid
Figure imgf000330_0001
Prepared according to General method D: ethyl-5-(2-hydroxyphenyl)isoxazole-3- carboxylic acid (500 mg, 2.15 mmol) and cyclobutanol (155 mg, 2.15 mmol) afforded 260 mg (42%>) of ethyl 5-[2-(cyclobutyloxy)phenyl]isoxazole-3-carboxylate as a yellow solid, which was hydrolyzed in MeOH (10 ml) and water (5 ml) by LiOH«H2O (300 mg, 7.1 mmol) to afford 200 mg (82%) of 5-[2-(cyclobutyloxy)phenyl]isoxazole-3- carboxylic acid as a yellow solid.
Analytical data 1H NMR (400 MHz, DMSO--i6) δ 7.91 (dd, 7= 1.5, 7.7 Hz, 1 H), 7.50 (m, 1 H), 7.10 (s, 1 H), 7.09 (m, 2 H), 4.90 (m, 1 H), 2.54 (m, 1 H), 2.14 (m, 2 H), 1.81 (m, 1 H), 1.71 (m, 1 H), 1.37 (d, 7= 6.0 Hz, 1 H);
Example 7.57: 5-Cyano-2-[({5-[2-(cyclobutyloxy)phenyl]isoxazol-3- yl}carbonyl)amino]benzoic acid
Figure imgf000331_0001
Prepared according to General method B: 5-[2-(cyclobutyloxy)phenyl]isoxazole-3- carboxylic acid (200 mg, 0.77 mmol) and tert-butyl-2-amino-5-cyano benzoate(154 mg, 0.7 mmol) afforded 140 mg (44%>) of t-butyl ester as a white solid, which was hydrolyzed by TFA (2 ml) in DCM (10 ml) to afford 67 mg (55%) of a white solid.
Analytical data lH NMR (400 MHz, OMSO-d6) δ 12.75 (s, 1 H), 8.85 (d, 7= 8.9 Hz, 1 H), 8.43 (d, 7 = 1.9 Hz, 1 H), 8.15 (dd, 7= 2.1, 8.9 Hz, 1 H), 7.95 (dd, 7= 1.7, 7.7 Hz, 1 H), 7.52 (m, 1 H), 7.24 (s, 1 H), 7.14 (t, 7= 7.7 Hz, 1 H), 7.10 (d, 7= 8.1 Hz, 1 H), 4.92 (pent, 7= 7.1 Hz, 1 H), 2.55 (m, 1 H), 2.18 (m, 2 H), 1.87 (tetra, 7= 10.4 Hz, 1 H), 1.71 (m, I H), 1.40 (d, 7= 6.0 Hz, 1 H).
Preparation of 5-[2-(Tetrahydrofuran-3-yloxy)phenyl]isoxazole-3-carboxyUc acid
Figure imgf000331_0002
Prepared according to General method D: ethyl-5-(2-hydroxyphenyi)isoxazole-3- carboxylic acid (500 mg, 2.15 mmol) and tetrahydrofuran-3-ol (155 mg, 2.15 mmol) afforded 1000 mg (100%) of ethyl 5-[2-(tetrahydrofuran-3-yloxy)phenyl]isoxazole-3- carboxylate as a yellow solid, which was hydrolyzed in MeOH (10 ml) and water (5 ml) by LiOH»H2O (300 mg, 7.1 mmol) to afford 810 mg (89%) of crude 5-[2- (tetrahydrofuran-3-yloxy)phenyl]isoxazole-3-carboxylic acid as a yellow solid.
Example 7.58: 5-Cyano-2-[({5-[2-(tetrahydrofuran-3-yloxy)phenyl]isoxazol-3- yl}carbonyl)amino]benzoic acid
Figure imgf000332_0001
Prepared according to General method B: 5-[2-(tetrahydrofuran-3- yloxy)phenyl]isoxazole-3-carboxylic acid (810 mg, 3.0 mmol) and tert-butyl-2-amino- 5-cyano benzoate (584 mg, 2.7 mmol) afforded 440 mg (35%) of t-butyl ester as a white solid, which was hydrolyzed by TFA (2 ml) in DCM (10 ml) to afford 410 mg ( 100%)) of a white solid.
Analytical data
1H NMR (400 MHz, DMSO- tf) δ 12.71 (s, 1 H), 8.84 (d, 7= 8.7 Hz, 1 H), 8.42 (d, 7 = 2.1 Hz, 1 H), 8.14 (dd, 7= 2.1, 8.7 Hz, 1 H), 7.96 (dd, 7= 1.7, 7.7 Hz, 1 H), 7.55 (m, 1 H), 7.28 (d, 7= 8.3 Hz, 1 H), 7.18 (s, 1 H), 7.17 (t, 7= 7.3 Hz, 1 H), 5.82 (m, 1 H), 3.94 (m, 3 H), 3.82 (m, 1 H), 2.33 (m, 1 H), 2.07 (m, 1 H).
Preparation of 5-[2-(Tetrahydro-2H-pyran-4-yloxy)phenyl]isoxazole-3-carboxyUc acid
Figure imgf000332_0002
Prepared according to General method D: ethyl-5-(2-hydroxyphenyl)isoxazole-3- carboxylic acid (500 mg, 2.15 mmol) and tetrahydro-2H-pyran-4-ol (219 mg, 2.15 mmol) afforded 1000 mg (100%) of ethyl 5-[2-(tetrahydro-2H-pyran-4- yloxy)phenyl]isoxazole-3-carboxylate as a white solid, which was hydrolyzed in MeOH (10 ml) and water (5 ml) by LiOH»H2O (300 mg, 7.1 mmol) to afford 780 mg (85%>) of 5-[2-(tetrahydro-2H-pyran-4-yloxy)phenyl]isoxazole-3-carboxylic acid as a white solid. Analytical data
JH NMR (400 MHz, DMSO- 6) δ 8.88 (s, 1 H), 7.92 (dd, 7= 1.7, 7.9 Hz, 1 H), 7.51 (m, 1 H), 7.35 (d, 7= 8.3 Hz, 1 H), 7.12 (t, 7= 7.3 Hz, 1 H), 7.10 (s, 1 H), 4.77 (m, 1 H), 3.86 (m, 2 H), 3.54 (m, 2 H), 2.07 (m, 2 H), 1.68 (m, 2 H).
Example 7.59: 5-Cyano-2-[({5-[2-(tetrahydro-2H-pyran-4-yloxy)phenyl]isoxazol- 3-yl}carbonyl)amino]benzoic acid
Figure imgf000333_0001
Prepared according to General method B: 5-[2-(tetrahydro-2H-pyran-4- yloxy)phenyl]isoxazole-3-carboxylic acid (780 mg, 2.7 mmol) and tert-butyl-2-amino- 5-cyano benzoate (535 mg, 2.5 mmol) afforded 950 mg (79%) of t-butyl ester as a brown solid, which was hydrolyzed by TFA (2 ml) in DCM (10 ml) to afford 350 mg ( 42%>) of a white solid.
Analytical data lH NMR (300 MHz, DMSO-^) δ 12.75 (s, 1 H), 8.86 (d, 7= 8.9 Hz, 1 H), 8.44 (d, 7 = 2.1 Hz, 1 H), 8.15 (dd, 7= 2.1, 8.9 Hz, 1 H), 7.96 (dd, 7= 1.5, 7.7 Hz, 1 H), 7.54 (m, 1 H), 7.38 (d, 7= 8.3 Hz, 1 H), 7.24 (s, 1 H), 7.15 (t, 7= 7.5 Hz, 1 H), 4.88 (hept, 7= 4.2 Hz, 1 H), 3.90 (t, 7= 4.1 Hz, 1 H), 3.86 (t, 7= 4.5 Hz, 1 H), 3.55 (m, 2 H), 2.09 (m, 2 H), 1.72 (m, 2 H).
Preparation of 5-(2-{[(lS,2R)-2-methylcyclopentyl]oxy}phenyl)isoxazole-3- carboxylic acid
Figure imgf000333_0002
Prepared according to General method D: ethyl-5-(2-hydroxyphenyl)isoxazole-3- carboxylic acid (500 mg, 2.15 mmol) and (lR,2R)-2-methylcyclopentanol (215 mg,
2.15 mmol) afforded 430 mg (64%) of ethyl 5-(2-{[(lS,2R)-2- methylcyclopentyl]oxy}phenyl)isoxazole-3-carboxylate as a yellow oil, which was hydrolyzed in MeOH (10 ml) and water (5 ml) by LiOH»H2O (300 mg, 7.1 mmol) to afford 360 mg (91 %) of 5-(2-{[(lS,2R)-2-methylcyclopentyl] oxy}phenyl)isoxazole-
3 -carboxylic acid as a white solid.
Analytical data
1H NMR (400 MHz, OMSO-d6) δ 7.90 (dd, 7= 1.7, 7.9 Hz, 1 H), 7.60 (m, 1 H), 7.27 (d, 7= 8.3 Hz, I H), 7.10 (m, 1 H), 7.08 (s, 1 H), 4.92 (dt, 7= 1.5, 4.5 Hz, 1 H), 2.19
(m, 1 H), 2.03 (m, 1 H), 1.90 (m, 1 H), 1.73 (m, 2 H), 1.62 (m, 1 H), 1.60 (m, 1 H),
1.05 (d, 7= 6.8 Hz, 3 H).
Example 7.60: 5-Cyano-2-({[5-(2-{[(lS,2R)-2-methylcyclopentyϊ] oxy}phenyl)isoxazol-3-yl] carbonyl} amino)benzoic acid
Figure imgf000334_0001
Prepared according to General method B: 5-(2-{[(lS,2R)-2- methylcyclopentyl]oxy}phenyl)isoxazole-3-carboxylic acid (360 mg, 1.3 mmol) and tert-butyl-2-amino-5-cyano benzoate(249 mg, 1.1 mmol) afforded 270 mg (49 %>) of t- butyl ester as a white solid, which was hydrolyzed by TFA (2 ml) in DCM (10 ml) to afford 250 mg ( 42%) of a white solid.
Analytical data
JH NMR (400 MHz, DMSO- 6) δ 12.77 (s, 1 H), 8.86 (d, 7= 8.9 Hz, 1 H), 8.43 (d, 7 = 8.1 Hz, I H), 8.13 (dd, 7= 2.1, 8.7 Hz, 1 H), 7.95 (dd, J= 1.7, 7.9 Hz, 1 H), 7.53 (m, 1 H), 7.30 (d, 7= 8.3 Hz, 1 H), 7.22 (s, 1 H), 7.13 (m, 1 H), 4.95 (m, 1 H), 2.21 (m, 1 H), 2.05 (m, 1 H), 1.93 (m, 1 H), 1.76 (m, 2 H), 1.65 (m, 1 H), 1.54 (m, 1 H),
1.07 (d, 7= 6.8 Hz, 3 H). Preparation of 5-[2-(2-Methoxy-l-methylethoxy)phenyl]isoxazole-3-carboxylic acid
Figure imgf000335_0001
Prepared according to General method D: ethyl-5-(2-hydroxyphenyl)isoxazole-3- carboxylate acid (500 mg, 2.15 mmol) and l-methoxypropan-2-ol (194 mg, 2.15 mmol) afforded 570 mg (87%) of ethyl 5-[2-(2-methoxy-l- methylethoxy)phenyl]isoxazole-3-carboxylate as a yellow oil, which was hydrolyzed in MeOH (10 ml) and water (5 ml) by LiOH»H2O (300 mg, 7.1 mmol) to afford 430 mg (83 %) of 5-[2-(2-methoxy-l-methylethoxy)phenyl]isoxazole-3-carboxylic acid as a white solid.
Analytical data lH NMR (300 MHz, DMSO--i6) δ 7.91 (dd, 7= 1.7, 7.9 Hz, 1 H), 7.50 (m, 1 H), 7.30 (d, 7= 8.3 Hz, 1 H), 7.21 (s, 1 H), 7.11 (m, 1 H), 4.86 (m, 1 H), 3.59 (d, 7= 4.5 Hz, 2 H), 3.32 (s, 3 H), 1.31 (d, 7= 6.2 Hz, 3 H).
Example 7.61 : 5-Cyano-2-[({5-[2-(2-methoxy-l-methylethoxy)phenyl]isoxazol-3- yl}carbonyl)amino]benzoic acid
Figure imgf000335_0002
Prepared according to General method B: 5-[2-(2-methoxy-l- methylethoxy)phenyl]isoxazole-3-carboxylic acid (430 mg, 1.6 mmol) and tert-butyl-2- amino-5-cyano benzoate (308 mg, 1.4 mmol) afforded 360 mg (54 %>) of t-butyl ester as a white solid, which was hydrolyzed by TFA (2 ml) in DCM (10 ml) to afford 160 mg (50 %) of a white solid.
Analytical data lH NMR (400 MHz, DMSO- 6) δ 12.75 (s, 1 H), 8.86 (d, 7= 8.9 Hz, 1 H), 8.43 (d, 7 = 2.1 Hz, 1 H), 8.14 (dd, 7= 2.1, 8.7 Hz, 1 H), 7.96 (dd, 7= 1.7, 7.9 Hz, 1 H), 7.53 (m, 1 H), 7.36 (s, 1 H), 7.33 (d, 7= 8.5 Hz, 1 H), 7.14 (t, 7= 7.1 Hz, 1 H), 4.88 (m, 1 H), 3.63 (d, 7= 4.4 Hz, 2 H), 3.35 (s, 3 H), 1.34 (d, 7= 6.3 Hz, 3 H).
Preparation of 5-[2-(l-Methylbutoxy)phenyl]isoxazole-3-carboxylic acid
Figure imgf000336_0001
Prepared according to General method D: ethyl-5-(2-hydroxyphenyl)isoxazole-3- carboxylate acid (500 mg, 2.15 mmol) and pentan-2-ol (189 mg, 2.15 mmol) afforded 530 mg (82%) of ethyl 5-[2-(l-methylbutoxy)phenyl]isoxazole-3-carboxylate as a yellow oil, which was hydrolyzed in MeOH (10 ml) and water (5 ml) by LiOH*H2O (300 mg, 7.1 mmol) to afford 450 mg (93%) of 5-[2-(l- methylbutoxy)phenyl]isoxazole-3 -carboxylic acid as a colorless oil.
Analytical data 'H NMR (300 MHz, DMSO--f6) δ 7.91 (dd, 7= 1.7, 7.9 Hz, 1 H), 7.50 (m, 1 H), 7.27 (d, 7= 8.3 Hz, 1 H), 7.10 (m, 1 H), 7.06 (s, 1 H), 4.73 (hex, 7= 6.0 Hz, 1 H), 1.69 (m, 2 H), 1.41 (m, 2 H), 1.32 (d, 7= 6.0 Hz, 3 H), 0.91 (t, 7= 7.4 Hz, 3 H).
Example 7.62: 5-Cyano-2-[({5-[2-(l-methylbutoxy)phenyl]isoxazol-3- yl}carbonyl)amino]benzoic acid
Figure imgf000337_0001
Prepared according to General method B: 5-[2-(l-methylbutoxy)phenyl]isoxazole-3- carboxylic acid (450 mg, 1.6 mmol) and tert-butyl-2-amino-5-cyano benzoate (324 mg, 1.5 mmol) afforded 320 mg (45 %) of t-butyl ester as a white solid, which was hydrolyzed by TFA (2 ml) in DCM ( 10 ml) to afford 170 mg (60%) of a white solid.
Analytical data
1H NMR (400 MHz, DMSO-J6) δ 12.79 (s, 7= 1 Hz, H), 8.86 (d, 7= 8.7 Hz, 1 H), 8.44 (d, 7= 2.1 Hz, 1 H), 8.14 (dd, 7= 2.1, 8.7 Hz, 1 H), 7.96 (dd, 7= 1.7, 7.7 Hz, 1 H), 7.64 (m, I H), 7.30 (d, 7= 8.5 Hz, 1 H), 7.21 (s, 1 H), 7.12 (t, 7= 7. 3Hz, IH), 4.76 (hex, 7= 6.2 Hz, 1 H), 1.79 (m, 1 H), 1.68 (m, 1 H), 1.45 (m, 2 H), 1.34 (d, 7= 6.0 Hz, 3 H), 0.92 (t, 7= 7.3 Hz, 3 H).
Preparation of 5-[2-(Cyclobutylmethoxy)phenyl]isoxazole-3-carboxylic acid
Figure imgf000337_0002
Prepared according to General method D: ethyl-5-(2-hydroxyphenyl)isoxazole-3- carboxylate acid (500 mg, 2.15 mmol) and cyclobutylmethanol (185 mg, 2.15 mmol) afforded 420 mg (65%) of ethyl 5-[2-(cyclobutylmethoxy)phenyl]isoxazole-3- carboxylate as a yellow oil, which was hydrolyzed in MeOH (10 ml) and water (5 ml) by LiOH»H2O (300 mg, 7.1 mmol) to afford 360 mg (94 %) of 5-[2-
(cyclobutylmethoxy)phenyl]isoxazole-3-carboxylic acid as a white solid. Analytical data
1H NMR (400 MHz, DMSO- 6) δ 7.92 (dd, 7= 1.7, 7.9 Hz, 1 H), 7.52 (m, 1 H), 7.24 (d, 7= 8.3 Hz, 1 H), 7.13 (t, 7= 7.7 Hz, 1 H), 7.07 (s, 1 H), 4.14 (d, 7= 6.6 Hz, 2 H), 2.86 (m, 1 H), 2.12 (m, 2 H), 1.95 (m, 4 H).
Example 7.63: 5-Cyano-2-[({5-[2-(cyclobutylmethoxy)phenyl]isoxazol-3- yl} carb onyl)amino] benzoic acid
Figure imgf000338_0001
Prepared according to General method B: 5-[2-(cyclobutylmethoxy)phenyl]isoxazole- 3-carboxylic acid (360 mg, 1.3 mmol) and tert-butyl-2-amino-5-cyano benzoate (261 mg, 1.2 mmol) afforded 470 mg (83 %») of t-butyl ester as a white solid, which was hydrolyzed by TFA (2 ml) in DCM (10 ml) to afford 340 mg (82%) of a white solid.
Analytical data 1H NMR (400 MHz, OMSO-d6) δ 12.73 (s, 1 H), 8.85 (d, 7= 8.7 Hz, 1 H), 8.42 (d, 7 = 2.1 Hz, I H), 8.12 (dd, 7= 2.1, 8.7 Hz, 1 H), 7.95 (dd, 7= 1.7, 7.7 Hz, 1 H), 7.54 (m, 1 H), 7.26 (d, 7= 8.3 Hz, 1 H), 7.20 (s, 1 H), 7.15 (m, 1 H), 4.16 (d, 7= 6.6 Hz, 2 H), 2.89 (m, 1 H), 2.14 (m, 2 H), 1.97 (m, 4 H).
Preparation of 5-[2-(Cyclohex-2-en-l-ylmethoxy)phenyl]isoxazole-3-carboxylic acid
Figure imgf000338_0002
Prepared according to General method D: ethyl-5-(2-hydroxyphenyl)isoxazole-3- carboxylate (500 mg, 2.15 mmol) and cyclobutylmethanol (241 mg, 2.15 mmol) afforded 390 mg (56%>) of ethyl 5-[2-(cyclohex-2-en-l-ylmethoxy)phenyl]isoxazole-3- carboxylate as a white soild, which was hydrolyzed in MeOH (10 ml) and water (5 ml) by LiOH*H2O (300 mg, 7.1 mmol) to afford 370 mg ( 100 %) of 5-[2-(cyclohex-2-en- l-ylmethoxy)phenyl]isoxazole-3-carboxylic acid as a white solid.
Analytical data
Η NMR (400 MHz, OMSO-dβ) δ 7.92 (dd, 7= 1.7, 7.9 Hz, 1 H), 7.52 (m, 1 H), 7.27 (d, 7= 8.3 Hz, 1 H), 7.13 (t, 7= 7.5 Hz, 1 H), 7.08 (s, 1 H), 5.71 (s, 2 H), 4.09 (d, 7 = 6.2 Hz, 2 H), 2.19 (m, 2 H), 2.08 (m, 2 H), 1.89 (m, 2 H), 1.41 (m, 1 H).
Example 7.64 : 5-Cyano-2- [({5- [2-(cyclobutylmethoxy)phenyl] isoxazol-3- yl} carb onyl)amino] benzoic acid
Figure imgf000339_0001
Prepared according to General method B: 5-[2-(cyclohex-2-en-l- ylmethoxy)phenyl]isoxazole-3-carboxylic acid (370 mg, 1.2 mmol) and tert-butyl-2- amino-5-cyano benzoate (299 mg, 1.4 mmol) afforded 200 mg (32 %) of t-butyl ester as a white solid, 190 mg of which was hydrolyzed by TFA (2 ml) in DCM (10 ml) to afford 158 mg (94%>) of a white solid.
Analytical data
1H NMR (400 MHz, DMSO- 6) δ 12.76 (s, 1 H), 8.86 (d, 7= 8.9 Hz, 1 H), 8.43 (d, 7 = 2.1 Hz, I H), 8.14 (dd, 7= 2.3, 8.9 Hz, 1 H), 7.76 (dd, 7= 1.7, 7.9 Hz, 1 H), 7.55 (m, 1 H), 7.30 (d, 7= 8.3 Hz, 1 H), 7.22 (s, 1 H), 7.16 (m, 1 H), 5.72 (s, 2 H), 4.12 (d, 7= 6.2 Hz, 2 H), 2.21 (m, 2 H), 2.10 (m, 2 H), 1.92 (m, 2 H), 1.43 (m, 1 H). Preparation of 5-[2-(Carboxymethoxy)phenyl]isoxazole-3-carboxylic acid
Figure imgf000340_0001
Prepared according to General method C: ethyl-5-(2-hydroxyphenyι)isoxazole-3- carboxylate (500 mg, 2.15 mmol) and 4-(chloroacetyl)morpholine (529 mg, 3.2 mmol) afforded 450 mg (56%) of ethyl 5-[2-(2-morpholin-4-yl-2- oxoethoxy)phenyl]isoxazole-3 -carboxylate as a white solid, which was hydrolyzed in MeOH (10 ml) and water (5 ml) by LiOH»H2O (300 mg, 7.1 mmol) to afford 380 mg (100 %) of 5-[2-(carboxymethoxy)phenyl]isoxazole-3-carboxylic acid as a white solid.
