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US 20100305117A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2010/0305117 A1 Herdewijn et al. (43) Pub. Date: Dec. 2, 2010

(54) SUBSTITUTED PTERIDINES USEFUL FOR Related U.S. Application Data THE TREATMENT AND PREVENTION OF VRAL (60) Provisional application No. 60/807,925, filed on Jul. 20, 2006. (75) Inventors: Piet André Maurits Maria Herdewijn, Rotselaar/Wezemaal O O (BE); Steven Cesar Alfons De Publication Classification Jonghe, Brussel (BE); William (51) Int. Cl. John Watkins, Saratoga, CA (US); A 6LX 3/59 (2006.01) Lee Shun Chong, Newark, CA C07D 475/04 (2006.01) (US) A 6LX 3/5.377 (2006.01) C07D 475/08 (2006.01) Correspondence Address: A6IP3 L/14 (2006.01) GLEAD SCIENCES INC 333 LAKESIDE DR FOSTER CITY, CA 94.404 (US) (52) U.S. Cl...... 514/232.5:544/258: 514/249; 544/118: 514/234.2:544/82 (73) Assignee: Gilead Sciences, Inc., Foster City, CA (US) (57) ABSTRACT (21) Appl. No.: 12/374,457 The invention provides 4,6-di- and 2,4,6-tri-substituted pte (22) PCT Filed: Jul. 20, 2007 ridine derivatives with a specific substitution pattern which exhibit a significant and selective activity against certain (86). PCT No.: PCT/BE07/00092 types of viral infections, in particular selectively inhibit rep lication of Flaviridae such as the virus, and are S371 (c)(1), useful for the prevention and treatment of such viral infec (2), (4) Date: Jan. 20, 2009 tions. US 2010/03051 17 A1 Dec. 2, 2010

SUBSTITUTED PTERDINES USEFUL FOR Unfortunately, this process fails to eradicate in most THE TREATMENT AND PREVENTION OF people; in fact, it may contribute to liver inflammation and, VRAL INFECTIONS ultimately, tissue necrosis. The ability of HCV to escape immune Surveillance is the Subject of much speculation. One FIELD OF THE INVENTION likely means of viral persistence relies on the presence of closely related but heterogeneous populations of viral 0001. The present invention relates to a group of novel genomes. Further studies of these quasi-species enable clas 4,6-di- and 2,4,6-trisubstituted pteridines and to their use as sification of several genotypes and Subtypes, which have biologically active ingredients for manufacturing medica clinical implications. ments for the prevention or treatment of viral infections, in 0005. The diagnosis of hepatitis C is rarely made during particular infections by a virus of the Flaviridae family, more the acute phase of the disease because the majority of people specifically for inhibiting replication of hepatitis C virus. The infected experience no symptoms during this phase of the present invention thus also relates to therapeutic and prophy disease. Those who do experience acute phase symptoms are lactic methods comprising administration of said specifically rarely ill enough to seek medical attention. The diagnosis of 4,6-di- and 2,4,6-trisubstituted pteridine derivatives, or pro chronic phase hepatitis C is also challenging due to the drugs thereof, to mammals, in particular human beings. absence or lack of specificity of symptoms until advanced liver disease develops, which may not occur until decades BACKGROUND OF THE INVENTION into the disease. 0002 There is a continuous need in the art for specific and 0006 Hepatitis C testing begins with serological blood highly therapeutically active compounds for preventing or tests used to detect antibodies to HCV. Anti-HCV antibodies treating infections due to Flaviridae and pathologic condi can be detected in about 80% of patients within 15 weeks after tions associated therewith, especially hepatitis C. In particu exposure, in more than 90% of patients within 5 months after lar, there is a need in the art to provide drugs which are active exposure, and in more than 97% of patients by 6 months after against hepatitis C in a minor dose in order to replace existing exposure. Overall, HCV antibody tests have a strong positive drugs having significant side effects and to decrease treatment predictive value for exposure to the hepatitis C virus, but may COStS. miss patients who have not yet developed antibodies (sero 0003. Hepatitis is an inflammation of the liver that is most conversion), or have an insufficient level of antibodies to often caused by infection with one of three viruses known as detect. Anti-HCV antibodies indicate exposure to the virus, hepatitis A, B or C. Hepatitis A virus (HAV) infection is the but cannot determine if ongoing infection is present. All per most common cause of acute hepatitis, and usually resolves sons with positive anti-HCV antibody tests must undergo spontaneously after several weeks of acute symptoms. Hepa additional testing for the presence of the hepatitis C virus titis B virus (HBV) and hepatitis C virus (HCV) are the most itself to determine whether current infection is present. The common viral causes of chronic hepatitis, usually defined as presence of HCV may be tested by using molecular nucleic liver inflammation persisting for more than six months. HCV acid testing methods such as, but not limited to, polymerase is the second most common cause of viral hepatitis in general chain reaction (PCR), mediated amplification and most common cause of chronic hepatitis. The World (TMA), or branched DNA amplification. All HCV nucleic Health Organization estimates that worldwide 170 million acid molecular tests have the capacity to detect not only people (3% of the world's population) are chronically whether the virus is present, but also to measure the amount of infected with HCV. These chronic carriers are at risk of devel virus present in the blood (the HCV viral load). The HCV oping cirrhosis and/or liver cancer. In studies with a 10 to 20 viral load is an important factor in determining the probability year follow-up, cirrhosis developed in 20-30% of the patients, of response to -base therapy, but does not indicate 1-5% of whom may develop liver cancer during the next then disease severity nor the likelihood of disease progression. years. The 15% to 45% of persons with acute hepatitis C who 0007. The goal of treatment is to prevent complications of do recover are not subject to long-term complications and do HCV infection. This is principally achieved by eradication of not need treatment. Since HCV and pestiviruses belong to the infection. Accordingly, treatment responses are frequently same virus family and share many similarities (such as, but characterized by the results of HCV RNA testing. Infection is not limited to, organization of the genome, analogous gene considered eradicated when there is a Sustained Virologic products and replication cycle), pestiviruses may be adopted response (SVR), defined as the absence of HCV RNA in as a model virus and surrogate for HCV. For example the serum by a sensitive test at the end of treatment and 6 months Bovine Viral Diarrhea Virus (BVDV) is closely related to later. Persons who achieve an SVR almost always have a hepatitis C virus (HCV) and may be used as a surrogate virus dramatic earlier reduction in the HCV RNA level, referred to in for HCV infection. as an early virologic response (EVR). Continued absence of 0004 HCV is a representative and highly significant detectable virus at termination of treatment is referred to as member of the Flaviviridae family, a family of positive-strand end of treatment response (ETR). A patient is considered RNA viruses. This family includes the following genera: relapsed when HCV RNA becomes undetectable on treat Genus Flavivirus (type species Yellow fever virus, others ment but is detected again after discontinuation of treatment. include West Nile virus and Dengue Fever), Genus Hepacivi Persons in whom HCV RNA levels remain stable on treat rus (type species Hepatitis C virus), and Genus Pestivirus ment are considered as non-responders, while those whose (type species Bovine viral diarrhea virus (BVDV), others HCV RNA levels decline but remain detectable are referred to include classical Swine fever or hog cholera). Contrary to as partial responders. other families of positive strand RNA viruses such as human 0008. Current standard of care for HCV treatment is a immunodeficiency virus (HIV), HCV seems incapable of combination of (pegylated) interferon alpha and the antiviral integrating into the host's genome. The primary immune drug for a period of 24 or 48 weeks, depending upon response to HCV is mounted by cytotoxic T lymphocytes. the viral genotype. Should treatment with pegylated ribavi US 2010/03051 17 A1 Dec. 2, 2010

rin-interferon not return a viral load reduction after 12 weeks, RNAaptamers, RNA decoys, and RNA interference. A major the chance of treatment success is less than 1%. Current drawback for Such nucleic acid based approach is the size and indication for treatment includes patients with proven hepa charge of the nucleic acids, and their usually low physiologi titis C virus infection and persistent abnormal liver function cal stability that do not allow for oral administration. Another tests. SVR of 75% or better occur in people with genotypes target option for therapy is by blocking viral entry into the cell HCV 2 and 3 within 24 weeks of treatment, about 50% in by obstruction of binding to HCV receptors such as, but not those with genotype 1 within 48 weeks of treatment and 65% limited to, CD 209L and L-SIGN. for those with genotype 4 within 48 weeks of treatment. 0014. There is a strong need in the art to improve, or to About 80% of hepatitis C patients in the United States exhibit provide alternatives to, the existing prophylactic or therapeu genotype 1, whereas genotype 4 is more common in the tic solutions to infections by a virus of the Flaviridae family, Middle East and Africa. more specifically HCV infection. In particular there is still a 0009 Best results have been achieved with the combina need in the art for providing alternative synthetic molecules tion of weekly Subcutaneous injections of long-acting having significant HCV replication inhibiting activity. There peginterferon alpha and oral ribavirin daily. are is also a need in the art for providing effective inhibiting substances naturally released by cells in the body after viral molecules which are free from the significant drawbacks of invasion. Interferon alfa-2b and peginterferon alfa-2b are the current drugs like pegylated interferon and ribavirin. synthetic versions of these Substances. The protein product is Meeting these various needs in the art constitutes the main manufactured by recombinant DNA-technology. Second goal of the present invention. generation interferons are further derivatized by binding to inert polyethylene glycol, thereby altering the pharmacoki SUMMARY OF THE INVENTION netic properties. Ribavirin is a , which disrupts viral replication of hepatitis C virus (HCV). 0015 The present invention is based on the unexpected 0010. The most common side effects of HCV treatment finding that a number of novel specifically substituted pte with (pegylated) interferon include: a decrease in white blood ridines, in particular 4,6-disubstituted pteridines and 2.4.6- cells and platelets, anemia, nausea, diarrhea, fever, chills, trisubstituted pteridines, are capable of exhibiting a signifi muscle and joint pain, difficulty in concentrating, thyroid cant and selective activity against certain types of viral dysfunction, hair loss, sleeplessness, irritability, mild to seri infections, provided that the Substituting pattern of Such pte ous depression, and rarely, Suicidal thoughts. Other serious ridines is suitably selected. In particular, these selected 4.6- adverse events include bone marrow toxicity, cardiovascular disubstituted pteridines and 2,4,6-trisubstituted pteridines are disorders, hypersensitivity, endocrine disorders, pulmonary capable of selectively inhibiting the replication of the hepa disorders, colitis, pancreatitis, and ophthalmologic disorders titis C virus. As a consequence, the present invention provides (eye and vision problems). (Pegylated) interferon may also pharmaceutical compositions comprising one or more 4.6- cause or make worse fatal or life-threatening neuropsychiat disubstituted pteridines and 2,4,6-trisubstituted pteridines in ric, autoimmune, ischemic, and infectious disorders. Patients combination with one or more pharmaceutically acceptable with persistently severe or worsening signs or symptoms of excipients. The present invention also provides prophylactic and therapeutic methods of treatment of higher mammals, in these conditions are advised to stop therapy. particular human beings, through the administration of an 0011. The most common side effect of HCV treatment with ribavirin is anemia, which can be treated with erythro effective amount of such selected 4,6-disubstituted pteridines poietin. Other side effects include mood swings, irritability, and 2,4,6-trisubstituted pteridines. anxiety, insomnia, abdominal pain, nervousness, breathless ness, rash, hair loss, dry skin, nausea, diarrhoea, loss of appe DEFINITIONS tite, dizziness and weight loss. Ribavirin can also cause birth 0016. Unless otherwise stated herein, the term "tri-substi defects. Ribavirin should not be taken in combination with tuted in relation to the pteridine structure means that three of certain HIV drugs such as, but not limited to, , the carbonatoms being in positions 2, 4 and 6 of the pteridine since lactic acidosis with fatal hepatic Steatosis (fatty liver) moiety (according to standard atom numbering for the pteri may occur. Special attention should be taken for treatment dine moiety) are Substituted with an atom or group of atoms with HIV co-infection. other than hydrogen. Unless otherwise stated herein, the term 0012. Although the liver is the primary target of infection, “di-substituted in relation to the pteridine structure means studies to better define the steps of HCV infection are greatly that two of the carbonatoms being in positions 4 and 6 of the hampered by the lack of a suitable animal model for such pteridine moiety (according to standard atom numbering for studies. The recent development of sub-genomic HCV RNA the pteridine moiety) are substituted with an atom or group of replicons capable of autonomous replication in the human atoms other than hydrogen. hepatoma cell line, Huh-7, has been a significant advance in 0017. As used herein with respect to a substituting radical, the study of HCV biology. The sub-genomic HCV RNA and unless otherwise stated, the term “C, alkyl means replicon system provides a cell-based assay to evaluate straight and branched chain Saturated acyclic hydrocarbon inhibitors of HCV enzymes like the protease, helicase, and monovalent radicals having from 1 to 7 carbonatoms such as, RNA-dependant RNA polymerase or to evaluate nucleic acid for example, methyl, ethyl, propyl. n-butyl, 1-methyl-ethyl targeting strategies like antisense RNA and ribozymes. (isopropyl), 2-methylpropyl (isobutyl), 1,1-dimethylethyl 0013 Targets for HCV Drug development include HCV (tert-butyl), 2-methyl-butyl, n-pentyl, dimethylpropyl, encoded enzymes, namely, NS2-3 and NS3-4A proteases, n-hexyl, 2-methylpentyl, 3-methylpentyl, n-heptyl and the NS3 helicase, and NS5B RNA dependant RNA polymerase. like. By analogy, the term “C. alkyl refers to such radicals Alternatively, HCV replication can be inhibited by blocking having from 1 to 4 carbon atoms, i.e. up to and including the conserved RNA elements employing a nucleic acid based butyl, and “C. alkyl refers to such radicals having from 1 approach including antisense oligonucleotides, ribozymes, to 12 carbon atoms. US 2010/03051 17 A1 Dec. 2, 2010

0018. As used herein with respect to a substituting radical, 0040 arylalkoxycarbonyl (for example benzyloxycar and unless otherwise stated, the term “acyl broadly refers to bonyl and the like): a Substituent derived from an acid such as an organic mono 0041 arylcarbamoyl (for example phenylcarbamoyl, carboxylic acid, a carbonic acid, a carbamic acid (resulting naphthylcarbamoyl and the like): into a carbamoyl substituent) or the thioacid or imidic acid 0.042 arylglyoxyloyl (for example phenylglyoxyloyl (resulting into a carbamidoyl Substituent) corresponding to and the like). said acids, and the term “sulfonyl refers to a substituent 0.043 arylthiocarbamoyl (for example phenylthiocar derived from an organic Sulfonic acid, wherein said acids bamoyl and the like); and comprise an aliphatic, aromatic or heterocyclic group in the 0044) arylcarbamidoyl (for example phenylcarbami molecule. A more specific kind of “acyl group within the doyl and the like). Scope of the above definition refers to a carbonyl (OXO) group 0045 Acyl groups may also originate from an heterocy adjacent to a C-7 alkyl, a Cso cycloalkyl, an aryl, an aryla clic monocarboxylic acids and include, but are not limited to, lkyl or a heterocyclic group, all of them being Such as herein the following: defined. Suitable examples of acyl groups are to be found 0046 heterocyclic-carbonyl, in which said heterocyclic below. group is as defined herein, preferably an aromatic or 0019 Acyl and sulfonyl groups originating from aliphatic non-aromatic 5- to 7-membered heterocyclic ring with or cycloaliphatic monocarboxylic acids are designated herein one or more heteroatoms selected from the group con as aliphatic or cycloaliphatic acyl and Sulfonyl groups and sisting of nitrogen, oxygen and Sulfur in said ring (for include, but are not limited to, the following: example thiophenoyl, furoyl pyrrollecarbonyl, nicoti 0020 alkanoyl (for example formyl, acetyl, propionyl, noyl and the like); and butyryl, isobutyryl, Valeryl, isovaleryl, pivaloyl and the 0047 heterocyclic-alkanoyl in which said heterocyclic like): group is as defined herein, preferably an aromatic or 0021 cycloalkanoyl (for example cyclobutanecarbo non-aromatic 5- to 7-membered heterocyclic ring with nyl, cyclopentane-carbonyl, cyclo-hexanecarbonyl, one or more heteroatoms selected from the group con 1-adamantanecarbonyl and the like); sisting of nitrogen, oxygen and Sulfur in said ring (for 0022 cycloalkyl-alkanoyl (for example cyclohexy example thiopheneneacetyl, furylacetyl, imidazolylpro lacetyl, cyclopentylacetyl and the like); pionyl, tetrazolylacetyl, 2-(2-amino-4-thiazolyl)-2- 0023 alkenoyl (for example acryloyl, methacryloyl, methoxyiminoacetyl and the like). crotonoyl and the like); 0048. As used herein with respect to a substituting radical, 0024 alkylthioalkanoyl (for example methylthioacetyl, and unless otherwise stated, the term "C-7 alkylene' means ethylthioacetyl and the like): the divalent hydrocarbon radical corres-ponding to the above 0025 alkanesulfonyl (for example mesyl ethanesulfo defined C, alkyl, such as methylene, bis(methylene), tris nyl, propanesulfonyl and the like); (methylene), tetramethylene, hexamethylene and the like. 0026 alkoxycarbonyl (for example methoxycarbonyl, 0049. As used herein with respect to a substituting radical, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbo and unless otherwise stated, the term "Clo cycloalkyl nyl, butoxycarbonyl, isobutoxycarbonyl and the like): means a mono- or polycyclic Saturated hydrocarbon monova 0027 alkylcarbamoyl (for example methylcarbamoyl lent radical having from 3 to 10 carbon atoms, such as for and the like): instance cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 0028 (N-alkyl)-thiocarbamoyl (for example (N-me cycloheptyl, cyclooctyl and the like, or a C7- polycyclic thyl)-thiocarbamoyl and the like): saturated hydrocarbon monovalent radical having from 7 to 0029 alkylcarbamidoyl (for example methylcarbami 10 carbon atoms such as, for instance, norbornyl, fenchyl, doyl and the like); and trimethyltricycloheptyl or adamanty1. 0030 alkoxyalkyl (for example methoxyalkyl, ethoxy 0050. As used herein with respect to a substituting radical, alkyl, propoxyalkyl and the like); and unless otherwise stated, the term "Cocycloalkyl-alkyl 0031 Acyl and sulfonyl groups may also originate from refers to an aliphatic Saturated hydrocarbon monovalent radi aromatic monocarboxylic acids and include, but are not lim cal (preferably a C-, alkyl such as defined above) to which a ited to, the following: Co cycloalkyl (Such as defined above) is already linked 0032 aroyl (for example benzoyl, toluoyl, xyloyl, Such as, but not limited to, cyclohexylmethyl, cyclopentylm 1-naphthoyl 2-naphthoyl and the like); ethyl and the like. 0033 arylalkanoyl (for example phenylacetyl and the 0051. As used herein with respect to a substituting radical, and unless otherwise stated, the term “Co cycloalkylene’ like): means the divalent hydrocarbon radical corresponding to the 0034) arylalkenoyl (for example cinnamoyl and the above defined Co cycloalkyl. like): 0052. As used herein with respect to a substituting radical, 0035 aryloxyalkanoyl (for example phenoxyacetyland and unless otherwise stated, the term “aryl” designates any the like): mono- or polycyclic aromatic monovalent hydrocarbon radi 0036) arylthioalkanoyl (for example phenylthioacetyl cal having from 6 up to 30 carbon atoms such as but not and the like): limited to phenyl, naphthyl, anthracenyl, phenantracyl, fluo 0037 arylaminoalkanoyl (for example N-phenylglycyl, ranthenyl, chrysenyl, pyrenyl, biphenylyl, terphenyl, picenyl, and the like): indenyl, biphenyl, indacenyl, benzocyclobutenyl, benzocy 0038 arylsulfonyl (for example benzenesulfonyl, tolu clooctenyl and the like, including fused benzo-Cas enesulfonyl, naphthalenesulfonyl and the like): cycloalkyl radicals (the latter being as defined above) Such as, 0039 aryloxycarbonyl (for example phenoxycarbonyl, for instance, indanyl, tetrahydronaphthyl, fluorenyl and the naphthyloxycarbonyl and the like): like, all of the said radicals being optionally substituted with US 2010/03051 17 A1 Dec. 2, 2010

