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WO2010083645A1 - PYRIMIDO[5,4-e][1,2,4]TRIAZINES AND USES THEREOF - Google Patents

PYRIMIDO[5,4-e][1,2,4]TRIAZINES AND USES THEREOF Download PDF

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Publication number
WO2010083645A1
WO2010083645A1 PCT/CN2009/070252 CN2009070252W WO2010083645A1 WO 2010083645 A1 WO2010083645 A1 WO 2010083645A1 CN 2009070252 W CN2009070252 W CN 2009070252W WO 2010083645 A1 WO2010083645 A1 WO 2010083645A1
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WO
WIPO (PCT)
Prior art keywords
pyrimido
triazin
phenyl
fluoro
amine
Prior art date
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Ceased
Application number
PCT/CN2009/070252
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French (fr)
Inventor
Ben Li
Li Chen
Renhai Chen
Peibin Zhai
Dean Cameron Baylis
Jonathan Coates
John Deadman
Eric Jones
David Rhodes
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Tali Digital Ltd
SHANGHAI TARGETDRUG CO Ltd
Original Assignee
Avexa Ltd
SHANGHAI TARGETDRUG CO Ltd
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Publication date
Application filed by Avexa Ltd, SHANGHAI TARGETDRUG CO Ltd filed Critical Avexa Ltd
Priority to PCT/CN2009/070252 priority Critical patent/WO2010083645A1/en
Publication of WO2010083645A1 publication Critical patent/WO2010083645A1/en
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals

Definitions

  • the present invention relates to novel pyrimido[5,4-e][l,2,4]triazine compounds and analogues thereof for the treatment of viral infections, particularly HCV infections.
  • the hepatitis C virus is an RNA virus that belongs to the family flaviviridae. HCV replicates in the cytoplasm of hepatocytes, but is not directly cytopathic. In -70% of cases, HCV causes a persistent infection that appears to rely on rapid production of virus and continuous cell-to-cell spread, along with a lack of vigorous T-cell immune response to HCV antigens.
  • the HCV turnover rate can be quite high with replication ranging between 10 10 to 10 12 virions per day, and a predicted viral half-life of 2 to 3 hours.
  • HCV Hepatitis C virus
  • HCV replication can be described as follows.
  • the virus attaches to a susceptible host cell via a specific receptor and the entire HCV genome is posited into the host cell cytoplasm and then translated into a single polyprotein which is then cleaved into the mature proteins.
  • Complementary (-)strand RNA is synthesized by the non- structural protein components of the proteo lyrically processed polyprotein and is used as a template for genomic progeny RNA synthesis. Assembly of the progeny HCV is thought to occur during budding, characteristically into cytoplasmic vacuoles rather than at the cell surface. Release occurs often without the imminent destruction of the infected cell.
  • NS5B gene-product which is an RNA-dependent RNA polymerase (RdRp) that catalyzes the replication of HCV.
  • RdRp RNA-dependent RNA polymerase
  • the enzyme is a prime target in the search for inhibitors of HCV replication and a variety of in vitro assays for HCV NS5B polymerase activity have been developed.
  • Specific inhibitors of the HCV polymerase identified from screening campaigns using the NS5B polymerase can be broadly classified as either non-nucleoside compounds that may affect an initiation step or nucleoside analogs that may inhibit polymerase elongation.
  • soluble forms of the NS5B protein have been crystallized to reveal an X-ray derived structure similar to other polymerases, but with an encircled active site.
  • Recent X-ray derived structures of compounds bound to NS5B reveal a variety of potentially distinct inhibitor pockets, many of which localize to the thumb domain.
  • HCV RNA polymerase also known as the NS5B gene-product or HCV NS5B polymerase
  • genotypes There are six known genotypes (numbered 1 through 6) and more than 50 subtypes (e.g., Ia, Ib, 2a). Frequent HCV mutations and numerous subtypes have made the search for specifically targeted antiviral agents with a high genetic barrier to selection of resistance challenging.
  • Genotype 1 is the most common in the United States (about 75 percent of cases). Genotypes 2 and 3 are present in only 10 to 20 percent of patients. Patients with genotypes 2 and 3 have a high response rate to treatment (approximately 75% success) whereas genotype 1 shows a lower rate of response to combination therapy (45 %) and requires a longer course of treatment.
  • the present invention provides a compound of Formula I or a pharmaceutically acceptable derivative, salt or prodrug thereof wherein:
  • Ri is selected from the group consisting of H, C 1-10 alkyl, aryl and heteroaryl;
  • each R 2 is independently selected from the group consisting of H, Ci_ioalkyl, Ci_iocycloalkyl, Ci_ 3 alkylaryl, aryl;
  • each R 3 is independently selected from the group consisting of H, Ci_ioalkyl, Ci_iocycloalkyl, Ci_ 3 alkylaryl, halo, aryl;
  • each R 4 and R 5 is independently selected from the group consisting of H, C 1-10 alkyl, Ci.iocycloalkyl, C 1-3 alkylaryl, and aryl; or
  • each R 7 is independently selected from the group consisting of H, Ci_i O alkyl, Ci_i 0 cycloalkyl, Ci_ 3 alkylaryl, aryl;
  • each R 8 is independently selected from the group consisting of H, C 1-10 alkyl, Ci_i 0 cycloalkyl, Ci_ 3 alkylaryl, halo, aryl;
  • each R 9 and Ri 0 is independently selected from the group consisting of H, C 1-10 alkyl, Ci_i 0 cycloalkyl, Ci_ 3 alkylaryl, and aryl; or
  • the present invention provides a method of treatment or prophylaxis of a viral infection in a subject comprising administering to said subject an effective amount of a compound of formula (I) or a pharmaceutically acceptable derivative, salt or prodrug thereof.
  • a compound of Formula I or a pharmaceutically acceptable derivative, salt or prodrug thereof in the preparation of a medicament for the treatment or prophylaxis of a viral infection in a subject.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound according to the first aspect and a pharmaceutically acceptable carrier, diluent or excipient.
  • the present invention provides a compound of Formula I or a pharmaceutically acceptable derivative, salt or prodrug thereof wherein:
  • Ri is selected from the group consisting of H, C 1-10 alkyl, aryl and heteroaryl;
  • each R 2 is independently selected from the group consisting of H, Ci_ioalkyl, Ci_iocycloalkyl, Ci_ 3 alkylaryl, aryl;
  • each R 3 is independently selected from the group consisting of H, Ci_ioalkyl, Ci_iocycloalkyl, Ci_ 3 alkylaryl, halo, aryl;
  • each R 4 and R 5 is independently selected from the group consisting of H, C 1-10 alkyl, Ci.iocycloalkyl, C 1-3 alkylaryl, and aryl; or
  • each R 7 is independently selected from the group consisting of H, Ci_i O alkyl, Ci_i 0 cycloalkyl, Ci_ 3 alkylaryl, aryl;
  • each R 8 is independently selected from the group consisting of H, C 1-10 alkyl, Ci_i 0 cycloalkyl, Ci_ 3 alkylaryl, halo, aryl;
  • each R 9 and Ri 0 is independently selected from the group consisting of H, C 1-10 alkyl, Ci_i 0 cycloalkyl, Ci_ 3 alkylaryl, and aryl; or
  • Ri is selected from the group consisting of aryl and heteroaryl.
  • Ri is optionally substituted phenyl.
  • the phenyl is substituted with one or more substituents independently selected from halo (more preferably fluoro), methoxy, and NHC(O)CH 3 .
  • Ri is 4-fluorophenyl.
  • Ri is 3,4-dimethoxyphenyl.
  • A is OR 2 wherein R 2 is methyl.
  • A is NR 4 R 5 .
  • R 4 is H and R 5 is Ci_i O alkyl.
  • R 4 is H and R5 is optionally substituted benzyl.
  • the one or more optional substituents are independently selected from the group consisting of halo (more preferably fluoro), SO 2 NH 2 , S O 2 NH(Ci. C 3 alky 1), and S O 2 N(Ci. C 3 alky I) 2
  • the heterocycle is selected from the group consisting of morpholine, piperidine,, and piperazine.
  • the compound of formula I is a compound of formula II or III, wherein Ri, A, R9, Rio and Ri 2 are as defined above.
  • halo or halogen refers to fluorine (fluoro), chlorine (chloro), bromine (bromo) or iodine (iodo).
  • alkyl either used alone or in compound terms such as NH(alkyl) or N(alkyl) 2 , refers to monovalent straight chain or branched hydrocarbon groups, having 1 to 3, 1 to 6, or 1 to 10 carbon atoms as appropriate.
  • suitable alkyl groups include, but are not limited to methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, pentyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 2-, 3- or 4-methylpentyl, 2-ethylbutyl, n-hexyl or 2-, 3-, 4- or 5-methylpentyl.
  • cycloalkyl refers to cyclic hydrocarbon groups. Suitable cycloalkyl groups include, but are not limited to cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
  • aryl refers to a C 6 -CiO aromatic hydrocarbon group, for example phenyl or naphthyl.
  • alkylaryl includes, for example, benzyl.
  • heterocycle when used alone or in compound words includes monocyclic, polycyclic, fused or conjugated hydrocarbon residues, preferably C 3 _ 6 ,wherein one or more carbon atoms (and where appropriate, hydrogen atoms attached thereto) are replaced by a heteroatom so as to provide a non-aromatic residue.
  • Suitable heteroatoms include, O, N and S. Where two or more carbon atoms are replaced, this may be by two or more of the same heteroatom or by different heteroatoms.
  • Suitable examples of heterocyclic groups may include pyrrolidinyl, piperidyl, piperazinyl, morpholino, quinolinyl, isoquinolinyl, thiomorpholino, dioxanyl,
  • heteroaryl includes a 5- or 6-membered heteroaromatic ring containing one or more heteroatoms selected from O, N and S.
  • Suitable examples of heteroaryl groups include furanyl, thiophenyl, tetrazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, imidazolyl, pyrazolyl, pyridinyl, pyrimidinyl, oxazolyl, oxadiazolyl etc.
  • the heteroaromatic ring may be fused to a 5- or 6-membered aromatic or heteroaromatic ring to form a bicyclic aromatic ring system eg benzofuran.
  • each alkyl, cycloalkyl, alkylaryl, aryl, heterocyclyl, or heteroaryl group may be optionally substituted with one or more of Ci-C 3 alkyl, C 3 -C 6 cycloalkyl, C 6 aryl, heterocyclyl, heteroaryl, d-C 3 alkylOH, alkylaryl, OH, OCi-C 3 alkyl, halo, CN, NO 2 , CO 2 H, CO 2 Ci_C 3 alkyl, CONH 2 , CONH(C i_C 3 alkyl), CON(C i_C 3 alkyl) 2 , NHCO(C i_C 3 alkyl), trifluoromethyl, NH 2 , NH(Ci_C 3 alkyl), N(Ci_C 3 alkyl) 2 , SO 2 NH 2 , S O 2 NH(Ci.
  • an optionally substituted aryl group may be 4-methylphenyl or 4-hydroxyphenyl group, and an optionally substituted alkyl group may be 2-hydroxyethyl, trifluoromethyl, or difluoromethyl.
  • Each optional alkyl, cycloalkyl, alkylaryl, aryl, heterocyclyl, or heteroaryl substituent may also be optionally substituted.
  • optional substituents also include suitable nitrogen protecting groups (see “Protective Groups in Organic Synthesis” Theodora Greene and Peter Wuts, third edition, Wiley Interscience, 1999).
  • salts of the compound of formula I are preferably pharmaceutically acceptable, but it will be appreciated that non-pharmaceutically acceptable salts also fall within the scope of the present invention, since these are useful as intermediates in the preparation of pharmaceutically acceptable salts.
  • pharmaceutically acceptable derivative may include any pharmaceutically acceptable salt, hydrate or prodrug, or any other compound which upon administration to a subject, is capable of providing (directly or indirectly) a compound of formula I or an antibacterially active metabolite or residue thereof.
  • Suitable pharmaceutically acceptable salts include, but are not limited to, salts of pharmaceutically acceptable inorganic acids such as hydrochloric, sulphuric, phosphoric, nitric, carbonic, boric, sulfamic, and hydrobromic acids, or salts of pharmaceutically acceptable organic acids such as acetic, propionic, butyric, tartaric, maleic, hydroxymaleic, fumaric, malic, citric, lactic, mucic, gluconic, benzoic, succinic, oxalic, phenylacetic, methanesulphonic, toluenesulphonic, benzenesulphonic, salicylic, sulphanilic, aspartic, glutamic, edetic, stearic, palmitic, oleic, lauric, pantothenic, tannic, ascorbic and valeric acids.
  • pharmaceutically acceptable inorganic acids such as hydrochloric, sulphuric, phosphoric, n
  • Base salts include, but are not limited to, those formed with pharmaceutically acceptable cations, such as sodium, potassium, lithium, calcium, magnesium, zinc, ammonium, alkylammonium such as salts formed from triethylamine, alkoxyammonium such as those formed with ethanolamine and salts formed from ethylenediamine, choline or amino acids such as arginine, lysine or histidine.
  • pharmaceutically acceptable cations such as sodium, potassium, lithium, calcium, magnesium, zinc, ammonium, alkylammonium such as salts formed from triethylamine, alkoxyammonium such as those formed with ethanolamine and salts formed from ethylenediamine, choline or amino acids such as arginine, lysine or histidine.
  • Basic nitrogen-containing groups may be quarternised with such agents as lower alkyl halide, such as methyl, ethyl, propyl, and butyl chlorides, bromides and iodides; dialkyl sulfates like dimethyl and diethyl sulfate; and others.
  • lower alkyl halide such as methyl, ethyl, propyl, and butyl chlorides, bromides and iodides
  • dialkyl sulfates like dimethyl and diethyl sulfate; and others.
  • This invention also encompasses pharmaceutical compositions containing prodrugs of compounds of formula I.
  • This invention also encompasses methods of treating or preventing a viral infection in a subject by administering prodrugs of compounds of the formula I.
  • Compounds of formula I having free amino, amido, hydroxy or carboxylic groups can be converted into prodrugs.
  • Prodrugs include compounds wherein an amino acid residue, or a polypeptide chain of two or more (eg, two, three or four) amino acid residues which are covalently joined to free amino, hydroxy and carboxylic acid groups of compounds of formula I.
  • the amino acid residues include the 20 naturally occurring amino acids commonly designated by three letter symbols and also include, 4-hydroxyproline, hydroxylysine, demosine, isodemosine, 3-methylhistidine, norvlin, beta-alanine, gamma-aminobutyric acid, citrulline, homocysteine, homoserine, ornithine and methionine sulfone.
  • Prodrugs also include compounds wherein carbonates, carbamates, amides and alkyl esters which are covalently bonded to the above substituents of formula I through the carbonyl carbon prodrug sidechain.
  • Prodrugs also include phosphate derivatives of compounds of formula I (such as acids, salts of acids, or esters) joined through a phosphorus-oxygen bond to a free hydroxyl of compounds of formula I.
  • the compounds of formula I may possess asymmetric centres and are therefore capable of existing in more than one stereoisomeric form.
  • the invention thus also relates to compounds in substantially pure isomeric form at one or more asymmetric centres eg., greater than about 90% ee, such as about 95% or 97% ee or greater than 99% ee, as well as mixtures, including racemic mixtures, thereof.
  • Such isomers may be prepared by asymmetric synthesis, for example using chiral intermediates, or by chiral resolution.
  • the compound is selcted from one of the following compounds:
  • the compound is selected from the compounds set out below:
  • the present invention provides a method of treatment or prophylaxis of a viral infection in a subject comprising administering to said subject an effective amount of a compound of formula (I) or a pharmaceutically acceptable derivative, salt or prodrug thereof.
  • a compound according to the first aspect or a pharmaceutically acceptable derivative, salt or prodrug thereof, or a composition according to the fourth aspect in the preparation of a medicament for the treatment or prophylaxis of a viral infection in a subject.
  • the term "effective amount” means the amount of the subject composition that will elicit the biological or medical response of a tissue, system, animal or human that is being sought by the researcher, veterinarian, medical doctor or other clinician.
  • administering a should be understood to mean providing a compound of the invention to the individual in need of treatment.
  • treatment does not necessarily mean that the viral infection is completely cured.
  • treatment encompasses any reduction in the viral load and/or inhibition of replication in the subject being treated.
  • the compounds of the present invention may be administered by any suitable means, for example, parenterally, such as by subcutaneous, intravenous, intramuscular, or intracisternal injection or infusion techniques (e.g., as sterile injectable aqueous or non-aqueous solutions or suspensions).
  • parenterally such as by subcutaneous, intravenous, intramuscular, or intracisternal injection or infusion techniques (e.g., as sterile injectable aqueous or non-aqueous solutions or suspensions).
  • mammals including, but not limited to, cows, sheep, goats, horses, dogs, cats, guinea pigs, rats or other bovine, ovine, equine, canine, feline, rodent or murine species can be treated.
  • the method can also be practiced in other species, such as avian species (e.g., chickens).
  • the subject is a human being, whether male or female.
  • the viral infection of the second and third aspects is a HCV infection.
  • the present invention provides pharmaceutical composition
  • a pharmaceutically acceptable carrier, diluent or excipient comprising a compound according to the first aspect and a pharmaceutically acceptable carrier, diluent or excipient.
  • compositions of the present invention may contain other therapeutic agents as described below, and may be formulated, for example, by employing conventional solid or liquid vehicles or diluents, as well as pharmaceutical additives of a type appropriate to the mode of desired administration (for example, excipients, binders, preservatives, stabilizers, flavors, etc.) according to techniques such as those well known in the art of pharmaceutical formulation.
  • compositions include those for oral, rectal, nasal, topical (including buccal and sub-lingual), vaginal or parenteral (including intramuscular, sub-cutaneous and intravenous) administration or in a form suitable for administration by inhalation or insufflation.
  • the compounds of the invention may thus be placed into the form of pharmaceutical compositions and unit dosages thereof, and in such form may be employed as solids, such as tablets or filled capsules, or liquids as solutions, suspensions, emulsions, elixirs or capsules filled with the same, all for oral use, in the form of suppositories for rectal administration; or in the form of sterile injectable solutions for parenteral (including subcutaneous) use.
  • composition as used herein is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts.
  • pharmaceutically acceptable it is meant the carrier, diluent or excipient must be compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.
  • compositions for the administration of the compounds of this invention may conveniently be presented in dosage unit form and may be prepared by any of the methods well known in the art of pharmacy. All methods include the step of bringing the active ingredient into association with the carrier which constitutes one or more accessory ingredients.
  • the pharmaceutical compositions are prepared by uniformly and intimately bringing the active ingredient into association with a liquid carrier or a finely divided solid carrier or both, and then, if necessary, shaping the product into the desired formulation.
  • the active object compound is included in an amount sufficient to produce the desired effect upon the process or condition of diseases.
  • composition is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts.
  • the pharmaceutical compositions may be in the form of a sterile injectable aqueous or oleagenous suspension.
  • This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above.
  • the sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example as a solution in 1,3-butane diol.
  • the acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution.
  • sterile, fixed oils are conventionally employed as a solvent or suspending medium.
  • any bland fixed oil may be employed including synthetic mono- or diglycerides.
  • fatty acids such as oleic acid find use in the preparation of injectables.
  • compositions and methods of the present invention may further comprise other therapeutically active compounds which are usually applied in the treatment of the above mentioned pathological conditions.
  • Selection of the appropriate agents for use in combination therapy may be made by one of ordinary skill in the art, according to conventional pharmaceutical principles.
  • the combination of therapeutic agents may act synergistically to effect the treatment or prevention of the various disorders described above. Using this approach, one may be able to achieve therapeutic efficacy with lower dosages of each agent, thus reducing the potential for adverse side effects.
  • an appropriate dosage level will generally be about 0.01 to 500 mg per kg patient body weight per day which can be administered in single or multiple doses.
  • the dosage level will be about 0.1 to about 250 mg/kg per day; more preferably about 0.5 to about 100 mg/kg per day.
  • a suitable dosage level may be about 0.01 to 250 mg/kg per day, about 0.05 to 100 mg/kg per day, or about 0.1 to 50 mg/kg per day. Within this range the dosage may be 0.05 to 0.5, 0..5 to 5 or 5 to 50 mg/kg per day.
  • compositions are preferably provided in the form of tablets containing 1.0 to 1000 milligrams of the active ingredient, particularly 1.0, 5.0, 10.0, 15.0. 20.0, 25.0, 50.0, 75.0, 100.0, 150.0, 200.0, 250.0, 300.0, 400.0, 500.0, 600.0, 750.0, 800.0, 900.0, and 1000.0 milligrams of the active ingredient for the symptomatic adjustment of the dosage to the patient to be treated.
  • the compounds may be administered on a regimen of 1 to 4 times per day, preferably once or twice per day.
  • N'-(2-chloro-5-nitropyrimidin-4-yl)benzohydrazide (0.2Og, 0.68 mmol) was added in small portions to the mixture of sodium methoxide (0.11 g, 2.04 mmol) and methanol (5 mL). After the reaction mixture was refluxed for 2 h the mixture was filtered, concentrated and subjected to flash chromatography to afford a brown solid (0.12 g, 61%).
  • Step D 7-Methoxy-3-phenyl-l ,2-dihydropyrimido[5,4-e] [ 1 ,2,4]triazine
  • N'-(2-chloro-5-nitropyrimidin-4-yl)-4- fluorobenzohydrazide prepared as step B in Example 1.1, 1.0 g, 3.21 mmol
  • benzyl amine (0.68 mL, 6.24 mmol
  • Et 3 N (1.80 mL, 12.84 mmol) in ethanol (30 mL)
  • the mixture was filtered and washed to give the title product as a pale yellow solid (1.20 g, 98%).
  • Step B Benzyl-[3-(4-fluoro-phenyl)-l,2-dihydro-pyrimido[5,4-e][l,2,4]triazin-7-yl]- amine
  • Example 3.3 The more polar product isloated from Example 3.2 is decribed in Example 3.3
  • Example 3.2 the more polar productt is the title compound as a pale yellow solid (0.050 g, 31%).
