WO2004096128A2 - Hiv integrase inhibitors - Google Patents

Hiv integrase inhibitors Download PDF

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Publication number
WO2004096128A2
WO2004096128A2 PCT/US2004/011759 US2004011759W WO2004096128A2 WO 2004096128 A2 WO2004096128 A2 WO 2004096128A2 US 2004011759 W US2004011759 W US 2004011759W WO 2004096128 A2 WO2004096128 A2 WO 2004096128A2
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WO
WIPO (PCT)
Prior art keywords
methyl
hydroxy
oxo
carboxamide
dihydropyrimidine
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PCT/US2004/011759
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French (fr)
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WO2004096128A3 (en
Inventor
B. Narasimhulu Naidu
Michael A. Walker
Margaret E. Sorenson
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Bristol-Myers Squibb Company
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Publication of WO2004096128A2 publication Critical patent/WO2004096128A2/en
Publication of WO2004096128A3 publication Critical patent/WO2004096128A3/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic 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
    • C07D487/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three 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, directly attached to ring carbon atoms
    • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
    • C07D239/52—Two oxygen atoms
    • C07D239/54—Two oxygen atoms as doubly bound oxygen atoms or as unsubstituted hydroxy radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three 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, directly attached to ring carbon atoms
    • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
    • C07D239/52—Two oxygen atoms
    • C07D239/54—Two oxygen atoms as doubly bound oxygen atoms or as unsubstituted hydroxy radicals
    • C07D239/545—Two oxygen atoms as doubly bound oxygen atoms or as unsubstituted hydroxy radicals with other hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/557—Two oxygen atoms as doubly bound oxygen atoms or as unsubstituted hydroxy radicals with other hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms, e.g. orotic acid
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic 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
    • C07D401/02—Heterocyclic 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
    • C07D401/04—Heterocyclic 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 directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic 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
    • C07D417/14—Heterocyclic 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 three or more hetero rings

Definitions

  • HIV expresses three enzymes, reverse transcriptase, an aspartyl protease and integrase, all of which are potential antiviral targets for the development of drugs for the treatment of AIDS.
  • integrase stands out as being the only viral enzyme not targeted by current therapy.
  • the integrase enzyme is responsible for insertion of the viral cDNA into the host cell genome, which is a critical step in the viral life cycle. There are a number of discrete steps involved in this process including processing of the viral cDNA by removal of two bases from each 3 '-terminus and joining of the recessed ends to the host DNA. Studies have shown that in the absence of a functional integrase enzyme HIV is not infectious. (Lafemina, R. L.; Schneider, C.
  • HIV Human immunodeficiency virus
  • AIDS acquired immune deficiency syndrome
  • Recent statistics indicate that as many as 33 million people worldwide are infected with the virus. In addition to the large number of individuals already infected, the virus continues to spread. Estimates from 1998 point to close to 6 million new infections in that year alone. In the same year there were approximately 2.5 million deaths associated with HIV and AIDS.
  • antiviral drugs available to combat the infection.
  • saquinavir, indinavir, ritonavir, nelfinavir and amprenavir are competitive inhibitors of the aspartyl protease expressed by HIV.
  • Zidovudine, didanosine, stavudine, lamivudine, zalcitabine and abacavir are nucleoside reverse transcriptase inhibitors that behave as substrate mimics to halt viral cDNA synthesis.
  • non-nucleoside reverse transcriptase inhibitors nevaripine, delavirdine and efavirenz inhibit the synthesis of viral cDNA via a non-competitive (or uncompetitive) mechanism. Used alone these drugs are effective in reducing viral replication. The effect is only temporary as the virus readily develops resistance to all known agents. However, combination therapy has proven very effective at both reducing virus and suppressing the emergence of resistance in a number of patients. In the US, where combination therapy is widely available, the number of HIV-related deaths has declined (Palella, F. J.; Delany, K. M.; Moorman, A. C; Loveless, M. O.; Furher, J.; Satten, G. A.; Aschman, D. J.; Holmberg, S. D. N. Engl. J. Med. 1998, 338, 853-860).
  • new antiviral agents preferably targeting other viral enzymes to reduce the rate of resistance and suppress viral replication even further.
  • a number of HIV integrase inhibitors have been reported. These include nucleotide-based inhibitors, known DNA binders, catechols and hydrazide containing derivatives (Neamati, N.; Sunder, S.; Pommier, Y., Drug Disc. Today, 1997, 2, 487).
  • WO 02/06246 discloses 2-aryl-4,5-dihydroxy-6-carboxypyrimidines as viral polymerase inhibitors which are proposed for use in treating hepatitis C virus infection.
  • Sunderland, C. J; Botta, M.; Aime, S.; and Raymond, K. N. Inorg. Chem. (2001) 40, 6746-6756 discloses the synthesis of 6-carboxamido-5,4-hydroxypyrimidinones as gadolinium chelating agents. This action makes the compounds useful for treating HIV infection and AIDS.
  • the invention also encompasses pharmaceutical compositions and methods for treating those infected with HIV. None in these references teaches or suggests the novel compounds of this invention or their use as HIV integrase inhibitors.
  • the invention encompasses a series of compounds of structural Formula I which inhibit HIV integrase. This action makes the compounds useful for treating HIV infection and AIDS.
  • the invention also encompasses pharmaceutical compositions and methods for treating those infected with HIV.
  • the invention comprises compounds of Formula I, including pharmaceutically acceptable salts and solvates, their pharmaceutical compositions, and their use in preventing HIV attachment and treating those infected with HIV.
  • the compounds of Formula I are described with the following meanings: B
  • A is methylene or 1,1-disubstituted ethylene
  • B is selected from the group consisting of
  • R 1 is phenyl, pyridinyl or dioxolanylphenyl and is unsubstituted or substituted with 1 to 3 R 3
  • R 2 is hydrogen, methyl, or OR 4 ;
  • R is independently selected from halo, Ci- ⁇ alkyl, C ⁇ - 2 perfluoroalkyl, Ci- ⁇ alkoxy, - ⁇ alkylthioxy, and cyano;
  • R is hydrogen or C h alky!
  • R 5 is Ar 1 or Ar 2 ;
  • R 6 is C ⁇ - 6 alkyl
  • Ar 1 is phenyl unsubstituted or substituted with 1-2 substituents selected from halo, C 1-6 alkoxy, CO 2 R 4 , N(R 4 )(SO 2 C 1-6 alkyl), SO 2 N(C 1-6 alkyl) 2 , and dioxothiazinanyl;
  • Ar 2 is a heteroaryl moiety selected from the group consisting of pyridinyl, pyrrolyl, furanyl, and imidazopyrimidinyl and is unsubstituted or substituted with 1-2 substituents selected from halo, C 1-6 alkyl, C 1-6 alkoxy, CO 2 R , N(R 4 )(SO 2 C 1-6 alkyl), SO 2 N(C 1-6 alkyl) 2) N(R 7 ) 2) and dioxothiazinanyl;
  • R 7 is hydrogen, C ⁇ alkyl, C 1-6 alkylOR 4 .
  • One aspect of the invention are compounds of Formula I wherein R 1 is phenyl unsubstituted or substituted with 1 to 3 R 3 .
  • R 1 is phenyl ssuubbssttiittuutteedd wwiitthh 11--221 R 3 selected from the group consisting of chloro, fluoro, methyl, and trifluoromethyl.
  • Another aspect of the invention are compounds of Formula I where R >2 is hydrogen.
  • Another aspect of the invention are compounds of Formula I where R 5 is Ar 1 .
  • Ar 1 is phenyl substituted with 1-2 R 3 selected from the group consisting of chloro, fluoro, methoxy, N(Me)SO 2 Me, SO2N(Me) 2 , SO 2 Me, and dioxothiazinanyl.
  • Another aspect of the invention are compounds of Formula I where R 5 is Ar 2 .
  • Another aspect of the invention are compounds of Formula I where Ar 2 is substituted with 1-2 substituents selected from the group consisting of chloro, fluoro, methyl, methoxy, dimethylamino, 2-hydroxyethylamino, di(2-hydroxyethyl)amino, N(Me)SO 2 Me, SO 2 N(Me) 2 , SO 2 Me, and dioxothiazinanyl.
  • Another aspect of the invention are compounds of Formula I where R 6 is methyl.
  • Some compounds of the invention are N-(4-fluorobenzyl)-2-(2,6-difluorophenyl)-5-hydroxy-l-methyl-6-oxo-l,6- dihydropyrimidine-4-carboxamide;
  • Alkyl and alkoxy includes straight and branched saturated hydrocarbon substituents.
  • Aryl includes carbocyclic and heterocyclic aromatic substituents.
  • the invention includes all pharmaceutically acceptable salt forms of the compounds.
  • Pharmaceutically acceptable salts are those in which the counter ions do not contribute significantly to the physiological activity or toxicity of the compounds and as such function as pharmacological equivalents. These salts can be made according to common organic techniques employing commercially available reagents. Some anionic salt forms include acetate, acistrate, besylate, bromide, chloride, citrate, fumarate, glucouronate, hydrobromide, hydrochloride, hydroiodide, iodide, lactate, maleate, mesylate, nitrate, pamoate, phosphate, succinate, sulfate, tartrate, tosylate, and xinofoate.
  • Some cationic salt forms include ammonium, aluminum, benzathine, bismuth, calcium, choline, diethylamine, diethanolamine, lithium, magnesium, meglumine, 4-phenylcyclohexylamine, piperazine, potassium, sodium, tromethamine, and zinc.
  • the invention also includes all solvated forms of the compounds, particularly hydrates. Solvates do not contribute significantly to the physiological activity or toxicity of the compounds and as such function as pharmacological equivalents. Solvates may form in stoichiometric amounts or may form from adventitious solvent or a combination of both. One type of solvate is hydrate, and some hydrated forms include monohydrate, hemihydrate, and dihydrate.
  • Certain compounds of Formula I may contain one or more chiral centers and exist in different optically active forms. When compounds of Formula I contain one chiral center, the compounds exist in two enantiomeric forms.
  • the present invention includes both enantiomers and mixtures of enantiomers such as racemic mixtures. The enantiomers may be resolved by methods known in the art. Alternatively, specific enantiomers may be synthesized by asymmetric synthesis using reactions known in the art.
  • the compounds of this invention can also exist as tautomers, as shown below; therefore the present invention also includes all tautomeric forms.
  • the ester 1-6 is condensed with amine 1-7 to give the amide 1-8.
  • the amide coupling reaction can be carried out under a variety of conditions such as those disclosed in Jerry March, Advanced Organic Chemistry, 3 rd edition, John Wiley & Sons, 1985.
  • the pyrimidinone II-5 is alkylated with a suitable electrophile under basic conditions. Then intermediate II-9 is coupled with amine II-6. The amides, II- 8 and 11-10 are then treated under conditions appropriate for cleaving the protecting group P.
  • alkyl groups where P is alkyl, this can be accomplished by BBr or other conditions known in the art.
  • P is a benzylic or substituted benzylic group
  • the ether can be cleaved under reductive conditions, oxidative conditions or acidic conditions.
  • Protecting groups, R useful for the synthesis of compounds such as 1-9 can be found in Greene, T. W. and Wutz, P. G. M. Protective Groups in Organic Synthesis, Second Edition, 1991, John Wiley and Sons, New York.
  • HIV integrase inhibitors belonging to a class of diketo acid compounds prevented viral integration and inhibited HIV-1 replication in cells (Hazuda et al. Science 2000, 287, 646).
  • HIV integrase inhibitors have been accepted into clinical trials for treating AIDS and HIV infection (Neamati Expert. Opin. Ther. Patents 2002, 12, 709, Pais and Burke Drugs Fut. 2002, 27, 1101).
  • another aspect of the invention is a method for treating HIV infection in a human patient comprising administering a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt or solvate thereof, with a pharmaceutically acceptable carrier.
  • Another aspect of the invention is a method for treating HIV infection in a human patient comprising administering a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt or solvate thereof, with a therapeutically effective amount of at least one other agent used for treatment of AIDS or HIV infection.
  • Some suitable agents are nucleoside HIV reverse transcriptase inhibitors, non-nucleoside HIV reverse transcriptase inhibitors, HIV protease inhibitors, HIV fusion inhibitors, HIV attachment inhibitors, CCR5 inhibitors, CXCR4 inhibitors, HIV budding or maturation inhibitors, and HIV integrase inhibitors.
  • compositions for treating HIV infection in a human patient comprising administering a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt or solvate thereof, with a pharmaceutically acceptable carrier.
  • “Combination,” “coadministration,” “concurrent,” and similar terms referring to the administration of compounds of Formula I with at least one anti-HIV agent mean that the components are part of a combination antiretroviral therapy or highly active antiretroviral therapy (HAART) as understood by practitioners in the field of AIDS and HIV infection.
  • HAART highly active antiretroviral therapy
  • “Therapeutically effective” means the amount of agent required to provide a meaningful patient benefit as understood by practitioners in the field of AIDS and HIV infection. In general, the goals of treatment are suppression of viral load, restoration and preservation of immunologic function, improved quality of life, and reduction of HIV-related morbidity and mortality.
  • Patient means a person infected with the HIV virus and suitable for therapy as understood by practitioners in the field of AIDS and HIV infection.
  • compositions comprised of a therapeutically effective amount of a compound of Formula I or its pharmaceutically acceptable salt and a pharmaceutically acceptable carrier and may contain conventional exipients.
  • a therapeutically effective amount is that which is needed to provide a meaningful patient benefit.
  • Pharmaceutically acceptable carriers are those conventionally known carriers having acceptable safety profiles.
  • Compositions encompass all common solid and liquid forms including capsules, tablets, losenges, and powders as well as liquid suspensions, syrups, elixers, and solutions. Compositions are made using common formulation techniques, and conventional excipients (such as binding and wetting agents) and vehicles (such as water and alcohols) are generally used for compositions.
  • Solid compositions are normally formulated in dosage units and compositions providing from about 1 to 1000 mg of the active ingredient per dose are preferred. Some examples of dosages are 1 mg, 10, mg, 100, mg, 250 mg, 500 mg, and 1000 mg. Generally, other antiretroviral agents will be present in a unit range similar to agents of that class used clinically. Typically, this 0.25-1000 mg/unit.
  • Liquid compositions are usually in dosage unit ranges. Generally, the liquid composition will be in a unit dosage range of 1-100 mg/mL. Some examples of dosages are 1 mg/mL, 10 mg/mL, 25, mg/mL, 50 mg/mL, and 100 mg/mL. Generally, other antiretroviral agents will be present in a unit range similar to agents of that class used clinically. Typically, this is 1-100 mg/mL.
  • the invention encompasses all conventional modes of administration; oral and parenteral methods are preferred.
  • the dosing regimen will be similar to other antiretroviral agents used clinically.
  • the daily dose will be 1-100 mg/kg body weight daily.
  • more compound is required orally and less parenterally.
  • the specific dosing regime will be determined by a physician using sound medical judgement.
  • the invention also encompasses methods where the compound is given in combination therapy. That is, the compound can be used in conjunction with, but separately from, other agents useftil in treating AIDS and HIV infection.
  • agents include HIV attachment inhibitors, CCR5 inhibitors, CXCR4 inhibitors, HIV cell fusion inhibitors, HIV integrase inhibitors, HIV nucleoside reverse transcriptase inhibitors, HIV non-nucleoside reverse transcriptase inhibitors, HIV protease inhibitors, budding and maturation inhibitors, immunomodulators, and anti- infectives.
  • Compound 1 will generally be given in a daily dose of 1-100 mg/kg body weight daily in conjunction with other agents.
  • the other agents generally will be given in the amounts used therapeutically.
  • the specific dosing regime will be determined by a physician using sound medical judgement. Table 1 lists some agents useful in treating AIDS and HIV infection which are suitable for this invention.
  • NMR nuclear magnetic resonance
  • reaction mixture was then cooled, concentrated and purified on silica gel column eluting with 1:3, 3:7 and 2:3 ethyl acetate/hexanes to give the title compound as a yellow oil (2.691 g, 76% yield).
  • N-(4-fluorobenzyl)-2-(2,6-difluorophenyl)-5-hydroxy-l-methyl-6-oxo-l,6- dihydropyrimidine-4-carboxamide A mixture of ester 2-(2,6-difluoro-phenyl)-5- hydroxy-l-methyl-6-oxo-l,6-dihydro-pyrimidine-4-carboxylic acid ethyl ester (91 mg, 0.2933 mmol) and 4-fluorobenzylamine (184 mg, 1.5 mmol) in toluene (2 mL) was heated at reflux for 3.5 h.
  • N-(3 ,4-dichlorobenzyl)-2-(2,6-difluorophenyl)-5-hydroxy-l -methyl-6-oxo-l ,6- dihydropyrimidine-4-carboxamide A mixture of ester 2-(2,6-difluoro-phenyl)-5- hydroxy-l-methyl-6-oxo-l,6-dihydro-pyrimidine-4-carboxylic acid ethyl ester (31 mg, 0.1 mmol) and 3,4-dichlorobenzylamine (88 mg, 0.5 mmol) in DMF (1 mL) was heated between 120-130 °C for 3 h.
  • N-(3,4-difluorobenzyl)-2-(2,6-difluorophenyl)-5-hydroxy-l-methyl-6-oxo-l,6- dihydropyrimidine-4-carboxam ⁇ de Prepared according to the procedure described for example 2 from 2-(2,6-difluoro-phenyl)-5-hydroxy- 1 -methyl-6-oxo- 1 ,6-dihydro- pyrimidine-4-carboxylic acid ethyl ester (31 mg, 0.1 mmol) and 3,4- difluorobenzylamine (72 mg, 0.5 mmol). The title product was obtained as an off- white solid (32.7 mg, 80% yield).
  • N-(4-chlorobenzyl)-2-(2,6-difluorophenyl)-5-hydroxy-l-methyl-6-oxo-l,6- dihydropyrimidine-4-carboxamide Prepared according to the procedure described for example 2 from 2-(2,6-difluoro-phenyl)-5-hydroxy-l-methyl-6-oxo-l,6-dihydro- pyrimidine-4-carboxylic acid ethyl ester (31 mg, 0.1 mmol) and 4-chlorobenzylamine (71 mg, 0.5 mmol). The title product was obtained as an off-white solid (32.3 mg, 80% yield).
  • N-(4-methylbenzyl)-2-(2, 6-difluorophenyl)-5-hydroxy-l -methyl-6-oxo-l, 6- dihydropyrimidine-4-carboxamide prepared according to the procedure described for example 2 from 2-(2,6-difluoro- ⁇ henyl)-5-hydroxy-l-methyl-6-oxo-l,6-dihydro- pyrimidine-4-carboxylic acid ethyl ester (31 mg, 0.1 mmol) and 4- methylbenzylamine (61 mg, 0.5 mmol). The title product was obtained as an off- white solid (32 mg, 83% yield).
  • N-(3,4-di ⁇ nethylbenzyl)-2-(2,6-difluorophenyl)-5-hydroxy-l-methyl-6-oxo-l,6- dihydropyrimidine-4-carboxamide Prepared according to the procedure described for example 2 from 2-(2,6-difluoro-phenyl)-5-hydroxy-l-methyl-6-oxo-l,6-dihydro- pyrimidine-4-carboxylic acid ethyl ester (31 mg, 0.1 mmol) and 3,4- dimethylbenzylamine (68 mg, 0.5 mmol). The title product was obtained as an off- white solid (32.7 mg, 82% yield).
  • N-(3-chloro-4-methylbenzyl)-2-(2, 6-difluorophenyl)-5-hydroxy-l-methyl-6- oxo-l,6-dihydropyrimidine-4-carboxamide prepared according to the procedure described for example 2 from 2-(2,6-difluoro-phenyl)-5-hydroxy-l-methyl-6-oxo- l,6-dihydro-pyrimidine-4-carboxylic acid ethyl ester (31 mg, 0.1 mmol) and 3- chloro-4-methylbenzylamine (78 mg, 0.5 mmol). The title product was obtained as an off-white solid (35.3 mg, 84% yield).
  • N-(2,4-difluorobenzyl)-2-(2, 6-difluorophenyl)-5-hydroxy-l -methyl-6-oxo-l ,6- dihydropyrimidine-4-carboxamide prepared according to the procedure described for example 2 from 2-(2,6-difluoro-phenyl)-5-hydroxy-l-methyl-6-oxo-l,6-dihydro- pyrimidine-4-carboxylic acid ethyl ester (31 mg, 0.1 mmol) and 2,4- difluorobenzylamine (72 mg, 0.5 mmol). The title product was obtained as an off- white solid (36.2 mg, 89% yield).
  • N-(2-methylbenzyl)-2-(2, 6-difluorophenyl)-5-hydroxy-l -methyl-6-oxo-l, 6- dihydropyrimidine-4-carboxamide prepared according to the procedure described for example 2 from 2-(2,6-difluoro-phenyl)-5-hydroxy-l-methyl-6-oxo-l,6-dihydro- pyrimidine-4-carboxylic acid ethyl ester (31 mg, 0.1 mmol) and 2- methylbenzylamine (61 mg, 0.5 mmol). The title product was obtained as an off- white solid (34.1 mg, 88.6% yield).
  • N-(4-fluoro-2-(trifluoromethyl)benzyl)-2-(2,6-difluorophenyl)-5-hydroxy-l- methyl-6-oxo-l,6-dihydropyrimidine-4-carboxamide prepared according to the procedure described for example 2 from 2-(2,6-difluoro-phenyl)-5-hydroxy-l- methyl-6-oxo-l,6-dihydro-pyrimidine-4-carboxylic acid ethyl ester (31 mg, 0.1 mmol) and 2-trifluoromethyl-4-fluorobenzylamine (97 mg, 0.5 mmol). The title product was obtained as an off-white solid (25.7 mg, 56% yield).
  • N-(4-(trifluoromethyl)benzyl)-2-(2,6-difluorophenyl)-5-hydroxy-l-methyl-6- oxo-l,6-dihydropyrimidine-4-carboxamide prepared according to the procedure described for example 2 from 2-(2,6-difluoro-phenyl)-5-hydroxy-l-methyl-6-oxo- l,6-dihydro-pyrimidine-4-carboxylic acid ethyl ester (31 mg, 0.1 mmol) and 4- trifluoromethylbenzylamine (88 mg, 0.5 mmol). The title product was obtained as an off-white solid (38.6 mg, 88% yield).
  • N-(2-(methylthio)benzyl)-2-(2,6-difluorophenyl)-5-hydroxy-l-n ⁇ thyl-6-oxo- l,6-dihydropyrimidine-4-carboxamide Prepared according to the procedure described for example 2 from 2-(2,6-difluoro-phenyl)-5-hydroxy-l-methyl-6-oxo- l,6-dihydro-pyrimidine-4-carboxylic acid ethyl ester (31 mg, 0.1 mmol) and 2- methylthiobenzylamine (77 mg, 0.5 mmol). The title product was obtained as an off- white solid (34.2 mg, 82% yield).
  • N-(3-fluoro-4-(trifluoromethyl)benzyl)-2-(2,6-difluorophenyl)-5-hydroxy-l- methyl-6-oxo-l,6-dihydropyrimidine-4-carboxamide prepared according to the procedure described for example 2 from 2-(2,6-difluoro-phenyl)-5-hydroxy-l- methyl-6-oxo-l,6-dihydro-pyrimidine-4-carboxylic acid ethyl ester (31 mg, 0.1 mmol) and 3-fluoro-4-trifluoromethylbenzylamine (97 mg, 0.5 mmol). The title product was obtained as an off-white solid (44.7 mg, 98% yield).
  • N-(3, 5-bis(trifluoromethyl)benzyl)-2-(2, 6-difluorophenyl)-5-hydroxy-l - methyl-6-oxo-l,6-dihydropyrimidine-4-carboxamide prepared according to the procedure described for example 2 from 2-(2,6-difluoro-phenyl)-5-hydroxy-l- methyl-6-oxo-l,6-dihydro-pyrimidine-4-carboxylic acid ethyl ester (31 mg, 0.1 mmol) and 2,5-ditrifluoromethyl-benzylamine (98 mg, 0.5 mmol). The title product was obtained as an off-white solid (43.6 mg, 86% yield).
  • N-(4-chlorobenzyl)-5-hydroxy-l -methyl-6-oxo-2-(pyridin-2-yl)-l, 6- dihydropyrimidine-4-carboxamide Prepared according to the procedure described for example 2 from 5-hydroxy-l-methyl-6-oxo-2-pyridin-2-yl-l,6-dihydro- pyrimidine-4-carboxylic acid ethyl ester (27.53 mg, 0.1 mmol) and 4- chlorobenzylamine (71 mg, 0.5 mmol). The title product was obtained as a TFA salt (brown solid, 10.3 mg, 21% yield).
  • N-(3,4-dichlorobenzyl)-5-hydroxy-l -methyl-6-oxo-2-(pyridin-2-yl)-l, 6- dihydropyrimidine-4-carboxamide Prepared according to the procedure described for example 2 from 5-hydroxy-l-methyl-6-oxo-2-pyridin-2-yl-l,6-dihydro- pyrimidine-4-carboxylic acid ethyl ester (27.53 mg, 0.1 mmol) and 3,4- dichlorobenzyla ine (71 mg, 0.5 mmol). The title product was obtained as a TFA salt (off-white solid, 18.6 mg, 36% yield).
  • N-(3,4-difluorobenzyl)-5-hydroxy-l-methyl-6-oxo-2-(pyridin-2-yl)-l,6- dihydropyrimidine-4-carboxamide Prepared according to the procedure described for example 2 from 5-hydroxy-l-methyl-6-oxo-2-pyridin-2-yl-l,6-dihydro- pyrimidine-4-carboxylic acid ethyl ester (27.53 mg, 0.1 mmol) and 3,4- difluorobenzylamine (72 mg, 0.5 mmol). The title product was obtained as a TFA salt (brown solid, 11.2 mg, 23% yield).
  • N-(4-methylbenzyl)-5-hydroxy-l-methyl-6-oxo-2-(pyridin-2-yl)-l,6- dihydropyrimidine-4-carboxamide Prepared according to the procedure described for example 2 from 5-hydroxy-l-methyl-6-oxo-2-pyridin-2-yl-l,6-dihydro- pyrimidine-4-carboxylic acid ethyl ester (27.53 mg, 0.1 mmol) and 4- methylbenzylamine (61 mg, 0.5 mmol). The title product was obtained as a TFA salt (brown solid, 14.3 mg, 31% yield).
