WO2011075747A1 - Therapeutic compounds - Google Patents

Therapeutic compounds Download PDF

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Publication number
WO2011075747A1
WO2011075747A1 PCT/US2010/061396 US2010061396W WO2011075747A1 WO 2011075747 A1 WO2011075747 A1 WO 2011075747A1 US 2010061396 W US2010061396 W US 2010061396W WO 2011075747 A1 WO2011075747 A1 WO 2011075747A1
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Prior art keywords
nmr
prepared
pyrimidin
title compound
similar manner
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PCT/US2010/061396
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French (fr)
Inventor
Brian A. Johns
Emile Johann Velthuisen
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Glaxosmithkline Llc
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Publication of WO2011075747A1 publication Critical patent/WO2011075747A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Definitions

  • the present invention relates to 1 -hydroxypyrido[2,3-d]pyrimidin-2(1 H)-one compounds of formula (I) that inhibit reverse transcriptase, particularly compounds of formula (I) that inhibit HIV reverse transcriptase, and still more particularly compounds of formula (I) that inhibit the RNase H domain of a human H IV reverse transcriptase.
  • HIV human immunodeficiency virus
  • AI DS acquired immunodeficiency syndrome
  • ARC AIDS-related complex
  • HIV is a retrovirus; the conversion of its RNA to DNA is accomplished through the action of the enzyme reverse transcriptase.
  • Compounds that inhibit the function of reverse transcriptase inhibit replication of HIV in infected cells. Such compounds are useful in the prevention or treatment of HIV infection in humans.
  • HIV reverse transcriptase contains two distinct active sites known as the polymerization and ribonuclease H motifs.
  • the reverse transcriptase protein consists of a p51 and p66 subunit which form a heterodimer.
  • the p51 subunit is formed through proteolytic cleavage of the p66 subunit.
  • the subunits have a common amino terminus with the longer p66 subunit consisting of additional residues that form the a ribonuclease H (RNase H) domain.
  • RNase H is a well known enzymatic motif that cleaves the RNA strand of DNA/RNA hybrid nucleic acid.
  • the action of H IV ribonuclease H is essential for viral replication and therefor the compounds of this invention are useful as antiviral agents.
  • the productive reverse transcription sequence involves several steps catalyzed by reverse transcriptase. Among those steps are RNA dependent DNA polymerization, ribonuclease cleavage of the template RNA and DNA dependent DNA polymerization. The process is a well characterized sequence beginning with a t-RNA primer binding to the HIV single stranded RNA (ss RNA). This begins a minus strand synthesis of DNA using the HIV RNA as template. This initial step is terminated resulting in strong stop (-) strand DNA.
  • ss RNA HIV single stranded RNA
  • the action of the HIV ribonuclease H active site is able to make cleavages in the RNA strand once the DNA synthesis has passed. This cleavage of the RNA template is essential for further production of viral DNA.
  • the first strand transfer event allows a repositioning of the strong stop DNA to the 3' end of the viral RNA. This can happen on the same strand or a different strand of viral RNA that is present. Further (-) strand DNA synthesis is then able to proceed.
  • the viral ribonuclease H makes several cuts in the RNA strand once the DNA is made.
  • H IV reverse transcriptase is an attractive target for the discovery of new therapeutics due to its important role in viral infections, particularly H IV infections.
  • Embodiments of the present invention features compounds that are H IV reverse transcriptase inhibitors and therefore are useful in the inhibition of H IV replication, the prevention and/or treatment of infection by HIV, and in the treatment of AIDS and/or ARC.
  • the present invention features compounds of formula (I): Detailed Description of Specific Embodiments
  • the present invention includes the compounds of formula (I), useful in treating or preventing viral infections, particularly retroviral infections, including human inmmunodeficiency virus (e.g. HIV-1 and HIV-2) infections, xenotropic murine leukemia virus (XMRV) infections and XMRV-related virus infections, human T-cell
  • human inmmunodeficiency virus e.g. HIV-1 and HIV-2
  • XMRV xenotropic murine leukemia virus
  • XMRV-related virus infections human T-cell
  • HTLV1 leukemia/lymphoma virus
  • HTLV2 human endogenous retrovirus
  • HERV human endogenous retrovirus
  • MS-associated retrovirus MS-associated retrovirus
  • H ERV H ERV associated with the HELLP syndrome and pre-eclampsia
  • HERV liked to schizophrenia and the HERV- K (HML2) family of retroviruses
  • pharmaceutical compositions comprising compounds of formula (I), and processes for preparing the compounds.
  • R 1 is hydrogen, halogen, -N R 2 R 3 , nitrogen-containing heterocycle connected via the nitrogen, HetZ, -OR 2 , -SR 2 ;
  • R 2 and R 3 are independently selected from the group consisting of
  • R 2 and R 3 may be taken together along with the nitrogen atom to form a 4-10 membered heterocyclic ring;
  • R 4 is selected from -(R 18 ) K -, ArylA, heteroarylA, heterocycle;
  • R 5 is independently selected from hydrogen, halogen, -(R 19 ) K -, arylB, heteroarylB, heterocycle, R z , two independent R 5 groups may be taken together to form a 4- 10 membered ring;
  • R z is selected from halogen, -(R 21 ) K (R Z )-, C -8 alkyl, d-C 8 haloalkyl, C 3- iocycloalkyl, -heterocycle, -R 6 , -CN, -NR 6 R 7 , -OR 6 , -C(0)OR 6 , -C(0)R 6 , -C(0)NR 6 R 7 , - C(0)HetY, -NR 6 C(0)R 7 , -NR 6 C(0)OR 7 , -NR 6 C(0)N R 7 R 8 , -NR 6 C(0)HetY, -OC(0)R 7 , - OC(0)OR 7 , -OC(0)NR 7 R 8 , -OC(0)HetY, -C(S)OR 6 , -C(S)R 6 , -C(S)NR 6 R 7 , -C(S)HetY, - NR 6 C(S)R 7 ,
  • R z' is selected from hydrogen, halogen, -(R 21 ) K (R Z" )-, C 1-8 alkyl, C C 8 haloalkyl, C 3- iocycloalkyl, -heterocycle, -R 6 , -CN, -N R 6 R 7 , -OR 6 , -C(0)OR 6 , -C(0)R 6 , -C(0)NR 6 R 7 , - C(0)HetY, -NR 6 C(0)R 7 , -NR 6 C(0)OR 7 , -NR 6 C(0)N R 7 R 8 , -NR 6 C(0)HetY, -OC(0)R 7 , - OC(0)OR 7 , -OC(0)NR 7 R 8 , -OC(0)HetY, -C(S)OR 6 , -C(S)R 6 , -C(S)NR 6 R 7 , -C(S)HetY, - NR 6 C(S)OR 6
  • R z is selected from hydrogen, halogen, C 1-8 alkyl, d-C 8 haloalkyl, C 3- iocycloalkyl, -heterocycle, -R 6 , -CN, -NR 6 R 7 , -OR 6 , -C(0)OR 6 , -C(0)R 6 , -C(0)NR 6 R 7 , - C(0)HetY, -NR 6 C(0)R 7 , -NR 6 C(0)OR 7 , -NR 6 C(0)N R 7 R 8 , -NR 6 C(0)HetY, -OC(0)R 7 , - OC(0)OR 7 , -OC(0)NR 7 R 8 , -OC(0)HetY, -C(S)OR 6 , -C(S)R 6 , -C(S)NR 6 R 7 , -C(S)HetY, - NR 6 C(S)R 7 , -NR 6 C(S)OR 7 , -
  • R 6 , R 7 and R 8 are independently selected from hydrogen, -(R 22 ) K (R Z )-, Ci_ 8 alkyl, C 3- i 0 cycloalkyl, arylB, heteroarylB, heterocycle, wherein any two of the R 6 , R 7 and R 8 may be taken together to form a 4-10 membered heterocyclic or heteroaryl ring;
  • HetY is a 4-8 membered heterocyclic ring containing one or more optionally substituted heteroatoms
  • alkyl, cycloalkyi, heterocycle, arylA, heteroarylA may be optionally substituted with 1 -4 substituents independently selected from the group consisting of hydrogen, halogen, -CF 3 , CrC 8 haloalkyl, -(R 9 ) p (R 10 ) q , , heterocycle optionally substituted with oxo, R z and arylB, wherein two independent substituents may be taken together to form a 4-10 membered ring;
  • heteroarylB may be optionally substituted with 1 -4 substituents independently selected from the group consisting of hydrogen, halogen, -CF 3 , Ci- C 8 haloalkyl, -(R 9 ) p (R 11 ) q , R z ; heterocycle, wherein two independent substituents may be taken together to form a 4-10 membered ring;
  • arylB may be optionally substituted with 1 -4 substituents independently selected from the group consisting of hydrogen, halogen, -CF 3 , Ci- C 8 haloalkyl, -(R 9 ) p (R 10 ) q , , heterocycle optionally substituted with oxo, R z and arylC, wherein two independent substituents may be taken together to form a 4-10 membered ring;
  • R 9 is selected from -(R 20 ) K -;
  • R-io is H, halogen, d -8 haloalkyl, heterocycle, arylB, heteroarylB, -R z ;
  • Rii is H, halogen, Ci -8 haloalkyl, heterocycle, arylC, heteroarylC, -R z ;
  • ArylC, heteroarylC may be optionally substituted with 1 -4 substituents independently selected from the group consisting of hydrogen, halogen, -Ci-C 8 haloalkyl, heterocycle, -R z ; wherein two independent substituents may be taken together to form a 4- 10 membered ring;
  • HetZ is selected from
  • T, U, V, X, Y, Z are chosen from O, -N(R 12 )-, S(0) n , and
  • R 18 is independently selected from -(C(R 14 )(R 15 ))j-, C 3 -i 0 cycloalkyl, C 3- ecycloalkenyl, C 3-8 alkynyl, heterocycle;
  • R 19 is independently selected from -(C(R 16 )(R 17 ))j-, C 3-10 cycloalkyl, C 3- ecycloalkenyl, C 3-8 alkynyl, heterocycle;
  • R 20 is independently selected from -(C(R 12 )(R 13 ))j-, C 3- i 0 cycloalkyl, C 3- ecycloalkenyl, C 3-8 alkynyl, heterocycle;
  • R 21 is independently selected from -(C(R 12 )(R 13 ))j-, C 3- i 0 cycloalkyl, C 3- ecycloalkenyl, C 3-8 alkynyl, heterocycle;
  • R 22 is independently selected from -(C(R 12 )(R 13 ))j-, C 3- i 0 cycloalkyl, C 3- scycloalkenyl, C 3-8 alkynyl, heterocycle;
  • n is O, 1 , or 2;
  • P is 0, 1 , 2 or 3;
  • Q is 0, 1 , 2 or 3;
  • J is 1 -8;
  • K is 1-8;
  • alkyl refers to a straight-chain or branched-chain saturated aliphatic hydrocarbon radical containing the specified number of carbon atoms.
  • alkyl radicals include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isoamyl, n-hexyl and the like.
  • cycloalkyl refers to a saturated or partially saturated carbocyclic ring composed of 3-10 carbons in any chemically stable configuration.
  • suitable carbocyclic groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and
  • alkenyl refers to a straight-chain or branched-chain alkyl group with at least one carbon-carbon double bond.
  • alkenyl radicals include, but are not limited to, ethenyl, propenyl, isopropenyl, butenyl, isobutenyl, pentenyl, hexenyl, hexadienyl and the like.
  • alkynyl refers to hydrocarbon groups of either a straight or branched configuration with one or more carbon-carbon triple bonds which may occur in any stable point along the chain, such as ethynyl, propynyl, butynyl, pentynyl, and the like.
  • alkoxy refers to an alkyl ether radical, wherein the term “alkyl” is defined above.
  • suitable alkyl ether radicals include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy and the like.
  • aryl alone or in combination with any other term, refers to a carbocyclic aromatic moiety (such as phenyl or naphthyl) containing the specified number of carbon atoms, preferably from 6-14 carbon atoms, and more preferably from 6-10 carbon atoms.
  • aryl radicals include, but are not limited to, phenyl, naphthyl, indenyl, azulenyl, fluorenyl, anthracenyl, phenanthrenyl, tetrahydronaphthyl, indanyl, phenanthridinyl and the like.
  • aryl also includes each possible positional isomer of an aromatic hydrocarbon radical, such as in 1 -naphthyl, 2-naphthyl, 5- tetrahydronaphthyl, 6-tetrahydronaphthyl, 1 -phenanthridinyl, 2-phenanthridinyl, 3- phenanthridinyl, 4-phenanthridinyl, 7-phenanthridinyl, 8-phenanthridinyl, 9-phenanthridinyl and 10-phenanthridinyl.
  • aryl radicals include, but are not limited to, phenyl, naphthyl, indenyl, azulenyl, fluorenyl, anthracenyl, phenanthrenyl, tetrahydronaphthyl, indanyl, phenanthridinyl and the like.
  • heterocycle refers to a 3- to 8- membered monocyclic heterocyclic ring or 8- to 1 1 - membered bicyclic heterocyclic ring system any ring of which is either saturated, partially saturated or unsaturated, and which may be optionally benzofused if monocyclic.
  • Each heterocycle consists of one or more carbon atoms and from one to four heteroatoms selected from the group consisting of N, O and S, and wherein the nitrogen and sulfur heteroatoms may optionally be oxidized, and the nitrogen atom may optionally be quaternized, and including any bicyclic group in which any of the above-defined heterocyclic rings is fused to a benzene ring.
  • the heterocyclic ring may be attached at any carbon or heteroatom, provided that the attachment results in the creation of a stable structure.
  • Preferred heterocycles include 5-7 membered monocyclic heterocycles and 8-10 membered bicyclic heterocycles.
  • reactive electrophile or “reactive electrophiles” means alkylating or acylating reagent. These compounds include alkyl halides, alkyl tosylates, alkyi mesylates and alkyi triflates. Additionally they include acid chlorides and the like. Compounds such as acetyl chloride, methyl iodide, allyl iodide, butyl iodide, methyl triflate, benzyl bromide are examples.
  • heterocyclic ring has substituents, it is understood that the substituents may be attached to any atom in the ring, whether a heteroatom or a carbon atom, provided that a stable chemical structure results.
  • Heteroaromatics or “heteroaryl” are included within the heterocycles as defined above and generally refers to a heterocycle in which the ring system is an aromatic monocyclic or polycyclic ring radical containing five to twenty carbon atoms, preferably five to ten carbon atoms, in which one or more ring carbons, preferably one to four, are each replaced by a heteroatom such as N, O, S and P.
  • heteroaryl groups include 5-6 membered monocyclic heteroaryls and 8 - 10 membered bicyclic heteroaryls. Also included within the scope of the term “heterocycle, "heterocyclic” or “heterocyclyl” is a group in which a non-aromatic heteroatom-containing ring is fused to one or more aromatic rings, such as in an indolinyl, chromanyl,
  • heterocycle, heterocyclic or “heterocyclyl” also included each possible positional isomer of a heterocyclic radical, such as in 1 -indolinyl, 2-indolinyl, 3-indolinyl.
  • heterocycles include imidazolyl, imidazolinoyl, imidazolidinyl, quinolyl, isoquinolyl, indolyl, indazolyl, indazolinolyl, perhydropyridazyl, pyridazyl, pyridyl, pyrrolyl, pyrrolinyl, pyrrolidinyl, pyrazolyl, pyrazinyl, quinoxolyl, piperidinyl, pyranyl, pyrazolinyl, piperazinyl, pyrimidinyl, pyridazinyl, morpholinyl, thiamorpholinyl, furyl, thienyl, triazolyl, thiazolyl, carbolinyl, tetrazolyl, thiazolidinyl, benzofuranoyl, thiamorpholinyl sulfone, oxazolyl, oxadiazol
  • heteroatom means nitrogen, oxygen, or sulfur and includes any oxidized form of nitrogen, such as N(O) ⁇ N + -0 " ⁇ and sulfur such as S(O) and S(0) 2 , and the quaternized form of any basic nitrogen.
  • halogen or "halo" means a substituent selected from fluorine, chlorine, bromine, and iodine, which is understood by those of skill in the art to include substituents written as -F, -CI, -Br and -I , respectively.
  • a combination of substituents or variables is permissible only if such a combination results in a stable or chemically feasible compound.
  • a stable compound or chemically feasible compound is one in which the chemical structure is not substantially altered when kept at a temperature of 40 °C or less, in the absence of moisture or other chemically reactive conditions, for at least a week.
  • structures depicted herein are also meant to include all stereochemical forms of the structure, i.e., the R and S configurations for each asymmetric center. Therefore, racemates and racemic mixtures, single enantiomers, diastereomeric mixtures and individual diastereoisomers of the present compounds are expressly included within the scope of the invention. Although the specific compounds exemplified herein may be depicted in a particular stereochemical configuration, compounds having either the opposite stereochemistry at any given chiral center or mixtures thereof are also envisioned.
  • structures depicted herein are also meant to include compounds which differ only in the presence of one or more isotopically enriched atoms.
  • compounds having the present structures except for the replacement of a hydrogen by a deuterium or tritium, or the replacement of a carbon by a 13 C- or 14 C-enriched carbon are also within the scope of this invention.
  • the term "pharmaceutically effective amount” refers to an amount effective in treating a virus infection, for example an H IV infection, in a patient either as monotherapy or in combination with other agents.
  • treating refers to the alleviation of symptoms of a particular disorder in a patient, or the improvement of an ascertainable measurement associated with a particular disorder, and may include the suppression of symptom recurrence in an asymptomatic patient such as a patient in whom a viral infection has become latent.
  • prophylactically effective amount refers to an amount effective in preventing a virus infection, for example an H IV infection, or preventing the occurrence of symptoms of such an infection, in a patient.
  • the term “pharmaceutically effective amount” refers to an amount effective in treating a virus infection, for example an H IV infection, in a patient either as monotherapy or in combination with other agents.
  • treating refers to the alleviation of symptoms of a particular disorder in a patient, or the improvement of an ascertainable measurement associated with a particular disorder, and may include
  • patient refers to a mammal, including a human.
  • pharmaceutically acceptable carrier or adjuvant refers to a carrier or adjuvant that may be administered to a patient, together with a compound of this invention, and which does not destroy the pharmacological activity thereof and is nontoxic when administered in doses sufficient to deliver a therapeutic amount of the antiviral agent.
  • treatment refers to the alleviation of symptoms of a particular disorder in a patient, or the improvement of an ascertainable measurement associated with a particular disorder, and may include the suppression of symptom recurrence in an asymptomatic patient such as a patient in whom a viral infection has become latent. Treatment may include prophylaxis which refers to preventing a disease or condition or preventing the occurrence of symptoms of such a disease or condition, in a patient.
  • patient refers to a mammal, including a human.
  • the term "subject” refers to a patient, animal or a biological sample.
  • biological sample includes, without limitation, cell cultures or extracts thereof; preparations of an enzyme suitable for in vitro assay; biopsied material obtained from a mammal or extracts thereof; and blood, saliva, urine, feces, semen, tears, or other body fluids or extracts thereof.
  • AIDS refers to acquired immunodeficiency syndrome. AIDS is a disease characterized by destruction of the immune system, particularly of CD4+ T-cells, with attendant susceptibility to opportunistic infections.
  • H lV-related reverse transcriptase means a reverse transcriptase from any variant of a human immunodeficiency virus (HIV), a reverse transcriptase from a human T-cell lymphotropic virus (“HTLV”), or a reverse transcriptase from any related immunodeficiency virus which targets a non-human mammal, such as a reverse transcriptase from a feline immunodeficiency virus (“FIV”), a reverse transcriptase from a feline leukemia virus (“FLV”), a reverse transcriptase from a simian
  • HlV-related reverse transcriptase includes, but is not limited to, a reverse transcriptase from HTLV-1 , HTLV-2, HTLV-3, HTLV-4, HIV-1 (formerly known as HTLV-3), HIV-2, FIV, FIV IV, BLV, MLV (murine leukemia virus), and simian viruses such as SRV1 -D.
  • a "reverse transcriptase inhibitor that is not a reverse transcriptase of formula 1 means any other reverse transcriptase inhibitor, whether synthetic, semi-synthetic, a small molecule, a peptide, a protein, a nucleic acid, an antisense nucleic acid compound, a miRNA compound, an siRNA compound, an antibody, and the like.