  • Step A N'-(5-Amino-2-chloropyrimidin-4-yl)-4-fluorobenzohydrazide
  • Step B 3-(4-Fluorophenyl)-7-methoxy-l,2-dihydropyrimido[5,4-e][l,2,4]triazine
  • Step C Ethyl- [3-(4-fluoro-phenyl)-7-methoxy-pyrimido[5,4-e][ 1,2,4] triazin-5-yl]- amine
  • N'-(2-chloro-5-nitropyrimidin-4-yl)-4- fluorobenzohydrazide prepared as step B in Example 1.1, 0.200 g, 0.643 mmol
  • methanol 15 mL
  • Pd(OH) 2 /C 0.040 g, 20%
  • the mixture was filtered, washed and concentrated to give crude amine as a brown oil (0.160 g, 100%).
  • Step B 3 -(4 -fluorophenyl) -1,2 -dihydropyrimido[ 5,4-e] ' [ 1 , 2, 4]triazine
  • Step C N-(4-fluorobenzyl)-3-(4-fluorophenyl)pyrimido[ 5,4-e] [1, 2,4] 'triazin-5-amine
  • a standard RdRP assay was performed with HCV NS5B in 20 uL reactions containing 20 mM Tris-Cl pH 7.0, 5 mM MgCl 2 , 5 mM MnCl 2 , 5mM DTT, 5U RNAsin, 100 ug/mL BSA, 400-500 ng of NS5B protein, 0.2 ug poly(C) template and 10 mM GTP plus ImCi [(X- 33 P]-GTP, at 25°C for 2 h. The reaction was terminated upon addition of 2 uL 0.45 M EDTA.

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Abstract

The present invention provides a com pound of Formula (I) or a pharmaceutically acceptable derivative, salt or prodrug thereof: Formula (I). The present invention further provides pharmaceutical compositions comprising a compound of formula I and methods of tr eating or preventing viral infections, particularly HCV infections, by admi nistering a compound of Formula (I).

Description

PYRIMIDO[5,4-e][l,2,4]TRIAZINES AND USES THEREOF
FIELD OF THE INVENTION
The present invention relates to novel pyrimido[5,4-e][l,2,4]triazine compounds and analogues thereof for the treatment of viral infections, particularly HCV infections.
BACKGROUND OF THE INVENTION
The hepatitis C virus is an RNA virus that belongs to the family flaviviridae. HCV replicates in the cytoplasm of hepatocytes, but is not directly cytopathic. In -70% of cases, HCV causes a persistent infection that appears to rely on rapid production of virus and continuous cell-to-cell spread, along with a lack of vigorous T-cell immune response to HCV antigens. The HCV turnover rate can be quite high with replication ranging between 1010 to 1012 virions per day, and a predicted viral half-life of 2 to 3 hours.
Chronic hepatitis C is the most common cause of chronic liver disease and cirrhosis, and the most common indication for liver transplantation in the United States (U.S.), Australia, and most of Europe. Approximately 170 million people are affected with HCV worldwide, comprising ~3% of the global population. Hepatitis C virus (HCV) is the most common chronic blood-borne infection in the U.S., and is involved in 40% of chronic liver disease.
HCV replication can be described as follows. The virus attaches to a susceptible host cell via a specific receptor and the entire HCV genome is posited into the host cell cytoplasm and then translated into a single polyprotein which is then cleaved into the mature proteins. Complementary (-)strand RNA is synthesized by the non- structural protein components of the proteo lyrically processed polyprotein and is used as a template for genomic progeny RNA synthesis. Assembly of the progeny HCV is thought to occur during budding, characteristically into cytoplasmic vacuoles rather than at the cell surface. Release occurs often without the imminent destruction of the infected cell. It is the NS5B gene-product which is an RNA-dependent RNA polymerase (RdRp) that catalyzes the replication of HCV. The enzyme is a prime target in the search for inhibitors of HCV replication and a variety of in vitro assays for HCV NS5B polymerase activity have been developed. Specific inhibitors of the HCV polymerase identified from screening campaigns using the NS5B polymerase can be broadly classified as either non-nucleoside compounds that may affect an initiation step or nucleoside analogs that may inhibit polymerase elongation.
In addition to its use in screening campaigns, soluble forms of the NS5B protein have been crystallized to reveal an X-ray derived structure similar to other polymerases, but with an encircled active site. Recent X-ray derived structures of compounds bound to NS5B reveal a variety of potentially distinct inhibitor pockets, many of which localize to the thumb domain.
The rapid viral replication and lack of error proofreading by the viral RNA polymerase also known as the NS5B gene-product or HCV NS5B polymerase are reasons why the HCV RNA genome mutates frequently. There are six known genotypes (numbered 1 through 6) and more than 50 subtypes (e.g., Ia, Ib, 2a...). Frequent HCV mutations and numerous subtypes have made the search for specifically targeted antiviral agents with a high genetic barrier to selection of resistance challenging.
The current standard for treatment of HCV is a 24 to 48 week course of a combination of pegylated interferon alpha (PEG-IFN) and ribavirin (RBV). Significantly, this treatment is relatively ineffective against the predominant genotypes in the U.S. and Europe. Genotype 1 is the most common in the United States (about 75 percent of cases). Genotypes 2 and 3 are present in only 10 to 20 percent of patients. Patients with genotypes 2 and 3 have a high response rate to treatment (approximately 75% success) whereas genotype 1 shows a lower rate of response to combination therapy (45 %) and requires a longer course of treatment.
In addition to the issue with efficacy against different genotypes, significant side affects (eg flu like symptoms, neuropsychiatric effects and anemia) are associated with the current combination therapy. SUMMARY OF THE INVENTION
In a first aspect, the present invention provides a compound of Formula I or a pharmaceutically acceptable derivative, salt or prodrug thereof wherein:
Figure imgf000004_0001
represents a double or single bond;
Ri is selected from the group consisting of H, C1-10alkyl, aryl and heteroaryl;
A is selected from the group consisting of H, OR2, SR2, SOR3, SO2R3, C(Rs)3, COR3, -CO2R3; =NR2, =0, NR4R5, -NR4SO2R5,
each R2 is independently selected from the group consisting of H, Ci_ioalkyl, Ci_iocycloalkyl, Ci_3alkylaryl, aryl;
each R3 is independently selected from the group consisting of H, Ci_ioalkyl, Ci_iocycloalkyl, Ci_3alkylaryl, halo, aryl;
each R4 and R5 is independently selected from the group consisting of H, C1-10alkyl, Ci.iocycloalkyl, C1-3alkylaryl, and aryl; or
R4 and R5 together with the heteroatom(s) to which they are attached form a 5- to 7-membered heterocycle, saturated or unsaturated, comprising 0-2 additional heteratoms selected from the group consisting of O, N and S, wherein said heterocycle is optionally substituted with one or more substituents selected from the group consisting of H, halo, C1-10alkyl, C1-10cycloalkyl, C^alkenyl, =0, C(O)C1-3alkyl, and NR4R5; B is selected from the group consisting of H, OR7, SR7, SOR8, SO2R8, C(R8)3, COR8, -CO2R8; =NR7, NR9Ri0, -NR9SO2Ri0,
each R7 is independently selected from the group consisting of H, Ci_iOalkyl, Ci_i0cycloalkyl, Ci_3alkylaryl, aryl;
each R8 is independently selected from the group consisting of H, C1-10alkyl, Ci_i0cycloalkyl, Ci_3alkylaryl, halo, aryl;
each R9 and Ri0 is independently selected from the group consisting of H, C1-10alkyl, Ci_i0cycloalkyl, Ci_3alkylaryl, and aryl; or
R9 and Ri0 together with the heteroatom(s) to which they are attached form a 5- to 7-membered heterocycle, saturated or unsaturated, comprising 0-2 additional heteratoms selected from the group consisting of O, N and S, wherein said heterocycle is optionally substituted with one or more susbstituents selected from the group consisting of H, halo, Ci_iOalkyl, Ci_i0cycloalkyl, Ci_6alkenyl, =0, C(0)Ci_3alkyl, and
In a second aspect, the present invention provides a method of treatment or prophylaxis of a viral infection in a subject comprising administering to said subject an effective amount of a compound of formula (I) or a pharmaceutically acceptable derivative, salt or prodrug thereof.
In a third aspect, there is provided the use of a compound of Formula I or a pharmaceutically acceptable derivative, salt or prodrug thereof in the preparation of a medicament for the treatment or prophylaxis of a viral infection in a subject.
In a fourth aspect, the present invention provides a pharmaceutical composition comprising a compound according to the first aspect and a pharmaceutically acceptable carrier, diluent or excipient. DETAILED DESCRIPTION OF THE INVENTION
In a first aspect, the present invention provides a compound of Formula I or a pharmaceutically acceptable derivative, salt or prodrug thereof wherein:
Figure imgf000006_0001
represents a double or single bond;
Ri is selected from the group consisting of H, C1-10alkyl, aryl and heteroaryl;
A is selected from the group consisting of H, OR2, SR2, SOR3, SO2R3, C(Rs)3, COR3, -CO2R3; =NR2, =0, NR4R5, -NR4SO2R5,
each R2 is independently selected from the group consisting of H, Ci_ioalkyl, Ci_iocycloalkyl, Ci_3alkylaryl, aryl;
each R3 is independently selected from the group consisting of H, Ci_ioalkyl, Ci_iocycloalkyl, Ci_3alkylaryl, halo, aryl;
each R4 and R5 is independently selected from the group consisting of H, C1-10alkyl, Ci.iocycloalkyl, C1-3alkylaryl, and aryl; or
R4 and R5 together with the heteroatom(s) to which they are attached form a 5- to 7-membered heterocycle, saturated or unsaturated, comprising 0-2 additional heteratoms selected from the group consisting of O, N and S, wherein said heterocycle is optionally substituted with Rn wherein Rn is one or more substituents selected from the group consisting of H, halo, C1-10alkyl, C1-3alkylaryl, C1-10cycloalkyl, C^alkenyl, =0, C(O)C i_3alkyl, and NR9Ri0.; B is selected from the group consisting of H, OR7, SR7, SOR8, SO2R8, C(R8)3, COR8, -CO2R8; =NR7, NR9Ri0, -NR9SO2Ri0,
each R7 is independently selected from the group consisting of H, Ci_iOalkyl, Ci_i0cycloalkyl, Ci_3alkylaryl, aryl;
each R8 is independently selected from the group consisting of H, C1-10alkyl, Ci_i0cycloalkyl, Ci_3alkylaryl, halo, aryl;
each R9 and Ri0 is independently selected from the group consisting of H, C1-10alkyl, Ci_i0cycloalkyl, Ci_3alkylaryl, and aryl; or
R9 and Ri0 together with the heteroatom(s) to which they are attached form a 5- to 7-membered heterocycle, saturated or unsaturated, comprising 0-2 additional heteratoms selected from the group consisting of O, N and S, wherein said heterocycle is optionally substituted with Ri2 wherein Ri2 is one or more substituents selected from the group consisting of H, halo, Ci_iOalkyl, Ci_3alkylaryl, Ci_i0cycloalkyl, Ci_6alkenyl, =0, C(O)C i_3alkyl, and NR9Ri0.
In an embodiment of the invention, Ri is selected from the group consisting of aryl and heteroaryl.
In one embodiment, Ri is optionally substituted phenyl. Preferably, the phenyl is substituted with one or more substituents independently selected from halo (more preferably fluoro), methoxy, and NHC(O)CH3.
In one preferred embodiment, Ri is 4-fluorophenyl.
In another preferred embdoment, Ri is 3,4-dimethoxyphenyl.
In one embodiment, A is OR2 wherein R2 is methyl.
In another embodiment, A is NR4R5.
In one form of this embodiment, R4 is H and R5 is Ci_iOalkyl. In another form, R4 is H and R5 is optionally substituted benzyl. Preferably, the one or more optional substituents are independently selected from the group consisting of halo (more preferably fluoro), SO2NH2, S O2NH(Ci. C3 alky 1), and S O2N(Ci. C3 alky I)2
In one embodiment, B is NR9R10 and R9 and Rio together with the heteroatom(s) to which they are attached form a 5- to 7-membered heterocycle, saturated or unsaturated, comprising 0-2 additional heterotoms selected from the group consisting of O, N and S, wherein said heterocycle is optionally substituted with one or more substituents selected from the group consisting of H, halo, C1-10alkyl, Ci_iocycloalkyl, Ci_6alkenyl, =0, C(O)C i-salkyl, and NR9Ri0.
In a preferred form, the heterocycle is selected from the group consisting of morpholine, piperidine,, and piperazine.
In a preferred form, the compound of formula I is a compound of formula II or III, wherein Ri, A, R9, Rio and Ri2 are as defined above.
Figure imgf000008_0001
II
Figure imgf000009_0001
III
As used herein, the term "halo" or "halogen" refers to fluorine (fluoro), chlorine (chloro), bromine (bromo) or iodine (iodo).
As used herein, the term "alkyl" either used alone or in compound terms such as NH(alkyl) or N(alkyl)2, refers to monovalent straight chain or branched hydrocarbon groups, having 1 to 3, 1 to 6, or 1 to 10 carbon atoms as appropriate. For example, suitable alkyl groups include, but are not limited to methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, pentyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 2-, 3- or 4-methylpentyl, 2-ethylbutyl, n-hexyl or 2-, 3-, 4- or 5-methylpentyl.
The term "cycloalkyl" as used herein, refers to cyclic hydrocarbon groups. Suitable cycloalkyl groups include, but are not limited to cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
The term "aryl" as used herein, refers to a C6-CiO aromatic hydrocarbon group, for example phenyl or naphthyl.
The term "alkylaryl" includes, for example, benzyl.
The term "heterocycle" when used alone or in compound words includes monocyclic, polycyclic, fused or conjugated hydrocarbon residues, preferably C3_6,wherein one or more carbon atoms (and where appropriate, hydrogen atoms attached thereto) are replaced by a heteroatom so as to provide a non-aromatic residue. Suitable heteroatoms include, O, N and S. Where two or more carbon atoms are replaced, this may be by two or more of the same heteroatom or by different heteroatoms. Suitable examples of heterocyclic groups may include pyrrolidinyl, piperidyl, piperazinyl, morpholino, quinolinyl, isoquinolinyl, thiomorpholino, dioxanyl,
2,2'-dimethyl-[l,3]-dioxolanyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydropyrrolyl etc.
The term "heteroaryl" includes a 5- or 6-membered heteroaromatic ring containing one or more heteroatoms selected from O, N and S. Suitable examples of heteroaryl groups include furanyl, thiophenyl, tetrazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, imidazolyl, pyrazolyl, pyridinyl, pyrimidinyl, oxazolyl, oxadiazolyl etc. The heteroaromatic ring may be fused to a 5- or 6-membered aromatic or heteroaromatic ring to form a bicyclic aromatic ring system eg benzofuran.
Unless otherwise stated, each alkyl, cycloalkyl, alkylaryl, aryl, heterocyclyl, or heteroaryl group may be optionally substituted with one or more of Ci-C3alkyl, C3-C6cycloalkyl, C6aryl, heterocyclyl, heteroaryl, d-C3alkylOH, alkylaryl, OH, OCi-C3alkyl, halo, CN, NO2, CO2H, CO2Ci_C3alkyl, CONH2, CONH(C i_C3alkyl), CON(C i_C3alkyl)2, NHCO(C i_C3alkyl), trifluoromethyl, NH2, NH(Ci_C3alkyl), N(Ci_C3alkyl)2, SO2NH2, S O2NH(Ci. C3 alkyl), S O2N(Ci. C3 alky I)2. For example, an optionally substituted aryl group may be 4-methylphenyl or 4-hydroxyphenyl group, and an optionally substituted alkyl group may be 2-hydroxyethyl, trifluoromethyl, or difluoromethyl. Each optional alkyl, cycloalkyl, alkylaryl, aryl, heterocyclyl, or heteroaryl substituent may also be optionally substituted.
Examples of optional substituents also include suitable nitrogen protecting groups (see "Protective Groups in Organic Synthesis" Theodora Greene and Peter Wuts, third edition, Wiley Interscience, 1999).
The salts of the compound of formula I are preferably pharmaceutically acceptable, but it will be appreciated that non-pharmaceutically acceptable salts also fall within the scope of the present invention, since these are useful as intermediates in the preparation of pharmaceutically acceptable salts.
The term "pharmaceutically acceptable derivative" may include any pharmaceutically acceptable salt, hydrate or prodrug, or any other compound which upon administration to a subject, is capable of providing (directly or indirectly) a compound of formula I or an antibacterially active metabolite or residue thereof.
Suitable pharmaceutically acceptable salts include, but are not limited to, salts of pharmaceutically acceptable inorganic acids such as hydrochloric, sulphuric, phosphoric, nitric, carbonic, boric, sulfamic, and hydrobromic acids, or salts of pharmaceutically acceptable organic acids such as acetic, propionic, butyric, tartaric, maleic, hydroxymaleic, fumaric, malic, citric, lactic, mucic, gluconic, benzoic, succinic, oxalic, phenylacetic, methanesulphonic, toluenesulphonic, benzenesulphonic, salicylic, sulphanilic, aspartic, glutamic, edetic, stearic, palmitic, oleic, lauric, pantothenic, tannic, ascorbic and valeric acids.
Base salts include, but are not limited to, those formed with pharmaceutically acceptable cations, such as sodium, potassium, lithium, calcium, magnesium, zinc, ammonium, alkylammonium such as salts formed from triethylamine, alkoxyammonium such as those formed with ethanolamine and salts formed from ethylenediamine, choline or amino acids such as arginine, lysine or histidine. General information on types of pharmaceutically acceptable salts and their formation is known to those skilled in the art and is as described in general texts such as "Handbook of Pharmaceutical salts'" P.H.Stahl, C.G.Wermuth, 1st edition, 2002, Wiley- VCH.
Basic nitrogen-containing groups may be quarternised with such agents as lower alkyl halide, such as methyl, ethyl, propyl, and butyl chlorides, bromides and iodides; dialkyl sulfates like dimethyl and diethyl sulfate; and others.
This invention also encompasses pharmaceutical compositions containing prodrugs of compounds of formula I. This invention also encompasses methods of treating or preventing a viral infection in a subject by administering prodrugs of compounds of the formula I. Compounds of formula I having free amino, amido, hydroxy or carboxylic groups can be converted into prodrugs.
Prodrugs include compounds wherein an amino acid residue, or a polypeptide chain of two or more (eg, two, three or four) amino acid residues which are covalently joined to free amino, hydroxy and carboxylic acid groups of compounds of formula I. The amino acid residues include the 20 naturally occurring amino acids commonly designated by three letter symbols and also include, 4-hydroxyproline, hydroxylysine, demosine, isodemosine, 3-methylhistidine, norvlin, beta-alanine, gamma-aminobutyric acid, citrulline, homocysteine, homoserine, ornithine and methionine sulfone. Prodrugs also include compounds wherein carbonates, carbamates, amides and alkyl esters which are covalently bonded to the above substituents of formula I through the carbonyl carbon prodrug sidechain. Prodrugs also include phosphate derivatives of compounds of formula I (such as acids, salts of acids, or esters) joined through a phosphorus-oxygen bond to a free hydroxyl of compounds of formula I.
It will also be recognised that the compounds of formula I may possess asymmetric centres and are therefore capable of existing in more than one stereoisomeric form. The invention thus also relates to compounds in substantially pure isomeric form at one or more asymmetric centres eg., greater than about 90% ee, such as about 95% or 97% ee or greater than 99% ee, as well as mixtures, including racemic mixtures, thereof. Such isomers may be prepared by asymmetric synthesis, for example using chiral intermediates, or by chiral resolution.