one or more substituents independently selected from the cyclooctyl, azacyclononyl, azabicyclononyl, tetrahydrofuryl, group consisting of halogen, amino, trifluoromethyl, tetrahydropyranyl. tetrahydropyronyl, tetrahydro hydroxyl, Sulfhydryl and nitro, such as for instance 4-fluo quinoleinyl, tetrahydrothienyl and dioxide thereof, dihy rophenyl, 4-chlorophenyl, 3,4-dichlorophenyl, 4-cyanophe drothienyl dioxide, dioxindolyl, dioxinyl, dioxenyl, dioxazi nyl, 2,6-dichlorophenyl, 2-fluorophenyl, 3-chlorophenyl, nyl, thioxanyl, thioxolyl, thiourazolyl, thiotriazolyl, 4-nitrophenyl, 3,5-dichlorophenyl and the like. thiopyranyl, thiopyronyl, coumarinyl, quinoleinyl, 0053 As used herein, e.g. with respect to a substituting oxyquinoleinyl, quinuclidinyl, Xanthinyl, dihydropyranyl. radical Such as the combination of Substituents in certain benzodihydrofuryl, benzothiopyronyl, benzothiopyranyl, positions of the pteridine ring together with the carbonatoms benzoxazinyl, benzoxazolyl, benzodioxolyl, benzodioxanyl. in the same positions of said ring, and unless otherwise stated, benzothiadiazolyl, benzotriazinyl, benzothiazolyl, benzox the term "homocyclic’ means a mono- or polycyclic, Satu azolyl, phenothioxinyl, phenothiazolyl, phenothienyl (ben rated or mono-unsaturated or polyunsaturated hydrocarbon Zothiofuranyl), phenopyronyl, phenoxazolyl pyridinyl, dihy radical having from 4 up to 15 carbonatoms but including no dropyridinyl, tetrahydropyridinyl, piperidinyl, morpholinyl, heteroatom in the said ring; for instance said combination of thiomorpholinyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazi Substituents may form a C- alkylene radical, such as tetram nyl, tetrazinyl, triazolyl, benzotriazolyl, tetrazolyl, imida ethylene, which cyclizes with the carbon atoms in certain Zolyl, pyrazolyl, thiazolyl, thiadiazolyl, isothiazolyl, positions of the pteridine ring. oxazolyl, oxadiazolyl pyrrolyl, furyl, dihydrofuryl, furoyl, 0054 As used herein with respect to a substituting radical hydantoinyl, dioxolanyl, dioxolyl, dithianyl, dithienyl, dithii (including the combination of Substituents in certain posi nyl, thienyl, indolyl, indazolyl, benzofuryl, quinolyl, tions of the pteridine ring together with the carbon atoms in quinazolinyl, quinoxalinyl, carbazolyl, phenoxazinyl, phe the same positions of said ring), and unless otherwise stated, nothiazinyl, Xanthenyl, purinyl, benzothienyl, naphthothie the terms "heterocyclic” and "heterocyclyl mean a mono- or nyl, thianthrenyl, pyranyl, pyronyl, benzopyronyl, isobenzo polycyclic, Saturated or mono-unsaturated or polyunsatu furanyl. chromenyl, phenoxathiinyl, indolizinyl, rated monovalent hydrocarbon radical having from 2 up to 15 quinolizinyl, isoquinolyl, phthalazinyl, naphthiridinyl, cin carbon atoms and including one or more heteroatoms in one nolinyl, pteridinyl, carbolinyl, acridinyl, perimidinyl, or more heterocyclic rings, each of said rings having from 3 to phenanthrolinyl, phenazinyl, phenothiazinyl, imidazolinyl, 10 atoms (and optionally further including one or more het imidazolidinyl, benzimidazolyl pyrazolinyl, pyrazolidinyl, eroatoms attached to one or more carbon atoms of said ring, pyrrolinyl, pyrrolidinyl, piperazinyl, uridinyl, thymidinyl, for instance in the form of a carbonyl or thiocarbonyl or cytidinyl, azirinyl, aziridinyl, diazirinyl, diaziridinyl, oxira Selenocarbonyl group, and/or to one or more heteroatoms of nyl, oxaziridinyl, dioxiranyl, thiranyl, aZetyl, dihydroaZetyl, said ring, for instance in the form of a Sulfone, Sulfoxide, aZetidinyl, oxetyl, oxetanyl, oxetanonyl, homopiperazinyl, N-oxide, phosphate, phosphonate or selenium oxide group), homopiperidinyl, thietyl, thietanyl, diazabicyclooctyl, diaz each of said heteroatoms being independently selected from etyl, diaziridinonyl, diaziridinethionyl, chromanyl, chro the group consisting of nitrogen, oxygen, Sulfur, selenium manonyl, thiochromanyl, thiochromanonyl, thiochromenyl, and phosphorus, also including radicals wherein a heterocy benzofuranyl, benzisothiazolyl, benzocarbazolyl, benzo clic ring is fused to one or more aromatic hydrocarbon rings chromonyl, benzisoalloxazinyl, benzocoumarinyl, thiocou for instance in the form of benzo-fused, dibenzo-fused and marinyl, phenometoxazinyl, phenoparoxazinyl, phentriazi naphtho-fused heterocyclic radicals; within this definition are nyl, thiodiazinyl, thiodiazolyl, indoxyl, thioindoxyl, included heterocyclic radicals such as, but not limited to, benzodiazinyl (e.g. phthalazinyl), phthalidyl, phthalimidinyl, diazepinyl, oxadiazinyl, thiadiazinyl, dithiazinyl, triazolonyl, phthalazonyl, alloxazinyl, dibenzopyronyl (i.e. Xanthonyl), diazepinonyl, triazepinyl, triazepinonyl, tetrazepinonyl, ben Xanthionyl, isatyl, isopyrazolyl, isopyrazolonyl, urazolyl, Zoquinolinyl, benzothiazinyl, benzothiazinonyl, benzoxathi urazinyl, uretinyl, uretidinyl. Succinyl. Succinimido, benzyl nyl, benzodioxinyl, benzodithiinyl, benzoxazepinyl, ben Sultimyl, benzylsultamyl and the like, including all possible Zothiazepinyl, benzodiazepinyl, benzodioxepinyl, isomeric forms thereof, wherein each carbon atom of said benzodithiepinyl, benzoxazocinyl, benzothiazocinyl, benzo heterocyclic ring may furthermore be independently Substi diazocinyl, benzoxathiocinyl, benzodioxocinyl, benzotriox tuted with a Substituent selected from the group consisting of epinyl, benzoxathiazepinyl, benzoxadiazepinyl, benzothiadi halogen, nitro, C, alkyl (optionally containing one or more azepinyl, benzotriazepinyl, benZOxathiepinyl, functions or radicals selected from the group consisting of benzotriazinonyl, benzoxazolinonyl, aZetidinonyl, azaspir carbonyl (oxo), alcohol (hydroxyl), ether (alkoxy), acetal, oundecyl, dithiaspirodecyl, selenazinyl, selenazolyl, sele amino, imino, oximino, alkyloximino, amino-acid, cyano, nophenyl, hypoxanthinyl, azahypo-Xanthinyl, bipyrazinyl, carboxylic acid ester or amide, nitro, thio C, alkyl, thio bipyridinyl, oxazolidinyl, diselenopyrimidinyl, benzo Co cycloalkyl, C, alkylamino, cycloalkylamino, alkeny dioxocinyl, benzopyrenyl, benzopyranonyl, benzophenazi lamino, cycloalkenylamino, alkynylamino, arylamino, aryla nyl, benzoquinolizinyl, dibenzocarbazolyl, dibenzoacridinyl, lkylamino, hydroxylalkylamino, mercaptoalkylamino, het dibenzophenazinyl, dibenzothiepinyl, dibenzoxepinyl, erocyclic-substituted alkylamino, heterocyclic amino, dibenzopyranonyl, dibenzoquinoxalinyl, dibenzothiazepi heterocyclic-Substituted arylamino, hydrazino, alkylhy nyl, dibenzisoquinolinyl, tetraazaadamantyl, thiatetraazaada drazino, phenylhydrazino, Sulfonyl, Sulfonamido and halo mantyl, oxauracil, oxazinyl, dibenzothiophenyl, dibenzo gen), C-7 alkenyl, C-7 alkynyl, halo C, alkyl, Co furanyl, oxazolinyl, oxazolonyl, azaindolyl azolonyl, cycloalkyl, aryl, arylalkyl, alkylaryl, alkylacyl, arylacyl, thiazolinyl, thiazolonyl, thiazolidinyl, thiazanyl, pyrimido hydroxyl, amino, C, alkylamino, cycloalkylamino, alkeny nyl, thiopyrimidonyl, thiamorpholinyl, azlactonyl, naph lamino, cycloalkenylamino, alkynylamino, arylamino, aryla thindazolyl, naphthindolyl, naphthothiazolyl, naphthothioX lkylamino, hydroxyalkylamino, mercaptoalkylamino, het olyl, naphthoXindolyl, naphthotriazolyl, naphthopyranyl. erocyclic-substituted alkylamino, heterocyclic amino, oXabicycloheptyl, aZabenzimidazolyl, azacycloheptyl, aza heterocyclic-Substituted arylamino, hydrazino, alkylhy US 2010/03051 17 A1 Dec. 2, 2010 drazino, phenylhydrazino, Sulfhydryl, C, alkoxy, Co cyclooctadienyl and the like, or a Czo polycyclic mono- or cycloalkoxy, aryloxy, arylalkyloxy, oxyheterocyclic, hetero polyunsaturated hydrocarbon mono-valent radical having cyclic-substituted alkyloxy, thio C, alkyl, thio Co from 7 to 10 carbon atoms such as dicyclopentadienyl, cycloalkyl, thioaryl, thioheterocyclic, arylalkylthio, hetero fenchenyl (including all isomers thereof. Such as C-pinole cyclic-substituted alkylthio, formyl, hydroxylamino, cyano, nyl), bicyclo[2.2.1]hept-2-enyl, bicyclo[2.2.1]hepta-2,5-di carboxylic acid or esters or thioesters or amides thereof, enyl, cyclofenchenyl and the like. thiocarboxylic acid or esters or thioesters or amides thereof; 0060. As used herein with respect to a substituting radical, depending upon the number of unsaturations in the 3 to 10 and unless otherwise stated, the term “C, alkynyl' defines atoms ring, heterocyclic radicals may be sub-divided into straight and branched chain hydrocarbon radicals containing heteroaromatic (or "heteroaryl) radicals and non-aromatic one or more triple bonds and optionally at least one double heterocyclic radicals; when a heteroatom of said non-aro bond and having from 2 to 7 carbon atoms such as, for matic heterocyclic radical is nitrogen, the latter may be Sub example, acetylenyl, 1-propynyl, 2-propynyl, 1-butynyl, stituted with a Substituent selected from the group consisting 2-butynyl, 2-pentynyl, 1-pentynyl, 3-methyl-2-butynyl, of C, alkyl, Co cycloalkyl, aryl, arylalkyl and alkylaryl. 3-hexynyl, 2-hexynyl, 1-penten-4-ynyl, 3-penten-1-ynyl, 0055 As used herein with respect to a substituting radical, 1.3-hexadien-1-ynyl and the like. and unless otherwise stated, the terms “C, alkoxy”, “C. 0061. As used herein with respect to a substituting radical, cycloalkoxy”, “aryloxy”, “arylalkoxy”, “oxyheterocyclic', and unless otherwise stated, the terms “arylalkyl”, “arylalk "heterocyclic-substituted alkoxy”, “thio C, alkyl, “thio enyl and "heterocyclic-substituted alkyl refer to an ali Co cycloalkyl”, “arylthio”, “arylalkylthio’ and “thiohet phatic Saturated or ethylenically unsaturated hydrocarbon erocyclic” refer to substituents wherein a carbon atom of a monovalent radical (preferably a C-7 alkyl or C-7 alkenyl C, alkyl, respectively a Co cycloalkyl, aryl, arylalkyl, radical such as defined above) onto which an aryl or hetero heterocyclic radical or heterocyclic-substituted alkyl (each of cyclic radical (such as defined above) is already bonded via a them such as defined herein), is attached to an oxygenatom or carbonatom, and wherein the said aliphatic radical and/or the a divalent Sulfur atom through a single bond Such as, but not said aryl or heterocyclic radical may be optionally substituted limited to, methoxy, ethoxy, propoxy, butoxy, pentoxy, iso with one or more substituents independently selected from propoxy, sec-butoxy, tert-butoxy, isopentoxy, cyclopropy the group consisting of halogen, amino, hydroxyl, Sulfhydryl, loxy, cyclobutyloxy, cyclopentyloxy, thiomethyl, thioethyl, C, alkyl, C, alkoxy, trifluoromethyl and nitro. Such as but thiopropyl, thiobutyl, thiopentyl, thiocyclopropyl, thiocy not limited to benzyl, 4-chlorobenzyl, 4-fluorobenzyl, 2-fluo clobutyl, thiocyclopentyl, thiophenyl, phenyloxy, benzyloxy, robenzyl, 3,4-dichlorobenzyl, 2,6-dichlorobenzyl, 3-methyl mercaptobenzyl and cresoxy, and various isomers of piperi benzyl, 4-methylbenzyl, 4-tert-butylbenzyl, phenylpropyl, dinoxy, 1-methylpiperidinoxy, pyrrolidinoxy, pyridinoxy, 1-naphthylmethyl, phenylethyl, 1-amino-2-phenylethyl, tetrahydrofuranyloxy, morpholino-ethoxy, piperaZinoethoxy, 1-amino-2-4-hydroxy-phenylethyl, 1-amino-2-indol-2-yl piperidinoethoxy, pyridinoethoxy, pyrrolidinoethoxy, piperi ethyl, Styryl, pyridylmethyl (including all isomers thereof), dinomethoxy, methylpyridinoxy, methylduinolinoxy, pyridi pyridylethyl, 2-(2-pyridyl)isopropyl, oxazolylbutyl, 2-thie nopropoxy and the like. nylmethyl, pyrrolylethyl, morpholinylethyl, imidazol-1-yl 0056. As used herein with respect to a substituting atom, ethyl, benzodioxolyl-methyl and 2-furylmethyl. and unless otherwise stated, the term halogen means any atom 0062. As used herein with respect to a substituting radical, selected from the group consisting of fluorine, chlorine, bro and unless otherwise stated, the terms “alkylaryland “alkyl mine and iodine. substituted heterocyclic” refer to an arylor, respectively, het 0057. As used herein with respect to a substituting radical, erocyclic radical (such as defined above) onto which are and unless otherwise stated, the term “halo C, alkyl means bonded one or more aliphatic Saturated or unsaturated hydro a C-, alkyl radical (such as above defined) in which one or carbon monovalent radicals, preferably one or more C-7 more hydrogen atoms are independently replaced by one or alkyl, C-, alkenyl or Co cycloalkyl radicals as defined more halogens (preferably fluorine, chlorine or bromine), above Such as, but not limited to, o-toluyl, m-toluyl, p-toluyl, such as but not limited to difluoromethyl, trifluoromethyl, 2.3-xylyl. 2,4-xylyl, 3,4-xylyl, o-cumenyl, m-cumenyl, p-cu trifluoroethyl, octafluoropentyl, dodecafluoro-heptyl, dichlo menyl, o-cymenyl, m-cymenyl, p-cymenyl, mesityl, tert-bu romethyl and the like. tylphenyl, lutidinyl (i.e. dimethylpyridyl), 2-methylaziridi 0058 As used herein with respect to a substituting radical, nyl, methylbenzimidazolyl, methylbenzofuranyl, and unless otherwise stated, the terms "C-, alkenyl' desig methylbenzothiazolyl, methylbenzotriazolyl, methylbenzox nate a straight and branched acyclic hydrocarbon monovalent azolyl and methylbenzselenazolyl. radical having one or more ethylenic unsaturations and hav 0063 As used herein with respect to a substituting radical, ing from 2 to 7 carbon atoms such as, for example, vinyl, and unless otherwise stated, the term “alkoxyaryl refers to an 1-propenyl, 2-propenyl(allyl), 1-butenyl, 2-butenyl, 2-pente aryl radical (such as defined above) onto which is (are) nyl, 3-pentenyl, 3-methyl-2-butenyl, 3-hexenyl, 2-hexenyl, bonded one or more C, alkoxy radicals as defined above, 2-heptenyl, 1,3-butadienyl, pentadienyl, hexadienyl, heptadi preferably one or more methoxy radicals, such as, but not enyl, heptatrienyl and the like, including all possible isomers limited to, 2-methoxyphenyl, 3-methoxyphenyl, 4-methox thereof. yphenyl, 3,4-dimethoxyphenyl, 2,4,6-trimethoxyphenyl, 0059. As used herein with respect to a substituting radical, methoxynaphthyl and the like. and unless otherwise stated, the term "Co cycloalkenyl 0064. As used herein with respect to a substituting radical, means a monocyclic mono- or polyunsaturated hydrocarbon and unless otherwise stated, the terms “alkylamino', monovalent radical having from 3 to 8 carbon atoms, such as “cycloalkylamino”, “alkenylamino”, “cyclo-alkenylamino', for instance cyclopropenyl, cyclobutenyl, cyclopentenyl, “arylamino”, “arylalkylamino”, “heterocyclic-substituted cyclopentadienyl, cyclohexenyl, cyclohexadienyl, cyclohep alkyl-amino”, “heterocyclic-substituted arylamino”, “hetero tenyl, cycloheptadienyl, cycloheptatrienyl, cyclooctenyl, cyclic amino', 'hydroxy-alkylamino”, “mercapto-alky US 2010/03051 17 A1 Dec. 2, 2010 lamino” and “alkynylamino” mean that respectively one (thus wherein R hydrogen or a cyclic or non-cyclic hydrocarbyl monosubstituted amino) or even two (thus disubstituted group and R is a cyclic or non-cyclic hydrocarbyl group. amino) C-7 alkyl, Cso cycloalkyl, C2-7 alkenyl, Cso 0067. As used herein with respect to a substituting radical, cycloalkenyl, aryl, arylalkyl, heterocyclic-substituted alkyl, and unless otherwise stated, the term "amino-acid refers to a heterocyclic-substituted aryl, heterocyclic (provided in this radical derived from a molecule having the chemical formula case the nitrogen atom is attached to a carbon atom of the HN CHR COOH, wherein R is the side group of atoms heterocyclic ring), mono- or polyhydroxy C, alkyl, mono characterising the amino-acid type; said molecule may be one or polymercapto C, alkyl, or C-, alkynyl radical(s) (each of of the 20 naturally-occurring amino-acids or any similar non them as defined herein, respectively, and including the pres naturally-occurring amino-acid. ence of optional substituents independently selected from the 0068. As used herein and unless otherwise stated, the term group consisting of halogen, amino, hydroxyl, Sulfhydryl, “stereoisomer' refers to all possible different isomericas well C, alkyl, C, alkoxy, trifluoromethyl and nitro) is/are as conformational forms which the compounds of the inven attached to a nitrogenatom through a single bond Such as, but tion may possess, in particular all possible stereochemically not limited to, anilino. 2-bromoanilino, 4-bromoanilino, and conformationally isomeric forms, all diastereomers, 2-chloroanilino, 3-chloroanilino, 4-chloroanilino, 3-chloro enantiomers and/or conformers of the basic molecular struc 4-methoxyanilino, 5-chloro-2-methoxy-anilino, 2,3-dim ture. Some compounds of the present invention may exist in ethylanilino, 2,4-dimethylanilino, 2,5-dimethylanilino, 2.6- different tautomeric forms, all of the latter being included dimethylanilino, 3,4-dimethylanilino, 2-fluoroanilino, within the scope of the present invention. 3-fluoroanilino, 4-fluoro-anilino, 3-fluoro-2-methoxya 0069. As used herein and unless otherwise stated, the term nilino, 3-fluoro-4-methoxyanilino, 2-fluoro-4-methyl “enantiomer means each individual optically active form of anilino, 2-fluoro-5-methylanilino, 3-fluoro-2-methylanilino, a compound of the invention, having an optical purity or 3-fluoro-4-methylanilino, 4-fluoro-2-methylanilino, enantiomeric excess (as determined by methods standard in 5-fluoro-2-methylanilino, 2-iodoanilino, 3-iodoanilino, 4-io the art) of at least 80% (i.e. at least 90% of one enantiomerand doanilino, 2-methoxy-5-methylanilino, 4-methoxy-2-methy at most 10% of the other enantiomer), preferably at least 90% lanilino, 5-methoxy-2-methylanilino, 2-ethoxyanilino, and more preferably at least 98%. 3-ethoxy-anilino, 4-ethoxyanilino, benzylamino, 2-meth 0070. As used herein and unless otherwise stated, the term oxybenzylamino, 3-methoxybenzylamino. 4-methoxyben “solvate” includes any combination which may beformed by Zylamino, 2-fluoro-benzylamino, 3-fluorobenzyl-amino, a pteridine derivative of this invention with a suitable inor 4-fluorobenzylamino, 2-chlorobenzylamino, 3-chlorobenzy ganic Solvent (e.g. hydrates) or organic solvent such as, but lamino, 4-chlorobenzylamino, 2-aminobenzylamino, diphe not limited to, alcohols, ketones, esters, ethers, nitriles and the nylmethyl-amino, C.-naphthylamino, methylamino, dimethy like. lamino, ethylamino, diethylamino, diethanolamino, isopropylamino, propenylamino, n-butylamino, tert-buty DETAILED DESCRIPTION OF THE INVENTION lamino, dibutylamino. 1,2-diaminopropyl, 1.3-diaminopro 0071. In a first aspect, the present invention relates to a pyl, 1,4-diaminobutyl, 1,5-diaminopentyl, 1,6-diamino group of novel 4,6-disubstituted and 2,4,6-trisubstituted pte hexyl, morpholinomethyl-amino, 4-morpholinoanilino, ridine derivatives. Without limitation, this group includes hydroxymethylamino, B-hydroxyethylamino, dicyclohexyl molecules selected from the group consisting of: amino and ethynylamino; this definition also includes mixed 0.072 6-(2,6-dichlorophenyl)-4-ethoxypteridin-2- disubstituted amino radicals wherein the nitrogen atom is amine, attached to two such radicals belonging to two different sub 0.073 3-(2-amino-4-ethoxypteridin-6-yl)benzonitrile sets of radicals, e.g. an alkyl radical and an alkenyl radical, or 0.074 4-ethoxy-6-(3-fluoro-4-methoxyphenyl)pteri to two different radicals within the same sub-set of radicals, din-2-amine e.g. methylethylamino; among di-substituted amino radicals, 0075 4-ethoxy-6-(4-(trifluoromethoxy)phenyl)pteri symmetrically-substituted amino radicals are more easily din-2-amine accessible and thus usually preferred from a standpoint of 0.076 6-(3.5-bis(trifluoromethyl)phenyl)-4-ethoxypte ease of preparation. ridin-2-amine 0065. As used herein with respect to a substituting radical, 0.077 4-ethoxy-6-(4-(trifluoromethyl)phenyl)pteridin and unless otherwise stated, the terms “(thio)carboxylic acid 2-amine ester”, “(thio)carboxylic acid thioester” and “(thio)-carboxy 0078 6-(4-chloro-3-fluorophenyl)-4-ethoxypteridin lic acid amide' refer to radicals wherein the carboxyl or 2-amine thiocarboxyl group is bonded to the hydrocarbonyl residue of 0079) 6-(3,5-dichlorophenyl)-4-ethoxypteridin-2- an alcohol, a thiol, a polyol, a phenol, a thiophenol, a primary amine or secondary amine, a polyamine, an amino-alcohol or 0080 6-(3,4-difluorophenyl)-4-ethoxypteridin-2- ammonia, the said hydrocarbonyl residue being selected from amine the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, 0081 4-ethoxy-6-(2-fluorophenyl)pteridin-2-amine cycloalkenyl, aryl, arylalkyl, alkylaryl, alkylamino, 0082 6-(2,6-difluorophenyl)-4-ethoxypteridin-2- cycloalkylamino, alkenylamino, cycloalkenylamino, ary amine lamino, arylalkylamino, heterocyclic-substituted alky 0.083 6-(3,5-difluorophenyl)-4-ethoxypteridin-2- lamino, heterocyclic amino, heterocyclic-substituted ary amine lamino, hydroxyalkylamino, mercapto-alkylamino or 0084 6-(2,3-difluorophenyl)-4-ethoxypteridin-2- alkynylamino (Such as above defined, respectively). amine 0066. As used herein with respect to a substituting radical, 0085 4-ethoxy-6-(3-fluorophenyl)pteridin-2-amine and unless otherwise stated, the term "sulfonamido” refers to I0086) dimethyl (4-(2-amino-4-ethoxypteridin-6-yl) a radical represented by the formula NR SOR, phenyl)methylphosphonate