  • Pharmaceutically acceptable salts of the compounds according to the invention include those derived from pharmaceutically acceptable inorganic and organic acids and bases.
  • suitable acids include hydrochloric, hydrobromic, sulfuric, nitric, perchloric, fumaric, maleic, phosphoric, glycolic, lactic, salicylic, succinic, toluene-p- sulfonic, tartaric, acetic, citric, methanesulfonic, ethanesulfonic, formic, benzoic, malonic, naphthalene-2-sulfonic and benzenesulfonic acids.
  • Other acids such as oxalic, while not in themselves pharmaceutically acceptable, may be employed in the preparation of salts useful as intermediates in obtaining the compounds of the invention and their
  • Salts derived from appropriate bases include alkali metal (e.g. sodium), alkaline earth metal (e.g., magnesium), ammonium, NW 4 + (wherein W is C 1-4 alkyl) and other amine salts.
  • Physiologically acceptable salts of a hydrogen atom or an amino group include salts or organic carboxylic acids such as acetic, lactic, tartaric, malic, isethionic, lactobionic and succinic acids; organic sulfonic acids such as methanesulfonic, ethanesulfonic, benzenesulfonic and p-toluenesulfonic acids and inorganic acids such as hydrochloric, sulfuric, phosphoric and sulfamic acids.
  • Physiologically acceptable salts of a compound with a hydroxy group include the anion of said compound in combination with a suitable cation such as Na + , NH 4 + , and NW 4 + (wherein W is a C ⁇ alkyl group).
  • Preferred salts include sodium, calcium, potassium, magnesium, choline, meglumine, hydrochloride, and quaternary ammonium.
  • any reference to any of the above compounds also includes a reference to a pharmaceutically acceptable salt thereof.
  • Salts of the compounds of the present invention may be made by methods known to a person skilled in the art. For example, treatment of a compound of the present invention with an appropriate base or acid in an appropriate solvent will yield the
  • Esters of the compounds of the present invention are independently selected from the following groups: (1 ) carboxylic acid esters obtained by esterification of the hydroxy groups, in which the non-carbonyl moiety of the carboxylic acid portion of the ester grouping is selected from straight or branched chain alkyl (for example, acetyl, n-propyl, t-butyl, or n- butyl), alkoxyalkyl (for example, methoxymethyl), aralkyl (for example, benzyl), aryloxyalkyl (for example, phenoxymethyl), aryl (for example, phenyl optionally substituted by, for example, halogen, C 1-4 alkyl, or Ci -4 alkoxy or amino); (2) sulfonate esters, such as alkyl- or aralkylsulfonyl (for example, methanesulfonyl); (3) amino acid esters (for example, L-valyl or L-isole
  • any alkyl moiety present advantageously contains from 1 to 18 carbon atoms, particularly from 1 to 6 carbon atoms, more particularly from 1 to 4 carbon atoms, Any cycloalkyl moiety present in such esters advantageously contains from 3 to 6 carbon atoms. Any aryl moiety present in such esters advantageously comprises a phenyl group.
  • the pre tion features a compound of formula (1 )
  • Compounds of the present invention are useful as HIV reverse transcriptase inhibitors, particularly as inhibitors of RNase H within HIV reverse transcriptase.
  • One aspect of the instant invention relates to methods of treating or preventing viral infection, for example an H IV infection, in a biological sample comprising contacting the biological sample with compounds of formula (I) or pharmaceutically acceptable derivatives thereof.
  • Another aspect of the instant invention relates to methods of treating or preventing viral infection, for example, an HIV infection, in a patient comprising administering to the patient a
  • the compounds according to the invention are particularly suited to the treatment or prophylaxis of HIV infections and associated conditions.
  • Reference herein to treatment extends to prophylaxis as well as the treatment of established infections, symptoms, and associated clinical conditions such as AIDS related complex (ARC), Kaposi's sarcoma, and AIDS dementia.
  • ARC AIDS related complex
  • Kaposi's sarcoma Kaposi's sarcoma
  • AIDS dementia AIDS related complex
  • the compounds of the present invention exhibit advantages over previously disclosed reverse transcriptase inhibitors, for example increased potency, metabolic stability, increased therapeutic index, or other pharmaceutical properties.
  • compositions may be formulated into compositions.
  • the composition is a pharmaceutical composition, which comprises a compound of formula (I) and pharmaceutically acceptable carrier, adjuvant or vehicle.
  • the composition comprises an amount of a compound of the present invention effective to treat or prevent viral infection, for example an HIV infection, in a biological sample or in a patient.
  • compounds of this invention and pharmaceutical compositions thereof which comprise an amount of a compound of the present innovation effective to inhibit viral replication or to treat or prevent a viral infection or disease or disorder, for example an H IV infection, and a pharmaceutically acceptable carrier, adjuvant or vehicle, may be formulated for administration to a patient, for example, for oral administration.
  • the present invention features compounds according to the invention for use in medical therapy, for example for the treatment or prophylaxis of a viral infection, for example an H IV infection and associated conditions.
  • the compounds according to the invention are especially useful for the treatment of AIDS and related clinical conditions such as AIDS related complex (ARC), progressive generalized lymphadenopathy (PGL), Kaposi's sarcoma, thrombocytopenic purpura, AI DS-related neurological conditions such as AIDS dementia complex, multiple sclerosis or tropical paraperesis, anti-HIV antibody-positive and HIV-positive conditions, including such conditions in asymptomatic patients.
  • AIDS related complex ARC
  • PDL progressive generalized lymphadenopathy
  • Kaposi's sarcoma Kaposi's sarcoma
  • thrombocytopenic purpura thrombocytopenic purpura
  • AI DS-related neurological conditions such as AIDS dementia complex, multiple sclerosis or tropical paraperesis, anti-HIV antibody-positive and HIV-positive conditions, including such
  • the present invention provides a method for the treatment or prevention of the symptoms or effects of a viral infection in an infected patient, for example, a mammal including a human, which comprises administering to said patient a pharmaceutically effective amount of a compound according to the invention.
  • the viral infection is a retroviral infection, in particular an HIV infection.
  • the present invention further includes the use of a compound according to the invention in the manufacture of a medicament for administration to a subject for the treatment of a viral infection, in particular and HIV infection.
  • the compounds according to the invention may also be used in adjuvant therapy in the treatment of HIV infections or HIV-associated symptoms or effects, for example Kaposi's sarcoma.
  • the present invention further provides a method for the treatment of a clinical condition in a patient, for example, a mammal including a human which clinical condition includes those which have been discussed hereinbefore, which comprises treating said patient with a pharmaceutically effective amount of a compound according to the invention.
  • the present invention also includes a method for the treatment or prophylaxis of any of the aforementioned diseases or conditions.
  • Certain of the compounds described herein contain one or more chiral centers, or may otherwise be capable of existing as multiple stereoisomers.
  • the scope of the present invention includes mixtures of stereoisomers as well as purified enantiomers or enantiomerically and/or diastereomerically enriched mixtures.
  • the individual isomers of the compounds of the present invention are also included within the scope of the invention, as well as any wholly or partially equilibrated mixtures thereof.
  • the present invention also includes the individual isomers of the compounds represented by the formulas above as mixtures with isomers thereof in which one or more chiral centers are inverted. Also, it is understood that any tautomers and mixtures of tautomers of the compounds of formula (I) are included within the scope of the compounds of formula (I).
  • the salts of the present invention are pharmaceutically acceptable salts.
  • Salts encompassed within the term “pharmaceutically acceptable salts” refer to nontoxic salts of the compounds of this invention.
  • Salts of the compounds of the present invention may comprise base addition salts derived from a removal of the hydroxyl group hydrogen on a compounds of formula (I).
  • Salts derived from appropriate bases include alkali metal (e.g. sodium), alkaline earth metal (e.g. , magnesium), ammonium, NW 4 + (wherein W is C-M alkyl) and other amine salts.
  • Physiologically acceptable salts of a compound with a hydroxy group include the anion of said compound in combination with a suitable cation such as Na + , NH 4 + , and NW 4 + (wherein W is a C ⁇ alkyl group).
  • Preferred salts include sodium, calcium, potassium, magnesium, choline, meglumine, hydrochloride, and quaternary ammonium.
  • Other salts, which are not pharmaceutically acceptable, may be useful in the preparation of compounds of this invention and these form a further aspect of the invention.
  • compositions which include therapeutically effective amounts of the compound of formula (I) or salts, solvates or hydrates thereof, and one or more pharmaceutically acceptable carriers, diluents, or excipients.
  • the compounds of the formula (I) or salt, solvate or hydrate thereof, are as described above.
  • the carrier(s), diluent(s) or excipient(s) must be acceptable in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.
  • a process for the preparation of a pharmaceutical formulation including admixing a compound of the formula (I), or salt, solvate or hydrate thereof, with one or more pharmaceutically acceptable carriers, diluents or excipients.
  • compositions may be presented in unit dose forms containing a predetermined amount of active ingredient per unit dose.
  • a unit may contain, for example, 100mg to 5g, 0.5mg to 1 g, 1 mg to 700mg, or 5mg to 100mg of a compound of the formula (I), depending on the condition being treated, the route of administration and the age, weight and condition of the patient, or pharmaceutical formulations may be presented in unit dose forms containing a predetermined amount of active ingredient per unit dose.
  • Preferred unit dosage formulations are those containing a daily dose or sub-dose, as herein above recited, or an appropriate fraction thereof, of an active ingredient.
  • such pharmaceutical formulations may be prepared by any of the methods well known in the pharmacy art.
  • compositions may be adapted for administration by any appropriate route, for example by the oral (including buccal or sublingual), rectal, nasal, topical (including buccal, sublingual or transdermal), vaginal or parenteral (including subcutaneous, intramuscular, intravenous or intradermal) route.
  • Such formulations may be prepared by any method known in the art of pharmacy, for example by bringing into association the active ingredient with the carrier(s) or excipient(s).
  • the present compound can be administered orally or parenterally.
  • the present compound can be also used as a conventional preparation, for example, as any dosage form of a solid agent such as tablets, powders, granules, capsules and the like; an aqueous agent; an oily suspension; or a liquid agent such as syrup and elixir.
  • the present compound can be used as an aqueous or oily suspension injectable, or a nasal drop.
  • conventional excipients, binders, lubricants, aqueous solvents, oily solvents, emulsifiers, suspending agents, preservatives, stabilizers and the like may be arbitrarily used.
  • an anti-HIV-drug particularly, an oral agent is preferable.
  • a preparation of the present invention is prepared by combining (e.g. mixing) a therapeutically effective amount of the present compound with a pharmaceutically acceptable carrier or diluent.
  • compositions adapted for oral administration may be presented as discrete units such as capsules or tablets; powders or granules; solutions or suspensions in aqueous or non-aqueous liquids; edible foams or whips; or oil-in-water liquid emulsions or water-in-oil liquid emulsions.
  • the active drug component can be combined with an oral, non-toxic pharmaceutically acceptable inert carrier such as ethanol, glycerol, water and the like.
  • an oral, non-toxic pharmaceutically acceptable inert carrier such as ethanol, glycerol, water and the like.
  • Powders are prepared by comminuting the compound to a suitable fine size and mixing with a similarly comminuted pharmaceutical carrier such as an edible carbohydrate, as, for example, starch or mannitol. Flavoring, preservative, dispersing and coloring agent can also be present.
  • Capsules are made by preparing a powder mixture, as described above, and filling formed gelatin sheaths.
  • Glidants and lubricants such as colloidal silica, talc, magnesium stearate, calcium stearate or solid polyethylene glycol can be added to the powder mixture before the filling operation.
  • a disintegrating or solubilizing agent such as agar-agar, calcium carbonate or sodium carbonate can also be added to improve the availability of the medicament when the capsule is ingested.
  • suitable binders include starch, gelatin, natural sugars such as glucose or beta-lactose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth or sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes and the like.
  • Lubricants used in these dosage forms include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride and the like.
  • Disintegrators include, without limitation, starch, methyl cellulose, agar, bentonite, xanthan gum and the like.
  • Tablets are formulated, for example, by preparing a powder mixture, granulating or slugging, adding a lubricant and disintegrant and pressing into tablets.
  • a powder mixture is prepared by mixing the compound, suitably comminuted, with a diluent or base as described above, and optionally, with a binder such as carboxymethylcellulose, an aliginate, gelatin, or polyvinyl pyrrolidone, a solution retardant such as paraffin, a resorption accelerator such as a quaternary salt and/or an absorption agent such as bentonite, kaolin or dicalcium phosphate.
  • a binder such as carboxymethylcellulose, an aliginate, gelatin, or polyvinyl pyrrolidone
  • a solution retardant such as paraffin
  • a resorption accelerator such as a quaternary salt
  • an absorption agent such as bentonite, kaolin or dicalcium phosphate.
  • the powder mixture can be granulated by wetting with a binder such as syrup, starch paste, acadia mucilage or solutions of cellulosic or polymeric materials and forcing through a screen.
  • a binder such as syrup, starch paste, acadia mucilage or solutions of cellulosic or polymeric materials and forcing through a screen.
  • the powder mixture can be run through the tablet machine and the result is imperfectly formed slugs broken into granules.
  • the granules can be lubricated to prevent sticking to the tablet forming dies by means of the addition of stearic acid, a stearate salt, talc or mineral oil.
  • the lubricated mixture is then compressed into tablets.
  • the compounds of the present invention can also be combined with a free flowing inert carrier and compressed into tablets directly without going through the granulating or slugging steps.
  • a clear or opaque protective coating consisting of a sealing coat of shellac, a coating of
  • Oral fluids such as solutions, syrups and elixirs can be prepared in dosage unit form so that a given quantity contains a predetermined amount of the compound.
  • Syrups can be prepared by dissolving the compound in a suitably flavored aqueous solution, while elixirs are prepared through the use of a non-toxic alcoholic vehicle.
  • Suspensions can be formulated by dispersing the compound in a non-toxic vehicle.
  • Solubilizers and emulsifiers such as ethoxylated isostearyl alcohols and polyoxy ethylene sorbitol ethers, preservatives, flavor additive such as peppermint oil or natural sweeteners or saccharin or other artificial sweeteners, and the like can also be added.
  • dosage unit formulations for oral administration can be microencapsulated.
  • the formulation can also be prepared to prolong or sustain the release as for example by coating or embedding particulate material in polymers, wax or the like.
  • the compounds of formula (I) or salts, solvates or hydrates thereof can also be administered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles and multilamellar vesicles.
  • liposomes can be formed from a variety of phospholipids, such as cholesterol, stearylamine or phosphatidylcholines.
  • the compounds of formula (I) or salts, solvates or hydrates thereof may also be delivered by the use of monoclonal antibodies as individual carriers to which the compound molecules are coupled.
  • the compounds may also be coupled with soluble polymers as targetable drug carriers.
  • Such polymers can include polyvinylpyrrolidone, pyran copolymer, polyhydroxypropylmethacrylamid-phenol, polyhydroxyethylaspartamidephenol, or polyethyleneoxidepolylysine substituted with palmitoyl residues.
  • the compounds may be coupled to a class of biodegradable polymers useful in achieving controlled release of a drug, for example, polylactic acid, polepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates and cross-linked or amphipathic block copolymers of hydrogels.
  • a class of biodegradable polymers useful in achieving controlled release of a drug, for example, polylactic acid, polepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates and cross-linked or amphipathic block copolymers of hydrogels.
  • compositions adapted for transdermal administration may be presented as discrete patches intended to remain in intimate contact with the epidermis of the recipient for a prolonged period of time.
  • the active ingredient may be delivered from the patch by iontophoresis as generally described in Pharmaceutical Research, 3(6), 318 (1986).
  • compositions adapted for topical administration may be formulated as ointments, creams, suspensions, lotions, powders, solutions, pastes, gels, sprays, aerosols or oils.
  • the formulations are preferably applied as a topical ointment or cream.
  • the active ingredient may be employed with either a paraffinic or a water-miscible ointment base.
  • the active ingredient may be formulated in a cream with an oil-in-water cream base or a water-in-oil base.
  • compositions adapted for topical administrations to the eye include eye drops wherein the active ingredient is dissolved or suspended in a suitable carrier, especially an aqueous solvent.
  • compositions adapted for topical administration in the mouth include lozenges, pastilles and mouth washes.
  • compositions adapted for rectal administration may be presented as suppositories or as enemas.
  • compositions adapted for nasal administration wherein the carrier is a solid include a coarse powder having a particle size for example in the range 20 to 500 microns which is administered in the manner in which snuff is taken, i.e. by rapid inhalation through the nasal passage from a container of the powder held close up to the nose.
  • Suitable formulations wherein the carrier is a liquid, for administration as a nasal spray or as nasal drops, include aqueous or oil solutions of the active ingredient.
  • Fine particle dusts or mists which may be generated by means of various types of metered, dose pressurized aerosols, nebulizers or insufflators.
  • compositions adapted for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams or spray formulations.
  • compositions adapted for parenteral administration include aqueous and non-aqueous sterile injection solutions which may contain antioxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents.
  • the formulations may be presented in unit-dose or multi-dose containers, for example sealed ampoules and vials, and may be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example water for injections, immediately prior to use.
  • Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets.
  • formulations may include other agents conventional in the art having regard to the type of formulation in question, for example those suitable for oral administration may include flavouring agents.
  • the pharmaceutical formulation containing a compound of formula I or a salt, solvate or hydrate thereof is a formulation adapted for parenteral administration.
  • the formulation is a long-acting parenteral formulation.
  • the formulation is a nano-particle formulation.
  • a therapeutically effective amount of a compound of the present invention will depend upon a number of factors including, for example, the age and weight of the human or other animal, the precise condition requiring treatment and its severity, the nature of the formulation, and the route of administration, and will ultimately be at the discretion of the attendant physician or veterinarian.
  • An effective amount of a salt or hydrate thereof may be determined as a proportion of the effective amount of the compound of formula (I) or salts, solvates or hydrates thereof per se.
  • the compounds of formula (I) or salts, solvates or hydrates thereof are believed to have activity in stopping or reducing the effects of HIV as a result of inhibition of HIV-1 reverse transcriptase.
  • a method of treating a virus susceptible to reverse transcriptase inhibition in a mammal including administering to said mammal a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, solvate or hydrate thereof.
  • the virus is H IV.
  • the reverse transcriptase is HIV-1 reverse transcriptase.
  • the mammal is a human.
  • a method of inhibiting HIV reverse transcriptase in a mammal including administering to said mammal a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, solvate or hydrate thereof.
  • the mammal is a human.
  • a method of treating reverse transcriptase inhibitor resistant HIV in a mammal comprising administering to said mammal a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, solvate or hydrate thereof.
  • the mammal is a human.
  • a method of preventing development of reverse transcriptase inhibitor resistant HIV in a mammal comprising administering to said mammal a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, solvate or hydrate thereof.
  • the mammal is a human.
  • the compounds of the present invention and their salts, solvates, hydrates or other pharmaceutically acceptable derivatives thereof, may be employed alone or in combination with other therapeutic agents.
  • the compounds of the present invention and any other pharmaceutically active agent(s) may be administered together or separately and, when administered separately, administration may occur simultaneously or sequentially, in any order.
  • the amounts of the compounds of the present invention and the other pharmaceutically active agent(s) and the relative timings of administration will be selected in order to achieve the desired combined therapeutic effect.
  • the administration in combination of a compound of the present invention and salts, solvates, hydrates or other pharmaceutically acceptable derivatives thereof with other treatment agents may be in combination by administration concomitantly in: (1 ) a unitary pharmaceutical composition including both compounds; or (2) separate pharmaceutical compositions each including one of the compounds.
  • the combination may be administered separately in a sequential manner wherein one treatment agent is administered first and the other second or vice versa. Such sequential administration may be close in time or remote in time.
  • the amounts of the compound(s) of formula (I) or salts, solvates or hydrates thereof and the other pharmaceutically active agent(s) and the relative timings of administration will be selected in order to achieve the desired combined therapeutic effect.
  • Examples of such other therapeutic agents include, but are not limited to, agents that are effective for the treatment of viral infections or associated conditions.
  • agents that are effective for the treatment of viral infections or associated conditions.