In one embodiment, the compound is selcted from one of the following compounds:
7-Methoxy-3-phenyl-pyrimido[5,4-e][l,2,4]triazine
7-Methoxy-3-phenyl-6H-pyrimido[5,4-e][l,2,4]triazin-5-one
7-Methoxy-3-phenyl-6H-pyrimido[5,4-e][l,2,4]triazin-5-ylideneamine
Ethyl-[3-(4-fluoro-phenyl)-7-methoxy-pyrimido[5,4-e][l,2,4]triazin-5-yl]-amine Benzyl-[3-(4-fluoro-phenyl)-7-methoxy-pyrimido[5,4-e][l,2,4]triazin-5-yl]-ami ne
Butyl- [3 -(4-fluoro-phenyl)-7-methoxy-pyrimido [5 ,4-e] [ 1 ,2,4]triazin-5 -yl] -amine
[3-(4-Fluoro-phenyl)-7-methoxy-pyrimido[5,4-e][l,2,4]triazin-5-yl]-isopropyl- amine
(4-Fluoro-benzyl)-[3-(4-fluoro-phenyl)-7-methoxy-pyrimido[5,4- e] [ 1 ,2,4]triazin-5-yl]-amine
[3-(4-Fluoro-phenyl)-pyrimido[5,4-e][l,2,4]triazin-7-yl]-methyl-amine
Butyl-[5-ethoxy-3-(4-fluoro-phenyl)-pyrimido[5,4-e][l,2,4]triazin-7-yl]-amine
Butyl-[3-(4-fluoro-phenyl)-l,2-dihydro-pyrimido[5,4-e][l,2,4]triazin-7-yl]- amine
Butyl-[3-(4-fluoro-phenyl)-5-methoxy-pyrimido[5,4-e][l,2,4]triazin-7-yl]-amine
Butyl-[3-(4-fluoro-phenyl)-pyrimido[5,4-e][l,2,4]triazin-7-yl]-amine
Ethyl-[3-(4-fluoro-phenyl)- 1 ,2-dihydro-pyrimido[5,4-e] [ 1 ,2,4]triazin-7-yl]- amine
[3-(4-Fluoro-phenyl)-pyrimido[5,4-e][l,2,4]triazin-7-yl]-isopropyl-amine
[3-(4-Fluoro-phenyl)-5-methoxy-pyrimido[5,4-e][l,2,4]triazin-7-yl]-isopropyl- amine
[5-Ethoxy-3-(4-fluoro-phenyl)-pyrimido[5,4-e][l,2,4]triazin-7-yl]-isopropyl- amine
Ethyl-[3-(4-fluoro-phenyl)-pyrimido[5,4-e][l,2,4]triazin-7-yl]-amine
Ethyl-[3-(4-fluoro-phenyl)-5-methoxy-pyrimido[5,4-e][l,2,4]triazin-7-yl]-amine
[5-Ethoxy-3-(4-fluoro-phenyl)-pyrimido[5,4-e][l,2,4]triazin-7-yl]-ethyl-amine Ethyl-[3-(4-fluoro-phenyl)-5-propoxy-pyrimido[5,4-e][l,2,4]triazin-7-yl]-amine
Benzyl-[3-(4-fluoro-phenyl)-l,2-dihydro-pyrimido[5,4-e][l,2,4]triazin-7-yl]- amine
Benzyl-[3-(4-fluoro-phenyl)-pyrimido[5,4-e][l,2,4]triazin-7-yl]-amine
Benzyl-[3-(4-fluoro-phenyl)-5-methoxy-pyrimido[5,4-e][l,2,4]triazin-7-yl]- amine
Benzyl-[5-ethoxy-3-(4-fluoro-phenyl)-pyrimido[5,4-e][l,2,4]triazin-7-yl]-amine
(4-Fluoro-benzyl)-[3-(4-fluoro-phenyl)-l,2-dihydro-pyrimido[5,4- e] [ 1 ,2,4]triazin-7-yl]-amine
(4-Fluoro-benzyl)-[3-(4-fluoro-phenyl)-pyrimido[5,4-e][l,2,4]triazin-7-yl]- amine
(4-Fluoro-benzyl)- [3 -(4-fluoro-phenyl)-5 -methoxy-pyrimido [5 ,4- e] [ 1 ,2,4]triazin-7-yl]-amine
[5-Ethoxy-3-(4-fluoro-phenyl)-pyrimido[5,4-e][l,2,4]triazin-7-yl]-(4-fluoro- benzyl)-amine
4-{[3-(4-Fluoro-phenyl)-pyrimido[5,4-e][l,2,4]triazin-7-ylamino]-methyl}- benzenesulfonamide
4-{[3-(4-Fluoro-phenyl)-l,2-dihydro-pyrimido[5,4-e][l,2,4]triazin-7-ylamino]- methyl} -benzenesulfonamide
(4-Fluoro-benzyl)-[3-(4-fluoro-phenyl)-5-morpholin-4-yl-pyrimido[5,4- e] [ 1 ,2,4]triazin-7-yl]-amine
(4-Fluoro-benzyl)-[3-(4-fluoro-phenyl)-5-(4-methyl-piperazin-l-yl)- pyrimido[5,4-e][l,2,4]triazin-7-yl]-amine 4-{[3-(4-Fluoro-phenyl)-pyrimido[5,4-e][l,2,4]triazin-7-ylamino]-methyl}-N,N- dimethyl-benzenesulfonamide
Benzyl-[3-(4-fluoro-phenyl)-5-morpholin-4-yl-pyrimido[5,4-e][l,2,4]triazin-7- yl] -amine
4-{[3-(4-Fluoro-phenyl)-5-morpholin-4-yl-pyrimido[5,4-e][l,2,4]triazin-7- ylamino]-methyl}-N,N-dimethyl-benzenesulfonamide
4-{[3-(4-Fluoro-phenyl)-5-(4-methyl-piperazin-l-yl)-pyrimido[5,4- e] [ 1 ,2,4]triazin-7-ylamino]-methyl} -N,N-dimethyl-benzenesulfonamide
Benzyl-[3 -(4-fluoro-phenyl)-5 -(4-methyl-piperazin- 1 -yl)-pyrimido [5 ,4- e][l,2,4]triazin-7-yl]-amine
4-{[3-(4-Fluoro-phenyl)-l,2-dihydro-pyrimido[5,4-e][l,2,4]triazin-7-ylamino]- methyl}-N-methyl-benzenesulfonamide
4- {[3 -(4-Fluoro-phenyl)-5 -(4-methyl-piperazin- l-yl)-pyrimido [5,4- e] [ 1 ,2,4]triazin-7-ylamino]-methyl} -N-methyl-benzenesulfonamide
4-{[3-(4-Fluoro-phenyl)-pyrimido[5,4-e][l,2,4]triazin-7-ylamino]-methyl}-N- methyl-benzenesulfonamide
[3-(3,4-Dimethoxy-phenyl)-l,2-dihydro-pyrimido[5,4-e][l,2,4]triazin-7-yl]-(4- fluoro-benzyl)-amine
[3-(3,4-Dimethoxy-phenyl)-pyrimido[5,4-e][l,2,4]triazin-7-yl]-(4-fluoro- benzyl)-amine
[3-(3,4-Dimethoxy-phenyl)-5-morpholin-4-yl-pyrimido[5,4-e][l,2,4]triazin-7- yl]-(4-fluoro-benzyl)-amine
[3 -(3, 4-Dimethoxy-phenyl)-5 -(4-methyl-piperazin- l-yl)-pyrimido [5,4- e] [ 1 ,2,4]triazin-7-yl]-(4-fluoro-benzyl)-amine N-5-Cyclohexyl-3-(3,4-dimethoxy-phenyl)-N-7-(4-fluoro-benzyl)-pyrimido[5,4- e] [ 1 ,2,4]triazine-5 ,7-diamine
3-(3,4-Dimethoxy-phenyl)-N-5-N-7-bis-(4-fluoro-benzyl)-pyrimido[5,4- e] [ 1 ,2,4]triazine-5 ,7-diamine
[3-(3,4-Dimethoxy-phenyl)-5-ethoxy-pyrimido[5,4-e][l,2,4]triazin-7-yl]-(4- fluoro-benzyl)-amine
N-[4-(7-Benzylamino-5-morpholin-4-yl-pyrimido[5,4-e][l,2,4]triazin-3-yl)- phenyl] -acetamide
l-[3-(4-Fluoro-phenyl)-7-imino-7,8-dihydro-5H-pyrimido[5,4-e][l,2,4]triazin- 6-yl]-ethanone
N-5-((S)-l-Benzyl-pyrrolidin-3-yl)-3-(3,4-dimethoxy-phenyl)-N-7-(4-fluoro- benzyl)-pyrimido [5 ,4-e] [ 1 ,2,4]triazine-5 ,7-diamine
Benzyl-[3-(4-fluoro-phenyl)-5-piperazin-l-yl-pyrimido[5,4-e][l,2,4]triazin-7- yl] -amine
3-(4-Fluoro-phenyl)-l,2-dihydro-pyrimido[5,4-e][l,2,4]triazin-7-ylamine
3-(4-Fluoro-phenyl)-5-(4-methyl-piperazin-l-yl)-pyrimido[5,4-e][l,2,4]triazin- 7-ylamine
4-{[3-(4-Fluoro-phenyl)-5-morpholin-4-yl-pyrimido[5,4-e][l,2,4]triazin-7- ylamino]-methyl}-benzenesulfonamide
3-(4-Fluoro-phenyl)-5-morpholin-4-yl-pyrimido[5,4-e][l,2,4]triazin-7-ylamine
3-(4-Fluoro-phenyl)-pyrimido[5,4-e][l,2,4]triazin-7-ylamine
5-Ethoxy-3-(4-fluoro-phenyl)-pyrimido[5,4-e][l,2,4]triazin-7-ylamine
[5-(4-Allylamino-piperidin-l-yl)-3-(4-fluoro-phenyl)-pyrimido[5,4- e] [ 1 ,2,4]triazin-7-yl]-benzyl-amine Benzyl-[3-(3,4-dimethoxy-phenyl)-l,2-dihydro-pyrimido[5,4-e][l,2,4]triazin-7- yl] -amine
Cyclohexyl-[3-(4-fluoro-phenyl)-l,2-dihydro-pyrimido[5,4-e][l,2,4]triazin-7- yl] -amine
4-{[3-(4-Fluoro-phenyl)-5-morpholin-4-yl-pyrimido[5,4-e][l,2,4]triazin-7- ylamino]-methyl}-N-methyl-benzenesulfonamide
1 -[7-Benzylamino-3-(4-fluoro-phenyl)-pyrimido[5,4-e] [ 1 ,2,4]triazin-5-yl]- piperidin-4-one
4-{[3-(4-Fluoro-phenyl)-5-(4-methyl-piperazin-l-yl)-pyrimido[5,4- e] [ 1 ,2,4]triazin-7-ylamino]-methyl} -benzenesulfonamide
[3-(4-Fluoro-phenyl)-l,2-dihydro-pyrimido[5,4-e][l,2,4]triazin-7-yl]-phenyl- amine
[3-(4-Fluoro-phenyl)-5-(4-methyl-piperazin-l-yl)-pyrimido[5,4-e][l,2,4]triazin- 7-yl]-phenyl-amine
[3-(4-Fluoro-phenyl)-5-morpholin-4-yl-pyrimido[5,4-e][l,2,4]triazin-7-yl]- phenyl-amine
[3-(4-Fluoro-phenyl)-pyrimido[5,4-e][l,2,4]triazin-7-yl]-phenyl-amine
Cyclohexyl-[3-(4-fluoro-phenyl)-5-morpholin-4-yl-pyrimido[5,4- e] [ 1 ,2,4]triazin-7-yl]-amine
Cyclohexyl-[3-(4-fluoro-phenyl)-pyrimido[5,4-e][l,2,4]triazin-7-yl]-amine
Benzyl-[3-(3,4-dimethoxy-phenyl)-5-ethoxy-pyrimido[5,4-e][l,2,4]triazin-7-yl]- amine
Benzyl-[3-(3,4-dimethoxy-phenyl)-5-(4-methyl-piperazin-l-yl)-pyrimido[5,4- e] [ 1 ,2,4]triazin-7-yl]-amine Benzyl-[3-(3,4-dimethoxy-phenyl)-5-morpholin-4-yl-pyrimido[5,4- e] [ 1 ,2,4]triazin-7-yl]-amine
Benzyl-[3-(3,4-dimethoxy-phenyl)-pyrimido[5,4-e][l,2,4]triazin-7-yl]-amine
3-(3,4-Dimethoxy-phenyl)-N-7-(4-fluoro-benzyl)-N-5-((S)-l-phenyl-ethyl)- pyrimido[5 ,4-e] [ 1 ,2,4]triazine-5 ,7-diamine
4-((5-ethoxy-3-(4-fluorophenyl)pyrimido[5,4-e][l,2,4]triazin-7- ylamino)methyl)-N-methylbenzenesulfonamide
N-cyclohexyl-5-ethoxy-3-(4-fluorophenyl)pyrimido[5,4-e][l,2,4]triazin-7-amine
3 -(3 ,4-Dimethoxyphenyl)-N-(4-fluorobenzyl)-5 -(piperazin- 1 -yl)pyrimido [5 ,4- e][l,2,4]triazin-7-amine
N-Cyclohexyl-3 -(4-fluoropheny l)-5 -(4-methylpiperazin- 1 -yl)pyrimido [5 ,4- e] [ 1 ,2,4]triazin-7-amine
l-(4-(7-(Benzylamino)-3-(4-fluorophenyl)pyrimido[5,4-e][l,2,4]triazin-5- yl)piperazin- 1 -yl)ethanone
l-(7-(Benzylamino)-3-(4-fluorophenyl)pyrimido[5,4-e][l,2,4]triazin-5- yl)piperidin-4-ol
4-((3-(4-Fluorophenyl)-5 -(piperazin- 1 -yl)pyrimido[5,4-e] [ 1 ,2,4]triazin-7- ylamino)methyl)benzenesulfonamide
7-Ethoxy-N-(4-fluorobenzyl)-3-(4-fluorophenyl)pyrimido[5,4-e][l,2,4]triazin-5- amine
N-(4-Fluorobenzyl)-3-(4-fluorophenyl)-7-propoxypyrimido[5,4-e][l,2,4]triazin- 5 -amine
7-Butoxy-N-(4-fluorobenzyl)-3-(4-fluorophenyl)pyrimido[5,4-e][l,2,4]triazin-5- amine N-Benzyl-5-(4-(cyclohexylamino)piperidin- 1 -yl)-3-(4- fluorophenyl)pyrimido[5,4-e][l,2,4]triazin-7-amine
N-Benzyl-5 -(4-(diethylamino)piperidin- 1 -yl)-3 -(4-fluorophenyl)pyrimido [5 ,4- e] [ 1 ,2,4]triazin-7-amine
N-Benzyl-5 -(4-(butylamino)piperidin-l-yl)-3-(4-fluorophenyl)pyrimido [5,4- e] [ 1 ,2,4]triazin-7-amine
N-Benzyl-5 -(4-(4-fluorobenzylamino)piperidin- 1 -yl)-3-(4- fluorophenyl)pyrimido[5,4-e][l,2,4]triazin-7-amine
5-(4-(Allylamino)piperidin-l-yl)-3-(3,4-dimethoxyphenyl)-N-(4- fluorobenzyl)pyrimido [5 ,4-e] [ 1 ,2,4]triazin-7-amine
3 -(3 ,4-Dimethoxyphenyl)-N-(4-fluorobenzyl)-5 -(4-morpholinopiperidin- 1 - yl)pyrimido[5,4-e][l,2,4]triazin-7-amine
3-(3,4-Dimethoxyphenyl)-N-(4-fluorobenzyl)-5-(4-(4- fluorobenzylamino)piperidin- 1 -yl)pyrimido [5 ,4-e] [ 1 ,2,4
Preferably, the compound is selected from the compounds set out below:
Figure imgf000020_0001
In a second aspect, the present invention provides a method of treatment or prophylaxis of a viral infection in a subject comprising administering to said subject an effective amount of a compound of formula (I) or a pharmaceutically acceptable derivative, salt or prodrug thereof.
In a third aspect, there is provided the use of a compound according to the first aspect or a pharmaceutically acceptable derivative, salt or prodrug thereof, or a composition according to the fourth aspect, in the preparation of a medicament for the treatment or prophylaxis of a viral infection in a subject. The term "effective amount" means the amount of the subject composition that will elicit the biological or medical response of a tissue, system, animal or human that is being sought by the researcher, veterinarian, medical doctor or other clinician.
The terms "administration of and or "administering a" compound should be understood to mean providing a compound of the invention to the individual in need of treatment.
As would be understood by those skilled in the art of treating viral infections, and particularly HCV infections, the term "treatment" does not necessarily mean that the viral infection is completely cured. The term "treatment" encompasses any reduction in the viral load and/or inhibition of replication in the subject being treated.
The compounds of the present invention may be administered by any suitable means, for example, parenterally, such as by subcutaneous, intravenous, intramuscular, or intracisternal injection or infusion techniques (e.g., as sterile injectable aqueous or non-aqueous solutions or suspensions).
In addition to primates, such as humans, a variety of other mammals can be treated according to the method of the present invention. For instance, mammals including, but not limited to, cows, sheep, goats, horses, dogs, cats, guinea pigs, rats or other bovine, ovine, equine, canine, feline, rodent or murine species can be treated. However, the method can also be practiced in other species, such as avian species (e.g., chickens). Preferbly, the subject is a human being, whether male or female.
Preferably, the viral infection of the second and third aspects is a HCV infection.
In a fourth aspect, the present invention provides pharmaceutical composition comprising a compound according to the first aspect and a pharmaceutically acceptable carrier, diluent or excipient.
The compositions of the present invention may contain other therapeutic agents as described below, and may be formulated, for example, by employing conventional solid or liquid vehicles or diluents, as well as pharmaceutical additives of a type appropriate to the mode of desired administration (for example, excipients, binders, preservatives, stabilizers, flavors, etc.) according to techniques such as those well known in the art of pharmaceutical formulation.
Pharmaceutical formulations include those for oral, rectal, nasal, topical (including buccal and sub-lingual), vaginal or parenteral (including intramuscular, sub-cutaneous and intravenous) administration or in a form suitable for administration by inhalation or insufflation. The compounds of the invention, together with a conventional adjuvant, carrier or diluent, may thus be placed into the form of pharmaceutical compositions and unit dosages thereof, and in such form may be employed as solids, such as tablets or filled capsules, or liquids as solutions, suspensions, emulsions, elixirs or capsules filled with the same, all for oral use, in the form of suppositories for rectal administration; or in the form of sterile injectable solutions for parenteral (including subcutaneous) use.
The term "composition" as used herein is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts. By "pharmaceutically acceptable" it is meant the carrier, diluent or excipient must be compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.
The pharmaceutical compositions for the administration of the compounds of this invention may conveniently be presented in dosage unit form and may be prepared by any of the methods well known in the art of pharmacy. All methods include the step of bringing the active ingredient into association with the carrier which constitutes one or more accessory ingredients. In general, the pharmaceutical compositions are prepared by uniformly and intimately bringing the active ingredient into association with a liquid carrier or a finely divided solid carrier or both, and then, if necessary, shaping the product into the desired formulation. In the pharmaceutical composition the active object compound is included in an amount sufficient to produce the desired effect upon the process or condition of diseases. As used herein, the term "composition" is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts.
The pharmaceutical compositions may be in the form of a sterile injectable aqueous or oleagenous suspension. This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example as a solution in 1,3-butane diol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil may be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid find use in the preparation of injectables.
The pharmaceutical composition and methods of the present invention may further comprise other therapeutically active compounds which are usually applied in the treatment of the above mentioned pathological conditions. Selection of the appropriate agents for use in combination therapy may be made by one of ordinary skill in the art, according to conventional pharmaceutical principles. The combination of therapeutic agents may act synergistically to effect the treatment or prevention of the various disorders described above. Using this approach, one may be able to achieve therapeutic efficacy with lower dosages of each agent, thus reducing the potential for adverse side effects.
When other therapeutic agents are employed in combination with the compounds of the present invention they may be used for example in amounts as noted in the Physician Desk Reference (PDR) or as otherwise determined by one of ordinary skill in the art.
In the treatment or prevention of conditions which require HIV inhibition or HIV integrase enzyme inhibition an appropriate dosage level will generally be about 0.01 to 500 mg per kg patient body weight per day which can be administered in single or multiple doses. Preferably, the dosage level will be about 0.1 to about 250 mg/kg per day; more preferably about 0.5 to about 100 mg/kg per day. A suitable dosage level may be about 0.01 to 250 mg/kg per day, about 0.05 to 100 mg/kg per day, or about 0.1 to 50 mg/kg per day. Within this range the dosage may be 0.05 to 0.5, 0..5 to 5 or 5 to 50 mg/kg per day. For oral administration, the compositions are preferably provided in the form of tablets containing 1.0 to 1000 milligrams of the active ingredient, particularly 1.0, 5.0, 10.0, 15.0. 20.0, 25.0, 50.0, 75.0, 100.0, 150.0, 200.0, 250.0, 300.0, 400.0, 500.0, 600.0, 750.0, 800.0, 900.0, and 1000.0 milligrams of the active ingredient for the symptomatic adjustment of the dosage to the patient to be treated. The compounds may be administered on a regimen of 1 to 4 times per day, preferably once or twice per day.
It will be understood, however, that the specific dose level and frequency of dosage for any particular patient may be varied and will depend upon a variety of factors including the activity of the specific compound employed, the metabolic stability and length of action of that compound, the age, body weight, general health, sex, diet, mode and time of administration, rate of excretion, drug combination, the severity of the particular condition, and the host undergoing therapy.
In order that the nature of the present invention may be more clearly understood preferred forms thereof will now be described by reference to the following non- limiting examples.
Reaction Schemes
Route 1
Figure imgf000025_0001
R2ONa
JCS, 1964, 4986
Figure imgf000025_0002
Route 2
Figure imgf000025_0003
Route 3
Figure imgf000026_0001
Route 4
Figure imgf000026_0002
Route 5
Figure imgf000026_0003
Route 6
Figure imgf000027_0001
Route 7
Figure imgf000027_0002
Route 8
Figure imgf000027_0003
Example 1 Compounds Made by Route 1
Example 1.1 7-Methoxy-3-phenyl-pyrimido[5,4-e][l,2,4]triazine
Figure imgf000028_0001
Step A: 2,4-Dichloro-5-nitropyrimidine
Figure imgf000028_0002
Following the procedure in Route 1, a mixture of 5-nitrouracil (5.0 g, 31.8 mmol), phosphoryl chloride (25.0 ml, 274 mmol) and dimethylaniline (6 ml, 47.8 mmol) was heated with occasional shaking, until the reaction commenced. When this had subsided the mixture was refluxed for 2 h, then cooled, and most of the phosphoryl chloride evaporated off under reduced pressure. The residue was poured on ice with vigorous stirring and, after 5 minutes, extracted with ether, the extract was washed with water and dried with Na2SO4. Removal of the ether and distillation of the residue gave the title compound as a pale yellow oil (4.2 g, 68%). 1H NMR (CDCl3, 300 MHz): δ 9.16 (s, IH).
Step B: N'-(2-Chloro-5-nitropyrimidin-4-yl)benzohydrazide
h
Figure imgf000028_0003
2, 4-dichloro-5-nitropyrimidine (0.4Og, 2.1 mmol) was dissolved in ethanol (10 m L) and cooled to 00C. Solid benzohydrazide (0.28 g, 2.1 mmol) was added in small portions during 0.5 h with stirring. The temperature was not allowed to rise above 100C during the addition. After stirring for a further 0.25 h, a solution of sodium hydrogen carbonate (0.5 mL) was added dropwise. The rate of addition was controlled so that the mixture was kept acidic and the temperature was maintained below 100C. The mixture was cooled overnight in a refrigerator, filtered, washed with a little cold ethanol and hexane and dried to give a yellow solid (0.45 g, 78%). MS (ESI, Pos. 1.5 kV) m/z 292.0 (M-H)".
Step C:N'-(2-Methoxy-5-nitropyrimidin-4-yl)benzohydrazide
MeOΛA-Vh H O
N'-(2-chloro-5-nitropyrimidin-4-yl)benzohydrazide (0.2Og, 0.68 mmol) was added in small portions to the mixture of sodium methoxide (0.11 g, 2.04 mmol) and methanol (5 mL). After the reaction mixture was refluxed for 2 h the mixture was filtered, concentrated and subjected to flash chromatography to afford a brown solid (0.12 g, 61%). 1H NMR (CDCl3, 300 MHz): δ 10.40 (br, IH), 9.16 (s, IH), 8.99 (br, IH), 7.89 (d, J = 8.1 Hz, 2H), 7.60 (t, J = 6.9 Hz, IH), 7.50 (t, J = 6.9 Hz, 2H), 4.03 (s, 3H).