Analytical data
1H NMR (400 MHz, DMSO--i6) δ 7.95 (dd, 7= 1.7, 7.9 Hz, 1 H), 7.62 (m, 1 H), 7.61 (s, 1 H), 7.17 (m, 2 H), 4.92 (s, 2 H).
Example 7.65: 2-({[2-(3-{[(2-Carboxy-4-cyanophenyl)amino]carbonyl}isoxazol- 5-yl)phenoxy] acetyl} amino)-5-cyanob enzoic acid
Figure imgf000340_0002
Prepared according to General method B: 5-[2-(carboxymethoxy)phenyl]isoxazole-3- carboxylic acid (380 mg, 1.4 mmol) and tert-butyl-2-amino-5-cyano benzoate (693 mg, 3.2 mmol) afforded 780 mg (89 %>) of t-butyl ester as a light yellow solid, 290 mg of which was hydrolyzed by TFA (2 ml) in DCM ( 10 ml) to afford 260 mg (99%) of a white solid. Analytical data
1H NMR (300 MHz, OMSO-d6) δ 12.72 (s, 1 H), 12.05 (s, 1 H), 8.84 (dd, 7= 3.0, 8.9 Hz, 2 H), 8.43 (d, 7= 2.1 Hz, 1 H), 8.30 (2.1, 7= 1 Hz, H), 8.15 (dd, 7= 1.9, 8.9 Hz, 1 H), 8.09 (dd, 7= 2.1, 8.9 Hz, 1 H), 8.01 (dd, 7= 1.3, 7.7 Hz, 1 H), 7.56 (t, 7= 8.3 Hz, 1 H), 7.53 (s, 1 H), 7.27 (d, 7= 8.3 Hz, 1 H), 7.23 (t, 7= 7.7 Hz, 1 H), 5.19 (s, 2 H).
Preparation of 5-[2-(l-Ethylpropoxy)phenyl]isoxazole-3-carboxyIic acid
Figure imgf000341_0001
Prepared according to General method D: ethyl-5-(2-hydroxyphenyl)isoxazole- carboxylate (500 mg, 2.15 mmol) and pentan-3-ol (189 mg, 2.15 mmol) afforded 330 mg (51%)) of ethyl 5-[2-(l-ethylpropoxy)phenyl]isoxazole-3-carboxylate as a white soild, which was hydrolyzed in MeOH (10 ml) and water (5 ml) by LiOH«H2O (300 mg, 7.1 mmol) to afford 240 mg (80%>) of 5-[2-(l-ethylpropoxy)phenyl]isoxazole-3- carboxylic acid as a yellow oil.
Analytical data
1H NMR (300 MHz, DMSO--i6) δ 7.92 (dd, 7= 1.7, 7.7 Hz, 1 H), 7.50 (m, 1 H), 7.26 (d, 7= 8.3 Hz, 1 H), 7.10 (t, 7= 7.2 Hz, 1 H), 7.05 (s, 1 H), 4.55 (pent, 7= 5.7 Hz, 1 H), 1.72 (m, 4 H), 0.91 (t, 7= 7.4 Hz, 6 H).
Example 7.66: 5-Cyano-2-[({5-[2-(l-ethylpropoxy)phenyl]isoxazol-3- yl}carbonyl)amino]benzoic acid
Figure imgf000341_0002
Prepared according to General method B: 5-[2-(l-ethylpropoxy)phenyl]isoxazole-3- carboxylic acid (240 mg, 0.9 mmol) and tert-butyl-2-amino-5-cyano benzoate (299 mg, 1.0 mmol) afforded 150 mg (36 %>) of t-butyl ester as a yellow solid, which was hydrolyzed by TFA (2 ml) in DCM (10 ml) to afford 120 mg (91%) of a white solid.
Analytical data
1H NMR (400 MHz, DMSO--iβ) δ 12.78 (s, 1 H), 8.85 (d, 7= 8.9 Hz, 1 H), 8.43 (d, 7 = 2.1 Hz, 1 H), 8.14 (dd, 7= 2.1, 8.7 Hz, 1 H), 7.96 (dd, 7= 1.7, 7.9 Hz, 1 H), 7.53 (m, 1 H), 7.30 (d, 7= 8.5 Hz, 1 H), 7.20 (s, 1 H), 7.12 (m, 1 H), 4.58 (pent, 7= 5.8 Hz, 1 H), 1.74 (m, 4 H), 0.93 (t, 7= 7.3 Hz, 6 H).
Preparation of 5- {2- [2-(4-Methyl-l ,3-thiazol-5-yl)ethoxy] phenyl} isoxazole-3- carboxylic acid
Figure imgf000342_0001
Prepared according to General method D: ethyl-5-(2-hydroxyphenyl)isoxazole-3- carboxylate (500 mg, 2.15 mmol) and 2-(4-methyl-l,3-thiazol-5-yl)ethanol (307 mg, 2.15 mmol) afforded 470 mg (62%) of ethyl 5-{2-[2-(4-methyl-l,3-thiazol-5- yl)ethoxy]phenyl}isoxazole-3 -carboxylate as a white solid, which was hydrolyzed in MeOH (10 ml) and water (5 ml) by LiOH«H2O (300 mg, 7.1 mmol) to afford 90 mg (21 %) of 5-{2-[2-(4-methyl-l,3-thiazol-5-yl)ethoxy]phenyl}isoxazole-3-carboxylic acid as a white solid.
Analytical data
1H NMR (300 MHz, OMSO-dβ) δ 8.82 (s, 1 H), 7.90 (dd, 7= 1.5, 7.7 Hz, 1 H), 7.53 (m, 1 H), 7.28 (d, 7= 8.3 Hz, 1 H), 7.14 (t, 7= 7.4 Hz, 1 H), 6.96 (s, 1 H), 4.39 (t, 7 = 6.0 Hz, 2 H), 3.35 (t, 7= 6.0 Hz, 2 H), 2.36 (s, 3 H).
Example 7.67: 5-Cyano-2-{[(5-{2-[2-(4-methyl-l,3-thiazol-5- yl)ethoxy]phenyl}isoxazol-3-yl)carbonyl] aminojbenzoic acid
Figure imgf000343_0001
Prepared according to General method B: 5-{2-[2-(4-methyl-l,3-thiazol-5- yl)ethoxy]phenyl}isoxazole-3-carboxylic acid (90 mg, 0.27 mmol) and tert-butyl-2- amino-5-cyano benzoate {66 mg, 0.3 mmol) afforded 60 mg (42 %>) of t-butyl ester as a yellow solid, which was hydrolyzed by TFA (2 ml) in DCM (10 ml) to afford 48 mg (89%) of a white solid.
Analytical data
1H NMR (400 MHz, DMSO--i6) δ 12.78 (s, 1 H), 8.86 (d, J= 8.7 Hz, 1 H), 8.82 (s, 1 H), 8.44 (d, 7= 2.1 Hz, 1 H), 8.15 (dd, 7= 2.1, 8.7 Hz, 1 H), 7.94 (dd, 7= 1.7, 7.9 Hz, 1 H), 7.56 (m, 1 H), 7.31 (d, 7= 8.3 Hz, 1 H), 7.17 (t, 7= 7.1 Hz, 1 H), 7.12 (s, 1 H), 4.42 (t, 7= 6.2 Hz, 2 H), 1.38 (t, 7= 6.0 Hz, 2 H), 2.38 (s, 3 H).
Preparation of 5-[2-(l-Cyclohexylethoxy)phenyl]isoxazole-3-carboxyJic acid
Figure imgf000343_0002
Prepared according to General method D: ethyl-5-(2-hydroxyphenyl)isoxazole-3- carboxylate (500 mg, 2.15 mmol) and 1-cyclohexylethanol (275 mg, 2.15 mmol) afforded 340 mg (47%>) of ethyl 5-[2-(l-cyclohexylethoxy)phenyl]isoxazole-3- carboxylate as a yellow oil, which was hydrolyzed in MeOH (10 ml) and water (5 ml) by LiOH»H2O (300 mg, 7.1 mmol) to afford 280 mg (89 %) of 5-[2-( 1 - cyclohexylethoxy)phenyl]isoxazole-3-carboxylic acid as a yellow oil. Analytical data
1H NMR (400 MHz, OMSO-d6) δ 7.90 (dd, 7= 1.7, 7.7 Hz, 1 H), 7.50 (m, 1 H), 7.27 (d, 7= 8.3 Hz, l H), 7.09 (m, 1 H), 7.08 (s, 1 H), 4.55 (m, 1 H), 1.88 (d, 7= 11.8 Hz, 1 H), 1.69 (m, 4 H), 1.26 (d, 7= 6.2 Hz, 3 H), 1.16 (m, 6 H).
Example 7.68: 5-Cyano-2-[({5-[2-(l-cyclohexylethoxy)phenyl]isoxazol-3- yl} carb onyl)amino] benzoic acid
Figure imgf000344_0001
Prepared according to General method B: 5-[2-(l-cyclohexylethoxy)phenyl]isoxazole- 3-carboxylic acid (280 mg, 0.9 mmol) and tert-butyl-2-amino-5-cyano benzoate (215 mg, 1.0 mmol) afforded 190 mg (42 %>) of t-butyl ester as a yellow solid, 80 mg of which was hydrolyzed by TFA (2 ml) in DCM (10 ml) to afford 61 mg (86%) of a white solid.
Analytical data
IH NMR (400 MHz, DMSO-d6) δ 12.75 (s, 1 H), 8.86 (d, J = 8.9 Hz, 1 H), 8.43 (d, J = 2.1 Hz, 1 H), 8.14 (dd, J = 2.1, 8.9 Hz, 1 H), 7.94 (dd, J = 1.7, 7.9 Hz, 1 H), 7.53 (m, 1 H), 7.30 (d, J = 8.5 Hz, 1 H), 7.23 (s, 1 H), 7.11 (m, 1 H), 4.59 (pent, J = 5.8 Hz, 1 H), 1.91 (d, J = 12.0 Hz, 1 H), 1.73 (m, 4 H), 1.28 (d, J = 6.2 Hz, 3 H), 1.16 (m, 6 H).
Preparation of 5-[2-(2-Oxobutoxy)phenyl]isoxazole-3-carboxylic acid
Figure imgf000344_0002
Prepared according to General method C: ethyl-5-(2-hydroxyρhenyl)isoxazole-3- carboxylate (500 mg, 2.15 mmol) and l-bromobutan-2-one (649 mg, 4.30 mmol) afforded 650 mg (100%>) of ethyl 5-[2-(2-oxobutoxy)phenyl]isoxazole-3-carboxylate as a yellow oil, 580 mg of which was hydrolyzed in MeOH (10 ml) and water (5 ml) by LiOH«H2O (300 mg, 7.1 mmol) to afford 520 mg (99 %) of 5-[2-(2- oxobutoxy)phenyl]isoxazole-3-carboxylic acid as a yellow oil.
Analytical data
1H NMR (300 MHz, OMSO-dβ) δ 7.95 (dd, 7= 1.7, 8.1 Hz, 1 H), 7.55 (s, 1 H), 7.61 (m, 1 H), 7.15 (m, 2 H), 5.11 (s, 2 H), 2.55 (tetra, 7= 7.4 Hz, 2 H), 1.02 (t, 7= 7.4 Hz, 3 H).
Example 7.69: 5-Cyano-2-[({5-[2-(2-oxobutoxy)phenyl]isoxazol-3- yl}carbonyl)amino] benzoic acid
Figure imgf000345_0001
Prepared according to General method B: 5-[2-(2-oxobutoxy)phenyl]isoxazole-3- carboxylic acid (520 mg, 1.9 mmol) and tert-butyl-2-amino-5-cyano benzoate (453 mg, 2.1 mmol) afforded 470 mg (52 %>) of t-butyl ester as a yellow solid, 170 mg of which was hydrolyzed by TFA (2 ml) in DCM (10 ml) to afford 140 mg (93%>) of a yellow solid.
Analytical data
1H NMR (400 MHz, DMSO-rf6) δ 12.75 (s, 1 H), 8.87 (d, 7= 8.9 Hz, 1 H), 8.43 (d, 7 = 2.1 Hz, 1 H), 8.15 (dd, 7= 2.1, 8.7 Hz, 1 H), 7.98 (dd, 7= 1.7, 8.1 Hz, 1 H), 7.68 (s, 1 H), 7.63 (m, 1 H), 7.18 (m, 2 H), 5.14 (s, 2 H), 2.56 (tetra, 7= 7.5 Hz, 2 H), 1.03 (t, 7= 7.3 Hz, 3 H).
Preparation of 5-[2-(2-Oxo-2-phenylethoxy)phenyl]isoxazole-3-carboxylic acid
Figure imgf000346_0001
Prepared according to General method C: ethyl-5-(2-hydroxyphenyl)isoxazole-3- carboxylate (500 mg, 2.15 mmol) and 2-bromo-l-phenylethanone (513 mg, 2.58 mmol) afforded 650 mg (86 %) of ethyl 5-[2-(2-oxo-2-phenylethoxy)phenyl]isoxazole- 3-carboxylate as a yellow oil, which was hydrolyzed in MeOH (10 ml) and water (5 ml) by LiOH«H2O (300 mg, 7.1 mmol) to afford 610mg (100 %) of 5-[2-(2-oxo-2- phenylethoxy)phenyl]isoxazole-3 -carboxylic acid as a yellow solid.
Analytical data 1H NMR (300 MHz, DMSO-e?6) δ 8.11 (d, 7= 7.2 Hz, 2 H), 7.99 (dd, 7= 1.5, 7.7 Hz, 1 H), 7.75 (s, 1 H), 7.71 (d, 7= 7.4 Hz, 1 H), 7.6 (m, 2 H), 7.53 (m, 1 H), 7.37 (d, J = 8.1 Hz, 1 H), 7.18 (t, 7= 7.7 Hz, 1 H), 5.84 (s, 2 H).
Example 7.70: 5-Cyano-2-[({5-[2-(2-oxo-2-phenylethoxy)phenyl]isoxazol-3- yl}carbonyl)amino]benzoic acid
Figure imgf000346_0002
Prepared according to General method B: 5-[2-(2-oxo-2- phenylethoxy)phenyl]isoxazole-3 -carboxylic acid (610 mg, 1.9 mmol) and tert-butyl-2- amino-5-cyano benzoate (453 mg, 2.1 mmol) afforded 600 mg (61 %>) of t-butyl ester as a yellow solid, 300 mg of which was hydrolyzed by TFA (2 ml) in DCM (10 ml) to afford 190 mg (100 %) of a white solid. Analytical data
1H NMR (300 MHz, OMSO-d6) δ 12.78 (s, 1 H), 8.89 (d, 7= 8.7 Hz, 1 H), 8.44 (d, 7 = 1.9 Hz, 1 H), 8.16 (dd, 7= 2.1, 8.7 Hz, 1 H), 8.12 (tetra, 7= 7.2 Hz, 2 H), 8.03 (dd, 7= 1.7, 7.9 Hz, 1 H), 7.88 (s, 1 H), 7.73 (m, 1 H), 7.61 (t, 7= 7.7 Hz, 2 H), 7.56 (m, 1 H), 7.39 (d, 7= 8.3 Hz, 1 H), 7.20 (t, 7= 7.7 Hz, 1 H), 5.88 (s, 2 H).
Preparation of 5-{2-[(5-Hydroxypentyl)oxy]phenyl}isoxazole-3-carboxylic acid
Figure imgf000347_0001
Prepared according to General method D: ethyl-5-(2-hydroxyphenyl)isoxazole-3- carboxylate (500 mg, 2.15 mmol) and 5-{[tert-butyl(dimethyl)silyl]oxy}pentan-l-ol (469 mg, 2.15 mmol) afforded 640 mg (69 %) of ethyl 5-{2-[(5-{[tert- butyl(dimethyl)silyl]oxy}pentyl)oxy]phenyl}isoxazole-3-carboxylate as a yellow oil, which was hydrolyzed in MeOH (10 ml) and water (5 ml) by LiOH«H2O (500 mg, 11.9 mmol) to afford 210mg (44 %>) of 5-{2-[(5-hydroxypentyl)oxy]phenyl}isoxazole- 3-carboxylic acid as a white solid.
Analytical data
1H NMR (400 MHz, OMSO-dβ) δ 7.85 (dd, 7= 1.7, 7.7 Hz, 1 H), 7.46 (m, 1 H), 7.20 (d, 7= 8.1 Hz, 1 H), 7.09 (dt, 7= 0.8, 7.5 Hz, 1 H), 6.91 (s, 1 H), 4.14 (t, 7= 6.3 Hz, 2 H), 3.41 (t, 7= 6.0 Hz, 2 H), 1.84 (pent, 7= 6.8 Hz, 2 H), 1.61 (pent, 7= 3.1 Hz, 4 H).
Example 7.71: 2-{[(5-{2-[(5-Chloropentyl)oxy]phenyl}isoxazol-3- yl)carbonyl] amino}-5-cyanobenzoic acid
Figure imgf000348_0001
Prepared according to General method B: 5-{2-[(5- hydroxypentyl)oxy]phenyl}isoxazole-3-carboxylic acid (251 mg, 0.79 mmol) and tert butyl-2-amino-5-cyano benzoate (206 mg, 0.94 mmol) afforded 90 mg (21 %) of t- butyl ester as a white solid, which was hydrolyzed by TFA (2 ml) in DCM (10 ml) to afford 62 mg (79%) of a white solid.
Analytical data
1H NMR (300 MHz, DMSO- ) δ 12.76 (s, 1 H), 8.85 (d, 7= 8.9 Hz, 1 H), 8.44 (d, 7 = 2.1 Hz, I H), 8.15 (dd, 7= 2.1, 8.9 Hz, 1 H), 7.95 (dd, 7= 1.5, 7.7 Hz, 1 H), 7.55 (m, I H), 7.29 (d, 7= 8.5 Hz, 1 H), 7.22 (s, 1 H), 7.15 (t, 7= 7.4 Hz, 1 H), 4.21 (t, 7 = 6.2 Hz, 2 H), 3.68 (t, 7= 6.6 Hz, 2 H), 1.83 (m, 4 H), 1.61 (m, 2 H).
Example 8: R4 as Benzoxazole and derivatives thereof
Preparation of 2- Amino-5-cyanob enzoic acid
Figure imgf000348_0002
To a slurry of methyl 2-amino-5-cyanobenzoate (9.55 g, 54.2 mmol) in methanol (200 mL) was added aqueous sodium hydroxide (30 mL, 6.0 molar, 180 mmol). This mixture was stirred at room temperature and became a solution after 1 hour. After a total of 27.5 hours, the solvent was evaporated, and the residue was dissolved in water (300 mL). This solution was washed with methylene chloride (2 X 200 mL) and then acidified with concentrated HCl. The product was extracted into ethyl acetate (500 mL). The organics were dried over MgSO4 and evaporated leaving the product as 8.57 g (97.5%o) of yellow solid that was used without further purification. Preparation of Benzyl 2-amino-5-cyanobenzoate
Figure imgf000349_0001
To a flask containing 2-amino-5-cyanobenzoic acid (8.57 g, 52.9 mmol) and cesium carbonate (17.2 g, 52.8 mmol) was added DMF (150 mL). Benzyl bromide (6.00 mL,
50.4 mmol) was added, resulting in the rapid formation of a precipitate. The mixture was stirred at room temperature for 6 hours and then added to a separatory funnel with methyl tert-butyl ether (500 mL). This mixture was washed with water (250 mL), saturated aqueous sodium bicarbonate (2 X 250 mL), and brine (250 mL). The organics were then filtered through a 1 " plug of silica gel. The plug was rinsed with methylene chloride, and the combined organics were evaporated leaving the product as
12.5 g of yellow solid (98.0% from benzyl bromide, 93.6% from acid). 1H NMR (400 MHz, OMSO-dβ) δ 8.09 (d, 7= 2.1 Hz, 1 H), 7.59 (dd, 7= 8.7, 2.1 Hz, 1 H), 7.45- 7.53 (m, 4 H), 7.41 (t, 7= 7.2 Hz, 2 H), 7.36 (t, 7= 7.1 Hz, 1 H), 6.88 (d, 7= 8.9 Hz, 1 H), 5.32 (s, 2 H).
Preparation of Benzyl l,3-benzoxazole-2-carboxylate
Figure imgf000349_0002
To a stirred solution of benzoxazole (1.32 g, 11.1 mmol, Aldrich) in THF (20 mL) at - 40 °C was added n-BuLi (6.5 mL of 1.6 M in hexanes, 10.4 mmol, Aldrich). The solution was stirred for 40 minutes at -40 °C and then added by cannula to a solution of benzyl cyanoformate (1.67 g, 10.4 mmol, Aldrich) in THF (20 mL) at -78 °C. The resulting mixture was stirred at -78 °C for 10 minutes, at —40 °C for 10 minutes, and then at room temperature for 20 minutes. It was then added to a separatory funnel with 200 mL of saturated aqueous NaHCO3. Product was extracted into 200 mL of EtOAc. The EtOAc was washed with another 200 mL of saturated NaHCO3 and 200 mL of brine. The EtOAc was dried over Na2SO and evaporated leaving an orange oil.
Product was purified by two successive chromatography runs using a Biotage Flash 40 M silica cartridge with 60%o CH2C12 in heptane as eluent. Yield was 473 mg of yellow solid.