  • N-(3,4-dimethylbenzyl)-5-hydroxy-l-methyl-6-oxo-2-(pyridin-2-yl)-l,6- dihydropyrimidine-4-carboxamide Prepared according to the procedure described for example 2 from 5-hydroxy-l-methyl-6-oxo-2-pyridin-2-yl-l,6-dihydro- pyrimidine-4-carboxylic acid ethyl ester (27.53 mg, 0.1 mmol) and 3,4- dimethylbenzylamine (68 mg, 0.5 mmol). The title product was obtained as a TFA salt (brown solid, 14.1 mg, 30% yield).
  • N-(3-chloro-4-methylbenzyl)-5-hydroxy-l -methyl-6-oxo-2-(pyridin-2-yl)-l, 6- dihydropyrimidine-4-carboxamide Prepared according to the procedure described for example 2 from 5-hydroxy-l-methyl-6-oxo-2-pyridin-2-yl-l,6-dihydro- pyrimidine-4-carboxylic acid ethyl ester (27.53 mg, 0.1 mmol) and 3-chloro-4- methylbenzylamine (78 mg, 0.5 mmol). The title product was obtained as a TFA salt (brown solid, 7.2 mg, 14% yield).
  • N-(4-fluorobenzyl)-5-hydroxy-l-methyl-6-oxo-2-(pyridin-2-yl)-l,6- dihydropyrimidine-4-carboxamide A mixture of 5-hydroxy-l-methyl-6-oxo-2 ⁇ pyridin-2-yl-l,6-dihydro-pyrimidine-4-carboxylic acid ethyl ester (27.53 mg, 0.1 mmol) and 4-fluorobenzylamine (63 mg, 0.5 mmol) in toluene (2 mL) was heated at reflux for 6 h then cooled, concentrated and purified by preparative HPLC (C18, methanol/H 2 O-0.1% TFA, gradient elution).
  • N-(3,4-dichlorobenzyl)-5-hydroxy-2-(2-methoxyphenyl)-l -methyl-6-oxo-l, 6- dihydropyrimidine-4-carboxamide Prepared according to the procedure described for example 2 from 5-Hydroxy-2-(2-methoxy-phenyl)-l-methyl-6-oxo-l,6-dihydro- pyrimidine-4-carboxylic acid ethyl ester (45.6 mg, 0.15 mmol) and 3,4- dichlorobenzylamine (132 mg, 0.75 mmol). The title product was obtained as a pink solid (55.5 mg, 85% yield).
  • N-(4-fluorobenzyl)-5-hydroxy-2-(2-methoxyphenyl)-l -methyl-6-oxo-l, 6- dihydropyrimidine-4-carboxamide Prepared according to the procedure described for example 2 from 5-hydroxy-2-(2-methoxy-phenyl)-l-methyl-6-oxo-l,6-dihydro- pyrimidine-4-carboxylic acid ethyl ester (45.6 mg, 0.15 mmol) and 4- fluorobenzylamine (95 mg, 0.75 mmol). The title product was obtained as a pink solid (37 mg, 64% yield).
  • N-(3,4-dimethylbenzyl)-5-hydroxy-2-(2-methoxyphenyl)-l-methyl-6-oxo-l,6- dihydropyrimidine-4-carboxamide Prepared according to the procedure described for example 2 from 5-hydroxy-2-(2-methoxy-phenyl)-l-methyl-6-oxo-l,6-dihydro- pyrimidine-4-carboxylic acid ethyl ester (45.6 mg, 0.15 mmol) and 3,4- dimethylbenzylamine (102 mg, 0.75 mmol). The title product was obtained as a brown solid (53.5 mg, 91% yield).
  • N-(3-chloro-4-methylbenzyl)-5-hydroxy-2-(2-methoxyphenyl)-l-methyl-6-oxo- l,6-dihydropyrimidine-4-carboxamide Prepared according to the procedure described for example 2 from 5-hydroxy-2-(2-methoxy-phenyl)-l-methyl-6-oxo-l,6- dihydro-pyrimidine-4-carboxylic acid ethyl ester (45.6 mg, 0.15 mmol) and 3-chloro- 4-methylbenzylamine (107 mg, 0.75 mmol). The title product was obtained as a brown solid (57.5 mg, 93% yield).
  • reaction mixture was then taken-up into ethyl acetate (150 mL), washed successively with water and brine (50 mL each), dried (MgSO4), filtered and concentrated to give yellow oil.
  • the crude product was purified on silica gel column (3:7 to 2:3 ethyl acetate/hexanes) to afford the title product as a white solid (2.9122 g, 64% yield).
  • N-(4-fluorobenzyl)-2-(4-fluoro-2-(methylsulfonyl)phenyl)-5-hydroxy-l- methyl-6-oxo-l,6-dihydropyrimidine-4-carboxamide prepared according to the procedure described for example 2 from 2-(4-fluoro-2-methanesulfonyl-phenyl)-5- hydroxy-l-methyl-6-oxo-l,6-dihydro-pyrimidine-4-carboxylic acid ethyl ester (55.56 mg, 0.15 mmol) and 4-fluorobenzylamine (125 mg, 1.0 mmol). The title product was obtained as a white solid (61 mg, 68% yield).
  • N-(3,4-dichlorobenzyl)-2-(4-fluoro-2-(methylsulfonyl)phenyl)-5-hydroxy-l- methyl-6-oxo-l,6-dihydropyrimidine-4-carboxamide prepared according to the procedure described for example 2 from 2-(4-fluoro-2-methanesulfonyl-phenyl)-5- hydroxy-l-methyl-6-oxo-l,6-dihydro-pyrimidine-4-carboxylic acid ethyl ester (74.07 mg, 0.20 mmol) and 3,4-dichlorobenzylamine (132 mg, 0.75 mmol).
  • N-(3,4-dimethylbenzyl)-2-(4-fluoro-2-(methylsulfonyl)phenyl)-5-hydroxy-l- methyl-6-oxo-l,6-dihydropyrimidine-4-carboxamide prepared according to the procedure described for example 2 from 2-(4-fluoro-2-methanesulfonyl-phenyl)-5- hydroxy-l-methyl-6-oxo-l,6-dihydro-pyrimidine-4-carboxylic acid ethyl ester (55.56 mg, 0.15 mmol) and 3,4-dimethylbenzylamine (102 mg, 0.75 mmol).
  • N-(2-Cyano-3-fluoro- ⁇ henyl)-N-methyl-methanesulfonamide N-(2-Cyano-3-fluoro- ⁇ henyl)-N-methyl-methanesulfonamide.
  • 2-fluoro-6-methylamino-benzonitrile 1.5 g, 10 mmol
  • LiHMDS 1M in THF, 16 mL, 16 mmol
  • the resulting pale yellow solution was stirred for an additional 30 min, then methanesulfonyl chloride (1.16 mL, 15 mmol) was added.
  • reaction mixture was then taken up in ethyl acetate (100 mL), washed successively with water and brine (50 mL each), dried (MgSO 4 ), filtered and concentrated to give a yellow oil.
  • the crude product was purified on silica gel column (2:3 to 3:2 ethyl acetate/hexanes) to afford the title compound as a viscous yellow oil (0.7453 g, 56% yield).
  • N-(4-fluorobenzyl)-2-(2,6-dimethoxyphenyl)-5-hydroxy-l-methyl-6-oxo-l,6- dihydropyrimidine-4-carboxamide Prepared according to the procedure described for example 2 from 2-(2,6-dimethoxy- ⁇ henyl)-5-hydroxy-l-methyl-6-oxo-l,6- dihydro-pyrimidine-4-carboxylic acid ethyl ester (50 mg, 0.15 mmol) and 4- fluorobenzylamine (125 mg, 1.0 mmol). The title product was obtained as a pink solid (48.7 mg, 79% yield).
  • N-(3,4-dichlorobenzyl)-2-(2,6-dimethoxyphenyl)-5-hydroxy-l-methyl-6-oxo- l,6-dihydropyrimidine-4-carboxamide Prepared according to the procedure described for example 2 from 2-(2,6-dimethoxy-phenyl)-5-hydroxy-l-methyl-6-oxo- l,6-dihydro- ⁇ yrimidine-4-carboxylic acid ethyl ester (74.07 mg, 0.20 mmol) and 3,4- dichlorobenzylamine (132 mg, 0.75 mmol). The title product was obtained as a pink solid (57.8 mg, 83% yield).
  • N-(3,4-dimethylbenzyl)-2-(2,6-dimethoxyphenyl)-5-hydroxy-l-methyl-6-oxo- l,6-dihydropyrimidine-4-carboxamide prepared according to the procedure described for example 2 from 2-(2,6-dimethoxy-phenyl)-5-hydroxy-l-methyl-6-oxo- l,6-dihydro-pyrimidine-4-carboxylic acid ethyl ester (50 mg, 0.15 mmol) and 3,4- dimethylbenzylamine (102 mg, 0.75 mmol). The title product was obtained as a brown solid (52 mg, 82% yield).
  • N-(3-chloro-4-methylbenzyl)-2-(2,6-dimethoxyphenyl)-5-hydroxy-l-methyl-6- oxo-l,6-dihydropyrimidine-4-carboxamide prepared according to the procedure described for example 2 from 2-(2,6-dimethoxy-phenyl)-5-hydroxy- l-methyl-6-oxo- l,6-dihydro-pyrimidine-4-carboxylic acid ethyl ester (50 mg, 0.15 mmol) and 3- chloro-4-methylbenzylamine (107 mg, 0.75 mmol). The title product was obtained as a pink solid (51.1 mg, 77% yield).
  • N-(4-fluorobenzyl)-5-hydroxy-l-methyl-2-(2-morpholinophenyl)-6-oxo-l,6- dihydropyrimidine-4-carboxarnide Prepared according to the procedure described for example 2 from 5-hydroxy-l-methyl-2-(2-morpholin-4-yl-phenyl)-6-oxo-l,6- dihydro-pyrimidine-4-carboxylic acid ethyl ester (0.05 g, 0.15 mmol) and 4- fluorobenzylamine (0.086 mL, 0.75 mmol). The title product was obtained as a TFA salt, lavender solid (0.0575 g, 87% yield).
  • N-(3,4-dichlorobenzyl)-5-hydroxy-l-methyl-2-(2-morpholinophenyl)-6-oxo- l,6-dihydropyrimidine-4 ⁇ carboxamide Prepared according to the procedure described for example 2 from 5-hydroxy-l-methyl-2-(2-morpholin-4-yl-phenyl)-6- oxo-l,6-dihydro-pyrimidine-4-carboxylic acid ethyl ester (0.05 g, 0.15 mmol) and 3,4-dichlorobenzylamine (0.10 mL, 0.75 mmol). The title product was obtained as a TFA salt, lavender foam (0.0461 g, 63% yield).
  • N-(3,4-dimethylbenzyl)-5-hydroxy-l-methyl-2-(2-morpholinophenyl)-6-oxo- l,6-dihydropyrimidine-4-carboxamide Prepared according to the procedure described for example 2 from 5-hydroxy-l-methyl-2-(2-mor ⁇ holin-4-yl-phenyl)-6- oxo-l,6-dihydro-pyrimidine-4-carboxylic acid ethyl ester (0.05 g, 0.15 mmol) and 3,4-dimethylbenzylamine (0.11 mL, 0.75 mmol).
  • the title product was obtained as a TFA salt, lavender foam (0.0440 g, 65% yield).
  • N-(3-chloro4-methylbenzyl)-5-hydroxy-l-methyl-2-(2-morpholinophenyl)-6- oxo-1, 6-dihydropyrimidine-4-carboxamide Prepared according to the procedure described for example 2 from 5-hydroxy-l-methyl-2-(2-morpholin-4-yl-phenyl)-6- oxo-l,6-dihydro-pyrimidine-4-carboxylic acid ethyl ester (0.05 g, 0.15 mmol) and 3- chloro-4-methylbenzylamine (0.11 mL, 0.75 mmol). The title product was obtained as a TFA salt, lavender foam (0.0266 g, 38% yield).
  • N-(4-fluorobenzyl)-2-(2-dimethylsulfamoylphenyl)-5-hydroxy-l-methyl-6-oxo- l,6-dihydropyrimidine-4 ⁇ carboxamide Prepared according to the procedure described for example 2 from 2-(2-dimethylsulfamoyl-phenyl)-5-hydroxy- 1 -methyl- 6-oxo-l,6-dihydro-pyrimidine-4-carboxylic acid ethyl ester (0.076 g, 0.2mmol), and 4-fluorobenzylamine (0.11 mL, 1.0 mmol). The title product was obtained as white needles (0.0549 g, 60% yield).
  • N-(3,4-dichlorobenzyl)-2-(2-dimethylsulfa ⁇ noylphenyl)-5-hydroxy-l-rnethyl-6- oxo-1, 6-dihydropyrimidine-4-carboxamide Prepared according to the procedure described for example 2 from 2-(2-dimethylsulfamoyl-phenyl)-5-hydroxy- 1 -methyl- 6-oxo-l,6-dihydro-pyrimidine-4-carboxylic acid ethyl ester (0.076 g, 0.2 mmol) and 3,4-dichlorobenzylamine (0.13 mL, 1.0 mmol). The title product was obtained as white needles (0.0569 g, 56% yield).
  • N-(3,4-dimethylbenzyl)-2-(2-dimethylsulfamoylphenyl)-5-hydroxy-l-methyl-6- oxo-1, 6-dihydropyrimidine-4-carboxamide Prepared according to the procedure described for example 2 from 2-(2-dimethylsulfamoyl-phenyl)-5-hydroxy- 1 -methyl- 6-oxo-l,6-dihydro-pyrimidine-4-carboxylic acid ethyl ester (0.076 g, 0.2 mmol) and 3,4-dimethylbenzylamine (0.14 mL, 1.0 mmol). The title product was obtained as white needles (0.0560 g, 60% yield).
  • N-(3-chloro-4-methylbenzyl)-2-(2-dimethylsulfamoylphenyl)-5-hydroxy-l- methyl-6-oxo-l,6-dihydropyrimidine-4-carboxamide prepared according to the procedure described for example 2 from 2-(2-dimethylsulfamoyl-phenyl)-5-hydroxy- l-methyl-6-oxo-l,6-dihydro-pyrimidine-4-carboxylic acid ethyl ester (0.076 g, 0.2 mmol) and 3-chloro-4-methylbenzylamine (0.14 mL, 1.0 mmol). The title product was obtained as white needles (0.0601 g, 61% yield).
  • Examples 53-105 were prepared according to the procedures described for examples 1-52.

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Abstract

The present invention relates to a series of pyrimidine compounds of Formula (I) which inhibit HIV integrase and to pharmaceutical compositions and methods of treatment for AIDS or ARC using these compounds.

Description

HIV INTEGRASE INHIBITORS
CROSS-REFERENCE TO RELATED APPLICATIONS
This application claims the benefit of US provisional application 60/465,176, filed April 24, 2003.
BACKGROUND OF THE INVENTION
HIV expresses three enzymes, reverse transcriptase, an aspartyl protease and integrase, all of which are potential antiviral targets for the development of drugs for the treatment of AIDS. However, integrase stands out as being the only viral enzyme not targeted by current therapy. The integrase enzyme is responsible for insertion of the viral cDNA into the host cell genome, which is a critical step in the viral life cycle. There are a number of discrete steps involved in this process including processing of the viral cDNA by removal of two bases from each 3 '-terminus and joining of the recessed ends to the host DNA. Studies have shown that in the absence of a functional integrase enzyme HIV is not infectious. (Lafemina, R. L.; Schneider, C. L.; Robbins, H. L.; Callahan, P. L.; LeGrow, K.; Roth, E.; Emini, E. A. J. Virol. 1992, 66, 7414-7419 and Englund, G.; Theodore, T. S.; Freed, E.; Engelman, A.; Martin, M. A. J. Virol 1995, 69, 3216-3219) Therefore, an inhibitor of integrase would be useful as a therapy for AIDS and HIV infection.
Human immunodeficiency virus (HIV) has been identified as the etiological agent responsible for acquired immune deficiency syndrome (AIDS), a fatal disease characterized by destruction of the immune system and the inability to fight off life threatening opportunistic infections. Recent statistics (UN AIDS: Report on the Global HIV/AIDS Epidemic, December 1998), indicate that as many as 33 million people worldwide are infected with the virus. In addition to the large number of individuals already infected, the virus continues to spread. Estimates from 1998 point to close to 6 million new infections in that year alone. In the same year there were approximately 2.5 million deaths associated with HIV and AIDS. There are currently a number of antiviral drugs available to combat the infection. These drugs can be divided into three classes based on the viral protein they target and their mode of action. In particular, saquinavir, indinavir, ritonavir, nelfinavir and amprenavir are competitive inhibitors of the aspartyl protease expressed by HIV. Zidovudine, didanosine, stavudine, lamivudine, zalcitabine and abacavir are nucleoside reverse transcriptase inhibitors that behave as substrate mimics to halt viral cDNA synthesis. The non-nucleoside reverse transcriptase inhibitors, nevaripine, delavirdine and efavirenz inhibit the synthesis of viral cDNA via a non-competitive (or uncompetitive) mechanism. Used alone these drugs are effective in reducing viral replication. The effect is only temporary as the virus readily develops resistance to all known agents. However, combination therapy has proven very effective at both reducing virus and suppressing the emergence of resistance in a number of patients. In the US, where combination therapy is widely available, the number of HIV-related deaths has declined (Palella, F. J.; Delany, K. M.; Moorman, A. C; Loveless, M. O.; Furher, J.; Satten, G. A.; Aschman, D. J.; Holmberg, S. D. N. Engl. J. Med. 1998, 338, 853-860).
Unfortunately, not all patients are responsive and a large number fail this therapy. In fact, approximately 30-50% of patients ultimately fail combination therapy. Treatment failure in most cases is caused by the emergence of viral resistance. Viral resistance in turn is caused by the rapid turnover of HIV-1 during the course of infection combined with a high viral mutation rate. Under these circumstances incomplete viral suppression caused by insufficient drag potency, poor compliance to the complicated drug regiment as well as intrinsic pharmacological barriers to exposure provides fertile ground for resistance to emerge. More disturbing are recent findings which suggest that low-level replication continues even when viral plasma levels have dropped below detectable levels (< 50 copies/ml) (Carpenter, C. C; Cooper, D. A.; Fischl, M. A.; Gatell, J. M.; Gazzard, B. G.; Hammer, S. M.; Hirsch, M. S.; Jacobsen, D. M.; Katzenstein, D. A.; Montaner, J. S.; Richman, D. D.; Saag, M. S.; Schechter, M.; Schooley, R. T.; Thompson, M. A.;
Vella, S.; Yeni, P. G.; Volberding, P. A. JAMA 2000, 283, 381-390). Clearly there is a need for new antiviral agents, preferably targeting other viral enzymes to reduce the rate of resistance and suppress viral replication even further. A number of HIV integrase inhibitors have been reported. These include nucleotide-based inhibitors, known DNA binders, catechols and hydrazide containing derivatives (Neamati, N.; Sunder, S.; Pommier, Y., Drug Disc. Today, 1997, 2, 487).
Certain pyrimidines and pyrimidinones have been disclosed. WO 02/06246 discloses 2-aryl-4,5-dihydroxy-6-carboxypyrimidines as viral polymerase inhibitors which are proposed for use in treating hepatitis C virus infection. Sunderland, C. J; Botta, M.; Aime, S.; and Raymond, K. N. Inorg. Chem. (2001) 40, 6746-6756 discloses the synthesis of 6-carboxamido-5,4-hydroxypyrimidinones as gadolinium chelating agents. This action makes the compounds useful for treating HIV infection and AIDS. The invention also encompasses pharmaceutical compositions and methods for treating those infected with HIV. Nothing in these references teaches or suggests the novel compounds of this invention or their use as HIV integrase inhibitors.
SUMMARY OF INVENTION
The invention encompasses a series of compounds of structural Formula I which inhibit HIV integrase. This action makes the compounds useful for treating HIV infection and AIDS. The invention also encompasses pharmaceutical compositions and methods for treating those infected with HIV.
..B
I
R2
DETAILED DESCRIPTION OF THE INVENTION
The invention comprises compounds of Formula I, including pharmaceutically acceptable salts and solvates, their pharmaceutical compositions, and their use in preventing HIV attachment and treating those infected with HIV. The compounds of Formula I are described with the following meanings: B
.V N
R
wherein
A is methylene or 1,1-disubstituted ethylene;
B is selected from the group consisting of
Figure imgf000005_0001
R1 is phenyl, pyridinyl or dioxolanylphenyl and is unsubstituted or substituted with 1 to 3 R3
R2 is hydrogen, methyl, or OR4;
R is independently selected from halo, Ci-βalkyl, Cι-2 perfluoroalkyl, Ci-βalkoxy, -δalkylthioxy, and cyano;
R is hydrogen or Chalky!;
R5 is Ar1 or Ar2;
R6 is Cι-6alkyl;
Ar1 is phenyl unsubstituted or substituted with 1-2 substituents selected from halo, C1-6alkoxy, CO2R4, N(R4)(SO2C1-6alkyl), SO2N(C1-6alkyl)2, and dioxothiazinanyl;
Ar2 is a heteroaryl moiety selected from the group consisting of pyridinyl, pyrrolyl, furanyl, and imidazopyrimidinyl and is unsubstituted or substituted with 1-2 substituents selected from halo, C1-6alkyl, C1-6alkoxy, CO2R , N(R4)(SO2C1-6alkyl), SO2N(C1-6alkyl)2)N(R7)2) and dioxothiazinanyl;
R7 is hydrogen, C^alkyl, C1-6alkylOR4.
One aspect of the invention are compounds of Formula I wherein R1 is phenyl unsubstituted or substituted with 1 to 3 R3.
Another aspect of the invention are compounds of Formula I where R1 is phenyl ssuubbssttiittuutteedd wwiitthh 11--221 R3 selected from the group consisting of chloro, fluoro, methyl, and trifluoromethyl.
Another aspect of the invention are compounds of Formula I where R >2 is hydrogen.
Another aspect of the invention are compounds of Formula I where R5 is Ar1.
Another aspect of the invention are compounds of Formula I where Ar1 is phenyl substituted with 1-2 R3 selected from the group consisting of chloro, fluoro, methoxy, N(Me)SO2Me, SO2N(Me)2, SO2Me, and dioxothiazinanyl.
Another aspect of the invention are compounds of Formula I where R5 is Ar2.
Another aspect of the invention are compounds of Formula I where Ar2 is substituted with 1-2 substituents selected from the group consisting of chloro, fluoro, methyl, methoxy, dimethylamino, 2-hydroxyethylamino, di(2-hydroxyethyl)amino, N(Me)SO2Me, SO2N(Me)2, SO2Me, and dioxothiazinanyl.
Another aspect of the invention are compounds of Formula I where R6 is methyl.