US 2010/03051 17 A1 Dec. 2, 2010

0228 4-ethylsulfanyl-6-(4-fluoro-phenyl)-pteridin-2- ylamine 0229 4-amino-6-(4-fluoro-phenyl)-pteridine-2,4-di R Nx a10 N R 0230 6-(4-fluoro-phenyl)-4-piperidin-1-yl-pteridin-2- N1 N n 3 ylamine us 2n 2 0231 N-4-cyclopropyl-6-(4-fluoro-phenyl)-pteridine R5 N N R4 2,4-diamine 0232 4-(2,6-dimethyl-morpholin-4-yl)-6-(4-fluoro wherein X represents an oxygen atom or a group with the phenyl)-pteridin-2-ylamine formula S(O), wherein m is an integer from 0 to 2, or a group 0233 N-4-cyclohexyl-6-(4-fluoro-phenyl)-pteridine with the formula NZ and wherein: 2,4-diamine (0250 R is a group selected from the group consisting 0234 N-4-benzyl-6-(4-fluoro-phenyl)-pteridine-2,4- of C-7 alkyl, C2-7 alkenyl, C2-7 alkynyl, Cao cycloalkyl, Co cycloalkenyl, aryl, alkylaryl, arylalkyl, diamine heterocyclic, heterocyclic-substituted alkyl and alkyl 0235 N-4-(3-methyl-benzyl)-6-(4-fluoro-phenyl)-pte Substituted heterocyclic, each of said groups being ridine-2,4-diamine optionally substituted with one or more substituents 0236 N-4-(3-fluoro-benzyl)-6-(4-fluoro-phenyl)-pte independently selected from the group consisting of ridine-2,4-diamine halogen, Calkyl, Calkoxy, C-7 alkenyl, C-7 alky nyl, halo C alkyl, Cso cycloalkoxy, aryloxy, aryla 0237 6-(4-fluoro-phenyl)-4-(4-methyl-piperazin-1- lkyloxy, oxyheterocyclic, heterocyclic-substituted alky yl)-pteridin-2-ylamine loxy, thio C, alkyl, thio Co cycloalkyl, thioaryl, 0238 6-(4-fluoro-phenyl)-4-piperazin-1-yl-pteridin-2- thioheterocyclic, arylalkylthio, heterocyclic-substituted ylamine alkylthio, formyl, hydroxyl, sulfhydryl, nitro, hydroxy 0239 N-4-cyclopropylmethyl-6-(4-fluoro-phenyl)- lamino, mercaptoamino, cyano, carboxylic acid or pteridine-2,4-diamine esters or thioesters oramides or thioamides or halides or anhydrides thereof, thiocarboxylic acid or esters or 0240 6-(4-fluoro-phenyl)-4-pyrrolidin-1-yl-pteridin thioesters or amides or thioamides or halides or anhy 2-ylamine drides thereof, carbamoyl, thiocarbamoyl, ureido, thio 0241 4-ethoxy-6-(4-fluoro-phenyl)-pteridine ureido, amino, alkylamino, cycloalkylamino, alkeny 0242 4-isopropoxy-6-(4-fluoro-phenyl)-pteridine lamino, cycloalkenylamino, alkynylamino, arylamino, arylalkylamino, hydroxyalkylamino, mercaptoalky 0243 4-(2-methoxy-ethoxy)-6-(4-fluoro-phenyl)-pte lamino, heterocyclic amino, hydrazino, alkylhydrazino ridine and phenyl-hydrazino, or R is a carboxyalkyl, car 0244 6-(4-Fluoro-phenyl)-pteridin-4-yl)-(4-methyl boxyaryl, thiocarboxyaryl or thiocarboxyalkyl group; cyclohexyl)-amine, 0251 Z is a group independently defined as R or Z is 0245 6-(4-Fluoro-phenyl)-pteridin-4-yl)-(4-methyl hydrogen or the group NZ together with R is either cyclohexyl)-amine, hydroxylamino oran optionally substituted heterocyclic group containing at least one nitrogen atom; 0246 6-(4-fluoro-phenyl)-4-morpholin-4-yl-pteridine, 0252 R is selected from the group consisting of amino; and alkanoylamino; thioalkanoylamino; carbamoyl; thio 0247 4-ethylsulfanyl-6-(4-fluoro-phenyl)-pteridine, carbamoyl, ureido; thio-ureido, Sulfonamido; hydroxy lamino; alkoxyamino; thioalkylamino; mercaptoamino, and/or a pharmaceutically acceptable addition salt thereof hydrazino; alkylhydrazino; phenylhydrazino; option and/or a stereoisomer thereof and/or a mono- or a di-N-oxide ally Substituted heterocyclic radicals; C, alkylamino; thereof and/or a solvate thereof and/or a pro-drug form arylamino: arylalkylamino; cycloalkylamino; alkeny thereof. lamino; cycloalkenylamino; heterocyclic amino; 0248. Each of the substituents present on positions 2, 4 hydroxyalkylamino: mercaptoalkylamino: C, alkoxy: and/or 6 of the pteridine scaffold of these molecules belongs Co cycloalkoxy; thio C, alkyl, arylsulfoxide: aryl to a broader class of substituents being defined in the section sulfone; heterocyclic sulfoxide; heterocyclic sulfone: “Definitions' herein-above. It should be understood that thio Co cycloalkyl, aryloxy: arylthio: arylalkyloxy; some alternative molecules differing from the molecules of arylalkylthio; oxyheterocyclic and thioheterocyclic the above list by replacing such a substituent with another radicals; similar Substituent of the same class, e.g. replacing 4-fluo 0253 R is hydrogen; and rophenyl with 4-chlorophenyl on position 6, may result in a 0254 R is aryl substituted with one or more substitu ents independently selected from the group consisting of very similar utility in medical treatment, therefore said alter aryl wherein said aryl is optionally substituted with aryl native molecules are also within the framework of the present carbonyl: (O,O-dialkylphosphonyl)-alkyl; alkanoyl; invention. halo-C, alkoxy; hydroxy-Czalkoxy; hydroxy-C-7 0249. In a second aspect, the present invention relates to a alkyl; alkylamino C, alkyl, ()-carboxy-alkanoy group of pteridine derivative represented by the structural lamino, mono-(C-7 cycloalkyl)aminocarbonyl, formula: cycloalkyl)aminocarbonyl, mono-(C, alkyl)aminocar US 2010/03051 17 A1 Dec. 2, 2010 10