Example 8.1: 2-[(l,3-Benzoxazol-2-ylcarbonyl)amino]-5-cyanobenzoic acid
Figure imgf000350_0001
To a solution of benzyl l,3-benzoxazole-2-carboxylate (233 mg, 0.920 mmol) in 1: 1 ethanol THF (20 mL) was added palladium on carbon (56 mg of 5%, Aldrich) and triethylamine (180 μL, 1.29 mmol, Aldrich). The mixture was stirred under 1 ATM of hydrogen for 2 hours and then filtered through a plug of celite. Removal ofthe solvent left the triethylamine salt as an orange oil (the protonated form ofthe acid rapidly decarboxylates and should be avoided). This oil was dissolved in CH2C12 (20 mL) and treated with DMF (20 μL) followed by oxalyl chloride (220 μL, 2.52 mmol, Aldrich). Solvent and excess oxalyl chloride were removed by rotary evaporation after 76 hours. The residue was dissolved in CH2C12 (20 mL), and benzyl 2-amino-5-cyanobenzoate (250 mg, 0.991 mmol) in pyridine (8 mL) was added. The mixture was stirred overnight and then added to a separatory funnel with 100 mL of CH2C12. This solution was washed with 2 X 100 of 1.0 M HCl and 100 mL of brine. Product was adsorbed onto silica gel and purified on a Biotage Flash 40 M siliga gel cartridge using CH2C12 as eluent. Product was collected as 218 mg of white solid as the benzyl ester. A mixture of benzyl 2-[(l,3-benzoxazol-2-ylcarbonyl)amino]-5-cyanobenzoate (168 mg, 0.423 mmol) and palladium on carbon (33 mg of 5%>, Aldrich) in 2: 1 THF/ethanol (30 mL) was stirred under 1 ATM of hydrogen for 25 minutes. The mixture was filtered through a plug of celite and then evaporated. The residue was dried at 100 °C under vacuum yielding 116 mg of white solid. 1H NMR (400 MHz, DMSO-D6) δ ppm 7.56 (t, 7=7.67 Hz, 1 H) 7.63 (t, 7=7.88 Hz, 1 H) 7.94 (d, 7=8.29 Hz, 1 H) 8.00 (d, 7=7.67 Hz, 1 H) 8.16 (dd, 7=8.81, 1.97 Hz, 1 H) 8.45 (d, 7=2.07 Hz, 1 H) 8.87 (d, 7=8.71 Hz, I H) 13.16 (s, I H).
Example 9: Rj as Pyrazine and Derivatives Thereof Example 9.1: 5-Cyano-2-({[5-(2-phenylethyl)pyrazin-2- yl] carbonyl} amino)benzoic acid
Figure imgf000351_0001
To a slurry of 5-[(E)-2-phenylethenyl]pyrazine-2-carboxylic acid (146 mg, 0.645 mmol, from RCC) in CH2C12 ( 15 mL) was added DMF ( 10 μL) followed by oxalyl chloride (100 μL, 1.15 mmol, Aldrich). An orange solution quickly resulted. Solvent and excess oxalyl chloride were removed by rotary evaporation after stirring overnight. The residue was dissolved in CH2C12 (15 mL), and benzyl 2-amino-5-cyanobenzoate (155 mg, 0.614 mmol) in pyridine (8 mL) was added. The mixture was stirred overnight and then added to a separatory funnel with 100 mL of CH2C12. This solution was washed with 2 X 100 of 1.0 M HCl and 100 mL of brine. Product was adsorbed onto silica gel and purified on a Biotage Flash 40 M silica gel cartridge using a gradient from CH2C12 to 2% EtOAc in CH2C12 as eluent. Product was collected as 138 mg of yellow solid as the benzyl ester. A mixture of benzyl 5-cyano-2-[({5-[(E)-2- phenylethenyl]pyrazm-2-yl}carbonyl)amino]benzoate (118 mg, 0.256 mmol) and palladium on carbon (46 mg of 5%>, Aldrich) in 1: 1 THF/ethanol (40 mL) was stirred under 1 ATM of hydrogen for 6.5 hours. The mixture was filtered through a plug of celite and then evaporated. The residue was recrystallized from ethanol/THF. The solids were washed with ethanol followed by heptane and then dried at 100 °C under vacuum yielding 37 mg of tan solid. 1H NMR (400 MHz, DMSO-D6) δ ppm 3.08 (t, 7=7.88 Hz, 2 H) 3.25 (t, 7=7.77 Hz, 2 H) 7.24 (m, 5 H) 8.12 (dd, 7=8.81, 1.97 Hz, 1 H) 8.42 (d, 7=1.87 Hz, 1 H) 8.70 (d, 7=1.04 Hz, 1 H) 8.98 (d, 7=8.71 Hz, 1 H) 9.28 (d, 7=1.24 Hz, 1 H) 13.28 (s, 1 H).
Preparation of 5-(Hexyloxy)pyrazine-2-carboxylic acid
Figure imgf000351_0002
Hexyl alcohol (30 mL, Aldrich) was added to a flask containing sodium (423 mg, 18.4 mmol), and the mixture was heated in a 60 °C oil bath for 45 minutes to dissolve the sodium. Methyl 5-chloropyrazine-2-carboxylate (1.62 g, 9.39 mmol, Lonza) was added, and the mixture was stirred in a 50 °C oil bath for 35 minutes. The mixture was added to a separatory funnel with 100 mL of CH2C12. This was washed with 100 mL of water, but solid material was present in the CH2C12 that would not dissolve. The CH2C12 was then washed with 100 mL of 1.0 M aqueous HCl, and everything dissolved. The CH2C12 was washed with another 100 mL of water, dried over MgSO4, and evaporated. The residual hexanol was distilled away, and the residue was purified on a Biotage Flash 40 M silica cartridge. Hexyl 5-hexyloxypyrazine-2-carboxylate eluted with CH2C12 followed by methyl 5-hexyloxypyrazine-2-caboxylate. Addition of methanol to the eluent resulted in the elution of 5-(hexyloxy)pyrazine-2-carboxylic acid followed by 5-chloropyrazine-2-carboxylic acid. The hexyloxy acid was isolated as 137 mg of white solid. Hexyl 5-hexyloxypyrazine-2-carboxylate was isolated as 1.64 g of colorless oil.
Example 9.2: 5-Cyano-2-({[5-(hexyloxy)pyrazin-2-yl]carbonyl}amino)benzoic acid
Figure imgf000352_0001
To a mixture of 5-(hexyloxy)pyrazine-2-carboxylic acid (271 mg, 1.21 mmol) in CH2C12 (15 mL) was added DMF (10 μL) followed by oxalyl chloride (160 μL, 1.83 mmol, Aldrich). Solvent and excess oxalyl chloride were removed by rotary evaporation after 2 hours. The residue was dissolved in CH2C12 (15 mL), and benzyl 2-amino-5-cyanobenzoate (288 mg, 1.14 mmol) in pyridine (6 mL) was added. The mixture was stirred overnight and then added to a separatory funnel with 100 mL of CH2C12. This solution was washed with 2 X 100 of 1.0 M HCl and 100 mL of brine. Product was adsorbed onto silica gel and purified on a Biotage Flash 40 M silica gel cartridge using CH2C12 as eluent. Product was collected as 205 mg of white solid as the benzyl ester. A mixture of benzyl 5-cyano-2-({[5-(hexyloxy)pyrazin-2- yl] carbonyl} amino)benzoate (169 mg, 0.369 mmol) and palladium on carbon (25 mg of 5%, Aldrich) in 6: 1 THF/ethanol (35 mL) was stirred under 1 ATM of hydrogen for 1 hour. The mixture was filtered through a plug of celite and then evaporated. The residue was twice suspended in methanol and evaporated. It was then suspended in CH2C12 and evaporated. It was then dried at 100 °C under vacuum yielding 122 mg of tan solid. JH NMR (400 MHz, DMSO-D6) δ ppm 0.88 (t, 7=7.05 Hz, 3 H) 1.32 (m, 4 H) 1.42 (m, 2 H) 1.77 (m, 2 H) 4.40 (t, 7=6.63 Hz, 2 H) 8.11 (dd, 7=8.81, 2.18 Hz, 1 H) 8.40 (d, 7=2.07 Hz, 1 H) 8.42 (d, 7=1.24 Hz, 1 H) 8.93 (d, 7=1.24 Hz, 1 H) 8.98 (d, 7=8.91 Hz, 1 H) 13.07 (s, 1 H).
Example 10: Rj as Oxazoles and Derivatives Thereof
SCHEME I Synthesis of Oxazole Esters/Acids
1. NaN(CHO)2 Et02CCOCl
2. EtOH HCl Et3N, CH2C12
Figure imgf000354_0002
Figure imgf000354_0001
Ph enacyl Halides (PH) Ph enacyl Amine (PA)
Figure imgf000354_0003
Amide Ester (AE) Oxazole Ester (OE) Oxazole Acid (OAE)
SCHEME II
Synthesis of Anthranilates
Figure imgf000354_0004
PHA-561050 PHA-561051
Figure imgf000354_0005
X = Br. I (PHA-5610 521 PHA-56 1053
Figure imgf000354_0006
SCHEME III Two Methods for Preparing the Targets
(A) - utilization of oxazole acids and tert-butyl anthranilates
Figure imgf000355_0001
Figure imgf000355_0002
Figure imgf000355_0003
(B) - Direct coupling of oxazole esters with anthranilic acids
Figure imgf000355_0004
PREPARATION OF PHENACYL HALIDES
Method A - bromination of methyl ketones
2-Bromo-3 '.Λ'-methylenedioxyacetophenone (PH-k):
Figure imgf000355_0005
10
3,4-Methylenedioxyacetophenone (20.0 g, 121.2 mmol ) was dissolved in CHCl3/EtOAc (700 mL/700 mL) followed by the addition of CuBr2 (40.6 g, 181.8 mmol, 1.5 eq). The reaction mixture was heated at reflux for 3 days. TLC (1/1 Hept/EtOAc) showed about 80% completion (product and S.M have close Rf). Solid was removed by filtration, washed with CHC13. The filtrate was concentrated on a rotavap to give an orange solid (27.77 g, 94 % yield, containing 21% unreacted starting material). The material iwas carried to the next step without further purification. 1H NMR (300 MHz, CDC13) 8 7.60 (d, IH), 7.40 (s, IH), 6.85 (d, IH), 6.20 (s, 2H), 4.40 (s, 2H). Yield: 94%
2-Bromo-2 '-(trifluoromethvDacetophenone (PH-g):
Figure imgf000356_0001
1HNMR (300 MHz, DMSO-de) δ 7.45-7.82 (m, 4H), 4.42 (s, 2 H). 92% yield (70% conversion)
4-(2-Bromo-acetyr)-benzonitrile (PH-I):
Figure imgf000356_0002
1H NMR (300 MHz, CDC13) δ 8.19 (d, IH), 7.80 (d, IH), 4.45 (s, 2H). Yield: 65%
3-(2-Bromo-acetylVbenzonitrile (PH-m):
Figure imgf000356_0003
1HNMR (300 MHz, DMSO-de) δ 8.53 (s, IH), 8.29 (d, 1H),8.14 (d, IH), 7.74 (t, 1 H), 5.03 (s, 2 H). 92% yield (75% conversion).
Method B - acylation of a aromatic heterocylcle with bromoacetyl bromide 2-Bromo-l-(l-methyl-lH-pyrrol-2-yr)-ethanone (PH-s):
Figure imgf000357_0001
N-methylpyrrole (lOg, 123mmol) was dissolved in 400 mL of dichloromethane. Bromoacetylbromide (1 eq) was added, and the solution stirred at 0°C for 4.5 h. The reaction mixture was washed with 10% NaHCO3 (2x1 L) and H2O (2x100 mL). The organic layer was dried over Na2SO4 and concentrated under vacuum. Chromatography gave 4.9 g. 1H NMR (300 MHz, CDC13) δ 7.15 (d, IH), 6.90 (d, IH), 6.18 (d, IH), 4.30 (s, 2H), 3.98 (s, 3H). Yield: 20%
PREPARATION OF PHENACYL AMINES Method A - using diformylimide sodium salt
2-Amino-l-(4-methoxy-phenyl)-ethanone hydrochloride(PA-b):
Figure imgf000357_0002
To a stirred solution of 2-Bromo-4'-methoxyacetophenone (20.0 g, 87.3 mmol) in CH3CN (90 mL), was added sodium diformylamide (9.95 g, 104.76 mmol, 1.2 eq). The resulting mixture was stirred for 2h at RT, and heated for 2 h at 70 °C (monitored by TLC). Solvent was removed under reduced pressure. Then EtOH (250 mL) and Cone. HCl (40 mL) were added. The reaction mixture was refluxed for lh. Solvent was removed by rotavap. The crude product was suspended in iPr-OH (100 mL) and stirred at RT O/N. The off-white pure product was obtained by filtration (17.28 g, 98%). 1H NMR (300 MHz, DMSO-ds) δ 8.4 (br), 8.0 (d, 2H), 7.1 (d, 2H), 4.5 (s, 2H), 3.9 (s, 3H). MS (APCr*) m z 166 (M-HC1). Yield: 98% 2-Ammo-3'-methoxyacetophenone hydrochloride (PA-a):
Figure imgf000358_0001
1HNMR (300 MHz, DMSO-ds) δ 8.50 (bs), 7.65 (d, IH), 7.50 (m, 2 H), 7.32 (dd, 1 H), 4.59 (bs, 2H), 3.83 (s, 3 H). 86% yield
2-Amino-4'-fluoroacetophenone hydrochloride (PA-d):
Figure imgf000358_0002
1HNMR (300 MHz, DMSO-dβ) δ 8.50 (bs) ( 8.15 (m, 2 H), 7.44 (m, 2 H), 4.65 (m, 2 H). 76% yield
2-Amino-acetophenone hydrochloride (PA-fl:
Figure imgf000358_0003
1HNMR (300 MHz, DMSO-de) δ 8.59 (bs), 8.06 (d, 2 H),7.67 (t, IH), 7.55 (t, 2 H), 4.53 (s, 2 H). 72% yield.
2-Amino-2'-(trifluoromethvD-acetophenone hydrochloride (PA-g):
Figure imgf000358_0004
1HNMR (300 MHz, DMSO-dβ) δ 8.64 (bs),7.88-8.11 (m, 4 H), 4.35 (s, 2 H). 18% yield
2-Amino-l-furan-2-yl-ethanone hydrochloride (PA-h):
Figure imgf000358_0005
'HNMR (300 MHz, DMSO-ds) δ 8.35 (bs), 8.15 (d, 1H),7.67 (d, IH), 6.82 (d, 1 H), 4.32 (s, 2 H). 82% yield.
1 2-AMINO-2 '-METHOXYACETOPHENONE HYDROCHLORIDE (PA-I):
Figure imgf000359_0001
1H NMR (300 MHz, DMSO-de) δ 8.31 (br), 7.85 (d, IH), 7.70 (t, IH), 7.27 (d, IH), 7.12 (t, IH), 4.35 (s, 2H), 3.95 (s, 3H). Yield: 83%
2-Amino-3'.4'-methylenedioxyacetophenone hydrochloride (PA-k):
Figure imgf000359_0002
1H NMR (300 MHz, DMSO-de) δ 8.39 (br), 7.65 (d, IH), 7.55 (d, IH), 7.13 (d, IH), 6.20 (s, 2H), 4.5 (s, 2H). Yield: 90%
2-Amino-4,-cvanoacetophenone hydrochloride (PA-D:
Figure imgf000359_0003
1H NMR (300 MHz, DMSO-de) δ 8.60 (br), 8.17 (d, 2H), 8.10 (d, 2H), 4.70 (s, 2H). Yield: 59%
2-Amino-3'-cvanoacetophenone hydrochloride (PA-n :
Figure imgf000359_0004
'HNMR (300 MHz, DMSO-d«) δ 8.71 (bs) 8.47 (s, IH), 8.29 (d, 1H),8.20 (d, IH), 7.82 (t, 1 H), 4.65 (d, 2 H). 77% yield.
2-Ammo-l-(l-methyl-l^-pyrrol-2-ylVethanone hydrochloride (PA-s):
Figure imgf000360_0001
LC/MS: MS {APCT m/z 139(M-HC1-1). Yield: 88%
PREPARATION OF AMIDE ESTERS
Ethyl [2-(4-methoxyphenylV2-oxoethyllamino-2-oxoethanoate (AE-b):
Figure imgf000360_0002
To a solution of 2-Amino-4'-methoxyacetophenone hydrochloride (17.28 g, 85.7 mmol) in DCM, was added triethylamine (25.1 mL, 179.97 mmol, 2.1 eq) followed by the addition of ethylchlorooxoacetate (9.7 mL, 86.6 mmol) slowly at 0°C under N2. The resulting mixture was stirred at 0°C for another 2.5 h. The reaction was quenched with H2O (200 mL). The organic phase was separated and the aqueous layer was extracted with DCM (2X50 mL). The combined organic layers were dried over MgSO . Solid was removed by filtration, and filtrate was concentrated to dryness under reduced pressure. The pure product was obtained by washing with Heptane/iPr- OH (200 mL/20 mL) in the yield of 96%.
JH NMR (300 MHz, CDC13) δ 8.1 (br), 8.0 (d, 2H), 7.0 (d, 2H), 4.8 (d, 2H), 4.4 (q, 2H), 3.9 (s, 3H), 1.4 (t, 3H). MS (APCI ) m/z 266 (M + 1). Yield: 96% Ethyl [2-(4-fluorophenvD-2-oxoethyllamino-2-oxoethanoate (AE-d^:
Figure imgf000361_0001
1H NMR (300 MHz, CDC13) δ 9.18 (bs), 8.14 (m, IH), 7.41 (m, 2H), 4.71 (d, 2H), 4.35 (q, 2H), 1.32 (t, 3 H). MS (APCf) m/z 254(M + 1). 80% yield
Ethyl [2-(2-trifluoromethylphenyl)-2-oxoethyll amino-2-oxoethanoate (AE-g^:
Figure imgf000361_0002
XH NMR (300 MHz, CDC13) δ 9.38 (bs), 7.70-7.95 (m, 4H), 4.55 (d, 2H), 4.35 (q, 2H), 1.32 (t, 3 H). 90% yield.
N-(2-Furan-2-yl-2-oxo-ethvI)-oxalamic acid ethyl ester (AE-h):
Figure imgf000361_0003
XH ΝMR (300 MHz, CDC13) δ 9.15 (bs), 8.09 (d, IH), 7.62 (d, IH), 6.79 (d, IH), 4.52 (d, 2H), 4.35 (q, 2H), 1.34 (t, 3 H). 85% yield.
Ethyl [2-(2-methoxyphenylV2-oxoethyllamino-2-oxoethanoate fAE-i):
Figure imgf000361_0004
lH ΝMR (300 MHz, CDC13) δ 8.15 (br), 7.98 (d, IH), 7.60 (t, IH), 7.30 (s, IH), 7.05 (m, IH), 4.80 (d, 2H), 4.45 (q, 2H), 4.00 (s, 3H), 1.45 (t, 3H). Yield: 88% Ethyl [2-(3.4-methylenedioxyphenvI)-2-oxoethyll amino-2-oxoethanoate (AE-k>:
Figure imgf000362_0001
1H NMR (300 MHz, CDC13) δ 8.10 (br), 7.60 (d, IH), 7.45 (s, IH), 6.90 (d, IH), 6.10 (s, 2H), 4.75 (d, 2H), 4.40 (q, 2H), 1.40 (t, 3H). Yield: 96%
Ethyl t2-(4-cvanophenvD-2-oxoethyl amino-2-oxoethanoate (AE-D:
Figure imgf000362_0002
1H NMR (300 MHz, CDC13) δ 8.10 (d, 2H), 7.85 (d, 2H), 4.85 (d, 2H), 4.40 (q, 2H), 1.45 (t, 3H). Yield: 66%
Ethyl f2-(3-cvanophenylV2-oxoethyllamino-2-oxoethanoate (AE-m):
Figure imgf000362_0003
1H NMR (300 MHz, CDC13) δ 9.24 (bs), 8.52 (s, IH), 8.29 (d, 1H),8.14 (d, IH), 7.74 (t, 1 H), 4.78 (d, 2H), 4.35 (q, 2H), 1.32 (t, 2H). 81% yield.
N-f2-d-Methyl-l//-pyιτol-2-yl)-2-oxo-ethyll-oxalamic acid ethyl ester (AE-s):
Figure imgf000362_0004
1H NMR (300 MHz, DMSO-de) δ 9.01 (bs), 7.22 (m, 2H), 6.18 (m, IH), 4.40 (d, 2H), 4.30 (q, 2H), 3.87 (s, 3H), 1.25 (t, 3H). 83% yield. 5-phenyl-oxazole-2-carboxylic acid ethyl ester (OE-fl:
Figure imgf000363_0001
Ethyl [2-phenyl-2-oxoethyl]amino-2-oxoethanoate (16.5 g, 71 mmol) was dissolved in 200 mL of anhydrous toluene in a 1 L Parr bottle. To the solution was added 21 mL (225 mmol, 3.15 eq) of POCl3. The Parr bottle was sealed, and the reaction mixture heated at an oil bath temperature of 110° C for 48 h. The solvent and POCl3 were removed under reduced pressure to give a brown oil. To the brown oil was added 300 mL H2O. The aqueous solution was extracted twice with 150 mL of dichloromethane. The combined organics were dried over MgSO , filtered and the solvent removed in vacuo. The resulting brown solid was recrystallized from 50 mL of EtOH to give 12.5 g of an orange solid (80% yield).
1H NMR (300 MHz, DMSO) δ 8.10 (s, IH), 7.82 (d, 2 H), 7.55 (m, 3 H), 4.43 (q, 2H), 1.35 (t, 3H). MS (APCI4) m/z 218(M + 1)
5-(3-methoxyphenvι)-oxazole-2-carboxylic acid ethyl ester (OE-a):
Figure imgf000363_0002
MS (APCI4) m/z 248(M + 1). Yield: 50%
5-(4-methoxyphenyr)-oxazole-2-carboxylic acid ethyl ester (OE-b):
Figure imgf000363_0003
1H NMR (300 MHz, CDC13) δ 7.7 (d, 2H), 7.4 (s, IH), 7.0 (d, 2H), 4.5 (q, 2H), 3.8 (s, 3H), 1.5 (t, 3H).