Some compounds of the invention are N-(4-fluorobenzyl)-2-(2,6-difluorophenyl)-5-hydroxy-l-methyl-6-oxo-l,6- dihydropyrimidine-4-carboxamide;
N-(3 ,4-dichlorobenzyl)-2-(2,6-difluorophenyl)-5-hydroxy- 1 -methyl-6-oxo- 1 ,6- dihydropyrimidine-4-carboxamide;
N-(3,4-difluorobenzyl)-2-(2,6-difluorophenyl)-5-hydroxy-l-methyl-6-oxo-l,6- dihydropyrimidine-4-carboxamide;
N-(4-chlorobenzyl)-2-(2,6-difluorophenyl)-5-hydroxy-l-methyl-6-oxo-l,6- dihydropyrimidine-4-carboxamide;
N-(4-methylbenzyl)-2-(2,6-difluorophenyl)-5-hydroxy-l-methyl-6-oxo-l,6- dihydropyrimidine-4-carboxamide;
N-(3,4-dimethylbenzyl)-2-(2,6-difluorophenyl)-5-hydroxy-l-methyl-6-oxo-l,6- dihydropyrimidine-4-carboxamide;
N-(3-chloro-4-methylbenzyl)-2-(2,6-difluorophenyl)-5-hydroxy- 1 -methyl-6-oxo- 1 ,6- dihydropyrimidine-4-carboxamide;
N-(2,4-difluorobenzyl)-2-(2,6-difluorophenyl)-5-hydroxy- 1 -methyl-6-oxo- 1 ,6- dihydropyrimidine-4-carboxamide;
N-(2-methylbenzyl)-2-(2,6-difluorophenyl)-5-hydroxy-l-methyl-6-oxo-l,6- dihydropyrimidine-4-carboxamide;
N-(4-fluoro-2-(trifluoromethyl)benzyl)-2-(2,6-difluorophenyl)-5-hydroxy-l-methyl- 6-oxo- 1 ,6-dihydroρyrimidine-4-carboxamide;
N-(4-(trifluoromethyl)benzyl)-2-(2,6-difluorophenyl)-5-hydroxy-l-methyl-6-oxo-l,6- dihydropyrimidine-4-carboxamide; N-(benzo[d] [1,3] dioxol-5-ylmethyl)-2-(2,6-difluorophenyl)-5-hydroxy- 1 -methyl-6- oxo- 1 ,6-dihydropyrimidine-4-carboxamide;
2-(2,6-difluorophenyl)-5-hydroxy- 1 -methyl-6-oxo-N-( 1 -phenylethyl)- 1 ,6- dihydropyrimidine-4-carboxamide;
N-(2-(methylthio)benzyl)-2-(2,6-difluorophenyl)-5-hydroxy-l-methyl-6-oxo-l,6- dihydropyrimidine-4-carboxamide;
N-(3-fluoro-4-(trifluoromethyl)benzyl)-2-(2,6-difluorophenyl)-5-hydroxy-l-methyl- 6-oxo- 1 ,6-dihydropyrimidine-4-carboxamide;
N-(3,5-bis(trifluoromethyl)benzyl)-2-(2,6-difluorophenyl)-5-hydroxy-l-methyl-6- oxo- 1 ,6-dihydropyrimidine-4-carboxamide;
2-(2,6-difluorophenyl)-5-hydroxy- 1 -methyl-6-oxo-N-(pyridin-2-ylmethyl)- 1 ,6- dihydropyrimidine-4-carboxamide;
N-benzyl-5-hydroxy- 1 -methyl-6-oxo-2-phenyl- 1 ,6-dihydropyrimidine-4- carboxamide;
N-(4-chlorobenzyl)-5-hydroxy-l-methyl-6-oxo-2-(pyridin-2-yl)-l,6- dihydropyrimidine-4-carboxamide;
N-(3 ,4-dichlorobenzyl)-5-hydroxy- 1 -methyl-6-oxo-2-(pyridin-2-yl)- 1 ,6- dihydropyrimidine-4-carboxamide;
N-(3,4-difluorobenzyl)-5-hydroxy-l-methyl-6-oxo-2-(pyridin-2-yl)-l,6- dihydropyrimidine-4-carboxamide;
N-(4-methylbenzyl)-5-hydroxy- 1 -methyl-6-oxo-2-(pyridin-2-yl)- 1 ,6- dihydropyrimidine-4-carboxamide; N-(3,4-dimethylbenzyl)-5-hydroxy-l-methyl-6-oxo-2-(pyridin-2-yl)-l,6- dihydropyrimidine-4-carboxamide;
N-(3-chloro-4-methylbenzyl)-5-hydroxy-l-methyl-6-oxo-2-(pyridin-2-yl)-l,6- dihydropyrimidine-4-carboxamide;
N-(4-fluorobenzyl)-5-hydroxy-l-methyl-6-oxo-2-(pyridin-2-yl)-l,6- dihydropyrimidine-4-carboxamide;
N-(3,4-dichlorobenzyl)-5-hydroxy-2-(2-methoxyphenyl)-l-methyl-6-oxo-l,6- dihydiOpyrimidine-4-carboxamide;
N-(4-fluorobenzyl)-5-hydroxy-2-(2-methoxyphenyl)-l-methyl-6-oxo-l,6- dihydropyrimidine-4-carboxamide;
N-(3 ,4-dimethylbenzyl)-5 -hydroxy-2-(2-methoxyphenyl)- 1 -methyl-6-oxo- 1 ,6- dihydropyrimidine-4-carboxamide;
N-(3-chloro-4-methylbenzyl)-5-hydroxy-2-(2-methoxyphenyl)- 1 -methyl-6-oxo- 1 ,6- dihydropyrimidine-4-carboxamide;
N-(4-fluorobenzyl)-2-(4-fluoro-2-(methylsulfonyl)phenyl)-5-hydroxy-l-methyl-6- oxo- 1 ,6-dihydropyrimidine-4-carboxamide;
N-(3 ,4-dichlorobenzyl)-2-(4-fluoro-2-(methylsulfonyl)phenyl)-5-hydroxy- 1 -methyl- 6-oxo- 1 ,6-dihydropyrimidine-4-carboxamide;
N-(3 ,4-dimethylbenzyl)-2-(4-fluoro-2-(methylsulf onyl)phenyl)-5-hydroxy- 1 -methyl- 6-oxo- 1 ,6-dihydropyrimidine-4-carboxamide;
N-(4-fluorobenzyl)-2-(2-fluoro-6-(N-methylmethan-3-ylsulfonamido)phenyl)-5- hydroxy- 1 -methyl-6-oxo- 1 ,6-dihydropyrimidine-4-carboxamide; N-(3,4-dichlorobenzyl)-2-(2-fluoro-6-(N-methylmethan-3-ylsulfonamido)phenyl)-5- hydroxy- 1 -methyl-6-oxo- 1 ,6-dihydropyrimidine-4-carboxamide;
N-(3-chloro-4-methylbenzyl)-2-(2-fiuoro-6-(N-methylmethan-3- ylsulfonamido)phenyl)-5-hydroxy-l-methyl-6-oxo-l,6-dihydropyrimidine-4- carboxamide;
N-(4-fluorobenzyl)-2-(2,6-dimethoxyphenyl)-5-hydroxy- l-methyl-6-oxo- 1 ,6- dihydropyrimidine-4-carboxamide;
N-(3,4-dichlorobenzyl)-2-(2,6-dimethoxyphenyl)-5-hydroxy-l-methyl-6-oxo-l,6- dihydropyrimidine-4-carboxamide;
N-(3 ,4-dimethylbenzyl)-2-(2,6-dimethoxyphenyl)-5-hydroxy- 1 -methyl-6-oxo- 1 ,6- dihydropyrimidine-4-carboxamide;
N-(3-chloro-4-methylbenzyl)-2-(2,6-dimethoxyphenyl)-5-hydroxy-l-methyl-6-oxo- l,6-dihydropyrimidine-4-carboxamide;
N-(4-fluorobenzyl)-5-hydroxy-l-methyl-2-(2-(l,l-Dioxo-lλ6-[l,2]thiazinan-2-yl)-6- oxo- 1 ,6-dihydropyrimidine-4-carboxamide;
N-(3,4-dichlorobenzyl)-5-hydroxy-l-methyl-2-(2-(l,l-Dioxo-lλ6-[l,2]thiazinan-2- yl)-6-oxo- 1 ,6-dihydropyrimidine-4-carboxamide;
N-(3,4-dimethylbenzyl)-5-hydroxy- 1 -methyl-2-(2-( 1 , 1 -Dioxo- 1 λ6- [ 1 ,2]thiazinan-2- yl)-6-oxo- 1 ,6-dihydropyrimidine-4-carboxamide;
N-(3-chloro-4-methylbenzyl)-5-hydroxy-l-methyl-2-(2-(l,l-Dioxo-lλ6- [1 ,2]thiazinan-2-yl)-6-oxo- 1 ,6-dihydropyrimidine-4-carboxamide; N-(4-fluorobenzyl)-5-hydroxy-l-methyl-2-(2-morpholinophenyl)-6-oxo-l,6- dihydropyrimidine-4-carboxamide;
N-(3 ,4-dichlorobenzyl)-5-hydroxy- 1 -methyl-2-(2-morpholinophenyl)-6-oxo- 1 ,6- dihydropyrimidine-4-carboxamide;
N-(3,4-dimethylbenzyl)-5-hydroxy-l-methyl-2-(2-morpholinophenyl)-6-oxo-l,6- dihydropyrimidine-4-carboxamide;
N-(3-chloro-4-methylbenzyI)-5-hydroxy-l-methyl-2-(2-morpholinophenyl)-6-oxo- l,6-dihydropyrimidine-4-carboxamide;
N-(4-fluorobenzyl)-2-(2-dimethylsulf amoylphenyl)-5-hydroxy- 1 -methyl-6-oxo- 1 ,6- dihydropyrimidine-4-carboxamide;
N-(3 ,4-dichlorobenzyl)-2-(2-dimethylsulfamoylρhenyl)-5-hydroxy- 1 -methyl-6-oxo- 1 ,6-dihydropyrimidine-4-carboxamide;
N-(3,4-dimethylbenzyl)-2-(2-dimethylsulfamoylphenyl)-5-hydroxy-l-methyl-6-oxo- 1 ,6-dihydropyrimidine-4-carboxamide;
N-(3-chloro-4-methylbenzyl)-2-(2-dimethylsulfamoylphenyl)-5-hydroxy-l-methyl-6- oxo- 1 ,6-dihydropyrimidine-4-carboxamide;
N-(4-fluorobenzyl)-5-hydroxy-2-(3-[2-(l,l-Dioxo-lλ6-[l,2]thiazinan-2-yl)-pyridin-2- yl] -)- 1 -methyl-6-oxo- 1 ,6-dihydropyrimidine-4-carboxamide;
N-(3,4-dichlorobenzyl)-5-hydroxy-2-(3-[2-(l,l-Dioxo-lλ6-[l,2]thiazinan-2-yl)- pyridin-2-yl]-)-l-methyl-6-oxo-l,6-dihydropyrimidine-4-carboxamide;
N-(3,4-dimethylbenzyl)-5-hydroxy-2-(3-[2-(l,l-Dioxo-lλ6-[l,2]thiazinan-2-yl)- pyridin-2-yl]-)-l-methyl-6-oxo-l,6-dihydropyrimidine-4-carboxamide; N-(3-chloro-4-methylbenzyl)-5-hydroxy-2-(3-[2-(l,l-Dioxo-lλ6-[l,2]thiazinan-2-yl)- pyridin-2-yl] -)- 1 -methyl-6-oxo- 1 ,6-dihydropyrimidine-4-carboxamide;
N-(4-fluorobenzyl)-5-hydroxy-2-(6-methoxyρyridin-3-yl)- 1 -methyl-6-oxo- 1 ,6- dihydropyrimidine-4-carboxamide;
N-(3,4-dichlorobenzyl)-5-hydroxy-2-(6-methoxypyridin-3-yl)-l-methyl-6-oxo-l,6- dihydropyrimidine-4-carboxamide;
N-(3,4-dimethylbenzyl)-5-hydroxy-2-(6-methoxypyridin-3-yl)- 1 -methyl-6-oxo- 1 ,6- dihydropyrimidine-4-carboxamide;
N-(4-fluorobenzyl)-5-hydroxy-2-(3 -methoxypyridin-2-yl)- 1 -methyl-6-oxo- 1 ,6- dihydropyrimidine-4-carboxamide;
N-(4-fluorobenzyl)-2-(3 -(dimethylamino)pyridin-2-yl)-5-hydroxy- 1 -methyl-6-oxo- l,6-dihydropyrimidine-4-carboxamide;
N-(3,4-dichlorobenzyl)-2-(3-(dimethylamino)pyridin-2-yl)-5-hydroxy-l-methyl-6- oxo- 1 ,6-dihydropyrimidine-4-carboxamide;
N-(3,4-dimethylbenzyl)-2-(3-(dimethylamino)pyridin-2-yl)-5-hydroxy-l-methyl-6- oxo- 1 ,6-dihydropyrimidine-4-carboxamide;
N-(3-chloro-4-methylbenzyl)-2-(3-(dimethylamino)pyridin-2-yl)-5-hydroxy- 1 - methyl-6-oxo- 1 ,6-dihydropyrimidine-4-carboxamide;
N-(4-fluorobenzyl)-5-hydroxy-l-methyl-6-oxo-2-phenyl-l,6-dihydropyrimidine-4- carboxamide;
N-(3,4-dichlorobenzyl)-5-hydroxy-l-methyl-6-oxo-2-phenyl-l,6-dihydropyrimidine- 4-carboxamide; N-(3,4-dimethylbenzyl)-5-hydroxy-l-methyl-6-oxo-2-phenyl-l,6-dihydropyrimidine- 4-carboxamide;
N-(3-chloro-4-methylbenzyl)-5-hydroxy-l-methyl-6-oxo-2-phenyl-l,6- dihydropyrimidine-4-carboxamide;
N-(4-fluorobenzyl)-5-hydroxy-2-(3-methoxyphenyl)-l-methyl-6-oxo-l,6- dihydropyrimidine-4-carboxamide;
N-(3,4-dichlorobenzyl)-5-hydroxy-2-(3-methoxyphenyl)- l-methyl-6-oxo-l ,6- dihydropyrimidine-4-carboxamide;
N-(3,4-dimethylbenzyl)-5-hydroxy-2-(3-methoxyphenyl)-l-methyl-6-oxo-l,6- dihydropyrimidine-4-carboxamide;
N-(4-fluorobenzyl)-5-hydroxy-2-(4-methoxyphenyl)-l-methyl-6-oxo-l,6- dihydroρyrimidine-4-carboxamide;
N-(3,4-dichlorobenzyl)-5-hydroxy-2-(4-methoxyphenyl)-l-methyl-6-oxo-l,6- dihydropyrimidine-4-carboxamide;
N-(3,4-dimethylbenzyl)-5-hydroxy-2-(4-methoxyphenyl)-l-methyl-6-oxo-l,6- dihydropyrimidine-4-carboxamide;
N-(4-fluorobenzyl)-5-hydroxy-2-[2-(2-hydroxyethylamino)phenyl]-l-methyl-6-oxo- l,6-dihydropyrimidine-4-carboxylate;
N-(3,4-dichlorobenzyl)-5-hydroxy-2-[2-(2-hydroxyethylamino)phenyl]-l-methyl-6- oxo- 1 ,6-dihydropyrimidine-4-carboxylate;
N-(4-fluorobenzyl)-2-(2-(bis(2-hydroxyethyl)amino)phenyl)-5-hydroxy-l-methyl-6- oxo- 1 ,6-dihydropyrimidine-4-carboxamide; 2-(4-((4-fluorobenzyl)carbamoyl)-5-hydroxy-l-methyl-6-oxo-l,6-dihydropyrimidin- 2-yl)benzoic acid;
2-(4-((3 ,4-dichlorobenzyl)carbamoyl)-5-hydroxy- 1 -methyl-6-oxo- 1 ,6- dihydropyrimidin-2-yl)benzoic acid;
N-(4-fluorobenzyl)-2-(2-(dimethylamino)phenyl)-5-hydroxy-l-methyl-6-oxo-l,6- dihydropyrimidine-4-carboxamide;
N-(3,4-dichlorobenzyl)-2-(2-(dimethylamino)phenyl)-5-hydroxy-l-methyl-6-oxo- 1 ,6-dihydropyrimidine-4-carboxamide; ,
N-(3,4-dimethylbenzyl)-2-(2-(dimethylamino)phenyl)-5-hydroxy-l-methyl-6-oxo- l,6-dihydropyrimidine-4-carboxamide;
N-(3-chloro-4-methylbenzyl)-2-(2-(dimethylamino)phenyl)-5-hydroxy-l-methyl-6- oxo- 1 ,6-dihydropyrimidine-4-carboxamide;
N-(4-fluorobenzyl)-2-(furan-2-yl)-5-hydroxy-l-methyl-6-oxo-l,6- dihydropyrimidine-4-carboxamide;
N~(3,4-dichlorobenzyl)-2-(furan-2-yl)-5-hydroxy-l-methyl-6-oxo-l,6- dihydropyrimidine-4-carboxamide;
N-(3,4-dimethylbenzyl)-2-(furan-2-yl)-5-hydroxy-l-methyl-6-oxo-l,6- dihydropyrimidine-4-carboxamide;
N-(3-chloro-4-methylbenzyl)-2-(furan-2-yl)-5-hydroxy-l-methyl-6-oxo-l,6- dihydropyrimidine-4-carboxamide;
N-(4-fluorobenzyl)-5-hydroxy-l-methyl-6-oxo-2-(pyridin-3-yl)-l,6- dihydropyrimidine-4-carboxamide; N-(3,4-dichlorobenzyl)-5-hydroxy-l-methyl-6-oxo-2-(pyridin-3-yl)-l,6- dihydropyrimidine-4-carboxamide;
N-(3,4-dimethylbenzyl)-5-hydroxy-l-methyl-6-oxo-2-(pyridin-3-yl)-l,6- dihydropyrimidine-4-carboxamide;
N-(3-chloro-4-methylbenzyl)-5-hydroxy-l-methyl-6-oxo-2-(pyridin-3-yl)-l,6- dihydropyrimidine-4-carboxamide;
N-(4-fluorobenzyl)-5-hydroxy-l-methyl-6-oxo-2-(pyridin-4-yl)-l,6- dihydropyrimidine-4-carboxamide;
N-(3,4-dichlorobenzyl)-5-hydroxy-l-methyl-6-oxo-2-(pyridin-4-yl)-l,6- dihydroρyrimidine-4-carboxamide;
N-(3,4-dimethylbenzyl)-5-hydroxy-l-methyl-6-oxo-2-(pyridin-4-yl)-l,6- dihydropyrimidine-4-carboxamide;
N-(3-chloro-4-methylbenzyl)-5-hydroxy- 1 -methyl-6-oxo-2-(pyridin-4-yl)- 1 ,6- dihydropyrimidine-4-carboxamide;
N-(4-fluorobenzyl)-2-(l,5-dimethyl-lH-pyrrol-2-yl)-5-hydroxy-l-methyl-6-oxo-l,6- dihydropyrimidine-4-carboxamide;
N-(3,4-dichlorobenzyl)-2-(l,5-dimethyl-lH-pyrrol-2-yl)-5-hydroxy-l-methyl-6-oxo- l,6-dihydropyrimidine-4-carboxamide;
N-(3,4-dimethylbenzyl)-2-(l,5-dimethyl-lH-pyrrol-2-yl)-5-hydroxy-l-methyl-6-oxo- l,6-dihydropyrimidine-4-carboxamide;
N-(3-chloro-4-methylbenzyl)-2-(l,5-dimethyl-lH-pyrrol-2-yl)-5-hydroxy-l-methyl- 6-oxo- 1 ,6-dihydropyrimidine-4-carboxamide; N-(4-fluorobenzyl)-2-(2,4-dimethylimidazo[l,5-a]pyrimidin-8-yl)-5-hydroxy-l- methyl-6-oxo- 1 ,6-dihydropyrimidine-4-carboxamide;
N-(3,4-dichlorobenzyl)-2-(2,4-dimethylimidazo[l,5-a]ρyrimidin-8-yl)-5-hydroxy-l- methyl-6-oxo- 1 ,6-dihydropyrimidine-4-carboxamide;
N-(3,4-methylbenzyl)-2-(2,4-dimethylimidazo[l,5-a]pyrimidin-8-yl)-5-hydroxy-l- methyl-6-oxo- 1 ,6-dihydropyrimidine-4-carboxamide
N-(3-chloro-4-methylbenzyl)-2-(2,4-dimethylimidazo[l,5-a]pyrimidin-8-yl)-5- hydroxy- 1 -methyl-6-oxo- 1 ,6-dihydropyrimidine-4-carboxamide.
2-(4-methylaminocarbonyl-phenyl)-5-hydroxy-l-methyl-6-oxo-l,6-dihydro- pyrimidine-4-carboxylic acid 4-fluorobenzylamide; and
N-(4-fluorobenzyl)-5-hydroxy- 1 -methyl-6-oxo-2-p-tolyl- 1 ,6-dihydropyrimidine-4- carboxamide;
"Alkyl" and "alkoxy" includes straight and branched saturated hydrocarbon substituents. "Aryl" includes carbocyclic and heterocyclic aromatic substituents.
The invention includes all pharmaceutically acceptable salt forms of the compounds. Pharmaceutically acceptable salts are those in which the counter ions do not contribute significantly to the physiological activity or toxicity of the compounds and as such function as pharmacological equivalents. These salts can be made according to common organic techniques employing commercially available reagents. Some anionic salt forms include acetate, acistrate, besylate, bromide, chloride, citrate, fumarate, glucouronate, hydrobromide, hydrochloride, hydroiodide, iodide, lactate, maleate, mesylate, nitrate, pamoate, phosphate, succinate, sulfate, tartrate, tosylate, and xinofoate. Some cationic salt forms include ammonium, aluminum, benzathine, bismuth, calcium, choline, diethylamine, diethanolamine, lithium, magnesium, meglumine, 4-phenylcyclohexylamine, piperazine, potassium, sodium, tromethamine, and zinc. The invention also includes all solvated forms of the compounds, particularly hydrates. Solvates do not contribute significantly to the physiological activity or toxicity of the compounds and as such function as pharmacological equivalents. Solvates may form in stoichiometric amounts or may form from adventitious solvent or a combination of both. One type of solvate is hydrate, and some hydrated forms include monohydrate, hemihydrate, and dihydrate.
Certain compounds of Formula I may contain one or more chiral centers and exist in different optically active forms. When compounds of Formula I contain one chiral center, the compounds exist in two enantiomeric forms. The present invention includes both enantiomers and mixtures of enantiomers such as racemic mixtures. The enantiomers may be resolved by methods known in the art. Alternatively, specific enantiomers may be synthesized by asymmetric synthesis using reactions known in the art.
The compounds of this invention can also exist as tautomers, as shown below; therefore the present invention also includes all tautomeric forms.
Figure imgf000017_0001
Svnthesitic Methods
General methods useful for the synthesis of the compounds of this invention are shown below. Related compounds can be made by reactions known in the art.
Synthetic methods for the preparation of pyrimidines similar to those described in the current invention have been published (Gardelli, C. et al PCT Appl. WO 02/06246). The compounds of the present invention can be synthesized according to Scheme I. In Scheme I, aryl nitrile 1-1 is reacted with N-hydroxylamine 1-2. The intermediate 1-3 generated from this reaction can be isolated but more often is reacted in one pot with dialkyl acetylenedicaboxylate 1-4 to yield the diesters l-5a or I-5b. The diesters l-5a or I-5b were converted to pyrimidine carboxylate 1-6 by heating at or above 120 °C in an appropriate solvent. The ester 1-6 is condensed with amine 1-7 to give the amide 1-8. The amide coupling reaction can be carried out under a variety of conditions such as those disclosed in Jerry March, Advanced Organic Chemistry, 3rd edition, John Wiley & Sons, 1985.
Scheme I
Figure imgf000018_0001
Figure imgf000018_0002
I-6 I-7 I-8
In Scheme II, an alternative pathway is shown in which the R6 group is introduced at a later stage of the synthesis. Synthetic methods for the preparation of pyrimidines similar to those described in the current invention have been published (Sunderland, J. S.; et al. Inorg. Chem. (2001), 40, 6756-6756). The compounds of the present invention can be synthesized according to Scheme II. In Scheme II, an oxalic acid diester II-l is condensed with glycolate II-2 using sodium hydride or a similar base. The intermediate II-3 generated from this reaction can be isolated but more often is reacted in one pot with an appropriately substituted amidine II-4 to yield the pyrimidinone heterocycle II-5. Intermediate II-5 is coupled with amine II- 6. Alternatively, the pyrimidinone II-5 is alkylated with a suitable electrophile under basic conditions. Then intermediate II-9 is coupled with amine II-6. The amides, II- 8 and 11-10 are then treated under conditions appropriate for cleaving the protecting group P. For alkyl groups, where P is alkyl, this can be accomplished by BBr or other conditions known in the art. Alternatively, when P is a benzylic or substituted benzylic group the ether can be cleaved under reductive conditions, oxidative conditions or acidic conditions. Protecting groups, R, useful for the synthesis of compounds such as 1-9 can be found in Greene, T. W. and Wutz, P. G. M. Protective Groups in Organic Synthesis, Second Edition, 1991, John Wiley and Sons, New York.
Scheme π
Figure imgf000019_0001
II-5 11-7
Figure imgf000019_0002
II-5 11-9 II-6
Figure imgf000019_0003
Pharmaceutical Compositions and Methods of Treatment
The compounds of this invention inhibit HIV integrase. HIV integrase inhibitors belonging to a class of diketo acid compounds prevented viral integration and inhibited HIV-1 replication in cells (Hazuda et al. Science 2000, 287, 646).
Recently, HIV integrase inhibitors have been accepted into clinical trials for treating AIDS and HIV infection (Neamati Expert. Opin. Ther. Patents 2002, 12, 709, Pais and Burke Drugs Fut. 2002, 27, 1101).
Accordingly, another aspect of the invention is a method for treating HIV infection in a human patient comprising administering a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt or solvate thereof, with a pharmaceutically acceptable carrier.
Another aspect of the invention is a method for treating HIV infection in a human patient comprising administering a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt or solvate thereof, with a therapeutically effective amount of at least one other agent used for treatment of AIDS or HIV infection. Some suitable agents are nucleoside HIV reverse transcriptase inhibitors, non-nucleoside HIV reverse transcriptase inhibitors, HIV protease inhibitors, HIV fusion inhibitors, HIV attachment inhibitors, CCR5 inhibitors, CXCR4 inhibitors, HIV budding or maturation inhibitors, and HIV integrase inhibitors.
Another aspect of the invention is a composition for treating HIV infection in a human patient comprising administering a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt or solvate thereof, with a pharmaceutically acceptable carrier. "Combination," "coadministration," "concurrent," and similar terms referring to the administration of compounds of Formula I with at least one anti-HIV agent mean that the components are part of a combination antiretroviral therapy or highly active antiretroviral therapy (HAART) as understood by practitioners in the field of AIDS and HIV infection.
"Therapeutically effective" means the amount of agent required to provide a meaningful patient benefit as understood by practitioners in the field of AIDS and HIV infection. In general, the goals of treatment are suppression of viral load, restoration and preservation of immunologic function, improved quality of life, and reduction of HIV-related morbidity and mortality.
"Patient" means a person infected with the HIV virus and suitable for therapy as understood by practitioners in the field of AIDS and HIV infection.
"Treatment," "therapy," "regimen," "HIV infection," "ARC," "AIDS" and related terms are used as understood by practitioners in the field of AIDS and HIV infection.
The compounds of this invention are generally given as pharmaceutical compositions comprised of a therapeutically effective amount of a compound of Formula I or its pharmaceutically acceptable salt and a pharmaceutically acceptable carrier and may contain conventional exipients. A therapeutically effective amount is that which is needed to provide a meaningful patient benefit. Pharmaceutically acceptable carriers are those conventionally known carriers having acceptable safety profiles. Compositions encompass all common solid and liquid forms including capsules, tablets, losenges, and powders as well as liquid suspensions, syrups, elixers, and solutions. Compositions are made using common formulation techniques, and conventional excipients (such as binding and wetting agents) and vehicles (such as water and alcohols) are generally used for compositions.
Solid compositions are normally formulated in dosage units and compositions providing from about 1 to 1000 mg of the active ingredient per dose are preferred. Some examples of dosages are 1 mg, 10, mg, 100, mg, 250 mg, 500 mg, and 1000 mg. Generally, other antiretroviral agents will be present in a unit range similar to agents of that class used clinically. Typically, this 0.25-1000 mg/unit.
Liquid compositions are usually in dosage unit ranges. Generally, the liquid composition will be in a unit dosage range of 1-100 mg/mL. Some examples of dosages are 1 mg/mL, 10 mg/mL, 25, mg/mL, 50 mg/mL, and 100 mg/mL. Generally, other antiretroviral agents will be present in a unit range similar to agents of that class used clinically. Typically, this is 1-100 mg/mL.
The invention encompasses all conventional modes of administration; oral and parenteral methods are preferred. Generally, the dosing regimen will be similar to other antiretroviral agents used clinically. Typically, the daily dose will be 1-100 mg/kg body weight daily. Generally, more compound is required orally and less parenterally. The specific dosing regime, however, will be determined by a physician using sound medical judgement.
The invention also encompasses methods where the compound is given in combination therapy. That is, the compound can be used in conjunction with, but separately from, other agents useftil in treating AIDS and HIV infection. Some of these agents include HIV attachment inhibitors, CCR5 inhibitors, CXCR4 inhibitors, HIV cell fusion inhibitors, HIV integrase inhibitors, HIV nucleoside reverse transcriptase inhibitors, HIV non-nucleoside reverse transcriptase inhibitors, HIV protease inhibitors, budding and maturation inhibitors, immunomodulators, and anti- infectives. In these combination methods, Compound 1 will generally be given in a daily dose of 1-100 mg/kg body weight daily in conjunction with other agents. The other agents generally will be given in the amounts used therapeutically. The specific dosing regime, however, will be determined by a physician using sound medical judgement. Table 1 lists some agents useful in treating AIDS and HIV infection which are suitable for this invention.