Step D: 7-Methoxy-3-phenyl-l ,2-dihydropyrimido[5,4-e] [ 1 ,2,4]triazine
Figure imgf000029_0001
The 5-nitropyrimidine (1.0 g, 3.46 mmol) was hydrogenated in methanol (15 mL) over palladium-carbon (0.2 g, 20%) at 20°C/760 mm. After 3 h, the mixture was filtered, concentrated and then was re-dissolved in dry methanol (10 mL) and methanolic HCl (15 mL). The mixture was heated under reflux for 3 h and concentrated to give crude triazine as an orange solid (0.79 g, 95%). MS (ESI, Pos. 1.5 kV) m/z 242.1 (M+H)+. Step E: 7-Methoxy-3-phenylpyrimido[5,4-e][l,2,4]triazine
Figure imgf000030_0001
A mixture of dihydro-triazine (0.15 g, 0.62 mmol), silver oxide (0.72 g, 3.1 mmol) and barium oxide (0.95 g, 6.2 mmol) was stirred in anhydrous tetrahydrofuran (20 mL) overnight under reflux. The filtrate was concentrated and purified through flash chromatography to give an orange red solid (0.022 g, 15%). 1H NMR (CDCl3, 300 MHz): δ 9.74 (s, IH), 8.72-8.70 (m, 2H), 7.62-7.60 (m, 3H), 4.35 (s, 3H); MS (ESI, Pos. 1.5 kV) m/z 272 (M+MeOH+H)+.
Example 2 Compounds Made by Route 2
Example 2.1 7-Methoxy-3-phenyl-6H-pyrimido[5,4-e][l,2,4]triazin-5-one
Figure imgf000030_0002
Following the procedure in Route 2, 1 N aqueous sodium hydroxide (10 mL, 10 mmol) was added dropwise to a solution of 7-methoxy-3-phenyl-l,2-dihydropyrimido[5,4- e][l,2,4]triazine (from Step D in Example 1.1, 0.20 g, 0.83 mmol) in methanol (5 mL) at 0 0C. After stirring at room temperature for Ih, the solution, adjusted to pH 3, was concentrated to 5 mL, filtered and washed to give the title product as a pale yellow solid (0.07 g, 33%). 1H NMR (CD3OD, 300 MHz): δ 8.60-8.57(m, 2H), 7.57-7.50 (m, 4H), 4.19 (s, 3H); MS (ESI, Pos. 1.5 kV) m/z 278 (M+Na)+. Example 3 Compounds Made by Route 3
Example 3.1 Benzyl-[3-(4-fluoro-phenyl)-l,2-dihydro-pyrimido[5,4- e][l,2,4]triazin-7-yl]-amine
Figure imgf000031_0001
Step A: N'-(2-(Benzylamino)-5-nitropyrimidin-4-yl)-4-fluorobenzohydrazide
Figure imgf000031_0002
Following the procedure in Route 3, N'-(2-chloro-5-nitropyrimidin-4-yl)-4- fluorobenzohydrazide (prepared as step B in Example 1.1, 1.0 g, 3.21 mmol) was added in small portions to a solution of benzyl amine (0.68 mL, 6.24 mmol) and Et3N (1.80 mL, 12.84 mmol) in ethanol (30 mL) at room temperature. After stirring for another 1 h, the mixture was filtered and washed to give the title product as a pale yellow solid (1.20 g, 98%). 1H NMR (DMSO-d6, 300 MHz): δ 10.62-10.12 (br, IH), 8.97-8.89 (m, 2H), 8.03-7.93 (m, 2H), 7.39-7.29 (m, 4H), 7.22-7.06 (m, 4H), 4.55 (d, J = 6.3 Hz, 0.5H), 4.35 (d, J = 6.3 Hz, 1.5H); MS (ESI, Pos. 1.5 kV) m/z 405 (M+Na)+.
Step B: Benzyl-[3-(4-fluoro-phenyl)-l,2-dihydro-pyrimido[5,4-e][l,2,4]triazin-7-yl]- amine
Figure imgf000031_0003
The above 5-nitropyrimidine (1.0 g, 2.62 mmol) was hydrogenated in methanol (20 niL) over palladium-carbon (0.2 g, 20%) at 20° C/l arm. After 3 h, the mixture was filtered, concentrated and then was re-dissolved in dry methanol (15 mL) and methanolic HCl (15 mL). The mixture was heated under reflux for 3 hr, concentrated and recrystallized from methanol to give the title compound as a brown powder (0.70 g, 80%). 1H NMR (DMSO-d6, 300 MHz): δ 10.97 (br, IH), 9.65 (s, IH), 8.54 (br, IH), 7.76-7.71 (m, 2H), 7.37-7.24 (m, 7H), 6.52 (s, IH), 4.37 (d, J = 6.3 Hz, 2H); MS (ESI, Pos. 1.5 kV) m/z 335.0 (M+H)+.
Example 3.2 Benzyl-[3-(4-fluoro-phenyl)-pyrimido[5,4-e][l,2,4]triazin-7-yl]-amine
Figure imgf000032_0001
A mixture of dihydro-triazine (From Example 3.1, 0.15 g, 0.45 mmol), silver oxide (0.31 g, 1.35 mmol) and Na2SO4 (5.0 g) was stirred in dry methanol (10 mL) under reflux overnight. The filtrate was concentrated and purified through flash chromatography to give two major products. The less polar product is the title compound as an orange red solid (0.030 g, 20%). 1H NMR (CDCl3, 300 MHz): δ 9.39 (s, IH), 8.67-8.62 (m, 2H), 7.49-7.24 (m, 7H), 6.29 (br, IH), 4.94 (d, J = 5.7 Hz, 2H); MS (ESI, Pos. 1.5 kV) m/z 333.0 (M+H)+.
The more polar product isloated from Example 3.2 is decribed in Example 3.3
Example 3.3 Benzyl-[3-(4-fluoro-phenyl)-5-methoxy-pyrimido[5,4-e][l,2,4]triazin- 7-yl]-amine
Figure imgf000033_0001
As the Example 3.2 exemplified, the more polar productt is the title compound as a pale yellow solid (0.050 g, 31%). 1H NMR (CDCl3, 300 MHz): δ 8.94 (d, J = 6.3 Hz, 0.2H), 8.85 (d, J = 6.3 Hz, 0.8H), 8.49-8.43 (m, 2H), 7.45-7.23 (m, 7H), 4.72 (d, J= 6.0 Hz, 1.6H), 4.67 (d, J = 6.0 Hz, 0.4H), 4.16 (s, 2.4H), 4.14 (s, 0.6H); MS (ESI, Pos. 1.5 kV) m/z 363.1 (M+H)+.
Example 3.4 Benzyl-[5-ethoxy-3-(4-fluoro-phenyl)-pyrimido[5,4-e][l,2,4]triazin-7- yl] -amine
Figure imgf000033_0002
A mixture of dihydro-triazine (From Example 3.1, 0.10 g, 0.30 mmol), silver oxide (0.21 g, 0.90 mmol) and Na2SO4 (5.0 g) was stirred in dry ethanol (10 mL) for 24 h under reflux. The filtrate was concentrated and purified through flash chromatography to give the title compound as a pale yellow solid (0.043 g, 38%). 1H NMR (DMSO-d6, 300 MHz): δ 8.90 (d, J= 6.3 Hz, 0.2H), 8.78 (d, J = 6.3 Hz, 0.8H), 8.47-8.42 (m, 2H), 7.44-7.22 (m, 7H), 4.71-4.58 (m, 4H), 1.48 (t, J = 7.2 Hz, 2.4H), 1.39 (t, J = 7.2 Hz, 0.6H); MS (ESI, Pos. 1.5 kV) m/z 363.1 (M+H)+. Example 3.5 Butyl-[3-(4-fluoro-phenyl)-l,2-dihydro-pyrimido[5,4-e][l,2,4]triazin- 7-yl]-amine
Figure imgf000034_0001
This compound was prepared substantially as described in Example 3.1 using appropriate starting materials. 1U NMR (DMSO-d6, 300 MHz): δ 10.93 (br, IH), 9.56 (s, IH), 8.07 (br, IH), 7.76-7.71 (m, 2H), 7.34-7.28 (m, 2H), 6.49 (s, IH), 3.18-3.16 (m, 2H), 1.50-1.41 (m, 2H), 1.36-1.24 (m, 2H), 0.88 (t, J = 7.5 Hz, 3H); MS (ESI, Pos. 1.5 kV) m/z 301.1 (M+H)+.
Example 3.6 Butyl-[3-(4-fluoro-phenyl)-pyrimido[5,4-e][l,2,4]triazin-7-yl]-amine
Figure imgf000034_0002
This compound was prepared substantially as described in Example 3.2 using appropriate starting materials. 1H NMR (CDCl3, 300 MHz): δ 9.34 (s, IH), 8.64-8.59 (m, 2H), 7.26-7.20 (m, 2H), 5.97 (br, IH), 3.75-3.68 (m, 2H), 1.79-1.69 (m, 2H), 1.55- 1.46 (m, 2H), 1.00 (t, J = 7.5 Hz, 3H); MS (ESI, Pos. 1.5 kV) m/z 299.1 (M+H)+.
Example 3.7 Butyl-[3-(4-fluoro-phenyl)-5-methoxy-pyrimido[5,4-e][l,2,4]triazin-7- yl] -amine
Figure imgf000035_0001
This compound was prepared substantially as described in Example 3.3 using appropriate starting materials. 1H NMR (CDCl3, 300 MHz): δ 8.62-8.57 (m, 2H), 7.25- 7.19 (m, 2H), 5.96 (br, 0.15H), 5.60 (br, 0.85H), 4.29 (s, 0.45H), 4.21 (s, 2.55H), 3.74- 3.57 (m, 2H), 1.78-1.68 (m, 2H), 1.57-1.47 (m, 2H), 1.01 (t, J = 7.5 Hz, 3H); MS (ESI, Pos. 1.5 kV) m/z 329 A (M+H)+.
Example 3.8 Butyl-[5-ethoxy-3-(4-fluoro-phenyl)-pyrimido[5,4-e][l,2,4]triazin-7- yl] -amine
Figure imgf000035_0002
This compound was prepared substantially as described in Example 3.4 using appropriate starting materials. 1H NMR (CDCl3, 300 MHz): δ 8.60-8.56 (m, 2H), 7.26- 7.17 (m, 2H), 6.47 (br, 0.25H), 5.54 (br, 0.75H), 4.75 (dd, J = 6.9, 6.9 Hz, 0.5H), 4.64 (dd, J = 6.9, 6.9 Hz, 1.5H), 3.71-3.55 (m, 2H), 1.68-1.42 (m, 6H), 0.99 (t, J = 7.2 Hz, 3H); MS (ESI, Pos. 1.5 kV) m/z 343.2 (M+H)+. Example 3.9 Ethyl-[3-(4-fluoro-phenyl)-l,2-dihydro-pyrimido[5,4-e][l,2,4]triazin- 7-yl]-amine
Figure imgf000036_0001
This compound was prepared substantially as described in Example 3.1 using appropriate starting materials. 1H NMR (DMSO-d6, 300 MHz): δ 10.94 (br, IH), 9.54 (s, IH), 8.07 (br, IH), 7.76-7.71 (m, 2H), 7.34-7.28 (m, 2H), 6.47 (s, IH), 3.25-3.16 (m, 2H), 1.09 (t, J = 7.2 Hz, 3H); MS (ESI, Pos. 1.5 kV) m/z 273.0 (M+H)+.
Example 3.10 Ethyl-[3-(4-fluoro-phenyl)-pyrimido[5,4-e][l,2,4]triazin-7-yl]-amine
Figure imgf000036_0002
This compound was prepared substantially as described in Example 3.2 using appropriate starting materials. 1H NMR (DMSO-d6, 300 MHz): δ 9.49 (s, IH), 8.73 (br, IH), 8.52-8.47 (m, 2H), 7.46-7.40 (m, 2H), 3.56-3.47 (m, 2H), 1.26 (t, J = 7.5 Hz, 3H); MS (ESI, Pos. 1.5 kV) m/z 271.1 (M+H)+.
Example 3.11 Ethyl-[3-(4-fluoro-phenyl)-5-methoxy-pyrimido[5,4-e][l,2,4]triazin- 7-yl]-amine
Figure imgf000036_0003
This compound was prepared substantially as described in Example 3.3 using appropriate starting materials. 1H NMR (CDCl3, 300 MHz): δ 8.62-8.57 (m, 2H), 7.27- 7.19 (m, 2H), 6.10 (br, 0.20H), 5.61 (br, 0.8H), 4.29 (s, 0.6H), 4.20 (s, 2.4H), 3.79-3.62 (m, 2H), 1.37 (t, J = 7.2 Hz, 3H); MS (ESI, Pos. 1.5 kV) m/z 301.0 (M+H)+.
Example 3.12 [5-Ethoxy-3-(4-fluoro-phenyl)-pyrimido[5,4-e][l,2,4]triazin-7-yl]- ethyl-amine
Figure imgf000037_0001
This compound was prepared substantially as described in Example 3.4 using appropriate starting materials. 1U NMR (CDCl3, 300 MHz): δ 8.62-8.58 (m, 2H), 7.28- 7.19 (m, 2H), 6.29 (br, 0.25H), 5.54 (br, 0.75H), 4.79-4.61 (m, 2H), 3.78-3.59 (m, 2H), 1.60-1.55 (m, 3H), 1.39-1.34 (m, 3H); MS (ESI, Pos. 1.5 kV) m/z 315.1 (M+H)+.
Example 3.13 Ethyl-[3-(4-fluoro-phenyl)-5-propoxy-pyrimido[5,4-e][l,2,4]triazin- 7-yl]-amine
Figure imgf000037_0002
This compound was prepared substantially as described in Example 3.4 using appropriate starting materials. 1U NMR (CDCl3, 300 MHz): δ 8.58-8.44 (m, 2H), 7.28- 7.19 (m, 2H), 5.58 (br, 0.4H), 4.69-4.49 (m, 2H), 3.75-3.71 (m, 2H), 3.21 (br, 0.6H), 2.04-1.94 (m, 2H), 1.38-1.34 (m, 3H), 1.16-1.09 (m, 3H); MS (ESI, Pos. 1.5 kV) m/z 329.0 (M+H)+. Example 3.14 (4-Fluoro-benzyl)-[3-(4-fluoro-phenyl)-l,2-dihydro-pyrimido[5,4- e][l,2,4]triazin-7-yl]-amine
Figure imgf000038_0001
This compound was prepared substantially as described in Example 3.1 using appropriate starting materials. 1H NMR (DMSO-d6, 300 MHz): δ 10.99 (br, IH), 9.67 (s, IH), 8.56 (br, IH), 7.78-7.73 (m, 2H), 7.39-7.30 (m, 4H), 7.27-7..17 (m, 2H), 6.53 (s, IH), 4.43 (d, J = 5.7 Hz, 2H); MS (ESI, Pos. 1.5 kV) m/z 353.1 (M+H)+.
Example 3.15 (4-Fluoro-benzyl)-[3-(4-fluoro-phenyl)-pyrimido[5,4-e][l,2,4]triazin- 7-yl]-amine
Figure imgf000038_0002
This compound was prepared substantially as described in Example 3.2 using appropriate starting materials. 1U NMR (CDCl3, 300 MHz): δ 9.40 (s, IH), 8.67-8.62 (m, 2H), 7.48-7.44 (m, 2H), 7.26-7.23 (m, 2H), 7.11-7.05 (m, 2H), 6.27 (br, IH), 4.91 (d, J = 5.7 Hz, 2H); MS (ESI, Pos. 1.5 kV) m/z 351.1 (M+H)+. Example 3.16 (4-Fluoro-benzyl)-[3-(4-fluoro-phenyl)-5-methoxy-pyrimido[5,4- e][l,2,4]triazin-7-yl]-amine
Figure imgf000039_0001
This compound was prepared substantially as described in Example 3.3 using appropriate starting materials. 1H NMR (DMSO-d6, 300 MHz): δ 8.91 (t, / = 6.3 Hz, 0.2H), 8.83 (t, J = 6.3 Hz, 0.8H), 8.47-8.42 (m, 2H), 7.49-7.38 (m, 4H), 7.19-7.13 (m, 2H), 4.68-4.62 (m, 2H), 4.15 (s, 3H); MS (ESI, Pos. 1.5 kV) m/z 381.1 (M+H)+.
Example 3.17 [5-Ethoxy-3-(4-fluoro-phenyl)-pyrimido[5,4-e][l,2,4]triazin-7-yl]-(4- fluoro-benzyl)-amine
Figure imgf000039_0002
This compound was prepared substantially as described in Example 3.4 using appropriate starting materials. 1H NMR (DMSO-d6, 300 MHz): δ 8.89 (t, J = 6.3 Hz, 0.2H), 8.78 (t, J = 6.3 Hz, 0.8H), 8.47-8.43 (m, 2H), 7.49-7.39 (m, 4H), 7.19-7.13 (m, 2H), 4.68-4.58 (m, 4H), 1.48 (t, J = 6.9 Hz, 0.6H), 1.40 (t, J= 6.9 Hz, 2.4H); MS (ESI, Pos. 1.5 kV) m/z 395.1 (M+H)+. Example 3.18 4-{[3-(4-Fluoro-phenyl)-l,2-dihydr o-pyr imido[5,4-e][l,2,4]triazin-7- ylamino]-methyl}-benzenesulfonamide
Figure imgf000040_0001
This compound was prepared substantially as described in Example 3.1 using appropriate starting materials. 1H NMR (DMSO-d6, 300 MHz): δ 11.00 (br, IH), 9.59 (s, IH), 8.57 (br, IH), 7.81-7.71 (m, 4H), 7.59-7.46 (m, 2H), 7.40 (s, 2H), 7.35-7.28 (m, 2H), 6.49 (s, IH), 4.53 (d, J = 6.3 Hz, 2H); MS (ESI, Pos. 1.5 kV) m/z 414.1 (M+H)+.
Example 3.19 4-{[3-(4-Fluoro-phenyl)-pyrimido[5,4-e][l,2,4]triazm-7-ylamino]- methylj-benzenesulfonamide
Figure imgf000040_0002
This compound was prepared substantially as described in Example 3.2 using appropriate starting materials. 1H NMR (DMSO-d6, 300 MHz): δ 9.59 (s, IH), 9.32 (t, J = 6.6 Hz, IH), 8.54-8.49 (m, 2H), 7.81 (d, J = 5.4 Hz, 2H), 7.63 (d, J = 5.4 Hz, 2H), 7.48-7.42 (m, 2H), 7.31 (s, 2H), 4.81 (d, J = 6.0 Hz, 2H); MS (ESI, Pos. 1.5 kV) m/z 410.1 (M-H)". Example 3.20 4-{[3-(4-Fluoro-phenyl)-l,2-dihydr o-pyr imido[5,4-e][l,2,4]triazin-7- ylamino]-methyl}-N-methyl-benzenesulfonamide
Figure imgf000041_0001
This compound was prepared substantially as described in Example 3.1 using appropriate starting materials. 1H NMR (DMSO-d6, 300 MHz): δ 10.99 (br, IH), 9.48 (s, IH), 8.53 (br, IH), 7.77-7.69 (m, 4H), 7.53-7.45 (m, 3H), 7.34-7.28 (m, 2H), 6.45 (s, IH), 4.53 (d, J = 5.7 Hz, 2H), 2.41 (d, J = 4.5 Hz, 3H); MS (ESI, Pos. 1.5 kV) m/z 428.2 (M+H)+.
Example 3.21 4-{[3-(4-Fluoro-phenyl)-pyrimido[5,4-e][l,2,4]triazm-7-ylamino]- methyl }-N-methyl-benzenesulfonamide
Figure imgf000041_0002
This compound was prepared substantially as described in Example 3.2 using appropriate starting materials. 1H NMR (DMSO-d6, 300 MHz): δ 9.59 (s, IH), 9.31 (t, J = 6.3 Hz, IH), 8.54-8.49 (m, 2H), 7.77 (d, J = 8.4 Hz, 2H), 7.66 (d, J = 8.4 Hz, 2H), 7.47-7.41 (m, 3H), 4.83 (d, J= 6.3 Hz, 2H), 2.40 (d, J= 5.4 Hz, 3H); MS (ESI, Pos. 1.5 kV) m/z 426.1 (M+H)+. Example 3.22 4-((5-Ethoxy-3-(4-fluorophenyl)pyrimido[5,4-e][l,2,4]triazin-7- ylamino)methyl)-N-methylbenzenesulfonamide
Figure imgf000042_0001
This compound was prepared substantially as described in Example 3.4 using appropriate starting materials. 1H NMR (DMSO-d6, 300 MHz): δ 8.95 (t, / = 6.3 Hz, 0.2H), 8.87 (t, J = 6.3 Hz, 0.8H), 8.48-8.43 (m, 2H), 7.77-7.73 (m, 2H), 7.67-7.58 (m, 2H), 7.45-7.39 (m, 3H), 4.79-4.54 (m, 4H), 2.40-2.37 (m, 3H), 1.49 (t, J = 7.2 Hz, 2.4H), 1.33 (t, / =7.2 Hz, 0.6H),; MS (ESI, Pos. 1.5 kV) m/z 470.1 (M+H)+.
Example 3.23 4-((3-(4-Fluorophenyl)pyrimido[5,4-e][l,2,4]triazin-7- ylamino)methyl)-N,N-dimethylbenzenesulfonamide
Figure imgf000042_0002
This compound was prepared substantially as described in Example 3.2 using appropriate starting materials. 1H NMR (DMSO-d6, 300 MHz): δ 9.61 (s, IH), 9.32 (t, J = 6.0 Hz, IH), 8.54-8.50 (m, 2H), 7.76-7.68 (m, 4H), 7.48-7.42 (m, 2H), 4.87 (d, J = 6.0 Hz, 2H), 2.60 (s, 6H); MS (ESI, Pos. 1.5 kV) m/z 440.1 (M+H)+. Example 3.24 [3-(3,4-Dimethoxy-phenyl)-l,2-dihydro-pyrimido[5,4- e][l,2,4]triazin-7-yl]-(4-fluoro-benzyl)-amine
Figure imgf000043_0001
This compound was prepared substantially as described in Example 3.1 using appropriate starting materials. 1U NMR (DMSO-d6, 300 MHz): δ 10.96 (br, IH), 9.68 (s, IH), 8.55 (br, IH), 7.39-7.27 (m, 4H), 7.22-7.15 (m, 2H), 7.02 (d, J= 9.0 Hz, IH), 6.60 (d, / = 4.8 Hz, IH), 4.42 (d, / = 6.0 Hz, 2H), 3.79 (s, 3H), 3.78 (s, 3H); MS (ESI, Pos. 1.5 kV) m/z 311 A (M+H)+.