Figure imgf000364_0001
Yield: 43%
5-(4-fhιorophenyr>-oxazole-2-carboxylic acid ethyl ester (OE-d):
Figure imgf000364_0002
1H NMR (300 MHz, DMSO) δ 8.05 (s, IH), 7.85 (m, 2H), 7.41 (m, 2H), 4.42 (q, 2H), 1.35 (t, 3H). Yield: 59%
5-(2-trifluoromethylphenyr>-oxazole-2-carboxyIic acid ethyl ester (OE-gl:
Figure imgf000364_0003
!H NMR (300 MHz, DMSO) δ 7.67-8.05 (m, 5 H), 4.43 (q, 2H), 1.35 (t, 3H). MS (APCr*) m/z 286(M + 1). 41% yield
5-furan-2-yl-oxazole-2-carboxylic acid ethyl ester fOE-h):
Figure imgf000364_0004
lH NMR (300 MHz, DMSO) δ 7.95 (s, 1H),7.72 (d, IH), 7.14(d, 1 H), 6.79 (d, IH),
4.37 (q, 2H), 1.38 (t, 3H).
MS {APCr /z 208(M + 1). 35% yield
5-(2-Methoxyphenyl)-oxazole-2-carboxyhc acid ethyl ester (OE-f):
Figure imgf000364_0005
XH NMR (300 MHz, CDC13) δ 7.90 (d, IH), 7.70 (s, IH), 7.38 (m, IH), 7.10 (d, IH), 7.04 (t, IH), 4.50 (q, 2H), 4.00 (s, 3H), 1.48 (t, 3H). MS {APC ) m/z 248(M + 1). Yield: 68%
5-(3.4-Methylenedioxyphenyr)-oxazole-2-carboxylic acid ethyl ester (OE-k>:
Figure imgf000365_0001
lH NMR (300 MHz, CDC13) δ 7.42 (s, IH), 7.27 (dd, IH), 7.20 (d, IH), 6.90 (d, IH), 6.06 (s, 2H), 4.50 (q, 2H), 1.48 (t, 3H). MS (APCI ) m/z 262(M + 1). Yield: 61%
5-(4-CvanophenvD-oxazole-2-carboxylic acid ethyl ester (OE-D:
Figure imgf000365_0002
XH NMR (300 MHz, CDC13) δ 7.90 (d, 2H), 7.78 (d, 2H), 7.68 (s, IH), 4.55 (q, 2H), 1.50 (t, 3H). MS {APC ) m/z 243(M + 1). Yield: 24%
5-(3-cvanophenvD-oxazole-2-carboxylic acid ethyl ester (OE-m):
Figure imgf000365_0003
XH NMR (300 MHz, DMSO) δ 8.39 (s, IH), 8.18 (m, 2 H), 7.92 (d, IH), 7.74 (t, 1 H), 4.41 (q, 2 H), 1.32 (t, 3 H). MS (APCI+) mz 243(M + l). 35% yield 5-(l-methyl-lH-Pyrrol-2-yl)-oxazoIe-2-carboxyIic acid ethyl ester (OE-s^:
Figure imgf000366_0001
1H NMR (300 MHz, DMSO) δ 7.58 (s, IH), 7.05 (s, 1 H), 6.58 (d, IH), 6.15 (d, 1 H), 4.41 (q, 2H), 3.83 (s, 3 H), 1.32 (t, 3 H). 14% yield
PREPARATION OF OXAZOLE ACIDS (as triethyl ammonium salts)
5-(4-fluorophenvD-oxazole-2-carboxyIic acid triethyl ammonium salt (OA-d):
Figure imgf000366_0002
5-(4-fluorophenyl)-oxazole-2-carboxylic acid ethyl ester (3.56 g, 15.1 mmol) was dissolved in 140 mL of THF/H2O (2.5 : 1). To this solution was added 3.3 g (5.2 eq) of LiOH H2O. The resulting solution was stirred at ambient temperature overnight. The reaction mixture was adsorbed onto 18 g of silica gel and placed on a pad of silica gel. The triethyl ammonium salt was eluted off the pad with 200 mL of 10% MeOH/10% Et3N/80% CH2C12. After concentrating the filtrate, 4.4 g of a brown oil was obtained (93% yield)
1H NMR (300 MHz, DMSO) δ 7.78 (m, 2 H), 7.60 (s, 1 H), 7.35 (m, 2 H), 3.15 (q, 6 H), 1.18 (t, 9 H). MS (APCI ) m/z 208(M + 1).
5-(4-methoxyphenyl')-oxazole-2-carboxylic acid triethyl ammonium salt (OA-b):
Figure imgf000366_0003
1H NMR (300 MHz, CDC13) δ 7.7 (d, 2H), 7.3 (s, IH), 6.9 (d, 2H), 3.9 (s, 3H), 3.2 (q, 6H), 1.4 (t, 9H). MS {APCV) m/z 220 [M (free acid) + 1]. Yield: 94%
5-(4-MethoxyphenylVoxazole-2-carboxylic acid triethyl ammonium salt (OA-i>:
Figure imgf000367_0001
1H NMR (300 MHz, CDC13) δ 8.00 (d, IH), 7.65 (s, IH), 7.30 (t, IH), 6.95 (m, 2H), 3.97 (s, 3H), 3.15 (q, 6H), 1.35 (t, 9H).
MS (APCI ) m/z 220[M (free acid) + 1]. Yield: 99%
PREPARATION OF ANTHRANILATES
tert-Butyl 2-nitrobenzoate:
Figure imgf000367_0002
To a mixture of 2-nitrobenzoic acid (80.2 g, 0.48 mol) in DCM (2 L) was added DMF (4 mL) followed by the dropwise (55 min) addition of a solution of oxalyl chloride (100 mL, 1.15 mol) in DCM (0.4 L). After stirring at RT for 6 h, the reaction mixture was evaporated to dryness using heptane to aid in the chasing off of residual oxalyl chloride. This process was repeated and the two residue acid chlorides combined. To a stirred and cooled (0°C) solution ofthe combined acid chloride in dry THF ( 2 L) was added a solution of potassium tert-butoxide (130 g, 1.16 mol) in dry
THF (1.4 L). The reaction mixture was stirred (~1 h), concentrated to one-fifth the original volume, dissolved in TBME (2 L) and then washed with 1 N NaOH (4 x 1.5
L), dried (Na2SO ), and evaporated to dryness (rotovap, then high vacuum) to give
194.8 g (yield of 91%) ofthe tert-butyl ester as a brown oil. 1H NMR (300 MHz, CDC13) δ 7.86 (dd, IH), 7.73 (dd, IH), 7.55-7.70 (m, 2 H), 1.58 (s, 9 H).
tert-Butyl 2-aminobenzoate:
Figure imgf000368_0001
To a mixture of tert-butyl 2-nitrobenzoate (194.8 g, 0.873 mol) in EtOH (2.5 L) in a 5 L Parr bottle was added 72 g of Raney Nickel 2800 (washed 5 times with ethanol). The system was degassed (suction) three times, each time replenishing the system with nitrogen gas. The system was then pressurized with hydrogen gas (30 psi) and 1.5 h later was repressurized to 50 psi of hydrogen. After overnight stirring, the pressure ofthe system had fallen to 30 psi and was repressurized to 50 psi. At the end ofthe day, the reaction was found to be complete. The reaction mixture was filtered thru Celite and evaporated to give 160.8 g (yield of 95%) ofthe aniline ester as a brown oil.
1H NMR (300 MHz, CDC13) δ 7.82 (dd, IH), 7.22 (ddd, IH), 6.55-6.65 (m, 2 H), 5.7 (br s), 1.58 (s, 9 H).
tert-Butyl 2-amino-5-bromobenzoate:
Figure imgf000368_0002
To a stirred and cooled (0°C) solution of tert-butyl 2-arninobenzoate (23.37 g, 120.9 mmol) in DMF (20 mL) was added a mixture of NBS (21.50 g, 120.8 mmol) in DMF (20 mL) over a period of 3-5 min (an additional 10 mL of DMF used to rinse the NBS container was added as well). After stirring for 4 h (0°C to RT), the reaction mixture was diluted with EtOAc (500 mL) and then washed with 1 N NaOH (3 x 300 mL), dried (Na2SO4), filtered, evaporated on to silica gel (48 g), and applied to a column of silica gel (620 g) packed in 80: 1 heptane/TBME. Elution was effected with 80: 1, 70: 1, and then 60:1 heptane/TBME to give (after evaporation of fractions) 25.99 g (yield of 79%) ofthe title product as a yellowish- white solid.
1H NMR (300 MHz, CDC13) δ 7.91 (d, IH), 7.30 (dd, IH), 6.53 (d, 1 H), 5.72 (br s), 1.58 (s, 9 H).
tert-Butyl 2-ammo-5-iodobenzoate:
Figure imgf000369_0001
To a stirred and cooled (0°C) solution of tert-butyl 2-aminobenzoate (71.3 g, 369 mmol) in DMF (25 mL) was added (dropwise) a mixture of NIS (87.0 g, 387 mmol) in DMF (150 mL). After removing the ice bath, the mixture was stirred for 4 h (RT), diluted with EtOAc (1500 mL), washed with 1 N NaOH (3 x 500 mL), dried (Na2SO4), filtered, evaporated on to silica gel (-150 g), and applied to a column of silica gel (1500 g) packed in 80: 1 heptane/TBME. Elution was effected with 80: 1 , 70: 1 , and then 60: 1 heptane/ TBME to give (after evaporation of desired fractions) 72.8 g (yield of 62%) of the title product as a solid.
1H NMR (300 MHz, CDC13) δ 8.06 (d, IH), 7.44 (dd, IH), 6.43 (d, 1 H), 5.75 (br s), 1.58 (s, 9 H).
tert-Butyl 2-amino-5-cvanobenzoate:
Figure imgf000369_0002
To a stirred and hot (internal temperature of 80-90°C) solution of tert-butyl 2-amino-5- iodobenzoate (60.4 g, 189 mmol) in pyridine (125 mL) was added CuCN (20.5 g, 229 mmol). The resulting reaction mixture was then stirred at a gentle reflux (internal temperature of 120°C) for 16 h, then allowed to cool to RT and diluted with EtOAc (150 mL) and heptane (25 mL). The copper salts were filtered off and the filtrate was then evaporated on to silica gel (80 g) and applied to a column of silica gel (1.2 Kg) packed in 8: 1 heptane/ EtOAc. Elution was effected beginning with 8: 1 and ending with 4: 1 heptane/EtOAc. Evaporation of fractions gave 36.1 g (yield of 87%) of cyanoanthranilate as a light yellow fluffy solid.
1H NMR (300 MHz, CDC13) δ 8.13 (d, IH), 7.42 (dd, IH), 6.65 (d, 1 H), -6.8 (very br s), 1.60 (s, 9 H).
Methyl 2-Amino-5-cvanobenzoate (methyl 5-cvanoanthranilate'):
Figure imgf000370_0001
Methyl 2-arnino-5-bromobenzoate (24.0 g, 104 mmol), zinc cyanide (8.02 g, 68.3 mmol), and Pd(PPh3)4 (2.02 g) were weighed into a three-necked flask, which was then purged with nitrogen. After adding DMF (130 mL), the reaction mixture was stirred in a hot oil bath (90°C) for 8 h. Because TLC revealed no change during the last 3 h, additional catalyst (2.00 g) was added and stirred in the hot oil bath overnight. Additional catalyst (1.00 g) and heating at 100°C was required to drive reaction to near completion. Reaction was poured into water (400 mL), extracted with EtOAc (700 mL), and the two-phase mixture filtered. The organic layer was removed, washed with saturated brine (4 x 200 mL), dried, filtered, and evaporated on to silica gel, and applied to a column of silica gel. Elution was effected using 4: 1 heptane/EtOAc to give 15.60 g (yield of 85%) ofthe methyl 5-cyanoanthranilate as a pale yellow solid.
Η NMR (300 MHz, CDC13) δ 8.19 (d, IH), 7.45 (dd, IH), 6.68 (d, 1 H), -6.3 (very br s), 3.90 (s, 3 H). 2-Amino-5-cvanobenzoic acid (5-cvanoanthranilic acid):
Figure imgf000371_0001
Methyl 2-amino-5-cyanobenzoate (5.0 g, 28.41 mmol) was dissolved in MeOH (105 mL). Then 6M NaOH (14 mL) was added. The resulting mixture was stirred at RT O/N. The reaction mixture was diluted with H2O (143 mL), washed with DCM to remove any unreacted S.M. The product was precipitated from aqueous layer by addition of cone. HCl to pH 1 and extracted with EtOAc (3 x 100 mL). The combined organic layers were dried over MgSO . Solid was removed by filtration, and filtrate was concentrated to dryness under reduced pressure. The light yellow product was obtained in the yield of 94% .
1H NMR (300 MHz, DMSO-dβ) δ 8.08 (d, IH), 7.56 (dd, IH), 7.50 (br), 6.85 (d, IH).
Method B - Through a two step process:
(1) Coupling Of An Oxazole Acid Chloride With A Tert-Butyl Anthranilate
t-Butyl (5-cvano-2-[5-(4-fluorophenylVoxazole-2-carbonyllamino)benzoate (PREfCN)-d):
Figure imgf000371_0002
5-(4-fluorophenyl)-oxazole-2-carboxylic acid triethyl ammonium salt (1 g, 3.25 mmol) was dissolved in 25 mL of CH2C12. To this solution was added 3 drops of DMF, followed by 1 mL (3.5 eq) of oxalyl chloride dropwise. The resultant brown/orange solution was stirred at ambient temperature overnight. The solvent and excess oxalyl chloride were removed in vacuo to give an orange solid. The solid was dissolved in 12.5 mL of CH2C12 and added dropwise to a solution of 2-amino-5-cyano-benzoic acid (0.65 g, 0.94 eq), pyridine (5 mL) in 12.5 mL of CH2C12. The reaction was stirred at ambient temperature for 5 h. The reaction mixture was diluted with 25 mL of TBME and washed with 50 mL of 1 N HCl, followed by 50 mL of brine solution. The organic layer was dried (MgSO ), filtered, and the solvent removed in vacuo. The resulting solid was dissolved in 20 mL of MeOH and CH2C12 added until precipitation occurred (15 mL). The solution was placed in the freezer overnight to aid in crystal formation. The white solid was collected by filtration to give 1.38 g ( 36% yield).
1H NMR (300 MHz, DMSO-ck) δ 8.84 (d, IH), 8.39 (d, IH), 8.15 (d, IH), 8.10 (s, IH), 7.95 (m, 2H), 7.42 (m, 2H), 2.05 (s, 9 H).
t-Butyl (5-cvano-2-[5-(3-methvoxyphenylVoxazole-2-carbonyllaminolbenzoate (PRE(CNVa):
Figure imgf000372_0001
JH NMR (300 MHz, CDC13) δ 12.59 (br), 8.78 (d, IH), 8.40 (s, IH), 8.20 (dd, IH), 8.17 (s, IH), 7.40 (m, 3H), 7.05 (m, IH), 3.85 (s, 3H), 1.70 (s, 9H). Yield: 15%
t-butyl(5-cvano-2-f5-(4-methvoxyphenylVoxazole-2-carbonyllaminolbenzoate (PRE(CN-b):
Figure imgf000372_0002
JH NMR (300 MHz, CDC13) δ 12.82 (br), 9.05 (d, IH), 8.35 (d, IH), 7.85 (dd, IH), 7.75 (dd, 2H), 7.45 (s, IH), 7.00 (d, 2H), 3.90 (s, 3H), 1.70 (s, 9H). Yield: 41% t-Butyl {5-cvano-2-[5-(2-methvoxyρhenylVoxazole-2-carbonyllamino)benzoate
Figure imgf000373_0001
:H NMR (300 MHz, CDC13) δ 12 89 (br), 9.05 (d, IH), 8 35 (s, IH), 8 03 (dd, IH), 7 85 (dd, IH), 7 80 (s, IH), 7 40 (m, IH), 7.10 (t, IH), 7 00 (d, IH), 4 00 (s, 3H), 1 70 (s, 9H)
MS (APCI*) m/z 420(M + 1). Yield 55%
(2) Deprotection of theTert-Butyl Ester
5-Cvano-2-([5-(4-fluorophenylVoxazole-2-carbonyllamino)benzoic acid (TKCNV
Figure imgf000373_0002
t-Butyl {5-cyano-2-[5-(4-fluorophenyl)-oxazole-2-carbonyl]arnino}benzoate (480 mg, 1 1 mmol) was dissolved in 22 mL of CH2C12. To this solution was added 7 mL of trifluoroacetic acid The resultant mixture was stirred at room temperature overnight, followed by 40°C (oil bath temperature) for 3 h. The solvent was removed in vacuo to give 420 mg of a light brown solid This solid was heated in 50 mL of MeOH to boiling in a 2 L erlenmeyer flask Dichloromethane was added dropwise to the solution (maintaing the boil) until the solid had mostly dissolved The solution was filtered hot to remove the insouble impurities The clear filtrate was then heated until the solution became quite cloudy The solution was cooled to room temperature and the placed in the freezer overnight The white solid that formed was collected by filtration to give 230 mg (57% yield) 1H NMR (300 MHz, DMSO-ds) δ 13.50 (br), 8.82 (d, IH), 8.41 (s, IH), 8.13 (dd, IH), 8.05 (s, IH), 7.92 (m, 2H), 7.42 (m, 2H).
5-Cvano-2-([5-(3-methoxyphenyl)-oxazole-2-carbonyllaminolbenzoic acid fTKCNVaϊ:
Figure imgf000374_0001
XH NMR (300 MHz, DMSO-dδ) δ 12.95 (br), 8.85 (d, IH), 8.43 (s, IH), 8.14 (d, IH), 8.09 (s, IH), 7.45 (m, 3H), 7.04 (m, IH), 3.84 (s, 3H).
5-Cvano-2-(f5-(4-methvoxyphenyl)-oxazoIe-2-carbonyllamino)benzoic acid (TKCNVb):
Figure imgf000374_0002
1H NMR (300 MHz, DMSO-de) δ 13.1 (br), 8.83 (d, IH), 8.45 (d, IH), 8.12 (dd, IH), 7.92 (s, IH), 7.80 (d, 2H), 7.10 (d, 2H), 3.86 (s, 3H).
5-Cvano-2-([5-(2-methvoxyphenylVoxazole-2-carbonyllaminolbenzoic acid
Figure imgf000374_0003
1H NMR (300 MHz, DMSO-dδ) δ 12.95 (br), 8.85 (d, IH), 8.45 (s, IH), 8.13 (dd, IH), 7.90 (s, IH), 7.85 (d, IH), 7.45 (m, IH), 7.25 (d, IH), 7.15 (t, IH), 4.00 (s, 3H). 5-Bromo-2-([5-(4-fluorophenyl)-oxazole-2-carbonyllaminolbenzoic acid (TI(BrV dli
Figure imgf000375_0001
1H NMR (300 MHz, DMSO-d*) δ 12.60 (br), 8.69 (d, IH), 8.14 (d, 1 H), 8.05 (s, IH), 7.92 (m, 3 H), 7.42 (m, 2H).
Method B - Direct Coupling Of Oxazole Esters With Anthranilic Acids
5-cyano-2-{[5-(2-furanyl)-oxazole-2-carbonyl]amino}benzoic acid (TI(CN)-h):
Figure imgf000375_0002
To a solution of 2-amino-5-cyano-benzoic acid (0.389 g, 2.4 mmol) and oxazole ester (1 eq) in DMF (5 mL) was added NaH (3 eq). The solution was allowed to stir at room temperature overnight. The reaction mixture was added dropwise to 100 mL of 1 N HCl with stirring. The carboxylic acid precipitated out and was collected by filtration. The tan solid was recrystallized from boiling EtOH to give 230 mg of an off white solid (yield of 32%).
1H NMR (300 MHz, DMSO-de) δ 12.91 (bs), 8.86 (d, IH), 8.45 (s, IH), 8.18 (dd, IH), 7.98 (s, IH), 7.84 (s, IH), 7.12 (d, IH), 6.78 (d, 1 H).
5-Cvano-2-[(5-phenyl-oxazole-2-carbonyl)aminolbenzoic acid (TKCNVf):
Figure imgf000376_0001
1H NMR (300 MHz, DMSO-d«) δ 12.71 (br), 8.84 (d, IH), 8.41 (s, IH), 8.14 (dd, IH), 8.10 (s, IH), 7.88 (d, 2H), 7.50 (m, 3H).
5-Cvano-2-([5-(2-trifluoromethylphenylVoxazole-2-carbonyllaminolbenzoic acid
(TKCNVg:
Figure imgf000376_0002
1H NMR (300 MHz, DMSO-ds) δ 12.71 (br), 8.82 (d, IH), 8.41 (s, IH), 8.14 (m, 3H), 7.88 (m, 2H), 7.74 (t, IH).
5-Cvano-2-(f5-f3,4-methylenedioxyphenylVoxazole-2-carbonyllaminolbenzoic acid rTKCNVk):
Figure imgf000376_0003
1H NMR (300 MHz, DMSO-d*) δ 12.95 (br), 8.87 (d, IH), 8.45 (d, IH), 8.13 (dd, IH), 7.95 (s, IH), 7.40-7.47 (m, 2H), 7.10 (d, IH), 6.17 (s, 2H).
5-Cvano-2-([5-(4-cvanophenyl)-oxazole-2-carbonyllamino)benzoic acid (TKCNV
Figure imgf000377_0001
1H NMR (300 MHz, DMSO-ds) δ 13.00 (br), 8.82 (d, IH), 8.43 (d, IH), 8.28 (s, IH), 8.12 (dd, IH), 8.04 (s, 4H).
5-Cvano-2-([5-(3-cvanophenyl)-oxazole-2-carbonyll aminolbenzoic acid (TKCNV
Figure imgf000377_0002
1H NMR (300 MHz, DMSO-de) δ 12.96 (br), 8.82 (d, IH), 8.37 (d, 2H), 8.25 (s, IH), 8.12 (dd, 2H), 7.93 (d, IH), 7.74 (t, IH).