bonyl, mono-(c)-dimethylamino-C, alkyl)aminocar cyclopropylamino-carbonyl)phenyl, 2,6-dichlorophenyl, bonyl, di-(C., alkyl)aminocarbonyl, mono-(hydroxy 3,4-dichlorophenyl, 2,4-dichlorophenyl, 2,3-dichlorophenyl, Calkyl)aminocarbonyl, formylamino, Sulfamoyl 3,5-dichlorophenyl, 3-(N,N-diethylaminocarbonyl)phenyl, (SONH2), arylamino-C, alkyl, C, alkylsulfonyl, 3,5-difluorophenyl, 3,5-difluoro-2-methoxyphenyl, 3,4-dif heterocyclyl-carbonyl, heterocyclyl-C, alkyl and het luorophenyl, 2,6-difluorophenyl, 2,5-difluorophenyl, 2,4-di erocyclyl, wherein said heterocyclyl is optionally Sub fluorophenyl, 2,3-difluorophenyl, 4-(N,N-dimethylamino) stituted with C, alkenyloxycarbonyl, C, alkyl or C, phenyl, 3-(N,N-dimethylamino)-phenyl, 2-(N.N- alkyloxycarbonyl, or R is a fused benzo-Css cycloalkyl dimethylamino)phenyl, 3-(N,N-dimethylaminocarbonyl) optionally substituted with oxo; or R is heterocyclyl phenyl, dimethylamino)ethylaminocarbonylphenyl, 4-(N'. substituted with one or more substituents independently N'-dimethylamino)ethyl-aminocarbonyl-phenyl, 3,5- Selected from the group consisting of acylamino, C, dimethylphenyl, 3,4-dimethylphenyl, 2,6-dimethylphenyl, alkylsulfonyl, arylsulfonyl, heterocyclyl-C, alkyl, het 2,6-dimethoxyphenyl, 2,5-dimethoxyphenyl, 2,4-dimethox erocyclyl-C, alkylamino, aryl and heterocyclyl, yphenyl, 3-1.3dioxolan-2-ylmethoxyphenyl, 4-ethoxyphe wherein said heterocyclyl is optionally substituted with nyl, 2-ethoxyphenyl, 3-(ethoxycarbonyl)methoxyphenyl, C, alkyl, arylsulfonyl or (di-C, alkylamino)-C-7 4-(ethoxycarbonyl)-methoxyphenyl, 4-ethoxycarbonylphe alkoxy, or said heterocyclyl is non-aromatic and nyl, 3-ethoxycarbonylphenyl, 2-ethoxycarbonylphenyl, 4-(3- includes a nitrogen atom Substituted with heterocyclyl ethoxycarbonylpiperidino)carboxamidophenyl, 4-ethylphe C, alkyl or a carboxylic acid or a C-, alkyl ester nyl, 4-fluorophenyl, 3-fluorophenyl, 2-fluorophenyl, thereof, 3-fluoro-4-formylphenyl, 4-fluoro-3-formylphenyl, and/or a pharmaceutically acceptable addition salt thereof 4-fluoro-2-methylphenyl, 2-fluoro-5-methylphenyl, and/or astereo-isomerthereofand/or a mono- or a di-N-oxide 2-fluoro-5-methoxyphenyl, 3-fluoro-4-methoxyphenyl, thereof and/or a solvate thereof and/or a pro-drug form 5-fluoro-2-methoxycarbonylphenyl, 2-fluoro-4-trifluorom thereof. ethylphenyl, 2-formylaminophenyl, 3-formylaminophenyl, 0255. A general description of methods for the synthesis 4-formylaminophenyl, 2-formyl-5-methoxyphenyl, of the compounds of the present invention has been provided 3-formyl-4-methoxyphenyl, 5-formyl-2-methoxyphenyl, in WO2005/021003, in particular in FIGS. 1 to 5 thereof and 2-formyl-5-methylphenyl, 4-formylphenyl, 3-formylphenyl, the corresponding description. Most of these methods make 2-formylphenyl, 4-hydroxy-3,5-dimethylphenyl, 3-(2-hy use of a boronic acid, or a pinacol ester thereof, for introduc droxyethyl)-aminocarbonylphenyl, 4-(2-hydroxyethyl)ami ing a substituent at position 6 of the pteridine core structure. nocarbonyl-phenyl, 3-hydroxy-4-methoxycarbonylphenyl, Processes for preparing Such organic boronic acid derivatives 4-hydroxy-3-methoxyphenyl, 4-(hydroxymethyl)phenyl, have been described for example in EP-B-1,019,414. For the 3-(hydroxymethyl)phenyl, 4-hydroxy-3-nitrophenyl, 4-hy purpose of the present invention, Suitable aryl-boronic acids droxyphenyl, 3-hydroxyphenyl, 2-hydroxyphenyl, 4-isopro include, but are not limited to, the following commercially poxyphenyl, 4-(4-isopropylpiperazinyl)phenyl, 4-isopropy available materials wherein the aryl group is 3-acetamidophe lphenyl, 4-methanesulfonamido-phenyl, nyl, 4-acetamidophenyl, 4-acetylphenyl, 3-acetylphenyl, 3-methanesulfonamidophenyl, 2-methanesulfonamido-phe 2-acetylphenyl, 5-acetyl-2-chlorophenyl, 4-acetyl-3-fluo nyl, 4-methanesulfonylphenyl, 2-methoxy-5-formylphenyl, rophenyl, 5-acetyl-2-fluorophenyl, 4-(4-allyloxycarbon 5-methoxy-2-formylphenyl, 4-methoxy-2-formylphenyl, ylpiperazino)phenyl, 3-aminocarbonylphenyl, 4-aminocar 4-methoxycarbonylphenyl, 3-methoxycarbonylphenyl, bonylphenyl, 2-amino-5-chlorophenyl, 4-amino-3- 2-methoxycarbonylphenyl, 3-methoxy-4-methoxycarbon methoxyphenyl, 3-aminophenyl, 2-amino-4-methylphenyl, ylphenyl, 2-methoxy-5-methoxycarbonylphenyl, 4-meth 2-amino-5-methylphenyl, 4-amino-2-methylphenyl, oxy-3-nitrophenyl, 4-methoxyphenyl, 3-methoxyphenyl, 5-amino-2-methylphenyl, 4-amino-3-nitrophenyl, 3-ami 2-methoxyphenyl, 2-methoxy-5-methylphenyl, 4-N-methyl nophenyl, 2-aminophenyl, 4-aminophenyl, 4-benzyloxyphe carboxamidophenyl, 4-methyl-phenyl, 3-methylphenyl, nyl, 3-benzyloxyphenyl, 2-benzyloxyphenyl, 4-benzyloxy 2-methylphenyl, 4-(N-methylamino)phenyl, 3-(4-methyl 2-fluorophenyl, 4-benzyloxy-3-fluorophenyl, 3-benzyloxy piperazine-1-carbonyl)phenyl, 4-(4-methylpiperazine-1-car 4-methoxyphenyl, 4-biphenyl, 3.5-bis(trifluoromethyl) bonyl)phenyl, 4-(methylthio)-phenyl, 3-(methylthio)phenyl, benzene, 4-bromophenyl, 3-bromophenyl, 4-bromo-2,5- 2-(methylthio)phenyl, 4-morpholinophenyl, 4-(morpholino dimethylphenyl, 2-bromo-5-fluorophenyl, 2-bromo-6- carbonyl)phenyl, 2-morpholinomethyl)phenyl, 4-nitrophe fluorophenyl, 4-n-butylphenyl, 4-isobutylphenyl, nyl, 3-nitrophenyl, 2-nitrophenyl, 4-phenoxyphenyl, 4-(N- 4-carboxyphenyl, 3-carboxyphenyl, 2-carboxyphenyl, 2-car phenylaminomethyl)phenyl, 4-(phenylcarbonyl)phenyl, boxy-5-fluorophenyl, 4-carboxy-3-fluorophenyl, 4-carboxy 4-(piperazine-1-carbonyl)phenyl, 4-piperazinylphenyl, 2-chlorophenyl, 5-carboxy-2-chlorophenyl, 4-carboxy-3- 3-succinamidophenyl, 4-succinamidophenyl, Sulfamoylphe chlorophenyl, 3-carboxyphenyl, 3-(3-carboxypropionyl nyl, 2-(toluene-4-Sulfonamido)phenyl, 3-(toluene-4-Sulfona amino)phenyl, 4-(3-carboxypropionylamino)phenyl, mido)phenyl, 4-(toluene-4-Sulfonamido)phenyl, 4-(tert-bu 2-chloro-5-formylphenyl, 3-chloro-4-fluorophenyl, toxycarbonylamino)-3-methoxyphenyl, 2-(tert 2-chloro-4-fluorophenyl, 4-chloro-2-fluorophenyl, 3-chloro butoxycarbonyl)phenyl, 3-(tert-butoxycarbonyl)phenyl, 4-hydroxy-5-methoxyphenyl, 2-chloro-5-hydroxymeth 4-(tert-butoxycarbonyl)phenyl, 4-tert-butylphenyl, 4-(tet ylphenyl, 3-chloro-5-methoxyphenyl, 2-chloro-4-meth rahydro-2H-pyran-2-yloxy)phenyl, 4-(2-thienyl)phenyl, ylphenyl, 2-chloro-5-methylphenyl, 2-chloro-5- 4-trifluoromethoxyphenyl, 4-(trimethylammonium)meth trifluoromethoxyphenyl, 3-chloro-5-trifluoromethylphenyl, ylphenyl, 2,4,6-trimethylphenyl, 3,4,5-trifluorophenyl, 2.3, 4-chloro-2-trifluoromethylphenyl, 4-chlorophenyl, 3-chlo 4-trifluorophenyl, 3-trifluoromethylphenyl, 4-trifluo rophenyl, 2-chlorophenyl, 4-cyanomethoxyphenyl, 3-cya romethoxyphenyl, 3-trifluoromethoxyphenyl, nomethoxyphenyl, 2-cyanomethoxyphenyl, 4-cyanophenyl, 2-trifluoromethylphenyl, 3-trifluoromethylphenyl, 4-trifluo 3-cyanophenyl, 2-cyanophenyl, 3,5-dibromophenyl, 3-(N- romethylphenyl, 3,4,5-trimethoxyphenyl, 4-vinylphenyl, US 2010/03051 17 A1 Dec. 2, 2010

6-benzyloxy-naphth-2-yl, naphth-1-yl, naphth-2-yl 4-(2-hy or mobile phases for use in combination with said polysac droxyethoxy)phenyl, 4'-benzoyl 1, 1'-biphenyl-4-yl, oxoin charide-based chiral stationary phases are hydrocarbons such dan-5-yl, (O,O-dimethylphosphonyl)methyl or 1-biphenylyl. as hexane and the like, optionally admixed with an alcohol 0256 For the purpose of making the compounds of the Such as ethanol, isopropanol and the like. The above mixture present invention, Suitable heterocyclic-boronic acids or ofenantiomers may alternatively be separated by making use pinacol esters thereof include, but are not limited to, the of microbial resolution or by resolving the diastereoisomeric following commercially available materials wherein the het salts formed with chiral acids such as mandelic acid, cam erocyclic group is 3.4-methylenedioxyphenyl (benzodiox phorsulfonic acid, tartaric acid, lactic acid and the like or with olyl), 2-acetamidopyridin-5-yl, 2-aminopyridin-5-yl, 2-ami chiral bases Such as brucine and the like. The resolving agent nopyrimidin-5-yl, 1,4-benzodioxan-6-yl, 2-benzothienyl, may be cleaved from the separated diastereoisomers, e.g. by 1-benzothien-3-yl, 1-benzothien-2-yl, 2-benzyloxypyridin treatment with acids or bases, in order to generate the pure 5-yl, 1-benzyl-1H-pyrazol-4-yl, 2-bromo-3-chloropyridin-4- enantiomers of the compounds of the invention. Conventional y1, 5-bromo-2,3-dihydrobenzobfuran-7-yl, 2-bromo-3-me resolution methods were compiled e.g. by Jaques et al. in thylpyridin-5-yl, 3-bromopyridin-5-yl, 2-bromopyridin-5-yl, "Enantiomers, Racemates and Resolution” (Wiley Inter 5-bromothien-2-yl, 2-chloro-6-isopropylpyridin-3-yl, science, 1981). 2-chloro-3-methylpyridin-5-yl, 2-4-(4-chlorophenylsulfo 0258 As noted above, one particular embodiment of this nyl)piperazin-1-ylpyridin-5-yl, 2-chloropyrid-4-yl, 2-chlo invention includes the various precursors or “pro-drug forms ropyrid-5-yl, 5-chlorothien-2-yl, dibenzob.dfuran-4-yl, of the 4,6-disubstituted and 2,4,6-trisubstituted pteridine 2-chloro-3-fluoropyridin-4-yl, dibenzob.dlthien-4-yl, 3,4- derivatives of the present invention. It may be desirable to dihydro-2H-1,5-benzodioxepin-7-y1, 3,6-dihydro-2H-pyri formulate the compounds of the present invention in the form dine-1-tert-butoxycarbonyl, 2,5-dibromo-3-pyridinyl, 2.6- of a chemical species which itself is not significantly biologi dichloro-pyridin-3-yl, 2,3-dihydro-1-benzofuran-5-yl, 2.6- cally-active but which, when delivered to the body of a human dimethoxypyridin-5-yl, 2,6-dimethoxypyridin-3-yl, 2,4- being or higher mammal, will undergo a chemical reaction dimethoxypyrimidin-5-yl, 3,5-dimethylisoxazol-4-yl, 2-(3- catalyzed by the normal function of the body, inter alia, N,N-dimethylaminopropoxy)pyridin-5-yl, 3,5- enzymes present in the stomach or in blood serum, said dimethylpyrazol-4-yl 1-1.3dioxolan-2-ylmethyl-1H chemical reaction having the effect of releasing a compound pyrazol-4-yl, 2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl, as defined herein. The term “pro-drug' thus relates to these 2,4-di(tert-butoxy)pyrimidin-5-yl, 2-ethoxypyridin-3-yl, species which are converted in vivo into the active pharma 2-fluoro-3-methylpyridin-5-yl, 2-fluoropyridin-3-yl 2-fluo ceutical ingredient. ropyridin-5-yl, 5-formyl-2-furyl, 5-formylthien-2-yl, furan 3-yl, furan-2-yl, 2-hydroxypyridin-5-yl, 5-indolyl, 1-isobu 0259. The pro-drugs of the present invention can have any tyl-1H-pyrazol-4-yl, isoquinolin-4-yl, 2-methoxypyridin-3- form suitable to the formulator, for example, esters are non y1, 2-methoxypyrimidin-5-yl, 5-methyl-1-benzothiophen-2- limiting common pro-drug forms. In the present case, how yl, 1-(3-methylbutyl)-1H-pyrazol-4-yl, 5-methylfuran-2-yl, ever, the pro-drug may necessarily exist in a form wherein a 1-methylindol-5-yl, 5-methyl-3-phenyl-4-isoxazolyl, 5-(me covalent bond is cleaved by the action of an enzyme present at thylthio)thien-2-yl, 2-(4-methylpiperazinyl)pyridin-4-yl, the target locus. For example, a C-C covalent bond may be 2-(4-methylpiperazinyl)pyridin-5-yl, 1-methyl-1H-pyrazol selectively cleaved by one or more enzymes at said target 4-yl, 3-methylpyridin-2-yl, 5-methylpyridin-2-yl, 5-meth locus and, therefore, a pro-drug in a form other than an easily ylpyridin-3-yl 4-methylthien-2-yl, 5-methylthien-2-yl, hydrolysable precursor, interalia an ester, an amide, and the 2-methoxypyridin-5-yl, 2-(2-morpholinoethylamino)-pyri like, may be used. din-5-yl, 2-(2-morpholinoethyl)-1H-pyrazol-4-yl, 2-(mor 0260 For the purpose of the present invention the term pholin-1-yl)-pyridin-5-yl, 1-(phenylsulfonyl)-1H-indol-3-yl, “therapeutically suitable pro-drug is defined herein as a 5-phenyl-2-thienyl, 2-(piperazin-1-yl)-pyridin-5-yl, 2-(pip compound modified in Such a way as to be transformed in erazin-1-yl)-pyridin-4-yl, 1-propyl-1H-pyrazol-4-yl, pyra vivo to the therapeutically active form, whether by way of a Zol-4-yl, pyridin-4-yl, pyridin-3-yl pyrimidin-5-yl 4-phe single or by multiple biological transformations, when in noxathiinyl, quinolin-8-yl, quinolin-3-yl, 2-(4-tert contact with the tissues of humans or mammals to which the butoxycarbonylpiperazinyl)-pyrid-4-yl, 1-tert pro-drug has been administered, and without undue toxicity, butoxycarbonyl-1H-pyrazol-4-yl, 1-tert-butoxycarbonyl-2- irritation, or allergic response, and achieving the intended pyrrolyl, 1-(tert-butoxycarbonyl)-5-bromo-1H-indol-2-yl, therapeutic outcome. 1-(tert-butoxycarbonyl)-1H-indol-5-yl, 1-(tert-butoxycarbo 0261. In another aspect, the present invention provides the nyl)-5-methoxy-1H-indol-2-yl, 1-thianthrenylthien-3-yl, use of 4,6-disubstituted and 2,4,6-trisubstituted pteridine thien-3-yl, thien-2-yl or 1,3,5-trimethyl-1H-pyrazol-4-yl. derivatives as defined herein-above for the manufacture of a 0257 Stereoisomers of the 4,6-disubstituted and 2.4.6- medicament for treating or preventing a viral infection, and trisubstituted pteridine derivatives of the present invention the corresponding method of treatment of a viral infection by may beformed by using reactants in their single enantiomeric administering an effective amount of such a 4,6-disubstituted form wherever possible in the manufacturing process, or by or 2,4,6-trisubstituted pteridine derivative to a patient in need resolving a mixture of Stereoisomers by conventional meth thereof. In one embodiment, said viral infection may be an ods. One such method is liquid chromatography using one or infection caused by a virus being a member of the Flaviviridae more Suitable chiral stationary phases including, for example, family. The Flaviviridae family is a family of positive-strand polysaccharides, in particular cellulose or amylose deriva RNA viruses which includes the following genera: tives. Commercially available, but non limiting, suitable 0262 Genus Flavivirus (type species include Yellow polysaccharide-based chiral stationary phases are Chiral fever virus, West Nile virus and Dengue Fever), CelTM CA, OA, OB, OC, OD, OF, OG, OJ and OK, and 0263 Genus Hepacivirus (type species includes Hepa ChiralpakTM AD, AS, OP(+) and OT(+). Appropriate eluents titis C virus), and US 2010/03051 17 A1 Dec. 2, 2010