Example 3.25 [3-(3,4-Dimethoxy-phenyl)-pyrimido[5,4-e][l,2,4]triazin-7-yl]-(4- fluoro-benzyl)-amine
Figure imgf000043_0002
This compound was prepared substantially as described in Example 3.2 using appropriate starting materials. 1H NMR (DMSO-d6, 300 MHz): δ 9.54 (s, 0.2H), 9.16 (br, 0.2H), 8.32 (br, 0.8H), 8.12-7.90 (m, IH), 7.88 (s, 0.8H), 7.49-7.38 (m, 3H), 7.21- 7.09 (m, 3H), 4.72-4.49 (m, 2H), 3.89-3.83 (m, 6H); MS (ESI, Pos. 1.5 kV) m/z 393.2 (M+H)+. Example 3.26 [3-(3,4-Dimethoxy-phenyl)-5-ethoxy-pyrimido[5,4-e][l,2,4]triazin-7- yl]-(4-fluoro-benzyl)-amine
Figure imgf000044_0001
This compound was prepared substantially as described in Example 3.4 using appropriate starting materials. 1U NMR (DMSO-d6, 300 MHz): δ 8.80 (br, 0.2H), 8.69 (br, 0.8H), 8.01-7.98 (m, 2H), 7.49-7.44 (m, 2H), 7.19-7.13 (m, 3H), 4.67-4.58 (m, 4H), 3.88, (s, 3H), 3.85 (s, 3H), 1.48 (t, J = 6.9 Hz, 2.4H), 1.39 (t, J = 6.9 Hz, 0.6H); MS (ESI, Pos. 1.5 kV) m/z All 2 (M+H)+.
Example 3.27 3-(4-Fluoro-phenyl)-l,2-dihydro-pyrimido[5,4-e][l,2,4]triazin-7- ylamine
Figure imgf000044_0002
This compound was prepared substantially as described in Example 3.1 using appropriate starting materials. 1H NMR (DMSO-d6, 300 MHz): δ 10.91 (br, IH), 9.54 (s, IH), 7.76-7.71 (m, 2H), 7.63 (br, 2H), 7.34-7.28 (m, 2H), 6.46 (br, IH); MS (ESI, Pos. 1.5 kV) m/z 428.2 (M+H)+. Example 3.28 3-(4-Fluoro-phenyl)-pyrimido[5,4-e][l,2,4]triazin-7-ylamine
Figure imgf000045_0001
This compound was prepared substantially as described in Example 3.2 using appropriate starting materials. 1H NMR (DMSO-d6, 300 MHz): δ 9.54 (s, IH), 8.49- 8.47 (m, 2H), 8.12 (br, 2H), 7.46-7.39 (m, 2H); MS (ESI, Pos. 1.5 kV) m/z 243.0 (M+H)+.
Example 3.29 5-Ethoxy-3-(4-fluoro-phenyl)-pyrimido[5,4-e][l,2,4]triazin-7- ylamine
Figure imgf000045_0002
This compound was prepared substantially as described in Example 3.4 using appropriate starting materials. 1H NMR (DMSO-d6, 300 MHz): δ 8.46-8.41 (m, 2H), 7.84 (br, IH), 7.69 (br, IH), 7.44-7.38 (m, 2H), 4.60 (q, J = 7.2 Hz, 2H), 1.45 (t, / =7.2 Hz, 3H); MS (ESI, Pos. 1.5 kV) m/z 287.1 (M+H)+.
Example 3.30 Benzyl-[3-(3,4-dimethoxy-phenyl)-l,2-dihydro-pyrimido[5,4- e][l,2,4]triazin-7-yl]-amine
Figure imgf000046_0001
This compound was prepared substantially as described in Example 3.1 using appropriate starting materials. 1H NMR (DMSO-d6, 300 MHz): δ 10.94 (br, IH), 9.48 (s, IH), 9.50 (br, IH), 7.37-7.23 (m, 7H), 7.04 (d, J = 8.4 Hz, IH), 6.52 (s, IH), 4.45 (d, J = 6.3 Hz, 2H), 3.79 (s, 3H), 3.78 (s, 3H); MS (ESI, Pos. 1.5 kV) m/z 377.1 (M+H)+.
Example 3.31 Benzyl-[3-(3,4-dimethoxy-phenyl)-pyrimido[5,4-e][l,2,4]triazin-7- yl] -amine
Figure imgf000046_0002
This compound was prepared substantially as described in Example 3.2 using appropriate starting materials. 1H NMR (DMSO-d6, 300 MHz): δ 9.52 (s, 0.5H), 9.20 (t, J = 6.3 Hz, IH), 8.15 (d, J= 8.4 Hz, 2H), 7.97 (s, IH), 7.43-7.14 (m, 6.5H), 4.72 (d, J = 6.3 Hz, 2H), 3.87 (s, 3H), 3.84 (s, 3H); MS (ESI, Pos. 1.5 kV) m/z 375.1 (M+H)+. Example 3.32 Benzyl-[3-(3,4-dimethoxy-phenyl)-5-ethoxy-pyrimido[5,4- e][l,2,4]triazin-7-yl]-amine
Figure imgf000047_0001
This compound was prepared substantially as described in Example 3.4 using appropriate starting materials. 1H NMR (DMSO-d6, 300 MHz): δ 8.70 (br, 0.5H), 8.00- 7.96 (m, 2H), 7.44-7.14 (m, 6.5H), 4.73-4.57 (m, 4H), 3.90-3.84 (m, 6H), 1.47-1.37 (m, 3H); MS (ESI, Pos. 1.5 kV) m/z 419.1 (M+H)+.
Example 3.33 Cyclohexyl-[3-(4-fluoro-phenyl)-l,2-dihydro-pyrimido[5,4- e][l,2,4]triazin-7-yl]-amine
Figure imgf000047_0002
This compound was prepared substantially as described in Example 3.1 using appropriate starting materials. 1U NMR (DMSO-d6, 300 MHz): δ 10.70 (br, IH), 9.76 (s, IH), 8.20 (d, J= 8.4 Hz, IH), 7.82-7.76 (m, 2H), 7.30-7.24 (m, 2H), 6.59 (s, IH), 3.61-3.55 (m, IH), 1.86-1.16 (m, 10H); MS (ESI, Pos. 1.5 kV) m/z 327.2 (M+H)+. Example 3.34 Cyclohexyl-[3-(4-fluoro-phenyl)-pyrimido[5,4-e][l,2,4]triazin-7-yl]- amine
Figure imgf000048_0001
This compound was prepared substantially as described in Example 3.2 using appropriate starting materials. 1H NMR (DMSO-d6, 300 MHz): δ 9.50 (s, IH), 8.70 (d, J = 8.4 Hz, IH), 8.52-8.47 (m, 2H), 7.45-7.40 (m, 2H), 3.96-3.95 (m, IH), 2.01-1.95 (m, 2H), 1.78-1.76 (m, 2H), 1.66-1.62 (m, IH), 1.42-1.34 (m, 4H), 1.32-1.21 (m, IH); MS (ESI, Pos. 1.5 kV) m/z 325.2 (M+H)+.
Example 3.35 N-Cyclohexyl-5-ethoxy-3-(4-fluorophenyl)pyrimido[5,4- e][l,2,4]triazin-7-amine
Figure imgf000048_0002
This compound was prepared substantially as described in Example 3.4 using appropriate starting materials. 1H NMR (DMSO-d6, 300 MHz): δ 8.44-8.40 (m, 2H), 8.15 (d, J = 8.4 Hz, IH), 7.42-7.36 (m, 2H), 4.63-4.54 (m, 2H), 3.97-3.94 (m, IH), 1.96-1.90 (m, 2H), 1.75-1.58 (m, 3H), 1.49-1.10 (m, 8H),; MS (ESI, Pos. 1.5 kV) m/z 369.1 (M+H)+. Example 3.36 [3-(4-Fluoro-phenyl)-l,2-dihydro-pyrimido[5,4-e][l,2,4]triazin-7-yl]- phenyl-amine
Figure imgf000049_0001
This compound was prepared substantially as described in Example 3.1 using appropriate starting materials. 1U NMR (DMSO-d6, 300 MHz): δ 11.04 (br, IH), 10.31 (s, IH), 9.57 (s, IH), 7.75-7.70 (m, 2H), 7.41-7.15 (m, 7H), 6.53 (br, IH); MS (ESI, Pos. 1.5 kV) m/z 321.1 (M+H)+.
Example 3.37 [3-(4-Fluoro-phenyl)-pyrimido[5,4-e][l,2,4]triazin-7-yl]-phenyl- amine
Figure imgf000049_0002
This compound was prepared substantially as described in Example 3.2 using appropriate starting materials. 1H NMR (DMSO-d6, 300 MHz): δ 10.87 (s, IH), 9.70 (s, IH), 857-8.53 (m, 2H), 8.09-8.06 (m, 2H), 7.49-7.40 (m, 4H), 7.16-7.13 (m, IH); MS (ESI, Pos. 1.5 kV) m/z 319.0 (M+H)+.
Example 3.38 [3-(4-Fluoro-phenyl)-pyrimido[5,4-e][l,2,4]triazin-7-yl]-methyl- amine
Figure imgf000050_0001
This compound was prepared substantially as described in Example 3.2 using appropriate starting materials. 1H NMR (DMSO-d6, 300 MHz): δ 9.51 (s, IH), 8.69- 8.66 (m, IH), 8.54-8.52 (m, 2H), 7.47-7.42 (m, 2H), 3.04 (d, J = 4.5 Hz, 3H); MS (ESI, Pos. 1.5 kV) m/z 257.0 (M+H)+.
Example 3.39 [3-(4-Fluoro-phenyl)-pyrimido[5,4-e][l,2,4]triazin-7-yl]-isopropyl- amine
Figure imgf000050_0002
This compound was prepared substantially as described in Example 3.2 using appropriate starting materials. 1H NMR (CDCl3, 300 MHz): δ 9.36 (s, IH), 8.66-8.61 (m, 2H), 7.28-7.22 (m, 2H), 5.86 (br, IH), 4.56-4.49 (m, IH), 1.43-1.40 (m, 6H); MS (ESI, Pos. 1.5 kV) m/z 285.1 (M+H)+.
Example 3.40 [3-(4-Fluoro-phenyl)-5-methoxy-pyrimido[5,4-e][l,2,4]triazin-7-yl]- isopropyl-amine
Figure imgf000051_0001
This compound was prepared substantially as described in Example 3.3 using appropriate starting materials. 1H NMR (CDCl3, 300 MHz): δ 8.62-8.56 (m, 2H), 7.28- 7.19 (m, 2H), 5.73 (br, 0.2H), 5.50 (br, 0.8H), 4.61-4.49 (m, IH), 4.29 (s, 0.6H), 4.20 (s, 2.4H), 1.39 (d, J = 6.3 Hz, 6H); MS (ESI, Pos. 1.5 kV) m/z 315.0 (M+H)+.
Example 3.41 [5-Ethoxy-3-(4-fluoro-phenyl)-pyrimido[5,4-e][l,2,4]triazin-7-yl]- isopropyl-amine
Figure imgf000051_0002
This compound was prepared substantially as described in Example 3.4 using appropriate starting materials. 1H NMR (DMSO-d6, 300 MHz): δ 8.48-8.42 (m, 2H), 8.31 (d, J = 7.8 Hz, 0.2H), 8.18 (d, J= 7.8 Hz, 0.8H), 7.45-7.39 (m, 2H), 4.69-4.56 (m, 2H), 4.36-4.17 (m, IH), 1.51-1.45 (m, 3H), 1.27-1.22 (m, 6H); MS (ESI, Pos. 1.5 kV) m/z 329.0 (M+H)+. Example 4 Compounds Made by Route 4
Example 4.1 (4-Fluoro-benzyl)-[3-(4-fluoro-phenyl)-5-morpholin-4-yl- pyrimido[5,4-e][l,2,4]triazin-7-yl]-amine
Figure imgf000052_0001
A mixture of dihydro-triazine (From Example 3.14, 0.10 g, 0.28 mmol), silver oxide (0.13 g, 0.56 mmol) and Na2SO4 (5.0 g) was stirred in morpholine (1 mL) and dry THF (10 mL) overnight under reflux. The filtrate was concentrated and purified through flash chromatography to give the title compound as a pale yellow solid (0.035 g, 28%). 1H NMR (DMSO-d6, 300 MHz): δ 8.37-8.18 (m, 3H), 8.18-8.10 (m, 0.4H),7.45-7.36 (m, 5H), 7.18-7.11 (m, 0.6H), 4.63-4.50 (m, 3H), 3.86-3.68 (m, 7H); MS (ESI, Pos. 1.5 kV) m/z 436.1 (M+H)+.
Example 4.2 (4-Fluoro-benzyl)-[3-(4-fluoro-phenyl)-5-(4-methyl-piperazin-l-yl)- pyrimido[5,4-e][l,2,4]triazin-7-yl]-amine
Figure imgf000052_0002
This compound was prepared substantially as described in Example 4.1 using appropriate starting materials. 1H NMR (DMSO-d6, 300 MHz): δ 8.37-8.33 (m, 2.3H), 8.17-8.10 (m, 0.7H), 7.45-7.37 (m, 4H), 7.17-7.11 (m, IH), 4.62-4.53 (m, 3H), 3.44- 3.27 (m, 4H), 2.55-2.50 (m, 3H), 2.25 (s, 2.3H), 2.22 (s, 0.7H); MS (ESI, Pos. 1.5 kV) m/z 449.1 (M+H)+.
Example 4.3 Benzyl-[3-(4-fluoro-phenyl)-5-morpholin-4-yl-pyrimido[5,4- e][l,2,4]triazin-7-yl]-amine
Figure imgf000053_0001
This compound was prepared substantially as described in Example 4.1 using appropriate starting materials. 1H NMR (DMSO-d6, 300 MHz): δ 8.36-8.18 (m, 3H), 7.41-7.23 (m, 7H), 4.66-4.35 (m, 5H), 3.82-3.73 (m, 5H); MS (ESI, Pos. 1.5 kV) m/z 418.1 (M+H)+.
Example 4.4 Benzyl-[3-(4-fluoro-phenyl)-5-(4-methyl-piperazin-l-yl)- pyrimido[5,4-e][l,2,4]triazin-7-yl]-amine
Figure imgf000053_0002
This compound was prepared substantially as described in Example 4.1 using appropriate starting materials. 1H NMR (DMSO-d6, 300 MHz): δ 8.36-8.31 (m, 2.4H), 8.15 (t, J = 6.0 Hz, 0.6H), 7.42-7.20 (m, 7H), 4.65-4.20 (m, 5H), 2.53-2.45 (m, 5H), 2.24 (s, 1.8H), 2.20 (s, 1.2H); MS (ESI, Pos. 1.5 kV) m/z 431.3 (M+H)+. Example 4.5 4-{[3-(4-Fluoro-phenyl)-5-morpholin-4-yl-pyrimido[5,4- e][l,2,4]triazin-7-ylamino]-methyl}-N,N-dimethyl-benzenesulfonamide
Figure imgf000054_0001
This compound was prepared substantially as described in Example 4.1 using appropriate starting materials. 1H NMR (DMSO-d6, 300 MHz): δ 8.37-8.24 (m, 3H), 7.73-7.59 (m, 4H), 7.42-7.37 (m, 2H), 4.77-4.38 (m, 4H), 3.83-3.66 (m, 4H), 3.42-3.20 (m, 2H), 2.59 (s, 6H); MS (ESI, Pos. 1.5 kV) m/z 525.2 (M+H)+.
Example 4.6 4-{[3-(4-Fluoro-phenyl)-5-(4-methyl-piperazin-l-yl)-pyrimido[5,4- e][l,2,4]triazin-7-ylamino]-methyl}-N,N-dimethyl-benzenesulfonamide
Figure imgf000054_0002
This compound was prepared substantially as described in Example 4.1 using appropriate starting materials. 1H NMR (DMSO-d6, 300 MHz): δ 8.37-8.25 (m, 3H), 7.73-7.59 (m, 4H), 7.43-7.37 (m, 2H), 4.76-4.34 (m, 3H), 3.45-3.20 (m, 4H), 2.59 (s, 6H), 2.49-2.25 (m, 3H), 2.25 (s, 2.3H), 2.17 (s, 0.7H); MS (ESI, Pos. 1.5 kV) m/z 538.2 (M+H)+. Example 4.7 4-{[3-(4-Fluoro-phenyl)-5-morpholin-4-yl-pyrimido[5,4- e][l,2,4]triazin-7-ylamino]-methyl}-N-methyl-benzenesulfonamide
Figure imgf000055_0001
This compound was prepared substantially as described in Example 4.1 using appropriate starting materials. 1H NMR (DMSO-d6, 300 MHz): δ 8.43-8.23 (m, 3H), 7.75-7.72 (m, 2H), 7.61-7.54 (m, 2H), 7.42-7.36 (m, 3H), 4.74-4.40 (m, 4H), 3.81-3.56 (m, 5H), 3.02-2.99 (m, IH), 2.40 (d, J = 4.8 Hz, 3H); MS (ESI, Pos. 1.5 kV) m/z 511.2 (M+H)+.
Example 4.8 4-{[3-(4-Fluoro-phenyl)-5-(4-methyl-piperazin-l-yl)-pyrimido[5,4- e][l,2,4]triazin-7-ylamino]-methyl}-N-methyl-benzenesulfonamide
Figure imgf000055_0002
This compound was prepared substantially as described in Example 4.1 using appropriate starting materials. 1H NMR (DMSO-d6, 300 MHz): δ 8.37-8.23 (m, 3H), 7.75-7.72 (m, 2H), 7.60-7.54 (m, 2H), 7.43-7.37 (m, 3H), 4.73-4.25 (m, 3H), 3.40-3.20 (m, 4H), 2.55-2.40 (m, 3H), 2.39 (d, J = 4.8 Hz, 3H), 2.25 (s, 2.3H), 2.18 (s, 0.7H); MS (ESI, Pos. 1.5 kV) m/z 524.2 (M+H)+. Example 4.9 [3-(3,4-Dimethoxy-phenyl)-5-morpholin-4-yl-pyrimido[5,4- e][l,2,4]triazin-7-yl]-(4-fluoro-benzyl)-amine
Figure imgf000056_0001
This compound was prepared substantially as described in Example 4.1 using appropriate starting materials. 1H NMR (DMSO-d6, 300 MHz): δ 8.35-8.30 (m, 0.3H), 8.20-8.10 (m, 0.7H), 7.91-7.88 (m, IH), 7.82 (s, IH), 7.45-7.39 (m, 2H), 7.17-7.12 (m, 3H), 4.63-4.30 (m, 3H), 3.86-3.56 (m, 9H), 3.40-3.25 (m, 4H); MS (ESI, Pos. 1.5 kV) m/z 478.3 (M+H)+.
Example 4.10 [3-(3,4-Dimethoxy-phenyl)-5-(4-methyl-piperazin-l-yl)- pyrimido[5,4-e][l,2,4]triazin-7-yl]-(4-fluoro-benzyl)-amine
Figure imgf000056_0002
This compound was prepared substantially as described in Example 4.1 using appropriate starting materials. 1H NMR (DMSO-d6, 300 MHz): δ 8.30 (br, 0.3H), 8.06 (br, 0.7H), 7.89-7.87 (m, IH), 7.81 (s, IH), 7.46-7.43 (m, 2H), 7.14-7.11 (m, 3H), 4.62- 4.25 (m, 3H), 3.85-3.78 (m, 6H), 3.40-3.20 (m, 4H), 2.50-2.40 (m, 3H), 2.24-2.16 (m, 3H); MS (ESI, Pos. 1.5 kV) m/z 491.3 (M+H)+. Example 4.11 N-5-Cyclohexyl-3-(3,4-dimethoxy-phenyl)-N-7-(4-fluoro-benzyl)- pyrimido[5,4-e][l,2,4]triazine-5,7-diamine
This compound was prepared substantially as described in Example 4.1 using appropriate starting materials. 1H NMR (DMSO-d6, 300 MHz): δ 8.63 (d, / = 7.2 Hz, 0.3H), 8.48 (d, J = 12 Hz, 0.7H), 8.31-8.10 (m, 3H), 7.46-7.39 (m, 2H), 7.17-7.11 (m, 3H), 4.62 (d, J = 5.7 Hz, 1.4H), 4.53 (d, J= 5.7 Hz, 0.6H), 4.20-4.10 (m, IH), 3.90 (s, 3H), 3.86 (s, 3H), 1.92-1.24 (m, 10H); MS (ESI, Pos. 1.5 kV) m/z 490.2 (M+H)+.
Example 4.12 3-(3,4-Dimethoxy-phenyl)-N-5-N-7-bis-(4-fluoro-benzyl)- pyrimido[5,4-e][l,2,4]triazine-5,7-diamine
Figure imgf000057_0002
This compound was prepared substantially as described in Example 4.1 using appropriate starting materials. 1U NMR (CDCl3, 300 MHz): δ 8.12 (s, IH), 8.04 (d, J = 8.1 Hz, IH), 7.51-7.26 (m, 5H), 7.07-6.92 (m, 5H), 6.45 (br, 0.4H), 5.63 (br, 0.6H), 4.83-4.73 (m, 4H), 3.96 (s, 3H), 3.89 (s, 3H); MS (ESI, Pos. 1.5 kV) m/z 516.2 (M+H)+. Example 4.13 N-[4-(7-Benzylamino-5-morpholin-4-yl-pyrimido[5,4- e][l,2,4]triazin-3-yl)-phenyl]-acetamide
Figure imgf000058_0001
This compound was prepared substantially as described in Example 4.1 using appropriate starting materials. 1H NMR (DMSO-d6, 300 MHz): δ 10.18 (s, IH), 8.25- 8.11 (m, 3H), 7.78-7.75 (m, 2H), 7.40-7.23 (m, 5H), 4.66-4.35 (m, 5H), 3.81-3.71 (m, 5H), 2.09 (s, 3H); MS (ESI, Pos. 1.5 kV) m/z 457.2 (M+H)+.