5-Cvano-2-{[5-(l-methyl-lH-pyrrol-2-ylVoxazole-2-carbonyllamino)benzoic acid (TKCNVs):
Figure imgf000377_0003
1H NMR (300 MHz, DMSO-de) δ 12.65 (br), 8.85 (d, IH), 8.41 (s, IH), 8.19 (dd, IH), 7.62 (s, IH), 7.10 (s, IH), 6.65 (dd, IH), 6.18 (t, IH).
5-Bromo-2-([5-(4-methvoxyphenyl)-oxazoIe-2-carbonyllaminolbenzoic acid fTKBrVIrt:
Figure imgf000378_0001
1H NMR (300 MHz, DMSO-d*) δ 12.60 (br), 8.65 (d, IH), 8.20 (s, IH), 7.90 (m, 2H), 7.80 (d, 2H), 7.10 (d, 2H), 3.80 (s, 3H).
5-Bromo-2-[(5-phenyl-oxazole-2-carbonyl)ammolbenzoic acid (TI(BrVfl:
Figure imgf000378_0002
lH NMR (300 MHz, DMSO-ds) δ 12.65 (br), 8.65 (d, IH), 8.19 (d, IH), 8.10 (s, IH), 7.90 (m, 3H), 7.50 (m, 3H).
5-Bromo-2-([5-(2-trifluoromethylphenyl)-oxazole-2-carbonvIlaminolbenzoic acid (TKBrt-g):
Figure imgf000378_0003
1H NMR (300 MHz, DMSO-ds) δ 12.67 (br), 8.65 (d, IH), 8.13 (d, IH), 7.76-7.98 (m, 6H).
5-Bromo-2-{[5-(2-mranyl)-oxazole-2-carbonyllaminolbenzoic acid (TKBrY-h):
Figure imgf000378_0004
1H NMR (300 MHz, DMSO-ds) δ 8.67 (d, IH), 8.16 (s, IH), 7.97 (s, IH), 7.92 (d, IH), 7.81 (s, IH), 7.09 (d, IH), 6.77 (d, 1 H).
5-Bromo-2-([5-(2-methvoxyphenylVoxazole-2-carbonyllaminolbenzoic acid
(TKBrt-f):
Figure imgf000379_0001
1H NMR (300 MHz, DMSO-ds) δ 12.65 (br), 8.64 (d, IH), 8.13 (d, IH), 7.84 (m, 3H), 7.44 (m, IH), 7.10 (m, 2H), 3.98 (s, 3H).
5-Bromo-2-([5- 3<4-methvIenedioxyphenyl)-oxazole-2-carbonyllaminolbenzoic acid rTIfBrt-k):
Figure imgf000379_0002
lH NMR (300 MHz, DMSO-ds) δ 12.63 (br), 8.63 (d, IH), 8.15 (d, IH), 7.89 (s, IH), 7.85 (dd, IH), 7.40 (d, IH), 7.34 (dd, IH), 7.10 (d, IH), 6.15 (s, 2H).
5-Bromo-2-([5-( -cvanophenvD-oxazole-2-carbonvπ aminolbenzoic acid (TKBr)-
Figure imgf000379_0003
1H NMR (300 MHz, DMSO-ds) δ 12.68 (br), 8.62 (d, IH), 8.24 (s, IH), 8.12 (d, IH), 8.01 (s, 4H), 7.86 (dd, IH). 5-Bromo-2- 5- 3-cvanophenyl oxazole-2-carbonyllaminolbenzoic acid (TItBrV m):
Figure imgf000380_0001
1H NMR (300 MHz, DMSO-ds) δ 12.71 (br), 8.64 (d, IH), 8.37 (s, IH), 8.14 (m, 3H), 7.88 (m, 2H), 7.74 (t, IH).
5-Bromo-2-([5-ri-methyl-lH-pyrrol-2-yl)-oxazole-2-carbonyllamino)benzoic acid (TKBrVsY.
Figure imgf000380_0002
lH NMR (300 MHz, DMSO-ds) δ 12.59 (br), 8.65 (d, IH), 8.14 (d, IH), 7.88 (dd, IH), 7.64 (s, IH), 7.04 (d, IH), 6.63 (dd, IH), 6.17 (dd, IH).
Example 11: Activity Data MIC Test Method
The in vitro MICs of test compounds were determined by a standard agar dilution method. A stock drug solution of each analog was prepared in the preferred solvent, usually DMSO:H2O (1:3). Serial 2-fold dilutions of each sample are made using 1.0 ml aliquots of sterile distilled water. To each 1.0 ml aliquot of drug was added 9 ml of molten Mueller Hinton agar medium. The drug-supplemented agar was mixed, poured into 15 x 100 mm petri dishes, and allowed to solidify and dry prior to inoculation.
Vials of each ofthe test organisms are maintained frozen in the vapor phase of a liquid nitrogen freezer. Test cultures are grown overnight at 35°C on the medium appropriate for the organism. Colonies are harvested with a sterile swab, and cell suspensions are prepared in Trypticase Soy broth (TSB) to equal the turbidity of a 0.5
McFarland standard. A 1 :20 dilution of each suspension was made in TSB. The plates containing the drug supplemented agar are inoculated with a 0.001 ml drop ofthe cell suspension using a Steers replicator, yielding approximately 104 to 105 cells per spot. The plates are incubated overnight at 35°C.
Following incubation the Minimum Inhibitory Concentration (MIC μg/ml), the lowest concentration of drug that inhibits visible growth ofthe organism, was read and recorded.
Figure imgf000381_0001
Figure imgf000382_0001
Figure imgf000383_0001
Figure imgf000384_0001
Figure imgf000385_0001
Figure imgf000386_0001
Figure imgf000387_0001
Figure imgf000388_0001
Figure imgf000389_0001
Figure imgf000390_0001
Figure imgf000391_0001
Figure imgf000392_0001
Figure imgf000393_0001
Figure imgf000394_0001
Figure imgf000395_0001
Figure imgf000396_0001
Figure imgf000397_0001
Figure imgf000398_0001
Figure imgf000399_0001
Figure imgf000400_0001
Figure imgf000401_0001
Figure imgf000402_0001
Figure imgf000403_0001
Figure imgf000404_0001
Figure imgf000405_0001
Figure imgf000406_0001
Figure imgf000407_0001
Figure imgf000408_0001
Figure imgf000409_0001
COMPOUND SAUR9218 MC
1
0.5
32
0.5
0.5
0.5
0.25
O" —H -'
Figure imgf000411_0001
Figure imgf000412_0001
Figure imgf000413_0001
Figure imgf000414_0001
Figure imgf000415_0001
Figure imgf000416_0001
Figure imgf000417_0001
Figure imgf000418_0001
Figure imgf000419_0001
Figure imgf000420_0001
Figure imgf000421_0001
Figure imgf000422_0001
Figure imgf000423_0001
Figure imgf000424_0001
Figure imgf000425_0001
Figure imgf000426_0001
Figure imgf000427_0001
Figure imgf000428_0001
Figure imgf000429_0001
Figure imgf000430_0001
Figure imgf000431_0001
Figure imgf000432_0001
Figure imgf000433_0001
Figure imgf000434_0001
Figure imgf000435_0001
Figure imgf000436_0001
Figure imgf000437_0001
Figure imgf000438_0001
Figure imgf000439_0001
Figure imgf000440_0001
Figure imgf000441_0001
Figure imgf000442_0001
Figure imgf000443_0001
Figure imgf000444_0001
Figure imgf000445_0001
Figure imgf000446_0001
Figure imgf000447_0001
Figure imgf000448_0001
Figure imgf000449_0001
Figure imgf000450_0001
Figure imgf000451_0001
Figure imgf000452_0001
Figure imgf000453_0001
Figure imgf000454_0001
Figure imgf000455_0001
Figure imgf000456_0001
Figure imgf000457_0001
Figure imgf000458_0001
Figure imgf000459_0001
Figure imgf000460_0001
Figure imgf000461_0001
Figure imgf000462_0001

Claims

What is claimed is:
1. A compound of formula I,
Figure imgf000463_0001
I or a pharmaceutically acceptable salt thereof, wherein
X = NH
Y = CO, CS, -C(=N-CN) or
X and Y together form an alkene, or C3-C5 cycloalkyl;
Figure imgf000463_0002
R2 is an electron withdrawing group; and j is an optionally substituted HET, provided that the HET is not simultaneously substituted with a surfonamide and a urea or thiourea.
2. The compound ofclaim 1 having a formula II
Figure imgf000463_0003
or a pharmaceutically acceptable salt thereof, wherein
X = NH Y = CO, CS, -C(=N-CN) or
X and Y together form an alkene, or C3-Cs cycloalkyl;
Figure imgf000463_0004
R2 is an electron withdrawing group;
R5 is -(CH2)k-S(O)i-R7, -NH-SO2-R7, -(CH2)k-W-R8, -NH-(CZι)-R8, -NH- (CZι)-NR8, substituted aryl, substituted Chalky., or substituted
Figure imgf000463_0005
Re is selected from H, halo, HET, -CN, NH2, NO2, alkyl, substituted alkyl, alkoxy, substituted alkoxy, -NH-CO-HET, and -NH-CO-aryl;
R7 is selected from alkyl, substituted alkyl, aryl, substituted aryl, -N(Qι5)2, HET, and substituted HET; Rg is H, alkyl, substituted alkyl, aryl, substituted aryl, HET, substituted HET, cycloalkyl, substituted cycloalkyl;
Each Q15 is independently H, alkyl, cycloalkyl, heterocycloalkyl, heteroaryl, phenyl, or naphthyl, each optionally substituted with 1-4 substituents independently selected from -F, -CI, -Br, -I, -OQι6, -SQι6, -S(O)26, -S(O)Qι6, -OS(O)26, -
Figure imgf000464_0001
C(O)Q16, -C(S)Q16, -C(O)OQi6, -OC(O)Qι6, -C(O)NQι66, -C(S)NQι66, -C(O)C(Qι6)2OC(O)Qi6, -CN, -NQι6C(O)Qi6, -NQι6C(S)Qι6, -NQ16C(O)NQι66, -NQ16C(S)NQι6Q16, -S(O)2NQι6Qi6, -NQι6S(O)26, -NQι6S(O)Qι6, -NQι6SQι6, - NO2, and -SNQiβQiβ The alkyl, cycloalkyl, and cycloalkenyi being furher optionally substituted with =O or =S;
Each Qi6 is independently selected from -H, alkyl, and cycloalkyl. The alkyl and cycloalkyl optionally including 1-3 halos;
W is O, S, -(CZ2)-, or -(CHZ3)-;
Figure imgf000464_0002
Z2 is =O, =S , =N-OH, =N-O-alkyl, or =N-O-substituted alkyl;
Z3 is -OH, -N=NH, -N-N-alkyl, -NH-alkyl, or -NH-substituted alkyl; i is 0, 1, or 2; and k is O, l, or 2.
3. The compound of claim 1 having a formula III
Figure imgf000464_0003
or a pharmaceutically acceptable salt thereof, wherein X = NH
Y = CO, CS, -C(=N-CN) or
X and Y together form an alkene, or C3-C5 cycloalkyl;
Figure imgf000465_0001
R2 is an electron withdrawing group;
R5 is -(CH2)k-S(O)i-R7, -NH-SO2-R7, -(CH2)k-W-R8, -NH-(CZι)-R8, -NH- (CZι)-NRg, substituted aryl, substituted Cι-4alkyl, or substituted Cι-4alkenyl;
R« is selected from H, halo, HET, -CN, NH2, NO2, alkyl, substituted alkyl, alkoxy, substituted alkoxy, -NH-CO-HET, and -NH-CO-aryl; R is selected from alkyl, substituted alkyl, aryl, substituted aryl, -N(Qu)2,
HET, and substituted HET;
Rg is H, alkyl, substituted alkyl, aryl, substituted aryl, HET, substituted HET, cycloalkyl, substituted cycloalkyl;
Each Q15 is independently H, alkyl, cycloalkyl, heterocycloalkyl, heteroaryl, phenyl, or naphthyl, each optionally substituted with 1-4 substituents independently selected from -F, -CI, -Br, -I, -OQι6, -SQι6, -S(O)26, -S(O)Qι6, -OS(O)26, -C(=NQι6)Q16, -S(O)2-N=S(O)(Qι6)2, -S(O)2-N=S(Q16)2, -SC(O)Q16, -NQι66, | -C(O)Qi6, -C(S)Qi6, -C(O)OQi6, -OC(O)Qι6, -C(O)NQι6Q16, -C(S)NQ166, -C(O)C(Qι6)2OC(O)Qi6, -CN, -NQι6C(O)Qι6, -NQι6C(S)Qι6, -NQι6C(O)NQι66, -NQι6C(S)NQι6Qi6, -S(O)2NQι66, -NQι6S(O)26, -NQι6S(O)Qι6, -NQι6SQι6, - NO2, and -SNQiβQiβ. The alkyl, cycloalkyl, and cycloalkenyi being furher optionally substituted with =O or =S;
Each Qi6 is independently selected from -H, alkyl, and cycloalkyl. The alkyl and cycloalkyl optionally including 1-3 halos; W is O, S, -(CZ2)-, or -(CHZ3)-;
Figure imgf000465_0002
Z2 is =O, =S , =N-OH, =N-O-alkyl, or =N-O-substituted alkyl; Z3 is -OH, -N=NH, -N=N-alkyl, -NH-alkyl, or -NH-substituted alkyl; i is 0, 1, or 2; and k is 0, 1, or 2.
4. The compound ofclaim 1 having a formula IV
Figure imgf000466_0001
or a pharmaceutically acceptable salt thereof, wherein
X = NH Y = CO, CS, -C(=N-CN) or
X and Y together form an alkene, or -C5 cycloalkyl;
Figure imgf000466_0002
R2 is an electron withdrawing group;
R5 is -(CH2)k-S(O)i-R7, -NH-SO2-R7, -(CH2)k-W-R8, -NH-fCZ -Rs, -NH- (CZι)-NRg, substituted aryl, substituted Cι.4alkyl, or substituted Cι- alkenyl;
Re is selected from H, halo, HET, -CN, NH2, NO2, alkyl, substituted alkyl, alkoxy, substituted alkoxy, -NH-CO-HET, and -NH-CO-aryl;
R7 is selected from alkyl, substituted alkyl, aryl, substituted aryl, -N(Qι5)2, HET, and substituted HET; Rs is H, alkyl, substituted alkyl, aryl, substituted aryl, HET, substituted HET, cycloalkyl, substituted cycloalkyl;
Each Q15 is independently H, alkyl, cycloalkyl, heterocycloalkyl, heteroaryl, phenyl, or naphthyl, each optionally substituted with 1-4 substituents independently selected from -F, -CI, -Br, -I, -OQι6, -SQι6, -S(O)26, -S(O)Qι6, -OS(O)26,
Figure imgf000466_0003
-C(O)Q16, -C(S)Q16, -C(O)OQι6, -OC(O)Qi6, -C(O)NQι66, -C(S)NQι6Qi6, -C(O)C(Qi6)2OC(O)Qi6, -CN, -NQι6C(O)Qι6, -NQ16C(S)Qι6, -NQι6C(O)NQ16Qi6, -NQι6C(S)NQι6Qi6, -S(O)2NQi6Qi6, -NQ16S(O)2Q16, -NQ16S(O)Qι6, -NQι6SQι6, -NO2, and -SNQiβQiβ- The alkyl, cycloalkyl, and cycloalkenyi being furher optionally substituted with =O or =S;
Each Qi6 is independently selected from -H, alkyl, and cycloalkyl. The alkyl and cycloalkyl optionally including 1-3 halos;
W is O, S, -(CZ2)-, or -(CHZ3)-; Z2 is =O, =S , =N-OH, =N-O-alkyl, or =N-O-substituted alkyl; Z3 is -OH, -N=NH, -N=N-alkyl, -NH-alkyl, or -NH-substituted alkyl; i is 0, 1, or 2; and k is 0, 1, or 2.
5. The compound ofclaim 1 having a formula V
Figure imgf000467_0001
V or a pharmaceutically acceptable salt thereof, wherein
X = NH
Y = CO, CS, -C(=N-CN) or
X and Y together form an alkene, or C3-C5 cycloalkyl;
Figure imgf000467_0002
R2 is an electron withdrawing group;
R5 is -CCH2)k-S(O)i-R7, -NH-SO2-R7, -(CH2)k-W-Rs, -NH-(CZι)-R8, -NH- (CZι)-NRg, substituted aryl, substituted Cι-4alkyl, or substituted Cι- alkenyl;
Re is selected from H, halo, HET, -CN, NH2, NO2, alkyl, substituted alkyl, alkoxy, substituted alkoxy, -NH-CO-HET, and -NH-CO-aryl;
R7 is selected from alkyl, substituted alkyl, aryl, substituted aryl, -N(Qi5)2, HET, and substituted HET;
Rs is H, alkyl, substituted alkyl, aryl, substituted aryl, HET, substituted HET, cycloalkyl, substituted cycloalkyl; Each Q15 is independently H, alkyl, cycloalkyl, heterocycloalkyl, heteroaryl, phenyl, or naphthyl, each optionally substituted with 1-4 substituents independently selected from -F, -CI, -Br, -I, -OQι6, -SQie, -S(O)26, -S(O)Qι6, -OS(O)26, -C(=NQ16)Q,6, -S(O)2-N=S(O)(Qιe)2, -S(O)2-N=S(Qι6)2, -SC(O)Qι6, -NQι66, -C(O)Qιe, -C(S)Qιe, -C(O)OQι6, -OC(O)Q16, -C(O)NQι6Q16, -C(S)NQι66, -C(O)C(Qι6)2OC(O)Q16, -CN, -NQι6C(O)Qιe, -NQι6C(S)Qι6, -NQι6C(O)NQι66, -NQι6C(S)NQ16Qi6, -S(O)2NQι6Q16, -NQι6S(O)26, -NQι6S(O)Qι6, -NQ16SQι6, -NO2, and -SNQιβQi6- The alkyl, cycloalkyl, and cycloalkenyi being furher optionally substituted with =O or =S;
Each Qi6 is independently selected from -H, alkyl, and cycloalkyl. The alkyl and cycloalkyl optionally including 1-3 halos;
W is O, S, -(CZ2)-, or -(CHZ3)-;
Figure imgf000468_0001
Z2 is =O, =S , =N-OH, =N-O-alkyl, or =N-O-substituted alkyl;
Z3 is -OH, -N=NH, -N=N-alkyl, -NH-alkyl, or -NH-substituted alkyl; i is 0, 1 , or 2; and k is 0, 1, or 2.
6. The compound of claim 1 having a formula XX
Figure imgf000468_0002
XX or a pharmaceutically acceptable salt thereof, wherein X = NH
Y = CO, CS, -C(=N-CN) or
X and Y together form an alkene, or C3-C5 cycloalkyl;
Figure imgf000468_0003
R2 is an electron withdrawing group; R5 is H, halo, NO2, CN, -(CH2)k-S(O)i-R7, -NH-SO2-R7, -(CH2)k-W-Rs -NH-
(CZι)-R8,-(CZι)-NH-R8, -NH-(CZι)-NRsRs, -(CH^-NRsRs, substituted aryl, substituted HET, substituted or substituted
Figure imgf000468_0004
Re is selected from H, halo, aryl, substituted aryl, HET, substituted HET, -CN, NH2, NO2, alkyl, substituted alkyl, alkoxy, substituted alkoxy, -(CH2) -S(O)i-R7, -NH- SO2-R7, -(CH2)k-W-Rs, -NH-(CZi)-Rs,-(CZi)-NH-Rs, -NH-(CZι)-NRsRs, or substituted Cι- alkenyl; R7 is selected from alkyl, substituted alkyl, aryl, substituted aryl, -N(Qι5)2,
HET, and substituted HET;
Each Rg is independently H, alkyl, substituted alkyl, -OQiβ, aryl, substituted aryl, HET, substituted HET, cycloalkyl, and substituted cycloalkyl, or two Rs substituents when attached to the same atom may be taken together to form a 5-8 membered ring, wherein the ring includes the atom to which the two Rs substituents attach;
Each Q15 is independently H, alkyl, cycloalkyl, heterocycloalkyl, heteroaryl, phenyl, or naphthyl, each optionally substituted with 1-4 substituents independently selected from -F, -CI, -Br, -I, -OQie, -SQ16, -S(O)26, -S(O)Q16, -OS(O)26, -C(=NQι6)Q16, -S(O)2-N=S(O)(Qι6)2, -S(O)2-N=S(Qιe)2, -SC(O)Qι6, -NQ16Q16, -C(O)Q16, -C(S)Qie, -C(O)OQιe, -OC(O)Qι6, -C(O)NQι6Qιe, -C(S)NQ166, -(O)C(Qιe)2OC(O)Q16, -CN, -NQι6C(O)Qι6, -NQ16C(S)Qι6, -NQι6C(O)NQιeQιe, -NQ16C(S)NQι66, -S(O)2NQι66, -NQ16S(O)2Q16, -NQ16S(O)Qie, -NQisSQie, -NO2, and -SNQieQie- The alkyl, cycloalkyl, and cycloalkenyi being further optionally substituted with =O or =S;
Each Qi6 is independently selected from -H, alkyl, cycloalkyl, phenyl, benzyl, - CH2-substituted phenyl, and Het in which each of alkyl, cycloalkyl, phenyl, and Het optionally include 1-3 halos;
W is O, S, -(CZ2)-, or -(CHZ3)-, provided that W is not S or O when R5 or Re are -(CH2)k-W-ORι6;
Figure imgf000469_0001
Z2 is =O, =S , =N-OH, -N-O-alkyl, or =N-O-substituted alkyl;
Z3 is -OH, -N=N-alkyl, -NH-alkyl, or -NH-substituted alkyl; i is 0, 1 , or 2; and k is 0, 1, or 2.
7. The compound ofclaim 6, wherein at least one of R5 and Re is a substituted phenyl or substituted HET.
8. The compound ofclaim 7, wherein at least one of R5 and Re is pyridine, pyrimidine, pyridazine, or pyrazine, each of which is optionally substituted with the substituents described for substituted HET.