0264 Genus Pestivirus (type species include Bovine able salt will be designed, i.e. the salt-forming acid or base viral diarrhea virus, classical Swine fever and hog chol will be selected so as to impart greater water-solubility, lower era). toxicity, greater stability and/or slower dissolution rate to the 0265. In a more preferred embodiment of this aspect of the substituted pteridine derivative of this invention. present invention, said Flavivirus is the Hepatitis C virus 0269. The present invention further provides the use of a (hereinafter referred as HCV). 4,6-disubstituted or 2,4,6-trisubstituted pteridine derivative 0266. In a third aspect, the present invention relates to a of the present invention, or a pharmaceutically acceptable salt pharmaceutical composition comprising as an active prin thereof, or a solvate thereof, or a stereoisomer thereof or a ciple at least one 4,6-disubstituted or 2,4,6-trisubstituted pte pro-drug form thereof, as a biologically-active ingredient, i.e. ridine derivative as defined above, e.g. in the form of a phar active principle, especially as a medicine or for the manufac maceutically acceptable salt. The latter include any ture of a medicament for the prevention or treatment of viral therapeutically active non-toxic addition salt which the 4.6- infections, especially infections due to Flaviridae, and patho disubstituted or 2,4,6-trisubstituted pteridine compounds of logic conditions associated therewith Such as, but not limited the present invention are able to form with a salt-forming to, hepatitis C. agent. Such addition salts may conveniently be obtained by 0270. The invention further relates to a pharmaceutical treating the pteridine derivatives of the invention with an composition comprising: appropriate salt-forming acid or base. For instance, 4,6-dis 0271 (a) one or more 4,6-disubstituted or 2,4,6-trisubsti ubstituted and 2,4,6-trisubstituted pteridine derivatives hav tuted pteridine derivatives selected from the group as ing basic properties may be converted into the corresponding defined above, and therapeutically active, non-toxic acid addition salt form by 0272 (b) one or more pharmaceutically acceptable carri treating the free base form with a suitable amount of an CS. appropriate acid following conventional procedures. 0273. In another embodiment, this invention provides Examples of Such appropriate salt-forming acids include, for combinations, preferably synergistic combinations, of one or instance, inorganic acids resulting in forming salts such as, more 4,6-disubstituted or 2,4,6-trisubstituted pteridine but not limited to, hydrohalides (e.g. hydrochloride and derivatives of this invention with one or more other antiviral hydrobromide), Sulfate, nitrate, phosphate, diphosphate, car agents. AS is conventional in the art, the evaluation of a bonate, bicarbonate, and the like; and organic monocarboxy synergistic effect in a drug combination may be made by lic or dicarboxylic acids resulting informing salts such as, for analyzing the quantification of the interactions between indi example, acetate, propanoate, hydroxyacetate, 2-hydrox Vidual drugs, using the median effect principle described by ypropanoate, 2-oxopropanoate, lactate, pyruvate, oxalate, Chou et al. in Adv. Enzyme Reg. (1984) 22:27. Briefly, this malonate. Succinate, maleate, fumarate, malate, tartrate, cit principle states that interactions (synergism, additivity, rate, methanesulfonate, ethanesulfonate, benzoate, 2-hy antagonism) between two drugs can be quantified using the droxybenzoate, 4-amino-2-hydroxy-benzoate, benzene combination index (hereinafter referred as CI) defined by the Sulfonate, p-toluenesulfonate, salicylate, p-aminosalicylate, following equation: pamoate, bitartrate, camphorsulfonate, edetate, 1.2- ethanedisulfonate, fumarate, glucoheptonate, gluconate, glutamate, hexylresorcinate, hydroxynaphthoate, hydroxy ED ED ethanesulfonate, mandelate, methylsulfate, pantothenate, CI ED -- ED Stearate, as well as salts derived from ethanedioic, pro panedioic, butanedioic, (Z)-2-butenedioic, (E)2-butenedioic, 2-hydroxy-butanedioic, 2,3-dihydroxybutanedioic, 2-hy wherein ED, is the dose of the first or respectively second droxy-1,2,3-propanetricarboxylic and cyclo-hexanesulfamic drug used alone (1a, 2a), or in combination with the second or acids, and the like. respectively first drug (1c, 2c), which is needed to produce a 0267 4,6-disubstituted and 2,4,6-trisubstituted pteridine given effect. The said first and second drug have synergistic or derivatives having acidic properties may be converted in a additive or antagonistic effects depending upon CI-1, CI=1. similar manner into the corresponding therapeutically active, or CD-1, respectively. As will be explained in more detail non-toxic base addition salt form. Examples of appropriate herein below, this principle may be applied to a number of salt-forming bases include, for instance, inorganic bases like desirable effects such as, but not limited to, anti-viral activity metallic hydroxides such as but not limited to those of alkali against HCV. and alkaline-earth metals like calcium, lithium, magnesium, 0274 The present invention further relates to a pharma potassium and sodium, or zinc, resulting in the corresponding ceutical composition or combined preparation having syner metal salt; organic bases Such as but not limited to ammonia, gistic effects against a viral infection, especially a hepatitis C alkylamines, benzathine, hydrabamine, arginine, lysine, virus infection, and containing: N,N'-dibenzylethylene-diamine, chloroprocaine, choline, 0275 (a) at least one 4,6-disubstituted and 2,4,6-trisubsti diethanolamine, ethylene-diamine, N-methyl-glucamine, tuted pteridine derivative selected from the group as procaine and the like. defined above, and 0268 Reaction conditions for treating the 4,6-disubsti 0276 (b) one or more other anti-viral agents, and tuted and 2,4,6-trisubstituted pteridine derivatives of this 0277 (c) optionally one or more pharmaceutical excipi invention with an appropriate salt-forming acid or base are ents or pharmaceutically acceptable carriers, similar to standard conditions involving the same acid or base for simultaneous, separate or sequential use in the treatment but different organic compounds with basic or acidic proper of a viral infection, in particular HCV infection. ties, respectively. Preferably, in view of its use in a pharma 0278 Suitable anti-viral agents for inclusion into the syn ceutical composition or in the manufacture of a medicament ergistic antiviral compositions or combined preparations of for treating specific diseases, the pharmaceutically accept this invention include, for instance, retroviral enzyme inhibi US 2010/03051 17 A1 Dec. 2, 2010 tors belonging to categories well known in the art, such as tions and may comprise as additives Sweeteners, flavoring HIV-1 IN inhibitors, nucleoside reverse transcriptase inhibi agents, coloring agents, preservatives and the like. Carrier tors (e.g. , , didanosine, , Zal materials and excipients are detailed herein below and may citabine and the like), non-nucleoside reverse transcriptase include, interalia, calcium carbonate, sodium carbonate, lac inhibitors (e.g. , and the like), other tose, calcium phosphate or sodium phosphate; granulating reverse transcriptase inhibitors (e.g. foScamet Sodium and the and disintegrating agents, binding agents and the like. The like), and HIV-1 protease inhibitors (e.g. , pharmaceutical composition or combined preparation of this , , and the like). Other suitable invention may be included in a gelatin capsule mixed with any antiviral agents include for instance acemannan, acyclovir, inert solid diluent or carrier material, or has the form of a soft , , alvircept, , aranotin, aril gelatin capsule, in which the ingredient is mixed with a water done, , avridine, , cipamfylline, cytara or oil medium. Aqueous dispersions may comprise the bio bine, desciclovir, disoxaril, , enviradene, logically active composition or combined preparation incom enviroXime, , famotine, fiacitabine, fialuridine, bination with a suspending agent, dispersing agent or wetting floxuridine, fosarilate, foSfonet, , , agent. Oil dispersions may comprise Suspending agents such kethoxal, , memotine, methisaZone, , as a vegetable oil. Rectal administration is also applicable, for pirodavir, Somantadine, , tillorone, , Val instance in the form of Suppositories or gels. Injection (e.g. , , Viroxime, Zinviroxime, , intramuscularly or intraperiteneously) is also applicable as a , ribavirine, , stallimycine, stato mode of administration, for instance in the form of injectable lon, and Xenazoic acid, and their pharmaceuti Solutions or dispersions, depending upon the disorder to be cally acceptable salts. treated and the condition of the patient. 0279 Especially relevant to this aspect of the invention is 0282. The term “pharmaceutically acceptable carrier or the inhibition of the replication of hepatitis C virus, in par excipient’ as used herein in relation to pharmaceutical com ticular in human beings and other mammals such as primates. positions and combined preparations means any material or Therefore, of particular relevance in the context of HCV substance with which the active principle, i.e. the 4,6-disub prevention or treatment is co-administration with one or more stituted or 2,4,6-trisubstituted pteridine derivative of the other agents aiming at HCV inhibition well known in the art, present invention, and optionally the one or more other anti Such as but not limited to, (pegylated) interferon alpha, rib viral agents, may beformulated in order to facilitate its appli avirin, an NS3 protease inhibitor (such as telaprivir), or cation or dissemination to the locus to be treated, for instance nucleoside- or non-nucleoside-based inhibitors of NS5B by dissolving, dispersing or diffusing the said composition, polymerase. Synergistic activity of the pharmaceutical com and/or to facilitate its storage, transport or handling without positions or combined preparations of this invention against impairing its effectiveness. The pharmaceutically acceptable viral infection may be readily determined by means of one or carrier may be a solid or a liquid or a gas which has been more tests such as, but not limited to, the isobologram compressed to form a liquid, i.e. the compositions of this method, as previously described by Elion et al. in J. Biol. invention can Suitably be used as concentrates, emulsions, Chem. (1954) 208:477-488 and by Baba et al. in Antimicrob. Solutions, granulates, dusts, sprays, aerosols, pellets or pow Agents Chemother. (1984) 25:515-517, using ECs for calcu ders. lating the fractional inhibitory concentration (hereinafter 0283 Suitable pharmaceutical carriers for use in the said referred as FIC). When the minimum FIC index correspond pharmaceutical compo-sitions and their formulation are well ing to the FIC of combined compounds (e.g., FIC+FIC) is known to those skilled in the art. There is no particular restric equal to 1.0, the combination is said to be additive; when it is tion to their selection within the present invention although, between 1.0 and 0.5, the combination is defined as sub-syn due to the usually low or very low water-solubility of the ergistic, and when it is lower than 0.5, the combination is by 4,6-disubstituted or 2,4,6-trisubstituted pteridine derivatives defined as synergistic. When the minimum FIC index is of this invention, special attention will be paid to the selection between 1.0 and 2.0, the combination is defined as sub-an of Suitable carrier combinations that can assist in properly tagonistic and, when it is higher than 2.0, the combination is formulating them in view of the expected time release profile. defined as antagonistic. Suitable pharmaceutical carriers include additives such as, 0280. The pharmaceutical composition or combined but not limited to, wetting agents, dispersing agents, Stickers, preparation with Synergistic activity against viral infection adhesives, emulsifying or Surface-active agents, thickening according to this invention may contain the 4,6-disubstituted agents, complexing agents, gelling agents, solvents, coatings, or 2,4,6-trisubstituted pteridine derivative over a broad con antibacterial and antifungal agents (for example phenol, Sor tent range depending on the contemplated use and the bic acid, chlorobutanol), isotonic agents (such as Sugars or expected effect of the preparation. Generally, the pteridine Sodium chloride) and the like, provided the same are consis derivative content of the combined preparation is within the tent with pharmaceutical practice, i.e. carriers and additives range of from 0.1 to 99.9% by weight, preferably from 1 to which do not create permanent damage to mammals, espe 99% by weight, more preferably from about 5 to 95% by cially humans. weight. 0284. The pharmaceutical compositions of the present 0281. The pharmaceutical compositions and combined invention may be prepared in any known manner, for instance preparations according to the present invention may be by homogeneously mixing, dissolving, spray-drying, coating administered orally or in any other suitable fashion. Oral and/or grinding the active ingredients, in a one-step or a administration is preferred and the preparation may have the multi-steps procedure, with the selected carrier material and, form of a tablet, aqueous dispersion, dispersable powder or where appropriate, the other additives such as Surface-active granule, emulsion, hard or soft capsule, syrup, elixir or gel. agents. may also be prepared by micronisation, for instance in The dosing forms may be prepared using any method known view to obtain them in the form of microspheres usually in the art for manufacturing these pharmaceutical composi having a diameter of about 1 to 10 Jum, namely for the manu US 2010/03051 17 A1 Dec. 2, 2010

facture of microcapsules for controlled or sustained release of oleate), glycerol, Sorbitan, Sucrose and pentaerythritol are the biologically active ingredient(s). also suitable non-ionic Surfactants for the purpose of the 0285 Suitable surface-active agents to be used in the phar present invention. maceutical compositions of the present invention are non 0287 Suitable cationic surfactants include, but are not ionic, cationic and/or anionic Surfactants having good emul limited to, quaternary ammonium salts, preferably halides, Sifying, dispersing and/or wetting properties. Suitable having four hydrocarbon radicals optionally substituted with halo, phenyl, Substituted phenyl or hydroxy; for instance qua anionic Surfactants include both water-soluble soaps and ternary ammonium salts containing as N-Substituent at least water-soluble synthetic Surface-active agents. Suitable soaps one C-C alkyl radical (e.g. cetyl, lauryl, palmityl, myristyl, include, but are not limited to, alkaline oralkaline-earth metal oleyland the like) and, as further sub-stituents, unsubstituted salts, unsubstituted or Substituted ammonium salts of higher orhalogenated lower alkyl, benzyl and/or hydroxy-C alkyl fatty acids (Co-C), e.g. the sodium or potassium salts of radicals. oleic or Stearic acid, or of natural fatty acid mixtures obtain 0288 A more detailed description of surface-active agents able form coconut oil or tallow oil. Synthetic surfactants suitable for this purpose may be found for instance in include Sodium or calcium salts of polyacrylic acids; fatty “McCutcheon's Detergents and Emulsifiers Annual (MC Sulphonates and Sulphates; Sulphonated benzimidazole Publishing Crop., Ridgewood, N.J., 1981), “Tensid-Taschen derivatives and alkylaryl-Sulphonates. Fatty Sulphonates or buch", 2" ed. (Hanser Verlag, Vienna, 1981) and “Encyclo sulphates are usually in the form of alkaline or alkaline-earth paedia of Surfactants (Chemical Publishing Co., New York, metal salts, unsubstituted ammonium salts or ammonium 1981). salts substituted with an alkyl or acyl radical having from 8 to 0289 Structure-forming, thickening or gel-forming 22 carbonatoms, e.g. the Sodium or calcium salt of lignoSul agents may be included into the pharmaceutical compositions phonic acid or dodecylsulphonic acid or a mixture of fatty and combined preparations of the present invention. Suitable alcohol Sulphates obtained from natural fatty acids, alkaline Such agents include in particular, but are not limited to, highly or alkaline-earth metal salts of Sulphuric or Sulphonic acid dispersed silicic acid, Such as the product commercially avail esters (such as sodium lauryl Sulphate) and Sulphonic acids of able under the trade name Aerosil; bentonites; tetraalkyl fatty alcohol/ethylene oxide adducts. Suitable sulphonated ammonium salts of montmorillonites (e.g., products com benzimidazole derivatives preferably contain 8 to 22 carbon mercially available under the trade name Bentone), wherein atoms. Examples of alkylarylsulphonates are the Sodium, each of the alkyl groups may contain from 1 to 20 carbon calcium or alkanolamine salts of dodecylbenzene Sulphonic atoms; cetostearyl alcohol and modified castor oil products acid or dibutyl-naphthalenesulphonic acid or a naphthalene (e.g. the product commercially available under the trade name Sulphonic acid/formaldehyde condensation product. Also Antisettle). Suitable are the corresponding phosphates, e.g. salts of phos 0290 Gelling agents which may be included into the phar phoric acid ester and an adduct of p-nonylphenol with ethyl maceutical compositions and combined preparations of the ene and/or propylene oxide, orphospholipids. Suitable phos present invention include, but are not limited to, cellulose pholipids for this purpose are the natural (originating from derivatives Such as carboxymethylcellulose, cellulose acetate animal or plant cells) or synthetic phospholipids of the cepha and the like; natural gums such as arabic gum, Xanthum gum, lin or lecithin type such as e.g. phosphatidylethanolamine, tragacanth gum, guar gum and the like; gelatin; silicon diox phosphatidylserine, phosphatidylglycerine, lysolecithin, car ide; synthetic polymers such as carbomers, and mixtures diolipin, dioctanylphosphatidylcholine, dipalmitoylphos thereof. Gelatin and modified celluloses represent a preferred hatidylcholine and their mixtures. class of gelling agents. 0286 Suitable non-ionic surfactants include, but are not 0291. Other optional excipients which may be included in limited to, poly-ethoxylated and polypropoxylated deriva the pharmaceutical compositions and combined preparations tives of alkylphenols, fatty alcohols, fatty acids, aliphatic of the present invention include additives such as, but not amines or amides containing at least 12 carbon atoms in the limited to, magnesium oxide; azo dyes; organic and inorganic molecule, alkylarenesulphonates and dialkylsulphosucci pigments such as titanium dioxide; UV-absorbers; stabilisers; nates, such as polyglycol ether derivatives of aliphatic and odor masking agents; viscosity enhancers; antioxidants such cycloaliphatic alcohols, Saturated and unsaturated fatty acids as, for example, ascorbyl palmitate, Sodium bisulfite, sodium and alkylphenols, said derivatives preferably containing 3 to metabisulfite and the like, and mixtures thereof; preservatives 10 glycol ether groups and 8 to 20 carbon atoms in the (ali Such as, for example, potassium Sorbate, sodium benzoate, phatic) hydrocarbon moiety and 6 to. 18 carbon atoms in the Sorbic acid, propyl gallate, benzylalcohol, methyl paraben, alkyl moiety of the alkylphenol. Further suitable non-ionic propyl paraben and the like; sequestering agents such as surfactants are water-soluble adducts of polyethylene oxide ethylene-diamine tetraacetic acid, flavoring agents such as with polypropylene glycol, ethylenediamino-polypropylene natural Vanillin; buffers such as citric acid and acetic acid; glycol preferably containing 1 to 10 carbon atoms in the alkyl extenders or bulking agents such as silicates, diatomaceous chain, which adducts contain 20 to 250 ethyleneglycol ether earth, magnesium oxide or aluminum oxide; densification groups and/or 10 to 100 propyleneglycol ether groups. Such agents such as magnesium salts; and mixtures thereof. compounds usually contain from 1 to 5 ethyleneglycol units 0292 Additional ingredients may be included in order to per propyleneglycol unit. Representative examples of non control the duration of action of the biologically-active ingre ionic Surfactants include, but are not limited to, nonylphenol dient in the compositions and combined preparations of the polyethoxyethanol, castor oil polyglycolic ethers, polypropy invention. Control release compositions may thus be lene/polyethylene oxide adducts, achieved by selecting appropriate pharmaceutically accept tributylphenoxypolyethoxyethanol, polyethyleneglycol and able polymer carriers such as for example polyesters, octylphenoxy-polyethoxyethanol. Fatty acid esters of poly polyamino-acids, polyvinyl-pyrrolidone, ethylene-vinyl ethylene Sorbitan (Such as polyoxyethylene Sorbitan tri acetate copolymers, methylcellulose, carboxy-methylcellu US 2010/03051 17 A1 Dec. 2, 2010