  • these agents are (1 -alpha, 2-beta, 3-alpha)-9-[2,3- bis(hydroxymethyl)cyclobutyl]guanine [(-)BHCG, SQ-34514, lobucavir]; 9-[(2R,3R,4S)-3,4- bis(hydroxy methyl)2-oxetanosyl]adenine (oxetanocin-G); acyclic nucleosides, for example acyclovir, valaciclovir, famciclovir, ganciclovir, and penciclovir; acyclic nucleoside phosphonates, for example (S)-1-(3-hydroxy-2-phosphonyl-methoxypropyl) cytosine (H PMPC), [[[2-(6-amino-9H
  • the present invention further includes the use of a compound according to the invention in the manufacture of a medicament for simultaneous or sequential administration with at least another therapeutic agent, such as those defined hereinbefore.
  • Compounds of the present invention may be administered with an agent known to inhibit or reduce the metabolism of compounds, for example ritonavir.
  • the present invention features a method for the treatment or prophylaxis of a disease as hereinbefore described by administration of a compound of the present invention in combination with a metabolic inhibitor. Such combination may be administered simultaneously or sequentially.
  • a suitable dose for each of the above-mentioned conditions will be in the range of 0.01 to 250 mg per kilogram body weight of the recipient (e.g. a human) per day, preferably in the range of 0.1 to 100 mg per kilogram body weight per day and most preferably in the range 0.5 to 30 mg per kilogram body weight per day and particularly in the range 1.0 to 20 mg per kilogram body weight per day.
  • all weights of active ingredient are calculated as the parent compound of formula (I) or (la); for salts or esters thereof, the weights would be increased proportionally.
  • the desired dose may be presented as one, two, three, four, five, six or more sub-doses administered at appropriate intervals throughout the day. In some cases the desired dose may be given on alternative days. These sub-doses may be administered in unit dosage forms, for example, containing 10 to 1000 mg or 50 to 500 mg, preferably 20 to 500 mg, and most preferably 50 to 400 mg of active ingredient per unit dosage form.
  • compositions of the present invention comprise at least one active ingredient, as defined above, together with one or more acceptable carriers thereof and optionally other therapeutic agents.
  • Each carrier must be acceptable in the sense of being compatible with the other ingredients of the composition and not injurious to the patient.
  • compositions include those suitable for oral, rectal, nasal, topical (including transdermal, buccal and sublingual), vaginal or parenteral (including subcutaneous, intramuscular, intravenous, intradermal, and intravitreal) administration.
  • the compositions may conveniently be presented in unit dosage form and may be prepared by any methods well known in the art of pharmacy. Such methods represent a further feature of the present invention and include the step of bringing into association the active ingredients with the carrier, which constitutes one or more accessory ingredients.
  • the compositions are prepared by uniformly and intimately bringing into association the active ingredients with liquid carriers or finely divided solid carriers or both, and then if necessary shaping the product.
  • the present invention further includes a pharmaceutical composition as hereinbefore defined wherein a compound of the present invention or a pharmaceutically acceptable derivative thereof and another therapeutic agent are presented separately from one another as a kit of parts.
  • compositions suitable for transdermal administration may be presented as discrete patches adapted to remain in intimate contact with the epidermis of the recipient for a prolonged period of time.
  • patches suitably contain the active compound 1 ) in an optionally buffered, aqueous solution or 2) dissolved and/or dispersed in an adhesive or 3) dispersed in a polymer.
  • a suitable concentration of the active compound is about 1 % to 25%, preferably about 3% to 15%.
  • the active compound may be delivered from the patch by electrotransport or iontophoresis as generally described in Pharmaceutical Research 3(6), 318 (1986).
  • compositions of the present invention suitable for oral administration may be presented as discrete units such as capsules, caplets, cachets or tablets each containing a predetermined amount of the active ingredients; as a powder or granules; as a solution or a suspension in an aqueous or non-aqueous liquid; or as an oil-in- water liquid emulsion or a water-in-oil liquid emulsion.
  • the active ingredient may also be presented as a bolus, electuary or paste.
  • a tablet may be made by compression or molding, optionally with one or more accessory ingredients.
  • Compressed tablets may be prepared by compressing in a suitable machine the active ingredients in a free-flowing form such as a powder or granules, optionally mixed with a binder (e.g. povidone, gelatin, hydroxypropylmethyl cellulose), lubricant, inert diluent, preservative, disintegrant (e.g. sodium starch glycolate, cross-linked povidone, cross-linked sodium carboxymethyl cellulose) surface-active or dispersing agent.
  • Molded tablets may be made by molding a mixture of the powdered compound moistened with an inert liquid diluent in a suitable machine.
  • the tablets may optionally be coated or scored and may be formulated so as to provide slow or controlled release of the active ingredients therein using, for example, hydroxypropylmethyl cellulose in varying proportions to provide the desired release profile. Tablets may optionally be provided with an enteric coating, to provide release in parts of the gut other than the stomach.
  • compositions suitable for topical administration in the mouth include lozenges comprising the active ingredients in a flavored base, usually sucrose and acacia or tragacanth; pastilles comprising the active ingredient in an inert basis such as gelatin and glycerin, or sucrose and acacia; and mouthwashes comprising the active ingredient in a suitable liquid carrier.
  • compositions suitable for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams or spray.
  • Pharmaceutical compositions may contain in addition to the active ingredient such carriers as are known in the art to be appropriate.
  • compositions for rectal administration may be presented as a suppository with a suitable carrier comprising, for example, cocoa butter or a salicylate or other materials commonly used in the art.
  • a suitable carrier comprising, for example, cocoa butter or a salicylate or other materials commonly used in the art.
  • the suppositories may be conveniently formed by admixture of the active combination with the softened or melted carrier(s) followed by chilling and shaping in molds.
  • compositions suitable for parenteral administration include aqueous and nonaqueous isotonic sterile injection solutions which may contain antioxidants, buffers, bacteriostats and solutes which render the pharmaceutical composition isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents; and liposomes or other microparticulate systems which are designed to target the compound to blood components or one or more organs.
  • compositions may be presented in unit-dose or multi-dose sealed containers, for example, ampoules and vials, and may be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example water for injection, immediately prior to use.
  • sterile liquid carrier for example water for injection
  • Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets of the kind previously described.
  • Unit dosage pharmaceutical compositions include those containing a daily dose or daily subdose of the active ingredients, as hereinbefore recited, or an appropriate fraction thereof.
  • compositions of this invention may include other agents conventional in the art having regard to the type of pharmaceutical composition in question, for example, those suitable for oral administration may include such further agents as sweeteners, thickeners and flavoring agents.
  • M molar
  • mM millimolar
  • Tr retention time
  • RP reverse phase
  • the compounds of the present invention may be prepared according to the following reactions schemes and examples, or modifications thereof using readily available starting materials, reagents and conventional synthesis procedures. In these reactions, it is also possible to make use of variants which are known to those of ordinary skill in the art.
  • a compound of formula I can be made starting with the commercially available 2-fluoronicotinic acid (1).
  • Thermal addition of O- benzylhydroxylamine under basic conditions followed by methyl ester formation provides ester 4.
  • This material can be acylated with an isocyanate.
  • 4- methoxybenzylisocyanate (5) may be used to provide compound 6.
  • This material can be cyclized under basic conditions to provide compound 7.
  • Removal of the 4-methoxybenzyl (PMB) group with eerie ammonium nitrate and the like provides imide derivative 8.
  • This material can be subjected to dehydrative chlorination conditions using POCI 3 optionally with a base to give chloroimidate 9 which can be treated with an amine to give intermediate 10.
  • Removal of the benzyl protecting group can be accomplished with HBr in acetic acid to provide a compound of formula l-a (Scheme 1 ).
  • intermediate urea can be cyclized with subsequent loss of the trichloracetyl group to provide compound 14.
  • Chloroimidate formation gives chloroimidate 15 and amine displacement as previously noted serves to provide compound 16.
  • the 4-methoxybenzyl ether can be cleaved under acidic conditions including but not limited to the use of trifluoroacetic acid in dichloromethane to give a compound of formula l-a.
  • Chloroimidate 15 can be used to provide other compounds of formula I as shown in scheme 3.
  • an alcohol or alkoxide nucleophile can be used to form a compound of formula l-b upon removal of the PMB protecting group.
  • Scheme 4 shows a particularly useful route whereby 2- fluoronicotonitrile (18) is reacted with the O-tert-butyl-hydroxylamine (19) to give nitrile 20. Hydrolysis of the nitrile to the corresponding acid followed by esterification with, e.g. , trimethysilyldiazomethane (TMSCHN 2 ) serves to provide 21 . This material can be subjected to urea formation and cyclization as described above to give compound 22. Chloroimidate formation and amine displacement gives compound 24, followed by acidic deprotection serve to provide a compound of formula l-a.
  • TMSCHN 2 trimethysilyldiazomethane
  • bromide 27 can be subjected to cross- coupling conditions well known to one skilled in the art to provide a compound such as 29.
  • Cross couplings may make use of boronic acid, tin or zinc coupling partners in the presence of a source of palladium (0). Deprotection as described above can serve to provide a compound of formula l-d.
  • bromide 27 can be modified to provide the boronic ester or acid 34 using the Suzuki-Miyaura cross coupling.
  • This material itself can be converted to a compound of formula I or can be further elaborated by coupling an aryl halide such as 35 under standard Suzuki conditions to provide a compound of formula l-f upon deprotection.
  • (l-f) Intermediate 37 shown in scheme 9 can be alkylated using methods known to one skilled in the art. Particularly useful conditions involved the use of sodium hydride as a base in anhydrous solvent. THF is a useful solvent in this case and reactive electrophiles such as methyl iodide can be used.
  • the N-alkyl intermediate 38 can be further reacted as previously described above under Suzuki conditions to provide a compound such as 40. This intermediate can be deprotected to provide a compound of formula l-g.
  • Chloride 33 can be used to react with secondary amines such as 41 .
  • the subsequent intermediate 42 can be further reacted with a compound such as 43 under Suzuki conditions to provide a compound like 44.
  • This material provides a compound of formula l-h upon deprotection (Scheme 10).
  • chloride 23 can be converted into a compound such as 48. This material can be subjected to raney-nickel reduction conditions to provide the corresponding amino derivative 50 which upon deprotection will give a compound of formula l-i (Scheme 1 1 ).
  • R 1 groups on the compounds included in the examples can be made by methods known in the literature or demonstrated in the schemes to produce novel intermediates without the need for undue experimentation. It will also be apparent the order of the chemical steps can in many instances be rearranged or the steps combined for the purpose of making a compounds of formula I . It will further be apparent that convergent or stepwise linear synthesis can be employed in many cases or may be adventitious in other examples. Examples 1 -344 are set forth below, and in Table 1 .
  • Example 1 1-hvdroxv-4-((r3-(4- morpho l)phenyl]methyl ⁇ amino)pyrido[2,3-d]pyrimidin-2(1 H)-one.
  • Example 2 1-hydroxy-4-(1 ,2,3,4-tetrahydro-1- naphthalenylamino)pyrido[2,3-d]pyrimidin-2(1 H)-one hydrobromide.
  • Example 3 4-[(cyclopropylmethyl)amino]-1-hydroxypyrido[2,3- d]pyrimidin-2(1 H)-one hydrobromide.
  • OCT 0 4-[(cyclopropylmethyl)amino]-1-hydroxypyrido[2,3- d]pyrimidin-2(1 H)-one hydrobromide.
  • Example 4 4- ⁇ [(4-Fluorophenyl)methyl]amino ⁇ -1 -hydroxypyrido[2,3- d]pyrimi hydrobromide.
  • Example 5 4- ⁇ [(4'-Chloro-4-biphenylyl)methyl]amino ⁇ -1 - hydroxypyrido[2,3-d]pyrimidin-2(1 H)-one hydrobromide.
  • Example 6 1-Hydroxy-4-( ⁇ [2- (methyl ethyl ⁇ amino)pyrido[2,3-d]pyrimidin-2(1 H)-one hydrobromide.
  • the title compound was prepared in a similar manner to example 1 to provide a white solid (7.1 mg, 19 %) as a TFA salt.
  • Example 7 1-Hydroxy-4- ⁇ [2-(4-morpholinyl)ethyl]amino ⁇ pyrido[2,3- d]pyrimi hydrobromide.
  • Example 8 4- ⁇ [(2,4-Difluorophenyl)methyl]amino ⁇ -1 - hydroxypyrido[2,3-d]pyrimidin-2(1 H)-one hydrobromide.
  • Example 9 1 -Hydroxy-4-[(2-thienylmethyl)amino]pyrido[2,3- d]pyrimi hydrobromide.
  • Example 11 4-(2, 3-Dihydro-1H-inden-1-ylamino)-1- hydroxypyrido[2,3-d]pyrimidin-2(1H)-one.
  • Example 12 1-Hydroxy-4- ⁇ [(1R)-1-phenylethyl]amino ⁇ pyrido[2,3- d ⁇ py ri m i d i n-2 ( 1 H)-o n e .
  • Example 13 1-Hydroxy-4- ⁇ [(4-methylphenyl)methyl]amino ⁇ pyrido[2,3- d ⁇ py ri m i d i n-2 ( 1 H)-o n e .
  • the title compound was prepared in a similar manner to example 1 as aTFAsalt.
  • 1 H NMR 300 MHz, CD 3 OD
  • Example 14 4-(Cyclopentylamino)-1-hydroxypyrido[2,3-d]pyrimidin- 2(1H)-o
  • Example 15 1-Hydroxy-4-[(2-methylpropyl)amino]pyrido[2,3- d ⁇ py ri m i d i n-2 ( 1 H)-o n e .
  • Example 16 4'- ⁇ [(1-Hdroxy-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidin-4- yl)amino]methyl ⁇ -2-biphenylcarboxylic acid.
  • Example 17 1-Hydroxy-4-( ⁇ [4- (methyloxy)phenyl]methyl ⁇ amino)pyrido[2,3-d]pyrimidin-2(1H)-one.
  • the title compound was prepared in a similar manner to example 1 as a TFA salt.
  • 1 H NMR 300 MHz, CD 3 OD
  • ppm 8.60-8.40 m,2H);7.26-7.24 (m,3H);6.90- 6.78 (m,2H);4.64 (m,2H);3.67 (m,3H); ES+ MS: 299 (M+1 ).
  • Example 18 4-(Butylamino)-1 -hydroxypyrido[2,3-d]pyrimidin-2(1 H)- one.
  • Example 19 1 -Hydroxy-4-[(2-phenylethyl)amino]pyrido[2,3- d ⁇ py ri m i d i n-2 ( 1 H)-o n e .
  • Example 20 1 -Hydroxy-4-[(phenylmethyl)amino]pyrido[2,3- d ⁇ py ri m i d i n-2 ( 1 H)-o n e .
  • Example 21 1 -Hydroxy-4-[(2-pyridinylmethyl)amino]pyrido[2,3- d ⁇ py ri m i d i n-2 ( 1 H)-o n e .
  • Example 22 1-Hydroxy-4-[(2-methylphenyl)amino]pyrido[2,3- d ⁇ py ri m i d i n-2 ( 1 H)-o n e .
  • Example 23 4-( ⁇ [2'-(Aminomethyl)-4-biphenylyl]methyl ⁇ amino)-1- hydroxypyrido[2,3-d]pyrimidin-2(1H)-one.
  • Example 24 4-(4-Biphenylylamino)-1-hydroxypyrido[2,3-d]pyrimidin- 2(1H)-o
  • Example 25 4-(Cyclopropylamino)-1-hydroxypyrido[2,3-d]pyrimidin- 2(1H)-one.
  • Example 26 1-Hydroxy-4-(1-pyrrolidinyl)pyrido[2,3-d]pyrimidin-2(1H)- one.
  • Example 27 4-(Cyclohexylamino)-1-hydroxypyrido[2,3-d]pyrimidin- 2(1H)-one.
  • Example 29 1 -Hydroxy-4-[(1 R)-1 ,2,3,4-tetrahydro-1 - naphthalenylamino]pyrido[2,3-d]pyrimidin-2(1 H)-one.
  • Example 30 1 -Hydroxy-4- ⁇ [2-(2-thienyl)ethyl]amino ⁇ pyrido[2,3- d ⁇ py ri m 1 H)-o n e .
  • Example 31 1 -Hydroxy-4-[(4,4,4-trifluorobutyl)amino]pyrido[2,3- d ⁇ py ri m i d i n-2 ( 1 H)-o n e .
  • the title compound was prepared in a similar manner to example 1 and isolated as a TFA salt.
  • Example 32 4-[(1 , 1 -Dimethylethyl)amino]-1 -hydroxypyrido[2,3- d ⁇ py ri m i d i n-2 ( 1 H)-o n e .
  • Example 33 1 -Hydroxy-4-[(3-thienylmethyl)amino]pyrido[2,3- d ⁇ py ri m i d i n-2 ( 1 H)-o n e .
  • Example 34 4-[(1 -Hydroxy-2-oxo-1 ,2-dihydropyrido[2,3-d]pyrimidin-4- yl)amino]benzonitrile.
  • Example 35 1 -Hydroxy-4-( ⁇ [5-(2-pyridinyl)-2- thienyl]methyl ⁇ amino)pyrido[2,3-d]pyrimidin-2(1 H)-one.
  • Example 36 1 -Hydroxy-4- ⁇ [3'-(4-morpholinyl)-4- biphenylyl]amino ⁇ pyrido[2,3-d]pyrimidin-2(1 H)-one.
  • Example 37 4-(Hexahydro-1 H-azepin-1 -yl)-1 -hydroxypyrido[2,3- d ⁇ py ri m i d i n-2 ( 1 H)-o n e .
  • the material converted to mostly trichloroacetyl urea.
  • the mixture was concentrated in vacuo and placed under high vacuum for 1 h. This residue was dissolved in MeOH and sodium methoxide (25 wt% in methanol) (1 .949 mL, 9.02 mmol) was added. Mixture was stirred overnight. An additional 1 mL of NaOMe was added but no change observed.
  • the reaction mixture was concentrated in vacuo and the residue was taken up in water and EtOAc. It was acidified with 1 ⁇ / HCI. Some solids formed and were filtered off. The mixture was extracted into EtOAc, washed with brine and dried over sodium sulfate.
  • Example 38 4-(4-Acetyl-1-piperazinyl)-1 -hydroxypyrido[2,3- d]pyrimidin-2(1 H)-one.
  • 2,4(1 H ,3H)-dione (20 mg, 0.085 mmol) and DIEA (1 .485 mL, 8.50 mmol) in toluene (2ml_) was added POCI3 (0.079 mL, 0.850 mmol). The mixture was heated at 100 °C for 45 min. Concentrated to dryness in a rotary evaporator and the residue was immediately taken up in DMF (2 ml). This solution was added to a solution of piperazine (732 mg, 8.50 mmol) in DMF (10 ml) dropwise and stirred at room temperature for 15 min.
  • Example 39 1 -Hydroxy-4- ⁇ [4- (trifluoromethyl)phenyl]amino ⁇ pyrido[2,3-d]pyrimidin-2(1 H)-one.
  • Example 40 1 -Hydroxy-4-(1 -piperazinyl)pyrido[2,3-d]pyrimidin-2(1 H)- one.
  • 2,4(1 H ,3H)-dione (20 mg, 0.085 mmol) and DIEA (1 .485 mL, 8.50 mmol) in toluene (2 mL) was added POCI3 (0.079 mL, 0.850 mmol). The mixture was heated at 100 °C for 45 min. Concentrated to dryness in a rotary evaporator and the residue was immediately taken up DMF (1 mL). Added 1 , 1 -dimethylethyl 1 -piperazinecarboxylate (190 mg, 1 .020 mmol) and stirred at room temperature for 15 min.
  • Example 41 1 -Hydroxy-4- ⁇ [3-(4-pyridinyl)phenyl]amino ⁇ pyrido[2,3- d ⁇ py ri m i d i n-2 ( 1 H)-o n e .
  • Example 42 4-( ⁇ 4'-[(Dimethylamino)methyl]-3-biphenylyl ⁇ amino)-1- hydroxypyrido[2,3-d]pyrimidin-2(1H)-one.
  • Example 43 1-Hydroxy-4-( ⁇ [3-(4- morpho hyl ⁇ amino)pyrido[2,3-d]pyrimidin-2(1H)-one.