9. The compound of claim 7, wherein the substituted phenyl has the formula
Figure imgf000470_0001
each Rio and Rn is selected from -F, -CI, -Br, -I, -OQie, -Qi6, -SQie, -S(O)2Q16, -S(O)Qi6, -OS(O)2Qιe, -SC(O)Qι6, -NQι66, - C(O)Qι6, -C(S)Qie, -C(O)OQι6, -OC(O)Q16, -C(O)NQ166, -C(S)NQι66, - (O)C(Qιe)2OC(O)Qιe, -CN, -NQι6C(O)Qι6, -NQ16C(S)Qι6, -NQ16C(O)NQι66, - NQi6C(S)NQieQi6, -S(O)2NQι66, -NQι6S(O)2Qιe, -NQι6S(O)Qι6, -NQieSQie, -NO2, and -SNQ16Q16.
10. The compound of claim of claim 8, wherein the substituted phenyl has the formula
Figure imgf000470_0002
11. The compound ofclaim 6, wherein one of R5 or Re is -NH-(CZι)-NRsRs.
12. The compound ofclaim 11, wherein -NRsRs forms a 5-8 membered ring.
13. The compound ofclaim 12, wherein the ring is moφholino, pyrrolidinyl, or piperdinyl.
14. The compound ofclaim 11, wherein at least one ofthe Rs substituents is benzyl or
-CH2-substituted phenyl.
15. The compound ofclaim 6, wherein one of R5 or Re is -(CH2)k-S(O)j-R7 or - NH-SO2-R7.
16. The compound ofclaim 15, wherein R7 is het, substituted het, alkyl, or substituted alkyl.
17. The compound ofclaim 16, wherein het is indolinyl, pyrrolindinyl, or indolyl, pyrrolyl.
18. The compound of claim 16, wherein sustituted het includes a het substituent substituted with 1-3 of halo or CN.
19. The compound ofclaim 16, wherein substituted alkyl is an alkyl substituted with 1-3 of OH, NH2, NHQι6, -NRsRs-
20. The compound ofclaim 1 having a formula XXX
Figure imgf000471_0001
XXX or a pharmaceutically acceptable salt thereof, wherein X = NH
Y = CO, CS, -C(=N-CN) or
X and Y together form an alkene, or -C5 cycloalkyl;
Figure imgf000472_0001
R2 is an electron withdrawing group;
R5 is H, halo, NO2, CN, -(CH2)k-S(O)i-R7, -NH-SO2-R7, -(CH2)k-W-Rs -NH- (CZι)-Rs,-(CZι)-NH-Rs, -NH-(CZι)-NRsRs, -(CH2)k-NRsRs, substituted aryl, substituted HET, substituted
Figure imgf000472_0002
or substituted Cι- alkenyl;
Re is selected from H, halo, aryl, substituted aryl, HET, substituted HET, -CN, NH2, NO2, alkyl, substituted alkyl, alkoxy, substituted alkoxy, -(CH2)k-S(O)i-R7, -NH- SO2-R7, -(CH2)k-W-Rs, -NH-(CZι)-Rs,-(CZι)-NH-Ri, -NH-(CZι)-NRsRs, or substituted Cι.4alkenyl; R7 is selected from alkyl, substituted alkyl, aryl, substituted aryl, -N(Qι5)2,
HET, and substituted HET;
Each Rs is independently H, alkyl, substituted alkyl, -OQie, aryl, substituted aryl, HET, substituted HET, cycloalkyl, and substituted cycloalkyl, or two Rs substituents when attached to the same atom may be taken together to form a 5-8 membered ring, wherein the ring includes the atom to which the two Rs substituents attach;
Each Q15 is independently H, alkyl, cycloalkyl, heterocycloalkyl, heteroaryl, phenyl, or naphthyl, each optionally substituted with 1-4 substituents independently selected from -F, -CI, -Br, -I, -OQie, -SQie, -S(O)26, -S(O)Qι6, -OS(O)26, -C(=NQιe)Qιe, -S(O)2-N=S(O)(Qιe)2, -S(O)2-N=S(Q16)2, -SC(O)Qι6, -NQieQie, -C(O)Qιe, -C(S)Qie, -C(O)OQι6, -OC(O)Qι6, -C(O)NQι6Qιe, -C(S)NQι6Q16, -(O)C(Qιe)2OC(O)Qιe, -CN, -NQι6C(O)Qι6, -NQ16C(S)Qι6, -NQι6C(O)NQιeQ16, -NQι6C(S)NQι6Qιe, -S(O)2NQι66, -NQι6S(O)26, -NQιeS(O)Qιe, -NQieSQie, -NO2, and -SNQieQie- The alkyl, cycloalkyl, and cycloalkenyi being further optionally substituted with =O or =S;
Each Qi6 is independently selected from -H, alkyl, cycloalkyl, phenyl, benzyl, - CH2-substituted phenyl, and Het in which each of alkyl, cycloalkyl, phenyl, and Het optionally include 1-3 halos;
W is O, S, -(CZ2)-, or -(CHZ3)-, provided that W is not S or O when R5 or Re are -(CH2) -W-ORι6;
Figure imgf000472_0003
Z2 is =O, =S , =N-OH, -N-O-alkyl, or =N-O-substituted alkyl;
Z3 is -OH, -N=N-alkyl, -NH-alkyl, or -NH-substituted alkyl; i is 0, 1, or 2; and k is O, 1, or 2.
21. The compound of claim 20, wherein at least one of R5 and Re is a substituted phenyl or substituted HET.
22. The compound of claim 21 , wherein at least one of R5 and Re is pyridine, pyrimidine, pyridazine, or pyrazine, each of which is optionally substituted with the substituents described for substituted HET.
23. The compound of claim 21 , wherein the substituted phenyl has the formula
Figure imgf000473_0001
1 , wherein each Ri0 and Rn is selected from -F, -CI, -Br, -I, -OQie, -Qi6, -SQie, -S(O)26, -S(O)Q16, -OS(O)26, -SC(O)Qι6, -NQieQie, - C(O)Qi6, -C(S)Qιe, -C(O)OQ,6, -OC(O)Qι6, -C(O)NQ16Q16, -C(S)NQ16Q16, - (O)C(Qιe)2OC(O)Qιe, -CN, -NQι6C(O)Qιe, -NQ16C(S)Qι6, -NQι6C(O)NQι6Qιe, - NQ16C(S)NQi6Qie, -S(O)2NQι66, -NQι6S(O)26, -NQι6S(O)Qι6, -NQieSQie, -NO2, and -SNQieQie.
24. The compound of claim of claim 23, wherein the substituted phenyl has the formula
Figure imgf000473_0002
25. The compound of claim 20, wherein one of R5 or Re is -NH-(CZι)-NRsRs.
26. The compound of claim 25, wherein -NRsRs forms a 5-8 membered ring.
27. The compound of claim 26, wherein the ring is moφholino, pyrrolidinyl, or piperdinyl.
28. The compound of 26, wherein at least one ofthe Rs substituents is benzyl or -CH2-substituted phenyl.
29. The compound ofclaim 20, wherein one of Rs or Re is -(CH2)k-S(O)i-R7 or - NH-SO2-R7.
30. The compound ofclaim 29, wherein R is het, substituted het, alkyl, or substituted alkyl.
31. The compound of claim 30, wherein het is indolinyl, pyrrolindinyl, or indolyl, pyrrolyl.
32. The compound of claim 30, wherein sustituted het includes a het substituent substituted with 1-3 of halo or CN.
33. The compound ofclaim 30, wherein substituted alkyl is an alkyl substituted with 1-3 of OH, NH2, NHQι6, -NRsRs-
34. The compound of claim 1 having a formula VII
Figure imgf000474_0001
VII or a pharmaceutically acceptable salt thereof, wherein X = NH
Y = CO, CS, -C(=N-CN) or
X and Y together form an alkene, or C3-C5 cycloalkyl;
Figure imgf000475_0001
R2 is an electron withdrawing group;
R5 is -(CH2)k-S(O)i-R7, -NH-SO2-R7, -(CH2)k-W-Rs, -NH-(CZι)-Rs, -NH- (CZι)-NRs, substituted aryl, substituted Cι- alkyl, or substituted
Figure imgf000475_0002
Re is selected from H, halo, HET, -CN, NH2, NO2, alkyl, substituted alkyl, alkoxy, substituted alkoxy, -NH-CO-HET, and -NH-CO-aryl; R is selected from alkyl, substituted alkyl, aryl, substituted aryl, -N(Qι5)2,
HET, and substituted HET;
Rs is H, alkyl, substituted alkyl, aryl, substituted aryl, HET, substituted HET, cycloalkyl, substituted cycloalkyl;
Each Q15 is independently H, alkyl, cycloalkyl, heterocycloalkyl, heteroaryl, phenyl, or naphthyl, each optionally substituted with 1-4 substituents independently selected from -F, -CI, -Br, -I, -OQie, -SQι6, -S(O)26, -S(O)Qι6, -OS(O)26, - C(=NQιe)Qιe, -S(O)2-N=S(O)(Qι6)2, -S(O)2-N=S(Qι6)2, -SC(O)Q16, -NQieQie, - C(O)Qi6, -C(S)Qιe, -C(O)OQιe, -OC(O)Qιe, -C(O)NQι6Qιe, -C(S)NQι6Qιe, -C(O)C(Qιe)2OC(O)Qιe, -CN, -NQι6C(O)Qι6, -NQι6C(S)Qι6, -NQ16C(O)NQι6Qιe, - NQieC(S)NQi6Qie, -S(O)2NQι6Qιe, -NQι6S(O)26, -NQ16S(O)Q16, -NQieSQie, -NO2, and -SNQ16Q16. The alkyl, cycloalkyl, and cycloalkenyi being furher optionally substituted with =O or =S;
Each Qi6 is independently selected from -H, alkyl, and cycloalkyl. The alkyl and cycloalkyl optionally including 1-3 halos; W is O, S, -(CZ2)-, or -(CHZ3)-;
Figure imgf000475_0003
Z2 is =O, =S , =N-OH, =N-O-alkyl, or =N-O-substituted alkyl;
Z3 is -OH, -N=NH, -N=N-alkyl, -NH-alkyl, or -NH-substituted alkyl; i is 0, 1, or 2; and k is 0, 1, or 2.
35. The compound of claim 1 having a formula VIII
Figure imgf000476_0001
VIII or a pharmaceutically acceptable salt thereof, wherein X = NH
Y = CO, CS, -C(=N-CN) or
X and Y together form an alkene, or C3-C5 cycloalkyl;
Figure imgf000476_0002
R2 is an electron withdrawing group; R5 is -(CH2)k-S(O)i-R7, -NH-SO2-R7, -(CH2)k-W-Rs, -NH-(CZ -Rs, -NH-
(CZι)-NRs, substituted aryl, substituted Cι- alkyl, or substituted Cι-4alkenyl; Re is selected from H, halo, Cι-C4 alkyl, -CN, NH2, NO2; R7 is selected from alkyl, substituted alkyl, aryl, substituted aryl, -N(Qi5)2, HET, and substituted HET; Rs is H, alkyl, substituted alkyl, aryl, substituted aryl, HET, substituted HET, cycloalkyl, substituted cycloalkyl;
Each Q15 is independently H, alkyl, cycloalkyl, heterocycloalkyl, heteroaryl, phenyl, or naphthyl, each optionally substituted with 1-4 substituents independently selected from -F, -CI, -Br, -I, -OQie, -SQie, -S(O)2Qιe, -S(O)Qι6, -OS(O)26, - C(=NQιe)Q16, -S(O)2-N=S(O)(Qιe)2, -S(O)2-N=S(Q,6)2, -SC(O)Q16, -NQι6Q16, - C(O)Qιe, -C(S)Qιe, -C(O)OQιe, -OC(O)Qιe, -C(O)NQι6Q16, -C(S)NQι6Q1e, -C(O)C(Qιe)2OC(O)Qιe, -CN, -NQι6C(O)Qι6, -NQ16C(S)Qι6, -NQι6C(O)NQι6Qιe, -NQι6C(S)NQ16Qιe, -S(O)2NQ16Q,6, -NQι6S(O)2Qιe, -NQι6S(O)Qι6, -NQι6SQι6, - NO2, and -SNQiβQiδ The alkyl, cycloalkyl, and cycloalkenyi being furher optionally substituted with =O or =S;
Each Q16 is independently selected from -H, alkyl, and cycloalkyl. The alkyl and cycloalkyl optionally including 1-3 halos; W is O, S, -(CZ2)-, or -(CHZ3)-;
Figure imgf000477_0001
Z2 is =O, =S , =N-OH, =N-O-alkyl, or =N-O-substituted alkyl; Z3 is -OH, -N=NH, -N=N-alkyl, -NH-alkyl, or -NH-substituted alkyl; i is 0, 1, or 2; and k is 0, 1, or 2.
36. The compound ofclaim 1 having a formula IX
Figure imgf000477_0002
IX or a pharmaceutically acceptable salt thereof, wherein
X = NH
Y = CO, CS, -C(=N-CN) or
X and Y together form an alkene, or C3-Cs cycloalkyl;
Figure imgf000477_0003
R2 is an electron withdrawing group;
R5 is -(CH2)k-S(O)i-R7, -NH-SO2-R7, -(CH2)k-W-Rs, -NH-(CZι)-Rs, -NH- (CZι)-NRs, substituted aryl, substituted Cι- alkyl, or substituted Cι-4alkenyl; Re is selected from H, halo, -CN, NH2, NO2, alkyl; R7 is selected from alkyl, substituted alkyl, aryl, substituted aryl, -N(Qιs)2,
HET, and substituted HET;
Rs is H, alkyl, substituted alkyl, aryl, substituted aryl, HET, substituted HET, cycloalkyl, substituted cycloalkyl;
Each Q15 is independently H, alkyl, cycloalkyl, heterocycloalkyl, heteroaryl, phenyl, or naphthyl, each optionally substituted with 1-4 substituents independently selected from -F, -CI, -Br, -I, -OQie, -SQie, -S(O)26, -S(O)Qι6, -OS(O)26, - C(=NQι6)Qιe, -S(O)2-N=S(O)(Qι6)2, -S(O)2-N=S(Qι6)2, -SC(O)Qι6, -NQι66, - C(O)Qιe, -C(S)Qιe, -C(O)OQι6, -OC(O)Q16, -C(O)NQι66, -C(S)NQι66, -C(O)C(Q16)2OC(O)Qιe, -CN, -NQι6C(O)Qιe, -NQι6C(S)Qιe, -NQι6C(O)NQι6Qιe, -NQι6C(S)NQ16Qi6, -S(O)2NQι6Qιe, -NQι6S(O)2Qιe, -NQι6S(O)Qι6, -NQieSQie, - NO2, and -SNQiβQiβ The alkyl, cycloalkyl, and cycloalkenyi being furher optionally substituted with =O or =S; Each Qi6 is independently selected from -H, alkyl, and cycloalkyl. The alkyl and cycloalkyl optionally including 1-3 halos;
W is O, S, -(CZ2)-, or -(CHZ3)-;
Figure imgf000478_0001
Z2 is =O, =S , =N-OH, =N-O-alkyl, or =N-O-substituted alkyl; Z3 is -OH, -N=NH, -N=N-alkyl, -NH-alkyl, or -NH-substituted alkyl; i is 0, 1, or 2; and k is O, l, or 2.
37. The compound ofclaim 1 having a formula X
Figure imgf000478_0002
X or a pharmaceutically acceptable salt thereof, wherein
X = NH Y = CO, CS, -C(=N-CN) or
X and Y together form an alkene, or C3-C5 cycloalkyl;
Figure imgf000478_0003
R2 is an electron withdrawing group;
R5 is -(CH2)k-S(O)i-R7, -NH-SO2-R7, -(CH2)k-W-Rs, -NH-(CZι)-Rs, -NH- (CZι)-NRs, substituted aryl, substituted Cι- alkyl, or substituted
Figure imgf000478_0004
Re is selected from H, halo, HET, -CN, NH2, NO2, alkyl, substituted alkyl, alkoxy, substituted alkoxy, -NH-CO-HET, and -NH-CO-aryl; R7 is selected from alkyl, substituted alkyl, aryl, substituted aryl, -N(Qι5)2, HET, and substituted HET;
Rs is H, alkyl, substituted alkyl, aryl, substituted aryl, HET, substituted HET, cycloalkyl, substituted cycloalkyl; Each Q15 is independently H, alkyl, cycloalkyl, heterocycloalkyl, heteroaryl, phenyl, or naphthyl, each optionally substituted with 1-4 substituents independently selected from -F, -CI, -Br, -I, -OQie, -SQie, -S(O)26, -S(O)Qι6, -OS(O)26, - C(=NQιe)Qιe, -S(O)2-N=S(O)(Qι6)2, -S(O)2-N=S(Qι6)2, -SC(O)Q16, -NQieQie, - C(O)Q16, -C(S)Qιe, -C(O)OQι6, -OC(O)Qι6, -C(O)NQι6Qιe, -C(S)NQι6Qιe, -C(O)C(Qιe)2OC(O)Qι6, -CN, -NQι6C(O)Q16, -NQι6C(S)Qι6, -NQι6C(O)NQι66, -NQ16C(S)NQιeQιe, -S(O)2NQι6Q16, -NQι6S(O)26, -NQι6S(O)Q16, -NQieSQie, - NO2, and -SNQι6Qi6. The alkyl, cycloalkyl, and cycloalkenyi being furher optionally substituted with =O or =S;
Each Qie is independently selected from -H, alkyl, and cycloalkyl. The alkyl and cycloalkyl optionally including 1-3 halos;
W is O, S, -(CZ2)-, or -(CHZ3)-;
Figure imgf000479_0001
Z2 is =O, =S , =N-OH, =N-O-alkyl, or =N-O-substituted alkyl;
Z3 is -OH, -N=NH, -N=N-alkyl, -NH-alkyl, or -NH-substituted alkyl; i is 0, 1 , or 2; and k is O, l, or 2.
38. The compound of claim 1 having a formula XI
Figure imgf000479_0002
XI or a pharmaceutically acceptable salt thereof, wherein
X = NH Y = CO, CS, -C(=N-CN) or
X and Y together form an alkene, or -C5 cycloalkyl;
Figure imgf000480_0001
R2 is an electron withdrawing group; R5 is -(CH2)k-S(O)i-R7, -NH-SO2-R7, -(CH2)k-W-Rs, -NH-(CZι)-Rs, -NH-
(CZι)-NRs, substituted aryl, substituted Cι- alkyl, or substituted Cι- alkenyl;
Re is selected from H, halo, HET, -CN, NH2, NO2, alkyl, substituted alkyl, alkoxy, substituted alkoxy, -NH-CO-HET, and -NH-CO-aryl;
R7 is selected from alkyl, substituted alkyl, aryl, substituted aryl, -N(Qi5)2, HET, and substituted HET;
Rs is H, alkyl, substituted alkyl, aryl, substituted aryl, HET, substituted HET, cycloalkyl, substituted cycloalkyl;
Each Q15 is independently H, alkyl, cycloalkyl, heterocycloalkyl, heteroaryl, phenyl, or naphthyl, each optionally substituted with 1-4 substituents independently selected from -F, -CI, -Br, -I, -OQie, -SQie, -S(O)26, -S(O)Qι6, -OS(O)26, -C(=NQ16)Q16, -S(O)2-N=S(O)(Qιe)2, -S(O)2-N=S(Qι6)2, -SC(O)Q16, -NQieQie, -C(O)Q16, -C(S)Qιe, -C(O)OQιe, -OC(O)Q16, -C(O)NQι6Qιe, -C(S)NQ166, -C(O)C(Qιe)2OC(O)Qιe, -CN, -NQι6C(O)Qιe, -NQι6C(S)Q16, -NQι6C(O)NQιeQιe, -NQi6C(S)NQ16Qie, -S(O)2NQ16Qιe, -NQι6S(O)26, -NQι6S(O)Qι6, -NQ16SQι6, -NO2, and -SNQiβQie The alkyl, cycloalkyl, and cycloalkenyi being furher optionally substituted with =O or -S;
Each Qi6 is independently selected from -H, alkyl, and cycloalkyl. The alkyl and cycloalkyl optionally including 1-3 halos;
W is O, S, -(CZ2)-, or -(CHZ3)-;
Figure imgf000480_0002
Z2 is =O, =S , =N-OH, =N-O-alkyl, or =N-O-substituted alkyl;
Z3 is -OH, -N=NH, -N=N-alkyl, -NH-alkyl, or -NH-substituted alkyl; i is 0, 1, or 2; and k is O, l, or 2.
39. The compound of claim 1 , wherein Y is -CO-.
40. The compound of claim 1 , wherein R2 is halo, -CN, -NO2, HET, substituted HET, aryl, substituted aryl, -(CO)-alkyl, -(CO)-substituted alkyl, -(CO)-aryl, -(CO)- substituted aryl, -(CO)-O-alkyl, -(CO)-O-substituted alkyl, -(CO)-O-aryl, -(CO)-O- substituted aryl, -OC(Z„)3, -C(Zn)3,
Figure imgf000481_0001
-SO2-C(Zn)3, -SO2-aryl, - CN(Qι7)2, -C(NQι7)Qπ. -CH=C(Q )2, -C≡C-Qπ, in which each Zn and Zm is independently H, halo, -CN, -NO2 -OH, or Cι- alkyl optionally substituted with 1-3 halo, -OH, NO2, provided that at least one of Zn is halo, -CN, or NO2.
41. The compound of claim 40, wherein R2 is Br, CI, F, I, -CN, formyl, methoxyimino, hyclroxyimino, -CH2-halo, CH2-CN, phenyl, thienyl, pyrazinyl, 1- methyl-lH-pyrrol-2-yl, pyridin-2-yl, chlorophenyl, nitrophenyl, cyanophenyl, chlorothienyl, methylthienyl, fluorophenyl, (trifluoromethy)phenyl, di (trifluoromethy)phenyl, difluorophenyl, dimethylisoxazolyl, dimethoxypyrimidinyl.