Table 1. ANTΓVIRALS
Figure imgf000023_0001
Figure imgf000024_0001
Figure imgf000025_0001
Figure imgf000026_0001
IMMUNOMODULATORS
Figure imgf000026_0002
Figure imgf000027_0001
Figure imgf000028_0001
ANTI-ΓNFECTIVES
Figure imgf000028_0002
DESCRIPTION OF SPECIFIC EMBODIMENTS
In the following experimental procedures, all temperatures are understood to in Centigrade (C) when not specified. The nuclear magnetic resonance (NMR) spectral characteristics refer to chemical shifts (δ) expressed in parts per million (ppm) versus tetramethylsilane (TMS) as reference standard. The relative area reported for the various shifts in the proton NMR spectral data corresponds to the number of hydrogen atoms of a particular functional type in the molecule. The nature of the shifts as to multiplicity is reported as broad singlet (bs or br s), broad doublet (bd or br d), broad triplet (bt or br t), broad quartet (bq or br q), singlet (s), multiplet (m), doublet (d), quartet (q), triplet (t), doublet of doublet (dd), doublet of triplet (dt), and doublet of quartet (dq). The solvents employed for taking NMR spectra are acetone-d6 (deuterated acetone), DMSO-d6 (perdeuterodimethylsulfoxide), D2O (deuterated water), CDC13 (deuterochloroform) and other conventional deuterated solvents.
The abbreviations used herein are conventional abbreviations widely employed in the art. Some of which are: calcd (calculated); DMSO (dimethylsulf oxide); EtOAc (ethyl acetate); HPLC (high-pressure liquid chromatography); LC/MS (liquid chromatography, mass spectroscopy); LDA (lithium diisopropyl amide); LiHMDS (lithium bis(trimethylsilyl)amide); SiO (silica gel); THF (tetrahydrofuran), TFA (trifluoroacetic acid), Me (methyl), Et (ethyl), Ph (phenyl), tBuOK (potassium tert-butoxide), NaOMe (sodium methoxide), NaOEt (sodium ethoxide), Boc (tert-butoxycarbonyl), and DEAD (diethylazo dicarboxylate).
Intermediate 1
Figure imgf000029_0001
2,6-Difluoro-N-hydroxy-N-methyl-benzamidine. To a stirred solution of 2,6- difluorobenzonitrile (5.565 g, 40 mmol) and N-methylhydroxylamine hydrochloride (10 g, 120 mmol) in 4:1 water/ethanol (100 mL) was added sodium carbonate (8.5 g, 80 mmol) in small portions and the resulting mixture stirred at 100 °C for 2 h. The mixture was then cooled, concentrated and the resulting residue suspended in hot MeOH/CHCl3 (1:9, 200 mL). The insoluble solids were removed by filtration and concentration of the filtrate gave the desired product as an off-white solid (7.50 g, 100% yield). 1HNMR (500 MHz, DMSO-d6) δ: 7.69-7.63 (1H, m), 7.29 (2H, t, J = 8.24 Hz), 6.90 (2H, s), 3.15 (3H, s). LCMS calcd for C8H9F2N2O (M + H): 187.07; found: 187.12.
Intermediate 2
Figure imgf000030_0001
3-(2,6-Difluoro-phenyl)-5-ethoxycarbonylmethyl-2-methyl-2,5-dihydro- [l,2,4]oxadiazole-5-carboxylic acid ethyl ester. A solution of diethyl acetylenedicarboxylate (1.60 mL, 10 mmol) and,2,6-difluoro-N-hydroxy-N-methyl- benzamidine (1.862g, 10 mmol) in ethyl alcohol (95% yield) was heated at 80 °C for 1 h. The reaction mixture was then cooled, concentrated and purified on silica gel column eluting with 1:3, 3:7 and 2:3 ethyl acetate/hexanes to give the title compound as a yellow oil (2.691 g, 76% yield). 1HNMR (500 MHz, CDC13) δ: 7.48-7.42 (1H, m), 6.99 (2H, t, J = 8.20 Hz), 4.37-4.24 (2H, m), 4.18 (2H, q, J = 7.02 Hz), 3.40 (1H, d, J 16.48 Hz), 3.11 (1H, d, J =16.48 Hz), 3.08 (3H, s), 1.32 (3H, t, J 7.02 Hz), 1.26 (3H, t, J = 7.02 Hz). LCMS calcd for C16H19F2N2O5 (M + H): 357.13; found: 357.38.'
Intermediate 3
Figure imgf000030_0002
2-(2,6-Difluoro-phenyl)-5-hydroxy-l-methyl-6-oxo-l,6-dihydro-pyrimidine-4- carboxylic acid ethyl ester. A solution of 3-(2,6-difluoro-phenyl)-5- ethoxycarbonylmethyl-2-methyl-2,5-dihydro-[l,2,4]oxadiazole-5-carboxylic acid ethyl ester (2.68 g,7.52 mmol) in xylenes (50 mL) was heated at reflux for 1.5 h and cooled to room temperature. The precipitate was filtered and dried to give the title compound as an off-white solid (1.4 g, 60% yield). 1HNMR (500 MHz, CDC13) δ: 10.96 (IH, s), 7.50-7.45 (IH, m), 7.04 (2H, t, J = 7.33 Hz), 4.51 (2H, q, J = 7.02 Hz), 3.41 (3H, s), 1.41 (3H, t, J = 7.02 Hz). HRMS (ESI) calcd for C14H13F2N2O4 (M + H): 311.0844; found: 311.0845.
EXAMPLE 1
Figure imgf000031_0001
N-(4-fluorobenzyl)-2-(2,6-difluorophenyl)-5-hydroxy-l-methyl-6-oxo-l,6- dihydropyrimidine-4-carboxamide. A mixture of ester 2-(2,6-difluoro-phenyl)-5- hydroxy-l-methyl-6-oxo-l,6-dihydro-pyrimidine-4-carboxylic acid ethyl ester (91 mg, 0.2933 mmol) and 4-fluorobenzylamine (184 mg, 1.5 mmol) in toluene (2 mL) was heated at reflux for 3.5 h. The reaction mixture was then, cooled, concentrated and purified by reverse phase preparative HPLC (C 18, methanol/H2O-0.1 %TFA, gradient elution). The fractions containing the product were combined and concentrated to give the title compound as an off-white solid (55 mg, 48% yield). 1HNMR (500 MHz, CDC13) δ: 12.30 (IH, s), 7.80 (IH, s), 7.49 (IH, t, J = 6.5 Hz), 7.34-7.22 (2H, m), 7.06-7.00 (4H, m), 4.55 (2H, d, J = 5.5 Hz), 3.40 (3H, s). HRMS (ESI) calcd for C19Hι5F3N3O3 (M + H): 390.1066; found: 390.1076. EXAMPLE 2
Figure imgf000032_0001
N-(3 ,4-dichlorobenzyl)-2-(2,6-difluorophenyl)-5-hydroxy-l -methyl-6-oxo-l ,6- dihydropyrimidine-4-carboxamide. A mixture of ester 2-(2,6-difluoro-phenyl)-5- hydroxy-l-methyl-6-oxo-l,6-dihydro-pyrimidine-4-carboxylic acid ethyl ester (31 mg, 0.1 mmol) and 3,4-dichlorobenzylamine (88 mg, 0.5 mmol) in DMF (1 mL) was heated between 120-130 °C for 3 h. The reaction mixture was then cooled and purified by preparative HPLC (C18, methanol H2O-0.1%TFA, gradient elution). The fractions containing the product were combined and concentrated to give the title compound as an off-white solid (41.2 mg, 94% yield). 1HNMR (500 MHz, CDC13) δ: 12.15 (IH, s), 7.84 (IH, t, J = 5.5 Hz), 7.53-7.47 (IH, m), 7.41-7.38 (2H, m), 7.16 (IH, dd, J = 8.24, 2.13 Hz), 7.06 (IH, dd, J = 8.54, 7.32 Hz), 4.53 (6.41 Hz), 3.41 (3H, s). HRMS (ESI) calcd for C19H14Cl2F3N3O3 (M + H): 340.0380; found:
340.0383. Anal, calcd for C19H13Cl2F3N3O3: C 51.83, H 2.97, N 9.54, CI 16.10, F 8.63; found: C 51.48, H 2.63, N 9.43, CI 15.71, F 8.52.
EXAMPLE 3
Figure imgf000032_0002
N-(3,4-difluorobenzyl)-2-(2,6-difluorophenyl)-5-hydroxy-l-methyl-6-oxo-l,6- dihydropyrimidine-4-carboxamϊde. Prepared according to the procedure described for example 2 from 2-(2,6-difluoro-phenyl)-5-hydroxy- 1 -methyl-6-oxo- 1 ,6-dihydro- pyrimidine-4-carboxylic acid ethyl ester (31 mg, 0.1 mmol) and 3,4- difluorobenzylamine (72 mg, 0.5 mmol). The title product was obtained as an off- white solid (32.7 mg, 80% yield). XHNMR (500 MHz, CDC13) δ: 12.18 (IH, s), 7.83 (IH, br s), 7.53-7.47 (IH, m), 7.15-7.02 (5H, m), 4.53 (2H, d, J = 6.41 Hz), 3.41 (3H, s). HRMS (ESI) calcd for C19H14F4N3O3 (M + H): 408.0971 ; found: 408.0969.
EXAMPLE 4
Figure imgf000033_0001
N-(4-chlorobenzyl)-2-(2,6-difluorophenyl)-5-hydroxy-l-methyl-6-oxo-l,6- dihydropyrimidine-4-carboxamide. Prepared according to the procedure described for example 2 from 2-(2,6-difluoro-phenyl)-5-hydroxy-l-methyl-6-oxo-l,6-dihydro- pyrimidine-4-carboxylic acid ethyl ester (31 mg, 0.1 mmol) and 4-chlorobenzylamine (71 mg, 0.5 mmol). The title product was obtained as an off-white solid (32.3 mg, 80% yield). 1HNMR (500 MHz, CDC13) δ: 12.25 (IH, s), 7.80 (IH, br s), 7.52-7.46 (IH, m), 7.81 (2H, d, J = 8.55 Hz), 7.25 (2H, d, J = 8.24 Hz), 7.05 (2H, dd, J = 8.54, 7.32 Hz), 4.55 (2H, d, J = 6.10 Hz), 3.41 (3H, s). HRMS (ESI) calcd for C19H15ClF2N3O3 (M + H): 406.0770; found: 406.0775.
EXAMPLE 5
Figure imgf000033_0002
N-(4-methylbenzyl)-2-(2, 6-difluorophenyl)-5-hydroxy-l -methyl-6-oxo-l, 6- dihydropyrimidine-4-carboxamide. Prepared according to the procedure described for example 2 from 2-(2,6-difluoro-ρhenyl)-5-hydroxy-l-methyl-6-oxo-l,6-dihydro- pyrimidine-4-carboxylic acid ethyl ester (31 mg, 0.1 mmol) and 4- methylbenzylamine (61 mg, 0.5 mmol). The title product was obtained as an off- white solid (32 mg, 83% yield). 1HNMR (500 MHz, CDC13) δ: 12.39 (IH, s), 7.55 (IH, br s), 7.51-7.45 (IH, m), 7.20 (2H, d, J = 7.94 Hz), 7.14 (2H, d, J = 7.63 Hz), 7.03 (2H, d, J = 8.55, 7.33 Hz), 4.54 (2H, d, J = 6.10 Hz), 3.40 (3H, s), 2.32 (3H, s). HRMS (ESI) calcd for C20H18F2N3O3 (M + H): 386.1316; found: 386.1313.
EXAMPLE 6
Figure imgf000034_0001
N-(3,4-diιnethylbenzyl)-2-(2,6-difluorophenyl)-5-hydroxy-l-methyl-6-oxo-l,6- dihydropyrimidine-4-carboxamide. Prepared according to the procedure described for example 2 from 2-(2,6-difluoro-phenyl)-5-hydroxy-l-methyl-6-oxo-l,6-dihydro- pyrimidine-4-carboxylic acid ethyl ester (31 mg, 0.1 mmol) and 3,4- dimethylbenzylamine (68 mg, 0.5 mmol). The title product was obtained as an off- white solid (32.7 mg, 82% yield). ]HNMR (500 MHz, CDC13) δ: 12.41 (IH, s), 7.74 (IH, br s), 7.51-7.45 (IH, m), 7.10-7.02 (5H, m), 4.51 (2H, d, J = 6.10 Hz), 3.40 (3H, s), 2.24 (3H,s), 2.23(3H, s). HRMS (ESI) calcd for C21H20F2N3O3 (M + H): 400.1473; found: 400.01464. EXAMPLE 7
Figure imgf000035_0001
N-(3-chloro-4-methylbenzyl)-2-(2, 6-difluorophenyl)-5-hydroxy-l-methyl-6- oxo-l,6-dihydropyrimidine-4-carboxamide. Prepared according to the procedure described for example 2 from 2-(2,6-difluoro-phenyl)-5-hydroxy-l-methyl-6-oxo- l,6-dihydro-pyrimidine-4-carboxylic acid ethyl ester (31 mg, 0.1 mmol) and 3- chloro-4-methylbenzylamine (78 mg, 0.5 mmol). The title product was obtained as an off-white solid (35.3 mg, 84% yield). 1HNMR (500 MHz, CDC13) δ: 12.27 (IH, s), 7.78 (IH, br s), 7.53-7.45 (IH, m), 7.31-7.03 (5H, m), 4.52 (2H, d, J = 3.96 Hz), 3.41 (3H, s), 2.33 (3H, s). HRMS (ESI) calcd for C20Hι7ClF2N3O3 (M + H): 420.0926; found: 420.0929.
EXAMPLE 8
Figure imgf000035_0002
N-(2,4-difluorobenzyl)-2-(2, 6-difluorophenyl)-5-hydroxy-l -methyl-6-oxo-l ,6- dihydropyrimidine-4-carboxamide. Prepared according to the procedure described for example 2 from 2-(2,6-difluoro-phenyl)-5-hydroxy-l-methyl-6-oxo-l,6-dihydro- pyrimidine-4-carboxylic acid ethyl ester (31 mg, 0.1 mmol) and 2,4- difluorobenzylamine (72 mg, 0.5 mmol). The title product was obtained as an off- white solid (36.2 mg, 89% yield). *HNMR (500 MHz, CDC13) δ: 12.13 (IH, s), 7.87 (IH, br s), 7.06 (2H, dd, J = 8.54, 7.33 Hz), 6.86-6.81 (2H, m), 6.75-6.69 (2H, m), 4.56 (2H, d, J = 6.41 Hz), 3.42 (3H, s). HRMS (ESI) calcd for C19Hι2F4N3O3 (M H): 406.0815; found: 406.0812.
EXAMPLE 9
Figure imgf000036_0001
N-(2-methylbenzyl)-2-(2, 6-difluorophenyl)-5-hydroxy-l -methyl-6-oxo-l, 6- dihydropyrimidine-4-carboxamide. Prepared according to the procedure described for example 2 from 2-(2,6-difluoro-phenyl)-5-hydroxy-l-methyl-6-oxo-l,6-dihydro- pyrimidine-4-carboxylic acid ethyl ester (31 mg, 0.1 mmol) and 2- methylbenzylamine (61 mg, 0.5 mmol). The title product was obtained as an off- white solid (34.1 mg, 88.6% yield). 1HNMR (500 MHz, CDC13) δ: 12.38 (IH, s), 7.63 (IH, br s), 7.51-7.45 (IH, m), 7.26-7.16 (4H, m), 7.04 (2H, dd, J = 8.54, 7.32 Hz), 4.59 (2H, d, J = 5.79 Hz), 3.40 (3H, s), 2.33 (3H, s). HRMS (ESI) calcd for C20H16F2N3O3 (M - H): 384.1160; found: 384.1171.
EXAMPLE 10
Figure imgf000036_0002
N-(4-fluoro-2-(trifluoromethyl)benzyl)-2-(2,6-difluorophenyl)-5-hydroxy-l- methyl-6-oxo-l,6-dihydropyrimidine-4-carboxamide. Prepared according to the procedure described for example 2 from 2-(2,6-difluoro-phenyl)-5-hydroxy-l- methyl-6-oxo-l,6-dihydro-pyrimidine-4-carboxylic acid ethyl ester (31 mg, 0.1 mmol) and 2-trifluoromethyl-4-fluorobenzylamine (97 mg, 0.5 mmol). The title product was obtained as an off-white solid (25.7 mg, 56% yield). 1HNMR (500 MHz, CDC13) δ: 12.07 (IH, s), 7.92 (IH, t, J = 5.34), 7.53-7.47 (IH, m), 7.36 (IH, s), 7.24 (2H, d, J = 8.24 Hz), 7.06 (2H, dd, J = 8.54, 7.33 Hz), 4.63 (2H, d, J = 6.41 Hz), 3.42 (3H, s). HRMS (ESI) calcd for C 0H12F6N3O3 (M - H): 456.0783; found: 456.0793.
EXAMPLE 11
Figure imgf000037_0001
N-(4-(trifluoromethyl)benzyl)-2-(2,6-difluorophenyl)-5-hydroxy-l-methyl-6- oxo-l,6-dihydropyrimidine-4-carboxamide. Prepared according to the procedure described for example 2 from 2-(2,6-difluoro-phenyl)-5-hydroxy-l-methyl-6-oxo- l,6-dihydro-pyrimidine-4-carboxylic acid ethyl ester (31 mg, 0.1 mmol) and 4- trifluoromethylbenzylamine (88 mg, 0.5 mmol). The title product was obtained as an off-white solid (38.6 mg, 88% yield). 1HNMR (500 MHz, CDC13) δ: 12.18 (IH, s), 7.88 (IH, t, J = 4.58), 7.60 (2H, d, J = 8.24 Hz), 7.53-7.47 (IH, m), 7.43 (2H, d J = 8.24 Hz), 7.05 (2H, dd, J = 8.24, 7.32 Hz), 4.65 (2H, d, J = 6.41 Hz), 3.42 (3H, s). HRMS (ESI) calcd for C20H13F5N3O3 (M - H): 438.0877; found: 438.0878.
EXAMPLE 12
Figure imgf000037_0002
N-(benzo[d][l,3]dioxol-5-ylmethyl)-2-(2, 6-difluorophenyl)-5-hydroxy-l - methyl-6-oxo-l,6-dihydropyrimidine-4-carboxamide. Prepared according to the procedure described for example 2 from 2-(2,6-difluoro-phenyl)-5-hydroxy-l- methyl-6-oxo-l,6-dihydro-pyrimidine-4-carboxylic acid ethyl ester (31 mg, 0.1 mmol) and piperonylamine (76 mg, 0.5 mmol). The title product was obtained as an off-white solid (18.6 mg, 45% yield). 1HNMR (500 MHz, CDC13) δ: 12.35 (IH, s), 7.74 (IH, br s), 7.52-7.46 (IH, m), 7.04 (2H, dd, J = 8.24, 7.33 Hz), 6.80 (IH, s), 6.78-6.74 (2H, m), 5.93 (2H, s), 4.48 (2H, d, J = 6.10 Hz), 3.40 (3H, s). HRMS (ESI) calcd for C20H14F2N3O5 (M - H): 414.0902; found: 414.0900.
EXAMPLE 13
Figure imgf000038_0001
2-(2, 6-difluorophenyl)-5-hydroxy-l -methyl-6-oxo-N-(l -phenylethyl)-!, 6- dihydropyrimidine-4-carboxamide. Prepared according to the procedure described for example 2 from 2-(2,6-difluoro-phenyl)-5-hydrόxy-l-methyl-6-oxo-l,6-dihydro- ρyrimidine-4-carboxylic acid ethyl ester (31 mg, 0.1 mmol) and α- methylbenzylamine (61 mg, 0.5 mmol). The title product was obtained as an off- white solid (24.6 mg, 64% yield). 1HNMR (500 MHz, CDC13) δ: 12.39 (IH, s), 7.71 (IH, d, J = 7.94 Hz), 7.54-7.48 (IH, m), 7.36-7.25 (5H, m), 7.06 (2H, dd, J = 14.65, 8.54 Hz), 5.22 (IH, qt, J = 7.02 Hz), 3.40 (3H, s), 1.58 (3H, d, J = 7.02 Hz). HRMS (ESI) calcd for C20H16F2N3O3 (M - H): 384.1160; found: 384.1161. EXAMPLE 14
Figure imgf000039_0001
N-(2-(methylthio)benzyl)-2-(2,6-difluorophenyl)-5-hydroxy-l-nιβthyl-6-oxo- l,6-dihydropyrimidine-4-carboxamide. Prepared according to the procedure described for example 2 from 2-(2,6-difluoro-phenyl)-5-hydroxy-l-methyl-6-oxo- l,6-dihydro-pyrimidine-4-carboxylic acid ethyl ester (31 mg, 0.1 mmol) and 2- methylthiobenzylamine (77 mg, 0.5 mmol). The title product was obtained as an off- white solid (34.2 mg, 82% yield). 1HNMR (500 MHz, CDC13) δ: 12.37 (IH, s), 7.92 (IH, br s), 7.55-7.44 (IH, m), 7.33-7.25 (2H, m), 7.17-7.14 (IH, m), 7.04 (2H, dd, J = 8.24, 7.32 Hz), 4.67 (2H, d, J = 6.10 Hz), 3.40 (3H, s), 2.44 (3H, s). HRMS (ESI) calcd for C2oHι6F2N3O3S (M - H): 416.0880; found: 416.0879.
EXAMPLE 15
Figure imgf000039_0002
N-(3-fluoro-4-(trifluoromethyl)benzyl)-2-(2,6-difluorophenyl)-5-hydroxy-l- methyl-6-oxo-l,6-dihydropyrimidine-4-carboxamide. Prepared according to the procedure described for example 2 from 2-(2,6-difluoro-phenyl)-5-hydroxy-l- methyl-6-oxo-l,6-dihydro-pyrimidine-4-carboxylic acid ethyl ester (31 mg, 0.1 mmol) and 3-fluoro-4-trifluoromethylbenzylamine (97 mg, 0.5 mmol). The title product was obtained as an off-white solid (44.7 mg, 98% yield). 1HNMR (500 MHz, CDC13) δ: 12.13 (IH, s), 7.88 (IH, br s), 7.57-7.47 (4H, m), 7.06 (2H, dd, J = 8.54, 7.32 Hz), 4.59 (2H, d, J = 6.41 Hz), 3.41 (3H, s). HRMS (ESI) calcd for C20H12F6N3O3 (M - H): 456.0782; found: 456.0788.
EXAMPLE 16
Figure imgf000040_0001
N-(3, 5-bis(trifluoromethyl)benzyl)-2-(2, 6-difluorophenyl)-5-hydroxy-l - methyl-6-oxo-l,6-dihydropyrimidine-4-carboxamide. Prepared according to the procedure described for example 2 from 2-(2,6-difluoro-phenyl)-5-hydroxy-l- methyl-6-oxo-l,6-dihydro-pyrimidine-4-carboxylic acid ethyl ester (31 mg, 0.1 mmol) and 2,5-ditrifluoromethyl-benzylamine (98 mg, 0.5 mmol). The title product was obtained as an off-white solid (43.6 mg, 86% yield). 1HNMR (500 MHz, CDC13) δ: 12.01 (IH, s), 7.98 (IH, t, J = 5.5 Hz), 7.80 (IH, s), 7.77 (2H, s), 7.54-7.47 (IH, m), 7.06 (2H, dd, J = 8.54, 7.32 Hz), 4.70 (2H, d, J = 6.41 Hz), 3.42 (3H, s). HRMS (ESI) calcd for C2ιH12F8N3O3 (M - H): 506.0751; found: 506.0762.
EXAMPLE 17
Figure imgf000040_0002
2-(2, 6-difluorophenyl)-5-hydroxy-l -methyl-6-oxo-N-(pyridin-2-ylmethyl)-l, 6- dihydropyrirnidine-4-carboxamide. Prepared according to the procedure described for example 2 from 2-(2,6-difluoro-ρhenyl)-5-hydroxy-l-methyl-6-oxo-l,6-dihydro- pyrimidine-4-carboxylic acid ethyl ester (31 mg, 0.1 mmol) and 2- (aminomethyl)pyridine (54 mg, 0.5 mmol). The title product was obtained as a TFA salt, white solid (11 mg, 23% yield). 1HNMR (500 MHz, CDC13) δ: 12.00-10.00 (2H, br s), 8.73 (IH, t, J = 5.49 Hz), 8.67 (IH, d, J = 4.88 Hz), 8.19 (IH, t, J = 7.78 Hz), 7.87 (IH, d, J = 7.94 Hz), 7.66 (IH, t, J = 6.56 Hz), 7.53-7.47 (IH, m), 7.05 (2H, dd, J = 8.54, 7.32 Hz), 4.97 (2H, d, J = 6.41 Hz), 3.40 (3H, s). HRMS (ESI) calcd for C18H15F2N4O3 (M + H): 373.1112; found: 373.1119.