  • Example 44 1-Hydroxy-4- ⁇ [3'-(4-morpholinyl)-3- biphen [2,3-d]pyrimidin-2(1H)-one.
  • Example 46 1 -Hydroxy-4- ⁇ [2-(methyloxy)ethyl]amino ⁇ pyrido[2,3- d ⁇ py ri m i d i n-2 ( 1 H)-o n e .
  • Example 47 1 -Hydroxy-4-( ⁇ [4-(4- morph l]methyl ⁇ amino)pyrido[2,3-d]pyrimidin-2(1 H)-one.
  • Example 49 1-Hydroxy-4- ⁇ [4-(4-pyridinyl)phenyl]amino ⁇ pyrido[2,3- d ⁇ py ri m n e .
  • Example 50 3'- ⁇ [(1-Hydroxy-2-oxo-1 ,2-dihydropyrido[2,3-d]pyrimidin- 4-yl)am rboxylic acid.
  • Example 51 4-[(3-Bomophenyl)amino]-1-hydroxypyrido[2,3- d ⁇ py ri m i d i n-2 ( 1 H)-o n e .
  • Example 52 4'-[(1 -Hydroxy-2-oxo-1 ,2-dihydropyrido[2,3-d]pyrimidin- 4-yl)am ide.
  • Example 53 4- ⁇ [3'-(Aminomethyl)-4-biphenylyl]amino ⁇ -1 - hydro (1 H)-one.
  • Example 54 1 -Hydroxy-4-( ⁇ 1 -methyl-1 -[4- (methyloxy)phenyl]ethyl ⁇ amino)pyrido[2,3-d]pyrimidin-2(1 H)-one.
  • Example 55 4-[(2-Furanylmethyl)amino]-1 -hydroxypyrido[2,3- d ⁇ py ri m i d i n-2 ( 1 H)-o n e .
  • Example 56 4'-[(1 -Hydroxy-2-oxo-1 ,2-dihydropyrido[2,3-d]pyrimidin- 4-yl)amino]-3-biphenylcarboxamide.
  • Example 57 1 -Hydroxy-4- ⁇ [4-(3-pyridinyl)phenyl]amino ⁇ pyrido[2,3- d ⁇ py ri m i d i n-2 ( 1 H)-o n e .
  • Example 58 1 -Hydroxy-4-( ⁇ [3-(1- piperidinylmethyl)phenyl]methyl ⁇ amino)pyrido[2,3-d]pyrimidin-2(1 H)-one.
  • Example 59 4-( ⁇ [3-(Aminomethyl)phenyl]methyl ⁇ amino)-1 - hydroxy in-2(1 H)-one.
  • Example 60 1 -Hydroxy-4- ⁇ [(4'-hydroxy-4- biphen [2,3-d]pyrimidin-2(1 H)-one.
  • Example 62 4-( ⁇ [4-(Aminomethyl)phenyl]methyl ⁇ amino)-1 - hydroxypyrido[2,3-d]pyrimidin-2(1 H)-one.
  • Example 63 1 -Hydroxy-4-(methylamino)pyrido[2,3-d]pyrimidin-2(1 H)- one.
  • Example 64 1 -Hydroxy-4- ⁇ [3-(3-pyridinyl)phenyl]amino ⁇ pyrido[2,3- d ⁇ py ri m -2 ( 1 H)-o n e .
  • Example 65 3'-[(1 -Hydroxy-2-oxo-1 ,2-dihydropyrido[2,3-d]pyrimidin- 4-yl)amino]-3-biphenylcarboxamide.
  • Example 66 4-[(3'-Amino-3-biphenylyl)amino]-1 -hydroxypyrido[2,3- d ⁇ py ri m -2 ( 1 H)-o n e .
  • Example 67 4-[(1 -Benzothien-2-ylmethyl)amino]-1 -hydroxypyrido[2,3- d ⁇ py ri m i d i n-2 ( 1 H)-o n e .
  • Example 68 4- ⁇ [(4'-Fluoro-3-biphenylyl)methyl]amino ⁇ -1 - hydroxypyrido[2,3-d]pyrimidin-2(1 H)-one.
  • Example 69 4-[(3-Biphenylylmethyl)amino]-1 -hydroxypyrido[2,3- d ⁇ py ri m i d i n-2 ( 1 H)-o n e .
  • Example 70 1 -Hydroxy-4-(3-pyridinylamino)pyrido[2,3-d]pyrimidin- 2(1 H)-o
  • Example 71 1 -Hydroxy-4-[(2-hydroxy-2- methylpropyl)amino]pyrido[2,3-d]pyrimidin-2(1 H)-one.
  • Example 72 4-[(1 -Hydroxy-2-oxo-1 ,2-dihydropyrido[2,3-d]pyrimidin-4- yl)amino]-A/-methyl-1 -piperidinecarboxamide.
  • Example 73 4- ⁇ 4-[(3,5-Difluorophenyl)carbonyl]-1-piperazinyl ⁇ -1- hydroxypyrido[2,3-d]pyrimidin-2(1H)-one.
  • Example 74 4,4'-(1,4-Piperazinediyl)bis(1-hydroxypyrido[2,3- cf]pyrimi -one).
  • Example 75 4- ⁇ 4-[(4-Fluorophenyl)carbonyl]-1-piperazinyl ⁇ -1- hydroxypyrido[2,3-d]pyrimidin-2(1H)-one.
  • the title compound was prepared in a similar manner to example 144 and isolated asaTFAsalt.
  • 1 H NMR 300MHz, DMSO-d 6 ) ⁇ 10.53 (s, 1H), 8.69 (d, 1H), 8.25 (d, 1H), 7.56-7.53 (m, 2H), 7.34-7.22 (m, 3H), 4.07-3.60 (m, 8H); ES + MS: 369.9 (M + 1).
  • Example 76 4-[(2,2'-Bithien-5-ylmethyl)amino]-1-hydroxypyrido[2,3- d ⁇ py ri m i d i n-2 ( 1 H)-o n e .
  • Example 77 4-[(3,5-Difluorophenyl)amino]-1-hydroxypyrido[2,3- d ⁇ py ri m i d i n-2 ( 1 H)-o n e .
  • Example 78 4- ⁇ 4-[(2,4-Dichlorophenyl)carbonyl]-1-piperazinyl ⁇ -1- hydroxypyrido[2,3-d]pyrimidin-2(1H)-one.
  • Example 80 4- ⁇ 4-[(2-Fluorophenyl)carbonyl]-1 -piperazinyl ⁇ -1 - hydroxypyrido[2,3-d]pyrimidin-2(1 H)-one.
  • Example 81 1 -Hydroxy-4-(4- ⁇ [2-(methyloxy)-3-pyridinyl]carbonyl ⁇ -1 - piperazinyl)pyrido[2,3-cf]pyrimidin-2(1 H)-one.
  • Example 82 4- ⁇ 4-[(3-Chlorophenyl)carbonyl]-1-piperazinyl ⁇ -1- hydroxypyrido[2,3-d]pyrimidin-2(1H)-one.
  • Example 83 1-Hydroxy-4- ⁇ [2-(4-morpholinyl)phenyl]amino ⁇ pyrido[2,3- d ⁇ py ri m i d i n-2 ( 1 H)-o n e .
  • Example 84 1-Hydroxy-4-(2-pyridinylamino)pyrido[2,3-d]pyrimidin-
  • Example 86 Methyl 4-[(1 -hydroxy-2-oxo-1 ,2-dihydropyrido[2,3- cf]pyrimidin-4-yl)amino]-1-piperidinecarboxylate.
  • Example 87 4-(4-Glycyl-1 -piperazinyl)-1 -hydroxypyrido[2,3- d ⁇ py ri m i d i n-2 ( 1 H)-o n e .
  • Example 88 4-[(1 -Glycyl-4-piperidinyl)amino]-1-hydroxypyrido[2,3- d ⁇ py ri m i d i n-2 ( 1 H)-o n e .
  • Example 89 4-[(1 -Hydroxy-2-oxo-1 ,2-dihydropyrido[2,3-d]pyrimidin-4- yl)amino]-1-piperidinecarboxamide.
  • Example 90 4-(1 -Hydroxy-2-oxo-1 ,2-dihydropyrido[2,3-d]pyrimidin-4- yl)-1 -piperazinecarboxamide.
  • Example 91 1 -Hydroxy-4-[4-(phenylsulfonyl)-1-piperazinyl]pyrido[2,3- d ⁇ py ri m i d i n-2 ( 1 H)-o n e .
  • Example 92 1-Hydroxy-4-[4-(2-pyridinylcarbonyl)-1- piperazinyl]pyrido[2,3-d]pyrimidin-2(1H)-one.
  • Example 93 1-Hydroxy-4-[4-(3-pyridinylcarbonyl)-1- piperazinyl]pyrido[2,3-d]pyrimidin-2(1H)-one.
  • Example 94 1-Hydroxy-4-[4-(methylsulfonyl)-1-piperazinyl]pyrido[2,3- d ⁇ py ri m i d i n-2 ( 1 H)-o n e .
  • Example 95 Ethyl 4-(1-hydroxy-2-oxo-1 ,2-dihydropyrido[2,3- cf]pyrimidin-4-yl)-1-piperazinecarboxylate.
  • Example 96 1-Hydroxy-4-( ⁇ 1-[(methyloxy)acetyl]-4- piperidinyl ⁇ amino)pyrido[2,3-d]pyrimidin-2(1H)-one.
  • Example 98 1 -Hydroxy-4-[4-(4-pyridinylcarbonyl)-1 - piperazinyl]pyrido[2,3-d]pyrimidin-2(1 H)-one.
  • Example 99 1 -Hydroxy-4-[4-(phenylmethyl)-1 -piperazinyl]pyrido[2,3- d ⁇ py ri m i d i n-2 ( 1 H)-o n e .
  • Example 100 1 -Hydroxy-4-[(2R)-2-methyl-4-(phenylsulfonyl)-1 - piperazinyl]pyrido[2,3-d]pyrimidin-2(1 H)-one.
  • Example 101 1-Hydroxy-4-[(1 -methyl-4-piperidinyl)amino]pyrido[2,3- d ⁇ py ri m i d i n-2 ( 1 H)-o n e .
  • Example 102 4- ⁇ [1-(2,2-Dimethylpropanoyl)-4-piperidinyl]amino ⁇ -1 - hydroxypyrido[2,3-d]pyrimidin-2(1 H)-one.
  • Example 103 4-(7,8-Dihydro-1,6-naphthyridin-6(5H)-yl)-1- hydroxypyrido[2,3-d]pyrimidin-2(1H)-one.
  • Example 104 1-Hydroxy-4- ⁇ (2R)-2-methyl-4-[(1S)-1-(2,3,5- trifluoro ]-1-piperazinyl ⁇ pyrido[2,3-d]pyrimidin-2(1H)-one.
  • Example 105 1-Hydroxy-4- ⁇ (2R)-4-[(1S)-2-hydroxy-1-phenylethyl]-2- methyl-1-piperazinyl ⁇ pyrido[2,3-d]pyrimidin-2(1H)-one.
  • Example 106 1-hydroxy-4- ⁇ [1 -(phenylacetyl)-4- piperidinyl]amino ⁇ pyrido[2,3-d]pyrimidin-2(1 H)-one.
  • Example 107 1-Hydroxy-4- ⁇ (2R)-2-methyl-4-[(2,3,5- trifluorophenyl)methyl]-1 -piperazinyl ⁇ pyrido[2,3-d]pyrimidin-2(1 H)-one.
  • Example 108 4-(Hexahydro-1 (2H)-azocinyl)-1-hydroxypyrido[2,3- d ⁇ py ri m i d i n-2 ( 1 H)-o n e .
  • Example 109 4-[(1-Acetyl-4-piperidinyl)amino]-1-hydroxypyrido[2,3- cflpyrimi
  • Example 110 1-Hydroxy-4-(methyloxy)pyrido[2,3-d]pyrimidin-2(1H)- one.
  • Example 1 1 : 1 -Hydroxy-4-(4-methyl-1-piperazinyl)pyrido[2,3- d ⁇ py ri m i d i n-2 ( 1 H)-o n e .
  • Example 1 12 1 -Hydroxypyrido[2,3-d]pyrimidine-2,4(1 -/,3H)-dione.
  • Example 1 13 1 -Hydroxy-4-[methyl(phenylmethyl)amino]pyrido[2,3- d ⁇ py ri m i d i n-2 ( 1 H)-o n e .
  • Example 1 14 Ethyl 3'- ⁇ [(1 -hydroxy-2-oxo-1 ,2-dihydropyrido[2,3- cf]pyrimidin-4-yl)amino]methyl ⁇ -3-biphenylcarboxylate.
  • Example 1 15 3'-[(1 -Hydroxy-2-oxo-1 ,2-dihydropyrido[2,3-d]pyrimidin- 4-yl)amino]-4-biphenylcarboxamide.
  • Example 116 1-Hydroxy-4- ⁇ [4'-(1-piperazinylcarbonyl)-3- biphenylyl]amino ⁇ pyrido[2,3-d]pyrimidin-2(1H)-one.
  • Example 117 3'-[(1-Hydroxy-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidin- 4-yl)amino]-A/-methyl-4-biphenylcarboxamide.
  • Example 118 4- ⁇ 4-[(3,4-Dichlorophenyl)carbonyl]-1-piperazinyl ⁇ -1- hydroxypyrido[2,3-d]pyrimidin-2(1H)-one.
  • Example 1 19 1-Hydroxy-4-[2-(phenylmethyl)-1 -piperidinyl]pyrido[2,3- d]pyrim ne.
  • Example 120 4-(1 ,4'-Bipiperidin-1 '-yl)-1 -hydroxypyrido[2,3- d]pyrimidin-2(1 H)-one.
  • Example 121 1 -Hydroxy-4- ⁇ 4-[2-(methyloxy)ethyl]-1 - piperazinyl ⁇ pyrido[2,3-d]pyrimidin-2(1 H)-one.
  • Example 122 1-Hydroxy-4- ⁇ [4'-(1-pyrrolidinylcarbonyl)-4- biphenylyl]amino ⁇ pyrido[2,3-d]pyrimidin-2(1H)-one.
  • Example 123 1-Hydroxy-4-( ⁇ [4'-(trifluoromethyl)-4- biphenylyl]methyl ⁇ amino)pyrido[2,3-d]pyrimidin-2(1H)-one.
  • Example 124 Ethyl 3'- ⁇ [(1-hydroxy-2-oxo-1 ,2-dihydropyrido[2,3- cf]pyrimidin-4-yl)amino]methyl ⁇ -4-biphenylcarboxylate.
  • Example 125 V-[2-(Dimethylamino)ethyl]-4'-[(1-hydroxy-2-oxo-1 ,2- dihydropyrido[2,3-d]pyrimidin-4-yl)amino]-4-biphenylcarboxamide.
  • Example 126 4- ⁇ [3'-(Aminomethyl)-3-biphenylyl]amino ⁇ -1 - hydro idin-2(1 H)-one.
  • Example 127 N-(4-chlorophenyl)-1 -(1 -hydroxy-2-oxo-1 ,2- dihydropyrido[2,3-d]pyrimidin-4-yl)-3-piperidinecarboxamide.
  • Example 128 Phenylmethyl ⁇ [(2R)-1 -(1-hydroxy-2-oxo-1 ,2- dihydropyrido[2,3-d]pyrimidin-4-yl)-2-pyrrolidinyl]methyl ⁇ carbamate.
  • Example 129 N-(4-chlorophenyl)-3- ⁇ [4-(1 -hydroxy-2-oxo-1 ,2- dihydropyrido[2,3-d]pyrimidin-4-yl)-1 -piperazinyl]methyl ⁇ benzamide.
  • Example 130 4'-[(1 -Hydroxy-2-oxo-1 ,2-dihydropyrido[2,3-d]pyrimidin- 4-yl)amino]- V-[2-(methyloxy)ethyl]-4-biphenylcarboxamide.
  • Example 131 1 -Hydroxy-4- ⁇ [4'-(1 -piperazinylcarbonyl)-4- biphenylyl]amino ⁇ pyrido[2,3-d]pyrimidin-2(1 H)-one.
  • Example 132 1 -Hydroxy-4-( ⁇ 4'-[(4-methyl-1 -piperazinyl)carbonyl]-4- biphenylyl ⁇ amino)pyrido[2,3-d]pyrimidin-2(1 H)-one.
  • Example 133 1-Hydroxy-4-[4-(phenylacetyl)-1-piperazinyl]pyrido[2,3- d ⁇ py ri m i d i n-2 ( 1 H)-o n e .
  • Example 134 1-Hydroxy-4-[4-(phenylcarbonyl)-1- piperazinyl]pyrido[2,3-d]pyrimidin-2(1H)-one.
  • Example 135 1-Hydroxy-4-[((1R)-2-hydroxy-1- ⁇ [(phenylmethyl)oxy]methyl ⁇ ethyl)amino]pyrido[2,3-d]pyrimidin-2(1H)-one.
  • Example 136 1 -Hydroxy-4- ⁇ [(2R)-2- pyrrolidinylmethyl]amino ⁇ pyrido[2,3-d]pyrimidin-2(1 H)-one.
  • Example 137 4-(4- ⁇ [4-(Aminomethyl)phenyl]carbonyl ⁇ -1 -piperazinyl)- 1-hydroxypyrido[2,3-d]pyrimidin-2(1 H)-one.
  • Example 138 4'-[(1 -Hydroxy-2-oxo-1 ,2-dihydropyrido[2,3-d]pyrimidin- 4-yl)amino]- V, V-dimethyl-4-biphenylcarboxamide.
  • Example 139 1 -Hydroxy-4- ⁇ [4'-(4-morpholinylcarbonyl)-4- biphenylyl]amino ⁇ pyrido[2,3-d]pyrimidin-2(1 H)-one.
  • Example 140 4- ⁇ 4-[(2,5-Difluorophenyl)carbonyl]-1 -piperazinyl ⁇ -1 - hydroxypyrido[2,3-d]pyrimidin-2(1 H)-one.
  • Example 141 1 -Hydroxy-4- ⁇ [4'-(1 -piperidinylcarbonyl)-4- biphenylyl]amino ⁇ pyrido[2,3-d]pyrimidin-2(1 H)-one.
  • Example 142 1-Hydroxy-4-[(1 .S-thiazol ⁇ -ylmethy aminolpyridop.S- cf] py ri m i d i n-2 ( 1 H)-o n e .
  • Example 143 4-(3-Fluoro-1 -piperidinyl)-1-hydroxypyrido[2,3- d]pyrimidin-2 1 H -one.
  • Example 144 4-(4,4-Difluoro-1-piperidinyl)-1-hydroxypyrido[2,3- d]pyrimidin-2(1 H)-one. a) 2-(Tert-butoxyamino)nicotinonitrile.
  • Example 145 4-(4-Fluoro-1 -piperidinyl)-1-hydroxypyrido[2,3- d]pyrimidin-2 1 H -one.
  • Example 146 1 -Hydroxy-4-(4-thiomorpholinyl)pyrido[2,3-d]pyrimidin- 2(1 H)-o
  • Example 147 1 -Hydroxy-4-[4-(1 H-imidazol-2-ylmethyl)-1 - piperazinyl]pyrido[2,3-d]pyrimidin-2(1 H)-one.
  • Example 148 4-(1 , 1 -Dioxido-4-thiomorpholinyl)-1 -hydroxypyrido[2,3- d]pyrimi H)-one.
  • Example 149 1 -Hydroxy-4-(4-morpholinyl)pyrido[2,3-d]pyrimidin-
  • Example 150a 4- ⁇ [2-(Aminomethyl)phenyl]amino ⁇ -1 - hydroxypyrido[2,3-d]pyrimidin-2(1 H)-one and Example 150b: 4- ⁇ [(2- aminop
  • Example 151 4- ⁇ 4-[(3-Fluorophenyl)carbonyl]-1 -piperazinyl ⁇ -1 - hydroxypyrido[2,3-d]pyrimidin-2(1 H)-one.
  • Example 152 1-Hydroxy-4-[(phenylmethyl)thio]pyrido[2,3-d]pyrimidin- 2(1 H)-o
  • Example 153 4- ⁇ 4-[(4-Hexylphenyl)carbonyl]-1 -piperazinyl ⁇ -1 - hydroxypyrido[2,3-d]pyrimidin-2(1 H)-one.