lose, protamine sulfate and the like. The rate of drug release examples, but the present invention is not limited thereto. The and duration of action may also be controlled by incorporat following examples are given by way of illustration only. ing the active ingredient into particles, e.g. microcapsules, of a polymeric Substance such as hydrogels, polylactic acid, hydroxymethyl-cellulose, polymethyl methacrylate and the Examples 1 to 73 other above-described polymers. Such methods include col loid drug delivery systems like liposomes, microspheres, Synthesis of 2-amino-4-ethoxy-6-substituted pte microemulsions, nanoparticles, nanocapsules and so on. ridines Depending on the route of administration, the pharmaceutical composition or combined preparation of the invention may 0299 The synthetic method may be represented schemati also require protective coatings. cally as follows: 0293 Pharmaceutical forms suitable for injectable use include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation thereof. Typical liquid pharmaceutically acceptable carriers for this purpose therefore include biocompatible aqueous buffers, ethanol, glycerol, propylene glycol, polyethylene glycol, complexing ls, agents such as cyclodextrins and the like, and mixtures N1 N N C thereof. Micorwave, 100°C., 10 min 0294 Other modes of local drug administration can also be used. For example, the selected biologically active agent HN - N - N - may be administered topically, in an ointment, gel or the like, or transdermally, using a conventional transdermal drug delivery system. 0295 Since, in the case of combined preparations includ ing the 4,6-disubstituted or 2,4,6-trisubstituted pteridine ls, derivative of the present invention and one or more other antiviral agents, both ingredients do not necessarily bring out N1 n N R their synergistic therapeutic effect directly at the same time in the patient to be treated, the said combined preparation may be in the form of a medical kit or package containing the two HN - N 1 N - ingredients in separate but adjacent form. In the latter context, each ingredient may therefore beformulated in a way suitable for an administration route different from that of the other 0300. The general procedure used for preparing 2-amino ingredient, e.g. one of them may be in the form of an oral or 6-aryl-4-ethoxy-pteridines and 2-amino-6-heteroaryl-4- parenteral formulation whereas the other is in the form of an ethoxy-pteridines starts from the common intermediate ampoule for intravenous injection or an aerosol. 2-amino-6-chloro-4-ethoxypteridine (described in WO 2005/ 0296. The present invention further relates to a method for 025574) as follows. A mixture of 2-amino-6-chloro-4-ethox treating a viral infection or a pthologic condition associated ypteridine (23 mg, 0.1 mmol), potassium carbonate (27 mg, therewith, including hepatitis C in a patient, preferably a 0.2 mmol), tetrakis(triphenylphosphine) palladium (8 mg, mammal, more preferably a human being. The method of this 0.007 mmol) and a suitable arylboronic or heteroarylboronic invention consists of administering to the patient in need thereof a therapeutically effective amount of a 4,6-disubsti acid, or a pinacol ester thereof (0.12 mmol) in dimethylether tuted or 2,4,6-trisubstituted pteridine derivative of the present (1.5 mL) and water (1 mL) was heated to 100° C. for 10 invention, optionally together with an effective amount of one minutes under microwave irradiation. Solvents were concen or more other antiviral agents, or a pharmaceutical composi trated in vacuo and the residue was purified by high perfor tion comprising the same. Such as disclosed above in exten mance liquid chromatography (hereinafter referred as HPLC) sive details. onto a C18 column with a gradient of HO, 0.1% TFA 0297. The therapeutically effective amount of the 4,6-dis acetonitrile, in order to afford the pure desired product. This ubstituted or 2,4,6-trisubstituted pteridine derivative to be procedure provided, with yield ranging from 5% to 65%, administered according to the present invention is usually in depending upon the aryl or heteroaryl group R introduced at the range of about 0.01 mg to 20 mg, preferably about 0.1 mg position 6 of the pteridine ring, the pure compounds shown in to 5 mg, per day per kg body weight for human beings. Depending upon the severity of the pathologic condition to be the table 1, which were characterized by their mass spectrum treated and the patient's condition, the said therapeutically MS. effective amount may be divided into several sub-units per day or may be administered at more than one day intervals. The patient to be treated may be any warm-blooded animal, OEt preferably a mammal, more preferably a human being, Suf N R fering from an infection by a virus being a member of the N1N n Flaviridae family, e.g. HCV, or a pathologic condition asso l 2n 2 ciated therewith. HN N N 0298. The present invention will be further described with reference to certain more specific embodiments and

US 2010/03051 17 A1 Dec. 2, 2010

Examples 74 to 140 The reaction mixture was refluxed for one hour. After cooling, the solvent was removed under reduced pressure. The residue Synthesis of 2-amino-4-morpholin-4-yl-6-substi was purified by flash chromatography (using 7% MeOH/ tuted-pteridines DCM as the eluent), providing the pure title compound in 0301 The scheme below shows a general procedure for 80% yield (4.6 g), which was characterized by mass spec the synthesis of 2-amino-4-morpholin-4-yl-6-substituted trometry as follows: MS (m/z) 233.3 M+H". pteridines. Synthesis of 4-morpholin-4-yl-8-oxy-pteridin-2-ylamine (Example 75) 0303 To a cooled (0° C.) solution of 4-morpholin-4-yl pteridin-2-ylamine (4.6 g. 20 mmol) in trifluroroacetic acid ON (80 mL) was added dropwise 5.1 mL of a 35% aqueous HO, glyoxal, ethanol Her solution. The reaction mixture was kept at 4°C. overnight. N N NH2 reflux, 1 h, The Solution was concentrated to dryness, providing crude o2HCI product (4.9 g, 98% yield) as a yellow powder. The crude 2 material was used without further purification, but was char HN N NH2 acterized by mass spectrometry as follows: MS (m/z). 249.3 O M+H". Synthesis of N-(6-chloro-4-morpholin-4-yl-pteridin O H2O, TFA 2-yl)-acetamide (Example 76) He 0° C. to 4°C., ofn 0304. A suspension of 4-morpholin-4-yl-8-oxy-pteridin 2-ylamine (2.3 g) in acetylchloride (25 mL) was stirred at -40 °C. Trifluoroacetic acid (12 mL) was then added dropwise. The resulting Solution was slowly warmed up to room tem C perature and stirred for one day. Reaction was carefully quenched with ice, followed by neutralization with ammo nium hydroxide solution. The aqueous phase was extracted C D with DCM repeatedly. The combined organic layers were CHCOCl, TFA, -40° C. to RT concentrated in vacuo and the residue was purified by flash N N1N n chromatography providing the pure title compound as a yel low solid (1.2g, 43% yield) was characterized by mass spec trometry as follows: MS (m/z) 309.2 M+H". HN N 0305 The general procedure used for preparing 2-amino 6-aryl-4-morpholino-pteridines and 2-amino-6-heteroaryl-4- morpholino-pteridines was as follows. A mixture of 2-amino 6-chloro-4-morpholino-pteridine (31 mg, 0.1 mmol), potassium carbonate (42 mg, 0.4 mmol), tetrakis(triph enylphosphine)palladium (8 mg, 0.007 mmol) and a suitable O arylboronic or heteroarylboronic acid, or a pinacol ester -- thereof (0.12 mmol), in dimethylether (2 mL) and water (1 Microwave, 110°C., 30 min mL) was heated to 110° C. for 30 minutes under microwave irradiation. Solvents were concentrated in vacuo and the resi due was purified by HPLC onto a C18 column with a gradient of HO, 0.1% TFA-acetonitrile. This procedure provided, ulco with yields ranging from 10% to 70%, depending upon the aryl or heteroaryl group R introduced at position 6 of the pteridine ring, the pure compounds which were characterized O by their mass spectrum MS as indicated in Table 2 below. OO Synthesis of 4-morpholin-4-yl-pteridin-2-ylamine (Example 74) 0302) To a solution of 2.5,6-triamino-4-morpholino-pyri midine dihydrochloride (7.08 g, 25 mmol) in ethanol (60 mL) was added glyoxal (405 solution in water, 2.9 mL, 25 mmol).

US 2010/03051 17 A1 Dec. 2, 2010 25

TABLE 2-continued

Example Compound name M-H

89 4-morpholino-6-(4-(morpholino 408.1 methyl)phenyl)pteridin-2-ylamine

a a a a Cr,C 90 6-(2,3-difluorophenyl)-4-morpholinopteridin-2- 345.2 ylamine

e a Cl 91 6-(2,3-dichlorophenyl)-4-morpholinopteridin-2- 377 amine

Y a a w C

92 F 6-(2-chloro-4-fluorophenyl)-4- 361.1 morpholinopteridin-2-ylamine

Y a Y

93 C F 6-(2,4-bis(trifluoromethyl)phenyl)-4- 4449 3 morpholinopteridin-2-ylamine

OCF

94 6-(2,4-difluorophenyl)-4-morpholinopteridin-2- 345.2 ylamine

95 C 6-(2,6-dichlorophenyl)-4-morpholinopteridin-2- 377 ylamine

96 CF3 6-(3,5-bis(trifluoromethyl)phenyl)-4- morpholinopteridin-2-ylamine

Cl CF

97 C 6-(4-chloro-3-fluorophenyl)-4- 361.3 morpholinopteridin-2-ylamine w OC

US 2010/03051 17 A1 Dec. 2, 2010 30

Example 141 -continued Synthesis of N-6-(4-Amino-phenyl)-4-morpholin-4- O yl-pteridin-2-yl)-acetamide 0306 Synthesis proceeds according to the following O A scheme:

HN JC C O

ON 0309 To a mixture of N-6-(4-Amino-phenyl)-4-morpho N C -> lin-4-yl-pteridin-2-yl)-acetamide (55 mg, 0.15 mmol) and O N1 N1 N diisopropylethylamine (78 uL, 0.15 mmol) in dimethylfor mamide (3 mL) was added cyclopropanecarbonyl chloride (14 ul, 0.15 mmol). The resulting mixture was stirred at room us N l N 2 N2 H temperature for 4 hours. Chloroform was then added to the O reaction mixture and extracted with Saturated aqueous Sodium bicarbonate solution and brine. The organic layer was dried over sodium Sulfate and concentrated to dryness to O NH2 provide 12 mg of Solid as crude product. This material was dissolved in methanol (2 mL) and added NaOMe (0.1 mL, 0.5 N in methanol). The mixture was then heated to 100°C. for 10 minutes under microwave irradiation. Solvents were concen trated in vacuo and the residue was purified by flash chroma tography (using 10% MeOH/DCM as the eluent), providing 4 CO mg of the desired product as a yellow solid, which was char acterized by its mass spectrum as follows: MS (m/z) 393.0 0307. A mixture of 2-amino-6-chloro-4-morpholino-pte M+H". ridine (600 mg, 1.9 mmol), potassium carbonate (394 mg. 66 mmol), tetrakis(triphenylphosphine) palladium (66 mg, Example 143 0.057 mmol) and 4-(4.4.5.5-tetramethyl-1,3,2dioxaboro Synthesis of 6-(2,3-difluoro-phenyl)-pteridine-2,4- lan-2-yl)-phenylamine (511 mg, 2.3 mmol) in dimethylether diamine (6 mL) and water (3 mL) was heated to 110°C. for 4 minutes under microwave irradiation. Solvents were concentrated in 0310 Synthesis proceeds according to the following vacuo and the resulting Solid was washed with water, metha scheme: nol, and dichloromethane to provide 502 mg (yield: 72%) of the desired product as an orange Solid, which was character ized by its mass spectrum as follows: MS (m/z) 366.8 M+H". ls, N He Example 142 N1 N n F Synthesis of cyclopropane carboxylic acid 4-(2- l 2n 2 F amino-4-morpholin-4-yl-pteridin-6-yl)-phenyl HN N N amide NH2 0308 Synthesis proceeds according to the following N scheme: N1N n F l 2n 2 F HN N N O O C D NH, I, y-, 0311. To a solution of 6-(2,3-difluoro-phenyl)-4-ethoxy N pteridin-2-ylamine (10 mg 0.03 mmol) in MeOH (1 mL) was N DIEA, DMF added 10 mL of a 30% aqueous ammonia solution. The mix O N1 'S --2. NaOMe ture was microwave at 130°C. for 20 minutes. The precipitate formed was collected by filtration and washed with water and ul N l N2 N 2 small amount of MeCH to provide 5 mg of the title compound H as a yellow solid (62% yield), which characterized by mass spectrometry as follows: MS (m/z) 275.7 M+H". US 2010/03051 17 A1 Dec. 2, 2010

Example 144 Synthesis of (S)-2-amino-N-(4-(2-amino-4-mor pholinopteridin-6-yl)phenyl)-3-hydroxypropanamide 0312

O MeOH HN N NH2 F OH O reflux, 1.5 hr N Ac2O/AcOH N N N R wherein ls - - l 2 2 HN N N HN N N F NH2 OH N 10 eq O N21 n 1.2.4 triazole Ho --- POCl, ACN Sa 2 R= C NH N N N H 1g 0313. The compound of example 139 (12 mg, 0.023 mmol) was stirred in 20%TFA/DCM (2 mL) solution for 20 (N y F minutes. The solvent was removed in vacuo and the residue N was purified by HPLC onto a C18 column with a gradient of N ROH HO, 0.1% TFA-acetonitrile, to provide the desired product O N 2 n --- which was characterized by mass spectrometry as follows: MS (m/z) 411.8 M+H". Example 145 Synthesis of (S)-2-amino-N-(4-(2-amino-4-mor pholinopteridin-6-yl)phenyl)-propanamide 0314)

O O Synthesis of 2-amino-4-hydroxy-6-(4-fluorophenyl)pteridine N N N R wherein (Example 146) 0317. To a boiling solution of 2.5,6-triamino-4-hydroxy l 2n 2 pyrimidine dihydrochloride (2.75 g, 12.9 mmol) in methanol HN N N (80 mL) was added a solution of 4-fluorophenylglyoxal NH2 monooxime (2.58 g. 15.5 mmol) in methanol (20 mL). The reaction mixture was heated under reflux for 5 hours. The precipitate formed was filtered off, washed with water, then s ethanol and diethyl ether, and dried under vacuum, providing R= C NH the title compound as a yellow powder in 45% yield (1.5 g), which was characterized by mass spectrometry as follows: MS (m/z) 258.1 M+H". Synthesis of 2-acetylamino-4-hydroxy-6-(4-fluo 0315. This product was prepared using the method of rophenyl)pteridine (Example 147) example 144 but starting from the compound of example 140. The resulting compound was characterized by mass spec 0318. A suspension of 2-amino-6-(4-fluorophenyl)pteri trometry as follows: MS (m/z) 395.8 M+H". dine (1 g, 3.9 mmol) in acetic anhydride (60 mL) and acetic acid (20 mL) was refluxed for 90 minutes until a clear solution Examples 146 to 163 was formed. By cooling down the reaction mixture in the Synthesis of 2-amino-4-alkoxy-6-(4-fluorophenyl)- refrigerator, the precipitate formed was filtered off, washed pteridines with ethyl acetate and diethyl ether, and dried under vacuum, 0316 The scheme below shows a general procedure for providing the title compound as a yellow powder in 87% yield the synthesis of 2-amino-4-alkoxy-6-(4-fluorophenyl)-pte (1.01 g), which was characterized by mass spectrometry as ridines. follows: MS (m/z) 300.1 M+H". US 2010/03051 17 A1 Dec. 2, 2010 32

Synthesis of 2-acetylamino-4-(1,2,4-triazolyl)-6-(4- hol (0.5 mL). The resulting mixture was heated at 100° C. for fluorophenyl)pteridine (Example 148) 10 minutes under microwave irradiation. After cooling, the Solution was concentrated in vacuo and the residue was puri 0319. To a suspension solution of 2-acetylamino-6-(4- fied by HPLC onto a C18 column with a gradient of HO, fluorophenyl)pteridine (517 mg, 1.73 mmol), 1,2,4-triazole 0.1% TFA-acetonitrile. This procedure provided, with yields (1.19 g, 17.3 mmol), diisopropylethylamine (1.5 mL, 8.65 ranging from 5% to 50%, depending upon the alkoxy group mmol) in acetonitrile (20 mL) was added dropwise phospho introduced at position 4 of the pteridine ring, the pure com rus oxychloride (0.32 mL, 3.46 mmol). The suspension was pounds, which were characterized by their mass spectrum as stirred at room temperature for 3 days. The precipitated was indicated in the following table 3. filtered off, washed with large amount of acetonitrile and diethyl ether. The resulting solid was dried under vacuum, providing the title compound as a yellow powder in 80% yield OR F (480 mg), which was characterized by mass spectrometry as follows: MS (m/z) 351.2 M+H". 21 N 0320. The general procedure used for preparing 2-amino- N 4-alkoxy-6-(4-fluorophenyl)-pteridines was as follows: ls 2 Potassium t-butoxide (0.1 mL, 1.0 M solution in THF) was HN N N added to a solution of 2-acetylamino-4-(1,2,4-triazolyl)-6-(4- fluorophenyl)pteridine (35 mg, 0.1 mmol) in a suitable alco

TABLE 3 Example R Compound name M-H 49 methyl 6-(4-Fluorophenyl)-4-methoxy-pteridin-2- 272.2 ylamine 50 isopropyl 6-(4-Fluorophenyl)-4-isopropoxy-pteridin-2- 3OO.1 ylamine 51 CHCH-OMe 6-(4-Fluorophenyl)-4-(2-methoxy-ethoxy)- 316.6 pteridin-2-ylamine 152 n-butyl 4-Butoxy-6-(4-fluorophenyl)-pteridin-2-ylamine 314.2 53 CHCF 6-(4-Fluorophenyl)-4-(2.2.2-trifluoro-ethoxy)- 340.1 pteridin-2-ylamine S4 s OH 4-2-Amino-6-(4-fluorophenyl)-pteridin-4-yloxy- 344.2 8. 2-methyl-butan-2-ol

55 s su-1N 6-(4-Fluorophenyl)-4-(2-morpholin-4-wl-ethoxy)-(Fluorophenyl)-4-(2-morp y y) 370.9 Null pteridin-2-ylamine 1S6 6-(4-Fluorophenyl)-4-(3-morpholin-4-yl- 385 O propoxy)-pteridin-2-ylamine s --- 157 4-Cyclopropylmethoxy-6-(4-fluorophenyl)- 312.3 x pteridin-2-ylamine

158 4-Cyclobutylmethoxy-6-(4-fluorophenyl)- 326.2 pteridin-2-ylamine

159 n-propyl 6-(4-Fluorophenyl)-4-propoxy-pteridin-2-ylamine 300.1 160 sec-butyl 4-sec-butoxy-6-(4-fluorophenyl)-pteridin-2- 314.4 ylamine 161 O) pteridin-2-ylamine6-(4-Fluorophenyl)-4-(tetrahydro-furan-3-yloxy)- 328.2 O 162 isobutyl 6-(4-Fluorophenyl)-4-isobutoxy-pteridin-2- 3.14.1 ylamine 163 benzyl 4-Benzyloxy-6-(4-fluorophenyl)-pteridin-2- 348.2 ylamine

(end of table 3) US 2010/03051 17 A1 Dec. 2, 2010 33

Example 164 Synthesis of 4-ethylthio-6-(4-fluorophenyl)-pteridin -continued 2-ylamine F NRR 0321 N N21 n ls 2 HN N N l S F N 0324. The general procedure used for preparing 2-amino N21 n 4-alkylamino-6-(4-fluorophenyl)-pteridines was as follows. 1s 2 Sodium methoxide (0.8 mL, 0.5N solution in methanol) was HN N N added to a mixture of 2-acetylamino-4-(1,2,4-triazolyl)-6-(4- fluorophenyl)pteridine (35 mg, 0.1 mmol) and corresponding 0322 This product, which was prepared according to a amines with the general formula NHRR' (0.2 mL). The result method similar to that of example 149, except for using ing mixture was heated at 100° C. for 10 minutes under Sodium ethane-thiolate as reagent and ethanol, was charac microwave irradiation. After cooling, the solution was con terized by mass spectrometry as follows: MS (m/z) 302.6 centrated in vacuo and the residue was purified by HPLC onto M+H". a C18 column with a gradient of H2O, 0.1%TFA-acetonitrile. This procedure provided, with yields ranging from 25% to Examples 165 to 176 60%, depending upon the amino group introduced at position Synthesis of 2-amino-4-alkylamino-6-(4-fluorophe 4 of the pteridine ring, the pure compounds which were nyl)-pteridines characterized by their mass spectrum MS as indicated in table 0323. The synthesis proceeds as follows: 4 below.