Example 4.14 N-5-((S)-l-Benzyl-pyrrolidin-3-yl)-3-(3,4-dimethoxy-phenyl)-N-7-(4- fluoro-benzyl)-pyrimido[5,4-e][l,2,4]triazine-5,7-diamine
Figure imgf000058_0002
This compound was prepared substantially as described in Example 4.1 using appropriate starting materials. 1H NMR (CDCl3, 300 MHz): δ 8.15-8.08 (m, 2H), 7.40- 7.26 (m, 7H), 7.04-7.01 (m, 3H), 6.29 (br, 0.3H), 5.57 (br, 0.7H), 4.81-4.70 (m, 3H), 4.04-3.94 (m, 6H), 3.94-3.64 (m, 3H), 3.00-2.97 (m, IH), 2.84-2.66 (m, 2H), 2.41-2.25 (m, 2H), 1.90-1.75 (m, IH); MS (ESI, Pos. 1.5 kV) m/z 567.3 (M+H)+. Example 4.15 Benzyl-[3-(4-fluoro-phenyl)-5-piperazin-l-yl-pyrimido[5,4- e][l,2,4]triazin-7-yl]-amine
Figure imgf000059_0001
This compound was prepared substantially as described in Example 4.1 using appropriate starting materials. 1H NMR (DMSO-d6, 300 MHz): δ 8.36-8.32 (m, 2.4H), 8.12 (t, J = 6.3 Hz, 0.6H), 7.42-7.20 (m, 7H), 4.65-4.20 (m, 4H), 3.45-3.20 (m, 2H), 2.93-2.86 (m, 4H); MS (ESI, Pos. 1.5 kV) m/z 417 '.1 (M+H)+.
Example 4.16 3-(4-Fluoro-phenyl)-5-(4-methyl-piperazin-l-yl)-pyrimido[5,4- e][l,2,4]triazin-7-ylamine
Figure imgf000059_0002
This compound was prepared substantially as described in Example 4.1 using appropriate starting materials. 1H NMR (DMSO-d6, 300 MHz): δ 8.36-8.31 (m, 2H), 7.43-7.37 (m, 2H), 7.26 (br, IH), 7.12 (br, IH), 4.35-4.20 (m, 3H), 3.48-3.20 (m, 2H), 2.54-2.51 (m, 3H), 2.23 (s, 3H); MS (ESI, Pos. 1.5 kV) m/z 341.1 (M+H)+. Example 4.17 4-{[3-(4-Fluoro-phenyl)-5-morpholm-4-yl-pyrimido[5,4- e][l,2,4]triazin-7-ylamino]-methyl}-benzenesulfonamide
Figure imgf000060_0001
This compound was prepared substantially as described in Example 4.1 using appropriate starting materials. 1H NMR (DMSO-d6, 300 MHz): δ 8.43-8.23 (m, 3H), 7.77-7.73 (m, 2H), 7.55-7.49 (m, 2H), 7.40-7.35 (m, 2H), 7.29 (s, 2H), 4.69-4.20 (m, 4H), 3.81-3.71 (m, 4H), 3.38-3.20 (m, 1.5H), 2.72-2.69 (m, 0.5H); MS (ESI, Pos. 1.5 kV) m/z 497.1 (M+H)+.
Example 4.18 3-(4-Fluoro-phenyl)-5-morpholin-4-yl-pyrimido[5,4-e][l,2,4]triazin- 7-ylamine
Figure imgf000060_0002
This compound was prepared substantially as described in Example 4.1 using appropriate starting materials. 1H NMR (DMSO-d6, 300 MHz): δ 8.43-8.23 (m, 3H), 7.77-7.73 (m, 2H), 7.55-7.49 (m, 2H), 7.40-7.35 (m, 2H), 7.29 (s, 2H), 4.69-4.20 (m, 4H), 3.81-3.71 (m, 4H), 3.38-3.20 (m, 1.5H), 2.72-2.69 (m, 0.5H); MS (ESI, Pos. 1.5 kV) m/z 328.0 (M+H)+. Example 4.19 l-[7-Benzylamino-3-(4-fluoro-phenyl)-pyrimido[5,4-e][l,2,4]triazin- 5-yl]-piperidin-4-one
Figure imgf000061_0001
This compound was prepared substantially as described in Example 4.1 using appropriate starting materials. 1H NMR (DMSO-d6, 300 MHz): δ 8.37-8.23 (m, 3H), , 7.40-7.19 (m, 7H), 4.65-4.20 (m, 4H), 3.50-3.20 (m, 3H), 2.66-2.53 (m, 3H); MS (ESI, Pos. 1.5 kV) m/z 430.2 (M+H)+.
Example 4.20 4-{[3-(4-Fluoro-phenyl)-5-(4-methyl-piperazin-l-yl)-pyrimido[5,4- e][l,2,4]triazin-7-ylamino]-methyl}-benzenesulfonamide
Figure imgf000061_0002
This compound was prepared substantially as described in Example 4.1 using appropriate starting materials. 1H NMR (DMSO-d6, 300 MHz): δ 8.40-8.21 (m, 3H), 7.77-7.74 (m, 2H), 7.55-7.49 (m, 2H), 7.41-7.35 (m, 2H), 7.26 (s, 2H), 4.67-4.20 (m, 4H), 3.32-3.20 (m, 2H), 2.53-2.40 (m, 4H), 2.23 (s, 2.3H), 2.18 (s, 0.7H); MS (ESI, Pos. 1.5 kV) m/z 510.1 (M+H)+. Example 4.21 [3-(4-Fluoro-phenyl)-5-(4-methyl-piperazin-l-yl)-pyrimido[5,4- e][l,2,4]triazin-7-yl]-phenyl-amine
Figure imgf000062_0001
This compound was prepared substantially as described in Example 4.1 using appropriate starting materials. 1H NMR (CDCl3, 300 MHz): δ 7.97-7.93 (m, 2H), 7.17- 6.88 (m, 8H), 4.63-4.45 (m, IH), 3.54-3.31 (m, IH), 2.44-2.18 (m, 9H); MS (ESI, Pos. 1.5 kV) m/z 417.1 (M+H)+.
Example 4.22 [3-(4-Fluoro-phenyl)-5-morpholm-4-yl-pyrimido[5,4- e][l,2,4]triazin-7-yl]-phenyl-amine
Figure imgf000062_0002
This compound was prepared substantially as described in Example 4.1 using appropriate starting materials. 1U NMR (CDCl3, 300 MHz): δ 8.06-7.94 (m, 2H), 7.21- 6.92 (m, 8H), 4.66-4.44 (m, IH), 3.74-3.53 (m, 7H); MS (ESI, Pos. 1.5 kV) m/z 404.1 (M+H)+. Example 4.23 Cyclohexyl-[3-(4-fluoro-phenyl)-5-morpholin-4-yl-pyrimido[5,4- e][l,2,4]triazin-7-yl]-amine
Figure imgf000063_0001
This compound was prepared substantially as described in Example 4.1 using appropriate starting materials. 1H NMR (DMSO-d6, 300 MHz): δ 8.34-8.28 (m, 2H), 7.57 (d, J = 8.1 Hz, 0.17H), 7.39 (d, J = 8.1 Hz, 0.83H), 7.40-7.34 (m, 2H), 4.41-4.32 (m, 3H), 3.91-3.73 (m, 6H), 1.92-1.84 (m, 2H), 1.75-1.72 (m, 2H), 1.64-1.59 (m, IH), 1.36-1.14 (m, 5H); MS (ESI, Pos. 1.5 kV) m/z 410.3 (M+H)+.
Example 4.24 Benzyl-[3-(3,4-dimethoxy-phenyl)-5-(4-methyl-piperazin-l-yl)- pyrimido[5,4-e][l,2,4]triazin-7-yl]-amine
Figure imgf000063_0002
This compound was prepared substantially as described in Example 4.1 using appropriate starting materials. 1H NMR (DMSO-d6, 300 MHz): δ 8.30 (br, 0.3H), 8.08 (br, 0.7H), 7.90-7.81 (m, 2H), 7.38-7.11 (m, 6H), 4.63-4.20 (m, 3H), 3.84-3.82 (m, 6H), 3.31-3.25 (m, 4H), 2.49-2.48 (m, 3H), 2.23-2.19 (m, 3H); MS (ESI, Pos. 1.5 kV) m/z 473.3 (M+H)+. Example 4.25 Benzyl-[3-(3,4-dimethoxy-phenyl)-5-morpholm-4-yl-pyrimido[5,4- e][l,2,4]triazin-7-yl]-amine
Figure imgf000064_0001
This compound was prepared substantially as described in Example 4.1 using appropriate starting materials. 1H NMR (DMSO-d6, 300 MHz): δ 8.30 (br, 0.3H), 8.10 (br, 0.7H), 7.90-7.82 (m, 2H), 7.39-7.11 (m, 6H), 4.64-4.20 (m, 3H), 3.85-3.60 (m, HH), 3.31-3.25 (m, 2H); MS (ESI, Pos. 1.5 kV) m/z 460.2 (M+H)+.
Example 4.26 3-(3,4-Dimethoxy-phenyl)-N-7-(4-fluoro-benzyl)-N-5-((S)-l-phenyl- ethyl)-pyrimido[5,4-e][l,2,4]triazine-5,7-diamine
Figure imgf000064_0002
This compound was prepared substantially as described in Example 4.1 using appropriate starting materials. 1U NMR (CDCl3, 300 MHz): δ 8.14-8.02 (m, 2H), 7.41- 7.22 (m, 7H), 7.06-6.91 (m, 3.4H), 5.59 (br, 0.6H), 5.42-5.37 (m, IH), 4.82-4.59 (m, 2H), 4.03-3.97 (m, 6H), 3.73 (q, J = 6.6 Hz, IH), 1.71 (d, J = 6.6 Hz, 3H); MS (ESI, Pos. 1.5 kV) m/z 512.3 (M+H)+. Example 4.27 3-(3,4-Dimethoxyphenyl)-N-(4-fluorobenzyl)-5-(piperazin-l- yl)pyrimido[5,4-e][l,2,4]triazin-7-amine
Figure imgf000065_0001
This compound was prepared substantially as described in Example 4.1 using appropriate starting materials. 1H NMR (DMSO-d6, 300 MHz): δ 8.30 (br, 0.3H), 8.05 (br, 0.7H), 7.91-7.81 (m, 2H), 7.43-7.37 (m, 2H), 7.16-7.08 (m, 3H), 4.60-4.20 (m, 3H), 3.84-3.83 (m, 6H), 3.31-3.25 (m, 3H), 2.89-2.80 (m, 4H); MS (ESI, Pos. 1.5 kV) m/z 411.1 (M+H)+.
Example 4.28 N-Cyclohexyl-3-(4-fluorophenyl)-5-(4-methylpiperazin-l- yl)pyrimido[5,4-e][l,2,4]triazin-7-amine
Figure imgf000065_0002
This compound was prepared substantially as described in Example 4.1 using appropriate starting materials. 1H NMR (DMSO-d6, 300 MHz): δ 8.35-8.33 (m, 2H), 7.70 (br, 0.3H), 7.55 (br, 0.7H), 7.41-7.36 (m, 2H), 4.32-4.20 (m, IH), 3.90-3.00 (m, 8H), 2.19 (s, 3H), 1.91-1.58 (m, 3H), 1.31-1.00 (m, 7H); MS (ESI, Pos. 1.5 kV) m/z 423.1 (M+H)+. Example 4.29 l-(4-(7-(Benzylamino)-3-(4-fluorophenyl)pyrimido[5,4- e][l,2,4]triazin-5-yl)piperazin-l-yl)ethanone
Figure imgf000066_0001
This compound was prepared substantially as described in Example 4.1 using appropriate starting materials. 1H NMR (DMSO-d6, 300 MHz): δ 8.41-8.19 (m, 3H), 7.42-7.18 (m, 7H), 4.64-4.20 (m, 3H), 3.69-3.60 (m, 3H), 3.40-3.00 (m, 4H), 2.06-1.96 (m, 3H); MS (ESI, Pos. 1.5 kV) m/z 459.1 (M+H)+.
Example 4.30 l-(7-(Benzylamino)-3-(4-fluorophenyl)pyrimido[5,4-e][l,2,4]triazin- 5-yl)piperidin-4-ol
Figure imgf000066_0002
This compound was prepared substantially as described in Example 4.1 using appropriate starting materials. 1U NMR (CDCl3, 300 MHz): δ 8.41-8.25 (m, 2H), 7.43- 7.19 (m, 7H), 6.67 (br, 0.4H), 5.55 (br, 0.6H), 5.21-3.75 (m, 7H), 2.14-2.01 (m, 2H), 1.83-1.71 (m, 2H); MS (ESI, Pos. 1.5 kV) m/z 432.1 (M+H)+. Example 4.31 4-((3-(4-Fluorophenyl)-5-(piperazin-l-yl)pyrimido[5,4- e][l,2,4]triazin-7-ylamino)methyl)benzenesulfonamide
Figure imgf000067_0001
This compound was prepared substantially as described in Example 4.1 using appropriate starting materials. 1H NMR (DMSO-d6, 300 MHz): δ 8.33-8.17 (m, 3H), 7.77-7.74 (m, 2H), 7.55-7.48 (m, 2H), 7.39-7.36 (m, 2H), 7.28 (s, 2H), 4.68-4.20 (m, 3H), 3.40-3.20 (m, 3H), 2.89-2.60 (m, 4H); MS (ESI, Pos. 1.5 kV) m/z 496.2 (M+H)+.
Example 5 Compounds Made by Route 5
Example 5.1 7-Methoxy-3-phenyl-6H-pyrimido[5,4-e][l,2,4]triazin-5-ylideneamine
Figure imgf000067_0002
Following the procedure in Route 5, NH3.H2O (10 mL) was added dropwise to a solution of 7-methoxy-3-phenyl-l,2-dihydropyrimido[5,4-e][l,2,4]triazine (from Step D in Example 1.1, 0.20 g, 0.83 mmol) in methanol (5 mL) at 0 0C. After stirring at room temperature for 1 h, the solution was filtered and washed with water and ethyl acetate to give the title product as a pale yellow solid (0.072 g, 35%). 1H NMR
(DMSO-d6, 300 MHz):δ 9.00 (br, IH), 8.69-8.65(m, 2H), 7.62-7.55 (m, 4H), 4.00 (s, 3H); MS (ESI, Pos. 1.5 kV) m/z 255 (M+H)+. Example 5.2 Ethyl-[3-(4-fluoro-phenyl)-7-methoxy-pyrimido[5,4-e][l,2,4]triazin-5- yl] -amine
Figure imgf000068_0001
Step A: N'-(5-Amino-2-chloropyrimidin-4-yl)-4-fluorobenzohydrazide
Figure imgf000068_0002
Following the procedure in Route 5, to 10 mL of 1.5% AcOH was added Fe powder (1.91 g, 34.1 mmol). After the foaming had subsided, N'-(2-chloro-5-nitropyrimidin-4- yl)-4-fluorobenzohydrazide (prepared as step B in Example 1.1, 1.06 g, 3.41 mmol) was added in small portions to the mixture with vigorous stirring. Then the reaction mixture was heated with stirring at 800C for Ih and 20 mL of ethyl acetate was added, filtered, washed and concentrated to give the title product as a pale yellow foam (0.90 g, 94%), which was used in the next step without further purification. MS (ESI, Pos. 1.5 kV) m/z 282.0 (M+H)+.
Step B: 3-(4-Fluorophenyl)-7-methoxy-l,2-dihydropyrimido[5,4-e][l,2,4]triazine
Figure imgf000068_0003
Following the procedure in Route 5, the crude amine from step A was dissolved in dry methanol (10 mL) and methanolic HCl (15 mL). The mixture was heated under reflux for 3 h and concentrated to give crude triazine as an orange solid (0.80 g, 96%). MS (ESI, Pos. 1.5 kV) m/z 260.1 (M+H)+. Step C: Ethyl- [3-(4-fluoro-phenyl)-7-methoxy-pyrimido[5,4-e][ 1,2,4] triazin-5-yl]- amine
Figure imgf000069_0001
Following the procedure in Route 5, a mixture of dihydro-triazine (From Step B, 0.10 g, 0.38 mmol) and EtNH2 (2.0 mL) in 10 mL of methanol was stirred at room temperature overnight. The solution was concentrated and purified through flash chromatography to give the title compound as a pale yellow solid (0.055 g, 48%). 1H NMR (CDCl3, 300 MHz):δ 8.61-8.56 (m, 2H), 7.32-7.21 (m, 3H), 4.21 (s, 3H), 3.80-3.75 (m, 2H), 1.41 (t, J = 12 Hz, 3H); MS (ESI, Pos. 1.5 kV) m/z 301 (M+H)+.
Example 5.3 Benzyl-[3-(4-fluoro-phenyl)-7-methoxy-pyrimido[5,4-e][l,2,4]triazin- 5-yl]-amine
Figure imgf000069_0002
This compound was prepared substantially as described in Example 5.2 using appropriate starting materials. 1H NMR (CDCl3, 300 MHz):δ 8.58-8.53 (m, 2H), 7.54 (br, IH), 7.41-7.38 (m, 5H), 7.25-7.18 (m, 2H), 4.92 (d, J = 5.7 Hz, 2H), 4.23 (s, 3H); MS (ESI, Pos. 1.5 kV) m/z 363 (M+H)+. Example 5.4 [3-(4-Fluoro-phenyl)-7-methoxy-pyrimido[5,4-e][l,2,4]triazin-5-yl]- isopropyl-amine
Figure imgf000070_0001
This compound was prepared substantially as described in Example 5.2 using appropriate starting materials. 1U NMR (CDCl3, 300 MHz):δ 8.61-8.56 (m, 2H), 7.32- 7.21 (m, 3H), 4.20 (s, 3H), 3.76-3.69 (m, 2H), 1.80-1.75 (m, 2H), 1.53-1.46 (m, 2H), 1.00 (t, J = 7.2 Hz, 3H); MS (ESI, Pos. 1.5 kV) m/z 329 (M+H)+.
Example 5.5 (4-Fluoro-benzyl)-[3-(4-fluoro-phenyl)-7-methoxy-pyrimido[5,4- e][l,2,4]triazin-5-yl]-amine
Figure imgf000070_0002
This compound was prepared substantially as described in Example 5.2 using appropriate starting materials. 1U NMR (CDCl3, 300 MHz):δ 8.61-8.56 (m, 2H), 7.27- 7.21 (m, IH), 7.13-7.10 (m, IH), 4.63-4.51 (m, IH), 4.20 (s, 3H), 1.42 (d, J = 6.6 Hz, 3H); MS (ESI, Pos. 1.5 kV) m/z 315 (M+H)+. Example 5.6 N-(4-Fluorobenzyl)-3-(4-fluorophenyl)-7-methoxypyrimido[5,4- e][l,2,4]triazin-5-amine
Figure imgf000071_0001
This compound was prepared substantially as described in Example 5.2 using appropriate starting materials. 1H NMR (CDCl3, 300 MHz):δ 8.71-8.52 (m, 2H), 7.54 (br, IH), 7.42-7.38 (m, 2H), 7.25-7.18 (m, 2H), 7.11-7.05 (m, 2H), 4.89 (d, J = 6.0 Hz, 2H), 4.23 (s, 3H); MS (ESI, Pos. 1.5 kV) m/z 381 (M+H)+.
Example 5.7 7-Ethoxy-N-(4-fluorobenzyl)-3-(4-fluorophenyl)pyrimido[5,4- e][l,2,4]triazin-5-amine
Figure imgf000071_0002
This compound was prepared substantially as described in Example 5.2 using appropriate starting materials. 1U NMR (CDCl3, 300 MHz):δ 8.71-8.52 (m, 2H), 7.54 (br, IH), 7.42-7.38 (m, 2H), 7.25-7.18 (m, 2H), 7.11-7.05 (m, 2H), 4.89 (d, J = 6.0 Hz, 2H), 4.23 (s, 3H); MS (ESI, Pos. 1.5 kV) m/z 381 (M+H)+. Example 5.8 N-(4-Fluorobenzyl)-3-(4-fluorophenyl)-7-propoxypyrimido[5,4- e][l,2,4]triazin-5-amine
Figure imgf000072_0001
This compound was prepared substantially as described in Example 5.2 using appropriate starting materials. 1U NMR (CDCl3, 300 MHz):δ 8.59-8.55 (m, 2H), 7.52 (br, IH), 7.45-7.40 (m, 2H), 7.23-7.20 (m, 2H), 7.14-7.13 (m, 2H), 4.93 (d, J = 6.0 Hz, 2H), 4.60 (t, J = 6.9 Hz, 2H), 2.01-1.89 (m, 2H), 1.11 (t, J = 7.2 Hz, 3H); MS (ESI, Pos. 1.5 kV) m/z 409.2 (M+H)+.
Example 5.9 7-Butoxy-N-(4-fluorobenzyl)-3-(4-fluorophenyl)pyrimido[5,4- e][l,2,4]triazin-5-amine
Figure imgf000072_0002
This compound was prepared substantially as described in Example 5.2 using appropriate starting materials. 1H NMR (CDCl3, 300 MHz):δ 8.59-8.55 (m, 2H), 7.52 (br, IH), 7.45-7.40 (m, 2H), 7.26-7.23 (m, 2H), 7.14-7.08 (m, 2H), 4.93 (d, J= 5.7 Hz, 2H), 4.64 (t, J= 6.6 Hz, 2H), 1.96-1.86 (m, 2H), 1.57-1.50 (m, 2H), 1.02 (t, J = 7.2 Hz, 3H); MS (ESI, Pos. 1.5 kV) m/z 423.2 (M+H)+.
Example 5.10 l-[7-Ethoxy-3-(4-fluoro-phenyl)-pyrimido[5,4-e][l,2,4]triazin-5-yl]- piperidin-4-one
Figure imgf000073_0001
This compound was prepared substantially as described in Example 5.2 using appropriate starting materials. 1U NMR (CDCl3, 300 MHz):δ 8.50-8.45 (m, 2H), 7.28- 7.22 (m, 2H), 5.15-4.99 (m, 2H), 4.68 (q, J = 7.2 Hz, 2H), 4.49-4.35 (m, 2H), 2.80-2.76 (m, 4H), 1.54 (t, J = 7.2 Hz, 3H); MS (ESI, Pos. 1.5 kV) m/z 369.1 (M+H)+.