  • Example 154 1 -Hydroxy-4- ⁇ [4'-(4-morpholinylcarbonyl)-3- biphenylyl]amino ⁇ pyrido[2,3-d]pyrimidin-2(1 H)-one.
  • Example 155 1 -Hydroxy-4- ⁇ [4'-(1-pyrrolidinylcarbonyl)-3- biphenylyl]amino ⁇ pyrido[2,3-d]pyrimidin-2(1 H)-one.
  • Example 156 1-Hydroxy-4- ⁇ [4'-(1-piperidinylcarbonyl)-3- biphenylyl]amino ⁇ pyrido[2,3-d]pyrimidin-2(1H)-one.
  • Example 157 4'-[(1-Hydroxy-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidin- 4-yl)amino]-4-biphenylcarboxylic acid.
  • Example 158 1-Hydroxy-4- ⁇ [4'-(4-morpholinyl)-3- biphenylyl]amino ⁇ pyrido[2,3-d]pyrimidin-2(1H)-one.
  • Example 159 4'-[(1-Hydroxy-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidin- 4-yl)amino]-3-biphenylcarboxylic acid.
  • Example 160 1-Hydroxy-4- ⁇ [4'-(4-morpholinyl)-4- biphen yrimidin-2(1H)-one.
  • Example 161 1-Hydroxy-4- ⁇ [3'-(trifluoromethyl)-4- biphen d]pyrimidin-2(1H)-one.
  • Example 162 4-[(3',5'-Dichloro-4-biphenylyl)amino]-1- hydroxypyrido[2,3-d]pyrimidin-2(1H)-one.
  • Example 163 1 -Hydroxy-4- ⁇ [3'-(methyloxy)-4- biphenylyl]amino ⁇ pyrido[2,3-d]pyrimidin-2(1 H)-one.
  • Example 164 4-[(4'-Amino-4-biphenylyl)amino]-1 -hydroxypyrido[2,3- d ⁇ py ri m i d i n-2 ( 1 H)-o n e .
  • Example 165 1 -Hydroxy-4-(4- ⁇ [4-methyl-3,5- bis(methyloxy)phenyl]carbonyl ⁇ -1 -piperazinyl)pyrido[2,3-d]pyrimidin-2(1 H)-one.
  • Example 166 4-[(3'-Chloro-4-biphenylyl)amino]-1 -hydroxypyrido[2,3- d ⁇ py ri m i d i n-2 ( 1 H)-o n e .
  • Example 167 1-Hydroxy-4-[(3'-methyl-4-biphenylyl)amino]pyrido[2,3- d ⁇ py ri m i d i n-2 ( 1 H)-o n e .
  • Example 168 ethyl 3'-[(1 -Hydroxy-2-oxo-1 ,2-dihydropyrido[2,3- cf]pyrimidin-4-yl)amino]-3-biphenylcarboxylate.
  • Example 169 ethyl 4'-[(1-Hydroxy-2-oxo-1,2-dihydropyrido[2,3- cf]pyrimidin-4-yl)amino]-3-biphenylcarboxylate.
  • Example 170 4'-[(1-Hydroxy-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidin- 4-yl)amino]-3-biphenylcarbonitrile.
  • Example 171 3'-[(1-Hydroxy-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidin- 4-yl)amino]-A/-phenyl-4-biphenylcarboxamide. [00571] The title compound was prepared in a similar manner to example 37 and isolated asanTFAsalt.
  • Example 172 4'-[(1-Hydroxy-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidin- 4-yl)amino]-A/-phenyl-4-biphenylcarboxamide.
  • Example 173 A/- ⁇ 4'-[(1-Hydroxy-2-oxo-1,2-dihydropyrido[2,3- cf]pyrimidin-4-yl)amino]-4-biphenylyl ⁇ acetamide.
  • Example 174 1-Hydroxy-4-[(4'-methyl-4-biphenylyl)amino]pyrido[2,3- d ⁇ py ri m n e .
  • Example 175 1 -Hydroxy-4- ⁇ [3'-(trifluoromethyl)-3- biphenylyl]amino ⁇ pyrido[2,3-d]pyrimidin-2(1 H)-one.
  • Example 176 4-[(3',5'-Dichloro-3-biphenylyl)amino]-1 - hydroxypyrido[2,3-d]pyrimidin-2(1 H)-one.
  • Example 177 4-[(3'-Chloro-3-biphenylyl)amino]-1 -hydroxypyrido[2,3- d ⁇ py ri m i d i n-2 ( 1 H)-o n e .
  • Example 178 1-Hydroxy-4-[(3'-methyl-3-biphenylyl)amino]pyrido[2,3- d ⁇ py ri m i d i n-2 ( 1 H)-o n e .
  • Example 179 1-Hydroxy-4- ⁇ [3'-(1-piperidinylcarbonyl)-3- biphen yrimidin-2(1H)-one.
  • Example 180 1-Hydroxy-4- ⁇ [3'-(1-pyrrolidinylcarbonyl)-3- biphen yrimidin-2(1H)-one.
  • Example 181 1-Hydroxy-4- ⁇ [4'-(methylamino)-3- biphenylyl]amino ⁇ pyrido[2,3-d]pyrimidin-2(1H)-one.
  • the title compound was prepared in a similar manner to example 144 and isolated as an TFA salt.
  • H NMR (300MHz, DMSO-d 6 ) ⁇ 9.94 (s, 1H), 8.80 (d, 1H), 8.74 (d, 1H), 7.94 (s, 1H), 7.74 (d, 1H), 7.49-7.34 (m, 5H), 6.70 (d, 2H), 2.74 (s, 3H); ES + MS: 360.2 (M + 1).
  • Example 182 3'-[(1-Hydroxy-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidin- 4-yl)amino]-3-biphenylcarboxylic acid.
  • Example 183 3'-[(1-Hydroxy-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidin- 4-yl)ami biphenylcarboxamide.
  • Example 184 1-Hydroxy-4-( ⁇ 3'-[(4-methyl-1-piperazinyl)carbonyl]-4- biphenylyl ⁇ amino)pyrido[2,3-d]pyrimidin-2(1H)-one.
  • Example 185 1 -Hydroxy-4- ⁇ [3'-(4-morpholinylcarbonyl)-4- biphenylyl]amino ⁇ pyrido[2,3-d]pyrimidin-2(1 H)-one.
  • Example 186 1 -Hydroxy-4- ⁇ [3'-(1 -piperazinylcarbonyl)-3- biphenylyl]amino ⁇ pyrido[2,3-d]pyrimidin-2(1 H)-one.
  • Example 187 3'-[(1 -Hydroxy-2-oxo-1 ,2-dihydropyrido[2,3-d]pyrimidin- 4-yl)am biphenylcarboxamide.
  • Example 189 4-[(4'-Chloro-3-biphenylyl)amino]-1-hydroxypyrido[2,3- d] py ri m i d i n-2 (1H)-o n e .
  • Example 190 1-Hydroxy-4- ⁇ [4'-(methyloxy)-3- biphenylyl]amino ⁇ pyrido[2,3-d]pyrimidin-2(1H)-one.
  • Example 191 1-Hydroxy-4- ⁇ [3'-(methyloxy)-3- biphenylyl]amino ⁇ pyrido[2,3-d]pyrimidin-2(1H)-one.
  • Example 192 N-[2-(Dimethylamino)ethyl]-3'-[(1-hydroxy-2-oxo-1,2- dihydropyrido[2,3-d]pyrimidin-4-yl)amino]-3-biphenylcarboxamide.
  • Example 193 1-Hydroxy-4-[(3'-hydroxy-3- biphenylyl)amino]pyrido[2,3-d]pyrimidin-2(1H)-one.
  • Example 194 3'-[(1-Hydroxy-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidin- 4-yl)amino]-3-biphenylcarbonitrile.
  • Example 195 3'-[(1 -Hydroxy-2-oxo-1 ,2-dihydropyrido[2,3-d]pyrimidin- 4-yl)amino]-4-biphenylcarboxylic acid.
  • Example 196 1-Hydroxy-4-[(4'-methyl-3-biphenylyl)amino]pyrido[2,3- d ⁇ py ri m i d i n-2 ( 1 H)-o n e .
  • Example 197 4-(3-Biphenylylamino)-1 -hydroxypyrido[2,3-d]pyrimidin- 2(1 H)-o
  • Example 199 3-[(1-Hydroxy-2-oxo-1 ,2-dihydropyrido[2,3-d]pyrimidin- 4-yl)amino]benzonitrile.
  • Example 200 4-[(3'-amino-3-biphenylyl)amino]-1 -hydroxypyrido[2,3- d]pyrimi
  • Example 201 1 -Hydroxy-4- ⁇ [3-(3-pyridinyl)phenyl]amino ⁇ pyrido[2,3- d]pyrimidin-2(1 H)-one.
  • Example 202 1 -Hydroxy-4- ⁇ [4'-(trifluoromethyl)-3- biphenylyl]amino ⁇ pyrido[2,3-d]pyrimidin-2(1 H)-one.
  • Example 203 4- ⁇ [(4-Bromophenyl)methyl]amino ⁇ -1 - hydroxy d]pyrimidin-2(1 H)-one.
  • Example 204 1 -Hydroxy-4- ⁇ [3'-(methylamino)-3- biphenylyl]amino ⁇ pyrido[2,3-d]pyrimidin-2(1 H)-one.
  • Example 205 1-Hydroxy-4- ⁇ [3'-(1-piperidinylcarbonyl)-4- biphenylyl]amino ⁇ pyrido[2,3-d]pyrimidin-2(1H)-one.
  • Example 206 1-Hydroxy-4- ⁇ [4-(2- naphthalenyl)phenyl]amino ⁇ pyrido[2,3-c]pyrimidin-2(1H)-one.
  • Example 207 4'-[(1-Hydroxy-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidin- 4-yl)amino]-V-[2-(methyloxy)ethyl]-3-biphenylcarboxamide.
  • Example 208 1 -Hydroxy-4-( ⁇ 3'-[(4-methyl-1 -piperazinyl)carbonyl]-4- biphen midin-2(1 H)-one.
  • Example 209 1 -Hydroxy-4- ⁇ [3'-(1-pyrrolidinylcarbonyl)-4- biphenylyl]amino ⁇ pyrido[2,3-d]pyrimidin-2(1 H)-one.
  • Example 210 1 -Hydroxy-4- ⁇ [4'-(trifluoromethyl)-4- biphenylyl]amino ⁇ pyrido[2,3-d]pyrimidin-2(1 H)-one.
  • Example 21 1 4'-[(1 -Hydroxy-2-oxo-1 ,2-dihydropyrido[2,3-d]pyrimidin- 4-yl)am itrile.
  • Example 213 1-Hydroxy-4- ⁇ [3-(3-quinolinyl)phenyl]amino ⁇ pyrido[2,3- d]pyrimidin-2(1 H)-one.
  • Example 214 1 -Hydroxy-4-( ⁇ 4-[6-(methyloxy)-3- pyridinyl]phenyl ⁇ amino)pyrido[2,3-d]pyrimidin-2(1 H)-one.
  • Example 215 1 -Hydroxy-4-( ⁇ 4-[5-(methyloxy)-3- pyridinyl]phenyl ⁇ amino)pyrido[2,3-d]pyrimidin-2(1 H)-one.
  • Example 216 4- ⁇ [4-(6-Fluoro-3-pyridinyl)phenyl]amino ⁇ -1 - hydroxypyrido[2,3-d]pyrimidin-2(1 H)-one.
  • Example 217 1 -Hydroxy-4-( ⁇ 3-[6-(methyloxy)-3- pyridinyl]phenyl ⁇ amino)pyrido[2,3-d]pyrimidin-2(1 H)-one.
  • Example 218 1 -Hydroxy-4-( ⁇ 3-[5-(methyloxy)-3- pyridinyl]phenyl ⁇ amino)pyrido[2,3-d]pyrimidin-2(1 H)-one.
  • Example 219 4- ⁇ [3-(6-Fluoro-3-pyridinyl)phenyl]amino ⁇ -1- hydroxypyrido[2,3-d]pyrimidin-2(1 H)-one.
  • Example 220 4'-[(1 -Hydroxy-2-oxo-1 ,2-dihydropyrido[2,3-d]pyrimidin- 4-yl)amino]-A/,A/-dimethyl-3-biphenylcarboxamide.
  • Example 221 4'-[(1 -Hydroxy-2-oxo-1 ,2-dihydropyrido[2,3-d]pyrimidin- 4-yl)amino]-A/-methyl-3-biphenylcarboxamide.
  • Example 222 1 -Hydroxy-4- ⁇ [3'-(4-morpholinylcarbonyl)-3- biphen -d]pyrimidin-2(1 H)-one.
  • Example 223 1-Hydroxy-4-[(3'-hydroxy-4- biphenylyl)amino]pyrido[2,3-d]pyrimidin-2(1 H)-one.
  • Example 224 (3R)-N-(4-chlorophenyl)-1-(1 -hydroxy-2-oxo-1 ,2- dihydropyrido[2,3-d]pyrimidin-4-yl)-3-piperidinecarboxamide.
  • Example 225 (3S)-N-(4-chlorophenyl)-1 -(1 -hydroxy-2-oxo-1 ,2- dihydropyrido[2,3-d]pyrimidin-4-yl)-3-piperidinecarboxamide.
  • Example 226 4-[(4'-Chloro-4-biphenylyl)amino]-1 -hydroxypyrido[2,3- d ⁇ py ri m i d i n-2 ( 1 H)-o n e .
  • Example 227 1 -Hydroxy-4- ⁇ [3'-(1 -piperazinylcarbonyl)-4- biphenylyl]amino ⁇ pyrido[2,3-d]pyrimidin-2(1 H)-one.
  • Example 228 1-Hydroxy-4- ⁇ [4-(1 - naphthalenyl)phenyl]amino ⁇ pyrido[2,3-c ]pyrimidin-2(1 H)-one.
  • Example 230 3'-[(1-Hydroxy-2-oxo-1 ,2-dihydropyrido[2,3-d]pyrimidin- 4-yl)amino]-A/-phenyl-3-biphenylcarboxamide.
  • Example 231 3'-[(1-Hydroxy-2-oxo-1 ,2-dihydropyrido[2,3-d]pyrimidin- 4-yl)amino]- V-[2-(methyloxy)ethyl]-3-biphenylcarboxamide.
  • Example 232 4- ⁇ [(3-Bromophenyl)methyl]amino ⁇ -1 - hydroxypyrido[2,3-d]pyrimidin-2(1 H)-one.
  • Example 233 3'-[(1-Hydroxy-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidin- 4-yl)amino]-A/,A/-dimethyl-3-biphenylcarboxamide.
  • Example 234 3'-[(1-Hydroxy-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidin- 4-yl)amino]-A/-methyl-3-biphenylcarboxamide.
  • Example 235 1-Hydroxy-4-( ⁇ 4'-[(4-methyl-1-piperazinyl)carbonyl]-3- biphenylyl ⁇ amino)pyrido[2,3-d]pyrimidin-2(1H)-one.
  • Example 236 4'- ⁇ [(1 -Hydroxy-2-oxo-1 ,2-dihydropyrido[2,3- cf]pyrimidin-4-yl)amino]methyl ⁇ - V-phenyl-4-biphenylcarboxamide.
  • Example 237 V-[2-(Dimethylamino)ethyl]-3'-[(1 -hydroxy-2-oxo-1 ,2- dihydropyrido[2,3-d]pyrimidin-4-yl)amino]-4-biphenylcarboxamide.
  • Example 238 5- ⁇ 3-[(1 -Hydroxy-2-oxo-1 ,2-dihydropyrido[2,3- d]pyrimidin-4-yl)amino]phenyl ⁇ -2-pyridinecarbonitrile.
  • Example 239 5- ⁇ 3-[(1 -Hydroxy-2-oxo-1 ,2-dihydropyrido[2,3- d]pyrimidin-4-yl)amino]phenyl ⁇ -3-pyridinecarbonitrile.
  • Example 240 4- ⁇ [3-(5-Fluoro-3-pyridinyl)phenyl]amino ⁇ -1 - hydroxypyrido[2,3-d]pyrimidin-2(1 H)-one.
  • Example 241 1 -Hydroxy-4-( ⁇ 4-[2-(methyloxy)-4- pyridinyl]phenyl ⁇ amino)pyrido[2,3-d]pyrimidin-2(1 H)-one.
  • Example 242 1 -Hydroxy-4-( ⁇ 3-[2-(methyloxy)-4- pyridinyl]phenyl ⁇ amino)pyrido[2,3-d]pyrimidin-2(1 H)-one.
  • Example 243 1 -Hydroxy-4- ⁇ [4-(2-pyridinyl)phenyl]amino ⁇ pyrido[2,3- d]pyrimidin-2(1 H)-one.
  • Example 244 1 -Hydroxy-4- ⁇ [3-(2-pyridinyl)phenyl]amino ⁇ pyrido[2,3- d]pyrimidin-2(1 H)-one.
  • Example 245 3- ⁇ 4-[(1 -Hydroxy-2-oxo-1 ,2-dihydropyrido[2,3- d]pyrimidin-4-yl)amino]phenyl ⁇ -4-pyridinecarboxamide.
  • Example 246 3- ⁇ 4-[(1 -Hydroxy-2-oxo-1 ,2-dihydropyrido[2,3- d]pyrimidin-4-yl)amino]phenyl ⁇ -4-pyridinecarbonitrile.
  • Example 247 3- ⁇ 3-[(1 -Hydroxy-2-oxo-1 ,2-dihydropyrido[2,3- d]pyrimidin-4-yl)amino]phenyl ⁇ -4-pyridinecarboxamide.

Abstract

1-hydroxypyrido[2,3-c/]pyrimidin-2(1 H)-one compounds that inhibit reverse transcriptase, particularly 1-hydroxypyrido[2,3-d]pyrimidin-2(1 H)-one compounds that inhibit the RNase H domain of a human HIV reverse transcriptase, and solvates, hydrates and pharmaceutically acceptable salts thereof, and methods of using same.

Description

THERAPEUTIC COMPOUNDS
FIELD OF THE INVENTION
[0001] The present invention relates to 1 -hydroxypyrido[2,3-d]pyrimidin-2(1 H)-one compounds of formula (I) that inhibit reverse transcriptase, particularly compounds of formula (I) that inhibit HIV reverse transcriptase, and still more particularly compounds of formula (I) that inhibit the RNase H domain of a human H IV reverse transcriptase.
BACKGROUND ART
[0002] The human immunodeficiency virus ("HIV") is the causative agent for acquired immunodeficiency syndrome ("AI DS"), a disease characterized by the destruction of the immune system, particularly of CD4+ T-cells, with attendant susceptibility to opportunistic infections, and its precursor AIDS-related complex ("ARC"), a syndrome characterized by symptoms such as persistent generalized lymphadenopathy, fever and weight loss. HIV is a retrovirus; the conversion of its RNA to DNA is accomplished through the action of the enzyme reverse transcriptase. Compounds that inhibit the function of reverse transcriptase inhibit replication of HIV in infected cells. Such compounds are useful in the prevention or treatment of HIV infection in humans.
[0003] HIV reverse transcriptase contains two distinct active sites known as the polymerization and ribonuclease H motifs. The reverse transcriptase protein consists of a p51 and p66 subunit which form a heterodimer. The p51 subunit is formed through proteolytic cleavage of the p66 subunit. The subunits have a common amino terminus with the longer p66 subunit consisting of additional residues that form the a ribonuclease H (RNase H) domain. The RNase H is a well known enzymatic motif that cleaves the RNA strand of DNA/RNA hybrid nucleic acid. The action of H IV ribonuclease H is essential for viral replication and therefor the compounds of this invention are useful as antiviral agents. [0004] The productive reverse transcription sequence involves several steps catalyzed by reverse transcriptase. Among those steps are RNA dependent DNA polymerization, ribonuclease cleavage of the template RNA and DNA dependent DNA polymerization. The process is a well characterized sequence beginning with a t-RNA primer binding to the HIV single stranded RNA (ss RNA). This begins a minus strand synthesis of DNA using the HIV RNA as template. This initial step is terminated resulting in strong stop (-) strand DNA. The action of the HIV ribonuclease H active site is able to make cleavages in the RNA strand once the DNA synthesis has passed. This cleavage of the RNA template is essential for further production of viral DNA. Upon cleavage and dissociation of the original template segment of the RNA strand, the first strand transfer event allows a repositioning of the strong stop DNA to the 3' end of the viral RNA. This can happen on the same strand or a different strand of viral RNA that is present. Further (-) strand DNA synthesis is then able to proceed. During this sequence, the viral ribonuclease H makes several cuts in the RNA strand once the DNA is made. However a highly conserved region called the polypurine tract of the viral RNA is preserved and serves as the primer for (+) strand DNA synthesis. After (+) strand DNA synthesis, ribonuclease H again is responsible for removal of the original t-RNA and polypurine tract primers. At this point bidirectional DNA synthesis can occur once the second strand transfer event is achieved.