(y F R

N N NHRR N21 n O N21 n He ls 2 us N lsN N 2 HN N N H

TABLE 4 Example R Compound name M-H 16S NH, 4-amino-6-(4-fluorophenyl)-pteridine-2,4- 257.2 diamine

166 6-(4-Fluorophenyl)-4-piperidin-1-yl-pteridin-2- 325.2 ylamine N

167 NH-cyclo- N-4-Cyclopropyl-6-(4-fluorophenyl)-pteridine- 297.1 propyl 2,4-diamine

168 4-(2,6-Dimethylmorpholin-4-yl)-6-(4-fluoro- 355.1 phenyl)-pteridin-2-ylamine NullsO 169 N-4-Cyclohexyl-6-(4-fluorophenyl)-pteridine- 339.2 2,4-diamine US 2010/03051 17 A1 Dec. 2, 2010 34

TABLE 4-continued

Example R Compound name M-H

170 N-4-Benzyl-6-(4-fluorophenyl)-pteridine-2,4- 347.2 diamine H N

171 N-4-(3-Methyl-benzyl)-6-(4-fluorophenyl)- 347.2 pteridine-2,4-diamine w Nul 172 N-4-(3-Fluorobenzyl)-6-(4-fluorophenyl)- 351.2 pteridine-2,4-diamine H w N F

173 6-(4-Fluorophenyl)-4-(4-methylpiperazin-1-yl)- 340.2 rsu N1 pteridin-2-ylamine 174 6-(4-Fluorophenyl)-4-piperazin-1-yl-pteridin-2- 326.2 Nu NH ylamine 175 N-4-Cyclopropylmethyl-6-(4-fluorophenyl)- 3.11.2 H pteridine-2,4-diamine N

176 6-(4-Fluorophenyl)-4-pyrrollidin-1-yl-pteridin-2- 311.2 ylamine N

(end of table 4)

Examples 177 and 178 -continued Synthesis of 6-(4-Fluorophenyl)-4-1.2.4 triazol-1- N yl-pteridine f y F 0325 Synthesis proceeded in two steps as shown in the following scheme: N21 ls, le C O O \ Synthesis of 6-(4-fluorophenyl)-3H-pteridin-4-one (Example 177) NH2 NS N HO F 0326 To a boiling solution of 4,5-Diamino-6-hydroxy HCI pyrimidine hydrochloride (1.5g, 9.23 mmol) in methanol (60 ls MeOH mL) was added a solution of 4-fluoropheynlglyoxal N NH2 monooxime (2.0 g, 12 mmol) in methanol (20 mL). The reaction mixture was heated under reflux for 1 hour. After cooling, the precipitate formed was filtered off, washed with diethyl ether, and dried under vacuum, providing the title F compound as a yellow powder in 68% yield (1.51 g) which O was characterized by its mass spectrum as follows: MS (m/z) N 10 eq1,2,4-triazole 243.4 M+H". HN n Ho POCl3, ACN Synthesis of 6-(4-fluorophenyl)-4-1,2,4-triazol-1-yl ls 2 pteridine (Example 178) N N 0327. To a solution of the compound of example 177 (250 mg, 1.03 mmol), 1,2,4-triazole (285 mg, 4.13 mmol) and US 2010/03051 17 A1 Dec. 2, 2010 diisopropylethylamine (0.72 mL, 4.13 mmol) in acetonitrile Examples 182 to 184 (8 mL) phosphorus oxychloride (0.24 mL, 2.58 mmol) was added dropwise. The Suspension was stirred at room tempera Synthesis of 4-amino-6-(4-fluorophenyl)-pteridines ture for 3 days. The precipitated was filtered off, washed with 0330 large amount of acetonitrile and diethyl ether. The resulting Solid was dried under vacuum, providing the title compound as a yellow powder in 99% yield (300 mg), which was char acterized by mass spectrometry as follows: MS (m/z) 294.0 F M+H". (y RRNH N Ho Examples 179 to 181 N21 n

Synthesis of 4-alkoxy-6-(4-fluorophenyl)-pteridines lsN N 2 F 0328 Synthesis proceeded as follows: NRR N N21 n ls 2 YN F N N ROK N 0331. The general procedure used for preparing 4-amino N21 n 6-(4-fluorophenyl)-pteridines was as follows. A mixture of (4-fluorophenyl)-4-1.2.4 triazol-1-yl-pteridine (30 mg, 0.1 lsN N 2 mmol) and a suitable amine (0.1 mL) in dioxane (0.5 mL) was heated at 100° C. for 7 minutes under microwave irradiation. After cooling, the Solution was concentrated in vacuo and the residue was purified by HPLC onto a C18 column with a R No F gradient of HO, 0.1%TFA-acetonitrile. This procedure pro vided, with yields ranging from 50% to 60%, depending upon N the amino group introduced at position 4 of the pteridine ring, N21 n the pure compounds which were characterized by their mass spectrum as indicated in table 6. lsN N2

F 0329. The general procedure used for preparing 4-alkoxy R 6-(4-fluorophenyl)-pteridines was as follows. Potassium N t-butoxide (0.1 mL, 1.0 M solution in THF) was added to a N21 n solution of 6-(4-fluorophenyl)-4-1.2.4 triazol-1-yl-pteridine (30 mg, 0.1 mmol) in a suitable alcohol (0.5 mL). The result lsN N2 ing mixture was heated at 70° C. for 5 minutes under micro wave irradiation. After cooling, the Solution was concentrated in vacuo and the residue was purified by HPLC onto a C18 TABLE 6 column with a gradient of HO, 0.1% TFA-acetonitrile. This procedure provided, with yields ranging from 25% to 70%, Example R Compound name M-H depending upon the alkoxy group introduced at position 4 of 182 H 6-(4-Fluoro-phenyl)- 338.8 the pteridine ring, the pure compounds which were charac N pteridin-4-yl)-(4-methyl terized by their mass spectrum MS as indicated in the follow Y cyclohexyl)-amine, ing table 5. isomer A

TABLE 5 183 H 6-(4-Fluoro-phenyl)- 338.8 N pteridin-4-yl)-(4-methyl Example R Compound name M-H • cyclohexyl)-amine, isomer B 179 ethyl 4-ethoxy-6- 271.2 (4-fluorophenyl)pteridine 18O isopropyl 4-isopropoxy-6-(4-fluorophenyl)- 285.2 184 6-(4-Fluoro-phenyl)-4- 312.2 pteridine morpholin-4-yl-pteridine 181 CHCH-OMe 4-(2-methoxy-ethoxy)-6-(4-fluoro- 301.1 phenyl)-pteridine u US 2010/03051 17 A1 Dec. 2, 2010 36

Example 185 added to the pre-specified wells in column 1 of a polypro pylene 384-well plate. This plate was then placed on a Synthesis of 4-ethylthio-6-(4-fluorophenyl)-pteridine Precision 2000 Workstation in order to start serial dilution. 0332 After serial dilution, 2 LL of the solution was transferred from the 384-well plate to a 96-well cell culture plate containing 100 uL of cell media on a Biomek FX Work station. The DMSO concentration in the final assay condi tion was 0.5% after cells have been added to the plate and (y the total volume in each well was brought to 200 uL. NaSEt Step 2: to each well of the serial dilution plate prepared in step N He 1, 100 uL of cell media containing 6000 suspended Huh-7 N21 n HCV replicon cells was added with a Multidrop workstation. Plates were incubated for 3 days at 37° C. with 5% CO. lsN N 2 Step 3: detection: 0337 1) with respect to the ECs assay, the media in a l F 96-well cell culture plate was aspirated with a Biotek S EL405 plate-washer. A volume of 200 u, of a solution N containing a 1:1 mixture of a cell-lysis buffer (commer N21 n cially available from Promega, Luciferase Cell Culture Lysis 5X Reagent, cat. #E1531) and a luciferase substrate ls - - Solution (commercially available from Promega, N N Luciferase Assay, cat. #E4550) was added to each well of the plate with Multidrop. The plate was incubated for 30 0333 Sodium ethane thiolate (9 mg, 0.11 mmol) was minutes at room temperature before the luminescence sig added to a solution of (4-Fluoro-phenyl)-4-1,2,4-triazol-1- nal was measured with a TopCount plate-reader. yl-pteridine (30 mg, 0.1 mmol) in ethanol (0.5 mL). The 0338 2) with respect to the CCs assay, 100 uL of a pre resulting mixture was heated at 70° C. for 5 minutes under mixed CellTiter-Glo (commercially available from microwave irradiation. After cooling, the solution was con Promega, cat. iiG7572) solution was added directly to the centrated in vacuo and the residue was purified by HPLC onto cell culture in each well of the plate and the luminescence a C18 column with a gradient of H2O, 0.1%TFA-acetonitrile, signal was measured with a TopCount plate-reader after 10 to provide 3.8 mg (yield 13%) of the desired product which minutes of incubation at room temperature. was characterized by mass spectrometry as follows: MS (m/z) 0339 Table 7 shows ECs and CCso values determined in 287.2 M+H". the above assay for 2-amino-pteridine derivatives synthesized according to the methods described in the examples above. Example 186 Results are expressed by the following data: Anti-HCV Assay/Replicon Assay 0340 the 50% effective concentration (ECs), i.e. the concentration that protects 50% of the cell monolayer 0334) The anti HCV activity of specifically substituted from virus-induced cythopathic effect. pteridine derivatives was tested in a human hepatoma Huh-7 0341 the 50% cytostatic concentration (CCs), i.e. the cell line harbouring a HCV replicon. The assay comprised the concentration that results in 50% inhibition of cell following steps: growth. Step 1: compound preparation and serial dilution involved the following alternatives, depending upon the water Solubility of TABLE 7 pteridine derivative being tested: 0335) 1... with respect to water soluble pteridine deriva ECso CCso (A < 0.3 M: (A < 10 M: tives, 500 uL of solution in cell media (DMEM, 10% FBS, 0.3 M< B < 1 M: B 10-20 M: P/S, L-Glutamine) was prepared with a concentration that Example 1 M< C < 10M) C >20 iM) is twice the concentration of the starting final serial dilution concentration. 150 uL of the solution was added to the 27 pre-specified wells in column 1 of a 96-well cell culture 30 plate (PerkinElmer, white plate, cat. #6005181, for EC50 31 assay; black plate, cat. #6005182 for CC50 assay). The rest S4 57 of the plate, i.e. columns 2-12, was filled with 100 uL of 69 cell media. The plate was then placed on a Precision 2000 78 Workstation in order to start serial dilution. Pteridine com 79 pounds were diluted three times each step from column 1 to 8O 82 column 10. Column 11 was used as a blank control (no 84 pteridine compound added). 85 0336 2. With respect to poorly water soluble pteridine 86 derivatives, DMSO was used as a solvent, and serial dilu 89 90 tion was performed in 50% DMSO in water, in a 384-well 91 plate. A solution containing the relevant compound at 100 92 fold the concentration of the starting final serial dilution 93 concentration was prepared in 50% DMSO in water and US 2010/03051 17 A1 Dec. 2, 2010 37

0353. 4-morpholino-6-(2-benzyloxyphenyl)pteridin-2- TABLE 7-continued ylamine, 0354) 4-morpholino-6-(3-benzyloxy-4-methoxyphe ECso CCso nyl)pteridin-2-ylamine. (A < 0.3 uM: (A < 10 M: 0.3 M < B < 1 M: B 10-20 IM; 0355 4-morpholino-6-(4-biphenyl)pteridin-2- Example 1 M < C < 10 M) C > 20 M) ylamine, 0356 4-morpholino-6-(4-n-butyl phenyl)pteridin-2- 95 108 ylamine, 109 0357 4-morpholino-6-(4-isobutylphenyl)pteridin-2- 110 ylamine, 111 0358) 4-morpholino-6-(4-carboxy-3-fluorophenyl)pte 112 113 ridin-2-ylamine, 114 0359 4-morpholino-6-(3-(3-carboxypropionylamino) 120 phenyl)pteridin-2-ylamine, 121 0360 4-morpholino-6-(4-(3-carboxypropionylamino) 123 126 phenyl)pteridin-2-ylamine, 127 0361 4-morpholino-6-(3-chloro-4-hydroxy-5-meth 129 oxyphenyl)pteridin-2-ylamine, 130 0362 4-morpholino-6-(2-chloro-5-hydroxymeth 133 136 ylphenyl)pteridin-2-ylamine, 137 0363 4-morpholino-6-(4-cyanomethoxyphenyl)pteri 138 din-2-ylamine, 140 0364) 4-morpholino-6-(3-cyanomethoxyphenyl)pteri 142 143 din-2-ylamine. 144 0365 4-morpholino-6-(2-cyanomethoxyphenyl)pteri 145 din-2-ylamine, 149 0366) 4-morpholino-6-(4-cyanophenyl)pteridin-2- 150 152 ylamine, 154 0367 4-morpholino-6-(3-cyanophenyl)pteridin-2- 157 ylamine, 159 0368 4-morpholino-6-(2-cyanophenyl)pteridin-2- 164 ylamine, (end of table 7) 0369) 4-morpholino-6-(3-(N-cyclopropylaminocarbo nyl)phenyl)pteridin-2-ylamine, 0370 4-morpholino-6-(3-(N,N-diethylaminocarbonyl) Examples 200 to 395 phenyl)pteridin-2-ylamine. 0371 4-morpholino-6-(3-(N,N-dimethylamino)phe Synthesis of 2-amino-4-morpholino-6-(2-fluorophe nyl)pteridin-2-ylamine, nyl)pteridine Analogues 0372 4-morpholino-6-(2-(N,N-dimethylamino)phe (0342. The experimental procedure of example 77 is nyl)pteridin-2-ylamine, repeated, except that other arylboronic acids or heteroarylbo 0373) 4-morpholino-6-(3-(N,N-dimethylaminocarbo ronic acids, or esters thereof, are used instead of 2-fluorophe nyl)phenyl)pteridin-2-ylamine, nylboronic acid. In this way the following compounds are 0374 4-morpholino-6-(3-(N',N'-dimethylamino)ethy obtained in similar yields: laminocarbonylphenyl)-pteridin-2-ylamine, (0343 4-morpholino-6-(4-(4-allyloxycarbonylpiper 0375) 4-morpholino-6-(4-(N',N'-dimethylamino)ethy azino)phenyl)pteridin-2-ylamine, laminocarbonylphenyl)-pteridin-2-ylamine, (0344) 4-morpholino-6-(3-aminocarbonylphenyl)pteri 0376) 4-morpholino-6-(341.3dioxolan-2-ylmethox din-2-ylamine, yphenyl)pteridin-2-ylamine, (0345 4-morpholino-6-(4-aminocarbonylphenyl)pteri 0377 4-morpholino-6-(3-(ethoxycarbonyl)methox din-2-ylamine, yphenyl)pteridin-2-ylamine, (0346) 4-morpholino-6-(2-amino-5-chlorophenyl)pteri 0378 4-morpholino-6-(4-(ethoxycarbonyl)methox din-2-ylamine, yphenyl)pteridin-2-ylamine, (0347 4-morpholino-6-(4-amino-3-methoxyphenyl) 0379 4-morpholino-6-(4-ethoxycarbonylphenyl)pteri pteridin-2-ylamine, din-2-ylamine, (0348 4-morpholino-6-(2-amino-4-methylphenyl)pte 0380 4-morpholino-6-(3-ethoxycarbonylphenyl)pteri ridin-2-ylamine, din-2-ylamine, (0349 4-morpholino-6-(2-amino-5-methylphenyl)pte 0381 4-morpholino-6-(2-ethoxycarbonylphenyl)pteri ridin-2-ylamine, din-2-ylamine, 0350 4-morpholino-6-(4-amino-2-methyl phenyl)pte (0382 4-morpholino-6-(4-(3-ethoxycarbonylpiperi ridin-2-ylamine, dino)carboxamidophenyl)-pteridin-2-ylamine, 0351 4-morpholino-6-(5-amino-2-methyl phenyl)pte (0383 4-morpholino-6-(4-formylaminophenyl)pteri ridin-2-ylamine, din-2-ylamine, 0352) 4-morpholino-6-(4-amino-3-nitrophenyl)pteri 0384 4-morpholino-6-(3-formylaminophenyl)pteri din-2-ylamine, din-2-ylamine,