Example 6 Compounds Made by Route 6
Example 6.1 [5-(4-Allylamino-piperidin-l-yl)-3-(4-fluoro-phenyl)-pyrimido[5,4- e][l,2,4]triazin-7-yl]-benzyl-amine
Figure imgf000073_0002
Following the procedure in Route 6, to a solution of the ketone (Example 4.15, 0.069 g, 0.16 mmol) in dichloromethane (20 mL) was added allyl amine (0.1 mL, 0.20 mmol) and NaBH(OAC)3 (0.053 g, 0.25 mmol). Then acetic acid (0.01 mL, 0.16 mmol) was added dropwise to the mixture at 00C, and it was allowed to warm to room temperature and stirred overnight. The solution was filtered, extracted with ethyl acetate and 1 N aqueous sodium hydroxide, dried, concentrated and purified through flash chromatography to give the title compound as a pale yellow solid (0.044 g, 58%). 1H NMR (DMSO-d6, 300 MHz): δ 8.38-8.20 (m, 3H), 7.47-7.21 (m, 7H), 5.98-5.92 (m, IH), 5.47-5.31 (m, 2H), 4.64 (d, J = 6.0 Hz, 1.2H), 4.54 (d, J = 6.0 Hz, 0.8H), 3.55- 3.40 (m, 6H), 2.24-2.20 (m, 2H), 1.74-1.70 (m, 2H); MS (ESI, Pos. 1.5 kV) m/z 471.3 (M+H)+.
Example 6.2 N-Benzyl-5-(4-(cyclohexylamino)piperidin-l-yl)-3-(4- fluorophenyl)pyrimido[5,4-e][l,2,4]triazin-7-amine
Figure imgf000074_0001
This compound was prepared substantially as described in Example 6.1 using appropriate starting materials. 1U NMR (CDCl3, 300 MHz): δ 8.44-8.42 (m, 2H), 7.43- 7.19 (m, 7H), 6.24 (br, 0.3H), 5.53 (br,0.7H), 4.85-4.69 (m, 2H), 3.09-3.07 (m, IH), 2.65-2.62 (m, IH), 2.14-2.10 (m, 2H), 1.94-1.90 (m, 2H), 1.78-1.08 (m, 14H); MS (ESI, Pos. 1.5 kV) m/z 513.3 (M+H)+.
Example 6.3 N-Benzyl-5-(4-(diethylamino)piperidin-l-yl)-3-(4- fluorophenyl)pyrimido[5,4-e][l,2,4]triazin-7-amine
Figure imgf000075_0001
This compound was prepared substantially as described in Example 6.1 using appropriate starting materials. 1H NMR (DMSO-d6, 300 MHz): δ 8.45-8.42 (m, 2H), 7.43-7.19 (m, 7H), 6.24 (br, 0.3H), 5.53 (br,0.7H), 4.85-4.69 (m, 2H), 3.09-3.07 (m, IH), 2.65-2.62 (m, IH), 2.14-2.10 (m, 2H), 1.94-1.90 (m, 2H), 1.78-1.08 (m, 14H); MS (ESI, Pos. 1.5 kV) m/z 487.4 (M+H)+.
Example 6.4 N-Benzyl-5-(4-(butylamino)piperidin-l-yl)-3-(4- fluorophenyl)pyrimido[5,4-e][l,2,4]triazin-7-amine
Figure imgf000075_0002
This compound was prepared substantially as described in Example 6.1 using appropriate starting materials. 1U NMR (CDCl3, 300 MHz): δ 8.50-8.41 (m, 2H), 7.43- 7.18 (m, 7H), 6.30 (br, 0.3H), 5.50 (br,0.7H), 4.86-4.69 (m, 2H), 2.96-2.85 (m, IH), 2.76-2.71 (m, IH), 2.12-1.24 (m, 13H), 0.99-0.92 (m, 3H); MS (ESI, Pos. 1.5 kV) m/z 487.2 (M+H)+. Example 6.5 N-Benzyl-5-(4-(4-fluorobenzylamino)piperidin-l-yl)-3-(4- fluorophenyl)pyrimido[5,4-e][l,2,4]triazin-7-amine
Figure imgf000076_0001
This compound was prepared substantially as described in Example 6.1 using appropriate starting materials. 1H NMR (DMSO-d6, 300 MHz): δ 8.35-8.11 (m, 3H), 7.41-7.09 (m, HH), 4.63 (d, J = 6.6 Hz, 1.5H), 4.52 (d, J = 6.6 Hz, 0.5H), 3.76-3.72 (m, 2H), 3.45-3.20 (m, 4H), 2.81-2.78 (m, IH), 2.00-1.98 (m, 2H), 1.50-1.44 (m, 2H); MS (ESI, Pos. 1.5 kV) m/z 539.3 (M+H)+.
Example 6.6 5-(4-(Allylamino)piperidin-l-yl)-3-(3,4-dimethoxyphenyl)-N-(4- fluorobenzyl)pyrimido[5,4-e][l,2,4]triazin-7-amine
Figure imgf000076_0002
This compound was prepared substantially as described in Example 6.1 using appropriate starting materials. 1H NMR (CDCl3, 300 MHz): δ 8.07-7.99 (m, 2H), 7.41- 7.28 (m, 2H), 7.03-7.00 (m, 3H), 6.40 (br, 0.3H), 5.99-5.90 (m, IH), 5.48 (br, 0.7H), 5.26-5.13 (m, 2H), 4.82-4.69 (m, 2H), 4.03-3.99 (m, 6H), 3.78-3.71 (m, IH), 3.37-3.29 (m, 3H), 2.97-2.90 (m, IH), 2.10-2.00 (m, 2H), 1.58-1.40 (m, 4H); MS (ESI, Pos. 1.5 kV) m/z 531.3 (M+H)+. Example 6.7 3-(3,4-Dimethoxyphenyl)-N-(4-fluorobenzyl)-5-(4- morpholinopiperidin-l-yl)pyrimido[5,4-e][l,2,4]triazin-7-amine
Figure imgf000077_0001
This compound was prepared substantially as described in Example 6.1 using appropriate starting materials. 1U NMR (CDCl3, 300 MHz): δ 8.09-7.98 (m, 2H), 7.41- 7.28 (m, 2H), 7.04-7.00 (m, 3H), 6.31 (br, 0.7H), 5.48 (br, 0.3H), 4.82-4.69 (m, 3H), 4.15-4.00 (m, 7H), 3.75-3.51 (m, 4H), 2.65-2.60 (m, 4H), 2.20-2.00 (m, 3H), 1.80-1.65 (m, 4H); MS (ESI, Pos. 1.5 kV) m/z 561.3 (M+H)+.
Example 6.8 3-(3,4-Dimethoxyphenyl)-N-(4-fluorobenzyl)-5-(4-(4- fluorobenzylamino)piperidin-l-yl)pyrimido[5,4-e][l,2,4]triazin-7-amine
Figure imgf000077_0002
This compound was prepared substantially as described in Example 6.1 using appropriate starting materials. 1H NMR (CDCl3, 300 MHz): δ 8.37-7.73 (m, 2.5H), 7.32-7.25 (m, 3.5H), 7.01-6.99 (m, 5H), 5.99 (br, 0.5H), 5.50-5.30 (m, 0.5H), 4.79-4.66 (m, 2.5H), 3.99-3.85 (m, 8H), 3.77-2.97 (m, 2H), 2.21-1.95 (m, 2H), 1.80-0.80 (m, 4H); MS (ESI, Pos. 1.5 kV) m/z 599.3 (M+H)+. Example 7 Compounds Made by Route 7
Example 7.1 3-(3,4-Dimethoxyphenyl)-N-(4-fluorobenzyl)-5-(4-isopentylpiperazin- l-yl)pyrimido[5,4-e][l,2,4]triazin-7-amine
Figure imgf000078_0001
Following the procedure in Route 7, 3-methyl butanal (0.01 g, 0.13 mmol) and glacial acetic acid (0.1 mL) was added into a solution of the amine (Example 4.27, 0.050 g, 0.1 mmol) in dichloromethane (10 mL). After refluxed for 30 min, NaBH(OAc)3 (0.033 g, 0.16 mmol) was added and the solution was refluxed for additional 2 h. The solution was filtered, extracted with ethyl acetate and 1 N aqueous sodium hydroxide, dried, concentrated and purified through flash chromatography to give the title compound as a pale yellow solid (0.040 g, 70%). 1H NMR (DMSO-d6, 300 MHz): δ 8.30 (br, 0.3H), 8.11 (br, 0.7H), 7.92-7.84 (m, 2H), 7.45-7.36 (m, 2H), 7.18-7.13 (m, 3H), 4.62-4.20 (m, 3H), 3.87 (s, 3H), 3.81 (s, 3H), 3.34-3.25 (m, 3H), 2.58-2.45 (m, 4H), 2.37-2.28 (m, 2H), 1.66-1.54 (m, IH), 1.40-1.33 (m, 2H), 0.95-0.90 (m, 6H); MS (ESI, Pos. 1.5 kV) m/z 547.3 (M+H)+.
Example 7.2 5-(4-Butylpiperazm-l-yl)-3-(3,4-dimethoxyphenyl)-N-(4- fluorobenzyl)pyrimido[5,4-e][l,2,4]triazin-7-amine
Figure imgf000079_0001
This compound was prepared substantially as described in Example 7.1 using appropriate starting materials. 1H NMR (DMSO-d6, 300 MHz): δ 8.30 (br, 0.3H), 8.09 (br, 0.7H), 7.91-7.82 (m, 2H), 7.43-7.36 (m, 2H), 7.16-7.10 (m, 3H), 4.60-4.20 (m, 3H), 3.85 (s, 3H), 3.83 (s, 3H), 3.34-3.25 (m, 3H), 2.57-2.47 (m, 4H), 2.32-2.29 (m, 2H), 1.46-1.29 (m, 4H), 0.88 (t, J= 7.2 Hz, 3H); MS (ESI, Pos. 1.5 kV) m/z 533.3 (M+H)+.
Example 7.3 3-(3,4-Dimethoxyphenyl)-N-(4-fluorobenzyl)-5-(4-propylpiperazin-l- yl)pyrimido[5,4-e][l,2,4]triazin-7-amine
Figure imgf000079_0002
This compound was prepared substantially as described in Example 7.1 using appropriate starting materials. 1H NMR (DMSO-d6, 300 MHz): δ 8.40-8.09 (m, IH), 7.93-7.85 (m, 2H), 7.45-7.38 (m, 2H), 7.18-7.14 (m, 3H), 4.62-4.20 (m, 3H), 3.88 (s, 3H), 3.85 (s, 3H), 3.41-3.28 (m, 3H), 3.09-3.06 (m, IH), 2.85-2.70 (m, IH), 2.59-2.45 (m, 4H), 1.70-1.40 (m, 2H), 0.94-0.86 (m, 3H); MS (ESI, Pos. 1.5 kV) m/z 519.3 (M+H)+.
Example 7.4 3-(3,4-Dimethoxyphenyl)-N-(4-fluorobenzyl)-5-(4-isopropylpiperazin- l-yl)pyrimido[5,4-e][l,2,4]triazin-7-amine
Figure imgf000080_0001
This compound was prepared substantially as described in Example 7.1 using appropriate starting materials. 1H NMR (DMSO-d6, 300 MHz): δ 8.30 (br, 0.3H), 8.10 (br, 0.7H), 7.86-7.82 (m, 2H), 7.40-7.36 (m, 2H), 7.15-7.09 (m, 3H), 4.60-4.20 (m, 3H), 3.85 (s, 3H), 3.82 (s, 3H), 3.45-3.00 (m, 3H), 2.66-2.47 (m, 5H), 1.00-0.98 (m, 6H); MS (ESI, Pos. 1.5 kV) m/z 519.3 (M+H)+.
Example 7.5 3-(3,4-Dimethoxyphenyl)-5-(4-ethylpiperazin-l-yl)-N-(4- fluorobenzyl)pyrimido[5,4-e][l,2,4]triazin-7-amine
Figure imgf000080_0002
This compound was prepared substantially as described in Example 7.1 using appropriate starting materials. 1H NMR (DMSO-d6, 300 MHz): δ 8.30 (br, 0.3H), 8.10 (br, 0.7H), 7.90-7.82 (m, 2H), 7.43-7.38 (m, 2H), 7.15-7.11 (m, 3H), 4.60-4.20 (m, 3H), 3.85 (s, 3H), 3.82 (s, 3H), 3.40-3.25 (m, 3H), 2.61-2.45 (m, 4H), 2.41-2.36 (m, 2H), 1.03 (t, J = 6.0 Hz, 3H); MS (ESI, Pos. 1.5 kV) m/z 505.3 (M+H)+.
Example 7.6 5-(4-Cyclohexylpiperazin-l-yl)-3-(3,4-dimethoxyphenyl)-N-(4- fluorobenzyl)pyrimido[5,4-e][l,2,4]triazin-7-amine
Figure imgf000081_0001
This compound was prepared substantially as described in Example 7.1 using appropriate starting materials. 1H NMR (DMSO-d6, 300 MHz): δ 8.30 (br, 0.3H), 8.10 (br, 0.7H), 7.92-7.84 (m, 2H), 7.44-7.37 (m, 2H), 7.15-7.10 (m, 3H), 4.62-4.20 (m, 3H), 3.88 (s, 3H), 3.85 (s, 3H), 3.40-3.25 (m, 3H), 2.74-2.45 (m, 4H), 2.35-2.25 (m, IH), 1.81-1.10 (m, 10H); MS (ESI, Pos. 1.5 kV) m/z 559.3 (M+H)+.
Example 7.7 5-(4-Benzylpiperazm-l-yl)-3-(3,4-dimethoxyphenyl)-N-(4- fluorobenzyl)pyrimido[5,4-e][l,2,4]triazin-7-amine
Figure imgf000081_0002
This compound was prepared substantially as described in Example 7.1 using appropriate starting materials. 1H NMR (DMSO-d6, 300 MHz): δ 8.30 (br, 0.3H), 8.10 (br, 0.7H), 7.92-7.83 (m, 2H), 7.42-7.28 (m, 7H), 7.15-7.12 (m, 3H), 4.62-4.20 (m, 5H), 3.89-3.84 (m, 8H), 3.56-3.34 (m, 3H), 2.62-2.51 (m, 4H); MS (ESI, Pos. 1.5 kV) m/z 567.3 (M+H)+.
Example 7.8 3-(3,4-Dimethoxyphenyl)-N-(4-fluorobenzyl)-5-(4-(4- methoxybenzyl)piperazin-l-yl)pyrimido[5,4-e][l,2,4]triazin-7-amine
Figure imgf000082_0001
This compound was prepared substantially as described in Example 7.1 using appropriate starting materials. 1H NMR (DMSO-d6, 300 MHz): δ 8.30 (br, 0.3H), 8.10 (br, 0.7H), 7.87-7.80 (m, 2H), 7.40-7.38 (m, 2H), 7.24-7.10 (m, 5H), 6.90-6.87 (m, 2H), 4.60-4.20 (m, 3H), 3.85 (s, 3H), 3.82 (s, 3H), 3.72 (s, 2H), 3.47-3.34 (m, 3H), 2.57-2.47 (m, 4H); MS (ESI, Pos. 1.5 kV) m/z 597.3 (M+H)+.
Example 7.9 N-Benzyl-5-(4-butylpiperazm-l-yl)-3-(4-fluorophenyl)pyrimido[5,4- e][l,2,4]triazin-7-amine
Figure imgf000082_0002
This compound was prepared substantially as described in Example 7.1 using appropriate starting materials. 1H NMR (CDCl3, 300 MHz): δ 8.50-8.41 (m, 2H), 7.43- 7.19 (m, 7H), 6.60 (br, 0.4H), 5.55 (br, 0.6H), 4.95-4.69 (m, 4H), 4.50-3.20 (m, 3H), 2.64-2.52 (m, 3H), 2.42-2.35 (m, 2H), 1.59-1.46 (m, 2H), 1.42-1.33 (m, 2H), 0.97 (t, / = 7.2 Hz, 3H); MS (ESI, Pos. 1.5 kV) m/z 473.3 (M+H)+.
Example 7.10 N-Benzyl-3-(4-fluorophenyl)-5-(4-isopentylpiperazin-l- yl)pyrimido[5,4-e][l,2,4]triazin-7-amine
Figure imgf000083_0001
This compound was prepared substantially as described in Example 7.1 using appropriate starting materials. 1H NMR (CDCl3, 300 MHz): δ 8.50-8.43 (m, 2H), 7.44- 7.20 (m, 7H), 6.12 (br, 0.4H), 5.53 (br, 0.6H), 4.94-4.69 (m, 4H), 4.50-4.00 (m, IH), 2.66-2.50 (m, 3H), 2.46-2.41 (m, 2H), 1.69-1.57 (m, 3H), 1.47-1.41 (m, 2H), 0.96 (t, / = 6.6 Hz, 3H); MS (ESI, Pos. 1.5 kV) m/z 487.2 (M+H)+.
Example 7.11 N-Benzyl-3-(4-fluorophenyl)-5-(4-isopropylpiperazin-l- yl)pyrimido[5,4-e][l,2,4]triazin-7-amine
Figure imgf000083_0002
This compound was prepared substantially as described in Example 7.1 using appropriate starting materials. 1H NMR (CDCl3, 300 MHz): δ 8.43-8.41 (m, 2H), 7.44- 7.20 (m, 7H), 6.15 (br, 0.4H), 5.55 (br, 0.6H), 4.87-4.70 (m, 4H), 4.20-4.00 (m, IH), 2.80-2.39 (m, 6H), 1.10 (d, J= 6.0 Hz, 6H); MS (ESI, Pos. 1.5 kV) m/z 459.2 (M+H)+.
Example 7.12 N-Benzyl-3-(4-fluorophenyl)-5-(4-(4-methoxybenzyl)piperazin-l- yl)pyrimido[5,4-e][l,2,4]triazin-7-amine
Figure imgf000085_0001
This compound was prepared substantially as described in Example 7.1 using appropriate starting materials. 1U NMR (CDCl3, 300 MHz): δ 8.45-8.39 (m, 2H), 7.44- 7.20 (m, 9H), 6.92 (d, J= 8.4 Hz, 2H), 6.75 (br, 0.4H), 5.50 (br, 0.6H), 4.92-4.67 (m, 4H), 4.08-4.05 (m, IH), 3.84 (s, 3H), 3.70-3.53 (m, 2H), 2.64-2.58 (m, 3H), 1.95-1.91 (m, 2H); MS (ESI, Pos. 1.5 kV) m/z 537.2 (M+H)+.
Example 8 Compounds Made by Route 8
Example 8.1 N-(4-fluorobenzyl)-3-(4-fluorophenyl)pyrimido[5,4-e][l,2,4]triazin-5- amine
Figure imgf000085_0002
Step A: N'-(5-aminopyrimidin-4-yl)-4-fluorobenzohydrazide
Figure imgf000085_0003
Following the procedure in Route 8, N'-(2-chloro-5-nitropyrimidin-4-yl)-4- fluorobenzohydrazide (prepared as step B in Example 1.1, 0.200 g, 0.643 mmol) was hydrogenated in methanol (15 mL) over Pd(OH)2/C (0.040 g, 20%) at 20 °C/5 atm. After 12 h, the mixture was filtered, washed and concentrated to give crude amine as a brown oil (0.160 g, 100%). MS (ESI, Pos. 1.5 kV) m/z 248.1 (M+H)+.
Step B: 3 -(4 -fluorophenyl) -1,2 -dihydropyrimido[ 5,4-e] '[ 1 , 2, 4]triazine
Figure imgf000086_0001
The above crude amine was dissolved in dry methanol (5 mL) and methanolic HCl (5 mL). The mixture was heated under reflux for 3 hr and concentrated to give the title compound as a brown powder (0.121 g, 82%). MS (ESI, Pos. 1.5 kV) m/z 230.1 (M+H)+.
Step C: N-(4-fluorobenzyl)-3-(4-fluorophenyl)pyrimido[ 5,4-e] [1, 2,4] 'triazin-5-amine
Figure imgf000086_0002
This compound was prepared substantially as described in Example 4.1 using appropriate starting materials. 1H NMR (CDCl3, 300 MHz):δ 8.90 (s, IH), 8.69-8.65 (m, 2H), 7.64 (br, IH), 7.47-7.43 (m, 2H), 7.30-7.24 (m, 2H), 7.14-7.09 (m, 2H), 4.96 (d, / = 6.0 Hz, 2H); MS (ESI, Pos. 1.5 kV) m/z 351.1 (M+H)+.
Example 8.2 l-[3-(4-Fluoro-phenyl)-pyrimido[5,4-e][l,2,4]triazm-5-yl]-piperidin- 4-one
Figure imgf000087_0001
This compound was prepared substantially as described in Example 8.1 using appropriate starting materials. 1U NMR (CDCl3, 300 MHz):δ 8.84 (s, IH), 8.56-8.52 (m, 2H), 7.29-7.24 (m, 2H), 5.11-4.44 (m, 4H), 2.80 (br m, 4H); MS (ESI, Pos. 1.5 kV) m/z 325.0 (M+H)+.
Example 8.3 [3-(4-Fluoro-phenyl)-pyrimido[5,4-e][l,2,4]triazin-5-yl]-((S)-l- phenyl-ethyl)-amine
Figure imgf000087_0002
This compound was prepared substantially as described in Example 8.1 using appropriate starting materials. 1H NMR (CDCl3, 300 MHz):δ 8.83 (s, IH), 8.67-8.63 (m, 2H), 7.53-7.23 (m, 8H), 5.69-5.60 (m, IH), 1.79 (d, J = 7.2 Hz, 3H); MS (ESI, Pos. 1.5 kV) m/z 347.1 (M+H)+. Example 9 Assays
Example 9.1 NS5B
A standard RdRP assay was performed with HCV NS5B in 20 uL reactions containing 20 mM Tris-Cl pH 7.0, 5 mM MgCl2, 5 mM MnCl2, 5mM DTT, 5U RNAsin, 100 ug/mL BSA, 400-500 ng of NS5B protein, 0.2 ug poly(C) template and 10 mM GTP plus ImCi [(X-33P]-GTP, at 25°C for 2 h. The reaction was terminated upon addition of 2 uL 0.45 M EDTA.
2 uL of each reaction was spotted onto a GF-DEAE fϊltermat and dried at 55°C for 1 h. The fϊltermat was subjected to three ten minute washes in 30 mM sodium citrate, 0.3 M NaCl solution, rinsed twice in D-H2O, twice in ethanol, and dried at 55°C for 2 h. The dried fϊltermat was analysed by phosphorimager.