[0005] There is continued need to find new therapeutic agents to treat human diseases. H IV reverse transcriptase is an attractive target for the discovery of new therapeutics due to its important role in viral infections, particularly H IV infections.
SUMMARY OF THE INVENTION
[0006] Embodiments of the present invention features compounds that are H IV reverse transcriptase inhibitors and therefore are useful in the inhibition of H IV replication, the prevention and/or treatment of infection by HIV, and in the treatment of AIDS and/or ARC. The present invention features compounds of formula (I):
Figure imgf000003_0001
Detailed Description of Specific Embodiments
[0008] Definitions. As used in this description and the accompanying claims, the following terms shall have the meanings indicated, unless the context otherwise requires:
[0009] The present invention includes the compounds of formula (I), useful in treating or preventing viral infections, particularly retroviral infections, including human inmmunodeficiency virus (e.g. HIV-1 and HIV-2) infections, xenotropic murine leukemia virus (XMRV) infections and XMRV-related virus infections, human T-cell
leukemia/lymphoma virus (HTLV1 ) infections, HTLV2 infections, human endogenous retrovirus (HERV) infections, including MS-associated retrovirus (MSRV ), H ERV associated with the HELLP syndrome and pre-eclampsia, HERV liked to schizophrenia, and the HERV- K (HML2) family of retroviruses, pharmaceutical compositions comprising compounds of formula (I), and processes for preparing the compounds.
[0010] In one embodiment of the invention there is provided a compound of formula
Figure imgf000004_0001
(I)
wherein
[0011] R1 is hydrogen, halogen, -N R2R3, nitrogen-containing heterocycle connected via the nitrogen, HetZ, -OR2, -SR2;
[0012] R2 and R3 are independently selected from the group consisting of
-(R4)p(R5)q, R2 and R3 may be taken together along with the nitrogen atom to form a 4-10 membered heterocyclic ring;
[0013] R4 is selected from -(R18)K-, ArylA, heteroarylA, heterocycle;
[0014] R5 is independently selected from hydrogen, halogen, -(R19)K-, arylB, heteroarylB, heterocycle, Rz, two independent R5 groups may be taken together to form a 4- 10 membered ring;
[0015] Rz is selected from halogen, -(R21)K(RZ )-, C -8alkyl, d-C8haloalkyl, C3- iocycloalkyl, -heterocycle, -R6, -CN, -NR6R7, -OR6, -C(0)OR6, -C(0)R6, -C(0)NR6R7, - C(0)HetY, -NR6C(0)R7, -NR6C(0)OR7, -NR6C(0)N R7R8, -NR6C(0)HetY, -OC(0)R7, - OC(0)OR7, -OC(0)NR7R8, -OC(0)HetY, -C(S)OR6, -C(S)R6, -C(S)NR6R7, -C(S)HetY, - NR6C(S)R7, -NR6C(S)OR7, -NR6C(S)NR7R8, -N R6C(S)HetY, -OC(S)R7, -OC(S)OR7, - OC(S)NR7R8, -OC(S)HetY, -C(N R8)OR6, -C(N R8)R6, -C(N R8)NR6R7, -C(NR8)HetY, - NR6C(NR8)R7, -NR6C(NR8)OR7, -NR6C(NR8)NR7R8, -NR6C(NR8)HetY, -OC(NR8)R7, - OC(NR8)OR7, -OC(NR8)NR7R8, -OC(NR8)HetY, -S(0)nOR6, -S(0)nR6, -S(0)nNR6R7, - S(0)nHetY, -NR6S(0)nR7, -N R6S(0)nOR7, -NR6S(0)nNR7R8, -NR6S(0)nHetY, -N3, -N02, - BOR6OR7;
[0016] Rz' is selected from hydrogen, halogen, -(R21)K(RZ")-, C1-8alkyl, C C8haloalkyl, C3-iocycloalkyl, -heterocycle, -R6, -CN, -N R6R7, -OR6, -C(0)OR6, -C(0)R6, -C(0)NR6R7, - C(0)HetY, -NR6C(0)R7, -NR6C(0)OR7, -NR6C(0)N R7R8, -NR6C(0)HetY, -OC(0)R7, - OC(0)OR7, -OC(0)NR7R8, -OC(0)HetY, -C(S)OR6, -C(S)R6, -C(S)NR6R7, -C(S)HetY, - NR6C(S)R7, -NR6C(S)OR7, -NR6C(S)NR7R8, -N R6C(S)HetY, -OC(S)R7, -OC(S)OR7, - OC(S)NR7R8, -OC(S)HetY, -C(N R8)OR6, -C(N R8)R6, -C(N R8)NR6R7, -C(NR8)HetY, - NR6C(NR8)R7, -NR6C(NR8)OR7, -NR6C(NR8)NR7R8, -NR6C(NR8)HetY, -OC(NR8)R7, - OC(NR8)OR7, -OC(NR8)NR7R8, -OC(NR8)HetY, -S(0)nOR6, -S(0)nR6, -S(0)nNR6R7, - S(0)nHetY, -NR6S(0)nR7, -N R6S(0)nOR7, -NR6S(0)nNR7R8, -NR6S(0)nHetY, -N3, -N02, - BOR6OR7;
[0017] Rz is selected from hydrogen, halogen, C1-8alkyl, d-C8haloalkyl, C3- iocycloalkyl, -heterocycle, -R6, -CN, -NR6R7, -OR6, -C(0)OR6, -C(0)R6, -C(0)NR6R7, - C(0)HetY, -NR6C(0)R7, -NR6C(0)OR7, -NR6C(0)N R7R8, -NR6C(0)HetY, -OC(0)R7, - OC(0)OR7, -OC(0)NR7R8, -OC(0)HetY, -C(S)OR6, -C(S)R6, -C(S)NR6R7, -C(S)HetY, - NR6C(S)R7, -NR6C(S)OR7, -NR6C(S)NR7R8, -N R6C(S)HetY, -OC(S)R7, -OC(S)OR7, - OC(S)NR7R8, -OC(S)HetY, -C(N R8)OR6, -C(N R8)R6, -C(N R8)NR6R7, -C(NR8)HetY, - NR6C(NR8)R7, -NR6C(NR8)OR7, -NR6C(NR8)NR7R8, -NR6C(NR8)HetY, -OC(NR8)R7, - OC(NR8)OR7, -OC(NR8)NR7R8, -OC(NR8)HetY, -S(0)nOR6, -S(0)nR6, -S(0)nNR6R7, - S(0)nHetY, -NR6S(0)nR7, -N R6S(0)nOR7, -NR6S(0)nNR7R8, -NR6S(0)nHetY, -N3, -N02, - BOR6OR7;
[0018] R6, R7 and R8 are independently selected from hydrogen, -(R22)K(RZ )-, Ci_ 8alkyl, C3-i0cycloalkyl, arylB, heteroarylB, heterocycle, wherein any two of the R6, R7 and R8 may be taken together to form a 4-10 membered heterocyclic or heteroaryl ring;
[0019] HetY is a 4-8 membered heterocyclic ring containing one or more optionally substituted heteroatoms;
[0020] wherein alkyl, cycloalkyi, heterocycle, arylA, heteroarylA may be optionally substituted with 1 -4 substituents independently selected from the group consisting of hydrogen, halogen, -CF3, CrC8haloalkyl, -(R9)p(R10)q, , heterocycle optionally substituted with oxo, Rz and arylB, wherein two independent substituents may be taken together to form a 4-10 membered ring;
[0021] and wherein heteroarylB may be optionally substituted with 1 -4 substituents independently selected from the group consisting of hydrogen, halogen, -CF3, Ci- C8haloalkyl, -(R9)p(R11)q, Rz; heterocycle, wherein two independent substituents may be taken together to form a 4-10 membered ring;
[0022] and wherein arylB may be optionally substituted with 1 -4 substituents independently selected from the group consisting of hydrogen, halogen, -CF3, Ci- C8haloalkyl, -(R9)p(R10)q, , heterocycle optionally substituted with oxo, Rz and arylC, wherein two independent substituents may be taken together to form a 4-10 membered ring;
[0023] R9 is selected from -(R20)K-;
[0024] R-io is H, halogen, d-8haloalkyl, heterocycle, arylB, heteroarylB, -Rz;
[0025] Rii is H, halogen, Ci-8haloalkyl, heterocycle, arylC, heteroarylC, -Rz;
[0026] ArylC, heteroarylC may be optionally substituted with 1 -4 substituents independently selected from the group consisting of hydrogen, halogen, -Ci-C8haloalkyl, heterocycle, -Rz; wherein two independent substituents may be taken together to form a 4- 10 membered ring;
[0027] HetZ is selected from
Figure imgf000006_0001
Figure imgf000006_0002
[0028] wherein T, U, V, X, Y, Z are chosen from O, -N(R12)-, S(0)n, and
-C(R12)(R13)- optionally substituted with oxo to form a saturated, partially unsaturated or aryl ring fused to ring A which is a 5 or 6 membered arylA or heteroarylA ring;
[0029] R12 and R13 are independently selected from hydrogen, halogen, -NR6R7, - OR6, C1-8alkyl, d-C8haloalkyl, C3-iocycloalkyl, C2-8alkenyl, C3-8cycloalkenyl, C3-8alkynyl, and - Rz, R12 and R13 substituents may be combined to form a 3-8 membered ring, form a double bond, or form an oxo (=0) as the valence allows;
[0030] R14 and R15 are independently selected from hydrogen, halogen, -NR6R7, - OR6, C1-8alkyl, d-C8haloalkyl, C3-10cycloalkyl, C2-8alkenyl, C3-8cycloalkenyl, C3-8alkynyl, and - Rz, R14 and R15 substituents may be combined to form a 3-8 membered ring, form a double bond, form a triple bond, or form an oxo (=0) as the valence allows;
[0031] R16 and R17 are independently selected from hydrogen, halogen, -NR6R7, - OR6, C1-8alkyl, d-Cshaloalkyl, C3-iocycloalkyl, C2-8alkenyl, C3-8cycloalkenyl, C3-8alkynyl, and - Rz, R16 and R17 substituents may be combined to form a 3-8 membered ring, form a double bond, form a triple bond, or form an oxo (=0) as the valence allows;
[0032] R18 is independently selected from -(C(R14)(R15))j-, C3-i0cycloalkyl, C3- ecycloalkenyl, C3-8alkynyl, heterocycle;
[0033] R19 is independently selected from -(C(R16)(R17))j-, C3-10cycloalkyl, C3- ecycloalkenyl, C3-8alkynyl, heterocycle;
[0034] R20 is independently selected from -(C(R12)(R13))j-, C3-i0cycloalkyl, C3- ecycloalkenyl, C3-8alkynyl, heterocycle;
[0035] R21 is independently selected from -(C(R12)(R13))j-, C3-i0cycloalkyl, C3- ecycloalkenyl, C3-8alkynyl, heterocycle;
[0036] R22 is independently selected from -(C(R12)(R13))j-, C3-i0cycloalkyl, C3- scycloalkenyl, C3-8alkynyl, heterocycle;
[0037] n is O, 1 , or 2;
[0038] P is 0, 1 , 2 or 3;
[0039] Q is 0, 1 , 2 or 3;
[0040] J is 1 -8;
[0041] K is 1-8;
[0042] or a pharmaceutically acceptable salt thereof.
[0043] A used herein the term "alkyl", alone or in combination with any other term, refers to a straight-chain or branched-chain saturated aliphatic hydrocarbon radical containing the specified number of carbon atoms. Examples of alkyl radicals include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isoamyl, n-hexyl and the like.
[0044] The term "cycloalkyl" refers to a saturated or partially saturated carbocyclic ring composed of 3-10 carbons in any chemically stable configuration. Examples of suitable carbocyclic groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and
cyclohexenyl.
[0045] The term "alkenyl," alone or in combination with any other term, refers to a straight-chain or branched-chain alkyl group with at least one carbon-carbon double bond. Examples of alkenyl radicals include, but are not limited to, ethenyl, propenyl, isopropenyl, butenyl, isobutenyl, pentenyl, hexenyl, hexadienyl and the like.
[0046] The term "alkynyl" refers to hydrocarbon groups of either a straight or branched configuration with one or more carbon-carbon triple bonds which may occur in any stable point along the chain, such as ethynyl, propynyl, butynyl, pentynyl, and the like.
[0047] The term "alkoxy" refers to an alkyl ether radical, wherein the term "alkyl" is defined above. Examples of suitable alkyl ether radicals include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy and the like.
[0048] The term "aryl" alone or in combination with any other term, refers to a carbocyclic aromatic moiety (such as phenyl or naphthyl) containing the specified number of carbon atoms, preferably from 6-14 carbon atoms, and more preferably from 6-10 carbon atoms. Examples of aryl radicals include, but are not limited to, phenyl, naphthyl, indenyl, azulenyl, fluorenyl, anthracenyl, phenanthrenyl, tetrahydronaphthyl, indanyl, phenanthridinyl and the like. Unless otherwise indicated, the term "aryl" also includes each possible positional isomer of an aromatic hydrocarbon radical, such as in 1 -naphthyl, 2-naphthyl, 5- tetrahydronaphthyl, 6-tetrahydronaphthyl, 1 -phenanthridinyl, 2-phenanthridinyl, 3- phenanthridinyl, 4-phenanthridinyl, 7-phenanthridinyl, 8-phenanthridinyl, 9-phenanthridinyl and 10-phenanthridinyl. Examples of aryl radicals include, but are not limited to, phenyl, naphthyl, indenyl, azulenyl, fluorenyl, anthracenyl, phenanthrenyl, tetrahydronaphthyl, indanyl, phenanthridinyl and the like.
[0049] The term "heterocycle," "heterocyclic," and "heterocyclyl" as used herein, refer to a 3- to 8- membered monocyclic heterocyclic ring or 8- to 1 1 - membered bicyclic heterocyclic ring system any ring of which is either saturated, partially saturated or unsaturated, and which may be optionally benzofused if monocyclic. Each heterocycle consists of one or more carbon atoms and from one to four heteroatoms selected from the group consisting of N, O and S, and wherein the nitrogen and sulfur heteroatoms may optionally be oxidized, and the nitrogen atom may optionally be quaternized, and including any bicyclic group in which any of the above-defined heterocyclic rings is fused to a benzene ring. The heterocyclic ring may be attached at any carbon or heteroatom, provided that the attachment results in the creation of a stable structure. Preferred heterocycles include 5-7 membered monocyclic heterocycles and 8-10 membered bicyclic heterocycles.
[0050] As used herein, the term "reactive electrophile" or "reactive electrophiles" means alkylating or acylating reagent. These compounds include alkyl halides, alkyl tosylates, alkyi mesylates and alkyi triflates. Additionally they include acid chlorides and the like. Compounds such as acetyl chloride, methyl iodide, allyl iodide, butyl iodide, methyl triflate, benzyl bromide are examples.
[0051] When the heterocyclic ring has substituents, it is understood that the substituents may be attached to any atom in the ring, whether a heteroatom or a carbon atom, provided that a stable chemical structure results. "Heteroaromatics" or "heteroaryl" are included within the heterocycles as defined above and generally refers to a heterocycle in which the ring system is an aromatic monocyclic or polycyclic ring radical containing five to twenty carbon atoms, preferably five to ten carbon atoms, in which one or more ring carbons, preferably one to four, are each replaced by a heteroatom such as N, O, S and P. Preferred heteroaryl groups include 5-6 membered monocyclic heteroaryls and 8 - 10 membered bicyclic heteroaryls. Also included within the scope of the term "heterocycle, "heterocyclic" or "heterocyclyl" is a group in which a non-aromatic heteroatom-containing ring is fused to one or more aromatic rings, such as in an indolinyl, chromanyl,
phenanthridinyl or tetrahydro-quinolinyl, where the radical or point of attachment is on the non-aromatic heteroatom-containing ring. Unless otherwise indicated, the term
"heterocycle, "heterocyclic" or "heterocyclyl" also included each possible positional isomer of a heterocyclic radical, such as in 1 -indolinyl, 2-indolinyl, 3-indolinyl. Examples of heterocycles include imidazolyl, imidazolinoyl, imidazolidinyl, quinolyl, isoquinolyl, indolyl, indazolyl, indazolinolyl, perhydropyridazyl, pyridazyl, pyridyl, pyrrolyl, pyrrolinyl, pyrrolidinyl, pyrazolyl, pyrazinyl, quinoxolyl, piperidinyl, pyranyl, pyrazolinyl, piperazinyl, pyrimidinyl, pyridazinyl, morpholinyl, thiamorpholinyl, furyl, thienyl, triazolyl, thiazolyl, carbolinyl, tetrazolyl, thiazolidinyl, benzofuranoyl, thiamorpholinyl sulfone, oxazolyl, oxadiazolyl, benzoxazolyl, oxopiperidinyl, oxopyrrolidinyl, oxoazepinyl, azepinyl, isoxozolyl, isothiazolyl, furazanyl, tetrahydropyranyl, tetrahydrofuranyl, thiazolyl, thiadiazoyl, dioxolyl, dioxinyl, oxathiolyl, benzodioxolyl, dithiolyl, thiophenyl, tetrahydrothiophenyl, sulfolanyl, dioxanyl, dioxolanyl, tetahydrofurodihydrofuranyl, tetrahydropyranodihydrofuranyl, dihydropyranyl, tetradyrofurofuranyl and tetrahydropyranofuranyl.
[0052] The term "heteroatom" means nitrogen, oxygen, or sulfur and includes any oxidized form of nitrogen, such as N(O) {N+-0"} and sulfur such as S(O) and S(0)2, and the quaternized form of any basic nitrogen.
[0053] The term "halogen" or "halo" means a substituent selected from fluorine, chlorine, bromine, and iodine, which is understood by those of skill in the art to include substituents written as -F, -CI, -Br and -I , respectively. Thus, haloalkyl, for example, includes substituents such as -CHI2, -CH2F, -CCI=CHCI, -CHBrCH2Br and the like.
[0054] A combination of substituents or variables is permissible only if such a combination results in a stable or chemically feasible compound. A stable compound or chemically feasible compound is one in which the chemical structure is not substantially altered when kept at a temperature of 40 °C or less, in the absence of moisture or other chemically reactive conditions, for at least a week.
[0055] Unless otherwise stated, structures depicted herein are also meant to include all stereochemical forms of the structure, i.e., the R and S configurations for each asymmetric center. Therefore, racemates and racemic mixtures, single enantiomers, diastereomeric mixtures and individual diastereoisomers of the present compounds are expressly included within the scope of the invention. Although the specific compounds exemplified herein may be depicted in a particular stereochemical configuration, compounds having either the opposite stereochemistry at any given chiral center or mixtures thereof are also envisioned.
[0056] Unless otherwise stated, structures depicted herein are also meant to include compounds which differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the present structures except for the replacement of a hydrogen by a deuterium or tritium, or the replacement of a carbon by a 13C- or 14C-enriched carbon are also within the scope of this invention.
[0057] It will be apparent to one skilled in the art that certain compounds of this invention may exist in alternative tautomeric forms. All such tautomeric forms of the present compounds are within the scope of the invention. Unless otherwise indicated, the representation of either tautomer is meant to include the other.