EXAMPLE 18
Figure imgf000041_0001
N-benzyl-5-hydroxy-l-methyl-6-oxo-2-phenyl-l,6-dihydropyrimidine-4- carboxamide. Prepared according to the procedure described for example 2 from 2- (2,6-difluoro-phenyl)-5-hydroxy- 1 -methyl-6-oxo- 1 ,6-dihydro-pyrimidine-4- carboxylic acid ethyl ester (62 mg, 0.2 mmol) and benzylamine (64 mg, 0.6 mmol). The title product was obtained as a white solid (45 mg, 61% yield). 1HNMR (500 MHz, CDC13) δ:). 12.38 (IH, s), 7.82 (IH, br s), 7.53-7.47 (IH, m), 7.37-7.29 (5H, m), 7.25-7.26 (2H, m), 7.07-7.04 (2H, m), 4.60 (2H, d, J = 5.8 Hz), 3.42 (3H, s). HRMS calcd for C19Hι6F2N3O3 (M + H): 372.1160; found: 372.1156. Anal. Cald for Cι9H15F2N3O3: C, 61.45, H, 4.07; N, 11.31; found: C, 61.12, H, 3.77; N, 11.06
Intermediate 4
Figure imgf000041_0002
5-Methoxycarbonylmethyl-2-methyl-3-pyridin-2-yl-2,5-dihydro- [1 ,2,4]oxadiazole-5-carboxylic acid ethyl ester. To a stirred solution of 2- cyanopyridine (2.08 g, 20 mmol) and N-methylhydroxylamine hydrochloride (1.66 g, 20 mmol) in 1:1 water/ethanol (30 mL) was added sodium carbonate (1.04 g, 10 mmol) in small portions. LCMS analysis after 5 min indicated that the reaction was complete. To this was added diethyl acetylenedicarboxylate (3.2 mL, 20 mmol) and the reaction mixture stirred for additional 20 min at room temperature. LCMS analysis of the resulting dark-green reaction showed that the reaction was complete. The reaction mixture was taken up into ethyl acetate (200 mL) and washed successively with water (2 X 25 mL) and brine (25 mL)., and the organic layer dried (Na2SO4), filtered and concentrated to give brown oil which was passed through a plug of silica gel (1:1 hexanes/ethyl acetate). The filtrate was concentrated to give the title compound as a yellow oil (6.87 g). LCMS calcd for C15H20N3O5 (M + H): 322.14 ; found: 322.08.
Intermediate 5
Figure imgf000042_0001
5-Hydroxy-l-methyl-6-oxo-2-pyridin-2-yl-l,6-dihydro-pyrimidine-4- carboxylic acid ethyl ester. A solution of 5-methoxycarbonylmethyl-2-methyl-3- pyridin-2-yl-2,5-dihydro-[l,2,4]oxadiazole-5-carboxylic acid ethyl ester in xylenes (40 mL) was heated at reflux for 1 h. The reaction mixture was cooled and purified on silica gel column (CH2Cl2/5-20% methanol). The fractions containing the product were combined and concentrated to give the title compound as a brown powder
(0.705 g, 12.8% yield). 1HNMR (500 MHz, CDC13) δ: 10.75 (IH, br s), 8,66 (IH, d, J = 4.89 Hz), 7.87 (IH, td, J = 7.7, 1.5 Hz), 7.80 (IH, d, J = 7.94 Hz), 7.42-7.39 (IH, m), 4.49 (2H, q, J = 7.02 Hz), 3.63 (3H, s), 1.43 (3H, s). HRMS (ESI) calcd for Cι3H14N3O4 (M + H): 276.098465 ; found: 276.0995. EXAMPLE 19
Figure imgf000043_0001
N-(4-chlorobenzyl)-5-hydroxy-l -methyl-6-oxo-2-(pyridin-2-yl)-l, 6- dihydropyrimidine-4-carboxamide. Prepared according to the procedure described for example 2 from 5-hydroxy-l-methyl-6-oxo-2-pyridin-2-yl-l,6-dihydro- pyrimidine-4-carboxylic acid ethyl ester (27.53 mg, 0.1 mmol) and 4- chlorobenzylamine (71 mg, 0.5 mmol). The title product was obtained as a TFA salt (brown solid, 10.3 mg, 21% yield). 1HNMR (500 MHz, CDC13) δ: 12.19 (IH, s), 8.70 (IH, d, J = 4.28 Hz), 7.91 (IH, br s), 7.87 (IH, t, J = 6.41 Hz), 7.66 (IH, t, J = 7.63 Hz), 7.44 (IH, dd, J = 7.48, 5.04 Hz), 7.31-7.24 (4H, m), 4.57 (2H, d, J = 6.41 Hz), 3.59 (3H, s). HRMS (ESI) calcd for Cι8Hι6ClN4O3 (M + H): 371.0911; found: 371.0912.
EXAMPLE 20
Figure imgf000043_0002
N-(3,4-dichlorobenzyl)-5-hydroxy-l -methyl-6-oxo-2-(pyridin-2-yl)-l, 6- dihydropyrimidine-4-carboxamide. Prepared according to the procedure described for example 2 from 5-hydroxy-l-methyl-6-oxo-2-pyridin-2-yl-l,6-dihydro- pyrimidine-4-carboxylic acid ethyl ester (27.53 mg, 0.1 mmol) and 3,4- dichlorobenzyla ine (71 mg, 0.5 mmol). The title product was obtained as a TFA salt (off-white solid, 18.6 mg, 36% yield). 1HNMR (500 MHz, CDC13) δ: 12.17 (IH, s), 8.71 (IH, d, J = 3.97 Hz), 7.92 (IH, br s), 7.90 (IH, t, J = 7.63 Hz), 7.68 (IH, d, J = 7.63 Hz), 7.46 (IH, dd, J = 7.37, 5.18 Hz), 7.41-7.39 (2H, m), 7.16 (IH, dd, J = 8.39, 1.98 Hz), 4.55 (2H, d, J = 6.41 Hz), 3.59 (3H, s). HRMS (ESI) calcd for C18H15Cl2N4O3 (M + H): 405.0521; found: 405.0515.
EXAMPLE 21
Figure imgf000044_0001
N-(3,4-difluorobenzyl)-5-hydroxy-l-methyl-6-oxo-2-(pyridin-2-yl)-l,6- dihydropyrimidine-4-carboxamide. Prepared according to the procedure described for example 2 from 5-hydroxy-l-methyl-6-oxo-2-pyridin-2-yl-l,6-dihydro- pyrimidine-4-carboxylic acid ethyl ester (27.53 mg, 0.1 mmol) and 3,4- difluorobenzylamine (72 mg, 0.5 mmol). The title product was obtained as a TFA salt (brown solid, 11.2 mg, 23% yield). 1HNMR (500 MHz, CDC13) δ: 12.18 (IH, s), 8.72 (IH, d, J = 4.88 Hz), 8.02 (IH, br s), 7.91 (IH, td, J = 1.63, 7.78 Hz), 7.69 (IH, d, J = 7.63 Hz), 7.48 (IH, dd, J = 7.63, 4.88 Hz), 7.17-7.03 (3H, m), 4.55 (2H, d, J = 6.41 Hz), 3.60 (3H, s). HRMS (ESI) calcd for C18H15F2N O3 (M + H): 373.1112; found: 373.1117.
EXAMPLE 22
Figure imgf000044_0002
N-(4-methylbenzyl)-5-hydroxy-l-methyl-6-oxo-2-(pyridin-2-yl)-l,6- dihydropyrimidine-4-carboxamide. Prepared according to the procedure described for example 2 from 5-hydroxy-l-methyl-6-oxo-2-pyridin-2-yl-l,6-dihydro- pyrimidine-4-carboxylic acid ethyl ester (27.53 mg, 0.1 mmol) and 4- methylbenzylamine (61 mg, 0.5 mmol). The title product was obtained as a TFA salt (brown solid, 14.3 mg, 31% yield). 1HNMR (500 MHz, CDC13) δ: 12.37 (IH, s), 8.70 (IH, d, J = 4.58 Hz), 7.91-7.85 (2H, m), 7.66 (IH, d, J = 7.94 Hz), 7.44 (IH, dd, J = 7.02, 4.88 Hz), 7.21 (2H, d, J = 7.93 Hz), 7.15 (IH, d, J = 7.93 Hz), 4.56 (2H, d, J = 6.11 Hz), 3.59 (3H, s), 2.32 (3H, s). HRMS (ESI) calcd for C19H19N4O3 (M + H): 351.1457; found: 351.1471.
EXAMPLE 23
Figure imgf000045_0001
N-(3,4-dimethylbenzyl)-5-hydroxy-l-methyl-6-oxo-2-(pyridin-2-yl)-l,6- dihydropyrimidine-4-carboxamide. Prepared according to the procedure described for example 2 from 5-hydroxy-l-methyl-6-oxo-2-pyridin-2-yl-l,6-dihydro- pyrimidine-4-carboxylic acid ethyl ester (27.53 mg, 0.1 mmol) and 3,4- dimethylbenzylamine (68 mg, 0.5 mmol). The title product was obtained as a TFA salt (brown solid, 14.1 mg, 30% yield). 1HNMR (500 MHz, CDC13) δ: 12.36 (IH, s), 8.69 (IH, d, J = 3.97 Hz), 7.88-7.85 (2H, m), 7.66 (IH, d, J = 7.94 Hz), 7.43 (IH, dd, J = 6.71, 4.88 Hz), 7.10-7.03 (3H, m), 4.53 (2H, d, J = 6.10 Hz), 3.59 (3H, s), 2.24 (3H, s), 2.23 (3H, s). HRMS (ESI) calcd for C2oH21N4O3 (M + H): 365.1614; found: 365.1617. EXAMPLE 24
Figure imgf000046_0001
N-(3-chloro-4-methylbenzyl)-5-hydroxy-l -methyl-6-oxo-2-(pyridin-2-yl)-l, 6- dihydropyrimidine-4-carboxamide. Prepared according to the procedure described for example 2 from 5-hydroxy-l-methyl-6-oxo-2-pyridin-2-yl-l,6-dihydro- pyrimidine-4-carboxylic acid ethyl ester (27.53 mg, 0.1 mmol) and 3-chloro-4- methylbenzylamine (78 mg, 0.5 mmol). The title product was obtained as a TFA salt (brown solid, 7.2 mg, 14% yield). 1HNMR (500 MHz, CDC13) δ: 12.23 (IH, s), 8.72 (IH, d, J = 4.27 Hz), 7.92 (IH, br s), 7.91 (IH, t, J = 7.18 Hz), 7.69 (IH, d, J = 7.63 Hz), 7.47 (IH, dd, J = 7.47, 5.04 Hz), 7.29 (IH, s), 7.19 (IH, d, J = 7.63 Hz), 7.11 (IH, d, J = 7.93 Hz), 4.54 (2H, d, J = 6.11 Hz), 3.60 (3H, s), 2.34 (3H, s). HRMS (ESI) calcd for C19H18ClN4O3 (M + H): 385.1068; found: 385.1076.
EXAMPLE 25
Figure imgf000046_0002
N-(4-fluorobenzyl)-5-hydroxy-l-methyl-6-oxo-2-(pyridin-2-yl)-l,6- dihydropyrimidine-4-carboxamide. A mixture of 5-hydroxy-l-methyl-6-oxo-2~ pyridin-2-yl-l,6-dihydro-pyrimidine-4-carboxylic acid ethyl ester (27.53 mg, 0.1 mmol) and 4-fluorobenzylamine (63 mg, 0.5 mmol) in toluene (2 mL) was heated at reflux for 6 h then cooled, concentrated and purified by preparative HPLC (C18, methanol/H2O-0.1% TFA, gradient elution). The fractions containing the product were combined and concentrated to give the title compound as a TFA salt (brown paste, 9.6 mg, 21% yield). ΗNMR (500 MHz, CDC13) δ: 12.52-12.30 (IH, br s), 8.71 (IH, d, J = 4.27 Hz), 7.90-7.84 (2H, m), 7.66 (IH, d, J = 7.63 Hz), 7.45 (IH, td, J = 7.63, 4.88 Hz), 7.30-7.27 (2H, m), 7.05-7.00 (2H, m), 4.57 (2H, d, J = 6.10 Hz), 3.58 (3H, s). HRMS (ESI) calcd for C18Hι6FN4O3 (M + H): 355.1207; found: 355.1215.
Intermediate 6
Figure imgf000047_0001
N-Hydroxy-2-methoxy-N-methyl-benzamidine. To a stirred solution of 2- methoxybenzonitrile (2.66 g, 20 mmol) and N-methylhydroxylamine hydrochloride (3.341 g, 40 mmol) in 2:1 water/ethanol (30 mL) was added sodium carbonate (2.332 g, 22 mmol) in small portions and the resulting pink solution stirred at 80 °C for 28 h. The reaction mixture was then concentrated and the residue stirred with CH2C12, filtered and concentrated to give crude product as a purple solid (3.3 g), which was used in the next step without further purification.
Intermediate 7
Figure imgf000047_0002
5-Ethoxycarbonylmethyl-3-(2-methoxy-phenyl)-2-methyl-2,5-dihydro- [1,2,4] oxadiazole-5 -carboxylic acid ethyl ester. To a stirred solution of N-hydroxy- 2-methoxy-N-methyl-benzamidine (3.3 g) in ethanol (100%) was added diethyl acetylenedicarboxylate (3.2 mL, 20 mmol) and the resulting mixture stirred for 2 h at room temperature. The reaction mixture was then concentrated and purified on silica gel column using (3:7 to 2:3 ethyl acetate/hexanes) to afford the title product as a yellow oil (4.93 g, 70% yield). XHNMR (500 MHz, CDC13) δ: 7.56 (IH, dd, 7.6, 1.5 Hz), 7.44 (IH, td, J = 7.6, 1.6 Hz), 6.99 (IH, t, 7.5 Hz), 6.95 (IH, d, J = 8.2 Hz), 4.36-4.10 (4H, m), 3.85 (3H, s), 3.43 (IH, d, J = 16.48 Hz), 3.05 (3H, s), 3.04 (IH, d, J =16.48 Hz), 1.32 (3H, t, J = 7.02 Hz), 1.25 (3H, t, J = 7.02 Hz). HRMS (ESI) calcd for C17H23N2O6 (M + H): 351.1556 ; found: 351.1553.
Intermediate 8
Figure imgf000048_0001
5-Hydroxy-2-(2-methoxy-phenyl)-l-methyl-6-oxo-l,6-dihydro-pyrimidine-4- carboxylic acid ethyl ester. A solution of 5-ethoxycarbonylmethyl-3-(2-methoxy- phenyl)-2-methyl-2,5-dihydro-[l,2,4]oxadiazole-5-carboxylic acid ethyl ester (4.916 g, 14.03 mmol) in xylenes (30 mL) was heated at reflux for 3 h, cooled to room temperature and diluted with hexanes (30 mL). The resulting' mixture was left in the refrigerator (5 °C) for 48 h. The liquid was decanted and dried to give the title product as a red solid (1.813 g, 43% yield). 1HNMR (500 MHz, CDC13) δ: 10.76 (IH, s), 7.45 (IH, td, J = 7.33, 1.53 Hz), 7.34 (IH, d, J = 7.32 Hz), 7.06 (IH, t, J = 7.32 Hz) 6.94 (IH, d, J = 8.55 Hz), 4.55-4.41 (2H, m), 3.79 (3H, s), 3.34 (3H, s), 1.40 (3H, t, J = 7.02 Hz). HRMS (ESI) calcd for C15H15N2O5 (M + H): 303..0981; found: 303.0980. EXAMPLE 26
Figure imgf000049_0001
N-(3,4-dichlorobenzyl)-5-hydroxy-2-(2-methoxyphenyl)-l -methyl-6-oxo-l, 6- dihydropyrimidine-4-carboxamide. Prepared according to the procedure described for example 2 from 5-Hydroxy-2-(2-methoxy-phenyl)-l-methyl-6-oxo-l,6-dihydro- pyrimidine-4-carboxylic acid ethyl ester (45.6 mg, 0.15 mmol) and 3,4- dichlorobenzylamine (132 mg, 0.75 mmol). The title product was obtained as a pink solid (55.5 mg, 85% yield). 1HNMR (500 MHz, CDC13) δ: 11.98 (IH, s), 7.95 (IH, t, J = 5.19 Hz), 7.49 (IH, td, J = 7.33, 1.83 Hz),7.40-7.38 (2H, m), 7.29 (IH, dd, J = 7.63, 1.83 Hz), 7.15 (IH, dd, J = 8.24, 1.83 Hz), 7.07 (IH, t, J = 8.24 Hz), 4.51 (2H, d, J = 6.41 Hz), 3.82 (3H, s), 3.35 (3H, s). HRMS (ESI) calcd for C20H18C12N3O4 (M + H): 434.0675; found: 434.0674.
EXAMPLE 27
Figure imgf000049_0002
N-(4-fluorobenzyl)-5-hydroxy-2-(2-methoxyphenyl)-l -methyl-6-oxo-l, 6- dihydropyrimidine-4-carboxamide. Prepared according to the procedure described for example 2 from 5-hydroxy-2-(2-methoxy-phenyl)-l-methyl-6-oxo-l,6-dihydro- pyrimidine-4-carboxylic acid ethyl ester (45.6 mg, 0.15 mmol) and 4- fluorobenzylamine (95 mg, 0.75 mmol). The title product was obtained as a pink solid (37 mg, 64% yield). 1HNMR (500 MHz, CDC13) δ: 12.13 (IH, s), 7.90 (IH, t, J = 5.50 Hz), 7.48 (IH, td, J = 7.02, 1.83 Hz), 7.29-7.26 (3H, m), 7.06 (IH, t, J = 7.33 Hz), 7.02-6.97 (3H, m),4.53 (2H, d, J = 6.41 Hz), 3.81 (3H, s), 3.34 (3H, s). HRMS (ESI) calcd for C20H19FN3O4 (M + H): 384.1360; found: 384.1370.
EXAMPLE 28
Figure imgf000050_0001
N-(3,4-dimethylbenzyl)-5-hydroxy-2-(2-methoxyphenyl)-l-methyl-6-oxo-l,6- dihydropyrimidine-4-carboxamide. Prepared according to the procedure described for example 2 from 5-hydroxy-2-(2-methoxy-phenyl)-l-methyl-6-oxo-l,6-dihydro- pyrimidine-4-carboxylic acid ethyl ester (45.6 mg, 0.15 mmol) and 3,4- dimethylbenzylamine (102 mg, 0.75 mmol). The title product was obtained as a brown solid (53.5 mg, 91% yield). 1HNMR (500 MHz, CDC13) δ: 12.50-11.95 (IH, br s), 7.85 (IH, t, J = 4.58 Hz), 7.47 (IH, td, J = 8.24, 1.83 Hz), 7.27 (IH, dd, J = 17.63, .83 Hz),7.09-7.02 (4H, m), 6.97 (IH, d, J = 8.24 Hz), 4.49 (2H, d, J = 5.79 Hz), 3.81 (3H, s), 3.34 (3H, s) 2.23 (3H, s), 2.22 (3H, s). HRMS (ESI) calcd for C22H24N3O4 (M + H): 394.1767; found: 394.1781.
EXAMPLE 29
Figure imgf000050_0002
N-(3-chloro-4-methylbenzyl)-5-hydroxy-2-(2-methoxyphenyl)-l-methyl-6-oxo- l,6-dihydropyrimidine-4-carboxamide. Prepared according to the procedure described for example 2 from 5-hydroxy-2-(2-methoxy-phenyl)-l-methyl-6-oxo-l,6- dihydro-pyrimidine-4-carboxylic acid ethyl ester (45.6 mg, 0.15 mmol) and 3-chloro- 4-methylbenzylamine (107 mg, 0.75 mmol). The title product was obtained as a brown solid (57.5 mg, 93% yield). 1HNMR (500 MHz, CDC13) δ: 12.04 (IH, br s), 7.90 (IH, t, J = 5.49 Hz), 7.48 (IH, td, J = 8.24, 1.83 Hz), 7.30-7.25 (2H, m), 7.17 (IH, d, J = 7.94 Hz), 7.10-7.05 (2H, m), 6.98 (IH, d, J = 8.55 Hz), 4.50 (2H, d, J 6.41 Hz), 3.82 (3H, s), 3.34 (3H, s), 2.34 (3H, s). HRMS (ESI) calcd for C21H21ClN3O4 (M + H): 414.1221; found: 414.1234.
Intermediate 9
Figure imgf000051_0001
5-Ethoxycarbonylmethyl-3-(4-fluoro-2-methanesulfonyl-phenyl)-2-methyl- 2,5-dihydro-[l,2,4]oxadiazole-5~carboxylic acid ethyl ester. To a stirred suspension of 4-fluoiO-2-(methylsulfonyl)benzonitrile (prepared according to the procedure described in Anthonyl, N. J. et al PCT Appl. WO 02/30931, 2002) (2.2 g, 11 mmol) and N-methylhydroxylamine hydrochloride (1.66 g, 20 mmol) in 1:1 water/ethanol (40 mL) was added sodium carbonate (1.06 g, 10 mmol) in small portions and the resulting mixture stirred at 80 °C for 3 h. The reaction mixture was concentrated and the residue was re-dissolved into 1:1 water :ethanol (50 mL). To this solution was added diethyl acetylene-dicarboxylate (1.92 mL, 12 mmol) and the resulting mixture stirred for 30 min at room temperature. The reaction mixture was then taken-up into ethyl acetate (150 mL), washed successively with water and brine (50 mL each), dried (MgSO4), filtered and concentrated to give yellow oil. The crude product was purified on silica gel column (3:7 to 2:3 ethyl acetate/hexanes) to afford the title product as a white solid (2.9122 g, 64% yield). 1HNMR (500 MHz, CDC13) δ: 7.89 (IH, dd, J = 8.09, 2.59 Hz), 7.62 (IH, dd, J = 8.39, 5.04 Hz), 7.40 (IH, td, J = 8.24, 2.44 Hz), 4.35-4.26 (2H, m), 4.19-4.13 (2H, m), 3.40 (3H, s), 3.38 (IH, d, J = 16.17 Hz), 3.15 (IH, d, J = 16.17 Hz), 3.02 (3H5 s), 1.36-1.30 (3H, m), 1.27-1.23 (3H, m). HRMS (ESI) calcd for C17H22FN2O7S (M + H): 417.1132 ; found: 417.1116.
Intermediate 10
Figure imgf000052_0001
2-(4-Fluoro-2-methanesulfonyl-phenyl)-5-hydroxy-l-methyl-6-oxo-l,6- dihydro-pyrimidine-4-carboxylic acid ethyl ester. A solution of 5- ethoxycarbonylmethyl-3-(4-fluoro-2-methanesulfonyl-phenyl)-2-methyl-2,5-dihydro- [l,2,4]oxadiazole-5-carboxylic acid ethyl ester (2.91 g, 6.988 mmol) in xylenes (30 mL) was placed in pre-heated oil bath and refluxed for 6 h,. Heating was stopped and the reaction mixture was allowed to cool slowly to room temperature. The precipitated product was separated by decanting the solvent, rinsed with ether and dried to give the title compound as a yellow solid (1.2192 g, 47% yield). 1HNMR (500 MHz, CDC13) δ: 10.57 (IH, s), 7.90 (IH, dd, J = 7.93, 2.44 Hz), 7.49-7.42 (2H, m), 4.54-4.47 (IH, m), 4.41-4.34 (IH, m), 3.31 (3H, s), 3.30 (3H, s), 1.35 (3H, t, J = 7.02 Hz). HRMS (ESI) calcd for C15H16FN2O6S (M + H): 371.0713; found: 371.0724. EXAMPLE 30
Figure imgf000053_0001
N-(4-fluorobenzyl)-2-(4-fluoro-2-(methylsulfonyl)phenyl)-5-hydroxy-l- methyl-6-oxo-l,6-dihydropyrimidine-4-carboxamide. Prepared according to the procedure described for example 2 from 2-(4-fluoro-2-methanesulfonyl-phenyl)-5- hydroxy-l-methyl-6-oxo-l,6-dihydro-pyrimidine-4-carboxylic acid ethyl ester (55.56 mg, 0.15 mmol) and 4-fluorobenzylamine (125 mg, 1.0 mmol). The title product was obtained as a white solid (61 mg, 68% yield). 1HNMR (500 MHz, CDC13) δ: 12.16 (IH, s), 7.87 (IH, dd, J = 7.78, 2.59 Hz), 7.53 (IH, t, J 5.50 Hz), 7.48 (IH, td, J = 7.86, 2.65 Hz), 7.41 (IH, dd, J = 8.54, 4.88 Hz), 7.23 (2H, dd, J = 8.55, 5.50 Hz), 7.00 (2H, t, J = 8.54 Hz), 4.55 (IH, dd, J = 14.95, 6.40 Hz), 4.51 (IH, dd, J = 14.95, 6.10 Hz), 3.26 (3H, s), 3.01 (3H, s). HRMS (ESI) calcd for C20H18F2N3O5S (M + H): 450.0935; found: 450.0941.
EXAMPLE 31
Figure imgf000053_0002
N-(3,4-dichlorobenzyl)-2-(4-fluoro-2-(methylsulfonyl)phenyl)-5-hydroxy-l- methyl-6-oxo-l,6-dihydropyrimidine-4-carboxamide. Prepared according to the procedure described for example 2 from 2-(4-fluoro-2-methanesulfonyl-phenyl)-5- hydroxy-l-methyl-6-oxo-l,6-dihydro-pyrimidine-4-carboxylic acid ethyl ester (74.07 mg, 0.20 mmol) and 3,4-dichlorobenzylamine (132 mg, 0.75 mmol). The title product was obtained as a pink solid (69 mg, 92% yield). 1HNMR (500 MHz, CDC13) δ: 12.00 (IH, s), 7.87 (IH, dd, J = 7.63, 2.45 Hz), 7.60 (IH, t, J =7.60 Hz), 7.50-7.42 (2H, m), 7.39 (IH, d, J = 7.93 Hz), 7.32 (IH, s), 7.11 (IH, d, J = 7.32 Hz), 4.55 (IH, dd, J = 15.26, 6.41 Hz), 4.49 (IH, dd, J = 15.26, 6.10 Hz), 3.26 (3H, s), 3.06 (3H, s). HRMS (ESI) calcd for C2oH17Cl2FN3O5S (M + H): 500.0250; found: 500.0259.