42. The compound of claim 1 , wherein R5 is -NH2, -SO2-NH-alkyl, -SO2-NH- substituted alkyl, -SO2-NH-aryl, -NH-SO2-aryl, -SO2-NH-substituted aryl, -NH-SO2- substituted aryl, -SO2-NH-HET, -SO2-NH-substituted HET, -SO2-N(alkyl)(substituted alkyl), -SO2-N(alkyl)(aryl), -SO2-N(alkyl)(substituted aryl), -SO2-N(alkyl)(HET), - SO2-N(alkyl)(substituted HET), -S-alkyl, -S -substituted alkyl, -O-alkyl, -O-aryl, -S- substituted alkyl, -CH2-S-alkyl, -CH2-S-substituted alkyl, -(CH2)2-S-alkyl, -(CH2)2-S- substituted alkyl, -C(O)-aryl, -C(O)H, -C(OH)-aryl, -C(N-OCH3)-aryl, -C(N-OH)-aryl, -C(O)-Cι-6cycloalkyl, -NH-C(O)-O-Cl-4alkyl, -NH-C(O)-aryl, -NH-C(O)-substituted aryl, -NH-C(O)-HET, -NH-C(O)-substituted HET, -NHC(O)NH-aryl, -NHC(O)NH- substituted aryl, -NHC(O)NH-het, -NHC(O)NH-substituted het.
43. The .compound ofclaim 42, wherein R5 is (diethylamino)sulfonyl, (lH-indol-5- yl)aminosulfonyl, (furylmethylamino) sulfonyl, (ethoxycarbonyl)- 1 -piperazinylsulfonyl, pyridmylethylaminosulfonyl, (benzylamino)sulfonyl, (2-hydroxy-l- methylethyl)aminosulfonyl, (4-carboxyanilino)sulfonyl, (3 ,4-dihydro- 1 (2H)- quinolinyl)sulfonyl, [2-(3,5-dimethoxyphenyl)ethyl]aminosulfonyl, [(3S)-3- hydroxypyrrolidinyl]sulfonyl, (ethylanilino)sulfonyl, (3,5-dimethoxyanilino)sulfonyl, (2- hydroxy-2-phenylethyl)(methyl)amino]sulfonyl, (2,3-dihydro- 1 H-indol- 1 -yl)sulfonyl, (5-methoxy-2,3-dihydro- lH-indol- 1 -yl)sulfonyl, (5-fluoro-2,3-dihydro- 1 H-indol- 1 - yl)sulfonyl, (lH-benzimidazol-1-yl) sulfonyl, (5-fluoro-l H-indol- l-yl)sulfonyl, (1H- indol- 1 -yl)sulfonyl, (6-fluoro- 1 H-indol- 1 -yl)sulfonyl, (5-chloro- 1 H-indol- 1 -yl)sulfonyl, (6-chloro- 1 H-indol- 1 -yl)sulfonyl, (6-chloro-5-fluoro- 1 H-indol- 1 -yl)sulfonyl, ( 1 H- pyrrol-1 -yl) sulfonyl, (5-methoxy- 1 H-indol- 1 -yl)sulfonyl, ( 1 H-pyrrolo[2,3-b]pyridin-l - yl)sulfonyl, (5-bromo-2,3-dihydro-lH-indol-l-yl)sulfonyl, (3,3-dimethyl-2,3-dihydro- 1 H-indol- l-yl)sulfonyl, (4-chlorophenyl)(methyl)amino]sulfonyl, benzylthio, methyl(pyriα'in-2-yl)amino]sulfonyl, ( 1 H-indol- 1 -yl)sulfonyl, (pyrrolidin- 1 -yl)sulfonyl, (2-methylpyrrolidin- 1 -yl)sulfonyl, (moφholin-4-yl)sulfonyl, (piperidin- 1 -yl)sulfonyl, (methoxy- 1 H-indol- 1 -yl)sulfonyl, {methyl[( 1 R)- 1 -phenylethyl] amino} sulfonyl, {methyl[( 1 S)- 1 -phenylethyl]amino} sulfonyl, [(2-ammophenyl)(methyl)amino]sulfonyl, (dipropylamino)sulfonyl, benzylsulfanyl, (dipropylarnino)sulfanyl, (dipropylamino)sulfϊnyl, [4-chloro(methyl)anilino]sulfonyl, (phenylthio)methyl, benzyloxy, 3-(ethylthio), (pyridin-4-ylmethyl)thio, phenoxy, phenylthio, (pyridin-4- y]methyl)thio, benzylthio, (l-phenylethyl)thio, cyclopentylthio, cyclopentylsulfinyl, benzoyl, hydroxy(phenyl)methyl, (methoxyimino)(phenyl)methyl,
(hydroxyimino)(phenyl)methyl, cyclopentylcarbonyl, berizoylamino, furoylarnino, (thien-2-ylacetyl)amino, (mesitylcarbonyl)amino, (l,3-benzodioxol-5- ylcarbonyl)amino, 3-(2,4-dimethoxyberιzoyl)amino, (phenylthio)acetylamino, (anilmocarbonyl)amino, (2,4-difluorophenyl)amino carbonylamino, (3- cyanophenyl)ammocarbonylamino, (3-acetylphenyl)ammocarbonylarnino, - (trifluoromethoxy)phenylsulfonylamino, (thien-2-ylacetyl)amino, (5-nitro-2- furoyl)amino, (5-chloro-2-methoxyphenyl)ammocarbonylamino, (4- phenoxyphenyl)ammocarbonylarnino, (4-acetylphenyl)ammocarbonylamino, phenylethynyl, 2-phenylethyl, 4-Chlorophenyl, benzyloxy, phenoxy, alkylthio, phenyl, dihalophenyl, amino, acetylamino, benzoylamino, phenylacetylamino, methylsulfonylamino, phenylsulfonylamino, benzylsulfonylamino, benzyloxy, hydroxy, 3-phenoxypropoxy, (2,3-dihydro- 1 ,4-benzodioxin-2-yl)methoxy, cyclobutylmethoxy, (2,2-dimethyl-l,3-dioxolan-4-yl)methoxy, 2,3-dihydroxypropoxy, cyclobutyloxy, 2- methoxy-1-methylethoxy, isopropoxy, cyclopropylmethoxy, cyclohexylmethoxy, 2- methoxyethoxy, tetrahydro-2H-pyran-2-yl-methoxy, (oxiran-2-yl)methoxy, 2-hydroxy- 3-isopropoxypropoxy, furylmethoxy, pentyloxy, phenylacetylamino, Benzoylamino, Acetyloxyacetylamino , cyclopentylcarbonylamino, 6-Chloropyridin-3 -ylcarbonylamino , isoxazol-5-ylcarbonylamino, 2,4-difluorobenzoylamino, fluoroacetylamino, Acetylamino, 4-Chlorophenylacetylamino, 4-methoxyphenylacetylamino, cyclopentylacetylamino, 3-fluoroberιzoylamino, 3-cyanophenylacetylamino, cyclohexylcarbonylamino, propionylamino, 5-methoxy-5-oxopentanoylamino, Butyrylamino, 4-Bromobenzoylamino, 3-phenylpropanoylamino, phenoxyacetylamino, 3-cyclopentylpropanoylamino, 3-methoxy-3-oxopropanoylamino, 2- ethylhexanoylamino, 3,4-dimethoxyphenylacetylamino, 3,5,5-trimethylhexanoylamino, cyclopropylcarbonylamino, methoxyacetylamino, 3-methylbutanoylarnino, pentanoylamino, 4,7,7-trimethyl-3-oxo-2-oxabicyclo[2.2.1 ]hept- 1 -ylcarbonylarnino, Chloro(phenyl)acetylamino, Benzyloxyacetylamino, 3-ethoxy-3-oxopropanoylamino, 1-Adamantylcarbonylamino, hexanoylamino, 2-phenylcyclopranolyamino, 2- phenylbutanoylamino, heptanoylamino, Acetyloxyphenylacetylamino, thien-2- .ylcarbonylamino, 2-methylbutanoylamino, 8-methoxy-8-oxooctanoylamino, 2- ethylbutanoylamino, octanoylamino, cyclobutylcarbonylamino, l,3-dioxo-l,3-dihydro- 2H-isoindol-2-yl, Benzylthio, moφholm-4-ylsulfonylbenzoylamino, lH-indol-2- ylcarbonylarnino, 1 -methyl- lH-mdol-2-ylcarbonylamino, 5-phenylisoxazol-3- ylcarbonylamino, 5-phenylpentanoylamino, 4-phenylbutanoylamino, 4-(4- methoxyphenyl)butanoylamino, 2-Chlorophenylacetylamino, 2,4- dic orophenylacetylamino, 3,4-dichlorophenylacetylamino, 3- Chlorophenylacetylamino, 3-(trifluoromethyl)phenylacetylamino, 3- methylphenylacetylamino, 4-tert-Butylphenylacetylamino, 3- methoxyphenylacetylamino, 2-methoxyphenylacetylamino, 2-methylphenylacetylamino, 4-(trifluoromethyl)phenylacetylamino, 4-isopropylphenylacetylamino, 4- methylphenylacetylamino, 4-fluorophenylacetylamino, 2- (trifluoromethyl)phenylacetylamino, 3-fluorophenylacetylamino, phenylthioacetylamino, naphthylacetylamino, naphthyloxyacetylamino, 2- propoxybenzoylamino, tetrahydrofuran-3-ylcarbonylamino, 1- methylcyclopropylcarbonylarnino, 4-ethoxyphenylacetylamino, 1 -Benzothien-3- ylacetylamino, l, -Biphenyl-4-ylcarbonylamino, 4-Butoxybenzoylamino, 2-(2- phenylethyl)benzoylamino, l, -Biphenyl-2-ylcarbonylarnino, 4- (ethylthio)benzoylamino, 2-(methylsulfonyl)benzoylamino, 2,6- dichlorophenylacetylamino, 1 , 1 '-Biphenyl-4-ylacetylamino, 1 ,3-Benzodioxol-5- ylacetylamino, 3,3-dimethylbutanoylamino, thien-2-ylacetylamino, 3-methyl-5- phenylisoxazol-4-ylcarbonylamino, [2-(2-methoxyethoxy)ethoxy]acetylamino, (2- hydroxybenzoyl)amino, prolylamino, (3-methylisoxazol-5-yl)acetylamino, and 4- Azido-3 -iodobenzoylamino .
44. The compound ofclaim 1, wherein R is H, halo, -CN, NH2, NO2, methyl, methoxy, -(CH2)2-OH, moφholinyl, and -(CH2)2-O-CO-CH3.
45. A compound selected from
5-cyano-2-[( 1 H-mdol-2-ylcarbonyl)amino]benzoic acid;
5-cyano-2-{[(5-methoxy-lH-mdol-2-yl)carbonyl]amino}benzoic acid; 2-({[5-(benzyloxy)-lH-mdol-2-yl]carbonyl}amino)-5-cyanobenzoic acid;
5-cyano-2- { [( 1 -methyl- 1 H-indol-2-yl)carbonyl] amino } benzoic acid;
2-( {[6-(benzyloxy)- 1 H-indol-2-yl] carbonyl} amino)-5-cyanobenzoic acid;
2-{[(7-chloro-lH-mdol-2-yl)carbonyl]amino}-5-cyanobenzoic acid;
5-cyano-2- {[(4-methoxy-lH-mdol-2-yl)carbonyl]amino}benzoic acid; 5-bromo-2-{[(l-methyl-lH-mdol-2-yl)carbonyl]amino}benzoic acid;
2- {[(6-chloro- 1 H-mdol-2-yl)carbonyl]amino} -5-cyanobenzoic acid;
2- { [( 1 -benzyl- 1 H-indol-2-yl)carbonyl] arnino} -5-cyanobenzoic acid;
5-cyano-2-{[(l-ethyl-lH-mdol-2-yl)carbonyl]arnino}benzoic acid;
5-cyano-2-( { [7-(phenylsulfonyl)- 1 H-indol-2-yl]carbonyl} amino)benzoic acid; 2-{[(l-allyl-lH-indol-2-yl)carbonyl]amino}-5-cyanobenzoic acid;
5-cyano-2-( {[1 -(cyclohexylmethyl)- 1 H-indol-2-yl] carbonyl} amino)benzoic acid;
5-cyano-2-( { [ 1 -(2-methoxyethyl)- 1 H-indol-2-yl] carbonyl} amino)benzoic acid;
5-cyano-2- { [( 1 -pentyl- 1 H-mdol-2-yl)carbonyl]amino} benzoic acid;
2-{[(l-butyl-lH-mdol-2-yl)carbonyl]amino}-5-cyanobenzoic acid; 5-cyano-2-{[(l-propyl-lH-mdol-2-yl)carbonyl]amino}benzoic acid;
5-chloro-2-{[(l-propyl-lH-mdol-2-yl)carbonyl]amino}benzoic acid;
2- {[( 1 -butyl- lH-mdol-2-yl)carbonyl]amino} -5-chlorobenzoic acid;
5-chloro-2-{[(l-pentyl-lH-mdol-2-yl)carbonyl]amino}benzoic acid;
5-chloro-2-( { [ 1 -(2-methoxyethyl)- 1 H-indol-2-yl] carbonyl} amino)benzoic acid; 5-chloro-2-( {[ 1 -(cyclohexylmethyl)- 1 H-indol-2-yl] carbonyl} amino)benzoic acid;
2- {[(l-allyl-lH-mdol-2-yl)carbonyl]amino}-5-chlorobenzoic acid;
2- {[( 1 -allyl- 1 H-mdol-2-yl)carbonyl]amino} -5-bromobenzoic acid;
5-bromo-2-({[l-(cyclohexylmethyl)-lH-mdol-2-yl]carbonyl}amino)benzoic acid;
5-bromo-2-( {[1 -(2-methoxyethyl)- lH-indol-2-yl] carbonyl} amino)benzoic acid; -bromo-2-{[(l-pentyl-lH-indol-2-yl)carbonyl]amino}benzoic acid; -bromo-2- { [( 1 -butyl- 1 H-mdol-2-yl)carbonyl]arnino} benzoic acid; -bromo-2- { [( 1 -propyl- 1 H-indol-2-yl)carbonyl] amino } benzoic acid; - {[(1 -benzyl- 1 H-indol-2-yl)carbonyl]amino} -5-chlorobenzoic acid; -{[(l-benzyl-lH-mdol-2-yl)carbonyl]amino}-5-bromobenzoic acid; -bromo-2- { [( 1 -isopropyl- 1 H-indol-2-yl)carbonyl] amino } benzoic acid; -cyano-2- {[(1 -isopropyl- 1 H-mdol-2-yl)carbonyl]arnino}benzoic acid; -chloro-2-{[(l-methyl-lH-indol-2-yl)carbonyl]amino}benzoic acid; -chloro-2- {[(1 -isobutyl- 1 H-indol-2-yl) carbonyl] amino} benzoic acid; -bromo-2-{[(l-isobutyl-lH-mdol-2-yl)carbonyl]amino}benzoic acid; -cyano-2-{[(l-isobutyl-lH-mdol-2-yl)carbonyl]amino}benzoic acid; -cyano-2-( {[ 1 -(3-phenylpropyl)- 1 H-indol-2-yl]carbonyl} amino)benzoic acid; -chloro-2-({[l-(3-phenylpropyl)-lH-mdol-2-yl]carbonyl}amino)benzoic acid; -bromo-2-( {[1 -(3-phenylpropyl)- lH-indol-2-yl]carbonyl} amino)benzoic acid; -chloro-2-({[7-(phenylsulfonyl)-lH-mdol-2-yl]carbonyl}arnino)benzoic acid; -bromo-2-( { [7-(phenylsulfonyl)- 1 H-indol-2-yl]carbonyl} amino)benzoic acid; -cyano-2-( {[1 -methyl-7-(phenylsulfonyl)- 1 H-indol-2-yl] carbonyl} amino)benzoic acid; -bromo-2-( { [ 1 -methyl-7-(phenylsulfonyl)- 1 H-indol-2-yl] carbonyl} arnino)benzoic acid; -chloro-2-( {[ 1 -methyl-7-(phenylsulfonyl)- 1 H-indol-2-yl] carbonyl} arnino)benzoic acid; -cyano-2-[( {7-[(phenylacetyl)amino]- 1 H-indol-2-yl} carbonyl)amino]benzoic acid; -( {[7-(benzoylamino)- 1 H-indol-2-yl]carbonyl} amino)-5-cyanobenzoic acid; -{[(7-{[(acetyloxy)acetyl]ammo}-lH-mdol-2-yl)carbonyl]arnino}-5-cyanobenzoic acid; -cyano-2-[( {7-[(cyclopentylcarbonyl)amino]- 1 H-indol-2-yl} carbonyl) aminojbenzoic acid; - {[(7-amino- 1 H-indol-2-yl) carbonyl] a ino} -5-cyanobenzoic acid; -{[(7-{[(6-chloropyridm-3-yl)carbonyl]ammo}-lH-mdol-2-yl)carbonyl]amino}-5- cyanobenzoic acid; -cyano-2-[({7-[(isoxazol-5-ylcarbonyl)ammo]-lH-mdol-2-yl}carbonyl)amino]benzoic acid; -cyano-2-[( {7-[(2,4-difluorobenzoyl)amino]- 1 H-indol-2-yl} carbonyl) amino]benzoic acid; -cyano-2-[( {7-[(fluoroacetyl)amino]- 1 H-indol-2-yl} carbonyl)amino]benzoic acid; -( { [7-(acetylamino) - 1 H-indol-2-yl] carbonyl} amino) - 5-cyanobenzoic acid; - { [(7- { [(4-chlorophenyl) acetyl] amino } - 1 H-indol-2-yl)carbonyl] amino } - 5- cyanobenzoic acid; -cyano-2- {[(7- {[(4-methoxyphenyl)acetyl]amino} - 1 H-indol-2- yl)carbonyl]amino}benzoic acid; -cyano-2-[({7-[(cyclopentylacetyl)anιmo]-lH-mdol-2-yl}carbonyl)amino]benzoic acid; -cyano-2-[( {7-[(3-fluorobenzoyl)amino]- 1 H-indol-2-yl} carbonyl) amino]benzoic acid; -cyano-2-[({7-[(cyclohexylcarbonyl)ammo]-lH-mdol-2-yl}carbonyl)amino]benzoic acid; -cyano-2-({[7-(propionylarnmo)-lH-mdol-2-yl]carbonyl}amino)benzoic acid; -cyano-2-[( {7-[(5-methoxy-5-oxopentanoyl)amino]- 1 H-indol-2- yl} carbonyl) amino]benzoic acid; -( { [7-(butyrylamino)- 1 H-indol-2-yl] carbonyl} amino)-5-cyanobenzoic acid; -[({7-[(4-bromobenzoyl)arnmo]-lH-mdol-2-yl}carbonyl)amino]-5-cyanobenzoic acid; -cyano-2-[( {7-[(3-phenylpropanoyl)amino]- 1 H-indol-2-yl} carbonyl) aminojbenzoic acid; -cyano-2-[({7-[(phenoxyacetyl)ammo]-lH-mdol-2-yl}carbonyl)amino]benzoic acid; -cyano-2-[({7-[(3-cyclopentylpropanoyl)amino]-lH-indol-2- yl} carbonyl) amino]benzoic acid; -cyano-2- [( {7- [(3 -methoxy-3 -oxopropanoyl) arnino] - 1 H-indol-2- yl}carbonyl)amino]benzoic acid; -cyano-2-[({7-[(2-ethymexanoyl)ammo]-lH-mdol-2-yl}carbonyl)amino]benzoic acid; -cyano-2- { [(7- { [(3 ,4-dimethoxyphenyl)acetyl]amino} - 1 H-indol-2- yl)carbonyl]amino}benzoic acid; -cyano-2-[({7-[(3,5,5-trimethylhexanoyl)amino]-lH-indol-2- yl}carbonyl)amino]benzoic acid; -cyano-2-[({7-[(cyclopropylcarbonyl)ammo]-lH-mdol-2-yl}carbonyl)amino]benzoic acid; -cyano-2-[({7-[(methoxyacetyl)arrano]-lH-mdol-2-yl}carbonyl)amino]benzoic acid; -cyano-2-[({7-[(3-methylbutanoyl)ammo]-lH-mdol-2-yl}carbonyl)amino]benzoic acid; -cyano-2-({[7-(pentanoylammo)-lH-mdol-2-yl]carbonyl}amino)benzoic acid; -cyano-2-{[(7-{[(4,7,7-trimethyl-3-oxo-2-oxabicyclo[2.2.1]hept-l- yl)carbonyl]ammo}-lH-mdol-2-yl)carbonyl]arnino}benzoic acid; -{[(7-{[chloro(phenyl)acetyl]ammo}-lH-mdol-2-yl)carbonyl]amino}-5-cyanobenzoic acid; -{[(7-{[(benzyloxy)acetyl]ammo}-lH-mdol-2-yl)carbonyl]amino}-5-cyanobenzoic acid; -cyano-2-[( {7-[(3-ethoxy-3-oxopropanoyl)amino]-lH-indol-2- yl}carbonyl)amino]benzoic acid; -[( {7-[(l -adamantylcarbonyl)amino]- 1 H-indol-2-yl} carbonyl)amino]-5-cyanobenzoic acid; -cyano-2-( {[7-(hexanoylamino)- 1 H-indol-2-yl] carbonyl} amino)benzoic acid; -cyano-2-[({7-[(2-phenylbutanoyl)anτmo]-lH-mdol-2-yl}carbonyl)amino]benzoic acid; -cyano-2-( {[7-(heptanoylarnino)- 1 H-indol-2-yl] carbonyl} amino)benzoic acid; - {[(7- {[(acetyloxy)(phenyl)acetyl]amino} - 1 H-indol-2-yl)carbonyl]amino} -5- cyanobenzoic acid; -cyano-2-{[(7-{[(2-phenylcyclopropyl)carbonyl]amino}-lH-indol-2- yl)carbonyl]arnino}benzoic acid; -cyano-2-[( {7-[(thien-2-ylcarbonyl)amino]- 