[0058] The term "pharmaceutically effective amount" refers to an amount effective in treating a virus infection, for example an H IV infection, in a patient either as monotherapy or in combination with other agents. The term "treating" as used herein refers to the alleviation of symptoms of a particular disorder in a patient, or the improvement of an ascertainable measurement associated with a particular disorder, and may include the suppression of symptom recurrence in an asymptomatic patient such as a patient in whom a viral infection has become latent. The term "prophylactically effective amount" refers to an amount effective in preventing a virus infection, for example an H IV infection, or preventing the occurrence of symptoms of such an infection, in a patient. As used herein, the term
"patient" refers to a mammal, including a human. [0059] The term "pharmaceutically acceptable carrier or adjuvant" refers to a carrier or adjuvant that may be administered to a patient, together with a compound of this invention, and which does not destroy the pharmacological activity thereof and is nontoxic when administered in doses sufficient to deliver a therapeutic amount of the antiviral agent.
[0060] The term "treatment" as used herein refers to the alleviation of symptoms of a particular disorder in a patient, or the improvement of an ascertainable measurement associated with a particular disorder, and may include the suppression of symptom recurrence in an asymptomatic patient such as a patient in whom a viral infection has become latent. Treatment may include prophylaxis which refers to preventing a disease or condition or preventing the occurrence of symptoms of such a disease or condition, in a patient. As used herein, the term "patient" refers to a mammal, including a human.
[0061] As used herein, the term "subject" refers to a patient, animal or a biological sample. The term "biological sample", as used herein, includes, without limitation, cell cultures or extracts thereof; preparations of an enzyme suitable for in vitro assay; biopsied material obtained from a mammal or extracts thereof; and blood, saliva, urine, feces, semen, tears, or other body fluids or extracts thereof.
[0062] As used herein the term "AIDS" refers to acquired immunodeficiency syndrome. AIDS is a disease characterized by destruction of the immune system, particularly of CD4+ T-cells, with attendant susceptibility to opportunistic infections.
[0063] As used herein the term "H lV-related reverse transcriptase" means a reverse transcriptase from any variant of a human immunodeficiency virus (HIV), a reverse transcriptase from a human T-cell lymphotropic virus ("HTLV"), or a reverse transcriptase from any related immunodeficiency virus which targets a non-human mammal, such as a reverse transcriptase from a feline immunodeficiency virus ("FIV"), a reverse transcriptase from a feline leukemia virus ("FLV"), a reverse transcriptase from a simian
immunodeficiency virus ("SIV"), a reverse transcriptase from a bovine leukemia virus ("BLV"), and a reverse transcriptase from an equine infectious anemia virus ("EIAV"), and other such reverse transcriptases. HlV-related reverse transcriptase includes, but is not limited to, a reverse transcriptase from HTLV-1 , HTLV-2, HTLV-3, HTLV-4, HIV-1 (formerly known as HTLV-3), HIV-2, FIV, FIV IV, BLV, MLV (murine leukemia virus), and simian viruses such as SRV1 -D. SRV2-D,SMP-D, sooty mangabey SIVSMMH4, macaque SIVMM142, macaque SIVMM251 , African green monkey STLV-l llagm, and MoMLV (Moloney murine leukemia virus). [0064] As used herein, a "reverse transcriptase inhibitor that is not a reverse transcriptase of formula 1 means any other reverse transcriptase inhibitor, whether synthetic, semi-synthetic, a small molecule, a peptide, a protein, a nucleic acid, an antisense nucleic acid compound, a miRNA compound, an siRNA compound, an antibody, and the like.
[0065] Throughout this specification, the word "comprise" or variations such as "comprises" or "comprising" will be understood to imply the inclusion of a stated integer or groups of integers but not the exclusion of any other integer or group of integers.
[0066] Pharmaceutically acceptable salts of the compounds according to the invention include those derived from pharmaceutically acceptable inorganic and organic acids and bases. Examples of suitable acids include hydrochloric, hydrobromic, sulfuric, nitric, perchloric, fumaric, maleic, phosphoric, glycolic, lactic, salicylic, succinic, toluene-p- sulfonic, tartaric, acetic, citric, methanesulfonic, ethanesulfonic, formic, benzoic, malonic, naphthalene-2-sulfonic and benzenesulfonic acids. Other acids, such as oxalic, while not in themselves pharmaceutically acceptable, may be employed in the preparation of salts useful as intermediates in obtaining the compounds of the invention and their
pharmaceutically acceptable acid addition salts.
[0067] Salts derived from appropriate bases include alkali metal (e.g. sodium), alkaline earth metal (e.g., magnesium), ammonium, NW4 + (wherein W is C1-4 alkyl) and other amine salts. Physiologically acceptable salts of a hydrogen atom or an amino group include salts or organic carboxylic acids such as acetic, lactic, tartaric, malic, isethionic, lactobionic and succinic acids; organic sulfonic acids such as methanesulfonic, ethanesulfonic, benzenesulfonic and p-toluenesulfonic acids and inorganic acids such as hydrochloric, sulfuric, phosphoric and sulfamic acids. Physiologically acceptable salts of a compound with a hydroxy group include the anion of said compound in combination with a suitable cation such as Na+, NH4 +, and NW4 + (wherein W is a C^alkyl group). Preferred salts include sodium, calcium, potassium, magnesium, choline, meglumine, hydrochloride, and quaternary ammonium.
[0068] Other compounds of this invention may be prepared by one skilled in the art following the teachings of the specification coupled with knowledge in the art using reagents that are readily synthesized or commercially available.
[0069] Any reference to any of the above compounds also includes a reference to a pharmaceutically acceptable salt thereof. [0070] Salts of the compounds of the present invention may be made by methods known to a person skilled in the art. For example, treatment of a compound of the present invention with an appropriate base or acid in an appropriate solvent will yield the
corresponding salt.
[0071] Esters of the compounds of the present invention are independently selected from the following groups: (1 ) carboxylic acid esters obtained by esterification of the hydroxy groups, in which the non-carbonyl moiety of the carboxylic acid portion of the ester grouping is selected from straight or branched chain alkyl (for example, acetyl, n-propyl, t-butyl, or n- butyl), alkoxyalkyl (for example, methoxymethyl), aralkyl (for example, benzyl), aryloxyalkyl (for example, phenoxymethyl), aryl (for example, phenyl optionally substituted by, for example, halogen, C1-4alkyl, or Ci-4alkoxy or amino); (2) sulfonate esters, such as alkyl- or aralkylsulfonyl (for example, methanesulfonyl); (3) amino acid esters (for example, L-valyl or L-isoleucyl); (4) phosphonate esters and (5) mono-, di- or triphosphate esters. The phosphate esters may be further esterified by, for example, a Ci-2o alcohol or reactive derivative thereof, or by a 2,3-di (C6-24)acyl glycerol.
[0072] In such esters, unless otherwise specified, any alkyl moiety present advantageously contains from 1 to 18 carbon atoms, particularly from 1 to 6 carbon atoms, more particularly from 1 to 4 carbon atoms, Any cycloalkyl moiety present in such esters advantageously contains from 3 to 6 carbon atoms. Any aryl moiety present in such esters advantageously comprises a phenyl group.
[0073] The pre tion features a compound of formula (1 )
Figure imgf000013_0001
formula (1 )
selected from an7 of the compounds prepared and disclosed in Examples 1 -344 that meet the limitations of formula (1 ), as well as solvates, hydrates and pharmaceutically acceptable salts thereof.
[0074] Compounds of the present invention are useful as HIV reverse transcriptase inhibitors, particularly as inhibitors of RNase H within HIV reverse transcriptase. One aspect of the instant invention relates to methods of treating or preventing viral infection, for example an H IV infection, in a biological sample comprising contacting the biological sample with compounds of formula (I) or pharmaceutically acceptable derivatives thereof. Another aspect of the instant invention relates to methods of treating or preventing viral infection, for example, an HIV infection, in a patient comprising administering to the patient a
therapeutically effective amount of compounds of formula (I) or pharmaceutically acceptable derivatives thereof.
[0075] The compounds according to the invention are particularly suited to the treatment or prophylaxis of HIV infections and associated conditions. Reference herein to treatment extends to prophylaxis as well as the treatment of established infections, symptoms, and associated clinical conditions such as AIDS related complex (ARC), Kaposi's sarcoma, and AIDS dementia.
[0076] The compounds of the present invention exhibit advantages over previously disclosed reverse transcriptase inhibitors, for example increased potency, metabolic stability, increased therapeutic index, or other pharmaceutical properties.
[0077] According to one embodiment of the invention, compounds of formula (I) or salts thereof may be formulated into compositions. In a preferred embodiment, the composition is a pharmaceutical composition, which comprises a compound of formula (I) and pharmaceutically acceptable carrier, adjuvant or vehicle. In one embodiment, the composition comprises an amount of a compound of the present invention effective to treat or prevent viral infection, for example an HIV infection, in a biological sample or in a patient. In another embodiment, compounds of this invention and pharmaceutical compositions thereof, which comprise an amount of a compound of the present innovation effective to inhibit viral replication or to treat or prevent a viral infection or disease or disorder, for example an H IV infection, and a pharmaceutically acceptable carrier, adjuvant or vehicle, may be formulated for administration to a patient, for example, for oral administration.
[0078] The present invention features compounds according to the invention for use in medical therapy, for example for the treatment or prophylaxis of a viral infection, for example an H IV infection and associated conditions. The compounds according to the invention are especially useful for the treatment of AIDS and related clinical conditions such as AIDS related complex (ARC), progressive generalized lymphadenopathy (PGL), Kaposi's sarcoma, thrombocytopenic purpura, AI DS-related neurological conditions such as AIDS dementia complex, multiple sclerosis or tropical paraperesis, anti-HIV antibody-positive and HIV-positive conditions, including such conditions in asymptomatic patients.
[0079] According to another aspect, the present invention provides a method for the treatment or prevention of the symptoms or effects of a viral infection in an infected patient, for example, a mammal including a human, which comprises administering to said patient a pharmaceutically effective amount of a compound according to the invention. According to one aspect of the invention, the viral infection is a retroviral infection, in particular an HIV infection.
[0080] The present invention further includes the use of a compound according to the invention in the manufacture of a medicament for administration to a subject for the treatment of a viral infection, in particular and HIV infection.
[0081] The compounds according to the invention may also be used in adjuvant therapy in the treatment of HIV infections or HIV-associated symptoms or effects, for example Kaposi's sarcoma.
[0082] The present invention further provides a method for the treatment of a clinical condition in a patient, for example, a mammal including a human which clinical condition includes those which have been discussed hereinbefore, which comprises treating said patient with a pharmaceutically effective amount of a compound according to the invention. The present invention also includes a method for the treatment or prophylaxis of any of the aforementioned diseases or conditions.
[0083] Certain of the compounds described herein contain one or more chiral centers, or may otherwise be capable of existing as multiple stereoisomers. The scope of the present invention includes mixtures of stereoisomers as well as purified enantiomers or enantiomerically and/or diastereomerically enriched mixtures. Also included within the scope of the invention are the individual isomers of the compounds of the present invention, as well as any wholly or partially equilibrated mixtures thereof. The present invention also includes the individual isomers of the compounds represented by the formulas above as mixtures with isomers thereof in which one or more chiral centers are inverted. Also, it is understood that any tautomers and mixtures of tautomers of the compounds of formula (I) are included within the scope of the compounds of formula (I).
[0084] Typically, the salts of the present invention are pharmaceutically acceptable salts. Salts encompassed within the term "pharmaceutically acceptable salts" refer to nontoxic salts of the compounds of this invention. Salts of the compounds of the present invention may comprise base addition salts derived from a removal of the hydroxyl group hydrogen on a compounds of formula (I). Salts derived from appropriate bases include alkali metal (e.g. sodium), alkaline earth metal (e.g. , magnesium), ammonium, NW4 + (wherein W is C-M alkyl) and other amine salts. Physiologically acceptable salts of a compound with a hydroxy group include the anion of said compound in combination with a suitable cation such as Na+, NH4 +, and NW4 + (wherein W is a C^alkyl group). Preferred salts include sodium, calcium, potassium, magnesium, choline, meglumine, hydrochloride, and quaternary ammonium. Other salts, which are not pharmaceutically acceptable, may be useful in the preparation of compounds of this invention and these form a further aspect of the invention.
[0085] While it is possible that, for use in therapy, therapeutically effective amounts of a compound of formula (I), as well as salts, solvates or hydrates thereof, may be administered as the raw chemical, it is possible to present the active ingredient as a pharmaceutical composition. Accordingly, the invention further provides pharmaceutical compositions, which include therapeutically effective amounts of the compound of formula (I) or salts, solvates or hydrates thereof, and one or more pharmaceutically acceptable carriers, diluents, or excipients. The compounds of the formula (I) or salt, solvate or hydrate thereof, are as described above. The carrier(s), diluent(s) or excipient(s) must be acceptable in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof. In accordance with another aspect of the invention there is also provided a process for the preparation of a pharmaceutical formulation including admixing a compound of the formula (I), or salt, solvate or hydrate thereof, with one or more pharmaceutically acceptable carriers, diluents or excipients.
[0086] Pharmaceutical formulations may be presented in unit dose forms containing a predetermined amount of active ingredient per unit dose. Such a unit may contain, for example, 100mg to 5g, 0.5mg to 1 g, 1 mg to 700mg, or 5mg to 100mg of a compound of the formula (I), depending on the condition being treated, the route of administration and the age, weight and condition of the patient, or pharmaceutical formulations may be presented in unit dose forms containing a predetermined amount of active ingredient per unit dose. Preferred unit dosage formulations are those containing a daily dose or sub-dose, as herein above recited, or an appropriate fraction thereof, of an active ingredient. Furthermore, such pharmaceutical formulations may be prepared by any of the methods well known in the pharmacy art.
[0087] Pharmaceutical formulations may be adapted for administration by any appropriate route, for example by the oral (including buccal or sublingual), rectal, nasal, topical (including buccal, sublingual or transdermal), vaginal or parenteral (including subcutaneous, intramuscular, intravenous or intradermal) route. Such formulations may be prepared by any method known in the art of pharmacy, for example by bringing into association the active ingredient with the carrier(s) or excipient(s).
[0088] The present compound can be administered orally or parenterally. In the case of oral administration, the present compound can be also used as a conventional preparation, for example, as any dosage form of a solid agent such as tablets, powders, granules, capsules and the like; an aqueous agent; an oily suspension; or a liquid agent such as syrup and elixir. In the case of parenteral administration, the present compound can be used as an aqueous or oily suspension injectable, or a nasal drop. Upon preparation of it, conventional excipients, binders, lubricants, aqueous solvents, oily solvents, emulsifiers, suspending agents, preservatives, stabilizers and the like may be arbitrarily used. As an anti-HIV-drug, particularly, an oral agent is preferable. A preparation of the present invention is prepared by combining (e.g. mixing) a therapeutically effective amount of the present compound with a pharmaceutically acceptable carrier or diluent.
[0089] Pharmaceutical formulations adapted for oral administration may be presented as discrete units such as capsules or tablets; powders or granules; solutions or suspensions in aqueous or non-aqueous liquids; edible foams or whips; or oil-in-water liquid emulsions or water-in-oil liquid emulsions.
[0090] For instance, for oral administration in the form of a tablet or capsule, the active drug component can be combined with an oral, non-toxic pharmaceutically acceptable inert carrier such as ethanol, glycerol, water and the like. Powders are prepared by comminuting the compound to a suitable fine size and mixing with a similarly comminuted pharmaceutical carrier such as an edible carbohydrate, as, for example, starch or mannitol. Flavoring, preservative, dispersing and coloring agent can also be present.
[0091] Capsules are made by preparing a powder mixture, as described above, and filling formed gelatin sheaths. Glidants and lubricants such as colloidal silica, talc, magnesium stearate, calcium stearate or solid polyethylene glycol can be added to the powder mixture before the filling operation. A disintegrating or solubilizing agent such as agar-agar, calcium carbonate or sodium carbonate can also be added to improve the availability of the medicament when the capsule is ingested.
[0092] Moreover, when desired or necessary, suitable binders, lubricants, disintegrating agents and coloring agents can also be incorporated into the mixture. Suitable binders include starch, gelatin, natural sugars such as glucose or beta-lactose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth or sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes and the like. Lubricants used in these dosage forms include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride and the like. Disintegrators include, without limitation, starch, methyl cellulose, agar, bentonite, xanthan gum and the like. Tablets are formulated, for example, by preparing a powder mixture, granulating or slugging, adding a lubricant and disintegrant and pressing into tablets. A powder mixture is prepared by mixing the compound, suitably comminuted, with a diluent or base as described above, and optionally, with a binder such as carboxymethylcellulose, an aliginate, gelatin, or polyvinyl pyrrolidone, a solution retardant such as paraffin, a resorption accelerator such as a quaternary salt and/or an absorption agent such as bentonite, kaolin or dicalcium phosphate. The powder mixture can be granulated by wetting with a binder such as syrup, starch paste, acadia mucilage or solutions of cellulosic or polymeric materials and forcing through a screen. As an alternative to granulating, the powder mixture can be run through the tablet machine and the result is imperfectly formed slugs broken into granules. The granules can be lubricated to prevent sticking to the tablet forming dies by means of the addition of stearic acid, a stearate salt, talc or mineral oil. The lubricated mixture is then compressed into tablets. The compounds of the present invention can also be combined with a free flowing inert carrier and compressed into tablets directly without going through the granulating or slugging steps. A clear or opaque protective coating consisting of a sealing coat of shellac, a coating of sugar or polymeric material and a polish coating of wax can be provided. Dyestuffs can be added to these coatings to distinguish different unit dosages.
[0093] Oral fluids such as solutions, syrups and elixirs can be prepared in dosage unit form so that a given quantity contains a predetermined amount of the compound. Syrups can be prepared by dissolving the compound in a suitably flavored aqueous solution, while elixirs are prepared through the use of a non-toxic alcoholic vehicle. Suspensions can be formulated by dispersing the compound in a non-toxic vehicle. Solubilizers and emulsifiers such as ethoxylated isostearyl alcohols and polyoxy ethylene sorbitol ethers, preservatives, flavor additive such as peppermint oil or natural sweeteners or saccharin or other artificial sweeteners, and the like can also be added.
[0094] Where appropriate, dosage unit formulations for oral administration can be microencapsulated. The formulation can also be prepared to prolong or sustain the release as for example by coating or embedding particulate material in polymers, wax or the like.
[0095] The compounds of formula (I) or salts, solvates or hydrates thereof, can also be administered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles and multilamellar vesicles. Liposomes can be formed from a variety of phospholipids, such as cholesterol, stearylamine or phosphatidylcholines.
[0096] The compounds of formula (I) or salts, solvates or hydrates thereof may also be delivered by the use of monoclonal antibodies as individual carriers to which the compound molecules are coupled. The compounds may also be coupled with soluble polymers as targetable drug carriers. Such polymers can include polyvinylpyrrolidone, pyran copolymer, polyhydroxypropylmethacrylamid-phenol, polyhydroxyethylaspartamidephenol, or polyethyleneoxidepolylysine substituted with palmitoyl residues. Furthermore, the compounds may be coupled to a class of biodegradable polymers useful in achieving controlled release of a drug, for example, polylactic acid, polepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates and cross-linked or amphipathic block copolymers of hydrogels.
[0097] Pharmaceutical formulations adapted for transdermal administration may be presented as discrete patches intended to remain in intimate contact with the epidermis of the recipient for a prolonged period of time. For example, the active ingredient may be delivered from the patch by iontophoresis as generally described in Pharmaceutical Research, 3(6), 318 (1986).
[0098] Pharmaceutical formulations adapted for topical administration may be formulated as ointments, creams, suspensions, lotions, powders, solutions, pastes, gels, sprays, aerosols or oils.
[0099] For treatments of the eye or other external tissues, for example mouth and skin, the formulations are preferably applied as a topical ointment or cream. When formulated in an ointment, the active ingredient may be employed with either a paraffinic or a water-miscible ointment base. Alternatively, the active ingredient may be formulated in a cream with an oil-in-water cream base or a water-in-oil base.
[00100] Pharmaceutical formulations adapted for topical administrations to the eye include eye drops wherein the active ingredient is dissolved or suspended in a suitable carrier, especially an aqueous solvent.
[00101] Pharmaceutical formulations adapted for topical administration in the mouth include lozenges, pastilles and mouth washes.
[00102] Pharmaceutical formulations adapted for rectal administration may be presented as suppositories or as enemas.