EXAMPLE 32
Figure imgf000054_0001
N-(3,4-dimethylbenzyl)-2-(4-fluoro-2-(methylsulfonyl)phenyl)-5-hydroxy-l- methyl-6-oxo-l,6-dihydropyrimidine-4-carboxamide. Prepared according to the procedure described for example 2 from 2-(4-fluoro-2-methanesulfonyl-phenyl)-5- hydroxy-l-methyl-6-oxo-l,6-dihydro-pyrimidine-4-carboxylic acid ethyl ester (55.56 mg, 0.15 mmol) and 3,4-dimethylbenzylamine (102 mg, 0.75 mmol). The title product was obtained as a pink solid (59.8 mg, 87% yield). 1HNMR (500 MHz, CDC13) δ: 12.25 (IH, s), 7.86 (IH, dd, J = 7.63, 2.44 Hz), 7.49-7.44 (2H, m), 7.41 (IH, dd, J = 8.54, 4.88 Hz), 7.07 (IH, d, J = 7.63 Hz), 7.01 (IH, s), 6.97 (IH, d, J = 7.63 Hz), 4.53 (IH, dd, J = 14.65, 6.41 Hz), 4.43 (IH, dd, J = 14.96, 5.49 Hz), 3.26 (3H, s), 3.01 (3H, s), 2.22 (6H, s). HRMS (ESI) calcd for C22H23FN3O5S (M + H): 460.1343; found: 460.1337. EXAMPLE 33
Figure imgf000055_0001
2-(4-Fluoro-2-methanesulfonyl-phenyl)-5-hydroxy-l -methyl-6-oxo-l,6- dihydro-pyrimidine-4-carboxylic acid 3-chloro-4-methyl-benzylamide. Prepared according to the procedure described for example 2 from 2-(4-fluoro-2- methanesulf onyl-phenyl)-5-hydroxy- 1 -methyl-6-oxo- 1 ,6-dihydro-pyrimidine-4- carboxylic acid ethyl ester (55.56 mg, 0.15 mmol) and 3-chloro-4- methylbenzylamine (107 mg, 0.75 mmol). The title product was obtained as a pink solid (58.6 mg, 81% yield). 1HNMR (500 MHz, CDC13) δ: 12.12 (IH, s), 7.87 (IH, dd, J = 7.63, 2.45 Hz), 7.53 (IH, t, J = 5.50 Hz), 7.48 (IH, td, J = 7.62, 2.74 Hz), 7.42 (IH, dd, J = 8.24, 4.89 Hz), 7.20 (IH, s), 7.17 (IH, d, J = 7.63 Hz), 7.05 (IH, d, J = 7.63 Hz), 4.57 (IH, dd, J = 14.95, 6.72 Hz), 4.43 (IH, dd, J = 14.95, 5.49 Hz), 3.26 (3H, s), 3.05 (3H, s), 2.33 (3H, s). HRMS (ESI) calcd for C2Η20CIFN3O5S (M + H): 480.0796; found: 480.0793.
Intermediate 11
Figure imgf000055_0002
2-Fluoro-6-methylamino-benzonitrile. To a stirred solution of 2,6- difluorobenzonitrile (3.5 g, 25.2 mmol) in ethanol (40 mL) was added 2 mL of methylamine (40 wt%, in H2O) and heated at 80 °C for 2 h. The mixture was then diluted with water and the resulting slurry extracted with dichloromethane (3 X 50 mL). The combined organic extracts were dried (Na SO4), filtered and concentrated to give the title product as a white solid (3.77 g, 99.6% yield). 1HNMR (500 MHz, CDCI3) δ: 7.35-7.31 (IH, m), 6.41-6.38 (2H, m), 4.74 (IH, br s), 2.93 (3H, d, J = 5.19 Hz). LCMS calcd for C8H8FN2 (M + H): 151.07; found: 151.07.
Intermediate 12
I CN o2s N γF
N-(2-Cyano-3-fluoro-ρhenyl)-N-methyl-methanesulfonamide. To a stirred solution of 2-fluoro-6-methylamino-benzonitrile (1.5 g, 10 mmol) in THF (50 mL) at -78 °C was added LiHMDS (1M in THF, 16 mL, 16 mmol) dropwise over 5 min. The resulting pale yellow solution was stirred for an additional 30 min, then methanesulfonyl chloride (1.16 mL, 15 mmol) was added. After 30 min, the reaction mixture was quenched with saturated NH4C1 (1 mL), diluted with ethyl acetate (100 mL), dried (MgSO4), filtered and concentrated to give viscous yellow oil. The crude product was purified on silica gel column (2:3 EtOAc/hexanes) to give the title compound as a white solid (1.5936 g, 70% yield). 1HNMR (500 MHz, CDC13) δ: 7.65-7.61 (IH, m), 7.86 (IH, d, J = 8.24 Hz), 7.22 (IH, t, J = 8.24 Hz), 3.38 (3H, s), 3.13 (3H, s). HRMS (ESI) calcd for C17H22FN2O7S (M + H): 417.1132; found: 417.1116.
Intermediate 13
Figure imgf000056_0001
5-Ethoxycarbonylmethyl-3-[2-fluoro-6-(methanesulfonyl-methyl-amino)- phenyl]-2-methyl-2,5-dihydro-[l, 2,4]oxadiazole-5-carboxylic acid ethyl ester. To a stirred suspension of N-(2-cyano-3-fluoro-phenyl)-N-methyl-methanesulfonamide (0.685 g, 3.0 mmol) and N-methylhydroxylamine hydrochloride (1.0 g, 12 mmol) in 1:1 water/ethanol (20 mL) was added sodium carbonate (0.936 g, 6 mmol) in small portions and the resulting mixture stirred at 80 °C for 4 h. The reaction mixture was concentrated and the residue re-dissolved into 1:1 water :ethanol (20 mL). To this solution was added diethyl acetylenedicarboxylate (0.64 mL, 4 mmol) and the mixture stirred for 1 h at room temperature. The reaction mixture was then taken up in ethyl acetate (100 mL), washed successively with water and brine (50 mL each), dried (MgSO4), filtered and concentrated to give a yellow oil. The crude product was purified on silica gel column (2:3 to 3:2 ethyl acetate/hexanes) to afford the title compound as a viscous yellow oil (0.7453 g, 56% yield). 1HNMR (500 MHz, CDC13) δ: 7.52-7.48 (IH, m), 7.31 (IH, d, J = 8.24 Hz), 7.18 (IH, t, J = 8.55 Hz), 4.35-4.25 (2H, m), 4.18 (2H, q, J = 7.02 Hz), 3.40 (IH, d, J = 16.48 Hz), 3.21 (3H, s), 3.09 (IH, d, J = 16.48 Hz), 3.09 (3H, s), 3.07 (3H, s), 1.33 (3H, t, J = 7.02 Hz), 1.26 (3H, t, J = 7.02 Hz). HRMS (ESI) calcd for Cι8H25FN3O7S (M + H): 446.1397; found: 446.1383.
Intermediate 14
Figure imgf000057_0001
2-[2-Fluoro-6-(methanesulfonyl-methyl-amino)-phenyl]-5-hydroxy-l-methyl- 6-oxo-l ,6-dihydro-pyrimidine-4-carboxylic acid ethyl ester. A solution of 5- ethoxycarbonylmethyl-3-[2-fluoro-6-(methanesulfonyl-methyl-amino)-phenyl]-2- methyl-2,5-dihydro-[l, 2,4]oxadiazole-5-carboxylic acid ethyl ester (740 mg, 1.6612 mmol) in xylenes (10 mL) was placed in a pre-heated oil bath and heated to reflux for 2 h. Heating was stopped and the reaction mixture was allowed to cool slowly to room temperature. The precipitated product was separated by decanting the solvent, then rinsed with ether and dried to give the title compound as a yellow solid (374.8 mg, 56% yield). 1HNMR (500 MHz, CDC13) δ: 10.65 (IH, s), 7.57-7.52 (IH, m), 7.28 (IH, d, J = 7.94 Hz), 7.22 (IH, t, J = 8.85 Hz)5 4.55-4.49 (IH, m), 4.40-4.33 (IH, m), 3.46 (3H, s), 3.30 (3H, s), 2.90 (3H, s)1.37 (3H, t, J = 7.02 Hz). HRMS (ESI) calcd for C16H19FN3O6S (M + H): 400.0979; found: 400.0979.
EXAMPLE 34
Figure imgf000058_0001
N-(4-fluorobenzyl)-2-(2-fluoro-6-(N-methylmethan-3-ylsulfonamido)phenyl)- 5-hydroxy-l-methyl-6-oxo-l,6-dihydropyrimidine-4-carboxamide. Prepared according to the procedure described for example 2 from 2-[2-fluoro-6- (methanesulfonyl-methyl-amino)-phenyl]-5-hydroxy-l-methyl-6-oxo-l,6-dihydro- pyrimidine-4-carboxylic acid ethyl ester (60 mg, 0.15 mmol) and 4- fluorobenzylamine (95 mg, 0.75 mmol). The title product was obtained as a pink solid (64.2 mg, 89% yield). 1HNMR (500 MHz, CDC13) δ: 12.14 (IH, s), 7.76 (IH, t, J = 5.50 Hz), 7.57-7.53 (IH, m), 7.28-7.21 (4H, m), 7.03-6.98 (2H, m), 4.59 (IH, dd, J = 14.65, 6.71 Hz), 4.47 (IH, dd, J = 14.96, 5.80 Hz), 3.42 (3H, s), 3.08 (3H, s), 2.86 (3H, s). HRMS (ESI) calcd for C21H21F2N4O5S (M + H): 479.1201; found: 479.1196.
EXAMPLE 35
Figure imgf000058_0002
N-(3,4-dichlorobenzyl)-2-(2-fluoro-6-(N-methylmethan-3- ylsulfonamido)phenyl)-5-hydroxy-l-methyl-6-oxo-l,6-dihydropyrimidine-4- carboxamide. Prepared according to the procedure described for example 2 from 2- [2-fluoro-6-(methanesulfonyl-methyl-amino)-phenyl]-5-hydroxy-l-methyl-6-oxo- l,6-dihydro-pyrimidine-4-carboxylic acid ethyl ester (60 mg, 0.15 mmol) and 3,4- dichlorobenzylamine (132 mg, 0.75 mmol). The title product was obtained as a pink solid (68.2 mg, 86% yield). 1HNMR (500 MHz, CDC13) δ: 12.00 (IH, s), 7.85 (IH, t, J = 5.50 Hz), 7.59-7.54 (IH, m), 7.39 (IH, d, J = 8.54 Hz), 7.38 (IH, s), 7.26-7.22 (2H, m), 7.15 (IH, dd, J = 8.24, 2.13 Hz), 4.59 (IH, dd, J = 15.26, 6.72 Hz), 4.45 (IH, dd, J = 15.26, 5.80 Hz), 3.43 (3H, s), 3.12 (3H, s), 2.91 (3H, s). HRMS (ESI) calcd for C21H20C12FN4O5S (M + H): 529.0516; found: 529.0505.
EXAMPLE 36
Figure imgf000059_0001
N-(3-chloro-4-methylbenzyl)-2-(2-fluoro-6-(N-7nethylmethan-3- ylsulfonamido)phenyl)-5-hydroxy-l-methyl-6-oxo-l,6-dihydropyrimidine-4- carboxamide. Prepared according to the procedure described for example 2 from 2- [2-fluoro-6-(methanesulfonyl-methyl-amino)-phenyl]-5-hydroxy- 1 -methyl-6-oxo- l,6-dihydro-pyrimidine-4-carboxylic acid ethyl ester (60 mg, 0.15 mmol) and 3- chloro-4-methylbenzylamine (107 mg, 0.75 mmol). The title product was obtained as a pink solid (59.8 mg, 78% yield). 1HNMR (500 MHz, CDC13) δ: 12.11 (IH, s), 7.76 (IH, t, J = 5.50 Hz), 7.58-7.53 (IH, m), 7.26-7.21 (3H, m), 7.17 (IH, d, J = 7.63 Hz), 7.08 (IH, dd, J = 7.93, 1.52 Hz), 4.58 (IH, dd, J = 14.95, 6.72 Hz), 4.43 (IH, dd, J = 14.95, 5.50 Hz), 3.43 (3H, s), 3.12 (3H, s), 2.87 (3H, s), 2.33 (3H, s). HRMS (ESI) calcd for C22H23ClFN4O5S (M + H): 509.1062; found: 509.1055. Intermediate 15
Figure imgf000060_0001
3 -(2, 6-Dimethoxy-phenyl)-5-ethoxycarbonylmethyl-2-methyl-2, 5-dihydro-
[l,2,4]oxadiazole-5-carboxylic acid ethyl ester. To a stirred suspension of 2,6- dimethoxy-benzonitrile (0.82 g, 5 mmol) and N-methylhydroxylamine hydrochloride (1.66 g, 20 mmol) in 1:1 water/ethanol (20 mL) was added sodium carbonate (1.05 g, 10 mmol) in small portions and the resulting mixture stirred at 80 °C for 24 h. The reaction mixture was concentrated and the residue was re-dissolved into 1 : 1 water :ethanol (25 mL). To this solution was added diethyl acetylenedicarboxylate (0.96 L, 6 mmol) and the resulting mixture stirred for 30 min at room temperature. The reaction mixture was then taken up in ethyl acetate (100 mL), washed successively with water and brine (50 mL each), dried (Na2SO ), filtered and concentrated to give a yellow oil. The crude product was purified on silica gel column (3:7 to 1 : 1 ethyl acetate/hexanes) to afford the title compound as a viscous yellow (1.5795 g, 83% yield). 1HNMR (500 MHz, CDC13) δ: 7.32 (IH, t, J = 8.24 Hz), 6.55 (2H, d, J = 8.24 Hz), 4.38-4.24 (2H, m), 4.20-4.14 (2H, m), 3.80 (6H, s), 3.48 (IH, d, J = 16.48 Hz), 3.03 (IH, d, J = 16.48 Hz), 3.02 (3H, s), 1.33 (3H, t, J = 7.02 Hz), 1.26 (3H, t, J = 7.02 Hz). HRMS (ESI) calcd for C18H25N2O7S (M + H): 381.1662; found: 381.1656.
Intermediate 16
Figure imgf000060_0002
2-(2,6-Dimethoxy-phenyl)-5-hydroxy-l-methyl-6-oxo-l,6-dihydro-pyrimidine- 4-carboxylic acid ethyl ester. A solution of 3-(2,6-dimethoxy-phenyl)-5- ethoxycarbonylmethyl-2-methyl-2,5-dihydro-[l,2,4]oxadiazole-5-carboxylic acid ethyl ester (1.577 g, 4.1457 mmol) in xylenes (15 mL) was placed in a pre-heated oil bath and refluxed for 2 h. Heating was stopped and the reaction mixture was allowed to cool slowly to room temperature. The precipitated product was separated by decanting the solvent, rinsed with ether and dried to give the title compound as a brown solid (1.386 g, 62% yield). 1HNMR (500 MHz, CDC13) δ: 10.83 (IH, s), 7.35 (IH, t, J = 8.54 Hz), 6.59 (2H, d, J = 8.54 Hz), 4.50 (2H, q, J = 7.02 Hz), 3.75 (6H, s), 3.28 (3H, s), 1.39 (3H, t, J = 7.02 Hz). HRMS (ESI) calcd for C16H19N2O6 (M + H): 335.1243; found: 335.1240.
EXAMPLE 37
Figure imgf000061_0001
N-(4-fluorobenzyl)-2-(2,6-dimethoxyphenyl)-5-hydroxy-l-methyl-6-oxo-l,6- dihydropyrimidine-4-carboxamide. Prepared according to the procedure described for example 2 from 2-(2,6-dimethoxy-ρhenyl)-5-hydroxy-l-methyl-6-oxo-l,6- dihydro-pyrimidine-4-carboxylic acid ethyl ester (50 mg, 0.15 mmol) and 4- fluorobenzylamine (125 mg, 1.0 mmol). The title product was obtained as a pink solid (48.7 mg, 79% yield). 'HNMR (500 MHz, CDC13) δ: 12.10 (IH, s), 7.92 (IH, t, J = 5.50 Hz), 7.39 (IH, t, J = 8.54 Hz), 7.30 (IH, d, J = 5.19 Hz), 7.28 (IH, d, J = 5.19 Hz), 7.00 (2H, t, J = 8.54 Hz), 6.62 (2H, d, J = 8.24 Hz), 4.52 (2H, d, J = 6.40 Hz), +3.75 (6H, s), 3.28 (3H, s). HRMS (ESI) calcd for C21H21FN3O5 (M + H): 414.1465; found: 414.1454. EXAMPLE 38
Figure imgf000062_0001
N-(3,4-dichlorobenzyl)-2-(2,6-dimethoxyphenyl)-5-hydroxy-l-methyl-6-oxo- l,6-dihydropyrimidine-4-carboxamide. Prepared according to the procedure described for example 2 from 2-(2,6-dimethoxy-phenyl)-5-hydroxy-l-methyl-6-oxo- l,6-dihydro-ρyrimidine-4-carboxylic acid ethyl ester (74.07 mg, 0.20 mmol) and 3,4- dichlorobenzylamine (132 mg, 0.75 mmol). The title product was obtained as a pink solid (57.8 mg, 83% yield). 1HNMR (500 MHz, CDC13) δ: 11.95 (IH, s), 7.97 (IH, t, J = 5.50 Hz), 7.41-7.38 (3H, m), 7.16 (IH, dd, J = 8.24, 2.14 Hz), 6.63 (2H, d, J = 8.24 Hz), 6.50 (2H, d, J = 6.40 Hz), 3.76 (6H, s), 3.29 (3H, s). HRMS (ESI) calcd for C21H2oCl2N3O5 (M + H): 464.0780; found: 464.0775.
EXAMPLE 39
Figure imgf000062_0002
N-(3,4-dimethylbenzyl)-2-(2,6-dimethoxyphenyl)-5-hydroxy-l-methyl-6-oxo- l,6-dihydropyrimidine-4-carboxamide. Prepared according to the procedure described for example 2 from 2-(2,6-dimethoxy-phenyl)-5-hydroxy-l-methyl-6-oxo- l,6-dihydro-pyrimidine-4-carboxylic acid ethyl ester (50 mg, 0.15 mmol) and 3,4- dimethylbenzylamine (102 mg, 0.75 mmol). The title product was obtained as a brown solid (52 mg, 82% yield). 1HNMR (500 MHz, CDC13) δ: 12.28 (IH, s), 7.88 (IH, t, J = 5.50 Hz), 7.38 (IH, t , J = 8.24 Hz), 7.10-7.03 (3H, m), 6.61 (2H, d, J = 8.54 Hz), 4.48 (2H, d, J = 6.11 Hz), 3.75 (6H, s), 3.28 (3H, s), 2.23 (3H, s), 2.22 (3H, s). HRMS (ESI) calcd for C23H26N3O5 (M + H): 424.1873; found: 424.1863.
EXAMPLE 40
Figure imgf000063_0001
N-(3-chloro-4-methylbenzyl)-2-(2,6-dimethoxyphenyl)-5-hydroxy-l-methyl-6- oxo-l,6-dihydropyrimidine-4-carboxamide. Prepared according to the procedure described for example 2 from 2-(2,6-dimethoxy-phenyl)-5-hydroxy- l-methyl-6-oxo- l,6-dihydro-pyrimidine-4-carboxylic acid ethyl ester (50 mg, 0.15 mmol) and 3- chloro-4-methylbenzylamine (107 mg, 0.75 mmol). The title product was obtained as a pink solid (51.1 mg, 77% yield). 1HNMR (500 MHz, CDC13) δ: 12.09 (IH, s), 7.92 (IH, t, J = 5.50 Hz), 7.39 (IH, t, J = 8.24 Hz), 7.28 (IH, d, J =1.22 Hz), 7.17 (IH, d, J = 7.63 Hz), 7.10 (IH, dd, J = 7.63, 1.53 Hz), 6.62 (2H, d, J = 8.24 Hz), 4.49 (2H, d, J = 6.40 Hz), 3.76 (6H, s), 3.28 (3H, s), 2.33 (3H, s). HRMS (ESI) calcd for C22H23ClN3O5 (M + H): 444.1326; found: 444.1327.
Intermediate 17
Figure imgf000063_0002
2-(l,l-Dioxo-lλ -[l,2]thiazinan-2-yl)-benzonitrile. To a suspension of sodium hydride (0.54 g, 95%, 20 mmol) in DMF (25 mL) was added [l,2]thiazinane 1,1-dioxide (2.70g, 20 mmol). After stirring the mixture at room temperature for 15 min, 2-fluorobenzonitrile (2.7 mL, 25 mmol) was added and the resulting mixture was stirred at 80 °C forlδ h, cooled, diluted with water and the resulting solid filtered. The mother liquor was concentrated and the residue was recrystalized from 1:1 ethyl acetate/hexanes to yield the title product as an orange solid (3.47g, 74% yield). 1HNMR (500 MHz, CDC13) δ: 7.69 (IH, dd, J = 7.63, 1.23 Hz), 7.62-7.55 (2H, m) 7.40 (IH, t, J = 7.63 Hz), 3.72 (2H, t, J = 5.19 Hz), 3.31 (2H, t, J = 6.10 Hz), 2.39-2.34 (2H, ), 2.04-1.99 (2H, m). LCMS calcd for CπH13N2O2S (M + H): 237.29; found: 237.26.
Intermediate 18
Figure imgf000064_0001
2-(l, 1 -Dioxo-lλ6-[l,2]thiazinan-2-yl)-N-hydroxy-N-methyl-henzamidine. To a stirred solution of 2-(l,l-dioxo-lλ6-[l,2]thiazman-2-yl)-benzonitrile and N- methylhydroxylamine hydrochloride (1.67 g, 20 mmol) in 1:1 water/ethanol (70 mL) was added sodium carbonate (1.06 g, 10 mmol) and the resulting mixture stirred at 90 °C for 18h. After cooling and concentration, the resulting residue was suspended in MeOH/CHCl3 (100 mL, 1:9). The insoluble solids were removed by filtration and concentration of the filtrate gave the crude product as an amber oil (3.5 g) that was carried on without further purification. LCMS calcd for Q2H17N3O3S (M + H): 284.35; found: 284.27.
Intermediate 19
Figure imgf000064_0002
3-[2-(l,l-Dioxo-lΛ6-[l,2]thiazinan-2-yl)-phenyl]-5-ethoxycarbonylmethyl-2- methyl-2,5-dϊhydro-[l,2,4]oxadiazole-5-carboxylic acid ethyl ester. To a stirred solution of 2-(l,l-dioxo-lλ6-[l,2]thiazinan-2-yl)-N-hydiOxy-N-methyl-benzamidine (3.5 g) in ethanol (100 mL, 200 proof) was added diethyl acetylene-dicarboxylate (3.2 mL, 20 mmol) and the resulting mixture stirred at room temperature for 30 min. The mixture was concentrated and purified on a silica gel column (10%-30% ethyl acetate/hexanes) to afford the title compound as a yellow oil (3.62 g, 40% yield). 1HNMR (300 MHz, CDC13) δ: 7.57 (2H, td, J = 7.14, 1.28 Hz,), 7.50 (IH, td, J = 7.68, 1.83 Hz), 7.39 (IH, td, J = 7.50,1.46 Hz), 4.34-4.22 (2H, m), 4.18 (2H, q, J = 7.08 Hz), 3.42 (IH, d, J = 16.47 Hz), 3.22-3.18 (2H, m), 3.07 (3H, s), 3.05 (IH, d, J = 16.46 Hz), 2.38-2.24 (2H, m), 2.00-1.42 (2H, m), 1.33 (3H, t, J = 7.14 Hz), 1.26 (3H, t, J = 7.14 Hz). HRMS calcd for C2oH28SN3O7 (M + H): 454.1648; found: 454.1650.
Intermediate 20
Figure imgf000065_0001
2-[2-(l,l-Dioxo-lλ6-[l,2]thiazinan-2~yl)-phenyl]-5-hydroxy-l-methyl-6-oxo- l,6-dihydro-pyrimidine-4-carboxylic acid ethyl ester. A solution of 3-[2-(l,l-dioxo- lλ6-[l,2]thiazinan-2-yl)-phenyl]-5-ethoxycarbonylmethyl-2-methyl-2,5-dihydro- [l,2,4]oxadiazole-5-carboxylic acid ethyl ester (3.62 g, 8.0 mmol) in xylenes (50 mL) was refluxed 3 h then cooled to room temperature. The mixture was stored at 5 °C for 5 h. The resulting precipitate was filtered to afford the title product as a pale orange solid (1.67 g, 51% yield). 1HNMR (300 MHz, CDC13) δ: 10.64 (IH, s), 7.65 (IH, dd, J = 8.05, 1.10 Hz), 7.53 (IH, td, J = 7.32, 1.46 Hz), 7.45, (IH, td, J = 7.68, 1.46 Hz), 7.35 (IH, dd, J = 7.32, 1.47 Hz), 4.59-4.49 (IH, m), 4.46-4.35 (IH, m), 3.75 (IH, td, J = 13.17, 2.93 Hz), 3.65-3.58 (IH, m), 3.41 (3H, s), 3.10 (IH, dt, J = 12.93, 4.21 Hz), 2.76 (IH, td, J = 12.45, 4.39 Hz), 2.36-2.10 (2H, m), 1.77-1.45 (2H, m), 1.38 (3H, t, J = 7.32 Hz). HRMS (ESI) calcd for C18H22N3O6S (M + H): 408.1277; found 408.1231.
EXAMPLE 41
Figure imgf000066_0001
N-(4-fluorobenzyl)-5-hydroxy-l-methyl-2-(2-(l,l-Dioxo-lλ6-[l,2]thiazinan-2- yl)-6-oxo-l,6-dihydropyrimidine-4-carboxamide. Prepared according to the procedure described for example 2 from 2-[2-(l,l-dioxo-lλ6-[l,2]thiazinan-2-yl)- phenyl] -5-hydroxy- 1 -methyl-6-oxo- 1 ,6-dihydro-pyrimidine-4-carboxylic acid ethyl ester (0.0814 g, 0.2mmol), and 4-fluorobenzylamine (0.11 mL, 1.0 mmol). The title product was obtained as a lavender solid (0.0626 g, 64% yield). 1HNMR (300 MHz, CDC13) δ: 12.12 (IH, s), 7.83 (IH, bs), 7.64 (IH, d, J = 7.32 Hz), 7.54 (IH, td J = 7.32, 1.46 Hz), 7.46 (IH, td, J = 7.69, 1.10 Hz), 7.33 (IH, d, J = 7.68 Hz), 7.28-7.23 (2H, m), 7.00 (2H, t, J = 8.42 Hz), 4.59 (IH, dd, J = 14.83, 6.78 Hz), 4.46 (IH, dd, J = 14.82, 6.04 Hz), 3.68-3.52 (IH, m), 3.44-3.33 (IH, m), 3.38 (3H, m), 3.14-2.94 (IH, m), 2.82-2.73 (IH, m), 2.30-2.06 (2H, m), 1.57-1.52 (IH, m), 1.34-1.19 (IH, m). HRMS (ESI) calcd for C23H22N4O5FS (M-H): 485.1295; found: 485.1286.