1 H-indol-2-yl} carbonyl) amino]benzoic acid; -cyano-2-[( {7-[(2-methylbutanoyl)amino]- 1 H-indol-2-yl} carbonyl)amino]benzoic acid; -cyano-2-[({7-[(8-methoxy-8-oxooctanoyl)amino]-lH-indol-2- yl}carbonyl)amino]benzoic acid; -cyano-2-[({7-[(2-ethylbutanoyl)ammo]-lH-mdol-2-yl}carbonyl)amino]benzoic acid; -cyano-2-({[7-(octanoylammo)-lH-indol-2-yl]carbonyl}amino)benzoic acid; -cyano-2-[({7-[(cyclobutylcarbonyl)ammo]-lH-mdol-2-yl}carbonyl)amino]benzoic acid; -cyano-2-( {[7-(l ,3-dioxo-l ,3-dihydro-2H-isoindol-2-yl)-lH-indol-2- yl] carbonyl} amino)benzoic acid; -( {[7-( {[2-(benzylthio)-l ,3-thiazol-4-yl]carbonyl} amino)- 1 H-indol-2- yl] carbonyl} amino)-5-cyanobenzoic acid; -cyano-2- { [(7- { [3 -(moφholin-4-ylsulfonyl)benzoyl] amino } - 1 H-indol-2- yl)carbonyl]amino}benzoic acid; -cyano-2-[( {7-[( 1 H-mdol-2-ylcarbonyl)amino]- lH-indol-2- yl}carbonyl)amino]benzoic acid; -cyano-2- {[(7- {[(1 -methyl-1 H-mdol-2-yl)carbonyl]arnino} - 1 H-indol-2- yl)carbonyl]amino}benzoic acid; -cyano-2-{[(7-{[(5-phenylisoxazol-3-yl)carbonyl]amino}-lH-indol-2- yl)carbonyl]amino}benzoic acid; -cyano-2-[({7-[(5-phenylpentanoyl)ammo]-lH-mdol-2-yl}carbonyl)amino]benzoic acid; -cyano-2-[( {7-[(4-phenylbutanoyl)amino]- 1 H-indol-2-yl} carbonyl)amino]benzoic acid; -cyano-2- { [(7- { [4-(4-methoxyphenyl)butanoyl] amino } - 1 H-indol-2- yl)carbonyl]arnino}benzoic acid; - {[(7- {[(2-chlorophenyl)acetyl]amino} - 1 H-indol-2-yl)carbonyl]amino} -5- cyanobenzoic acid; -cyano-2-{[(7-{[(2,4-dichlorophenyl)acetyl]arnino}-lH-indol-2- yl) carbonyl] amino} benzoic acid; -cyano-2- {[(7- {[(3,4-dichlorophenyl)acetyl]amino} - 1 H-indol-2- yl)carbonyl]amino}benzoic acid; -{[(7-{[(3-chlorophenyl)acetyl]arnmo}-lH-mdol-2-yl)carbonyl]amino}-5- cyanobenzoic acid; -cyano-2-( {[7-( { [3 -(trifluoromethyl)phenyl] acetyl} amino)- 1 H-indol-2- yl] carbonyl} amino)benzoic acid; -cyano-2-{[(7-{[(3-methylphenyl)acetyl]amino}-lH-indol-2- yl)carbonyl]amino}benzoic acid; - {[(7- {[(4-tert-butylphenyl)acetyl]amino} - 1 H-mdol-2-yl)carbonyl]amino} -5- cyanobenzoic acid; -cyano-2-{[(7-{[(3-methoxyphenyl)acetyl]arnino}-lH-indol-2- yl)carbonyl]amino}benzoic acid; -cyano-2-{[(7-{[(2-methoxyphenyl)acetyl]arnino}-lH-indol-2- yl)carbonyl]amino}benzoic acid; -cyano-2- {[(7- {[(2-methylphenyl)acetyl]amino} - 1 H-indol-2- yl) carbonyl] amino} benzoic acid; -cyano-2-({[7-({[4-(trifluoromethyl)phenyl]acetyl}arnino)-lH-indol-2- yl] carbonyl} amino)benzoic acid; -cyano-2-{[(7-{[(4-isopropylphenyl)acetyl]amino}-lH-indol-2- yl) carbonyl] amino} benzoic acid; -cyano-2-{[(7-{[(4-methylphenyl)acetyl]amino}-lH-indol-2- yl)carbonyl]amino}benzoic acid; -cyano-2- {[(7- {[(4-fluorophenyl)acetyl]amino} - 1 H-indol-2- yl)carbonyl]amino}benzoic acid; -cyano-2-( { [7-( { [2-(trifluoromethyl)phenyl]acetyl} amino)- 1 H-indol-2- yl] carbonyl} amino)benzoic acid; -cyano-2-{[(7-{[(3-fluorophenyl)acetyl]amino}-lH-indol-2- yl)carbonyl]amino}benzoic acid; -cyano-2-{[(7-{[(phenylthio)acetyl]arnmo}-lH-mdol-2-yl)carbonyl]amino}benzoic acid; -cyano-2-[({7-[(2-naphthylacetyl)amino]-lH-indol-2-yl}carbonyl)amino]benzoic acid; -cyano-2-[( {!-[{ 1 -naphthylacetyl)amino]- 1 H-indol-2-yl} carbonyl)amino]benzoic acid; -cyano-2- {[(7- {[(2-naphthyloxy)acetyl]amino} - 1 H-indol-2- yl)carbonyl]amino}benzoic acid; -cyano-2-[( {7-[(2-propoxybenzoyl)amino]- 1 H-indol-2-yl} carbonyl)amino]benzoic acid; -cyano-2-[( {7-[(tetrahydrofuran-3-ylcarbonyl)amino]- 1 H-indol-2- yl}carbonyl)amino]benzoic acid; -cyano-2- {[(7- {[(1 -methylcyclopropyl)carbonyl]amino} - 1 H-indol-2- yl)carbonyl]amino}benzoic acid; -cyano-2- {[(7- {[(4-ethoxyphenyl)acetyl]amino} -lH-indol-2- yl)carbonyl]amino}benzoic acid; -[( {7-[( 1 -benzothien-3-ylacetyl)amino]- 1 H-indol-2-yl} carbonyl)amino]-5- cyanobenzoic acid; -[( {7-[( 1 , 1 '-biphenyl-4-ylcarbonyl)amino]- 1 H-indol-2-yl} carbonyl)amino]-5- cyanobenzoic acid; -[( {7-[(4-butoxybenzoyl)amino]- 1 H-indol-2-yl} carbonyl)amino]-5-cyanobenzoic acid; -cyano-2- {[(7- {[2-(2-phenylethyl)benzoyl] amino} - 1 H-indol-2- yl)carbonyl]arnino}benzoic acid; -[( {7-[( 1 , 1 '-biphenyl-2-ylcarbonyl)amino]- 1 H-indol-2-yl} carbonyl)amino]-5- cyanobenzoic acid; -cyano-2- { [(7- { [4-(ethylthio)benzoyl] amino } - 1 H-indol-2-yl)carbonyl] amino } benzoic acid; -cyano-2- {[(7- {[2-(methylsulfonyl)benzoyl]amino} - 1 H-indol-2- yl)carbonyl]amino}benzoic acid; -cyano-2-{[(7-{[(2,6-dichlorophenyl)acetyl]amino}-lH-indol-2- yl)carbonyl]arnino}benzoic acid; -[( {7-[(l , 1 '-biphenyl-4-ylacetyl)amino]- 1 H-indol-2-yl} carbonyl)amino]-5- cyanobenzoic acid; -[({7-[(l,3-benzodioxol-5-ylacetyl)ammo]-lH-mdol-2-yl}carbonyl)amino]-5- cyanobenzoic acid; -cyano-2-[({7-[(3,3-dimethylbutanoyl)arnmo]-lH-mdol-2-yl}carbonyl)amino]benzoic acid; -cyano-2-[({7-[(thien-2-ylacetyl)ammo]-lH-mdol-2-yl}carbonyl)amino]benzoic acid; -cyano-2-{[(7-{[(3-methyl-5-phenylisoxazol-4-yl)carbonyl]amino}-lH-indol-2- yl) carbonyl] amino} benzoic acid; -cyano-2-( {[7-( {[2-(2-methoxyethoxy)ethoxy]acetyl} amino)- 1 H-indol-2- yl] carbonyl} amino)benzoic acid; -cyano-2-[({7-[(2-hydroxyberιzoyl)arnmo]-lH-mdol-2-yl}carbonyl)amino]benzoic acid; -cyano-2-( {[7-( {[4-(trifluoromethoxy)phenyl] sulfonyl} amino)- 1 H-indol-2- yl] carbonyl} amino)benzoic acid; -cyano-2-( {[7-(prolylarnino)-lH-indol-2-yl]carbonyl} arnino)benzoic acid; -cyano-2- {[(7- {[(3-methylisoxazol-5-yl)acetyl]amino} -lH-indol-2- yl) carbonyl] amino} benzoic acid; -[({7-[(benzylsulfonyl)ammo]-lH-mdol-2-yl}carbonyl)amino]-5-cyanobenzoic acid; -cy-mo-2-{[(l-methyl-7-{[3-(moφholm-4-ylsulfonyl)benzoyl]amino}-lH-indol-2- yl)carbonyl]amino}benzoic acid; -cyano-2- { [(7- { [(4-fluorophenyl)acetyl]amino} - 1 -methyl- 1 H-indol-2- yl) carbonyl] arnino} benzoic acid; -cyano-2-[({7-[(fluoroacetyl)ammo]-l-methyl-lH-mdol-2-yl}carbonyl)amino]benzoic acid; -cyano-2- {[( 1 -methyl-7- { [( 1 -methyl- 1 H-indol-2-yl)carbonyl]amino} - 1 H-indol-2- yl) carbonyl] amino} benzoic acid; -( {[6-(benzyloxy)- 1 -methyl- 1 H-indol-2-yl] carbonyl} amino)-5-cyanobenzoic acid; -cyano-2-{[(6-methoxy-l-methyl-lH-mdol-2-yl)carbonyl]amino}benzoic acid; -cyano-2-[( { 1 -methyl-7-[(moφholm-4-ylcarbonyl)arnino]- 1 H-indol-2- yl} carbonyl) amino]benzoic acid; -cyano-2-({[l-methyl-7-({[(tetrahydrofuran-2-ylmethyl)ammo]carbonyl}amino)-lH- indol-2-yl] carbonyl} amino)benzoic acid; -cyano-2-{[(7-hydroxy-l-methyl-lH-indol-2-yl)carbonyl]amino}benzoic acid; - {[(7- {[(benzylamino)carbonyl]amino} -1 -methyl- 1 H-indol-2-yl)carbonyl]amino} -5- cyanobenzoic acid; -cyano-2-( { [7-( { [(2,3 -dihydroxypropyl)amino]carbonyl} amino)- 1 -methyl- 1 H-indol-
2-yl]carbonyl}amino)benzoic acid; -[ {[(2- { [(2-carboxy-4-cyanophenyl)amino] carbonyl} - 1 -methyl- 1 H-indol-7- yl)amino]carbonyl} (methyl)amino]- 1 -deoxyhexitol; -cyano-2-( { [7-(2,3-dihydro- 1 ,4-benzodioxin-2-ylmethoxy)- 1 -methyl- 1 H-indol-2- yl] carbonyl} amino)benzoic acid; -( {[7-(benzyloxy)- 1 H-indol-2-yl] carbonyl} amino)-5-cyanobenzoic acid; -cyano-2-( { [ 1 -methyl-7-(3 -phenoxypropoxy) - 1 H-indol-2-yl] carbonyl} amino)benzoic acid; -cyano-2-( { [7-(cyclobutylmethoxy)- 1 -methyl- 1 H-indol-2-yl]carbonyl} amino)benzoic acid; -cyano-2-( { [7-(2-furylmethoxy)- 1 -methyl- 1 H-indol-2-yl] carbonyl} amino)benzoic acid; -cyano-2- {[(7- {[(4S)-2,2-dimethyl- 1 ,3 -dioxolan-4-yl]methoxy} - 1 -methyl- 1 H-indol-
2-yl)carbonyl]amino}benzoic acid; -cyano-2- {[(7- {[(2R)-2,3-dihydroxypropyl]oxy} - 1 -methyl- 1 H-indol-2- yl) carbonyl] a ino} benzoic acid; -cyano-2-( {[7-(cyclobutyloxy)- 1 -methyl- 1 H-indol-2-yl]carbonyl} amino)benzoic acid; -cyano-2-( { [7-(2-methoxy- 1 -methylethoxy)- 1 -methyl- 1 H-indol-2- yl] carbonyl} arnino)benzoic acid; -cyano-2- { [(7-isopropoxy- 1 -methyl- 1 H-mdol-2-yl)carbonyl]amino} benzoic acid; -( {[7-(benzyloxy)- 1 -methyl- lH-indol-2-yl] carbonyl} amino)-5-cyanobenzoic acid; - {[(6-sec-butoxy- 1 -methyl- 1 H-indol-2-yl)carbonyl]amino} -5-cyanobenzoic acid; - { [(6-butoxy- 1 -methyl- 1 H-indol-2-yl)carbonyl]amino} -5-cyanobenzoic acid; -cyano-2-( { [7-(cyclohexylmethoxy)- 1 -methyl- 1 H-indol-2-yl] carbonyl} amino)benzoic acid; -cyano-2-( { [7-(cyclopropylmethoxy)- 1 -methyl- 1 H-indol-2- . yl] carbonyl} amino)benzoic acid; -cyano-2-( { [ 1 -methyl-7-(tetrahydro-2H-pyran-2-ylmethoxy)- 1 H-indol-2- yl] carbonyl} amino)benzoic acid; -cyano-2-( { [ 1 -methyl-7-(pentyloxy)- 1 H-indol-2-yl] carbonyl} amino)benzoic acid; -cyano-2-( { [7-(2-methoxyethoxy)- 1 -methyl- 1 H-indol-2-yl] carbonyl} amino)benzoic acid; -cyano-2-({[7-(2-hydroxy-3-isopropoxypropoxy)-l-methyl-lH-indol-2- yl] carbonyl} amino)benzoic acid; -cyano-2-[( { 1 -methyl-7-[2-(methylthio)ethoxy]- lH-indol-2- yl}carbonyl)amino]benzoic acid; -[( {7-[(4-azido-3-iodoberιzoyl)amino]- 1 -methyl- lH-indol-2-yl} carbonyl)amino]-5- cyanobenzoic acid; -cyano-2-[({7-[(3-cyanobenzoyl)ammo]-lH-mdol-2-yl}carbonyl)amino]benzoic acid; -cyano-2-[( { 1 -methyl-6-[2-(trifluoromethyl)phenyl]- 1 H-indol-2- yl} carbonyl) amino]benzoic acid; -cyano-2-( {[1 -methyl-6-(2,3 ,4-trimethoxyphenyl)- 1 H-indol-2- yl] carbonyl} amino)benzoic acid; -iodo-2-{[(l-methyl-lH-mdol-2-yl)carbonyl]amino}benzoic acid; -( {[4-(benzylsulfanyl)-2-pyridinyl]carbonyl} arnino)-5-bromobenzoic acid; -( {[6-(berizylsulfanyl)-2-pyridinyl]carbonyl} arnino)-5-bromobenzoic acid; -bromo-2-({[3-chloro-5-(trMuoromethyl)-2-pyridmyl]carbonyl}amino)benzoic acid; -bromo-2-[(pyriάιn-2-ylcarbonyl)amino]benzoic acid; -bromo-2- {[(5-butylpyridm-2-yl)carbonyl]amino}benzoic acid; -bromo-2-[(qumolm-2-ylcarbonyl)amino]benzoic acid; -bromo-2- {[(6-bromopyridin-2-yl)carbonyl]amino}benzoic acid; - {[(3-benzoylpyridm-2-yl)carbonyl]amino} -5-bromobenzoic acid; - {[(6-bromopyridm-2-yl)carbonyl]amino}-5-cyanobenzoic acid; -cyano-2-[(pyridm-2-ylcarbonyl)arnino]benzoic acid; -cyano-2-[(quinolin-2-ylcarbonyl)amino]benzoic acid; -cyano-2-{[(2-phenylfuro[2,3-c]pyridm-5-yl)carbonyl]amino}benzoic acid; -cyano-2- {[(3-methylfuro[2,3-c]pyridm-5-yl)carbonyl]amino}benzoic acid; -({[4-(benzyloxy)pyridm-2-yl]carbonyl}amino)-5-bromobenzoic acid; -bromo-2- {[(4-chloro- 1 -oxidopyridm-2-yl)carbonyl]amino}benzoic acid; -( {[4-(benzyloxy)pyridin-2-yl] carbonyl} amino)-5-cyanobenzoic acid; -({[4-(benzyloxy)-l-oxidopyridin-2-yl]carbonyl}amino)-5-bromobenzoic acid; -({[4-(benzylthio)-l-oxidopyridm-2-yl]carbonyl}amino)-5-bromobenzoic acid; -cyano-2-[(isoqumolm-3-ylcarbonyl)amino]benzoic acid; -bromo-2-[(qumoxalm-2-ylcarbonyl)amino]benzoic acid; -bromo-2- {[(5-methylpyra-dn-2-yl)carbonyl]amino}benzoic acid; -cyano-2-[(pyrazm-2-ylcarbonyl)arnino]benzoic acid; -({[5-(benzylthio)pyrazin-2-yl] carbonyl} aιnino)-5-cyanobenzoic acid; -({[5-(benzylthio)pyrazm-2-yl]carbonyl}amino)-5-bromobenzoic acid; -({[6-(benzylthio)pyrazm-2-yl]carbonyl}amino)-5-cyanobenzoic acid; -( {[6-(benzylthio)pyrazm-2-yl]carbonyl}arnino)-5-bromobenzoic acid; -( {[5-(butylthio)pyrazm-2-yl]carbonyl}amino)-5-cyanobenzoic acid; -bromo-2-({[5-(sec-butylthio)pyrazm-2-yl]carbonyl}amino)benzoic acid; -bromo-2-( {[5-(butylthio)pyrazin-2-yl]carbonyl} amino)benzoic acid; -({[5-(butylthio)pyrazm-2-yl]carbonyl}arnino)-5-chlorobenzoic acid; -bromo-2-( {[5-(pentylthio)pyrazin-2-yl]carbonyl} amino)benzoic acid; -bromo-2-({[5-(hexylthio)pyrazm-2-yl]carbonyl}amino)benzoic acid; -( {[5-(sec-butylthio)pyrazin-2-yl]carbonyl} amino)-5-cyanobenzoic acid; -cyano-2-( {[5-(pentylthio)pyrazin-2-yl]carbonyl} amino)benzoic acid; -cyano-2- {[(5- {[3-(2-methoxyethoxy)propyl]thio}pyrazin-2- yl)carbonyl]amino}benzoic acid; 5-chloro-2-( {[5-(pentylthio)pyrazin-2-yl]carbonyl} amino)benzoic acid;
5-cyano-2-( {[5-(hexylthio)pyrazin-2-yl]carbonyl} amino)benzoic acid;
5-chloro-2-( { [5-(hexylthio)pyrazin-2-yl] carbonyl} amino)benzoic acid;
2-( {[5-(sec-butylthio)pyrazin-2-yl]carbonyl} amino)-5-chlorobenzoic acid; 5-bromo-2-{[(5-methoxypyrazm-2-yl)carbonyl]amino}benzoic acid;
5-cyano-2-( {[5-(2-phenylethyl)pyrazin-2-yl]carbonyl} amino)benzoic acid;
5-bromo-2-{[(5-{(E)-2-[(4S)-2,2-dimethyl-l,3-dioxolan-4-yl]ethenyl}pyrazin-2- yl)carbonyl]amino}benzoic acid;
5-cyano-2-( {[5-(isopentylthio)pyrazin-2-yl]carbonyl} amino)benzoic acid; 5-cyano-2-({[5-(isobutylthio)pyra2--n-2-yl]carbonyl}amino)benzoic acid;
5-cyano-2- {[(5-methoxypyrazin-2-yl)carbonyl]amino}benzoic acid;
5-cyano-2-( {[5-(hexyloxy)pyrazin-2-yl]carbonyl} amino)benzoic acid;
5-cyano-2-[( {5-[2-(trifluoromethyl)phenyl]pyrazin-2-yl} carbonyl)amino]benzoic acid;
5-cyano-2-[( {5-[(4-methoxybenzyl)thio]pyrazin-2-yl} carbonyl) amino]benzoic acid; 5-cyano-2-( {[5-(2-fluorophenyl)pyrazin-2-yl]carbonyl} amino)benzoic acid;
5-bromo-2-{[(5-{(E)-2-[(2S)-l,4-dioxaspiro[4.5]dec-2-yl]ethenyl}pyrazin-2- yl)carbonyl]amino}benzoic acid;
5-cyano-2-( {[5-(2-methylphenyl)pyrazin-2-yl]carbonyl} amino)benzoic acid;
5-cyano-2-({[5-(2,3,4-trimethoxyphenyl)pyrazm-2-yl]carbonyl}amino)benzoic acid; 5-cyano-2-({[5-(nonylthio)pyrazin-2-yl]carbonyl}amino)benzoic acid;
5-cyano-2-( {[5-(octylthio)pyrazin-2-yl]carbonyl} amino)benzoic acid;
5-cyano-2-({[5-(6-methoxypyridm-3-yl)pyrazm-2-yl]carbonyl}arnino)benzoic acid;
5-cyano-2- {[(5-phenylpyrazm-2-yl)carbonyl]amino}benzoic acid;
5-cyano-2-[( {5-[4-(methylsulfonyl)phenyl]pyrazin-2-yl} carbonyl)amino]benzoic acid; 5-cyano-2-( {[5-(3,5-dimethylisoxazol-4-yl)pyrazin-2-yl]carbonyl} amino)benzoic acid;
5-cyano-2-({[6-(hexylthio)pyridazin-3-yl] carbonyl} arnino)benzoic acid; and
5-cyano-2-[({6-[2-(trifluoromethyl)phenyl]pyriα^azm-3-yl}carbonyl)amino]benzoic acid.
46. A method for the sanitizing or disinfecting including administrating an effective amount ofthe antimicrobial compoundsof claim 1.
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