US 2010/03051 17 A1 Dec. 2, 2010 45

4-Cyclobutylmethoxy-6-(4-fluoro-phenyl)-pteridin-2- 40. A method of treatment or prevention of a viral infection ylamine, according to claim 34, wherein said at least one pteridine 6-(4-Fluoro-phenyl)-4-propoxy-pteridin-2-ylamine, derivative is administered together with one or more other 4-sec-Butoxy-6-(4-fluoro-phenyl)-pteridin-2-ylamine, antiviral drugs. 6-(4-Fluoro-phenyl)-4-(tetrahydro-furan-3-yloxy)-pteri din-2-ylamine, 41. A method of treatment or prevention of a viral infection 6-(4-Fluoro-phenyl)-4-isobutoxy-pteridin-2-ylamine, according to claim 40, wherein said other is 4-Benzyloxy-6-(4-fluoro-phenyl)-pteridin-2-ylamine, selected from the group consisting of interferon alpha, rib 4-Ethylsulfanyl-6-(4-fluoro-phenyl)-pteridin-2-ylamine, avirin, NS3 protease inhibitors, and nucleoside- or non 4-Amino-6-(4-fluoro-phenyl)-pteridine-2,4-diamine, nucleoside-based inhibitors of NS5B polymerase. 6-(4-Fluoro-phenyl)-4-piperidin-1-yl-pteridin-2-ylamine, 42. A pteridine derivative represented by the structural N-4-Cyclopropyl-6-(4-fluoro-phenyl)-pteridine-2,4-di formula: amine, 4-(2,6-Dimethyl-morpholin-4-yl)-6-(4-fluoro-phenyl)- pteridin-2-ylamine, R Nx N-4-Cyclohexyl-6-(4-fluoro-phenyl)-pteridine-2,4-di N R amine, N1 N N 3 N-4-Benzyl-6-(4-fluoro-phenyl)-pteridine-2,4-diamine, N-4-(3-Methyl-benzyl)-6-(4-fluoro-phenyl)-pteridine-2, l 2n 2 4-diamine, R3 N N R4 N-4-(3-Fluoro-benzyl)-6-(4-fluoro-phenyl)-pteridine-2,4- diamine, wherein X represents an oxygen atom or a group with the 6-(4-Fluoro-phenyl)-4-(4-methyl-piperazin-1-yl)-pteri formula S(O), wherein m is an integer from 0 to 2, or a group din-2-ylamine, with the formula NZ and wherein: 6-(4-Fluoro-phenyl)-4-piperazin-1-yl-pteridin-2-ylamine, R is a group selected from the group consisting of C, N-4-Cyclopropylmethyl-6-(4-fluoro-phenyl)-pteridine-2, alkyl, C2-7 alkenyl, C2-7 alkynyl, Cso cycloalkyl, Cao 4-diamine, cycloalkenyl, aryl, alkylaryl, arylalkyl, hetero-cyclyl, 6-(4-Fluoro-phenyl)-4-pyrrolidin-1-yl-pteridin-2- heterocyclic-substituted alkyl and alkyl-substituted het ylamine, erocyclyl, each of said groups being optionally Substi 4-Ethoxy-6-(4-fluoro-phenyl)-pteridine, tuted with one or more substituents inde-pendently 4-isopropoxy-6-(4-fluoro-phenyl)-pteridine, Selected from the group consisting of halogen, Ca 4-(2-methoxy-ethoxy)-6-(4-fluoro-phenyl)-pteridine, alkyl, Calkoxy, C-7 alkenyl, C-7 alkynyl, halo C. 6-(4-Fluoro-phenyl)-pteridin-4-yl)-(4-methyl-cyclo alkyl, Co cycloalkoxy, aryloxy, arylalkyloxy, oxyhet hexyl)-amine, erocyclic, heterocyclic-substituted alkyloxy, thio C, 6-(4-Fluoro-phenyl)-pteridin-4-yl)-(4-methyl-cyclo alkyl, thio Co cycloalkyl, thioaryl, thioheterocyclic, hexyl)-amine, arylalkylthio, heterocyclic-substi-tuted alkylthio. 6-(4-Fluoro-phenyl)-4-morpholin-4-yl-pteridine, and formyl, hydroxyl, Sulfhydryl, nitro, hydroxylamino, 4-Ethylsulfanyl-6-(4-fluoro-phenyl)-pteridine mercapto-amino, cyano, carboxylic acid or esters or and/or a pharmaceutically acceptable addition salt thereof thioesters or amides or thioamides or halides or anhy and/or astereo-isomerthereofand/or a mono- or a di-N-oxide drides thereof, thiocarboxylic acidoresters or thioesters thereof and/or a solvate thereof and/or a pro-drug form or amides or thioamides or halides or anhydrides thereof. thereof, carbamoyl, thiocarba-moyl, ureido, thio-ureido, 32. A pharmaceutical composition comprising as an active amino, alkylamino, cycloalkylamino, alkenylamino, principle at least one pteridine derivative according to claim cycloalkenylamino, alkynylamino, arylamino, arylalky 31 and one or more pharmaceutically acceptable excipients. lamino, hydroxyalkyl-amino, mercaptoalkylamino, het 33. A pharmaceutical composition according to claim 32, erocyclic amino, hydrazino, alkylhydrazino and phenyl and further comprising one or more other antiviral drugs. hydrazino, or R is a carboxyalkyl, carboxyaryl, 34. A method of treatment or prevention of an infection due thiocarboxyaryl or thiocarboxyalkyl group; to a virus, by administering to a patient in need thereof a Z is a group independently defined as R or Z is hydrogen therapeutically effective amount of a pteridine derivative or the group NZ together with R is either hydroxy according to claim 31. lamino or an optionally Substituted heterocyclic group 35. A method according to claim 34, wherein said virus containing at least one nitrogen atom; belongs to the Flaviridae family. R is selected from the group consisting of amino; alkanoy 36. A method according to claim 34, wherein said virus lamino; thioalkanoylamino; carbamoyl; thiocarbamoyl; belongs to a genus selected from the group consisting of ureido; thioureido, Sulfonamido; hydroxylamino; Genus Flavivirus, Genus Hepacivirus and Genus Pestivirus. alkoxyamino; thioalkylamino; mercaptoamino; 37. A method according to claim 34, wherein said virus is hydrazino; alkylhydrazino; phenylhydrazino; option hepatitis C virus. ally Substituted heterocyclyl: C, alkylamino: ary 38. A method according to claim 34, wherein said admin lamino: arylalkylamino; cycloalkylamino; alkeny istration is oral administration. lamino; cyclo-alkenylamino; heterocyclyl-amino; 39. A method according to claim 34, wherein said thera hydroxyalkylamino; mercaptoalkylamino: C, alkoxy; peutically effective amount is from 0.01 mg to 20 mg per day Co cycloalkoxy; thio C, alkyl, arylsulfoxide: aryl per kg bodyweight of said patient. sulfone; hetero-cyclic sulfoxide; heterocyclic sulfone: US 2010/03051 17 A1 Dec. 2, 2010 46

thio Co cycloalkyl, aryloxy: arylthio: arylalkyloxy; 4-morpholino-6-(4-carboxy-3-fluorophenyl)pteridin-2- arylalkylthio; oxyheterocyclic and thioheterocyclic ylamine, radicals; 4-morpholino-6-(3-(3-carboxypropionylamino)phenyl) R is hydrogen; and pteridin-2-ylamine, R is aryl substituted with one or more substituents inde 4-morpholino-6-(4-(3-carboxypropionylamino)phenyl) pendently selected from the group consisting of aryl pteridin-2-ylamine, wherein said aryl is optionally substituted with arylcar 4-morpholino-6-(3-chloro-4-hydroxy-5-methoxyphenyl) bonyl: (O,O-dialkylphosphonyl)-alkyl; alkanoyl; halo pteridin-2-ylamine, C, alkoxy; hydroxy-C, alkoxy; hydroxy-C, alkyl: 4-morpholino-6-(2-chloro-5-hydroxymethylphenyl)pteri di-C, alkylamino C, alkyl, co-carboxyalkanoy din-2-ylamine, lamino: mono-(C,cycloalkyl)aminocarbonyl, di-(C, 4-morpholino-6-(4-cyanomethoxyphenyl)pteridin-2- cycloalkyl)aminocarbonyl, mono-(C, alkyl)aminocar ylamine, bonyl, mono-(c)-dimethylamino-C, alkyl)aminocar 4-morpholino-6-(3-cyanomethoxyphenyl)pteridin-2- bonyl, di-(C., alkyl)aminocarbonyl, mono-(hydroxy ylamine, C, alkyl)aminocarbonyl, formylamino, SONH2, 4-morpholino-6-(2-cyanomethoxyphenyl)pteridin-2- arylamino-C, alkyl, C, alkylsulfonyl, heterocyclyl ylamine, carbonyl, heterocyclyl-C-7 alkyl and hetero-cyclyl, 4-morpholino-6-(4-cyanophenyl)pteridin-2-ylamine, wherein said heterocyclyl is optionally substituted with 4-morpholino-6-(3-cyanophenyl)pteridin-2-ylamine, C., alkenyloxy-carbonyl, C, alkyl or C, alkyloxy 4-morpholino-6-(2-cyanophenyl)pteridin-2-ylamine, carbonyl; or R is a fused benzo-Css cyclo-alkyl option 4-morpholino-6-(3-(N-cyclopropylaminocarbonyl)phe ally substituted with oxo; or R is heterocyclyl substi nyl)pteridin-2-ylamine, tuted with one or more substituents independently 4-morpholino-6-(3-(N,N-diethylaminocarbonyl)phenyl) selected from the group consisting of acylamino, C, pteridin-2-ylamine, alkylsulfonyl, arylsulfonyl, heterocyclyl-C-7 alkyl, het 4-morpholino-6-(3-(N,N-dimethylamino)phenyl)pteri erocyclyl-C, alkylamino, aryl and heterocyclyl, din-2-ylamine, wherein said heterocyclyl is optionally substituted with 4-morpholino-6-(2-(N,N-dimethylamino)phenyl)pteri C, alkyl, arylsulfonyl or (di-C, alkylamino)-C-7 din-2-ylamine, alkoxy, or said heterocyclyl is non-aromatic and 4-morpholino-6-(3-(N,N-dimethylaminocarbonyl)phe includes a nitrogen atom substituted with heterocyclyl nyl)pteridin-2-ylamine, C, alkyl or a carboxylic acid or a C-, alkyl ester 4-morpholino-6-(3-(N',N'-dimethylamino)ethylami thereof, nocarbonylphenyl)-pteridin-2-ylamine, and/or a pharmaceutically acceptable addition salt thereof 4-morpholino-6-(4-(N',N'-dimethylamino)ethylami and/or astereo-isomerthereofand/or a mono- or a di-N-oxide nocarbonylphenyl)-pteridin-2-ylamine, thereof and/or a solvate thereof and/or a pro-drug form 4-morpholino-6-(3-1,3dioxolan-2-ylmethoxyphenyl) thereof. pteridin-2-ylamine, 43. A pteridine derivative selected from the group consist 4-morpholino-6-(3-(ethoxycarbonyl)methoxyphenyl)pte ing of ridin-2-ylamine, 4-morpholino-6-(4-(4-allyloxycarbonylpiperazino)phe 4-morpholino-6-(4-(ethoxycarbonyl)methoxyphenyl)pte nyl)pteridin-2-ylamine, ridin-2-ylamine, 4-morpholino-6-(3-aminocarbonylphenyl)pteridin-2- 4-morpholino-6-(4-ethoxycarbonylphenyl)pteridin-2- ylamine, ylamine, 4-morpholino-6-(4-aminocarbonylphenyl)pteridin-2- 4-morpholino-6-(3-ethoxycarbonylphenyl)pteridin-2- ylamine, ylamine, 4-morpholino-6-(2-ethoxycarbonylphenyl)pteridin-2- 4-morpholino-6-(2-amino-5-chlorophenyl)pteridin-2- ylamine, ylamine, 4-morpholino-6-(4-(3-ethoxycarbonylpiperidino)car 4-morpholino-6-(4-amino-3-methoxyphenyl)pteridin-2- boxamidophenyl)-pteridin-2-ylamine, ylamine, 4-morpholino-6-(4-formylaminophenyl)pteridin-2- 4-morpholino-6-(2-amino-4-methylphenyl)pteridin-2- ylamine, ylamine, 4-morpholino-6-(3-formylaminophenyl)pteridin-2- 4-morpholino-6-(2-amino-5-methylphenyl)pteridin-2- ylamine, ylamine, 4-morpholino-6-(2-formylaminophenyl)pteridin-2- 4-morpholino-6-(4-amino-2-methyl phenyl)pteridin-2- ylamine, ylamine, 4-morpholino-6-(2-formyl-5-methoxyphenyl)pteridin-2- 4-morpholino-6-(5-amino-2-methyl phenyl)pteridin-2- ylamine, ylamine, 4-morpholino-6-(3-formyl-4-methoxyphenyl)pteridin-2- 4-morpholino-6-(4-amino-3-nitrophenyl)pteridin-2- ylamine, ylamine, 4-morpholino-6-(5-formyl-2-methoxyphenyl)pteridin-2- 4-morpholino-6-(2-benzyloxyphenyl)pteridin-2-ylamine, ylamine, 4-morpholino-6-(3-benzyloxy-4-methoxyphenyl)pteri 4-morpholino-6-(2-formyl-5-methyl phenyl)pteridin-2- din-2-ylamine, ylamine, 4-morpholino-6-(4-biphenyl)pteridin-2-ylamine, 4-morpholino-6-(4-formylphenyl)pteridin-2-ylamine, 4-morpholino-6-(4-n-butyl phenyl)pteridin-2-ylamine, 4-morpholino-6-(3-formylphenyl)pteridin-2-ylamine, 4-morpholino-6-(4-isobutylphenyl)pteridin-2-ylamine, 4-morpholino-6-(2-formylphenyl)pteridin-2-ylamine,

US 2010/03051 17 A1 Dec. 2, 2010 51

4-ethoxy-6-(1-methylindol-5-yl)pteridin-2-ylamine, 4-ethoxy-6-(1-(tert-butoxycarbonyl)-1H-indol-5-yl)pteri 4-ethoxy-6-(5-methyl-3-phenyl-4-isoxazolyl)pteridin-2- din-2-ylamine, ylamine, 4-ethoxy-6-(1-(tert-butoxycarbonyl)-5-methoxy-1H-in 4-ethoxy-6-(5-(methylthio)thien-2-yl)pteridin-2-ylamine, dol-2-yl)pteridin-2-ylamine, 4-ethoxy-6-(2-(4-methylpiperazinyl)pyridin-4-yl)pteri 4-ethoxy-6-(1-thianthrenylthien-3-yl)pteridin-2-ylamine, din-2-ylamine, and 4-ethoxy-6-(2-(4-methylpiperazinyl)pyridin-5-yl)pteri 4-ethoxy-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)pteridin-2- din-2-ylamine, ylamine. 4-ethoxy-6-(1-methyl-1H-pyrazol-4-yl)pteridin-2- 44. A pharmaceutical composition comprising as an active ylamine, principle at least one pteridine derivative according to claim 4-ethoxy-6-(3-methylpyridin-2-yl)pteridin-2-ylamine, 42 and one or more pharmaceutically acceptable excipients. 4-ethoxy-6-(5-methylpyridin-2-yl)pteridin-2-ylamine, 45. A pharmaceutical composition according to claim 44. 4-ethoxy-6-(5-methylpyridin-3-yl)pteridin-2-ylamine, and further comprising one or more other antiviral drugs. 4-ethoxy-6-(2-methoxypyridin-5-yl)pteridin-2-ylamine, 46. A method of treatment or prevention of an infection due 4-ethoxy-6-(4-methylthien-2-yl)pteridin-2-ylamine, to a virus, by administering to a patient in need thereof a 4-ethoxy-6-(5-methylthien-2-yl)pteridin-2-ylamine, therapeutically effective amount of a pteridine derivative 4-ethoxy-6-(2-(2-morpholinoethylamino)-pyridin-5-yl) according to claim 42. pteridin-2-ylamine, 47. A method of treatment or prevention of a viral infection 4-ethoxy-6-(2-(2-morpholinoethyl)-1H-pyrazol-4-yl)pte according to claim 46, wherein said virus belongs to the ridin-2-ylamine, Flaviridae family. 4-ethoxy-6-(2-(morpholin-1-yl)-pyridin-5-yl)pteridin-2- 48. A method of treatment or prevention of a viral infection ylamine, according to claim 46, wherein said virus belongs to a genus 4-ethoxy-6-(1-(phenylsulfonyl)-1H-indol-3-yl)pteridin selected from the group consisting of Genus Flavivirus, 2-ylamine, Genus Hepacivirus and Genus Pestivirus. 4-ethoxy-6-(5-phenyl-2-thienyl)pteridin-2-ylamine, 49. A method of treatment or prevention of a viral infection 4-ethoxy-6-(2-(piperazin-1-yl)-pyridin-5-yl)pteridin-2- according to claim 46, wherein said virus is hepatitis C virus. ylamine, 50. A method of treatment or prevention of a viral infection 4-ethoxy-6-(2-(piperazin-1-yl)-pyridin-4-yl)pteridin-2- according to claim 46, wherein said administration is oral ylamine, administration. 4-ethoxy-6-(1-propyl-1H-pyrazol-4-yl)pteridin-2- 51. A method of treatment or prevention of a viral infection ylamine, according to claim 46, wherein said therapeutically effective 4-ethoxy-6-(pyrazol-4-yl)pteridin-2-ylamine, amount is from 0.01 mg to 20 mg per day per kg bodyweight 4-ethoxy-6-(pyridin-4-yl)pteridin-2-ylamine, of said patient. 4-ethoxy-6-(4-phenoxathiinyl)pteridin-2-ylamine, 52. A method of treatment or prevention of a viral infection 4-ethoxy-6-(quinolin-8-yl)pteridin-2-ylamine, according to claim 46, wherein said at least one pteridine 4-ethoxy-6-(quinolin-3-yl)pteridin-2-ylamine, derivative is administered together with one or more other 4-ethoxy-6-(2-(4-tert-butoxycarbonylpiperazinyl)-pyrid antiviral drugs. 4-yl)pteridin-2-ylamine, 53. A method of treatment or prevention of a viral infection 4-ethoxy-6-(1-tert-butoxycarbonyl-1H-pyrazol-4-yl)pte according to claim 52, wherein said other antiviral drug is ridin-2-ylamine, selected from the group consisting of interferon alpha, rib 4-ethoxy-6-(1-tert-butoxycarbonyl-2-pyrrolyl)pteridin-2- avirin, NS3 protease inhibitors, and nucleoside- or non ylamine, nucleoside-based inhibitors of NS5B polymerase. 4-ethoxy-6-(1-(tert-butoxycarbonyl)-5-bromo-1H-indol 2-yl)pteridin-2-ylamine, c c c c c