Example 9.2 Replicon
Compounds were assayed for their ability to inhbit HCV according to the procedure described in: Chiaki Okusβi Jo Ann Rinaudo, Kristine Farrar, Frances Wells and Brent E. Korba, Antiviral Research 2005, 65(1), 23-34.
Example IU Activity Summary
Example # IC50 EC50 CC 50 Example # IC50 EC50 CC50
4.1 ++ ++ + 4.20 ++ ++ +
4.2 ++ ++ + 5.1 ++ + +
4.4 ++ +++ ++ 5.6 + ++ +
+++ < IuM; ++ 1 to 10 uM; + >10 uM
It will be appreciated by persons skilled in the art that numerous variations and/or modifications may be made to the invention as shown in the specific embodiments without departing from the scope of the invention as broadly described. The present embodiments are, therefore, to be considered in all respects as illustrative and not restrictive.

Claims

1. A compound of Formula I or a pharmaceutically acceptable derivative, salt or prodrug thereof wherein:
Figure imgf000090_0001
represents a double or single bond;
Ri is selected from the group consisting of H, C1-10alkyl, aryl and heteroaryl;
A is selected from the group consisting of H, OR2, SR2, SOR3, SO2R3, C(R3)3, COR3, - CO2R3; =NR2, =0, NR4R5, -NR4SO2R5,
each R2 is independently selected from the group consisting of H, Ci_ioalkyl, Ci_ locycloalkyl, Ci_3alkylaryl, aryl;
each R3 is independently selected from the group consisting of H, Ci_ioalkyl, C1- locycloalkyl, C1-3alkylaryl, halo, aryl;
each R4 and R5 is independently selected from the group consisting of H, C1-10alkyl, C1- locycloalkyl, C1-3alkylaryl, and aryl; or
R4 and R5 together with the heteroatom(s) to which they are attached form a 5- to 7- membered heterocycle, saturated or unsaturated, comprising 0-2 additional heteratoms selected from the group consisting of O, N and S, wherein said heterocycle is optionally substituted with Rn wherein Rn is one or more substituents selected from the group consisting of H, halo, C1-10alkyl, C1-3alkylaryl, C1-10cycloalkyl, C^alkenyl, =0, C(O)C i_3alkyl, and NR9Ri0.; B is selected from the group consisting of H, OR7, SR7, SOR8, SO2R8, C(R8)3, COR8, - CO2R8; =NR7, NR9Ri0, -NR9SO2Ri0,
each R7 is independently selected from the group consisting of H, Ci_ioalkyl, Ci_ locycloalkyl, Ci_3alkylaryl, aryl;
each R8 is independently selected from the group consisting of H, C1-10alkyl, Ci_ locycloalkyl, Ci_3alkylaryl, halo, aryl;
each R9 and Rio is independently selected from the group consisting of H, C1-10alkyl, Ci_iocycloalkyl, Ci_3alkylaryl, and aryl; or
R9 and Rio together with the heteroatom(s) to which they are attached form a 5- to 7- membered heterocycle, saturated or unsaturated, comprising 0-2 additional heteratoms selected from the group consisting of O, N and S, wherein said heterocycle is optionally substituted with Ri2 wherein Ri2 is one or more substituents selected from the group consisting of H, halo, Ci_ioalkyl, Ci_3alkylaryl, Ci_iocycloalkyl, Ci_6alkenyl, =0, C(O)C i_3alkyl, and NR9Ri0.
2. A compound according to claim 1 wherein Ri is selected from the group consisting of aryl and heteroaryl.
3. A compound according to claim 1 or claim 2 wherein Ri is optionally substituted phenyl.
4. A compound according to claim 3 wherein the phenyl is substituted with one or more substituents independently selected from halo (preferably fluoro), methoxy, and NHC(O)CH3.
5. A compound according to claim 4 wherein Ri is 4-fluorophenyl.
6. A compound according to claim 4 wherein Ri is 3,4-dimethoxyphenyl.
7. A compound ccording to claim 1 to 6 wherein A is OR2 and R2 is methyl.
8. A compound according to any one of claims 1 to 6 wherein A is NR4R5.
9. A compound according to claim 8 wherein R4 is H and R5 is Ci_ioalkyl.
10. A compound according to claim 8 wherein R4 is H and R5 is optionally substituted benzyl.
11. A compound according to claim 10 wherein the the one or more optional substituents are independently selected from the group consisting of halo (preferably fluoro), SO2NH2, S O2NH(Ci. C3 alky 1), and SO2N(Ci_C3alkyl)2
12. A compound according to any one of claims 1 to 11 wherein B is NR9R10 and R9 and Rio together with the heteroatom(s) to which they are attached form a 5- to 7- membered heterocycle, saturated or unsaturated, comprising 0-2 additional heterotoms selected from the group consisting of O, N and S, wherein said heterocycle is optionally substituted with one or more substituents selected from the group consisting of H, halo, Ci_ioalkyl, Ci_i0cycloalkyl, Ci_6alkenyl, =0, C(O)Ci_3alkyl, and NR9Ri0.
13. A compound according to claim 12 wherein the heterocycle is selected from the group consisting of morpholine, piperidine,, and piperazine.
14. A compound according to claim 1 wherein the compound of formula I is a compound of formula II or III, wherein Ri, A, R9, Ri0 and Ri2 are as defined above.
Figure imgf000092_0001
II
Figure imgf000093_0001
III
15. A compound according to claim 1 wherein the compound is selected from one of the following compounds:
7-Methoxy-3-phenyl-pyrimido[5,4-e][l,2,4]triazine
7-Methoxy-3-phenyl-6H-pyrimido[5,4-e][l,2,4]triazin-5-one
7-Methoxy-3-phenyl-6H-pyrimido[5,4-e][l,2,4]triazin-5-ylideneamine
Ethyl-[3-(4-fluoro-phenyl)-7-methoxy-pyrimido[5,4-e][l,2,4]triazin-5-yl]-amine
Benzyl-[3-(4-fluoro-phenyl)-7-methoxy-pyrimido[5,4-e][l,2,4]triazin-5-yl]- amine
Butyl-[3-(4-fluoro-phenyl)-7-methoxy-pyrimido[5,4-e][l,2,4]triazin-5-yl]-amine
[3-(4-Fluoro-phenyl)-7-methoxy-pyrimido[5,4-e][l,2,4]triazin-5-yl]-isopropyl- amine
(4-Fluoro-benzyl)-[3-(4-fluoro-phenyl)-7-methoxy-pyrimido[5,4- e] [ 1 ,2,4]triazin-5-yl]-amine
[3-(4-Fluoro-phenyl)-pyrimido[5,4-e][l,2,4]triazin-7-yl]-methyl-amine Butyl- [5 -ethoxy-3 -(4-fluoro-phenyl)-pyrimido [5 ,4-e] [ 1 ,2,4]triazin-7-yl] -amine
Butyl-[3-(4-fluoro-phenyl)-l,2-dihydro-pyrimido[5,4-e][l,2,4]triazin-7-yl]- amine
Butyl- [3 -(4-fluoro-phenyl)-5 -methoxy-pyrimido [5 ,4-e] [ 1 ,2,4]triazin-7-yl] -amine
Butyl-[3-(4-fluoro-phenyl)-pyrimido[5,4-e][l,2,4]triazin-7-yl]-amine
Ethyl-[3-(4-fluoro-phenyl)- 1 ,2-dihydro-pyrimido[5,4-e] [ 1 ,2,4]triazin-7-yl]- amine
[3-(4-Fluoro-phenyl)-pyrimido[5,4-e][l,2,4]triazin-7-yl]-isopropyl-amine
[3-(4-Fluoro-phenyl)-5-methoxy-pyrimido[5,4-e][l,2,4]triazin-7-yl]-isopropyl- amine
[5-Ethoxy-3-(4-fluoro-phenyl)-pyrimido[5,4-e][l,2,4]triazin-7-yl]-isopropyl- amine
Ethyl-[3-(4-fluoro-phenyl)-pyrimido[5,4-e][l,2,4]triazin-7-yl]-amine
Ethyl-[3-(4-fluoro-phenyl)-5-methoxy-pyrimido[5,4-e][l,2,4]triazin-7-yl]-amine
[5-Ethoxy-3-(4-fluoro-phenyl)-pyrimido[5,4-e][l,2,4]triazin-7-yl]-ethyl-amine
Ethyl-[3-(4-fluoro-phenyl)-5-propoxy-pyrimido[5,4-e][l,2,4]triazin-7-yl]-amine
Benzyl-[3-(4-fluoro-phenyl)-l,2-dihydro-pyrimido[5,4-e][l,2,4]triazin-7-yl]- amine
Benzyl-[3-(4-fluoro-phenyl)-pyrimido[5,4-e][l,2,4]triazin-7-yl]-amine
Benzyl-[3-(4-fluoro-phenyl)-5-methoxy-pyrimido[5,4-e][l,2,4]triazin-7-yl]- amine
Benzyl-[5-ethoxy-3-(4-fluoro-phenyl)-pyrimido[5,4-e][l,2,4]triazin-7-yl]-amine (4-Fluoro-benzyl)-[3-(4-fluoro-phenyl)-l,2-dihydro-pyrimido[5,4- e] [ 1 ,2,4]triazin-7-yl]-amine
(4-Fluoro-benzyl)-[3-(4-fluoro-phenyl)-pyrimido[5,4-e][l,2,4]triazin-7-yl]- amine
(4-Fluoro-benzyl)- [3 -(4-fluoro-phenyl)-5 -methoxy-pyrimido [5 ,4- e] [ 1 ,2,4]triazin-7-yl]-amine
[5-Ethoxy-3-(4-fluoro-phenyl)-pyrimido[5,4-e][l,2,4]triazin-7-yl]-(4-fluoro- benzyl)-amine
4-{[3-(4-Fluoro-phenyl)-pyrimido[5,4-e][l,2,4]triazin-7-ylamino]-methyl}- benzenesulfonamide
4-{[3-(4-Fluoro-phenyl)-l,2-dihydro-pyrimido[5,4-e][l,2,4]triazin-7-ylamino]- methyl} -benzenesulfonamide
(4-Fluoro-benzyl)-[3-(4-fluoro-phenyl)-5-morpholin-4-yl-pyrimido[5,4- e] [ 1 ,2,4]triazin-7-yl]-amine
(4-Fluoro-benzyl)-[3-(4-fluoro-phenyl)-5-(4-methyl-piperazin-l-yl)- pyrimido[5,4-e][l,2,4]triazin-7-yl]-amine
4-{[3-(4-Fluoro-phenyl)-pyrimido[5,4-e][l,2,4]triazin-7-ylamino]-methyl}-N,N- dimethyl-benzenesulfonamide
Benzyl-[3-(4-fluoro-phenyl)-5-morpholin-4-yl-pyrimido[5,4-e][l,2,4]triazin-7- yl] -amine
4-{[3-(4-Fluoro-phenyl)-5-morpholin-4-yl-pyrimido[5,4-e][l,2,4]triazin-7- ylamino]-methyl}-N,N-dimethyl-benzenesulfonamide
4-{[3-(4-Fluoro-phenyl)-5-(4-methyl-piperazin-l-yl)-pyrimido[5,4- e] [ 1 ,2,4]triazin-7-ylamino]-methyl} -N,N-dimethyl-benzenesulfonamide Benzyl-[3 -(4-fluoro-phenyl)-5 -(4-methyl-piperazin- 1 -yl)-pyrimido [5 ,4- e] [ 1 ,2,4]triazin-7-yl]-amine
4-{[3-(4-Fluoro-phenyl)-l,2-dihydro-pyrimido[5,4-e][l,2,4]triazin-7-ylamino]- methyl}-N-methyl-benzenesulfonamide
4- {[3 -(4-Fluoro-phenyl)-5 -(4-methyl-piperazin- l-yl)-pyrimido [5,4- e] [ 1 ,2,4]triazin-7-ylamino]-methyl} -N-methyl-benzenesulfonamide
4-{[3-(4-Fluoro-phenyl)-pyrimido[5,4-e][l,2,4]triazin-7-ylamino]-methyl}-N- methyl-benzenesulfonamide
[3-(3,4-Dimethoxy-phenyl)-l,2-dihydro-pyrimido[5,4-e][l,2,4]triazin-7-yl]-(4- fluoro-benzyl)-amine
[3-(3,4-Dimethoxy-phenyl)-pyrimido[5,4-e][l,2,4]triazin-7-yl]-(4-fluoro- benzyl)-amine
[3-(3,4-Dimethoxy-phenyl)-5-morpholin-4-yl-pyrimido[5,4-e][l,2,4]triazin-7- yl]-(4-fluoro-benzyl)-amine
[3 -(3, 4-Dimethoxy-phenyl)-5 -(4-methyl-piperazin- l-yl)-pyrimido [5,4- e] [ 1 ,2,4]triazin-7-yl]-(4-fluoro-benzyl)-amine
N-5-Cyclohexyl-3-(3,4-dimethoxy-phenyl)-N-7-(4-fluoro-benzyl)-pyrimido[5,4- e] [ 1 ,2,4]triazine-5 ,7-diamine
3-(3,4-Dimethoxy-phenyl)-N-5-N-7-bis-(4-fluoro-benzyl)-pyrimido[5,4- e] [ 1 ,2,4]triazine-5 ,7-diamine
[3-(3,4-Dimethoxy-phenyl)-5-ethoxy-pyrimido[5,4-e][l,2,4]triazin-7-yl]-(4- fluoro-benzyl)-amine
N-[4-(7-Benzylamino-5-morpholin-4-yl-pyrimido[5,4-e][l,2,4]triazin-3-yl)- phenyl] -acetamide l-[3-(4-Fluoro-phenyl)-7-imino-7,8-dihydro-5H-pyrimido[5,4-e][l,2,4]triazin- 6-yl]-ethanone
N-5-((S)-l-Benzyl-pyrrolidin-3-yl)-3-(3,4-dimethoxy-phenyl)-N-7-(4-fluoro- benzyl)-pyrimido [5 ,4-e] [ 1 ,2,4]triazine-5 ,7-diamine
Benzyl-[3-(4-fluoro-phenyl)-5-piperazin-l-yl-pyrimido[5,4-e][l,2,4]triazin-7- yl] -amine
3-(4-Fluoro-phenyl)-l,2-dihydro-pyrimido[5,4-e][l,2,4]triazin-7-ylamine
3-(4-Fluoro-phenyl)-5-(4-methyl-piperazin-l-yl)-pyrimido[5,4-e][l,2,4]triazin- 7-ylamine
4-{[3-(4-Fluoro-phenyl)-5-morpholin-4-yl-pyrimido[5,4-e][l,2,4]triazin-7- ylamino]-methyl}-benzenesulfonamide
3-(4-Fluoro-phenyl)-5-morpholin-4-yl-pyrimido[5,4-e][l,2,4]triazin-7-ylamine
3-(4-Fluoro-phenyl)-pyrimido[5,4-e][l,2,4]triazin-7-ylamine
5-Ethoxy-3-(4-fluoro-phenyl)-pyrimido[5,4-e][l,2,4]triazin-7-ylamine
[5 -(4- Allylamino-piperidin- 1 -yl)-3 -(4-fluoro-phenyl)-pyrimido [5 ,4- e] [ 1 ,2,4]triazin-7-yl]-benzyl-amine
Benzyl-[3-(3,4-dimethoxy-phenyl)-l,2-dihydro-pyrimido[5,4-e][l,2,4]triazin-7- yl] -amine
Cyclohexyl-[3-(4-fluoro-phenyl)-l,2-dihydro-pyrimido[5,4-e][l,2,4]triazin-7- yl] -amine
4-{[3-(4-Fluoro-phenyl)-5-morpholin-4-yl-pyrimido[5,4-e][l,2,4]triazin-7- ylamino]-methyl}-N-methyl-benzenesulfonamide
1 -[7-Benzylamino-3-(4-fluoro-phenyl)-pyrimido[5,4-e] [ 1 ,2,4]triazin-5-yl]- piperidin-4-one 4-{[3-(4-Fluoro-phenyl)-5-(4-methyl-piperazin-l-yl)-pyrimido[5,4- e] [ 1 ,2,4]triazin-7-ylamino]-methyl} -benzenesulfonamide
[3-(4-Fluoro-phenyl)-l,2-dihydro-pyrimido[5,4-e][l,2,4]triazin-7-yl]-phenyl- amine
[3-(4-Fluoro-phenyl)-5-(4-methyl-piperazin-l-yl)-pyrimido[5,4-e][l,2,4]triazin- 7-yl]-phenyl-amine
[3-(4-Fluoro-phenyl)-5-morpholin-4-yl-pyrimido[5,4-e][l,2,4]triazin-7-yl]- phenyl-amine
[3-(4-Fluoro-phenyl)-pyrimido[5,4-e][l,2,4]triazin-7-yl]-phenyl-amine
Cyclohexyl-[3-(4-fluoro-phenyl)-5-morpholin-4-yl-pyrimido[5,4- e] [ 1 ,2,4]triazin-7-yl]-amine
Cyclohexyl-[3-(4-fluoro-phenyl)-pyrimido[5,4-e][l,2,4]triazin-7-yl]-amine
Benzyl-[3-(3,4-dimethoxy-phenyl)-5-ethoxy-pyrimido[5,4-e][l,2,4]triazin-7-yl]- amine
Benzyl-[3 -(3 ,4-dimethoxy-phenyl)-5 -(4-methyl-piperazin- 1 -yl)-pyrimido [5 ,4- e] [ 1 ,2,4]triazin-7-yl]-amine
Benzyl-[3-(3,4-dimethoxy-phenyl)-5-morpholin-4-yl-pyrimido[5,4- e] [ 1 ,2,4]triazin-7-yl]-amine
Benzyl-[3-(3,4-dimethoxy-phenyl)-pyrimido[5,4-e][l,2,4]triazin-7-yl]-amine
3-(3,4-Dimethoxy-phenyl)-N-7-(4-fluoro-benzyl)-N-5-((S)-l-phenyl-ethyl)- pyrimido[5 ,4-e] [ 1 ,2,4]triazine-5 ,7-diamine
4-((5-ethoxy-3-(4-fluorophenyl)pyrimido[5,4-e][l,2,4]triazin-7- ylamino)methyl)-N-methylbenzenesulfonamide
N-cyclohexyl-5-ethoxy-3-(4-fluorophenyl)pyrimido[5,4-e][l,2,4]triazin-7-amine 3 -(3 ,4-Dimethoxyphenyl)-N-(4-fluorobenzyl)-5 -(piperazin- 1 -yl)pyrimido [5 ,4- e] [ 1 ,2,4]triazin-7-amine
N-Cyclohexyl-3 -(4-fluoropheny l)-5 -(4-methylpiperazin- 1 -yl)pyrimido [5 ,4- e] [ 1 ,2,4]triazin-7-amine
l-(4-(7-(Benzylamino)-3-(4-fluorophenyl)pyrimido[5,4-e][l,2,4]triazin-5- yl)piperazin- 1 -yl)ethanone
l-(7-(Benzylamino)-3-(4-fluorophenyl)pyrimido[5,4-e][l,2,4]triazin-5- yl)piperidin-4-ol
4-((3-(4-Fluorophenyl)-5 -(piperazin- 1 -yl)pyrimido[5,4-e] [ 1 ,2,4]triazin-7- ylamino)methyl)benzenesulfonamide
7-Ethoxy-N-(4-fluorobenzyl)-3-(4-fluorophenyl)pyrimido[5,4-e][l,2,4]triazin-5- amine
N-(4-Fluorobenzyl)-3-(4-fluorophenyl)-7-propoxypyrimido[5,4-e][l,2,4]triazin- 5 -amine
7-Butoxy-N-(4-fluorobenzyl)-3-(4-fluorophenyl)pyrimido[5,4-e][l,2,4]triazin-5- amine
N-Benzyl-5-(4-(cyclohexylamino)piperidin- 1 -yl)-3-(4- fluorophenyl)pyrimido[5,4-e][l,2,4]triazin-7-amine
N-Benzyl-5-(4-(diethylamino)piperidin-l-yl)-3-(4-fluorophenyl)pyrimido[5,4- e] [ 1 ,2,4]triazin-7-amine
N-Benzyl-5 -(4-(butylamino)piperidin- 1 -yl)-3 -(4-fluorophenyl)pyrimido [5 ,4- e] [ 1 ,2,4]triazin-7-amine
N-Benzyl-5 -(4-(4-fluorobenzylamino)piperidin- 1 -yl)-3-(4- fluorophenyl)pyrimido[5,4-e][l,2,4]triazin-7-amine 5 -(4-(Allylamino)piperidin- 1 -yl)-3 -(3 ,4-dimethoxyphenyl)-N-(4- fluorobenzyl)pyrimido[5,4-e][l,2,4]triazin-7-amine
3 -(3 ,4-Dimethoxyphenyl)-N-(4-fluorobenzyl)-5 -(4-morpholinopiperidin- 1 - yl)pyrimido[5,4-e][l,2,4]triazin-7-amine
3-(3,4-Dimethoxyphenyl)-N-(4-fluorobenzyl)-5-(4-(4- fluorobenzylamino)piperidin- 1 -yl)pyrimido [5 ,4-e] [ 1 ,2,4
16. A compound according to claim 1 wherein the compound is selected from the compounds set out below:
Figure imgf000100_0001
17. A pharmaceutical composition comprising a compound according to the any one of claims 1 to 16 and a pharmaceutically acceptable carrier, diluent or excipient
18. A method of treatment or prophylaxis of a viral infection in a subject comprising administering to said subject an effective amount of a compound according to any one of claims 1 to 16 or a pharmaceutically acceptable derivative, salt or prodrug thereof.
19. A use of a compound according to any one of claims 1 to 16 or a pharmaceutically acceptable derivative, salt or prodrug thereof, or a composition according to claim 17, in the preparation of a medicament for the treatment or prophylaxis of a viral infection in a subject.
20. A method according to claim 18 or a use according to claim 19 wherein the viral infection of the second and third aspects is a HCV infection.
PCT/CN2009/070252 2009-01-21 2009-01-21 PYRIMIDO[5,4-e][1,2,4]TRIAZINES AND USES THEREOF Ceased WO2010083645A1 (en)

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