EXAMPLE 42
Figure imgf000066_0002
N-(3, 4-dichlorobenzyl)-5-hydroxy-l -methyl-2-(2-(l, 1 -Dioxo-lλ6- [l,2]thiazinan-2-yl)-6-oxo-l,6-dihydropyrimidine-4-carboxamide. Prepared according to the procedure described for example 2 from 2-[2-(l,l-dioxo-lλ6- [ 1 ,2]thiazinan-2-yl)-phenyl]-5 -hydroxy- 1 -methyl-6-oxo- 1 ,6-dihydro-ρyrimidine-4- carboxylic acid ethyl ester (0.0814 g, 0.2 mmol) and 3,4-dichlorobenzylamine (0.13 mL, 1.0 mmol). The title product was obtained as white needles after recrystalization from MeOH H2O (0.0443 g, 41% yield). 1HNMR (300 MHz, CDC13) δ: 11.98 (IH, s), 7.90 (IH, bs), 7.65 (IH, d, J = 7.68 Hz), 7.55 (IH, td, J = 7.32, 1.46 Hz), 7.47 (IH, td, J = 7.69, 1.46 Hz), 7.40-7.33 (3H, m), 7.13 (IH, dd, J = 8.05, 1.83 Hz ), 4.60 (IH, dd, J = 15.18, 6.77 Hz), 4.43 (IH, dd, J = 15.00, 5.86 Hz), 3.62, (IH, bs), 3.49-3.34 (IH, m), 3.38 (3H, s), 3.05 (IH, bs), 2.89-2.75 (IH, ), 2.31-2.09 (2H, m), 1.70-1.54 (2H, m). HRMS (ESI) calcd for C23H23SCl2N4O5 (M+H): 537.0766; found: 537.0758.
EXAMPLE 43
Figure imgf000067_0001
N-(3,4-dimethylbenzyl)-5-hydroxy-l-methyl-2-(2-( 1 ,1 -Dioxo-1 λ6- [l,2]thiazinan-2-yl)-6-oxo-l,6-dϊhydropyrirnidine-4-carboxamide. Prepared according to the procedure described for example 2 from 2-[2-(l,l-dioxo-lλ6- [1 ,2]thiazinan-2-yl)-phenyl]-5-hydroxy- 1 -methyl-6-oxo- 1 ,6-dihydro-pyrimidine-4- carboxylic acid ethyl ester (0.0814 g, 0.2 mmol) and 3,4-dimethylbenzylamine (0.14 mL, 1.0 mmol). The title product was obtained as lavender needles after recrystalization from MeOH/H2O (0.0576 g, 58% yield). 1HNMR (300 MHz,
CDC13) δ: 12.23 (IH, s), 7.77 (IH, bs), 7.63 (IH, d, J = 7.32 Hz), 7.53 (IH, td, J = 7.31, 1.46 Hz), 7.45 (IH, td, J = 7.68, 0.98 Hz), 7.33 (IH, d, J = 7.32 Hz), 7.08-6.98 (3H, m), 4.55 (IH, dd, J = 14.81, 6.40 Hz), 4.43 (IH, dd, J = 14.64, 5.49 Hz), 3.62 (IH, bs), 3.37 (3H, s), 3.34 (IH, bs), 3.04 (IH, bs), 2.80-2.71 (IH, m), 2.22 (6H, s), 2.22-2.06 (2H, m), 1.64-1.52 (2H, m). HRMS (ESI) calcd for C25H29SN4O5 (M+H): 497.1859; found: 497.1847.
EXAMPLE 44
Figure imgf000068_0001
N-(3-chloro-4-methylbenzyl)-5-hydroxy-l-methyl-2-(2-(l,l-Dioxo-lλ6- [l,2]thiazinan-2-yl)-6-oxo-l,6-dihydropyrimidine-4-carboxamide. Prepared according to the procedure described for example 2 from 2-[2-(l,l-dioxo-lλ6- [ 1 ,2]thiazinan-2-yl)-phenyl]-5-hydroxy- 1 -methyl-6-oxo- 1 ,6-dihydro-pyrimidine-4- carboxylic acid ethyl ester (0.0814 g, 0.2 mmol) and 3-chloro-4-methylbenzylamine (0.14 mL, 1.0 mmol). The title product was obtained as white needles after recrystalization from MeOH/H2O (0.0416 g, 40% yield). 1HNMR (300 MHz,
CDC13) δ: 11.98 (IH, s), 7.84 (IH, bs), 7.64 (IH, d, J = 8.05 Hz), 7.54 (IH, td, J = 7.68, 1.83 Hz), 7.46 (IH, td, J = 7.68, 1.46 Hz), 7.34 (IH, dd, J = 7.32, 1.47 Hz), 7.23 (IH, d, J = 0.74 Hz), 7.17 (IH, d, J = 7.69 Hz), 7.07 (IH, dd, J = 7.69, 1.47 Hz), 4.61 (IH, dd, J = 15.19, 6.77 Hz), 4.40 (IH, dd, J = 15.00, 5.49 Hz), 3.62 (IH, bs), 3.42 (IH, bs) 3.38 (3H, s), 3.05 (IH, bs), 2.83-2.74 (IH, m), 2.33 (3H, s), 2.27-2.11 ( 2H, m), 1.63-1.60 (2H, m). HRMS (ESI) calcd for C24H26SClN4O5 (M+H): 517.1312; found: 517.1310.
Intermediate 21
Figure imgf000068_0002
N-Hydroxy-N-methyl-2-morpholin-4-yl-benzamidine. To a stirred solution of 2-(4-morpholino)benzonitrile (3.76 g, 20 mmol) and N-methylhydroxylamine hydrochloride (3.34 g, 40.0 mmol) in 1:1 water/ethanol (100 mL) was added sodium carbonate (2.12 g, 20 mmol) and the resulting mixture stirred at 90 °C overnight. After cooling and concentrating, the resulting residue was suspended in MeOH/CHCl3 (1:9). The insoluble solids were removed by filtration and concentration of the mother liquor gave the title product as an amber oil (3.8 g) that was carried on without further purification. LCMS calcd for C12H18N3O2 (M + H): 236.13; found: 236.31.
Intermediate 22
Figure imgf000069_0001
5-Ethoxycarbonylmethyl-2-methyl-3-(2-morpholin-4-yl-phenyl)-2,5-dihydro-
[1,2,4] oxadiazole-5 -carboxylic acid ethyl ester. To a stirred solution of N-hydroxy- N-methyl-2-morpholin-4-yl-benzamidine (3.8 g) in ethanol (100 mL, 200 proof) was added diethyl acetylene-dicarboxylate (3.2 mL, 20 mmol) and the resulting mixture stirred at room temperature for 30 min. The mixture was then concentrated and purified on a silica gel column (10% -30% ethyl acetate/hexanes) to afford the title compound (3.64 g, 45% yield). 1HNMR (300 MHz, CDC13) δ: 7.64 (IH, dd, J = 7.69, 1.83 Hz), 7.40 (IH, td, J = 8.05, 1.83 Hz), 7.02 (IH, t, J = 7.32 Hz), 6.97 (IH, d, J = 8.05 Hz) 4.31-4.20 (2H, m), 4.15 (2H, q, J = 7.08 Hz), 3.88-3.74 (4H, m), 3.38 (IH, d, J = 16.46 Hz), 3.12-2.92 (4H, m), 3.05 (3H, s), 3.03 (IH, d, J = 16.47 Hz), 1.29 (3H, t, J = 6.95 Hz), 1.25 (3H, t, J = 6.96 Hz). HRMS (ESI) calcd for C20H28N3O6 (M+H): 406.1978; found: 406.1975. Intermediate 23
Figure imgf000070_0001
5-Hydroxy-l-methyl-2-(2-morpholin-4-yl-phenyl)-6-oxo-l, 6-dihydro- pyrimidine-4-carboxylic acid ethyl ester. A solution of 5-ethoxycarbonylmethyl-2- methyl-3-(2-morpholin-4-yl-phenyl)-2,5-dihydro-[l,2,4]oxadiazole-5-carboxylic acid ethyl ester (3.64 g, 9.0 mmol) in xylenes (30 mL) was heated to reflux for 18 h then cooled to room temperature. Hexanes (30 mL) was added and the mixture stored at 5 °C for 5 h. The solution was decanted leaving a red residue that was purified by silica gel column (25%-50% ethyl acetate/hexanes) to afford the title product as an orange powder (0.4723 g, 14% yield). 1HNMR (300 MHz, CDC13) δ: 10.76 (IH, s), 7.46 (IH, td, J = 8.05, 1.46 Hz), 7.36 (IH, dd, J = 7.68, 1.83 Hz), 7.19 (IH, td, J = 7.32, 0.74 Hz), 7.11 (IH, d, J = 8.06 Hz), 4.58-4.38 (2H, m), 3.63-3.59 (4H, m), 3.36 (3H, s), 3.11-3.04 (2H, m), 2.82-2.75 (2H, m), 1.41 (3H, t, J = 7.32 Hz). HRMS (ESI) calcd for C18H22N3O5 (M+H): 360.1560; found: 360.1563.
EXAMPLE 45
Figure imgf000070_0002
N-(4-fluorobenzyl)-5-hydroxy-l-methyl-2-(2-morpholinophenyl)-6-oxo-l,6- dihydropyrimidine-4-carboxarnide. Prepared according to the procedure described for example 2 from 5-hydroxy-l-methyl-2-(2-morpholin-4-yl-phenyl)-6-oxo-l,6- dihydro-pyrimidine-4-carboxylic acid ethyl ester (0.05 g, 0.15 mmol) and 4- fluorobenzylamine (0.086 mL, 0.75 mmol). The title product was obtained as a TFA salt, lavender solid (0.0575 g, 87% yield). 1ΪINMR (500 MHz, CDC13) δ: 12.11 (IH, s), 7.89 (IH, t, J = 5.49 Hz), 7.48 (IH, t, J = 7.63 Hz), 7.29-7.27 (3H, m), 7.17 (IH, t, J = 7.63 Hz), 7.13 (IH, d, J = 8.24 Hz), 7.02 (2H, t, J = 8.55 Hz), 4.62-4.58, (IH, m), 4.50-4.46 (IH, m), 3.60 (4H, d, J = 2.75 Hz), 3.36 (3H, s), 3.01-2.98 (2H, ), 2.78-2.76 (2H, m). HRMS (ESI) calcd for C23H24FN4O4 (M+H): 439.1782; found 439.1767.
EXAMPLE 46
Figure imgf000071_0001
N-(3,4-dichlorobenzyl)-5-hydroxy-l-methyl-2-(2-morpholinophenyl)-6-oxo- l,6-dihydropyrimidine-4~carboxamide. Prepared according to the procedure described for example 2 from 5-hydroxy-l-methyl-2-(2-morpholin-4-yl-phenyl)-6- oxo-l,6-dihydro-pyrimidine-4-carboxylic acid ethyl ester (0.05 g, 0.15 mmol) and 3,4-dichlorobenzylamine (0.10 mL, 0.75 mmol). The title product was obtained as a TFA salt, lavender foam (0.0461 g, 63% yield). 1HNMR (500 MHz, CDC13) δ: 11.95 (IH, bs), 7.94 (IH, t, J = 5.50 Hz), 7.49 (IH, t, J = 7.63 Hz), 7.40 (IH, d, J = 8.24 Hz), 7.38 (IH, d, J = 0.91 Hz), 7.30 (IH, d, J = 7.33 Hz), 7.19 (IH, t, J = 7.33 Hz), 7.14 (2H, t, J = 8.09 Hz), 4.56-4.49 (2H, m), 3.61 (4H, s), 3.36 (3H, s), 2.99 (2H, bs), 2.79 (2H, bs). HRMS (ESI) calcd for C23H23Cli2N4O4 (M+H): 489.1096; found: 489.1080. EXAMPLE 47
Figure imgf000072_0001
N-(3,4-dimethylbenzyl)-5-hydroxy-l-methyl-2-(2-morpholinophenyl)-6-oxo- l,6-dihydropyrimidine-4-carboxamide. Prepared according to the procedure described for example 2 from 5-hydroxy-l-methyl-2-(2-morρholin-4-yl-phenyl)-6- oxo-l,6-dihydro-pyrimidine-4-carboxylic acid ethyl ester (0.05 g, 0.15 mmol) and 3,4-dimethylbenzylamine (0.11 mL, 0.75 mmol). The title product was obtained as a TFA salt, lavender foam (0.0440 g, 65% yield). 1HNMR (500 MHz, CDC13) δ: 7.84 (IH, t, J = 5.49 Hz), 7.49 (IH, t, J = 7.49 Hz), 7.28 (IH, d, J = 7.63 Hz), 7.18 (IH, t, J = 7.32 Hz), 7.14 (IH, d, J = 8.24 Hz), 7.09 (IH, d, J = 7.63 Hz), 7.07 (IH, s), 7.03 (IH, d, J = 7.63 Hz), 4.50 (2H, d, J = 5.80 Hz), 3.63 (4H, t, J = 4.57 Hz), 3.37 (3H, s), 2.89 (4H, bs), 2.23 (6H, s). HRMS (ESI) calcd for C25H29N4O4 (M+H): 449.2189; found: 449.2182.
I
EXAMPLE 48
Figure imgf000072_0002
N-(3-chloro4-methylbenzyl)-5-hydroxy-l-methyl-2-(2-morpholinophenyl)-6- oxo-1, 6-dihydropyrimidine-4-carboxamide. Prepared according to the procedure described for example 2 from 5-hydroxy-l-methyl-2-(2-morpholin-4-yl-phenyl)-6- oxo-l,6-dihydro-pyrimidine-4-carboxylic acid ethyl ester (0.05 g, 0.15 mmol) and 3- chloro-4-methylbenzylamine (0.11 mL, 0.75 mmol). The title product was obtained as a TFA salt, lavender foam (0.0266 g, 38% yield). 1HN R (500 MHz, CDC13) δ: 12.07 (IH, bs), 7.88 (IH, t, J = 6.10 Hz), 7.48 (IH, td, J = 6.71, 1.37 Hz), 7.30-7.27 (2H, m), 7.19-7.16 (2H, m), 7.13 (IH, d, J = 8.24 Hz), 7.09 (IH, d, J = 7.63 Hz), 4.56-4.53 (IH, m), 4.49-4.45 (m, IH), 3.61 (4H, d, J = 4.27 Hz), 3.36 (3H, s), 3.00 (2H, bs), 2.78 (2H, bs), 2.38 (3H, s). HRMS (ESI) calcd for C24H26ClN4O4 (M+H): 469.1643; found: 469.1628.
Intermediate 24
Figure imgf000073_0001
2-Cyano-N,N-dimethyl-benzenesulfonamide. A solution of 2- cyanobenzensulfonylchloride (2.0 g, 10 mmol), dimethyl amine (1.18 g, 10 mmol, 40wt% in water) and triethylamine (1.5 mL, 10 mmol) were stirred together at room temperature for 30 min. The resulting slurry was diluted with ethyl acetate and filtered. The filter cake was washed with ethyl acetate and the combined filterate was washed with water, dried (Na SO4) and concentrated to give the title product as orange plates (1.78 g, 85% yield). 1HNMR (300 MHz, CDC13) δ: 8.02 (lH,dd, J = 8.05, 1.46 Hz), 7.87 (IH, dd, J = 7.32, 1.47 Hz), 7.79-7.76 (2H, m), 2.86 (6H, s). LCMS calcd for C9HπN2O2S (M + H): 211.05; found: 211.09.
Intermediate 25
Figure imgf000073_0002
3-(2-Dimethylsulfamoyl-phenyl)-5-ethoxycarbonylmethyl-2-methyl-2,5- dihydro-[l,2,4]oxadiazole-5-carboxylic acid ethyl ester. To a solution of 2-cyano- N,N-dimethyl-benzenesulfonamide (4.68 g, 22.3 mmol) in ethanol/water (1:1, 150 mL) was added N-methylhydroxylamine hydrochloride (3.72 g, 44.6 mmol) followed by sodium carbonate (2.36 g, 22.3 mmol). The resulting mixture was stirred at 90 °C for 8 h then concentrated. The residue was triturated with MeOH/CHCl3 (10%) and filtered. The solution was concentrated leaving an orange residue that was dissolved in ethanol (50 mL). Added to this solution was diethyl acetylene-dicarboxylate (3.6 mL, 22.3 mmol) and the resulting mixture stirred at room temp for 30 min. The mixture was concentrated and purified by flash chromatography (25% to 50% EtOAc/Hexanes) to give the title product as a yellow oil (5.57 g, 58% over two steps). 1HNMR (300 MHz, CDC13) δ: 7.93-7.87 (IH, m), 7.66-7.60 (2H, m), 7.56- 7.51 (IH, m), 4.39-4.22 (2H,m), 4.16 (q, 2H, J = 7.20 Hz), 3.40 (IH, d, J = 16.47 Hz), 3.15 (IH, d, J = 16.47 Hz), 3.00 (3H, s), 2.82 (6H, s), 1.24 (6H, td, J = 6.95, 1.46 Hz). LCMS calcd for C18H26N3O7S (M + H): 428.14; found: 428.10.
Intermediate 26
Figure imgf000074_0001
2-(2-Dimethylsulfamoyl-phenyl)-5-hydroxy-l-methyl-6-oxo-l,6-dihydro- pyrimidine-4-carboxylic acid ethyl ester. A solution of 3-(2-dimethylsulfamoyl- ρhenyl)-5-ethoxycarbonylmethyl-2-methyl-2,5-dihydro-[l,2,4]oxadiazole-5- carboxylic acid ethyl ester (5.57g, 13 mmol) in xylenes (50 mL) was stirred at 140 °C for 8 h then cooled to room temperature. Hexanes (30 mL) was added and the mixture was stored at 5 °C for 18 h. The solution was filtered to give the title product as a yellow powder (2.47 g, 50% yield). 1HNMR (300 MHz, CDC13) δ: 10.63 (IH, s), 7.97-7.93 (IH, m), 7.73-7.64 (2H, m), 7.41-7.38 (IH, m), 4.58-4.47 (IH, m), 4.39- 4.28 (IH, m), 3.24 (3H, s), 2.78 (6H, s), 1.32 (3H, t, J = 6.95 Hz). LCMS calcd for C16H20N3O6S (M + H): 382.10; found: 382.08.
EXAMPLE 49
Figure imgf000075_0001
N-(4-fluorobenzyl)-2-(2-dimethylsulfamoylphenyl)-5-hydroxy-l-methyl-6-oxo- l,6-dihydropyrimidine-4~carboxamide. Prepared according to the procedure described for example 2 from 2-(2-dimethylsulfamoyl-phenyl)-5-hydroxy- 1 -methyl- 6-oxo-l,6-dihydro-pyrimidine-4-carboxylic acid ethyl ester (0.076 g, 0.2mmol), and 4-fluorobenzylamine (0.11 mL, 1.0 mmol). The title product was obtained as white needles (0.0549 g, 60% yield). 1HNMR (500 MHz, CDC13) δ: 12.08 (IH, s), 7.91 (IH, d, J = 7.33 Hz), 7.71-7.66 (3H, m), 7.37 (IH, dd, J = 7.32, 1.83 Hz), 7.22 (2H, q, J = 5.50 Hz), 7.00 (2H, t, J = 8.55 Hz), 4.62 (IH, dd, J = 15.26, 7.02 Hz), 4.40 (IH, dd, J = 14.64, 5.49 Hz), 3.23 (3H, s), 2.64 (6H, s). HRMS (ESI) calcd for C21H22FSN4O5 (M+H): 461.1295; found: 461.1300.
EXAMPLE 50
Figure imgf000075_0002
N-(3,4-dichlorobenzyl)-2-(2-dimethylsulfaιnoylphenyl)-5-hydroxy-l-rnethyl-6- oxo-1, 6-dihydropyrimidine-4-carboxamide. Prepared according to the procedure described for example 2 from 2-(2-dimethylsulfamoyl-phenyl)-5-hydroxy- 1 -methyl- 6-oxo-l,6-dihydro-pyrimidine-4-carboxylic acid ethyl ester (0.076 g, 0.2 mmol) and 3,4-dichlorobenzylamine (0.13 mL, 1.0 mmol). The title product was obtained as white needles (0.0569 g, 56% yield). 1HNMR (500 MHz, CDC13) δ: 11.93 (IH, s), 7.91 (IH, dd, J = 7.32 Hz), 7.74 (IH, t, J = 5.80 Hz), 7.72-7.67 (2H, m), 7.38 (2H, d, J = 7.93 Hz), 7.32 (IH, d, J = 1.83 Hz), 7.11 (IH, dd, J = 8.24, 1.83 Hz), 4.60 (IH, dd, J = 15.26, 7.02 Hz), 4.41 (IH, dd, J = 15.26, 5.80 Hz), 3.24 (3H, s), 2.69 (6H, s). HRMS (ESI) calcd for C2iH21SCl2N4O5 (M+H): 511.0610; found: 511.0612.
EXAMPLE 51
Figure imgf000076_0001
N-(3,4-dimethylbenzyl)-2-(2-dimethylsulfamoylphenyl)-5-hydroxy-l-methyl-6- oxo-1, 6-dihydropyrimidine-4-carboxamide. Prepared according to the procedure described for example 2 from 2-(2-dimethylsulfamoyl-phenyl)-5-hydroxy- 1 -methyl- 6-oxo-l,6-dihydro-pyrimidine-4-carboxylic acid ethyl ester (0.076 g, 0.2 mmol) and 3,4-dimethylbenzylamine (0.14 mL, 1.0 mmol). The title product was obtained as white needles (0.0560 g, 60% yield). 1HNMR (500 MHz, CDC13) δ: 12.19 (IH, s), 7.91 (IH, dd, J = 7.48, 1.68 Hz), 7.71-7.65 (2H, m), 7.61 (IH, m), 7.36 (IH, dd, J = 7.48, 1.68 Hz), 7.07 (IH, d, J = 7.33 Hz) 7.00 (IH, s), 6.96 (IH, d, J = 7.63 Hz), 4.57 (IH, dd, J = 14.65, 7.02 Hz), 4.37 (IH, dd, J = 14.65 Hz), 3.23 (3H, s), 2.63 (6H, s), 2.22 (6H, s). HRMS (ESI) calcd for C23H27SN4O5 (M + H): 471.1702; found 471.1708. EXAMPLE 52
Figure imgf000077_0001
N-(3-chloro-4-methylbenzyl)-2-(2-dimethylsulfamoylphenyl)-5-hydroxy-l- methyl-6-oxo-l,6-dihydropyrimidine-4-carboxamide. Prepared according to the procedure described for example 2 from 2-(2-dimethylsulfamoyl-phenyl)-5-hydroxy- l-methyl-6-oxo-l,6-dihydro-pyrimidine-4-carboxylic acid ethyl ester (0.076 g, 0.2 mmol) and 3-chloro-4-methylbenzylamine (0.14 mL, 1.0 mmol). The title product was obtained as white needles (0.0601 g, 61% yield). 1HNMR (500 MHz, CDC13) δ: 12.05 (IH, s), 7.92 (IH, dd, J = 7.47, 1.83 Hz), 7.72-7.66 (3H, m), 7.38 (IH, dd, J = 7.17, 2.29 Hz), 7.19 (IH, s), 7.16 (IH, d, J = 7.63 Hz), 7.04 (IH, d, J = 7.63 Hz), 4.61 (IH, dd, J = 14.95, 7.02 Hz), 4.36 (IH, dd, J = 14.96, 5.19 Hz), 3.24 (3H, s), 2.66 (6H, s), 2.32 (3H, s). HRMS (ESI) calcd for C22H2 ClN4O5S (M + H): 491.1156; found: 491.1159.
EXAMPLES 53-105
Examples 53-105 were prepared according to the procedures described for examples 1-52.
Figure imgf000078_0001
Figure imgf000079_0001
Figure imgf000080_0001
Figure imgf000081_0001
Figure imgf000082_0001
Figure imgf000083_0001
Figure imgf000084_0001
Figure imgf000085_0001
Figure imgf000086_0001
N-(3,4-dichlorobenzyl)-2-(2- (dimethylamino)phenyl)-5-hydroxy- 1 -methyl-6- oxo-l,6-dihydropyrimidine-4-carboxamide: 1H NMR (500 MHz, CDC13) δ: 11.94 (IH, bs), 8.01
80 (IH, s), 7.43 (IH, t, J = 7.3 Hz), 7.40-7.38 (2H,
Figure imgf000087_0001
m), 7.26 (IH, d, / = 7.6 Hz), 7.16 (IH, dd, = 8.1, 1.7 Hz), 7.10-7.06 (2H, m), 4.52 (2H, s), 3.31 (3H, s), 2.64 (6H, s). HRMS (M+H) calcd for C21H21Cl2N4O3: 447.09908; found: 447.0990.
N-(3 ,4-dimethylbenzyl)-2-(2- (dimethylamino)phenyl)-5-hydroxy- 1 -methyl-6- oxo-1 ,6-dihydropyrimidine-4-carboxamide: 1H NMR (500 MHz, CDC13) δ: 12.20 (IH, s), 7.42
81 (IH, t, J = 7.2 Hz), 7.23 (IH, d, J = 7.3 Hz), 7.10-
Figure imgf000087_0002
7.03 (5H, m), 4.50 (2H, d, /= 11.0 Hz), 3.31 (3H, s), 2.63 (6H, s), 2.23 (6H, s). HRMS (M+H) calcd for C23H27N4O3: 407.20833; found: 407.2088.
N-(3-chloro-4-methylbenzyl)-2-(2- (dimethylamino)phenyl)-5-hydroxy- 1 -methyl-6- oxo- 1 ,6-dihydropyrimidine-4-carboxamide: lB NMR (500 MHz, CDC13) δ: 12.06 (IH, s), 7.95
82 (IH, s), 7.42 (IH, t, J= 7.5 Hz), 7..28-7.25 (2H, m), 7.17 (IH, d, J = 7.9 Hz), 7.10-7.04 (3H, m), 4.51 (2H, d, /= 19.8 Hz), 3.31 (3H, s), 2.63 (6H, s), 2.33 (3H, s). HRMS (M+H) calcd for C22H24ClN4O3: 427.1537; found: 427.1540. ,
Figure imgf000088_0001
Figure imgf000089_0001
N-(3,4-dimethylbenzyl)-5-hydroxy-l-methyl-6- oxo-2-(pyridin-3-yl)-l,6-dihydropyrimidine-4-
O OH carboxamide: 1H NMR (500 MHz, CDC13) δ: 12.39 (IH, bs), 8.96 (IH, s), 8.86 (IH, s), 8.17
90 (IH, d, 7=7.3 Hz), 7.77 (2H, s), 7.13-7.00 (3H, m), 4.52 (2H, d, 7 = 4.0 Hz), 3.51 (3H, s), 2.23 (3H, s), 2.22 (3H, s). HRMS (M+H) calcd for C20H21N4O3: 365.16138; found: 365.1612.
N-(3-chloro-4-methylbenzyl)-5-hydroxy- 1 - methyl-6-oxo-2-(pyridin-3-yl)- 1 ,6- dihydropyrimidine-4-carboxamide: lB NMR υ UH (500 MHz, CDC13) δ: 12.37 (IH, bs), 9.01 (IH,
91 s), 8.87 (IH, s), 8.23 (IH, d, 7= 6.7 Hz), 7.85 (IH, s), 7.80 (IH, s), 7.26 (IH, s), 7.17 (IH, d, 7 = 7.6 Hz), 7.10 (IH, d, 7 = 8.8 Hz), 4.52 (2H, s), 3.51 (3H, s), 2.32 (3H, s). HRMS (M+H) calcd for C19H18ClN4O3: 385.10675; found: 385.1064.
N-(4-fluorobenzyl)-5-hydroxy-l-methyl-6-oxo-2- (pyridin-4-yl)- 1 ,6-dihydrapyrimidine-4-
O OH carboxamide: 1H NMR (500 MHz, DMSO) δ: 12.61 (IH, bs), 9.42 (IH, t, 7= 6.4 Hz), 8.81 (2H,
92 d, 7= 6.1 Hz), 7.77 (2H, d, 7= 6.1 Hz), 7.37-7.34 (2H, m), 7.16-7.13 (2H, m), 4.44 (2H, d, 7 = 6.41 Hz), 3.32 (3H, s). HRMS (M+H) calcd for C18H16FN4O3: 355.12065; found: 355.1206.
Figure imgf000091_0001
Figure imgf000092_0001
Figure imgf000093_0001
Figure imgf000094_0001
Figure imgf000095_0001
EXAMPLE 106 HIV-Integrase Inhibition Activity
To evaluate in-vitro activity against HIV-integrase, 5 pmole of biotin labeled substrate DNA was bound to 100 μg of Streptavidin coated PVT SPA beads (Amersham Pharmacia Biotech). Recombinant integrase (0.26 ng) was incubated with the beads for 90 min at 37 °C. Unbound enzyme was removed by washing the complex followed by addition of inhibitors and 0.1 fmol of P33 labeled target DNA. The reaction was stopped by adding EDTA to a final concentration of 10 mM. Samples were counted in TopCountNXT (Packard) and the CPM was used as a measure of integration. The reaction condition was as described in A. Engelman and R. Craigie , 7. Virol. 69, 5908-5911 (1995). The sequences of substrate and target DNA were described in Nucleic Acid Research 22,1121-1122 (1994). Using this assay, examples 1-98 were found to have an IC5o = 0.002 to 2 μM.
Although the invention has been described with respect to specific aspects, those skilled in the art will recognize that other aspects not specifically described herein are intended to be within the scope of the claims which follow.

Claims

CLAIMSWe claim:
1. A compound of Formula I, or a pharmaceutically acceptable salt or solvate thereof,
Figure imgf000096_0001
I wherein
A is methylene or 1,1-disubstituted ethylene;
B is selected from the group consisting of
Figure imgf000096_0002
R1 is phenyl, pyridinyl or dioxolanylphenyl and is unsubstituted or substituted with 1 to 3 R3;
R2 is hydrogen, methyl, or OR4;
R3 is independently selected from halo, Cι-6alkyl, Cι-2 perfluoroalkyl, Crβalkoxy, -ijalkylthioxy, and cyano;
R4 is hydrogen or Ci-βalkyl;
R5 is Ar1 or Ar2; R6 is d-6alkyl;
Ar1 is phenyl substituted with 1-2 substituents selected from halo, -βalkoxy, CO2R4, N(R4)(SO2C1-6alkyl), SO2N(C1-6alkyl)2, and dioxothiazinanyl;
Ar is a heteroaryl moiety selected from the group consisting of pyridinyl, pyrrolyl, furanyl, and imidazopyrimidinyl and is unsubstituted or substituted with 1-2 substituents selected from halo, C1-6alkyl, C1-6alkoxy, CO2R4, N(R4)(SO2Ci-6alkyl), SO2N(C1-6alkyl)2) N(R7)2, and dioxothiazinanyl; and
R ,7' is hydrogen, Cι-6alkyl, C1-6alkylOR4.
2. A compound of claim 1 wherein R1 is phenyl unsubstituted or substituted with 1 to 3 R3.
3. A compound of claim 2 where R1 is phenyl substituted with 1-2 R3 selected from the group consisting of chloro, fluoro, methyl, and trifluoromethyl.
4. A compound of claim 1 where R2 is hydrogen.
5. A compound of claim 1 where R5 is Ar1.
6. A compound of claim 5 where Ar1 is phenyl substituted with 1-2 R3 selected from the group consisting of chloro, fluoro, methoxy, N(Me)SO2Me, SO2N(Me)2, SO2Me, and dioxothiazinanyl.
7. A compound of claim 5 selected from the group consisting of
N-(4-fluorobenzyl)-2-(2,6-difluorophenyl)-5-hydroxy-l-methyl-6-oxo-l,6- dihydropyrimidine-4-carboxamide;
N-(3,4-dichlorobenzyl)-2-(2,6-difluorophenyl)-5-hydroxy-l-methyl-6-oxo-l,6- dihydropyrimidine-4-carboxamide; N-(3,4-difluorobenzyl)-2-(2,6-difluorophenyl)-5-hydroxy-l-methyl-6-oxo-l,6- dihydroρyrimidine-4-carboxamide;
N-(4-chlorobenzyl)-2-(2,6-difluorophenyl)-5-hydroxy- 1 -methyl-6-oxo- 1 ,6- dihydropyrimidine-4-carboxamide;
N-(4-methylbenzyl)-2-(2,6-difluorophenyl)-5-hydroxy- 1 -methyl-6-oxo- 1 ,6- dihydropyrimidine-4-carboxamide;
N-(3 ,4-dimethylbenzyl)-2-(2,6-difluorophenyl)-5-hydroxy- 1 -methyl-6-oxo- 1 ,6- dihydropyrimidine-4-carboxamide;
N-(3-chloro-4-methylbenzyl)-2-(2,6-difluorophenyl)-5-hydroxy- 1 -methyl-6-oxo- 1 ,6- dihydropyrimidine-4-carboxamide;
N-(2,4-difluorobenzyl)-2-(2,6-difluorophenyl)-5-hydroxy- 1 -methyl-6-oxo- 1 ,6- dihydropyrimidine-4-carboxamide;
N-(2-methylbenzyl)-2-(2,6-difluorophenyl)-5-hydroxy- 1 -methyl-6-oxo- 1 ,6- dihydropyrimidine-4-carboxamide;
N-(4-fluoro-2-(trifluoromethyl)benzyl)-2-(2,6-difluorophenyl)-5-hydroxy-l-methyl- 6-oxo- 1 ,6-dihydropyrimidine-4-carboxamide;
N-(4-(trifluoiOmethyl)benzyl)-2-(2,6-difluorophenyl)-5-hydroxy-l-methyl-6-oxo-l,6- dihydropyrimidine-4-carboxamide;
N-(benzo [d] [ 1 ,3]dioxol-5-ylmethyl)-2-(2,6-difluorophenyl)-5-hydroxy- 1 -methyl-6- oxo- 1 ,6-dihydropyrimidine-4-carboxamide;
2-(2,6-difluorophenyl)-5-hydroxy-l-methyl-6-oxo-N-(l-phenylethyl)-l,6- dihydropyrimidine-4-carboxamide; N-(2-(methylthio)benzyl)-2-(2,6-difluorophenyl)-5-hydroxy-l-methyl-6-oxo-l,6- dihydropyrimidine-4-carboxamide;
N-(3-fluoro-4-(trifluoromethyl)benzyl)-2-(2,6-difluorophenyl)-5-hydroxy-l-methyl- 6-oxo- 1 ,6-dihydropyrimidine-4-carboxamide;
N-(3,5-bis(trifluoromethyl)benzyl)-2-(2,6-difluorophenyl)-5-hydroxy-l-methyl-6- oxo- 1 ,6-dihydropyrimidine-4-carboxamide;
2-(2,6-difluorophenyl)-5-hydroxy-l-methyl-6-oxo-N-(pyridin-2-ylmethyl)-l,6- dihydropyrimidine-4-carboxamide;
N-(3,4-dichlorobenzyl)-5-hydroxy-2-(2-methoxyphenyl)-l-methyl-6-oxo-l,6- dihydropyrimidine-4-carboxamide;
N-(4-fluorobenzyl)-5-hydroxy-2-(2-methoxyphenyl)- 1 -methyl-6-oxo- 1 ,6- dihydropyrimidine-4-carboxamide;
N-(3,4-dimethylbenzyl)-5-hydroxy-2-(2-methoxyphenyl)-l-methyl-6-oxo-l,6- dihydropyrimidine-4-carboxamide;
N-(3-chloro-4-methylbenzyl)-5-hydroxy-2-(2-methoxyphenyl)-l-methyl-6-oxo-l,6- dihydropyrimidine-4-carboxamide;
N-(4-fluorobenzyl)-2-(4-fluoro-2-(methylsulfonyl)phenyl)-5-hydroxy- 1 -methyl-6- oxo- 1 ,6-dihydropyrimidine-4-carboxamide;
N-(3,4-dichlorobenzyl)-2-(4-fluoro-2-(methylsulfonyl)phenyl)-5-hydroxy-l-methyl- 6-oxo- 1 ,6-dihydropyrimidine-4-carboxamide;
N-(3 ,4-dimethylbenzyl)-2-(4-fluoro-2-(methylsulfonyl)phenyl)-5-hydroxy- 1 -methyl- 6-oxo- 1 ,6-dihydropyrimidine-4-carboxamide; N-(4-fluorobenzyl)-2-(2-fluoro-6-(N-methylmethan-3-ylsulfonamido)phenyl)-5- hydroxy- 1 -methyl-6-oxo- 1 ,6-dihydropyrimidine-4-carboxamide;
N-(3,4-dichlorobenzyl)-2-(2-fluoro-6-(N-methylmethan-3-ylsulfonamido)phenyl)-5- hydroxy- 1 -methyl-6-oxo- 1 ,6-dihydropyrimidine-4-carboxamide;
N-(3-chloro-4-methylbenzyl)-2-(2-fluoro-6-(N-methylmethan-3- ylsulfonamido)phenyl)-5-hydroxy- 1 -methyl-6-oxo- 1 ,6-dihydropyrimidine-4- carboxamide;
N-(4-fluorobenzyl)-2-(2,6-dimethoxyphenyl)-5-hydroxy-l-methyl-6-oxo-l,6- dihydropyrimidine-4-carboxamide;
N-(3,4-dichlorobenzyl)-2-(2,6-dimethoxyphenyl)-5-hydroxy-l-methyl-6-oxo-l,6- dihydropyrimidine-4-carboxamide;
N-(3,4-dimethylbenzyl)-2-(2,6-dimethoxyphenyl)-5-hydroxy-l-methyl-6-oxo-l,6- dihydropyrimidine-4-carboxamide;
N-(3-chloro-4-methylbenzyl)-2-(2,6-dimethoxyphenyl)-5-hydroxy- 1 -methyl-6-oxo- l,6-dihydropyrimidine-4-carboxamide;
N-(4-fluorobenzyl)-5-hydroxy-l-methyl-2-(2-(l,l-Dioxo-lλ6-[l,2]thiazinan-2-yl)-6- oxo- 1 ,6-dihydropyrimidine-4-carboxamide;
N-(3,4-dichlorobenzyl)-5-hydroxy-l-methyl-2-(2-(l,l-Dioxo-lλ6-[l,2]thiazinan-2- yl)-6-oxo- 1 ,6-dihydropyrimidine-4-carboxamide;
N-(3 ,4-dimethylbenzyl)-5-hydroxy- 1 -methyl-2-(2-( 1 , 1 -Dioxo- lλ6-[ 1 ,2] thiazinan-2- yl)-6-oxo-l ,6-dihydropyrimidine-4-carboxamide; N-(3-chloro-4-methylbenzyl)-5-hydroxy- 1 -methyl-2-(2-( 1 , 1 -Dioxo- lλ6- [1 ,2]thiazinan-2-yl)-6-oxo-l ,6-dihydropyrimidine-4-carboxamide;
N-(3-chloro-4-methylbenzyl)-5-hydroxy-l-methyl-2-(2-morpholinophenyl)-6-oxo- 1 ,6-dihydropyrimidine-4-carboxamide;
N-(4-fluorobenzyl)-2-(2-dimethylsulfamoylphenyl)-5-hydroxy- 1 -methyl-6-oxo- 1 ,6- dihydropyrimidine-4-carboxamide;
N-(3,4-dichlorobenzyl)-2-(2-dimethylsulfamoylphenyl)-5-hydroxy-l-methyl-6-oxo- l,6-dihydropyrimidine-4-carboxamide;
N-(3,4-dimethylbenzyl)-2-(2-dimethylsulfamoylphenyl)-5-hydroxy-l-methyl-6-oxo- l,6-dihydropyrimidine-4-carboxamide;
N-(3-chloro-4-methylbenzyl)-2-(2-dimethylsulfamoylphenyl)-5-hydroxy-l-methyl-6- oxo- 1 ,6-dihydropyrimidine-4-carboxamide;
N-(4-fluorobenzyl)-5-hydroxy-2-(3-methoxyphenyl)-l-methyl-6-oxo-l,6- dihydropyrimidine-4-carboxamide;
N-(3,4-dichlorobenzyl)-5-hydroxy-2-(3-methoxyphenyl)-l-methyl-6-oxo-l,6- dihydropyrimidine-4-carboxamide;
N-(3,4-dimethylbenzyl)-5-hydroxy-2-(3-methoxyphenyl)-l-methyl-6-oxo-l,6- dihydropyrimidine-4-carboxamide;
N-(4-fluorobenzyl)-5-hydroxy-2-(4-methoxyphenyl)- 1 -methyl-6-oxo- 1 ,6- dihydropyrimidine-4-carboxamide;
N-(3 ,4-dichlorobenzyl)-5-hydroxy-2-(4-methoxyphenyl)- 1 -methyl-6-oxo- 1 , 6- dihydropyrimidine-4-carboxamide; N-(3,4-dimethylbenzyl)-5-hydroxy-2-(4-methoxyphenyl)-l-methyl-6-oxo-l,6- dihydropyrimidine-4-carboxamide;
2-(4-((4-fluorobenzyl)carbamoyl)-5-hydroxy-l-methyl-6-oxo-l,6-dihydropyrimidin- 2-yl)benzoic acid;
2-(4-((3 ,4-dichlorobenzyl)carbamoyl)-5-hydroxy- 1 -methyl-6-oxo- 1 ,6- dihydropyrimidin-2-yl)benzoic acid; and
2-(4-methylaminicarbonyl-phenyl)-5-hydroxy-l-methyl-6-oxo-l,6-dihydro- pyrimidine-4-carboxylic acid 4-fluorobenzylamide; and
or a pharmaceutically acceptable salt or solvate thereof.
8. A compound of claim 1 where R5 is Ar2.
9. A compound of claim 8 where Ar is substituted with 1-2 substituents selected from the group consisting of chloro, fluoro, methyl, methoxy, dimethylamino, 2-hydroxyethylamino, di(2-hydroxyethyl)amino, N(Me)SO2Me, SO2N(Me)2, SO2Me, and dioxothiazinanyl.
10. A compound of claim 8 selected from the group consisting of
N-(4-chlorobenzyl)-5-hydroxy- 1 -methyl-6-oxo-2-(pyridin-2-yl)- 1 ,6- dihydropyrimidine-4-carboxamide;
N-(3,4-dichlorobenzyl)-5-hydroxy-l-methyl-6-oxo-2-(pyridin-2-yl)-l,6- dihydropyrimidine-4-carboxamide;
N-(3,4-difluorobenzyl)-5-hydroxy- 1 -methyl-6-oxo-2-(pyridin-2-yl)- 1 ,6- dihydropyrimidine-4-carboxamide; N-(4-methylbenzyl)-5-hydroxy- 1 -methyl-6-oxo-2-(pyridin-2-yl)- 1 ,6- dihydropyrimidine-4-carboxamide;
N-(3,4-dimethylbenzyl)-5-hydroxy-l-methyl-6-oxo-2-(pyridin-2-yl)-l,6- dihydropyrimidine-4-carboxamide;
N-(3-chloro-4-methylbenzyl)-5-hydroxy- 1 -methyl-6-oxo-2-(pyridin-2-yl)- 1 ,6- dihydroρyrimidine-4-carboxamide;
N-(4-fluorobenzyl)-5-hydroxy-l-methyl-6-oxo-2-(pyridin-2-yl)-l,6- dihydropyrimidine-4-carboxamide;
N-(4-fluorobenzyl)-5-hydroxy-2-(3-[2-(l,l-Dioxo-lλ6-[l,2]thiazinan-2-yl)-pyridin-2- yl]-)-l-methyl-6-oxo-l,6-dihydropyrimidine-4-carboxamide;
N-(3,4-dichlorobenzyl)-5-hydroxy-2-(3-[2-(l,l-Dioxo-lλ6-[l,2]thiazinan-2-yl)- pyridin-2-yl]-)-l-methyl-6-oxo-l,6-dihydropyrimidine-4-carboxamide;
N-(3,4-dimethylbenzyl)-5-hydroxy-2-(3-[2-(l,l-Dioxo-lλ6-[l,2]thiazinan-2-yl)- pyridin-2-yl]-)-l-methyl-6-oxo-l,6-dihydropyrimidine-4-carboxamide;
N-(3-chloro-4-methylbenzyl)-5-hydroxy-2-(3-[2-(l,l-Dioxo-lλ6-[l,2]thiazinan-2-yl)- pyridin-2-yl]-)-l-methyl-6-oxo-l,6-dihydropyrimidine-4-carboxamide;
N-(4-fluorobenzyl)-5-hydroxy-2-(6-methoxypyridin-3-yl)-l-methyl-6-oxo-l,6- dihydropyrimidine-4-carboxamide;
N-(3,4-dichlorobenzyl)-5-hydroxy-2-(6-methoxypyridin-3-yl)-l-methyl-6-oxo-l,6- dihydropyrimidine-4-carboxamide;
N-(3,4-dimethylbenzyl)-5-hydroxy-2-(6-methoxypyridin-3-yl)-l-methyl-6-oxo-l,6- dihydropyrimidine-4-carboxamide; N-(4-fluorobenzyl)-5-hydroxy-2-(3-methoxypyridin-2-yl)-l-methyl-6-oxo-l,6- dihydropyrimidine-4-carboxamide;
N-(4-fiuorobenzyl)-2-(3-(dimethylamino)pyridin-2-yl)-5-hydroxy-l-methyl-6-oxo- 1 ,6-dihydropyrimidine-4-carboxamide;
N-(3,4-dichlorobenzyl)-2-(3-(dimethylamino)pyridin-2-yl)-5-hydroxy-l-methyl-6- oxo- 1 ,6-dihydropyrimidine-4-carboxamide;
N-(3,4-dimethylbenzyl)-2-(3-(dimethylamino)pyridin-2-yl)-5-hydroxy-l-methyl-6- oxo- 1 ,6-dihydropyrimidine-4-carboxamide;
N-(3-chloro-4-methylbenzyl)-2-(3-(dimethylamino)pyridin-2-yl)-5-hydroxy-l- methyl-6-oxo- 1 ,6-dihydropyrimidine-4-carboxamide;
N-(4-fluorobenzyl)-2-(furan-2-yl)-5-hydroxy-l-methyl-6-oxo-l,6- dihydropyrimidine-4-carboxamide;
N-(3,4-dichlorobenzyl)-2-(furan-2-yl)-5-hydroxy-l-methyl-6-oxo-l,6- dihydropyrimidine-4-carboxamide;
N-(3,4-dimethylbenzyl)-2-(furan-2-yl)-5-hydroxy-l-methyl-6-oxo-l,6- dihydropyrimidine-4-carboxamide;
N-(3-chloro-4-methylbenzyl)-2-(furan-2-yl)-5-hydroxy-l-methyl-6-oxo-l,6- dihydropyrimidine-4-carboxamide;
N-(4-fluorobenzyl)-5-hydroxy-l-methyl-6-oxo-2-(pyridin-3-yl)-l,6- dihydropyrimidine-4-carboxamide;
N-(3,4-dichlorobenzyl)-5-hydroxy-l-methyl-6-oxo-2-(pyridin-3-yl)-l,6- dihydropyrimidine-4-carboxamide; N-(3,4-dimethylbenzyl)-5-hydroxy-l-methyl-6-oxo-2-(pyridin-3-yl)-l,6- dihydropyrimidine-4-carboxamide;
N-(3-chloro-4-methylbenzyl)-5-hydroxy-l-methyl-6-oxo-2-(pyridin-3-yl)-l,6- dihydropyrimidine-4-carboxamide;
N-(4-fluorobenzyl)-5-hydroxy- 1 -methyl-6-oxo-2-(ρyridin-4-yl)- 1 ,6- dihydropyrimidine-4-carboxamide ;
N-(3,4-dichlorobenzyl)-5-hydroxy-l-methyl-6-oxo-2-(pyridin-4-yl)-l,6- dihydropyrimidine-4-carboxamide;
N-(3,4-dimethylbenzyl)-5-hydroxy-l-methyl-6-oxo-2-(pyridin-4-yl)-l,6- dihydropyrimidine-4-carboxamide;
N-(3-chloro-4-methylbenzyl)-5-hydroxy-l-methyl-6-oxo-2-(pyridin-4-yl)-l,6- dihydropyrimidine-4-carboxamide;
N-(4-fluorobenzyl)-2-(l ,5-dimethyl- lH-pyrrol-2-yl)-5-hydroxy- 1 -methyl-6-oxo- 1 ,6- dihydropyrimidine-4-carboxamide;
N-(3,4-dichlorobenzyl)-2-(l,5-dimethyl-lH-pyrrol-2-yl)-5-hydroxy-l-methyl-6-oxo- l,6-dihydropyrimidine-4-carboxamide;
N-(3,4-dimethylbenzyl)-2-(l,5-dimethyl-lH-pyrrol-2-yl)-5-hydroxy-l-methyl-6-oxo- 1 ,6-dihydropyrimidine-4-carboxamide;
N-(3-chloro-4-methylbenzyl)-2-( 1 ,5-dimethyl- 1 H-pyrrol-2-yl)-5-hydroxy- 1 -methyl- 6-oxo- 1 ,6-dihydropyrimidine-4-carboxamide;
N-(4-fluorobenzyl)-2-(2,4-dimethylimidazo[l,5-a]pyrimidin-8-yl)-5-hydroxy-l- methyl-6-oxo- 1 ,6-dihydropyrimidine-4-carboxamide; N-(3,4-dichlorobenzyl)-2-(2,4-dimethylimidazo[l,5-a]pyrimidin-8-yl)-5-hydroxy-l- methyl-6-oxo- 1 ,6-dihydroρyrimidine-4-carboxamide;
N-(3,4-methylbenzyl)-2-(2,4-dimethylimidazo[l,5-a]pyrimidin-8-yl)-5-hydroxy-l- methyl-6-oxo-l,6-dihydropyrimidine-4-carboxamide; and
N-(3-chloro-4-methylbenzyl)-2-(2,4-dimethylimidazo[l,5-a]pyrimidin-8-yl)-5- hydroxy-l-methyl-6-oxo-l,6-dihydropyrimidine-4-carboxamide;
or a pharmaceutically acceptable salt or solvate thereof.
11. A compound of claim 1 where R is methyl.
12. A composition useful for treating HIV infections comprising a therapeutic amount of a compound of claim 1, or a salt or solvate thereof, and a pharmaceutically acceptable carrier.
13. A method of inhibiting HIV integrase which comprises administering to a patient a therapeutically effective amount of a compound of Claim 1, or a pharmaceutically acceptable salt or solvate thereof.
14. A method of treating HIV infection in a patient comprising the administration of a therapeutically effective amount of a compound of Claim 1, or a pharmaceutically acceptable salt or solvate thereof.
15. A method of treating HIV infection in a patient comprising administering a therapeutically effective amount of a compound of claim 1 with at least one other agent for treating HIV selected from the group consisting of HIV reverse transcriptase inhibitors, non-nucleoside HIV reverse transcriptase inhibitors, HIV protease inhibitors, HIV fusion inhibitors, HIV attachment inhibitors, CCR5 inhibitors, CXCR4 inhibitors, HIV budding or maturation inhibitors, and HIV integrase inhibitors.
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* Cited by examiner, † Cited by third party
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Families Citing this family (25)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
MXPA04003932A (en) * 2001-10-26 2004-06-18 Angeletti P Ist Richerche Bio N-substituted hydroxypyrimidinone carboxamide inhibitors of hiv integrase.
WO2003035076A1 (en) * 2001-10-26 2003-05-01 Istituto Di Ricerche Di Biologia Molecolare P. Angeletti Spa Dihydroxypyrimidine carboxamide inhibitors of hiv integrase
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Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003035076A1 (en) * 2001-10-26 2003-05-01 Istituto Di Ricerche Di Biologia Molecolare P. Angeletti Spa Dihydroxypyrimidine carboxamide inhibitors of hiv integrase

Family Cites Families (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002070491A1 (en) 2001-03-01 2002-09-12 Shionogi & Co., Ltd. Nitrogenous heteroaromatic ring derivative having hiv integrase inhibitory activity
DK2266958T1 (en) 2001-08-10 2016-04-04 Shionogi & Co antiviral
DE10139829A1 (en) 2001-08-14 2003-03-06 Bioconsult Ges Fuer Biotechnol Additive to stabilize biomass
MXPA04003932A (en) 2001-10-26 2004-06-18 Angeletti P Ist Richerche Bio N-substituted hydroxypyrimidinone carboxamide inhibitors of hiv integrase.
JP2004244320A (en) 2003-02-10 2004-09-02 Shionogi & Co Ltd Nitrogen-containing heterocyclic antiviral agent

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003035076A1 (en) * 2001-10-26 2003-05-01 Istituto Di Ricerche Di Biologia Molecolare P. Angeletti Spa Dihydroxypyrimidine carboxamide inhibitors of hiv integrase

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US8664248B2 (en) 2010-01-22 2014-03-04 Taimed Biologics, Inc. Derivatives of pyridoxine for inhibiting HIV integrase
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