[00103] Pharmaceutical formulations adapted for nasal administration wherein the carrier is a solid include a coarse powder having a particle size for example in the range 20 to 500 microns which is administered in the manner in which snuff is taken, i.e. by rapid inhalation through the nasal passage from a container of the powder held close up to the nose. Suitable formulations wherein the carrier is a liquid, for administration as a nasal spray or as nasal drops, include aqueous or oil solutions of the active ingredient.
[00104] Pharmaceutical formulations adapted for administration by inhalation include fine particle dusts or mists, which may be generated by means of various types of metered, dose pressurized aerosols, nebulizers or insufflators.
[00105] Pharmaceutical formulations adapted for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams or spray formulations.
[00106] Pharmaceutical formulations adapted for parenteral administration include aqueous and non-aqueous sterile injection solutions which may contain antioxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents. The formulations may be presented in unit-dose or multi-dose containers, for example sealed ampoules and vials, and may be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example water for injections, immediately prior to use. Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets.
[00107] It should be understood that in addition to the ingredients particularly mentioned above, the formulations may include other agents conventional in the art having regard to the type of formulation in question, for example those suitable for oral administration may include flavouring agents.
[00108] In one embodiment, the pharmaceutical formulation containing a compound of formula I or a salt, solvate or hydrate thereof is a formulation adapted for parenteral administration. In another embodiment, the formulation is a long-acting parenteral formulation. In a further embodiment, the formulation is a nano-particle formulation.
[00109] A therapeutically effective amount of a compound of the present invention will depend upon a number of factors including, for example, the age and weight of the human or other animal, the precise condition requiring treatment and its severity, the nature of the formulation, and the route of administration, and will ultimately be at the discretion of the attendant physician or veterinarian. An effective amount of a salt or hydrate thereof, may be determined as a proportion of the effective amount of the compound of formula (I) or salts, solvates or hydrates thereof per se.
[00110] The compounds of formula (I) or salts, solvates or hydrates thereof are believed to have activity in stopping or reducing the effects of HIV as a result of inhibition of HIV-1 reverse transcriptase. [00111] Accordingly, there is provided a method of treating a virus susceptible to reverse transcriptase inhibition in a mammal, including administering to said mammal a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, solvate or hydrate thereof. In one embodiment, the virus is H IV. In another embodiment, the reverse transcriptase is HIV-1 reverse transcriptase. In one embodiment, the mammal is a human.
[00112] In another aspect of the present invention, there is provided a method of inhibiting HIV reverse transcriptase in a mammal, including administering to said mammal a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, solvate or hydrate thereof. In one embodiment, the mammal is a human.
[00113] In another aspect of the present invention, there is provided a method of treating reverse transcriptase inhibitor resistant HIV in a mammal, comprising administering to said mammal a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, solvate or hydrate thereof. In one embodiment, the mammal is a human.
[00114] In another aspect of the present invention, there is provided a method of preventing development of reverse transcriptase inhibitor resistant HIV in a mammal, comprising administering to said mammal a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, solvate or hydrate thereof. In one embodiment, the mammal is a human.
[00115] The compounds of the present invention and their salts, solvates, hydrates or other pharmaceutically acceptable derivatives thereof, may be employed alone or in combination with other therapeutic agents. The compounds of the present invention and any other pharmaceutically active agent(s) may be administered together or separately and, when administered separately, administration may occur simultaneously or sequentially, in any order. The amounts of the compounds of the present invention and the other pharmaceutically active agent(s) and the relative timings of administration will be selected in order to achieve the desired combined therapeutic effect. The administration in combination of a compound of the present invention and salts, solvates, hydrates or other pharmaceutically acceptable derivatives thereof with other treatment agents may be in combination by administration concomitantly in: (1 ) a unitary pharmaceutical composition including both compounds; or (2) separate pharmaceutical compositions each including one of the compounds. Alternatively, the combination may be administered separately in a sequential manner wherein one treatment agent is administered first and the other second or vice versa. Such sequential administration may be close in time or remote in time. The amounts of the compound(s) of formula (I) or salts, solvates or hydrates thereof and the other pharmaceutically active agent(s) and the relative timings of administration will be selected in order to achieve the desired combined therapeutic effect.
[00116] Examples of such other therapeutic agents include, but are not limited to, agents that are effective for the treatment of viral infections or associated conditions. Among these agents are (1 -alpha, 2-beta, 3-alpha)-9-[2,3- bis(hydroxymethyl)cyclobutyl]guanine [(-)BHCG, SQ-34514, lobucavir]; 9-[(2R,3R,4S)-3,4- bis(hydroxy methyl)2-oxetanosyl]adenine (oxetanocin-G); acyclic nucleosides, for example acyclovir, valaciclovir, famciclovir, ganciclovir, and penciclovir; acyclic nucleoside phosphonates, for example (S)-1-(3-hydroxy-2-phosphonyl-methoxypropyl) cytosine (H PMPC), [[[2-(6-amino-9H-purin-9-yl)ethoxy] methyl]phosphinylidene] 5/s(oxymethylene)- 2,2-dimethyl propanoic acid (5/s-POM PMEA, adefovir dipivoxil), [[(1 R)-2-(6-amino-9H- purin-9-yl)-1 -methylethoxy]methyl] phosphonic acid (tenofovir), and (R)-[[2-(6-Amino-9H- purin-9-yl)-1 -methylethoxy]methyl]phosphonic acid 5/s-(isopropoxycarbonyloxymethyl)ester (5/s-POC-PMPA); ribonucleotide reductase inhibitors, for example 2-acetylpyridine 5-[(2- chloroanilino)thiocarbonyl) thiocarbonohydrazone and hydroxyurea; nucleoside reverse transcriptase inhibitors, for example 3'-azido-3'-deoxythymidine (AZT, zidovudine), 2', 3'- dideoxycytidine (ddC, zalcitabine), 2',3'-dideoxyadenosine, 2',3'-dideoxyinosine (ddl, didanosine), 2',3'-didehydrothymidine (d4T, stavudine), (-)-beta-D-2,6-diaminopurine dioxolane (DAPD), 3'-azido-2',3'-dideoxythymidine-5'-H-phosphophonate (phosphonovir), 2'-deoxy-5-iodo-uridine (idoxuridine), (-)-c/s-1 -(2-hydroxymethyl)-1 ,3-oxathiolane 5-yl)- cytosine (lamivudine), c/s-1 -(2-(hydroxymethyl)-1 ,3-oxathiolan-5-yl)-5-fluorocytosine (FTC), 3'-deoxy-3'-fluorothymidine, 5-chloro-2',3'-dideoxy-3'-fluorouridine, (-)-c/s-4-[2-amino-6- (cyclo-propylamino)-9H-purin-9-yl]-2-cyclopentene-1 -methanol (abacavir), 9-[4-hydroxy-2- (hydroxymethyl)but-1 -yl]-guanine (H2G), ABT-606 (2HM-H2G) and ribavirin; protease inhibitors, for example indinavir, ritonavir, nelfinavir, amprenavir, saquinavir, fosamprenavir, (R)-N-tert-butyl-3-[(2S,3S)-2-hydroxy-3-N-[(R)-2-N-(isoquinolin-5-yloxyacetyl)amino-3- methylthio-propanoyl]amino-4-phenylbutanoyl]-5,5-dimethyl-1 ,3-thiazolidine-4-carboxamide (KNI-272), 4R-(4alpha, 5alpha,6beta)]-1 ,3-5/'s[(3-aminophenyl)methyl]hexahydro-5,6- dihydroxy-4,7-5/s(phenylmethyl)-2H-1 ,3-diazepin-2-one dimethanesulfonate (mozenavir), 3- [1 -[3-[2-(5-trifluoromethylpyridinyl)-sulfonylamino]phenyl]propyl]-4- hydroxy-6alpha- phenethyl-6beta-propyl-5,6-dihydro-2-pyranone (tipranavir), N'-[2(S)-Hydroxy-3(S)-[N- (methoxycarbonyl)-l-tert-leucylamino]-4-phenylbutyl-N alpha-(methoxycarbonyl)-N'-[4-(2- pyridyl)benzyl]-L- tert-leucylhydrazide (BMS-232632), 3-(2(S)-Hydroxy-3(S)-(3-hydroxy-2- methylbenzamido)-4-phenylbutanoyl)-5,5-dimethyl-N-(2-methylbenzyl)thi
carboxamide (AG-1776), N-(2(R)-hydroxy-1 (S)-indanyl)-2(R)-phenyl-methyl-4(S)-hydroxy-5- (1 -(1-(4-benzo[b]furanylmethyl)-2(S)-N'-(tert-butyl carboxamido)piperazinyl)pentanamide (MK-944A); interferons such as ointerferon; renal excretion inhibitors such as probenecid; nucleoside transport inhibitors such as dipyridamole, pentoxifylline, N-acetylcysteine (NAC), Procysteine, otrichosanthin, phosphonoformic acid; as well as immunomodulators such as interleukin I I or thymosin, granulocyte macrophage colony stimulating factors, erythropoietin, soluble CD4 and genetically engineered derivatives thereof; non-nucleoside reverse transcriptase inhibitors (NNRTIs), for example nevirapine (BI-RG-587), alpha-((2-acetyl-5- methylphenyl)amino)-2,6-dichloro-benzeneacetamide (loviride), 1 -[3-(isopropyl amino)-2- pyridyl]-4-[5-(methanesulfonamido)-1 H-indol-2-ylcarbonyl]piperazine
monomethanesulfonate (delavirdine), (10R, 1 1 S, 12S)-12-Hydroxy-6, 6, 10, 1 1 -tetramethyl- 4-propyl-1 1 , 12-dihydro-2H, 6H , 10H-benzo(1 , 2-b:3, 4-b':5, 6-b")tripyran-2-one ((+) calanolide A), (4S)-6-Chloro-4-[1 E)-cyclopropyl ethenyl)-3,4- dihydro-4-(trifluoromethyl)- 2(1 H)-quinazolinone (DPC-083), (S)-6-chloro-4-(cyclopropyl ethynyl)-1 ,4-dihydro-4- (trifluoromethyl)-2H-3, 1 -benzoxazin-2-one (efavirenz, DMP 266), 1 -(ethoxy methyl)-5-(1- methylethyl)-6-(phenylmethyl)-2,4(1 H ,3H)-pyrimidinedione (MKC-442), and 5-(3,5-dichloro phenyl)thio-4-isopropyl-1 -(4-pyridyl)methyl-1 H-imidazol-2-ylmethyl carbamate (capravirine), 4-({6-amino-5-bromo-2-[(4-cyanophenyl)amino]-4-pyrimidinyl}oxy)-3,5-dimethylbenzonitrile (etravirine, TMC-125), 4-{[4-({4-[(E)-2-cyanoethenyl]-2,6-dimethylphenyl}amino)-2- pyrimidinyl]amino}benzonitrile (rilpivirine, TMC-278), methyl [2-(aminocarbonyl)-5-chloro-1 H- indol-3-yl]{3-[(E)-2-cyanoethenyl]-5-methylphenyl}phosphinate (Idenix IDX899); glycoprotein 120 antagonists, for example PRO-2000, PRO-542 and 1 ,4-bis[3-[(2, 4- dichlorophenyl)carbonyl amino]-2-oxo-5,8-disodiumsulfanyl]naphthalyl-2, 5- dimethoxyphenyl-1 , 4-dihydrazone (FP-21399); cytokine antagonists, for example reticulose (Product-R), 1 , 1 '-azobis-formamide (ADA), 1 , 1 1-(1 ,4-phenylenebis (methylene))bis- 1 ,4,8, 1 1 -tetraazacyclotetradecane octahydrochloride (AMD-3100); fusion inhibitors, for example T-20 and T-1249; and integrase inhibitors raltegravir, elvitegravir, GSK1349572, GSK1265744, GSK1247303.
[00117] The present invention further includes the use of a compound according to the invention in the manufacture of a medicament for simultaneous or sequential administration with at least another therapeutic agent, such as those defined hereinbefore. [00118] Compounds of the present invention may be administered with an agent known to inhibit or reduce the metabolism of compounds, for example ritonavir.
Accordingly, the present invention features a method for the treatment or prophylaxis of a disease as hereinbefore described by administration of a compound of the present invention in combination with a metabolic inhibitor. Such combination may be administered simultaneously or sequentially.
[00119] In general a suitable dose for each of the above-mentioned conditions will be in the range of 0.01 to 250 mg per kilogram body weight of the recipient (e.g. a human) per day, preferably in the range of 0.1 to 100 mg per kilogram body weight per day and most preferably in the range 0.5 to 30 mg per kilogram body weight per day and particularly in the range 1.0 to 20 mg per kilogram body weight per day. Unless otherwise indicated, all weights of active ingredient are calculated as the parent compound of formula (I) or (la); for salts or esters thereof, the weights would be increased proportionally. The desired dose may be presented as one, two, three, four, five, six or more sub-doses administered at appropriate intervals throughout the day. In some cases the desired dose may be given on alternative days. These sub-doses may be administered in unit dosage forms, for example, containing 10 to 1000 mg or 50 to 500 mg, preferably 20 to 500 mg, and most preferably 50 to 400 mg of active ingredient per unit dosage form.
[00120] While it is possible for the active ingredient to be administered alone, it is preferable to present it as a pharmaceutical composition. The compositions of the present invention comprise at least one active ingredient, as defined above, together with one or more acceptable carriers thereof and optionally other therapeutic agents. Each carrier must be acceptable in the sense of being compatible with the other ingredients of the composition and not injurious to the patient.
[00121] Pharmaceutical compositions include those suitable for oral, rectal, nasal, topical (including transdermal, buccal and sublingual), vaginal or parenteral (including subcutaneous, intramuscular, intravenous, intradermal, and intravitreal) administration. The compositions may conveniently be presented in unit dosage form and may be prepared by any methods well known in the art of pharmacy. Such methods represent a further feature of the present invention and include the step of bringing into association the active ingredients with the carrier, which constitutes one or more accessory ingredients. In general, the compositions are prepared by uniformly and intimately bringing into association the active ingredients with liquid carriers or finely divided solid carriers or both, and then if necessary shaping the product. [00122] The present invention further includes a pharmaceutical composition as hereinbefore defined wherein a compound of the present invention or a pharmaceutically acceptable derivative thereof and another therapeutic agent are presented separately from one another as a kit of parts.
[00123] Compositions suitable for transdermal administration may be presented as discrete patches adapted to remain in intimate contact with the epidermis of the recipient for a prolonged period of time. Such patches suitably contain the active compound 1 ) in an optionally buffered, aqueous solution or 2) dissolved and/or dispersed in an adhesive or 3) dispersed in a polymer. A suitable concentration of the active compound is about 1 % to 25%, preferably about 3% to 15%. As one particular possibility, the active compound may be delivered from the patch by electrotransport or iontophoresis as generally described in Pharmaceutical Research 3(6), 318 (1986).
[00124] Pharmaceutical compositions of the present invention suitable for oral administration may be presented as discrete units such as capsules, caplets, cachets or tablets each containing a predetermined amount of the active ingredients; as a powder or granules; as a solution or a suspension in an aqueous or non-aqueous liquid; or as an oil-in- water liquid emulsion or a water-in-oil liquid emulsion. The active ingredient may also be presented as a bolus, electuary or paste.
[00125] A tablet may be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared by compressing in a suitable machine the active ingredients in a free-flowing form such as a powder or granules, optionally mixed with a binder (e.g. povidone, gelatin, hydroxypropylmethyl cellulose), lubricant, inert diluent, preservative, disintegrant (e.g. sodium starch glycolate, cross-linked povidone, cross-linked sodium carboxymethyl cellulose) surface-active or dispersing agent. Molded tablets may be made by molding a mixture of the powdered compound moistened with an inert liquid diluent in a suitable machine. The tablets may optionally be coated or scored and may be formulated so as to provide slow or controlled release of the active ingredients therein using, for example, hydroxypropylmethyl cellulose in varying proportions to provide the desired release profile. Tablets may optionally be provided with an enteric coating, to provide release in parts of the gut other than the stomach.
[00126] Pharmaceutical compositions suitable for topical administration in the mouth include lozenges comprising the active ingredients in a flavored base, usually sucrose and acacia or tragacanth; pastilles comprising the active ingredient in an inert basis such as gelatin and glycerin, or sucrose and acacia; and mouthwashes comprising the active ingredient in a suitable liquid carrier.
[00127] Pharmaceutical compositions suitable for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams or spray. Pharmaceutical compositions may contain in addition to the active ingredient such carriers as are known in the art to be appropriate.
[00128] Pharmaceutical compositions for rectal administration may be presented as a suppository with a suitable carrier comprising, for example, cocoa butter or a salicylate or other materials commonly used in the art. The suppositories may be conveniently formed by admixture of the active combination with the softened or melted carrier(s) followed by chilling and shaping in molds.
[00129] Pharmaceutical compositions suitable for parenteral administration include aqueous and nonaqueous isotonic sterile injection solutions which may contain antioxidants, buffers, bacteriostats and solutes which render the pharmaceutical composition isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents; and liposomes or other microparticulate systems which are designed to target the compound to blood components or one or more organs. The pharmaceutical compositions may be presented in unit-dose or multi-dose sealed containers, for example, ampoules and vials, and may be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example water for injection, immediately prior to use. Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets of the kind previously described.
[00130] Unit dosage pharmaceutical compositions include those containing a daily dose or daily subdose of the active ingredients, as hereinbefore recited, or an appropriate fraction thereof.
[00131] It should be understood that in addition to the ingredients particularly mentioned above the pharmaceutical compositions of this invention may include other agents conventional in the art having regard to the type of pharmaceutical composition in question, for example, those suitable for oral administration may include such further agents as sweeteners, thickeners and flavoring agents.
[00132] As used herein the symbols and conventions used in these processes, schemes and examples are consistent with those used in the contemporary scientific literature, for example, the Journal of the American Chemical Society or the Journal of Biological Chemistry. Standard single-letter or three-letter abbreviations are generally used to designate amino acid residues, which are assumed to be in the L- configuration unless otherwise noted. Unless otherwise noted, all starting materials were obtained from commercial suppliers and used without further purification. Specifically, the following abbreviations may be used in the examples and throughout the specification:
[00133] g (gram); mg (milligram);
[00134] L (liter); ml. (milliliter);
[00135] μΙ_ (microliter); psi (pounds per square inch)
[00136] M (molar); mM (millimolar);
[00137] i. v. (intravenous); Hz (Hertz);
[00138] MHz (megahertz); mol (moles);
[00139] mmol (millimole); rt (room temperature);
[00140] min (minute); h (hours);
[00141] mp (melting point); TLC (thin layer chromatography);
[00142] Tr (retention time); RP (reverse phase);
[00143] eq (equivalents); nM (nanomolar);
[00144] Unless otherwise indicated, ε ill temperatures are expressed in oC
(degrees Centigrade). All reactions are conducted under an inert atmosphere at room temperature unless otherwise noted. All reference to brine refers to a saturated aqueous solution of NaCI.
[00145] 1 H NMR spectra were recorded on a Varian INOVA-400 (400 MHz) or a Bruker Avance 3 (400 or 500 MHz) spectrometer. Chemical shifts are expressed in parts per million (ppm, δ units). Coupling constants are in units of hertz (Hz). Splitting patterns describe apparent multiplicities and are designated as s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet), br (broad).
[00146] The compounds of the present invention may be prepared according to the following reactions schemes and examples, or modifications thereof using readily available starting materials, reagents and conventional synthesis procedures. In these reactions, it is also possible to make use of variants which are known to those of ordinary skill in the art.
[00147] The compounds of the present invention are readily prepared by methods outlined in Schemes 1-1 1 or by methods known to one skilled in the art.
[00148] By way of example a compound of formula I can be made starting with the commercially available 2-fluoronicotinic acid (1). Thermal addition of O- benzylhydroxylamine under basic conditions followed by methyl ester formation provides ester 4. This material can be acylated with an isocyanate. In this case, 4- methoxybenzylisocyanate (5) may be used to provide compound 6. This material can be cyclized under basic conditions to provide compound 7. Removal of the 4-methoxybenzyl (PMB) group with eerie ammonium nitrate and the like provides imide derivative 8. This material can be subjected to dehydrative chlorination conditions using POCI3 optionally with a base to give chloroimidate 9 which can be treated with an amine to give intermediate 10. Removal of the benzyl protecting group can be accomplished with HBr in acetic acid to provide a compound of formula l-a (Scheme 1 ).
[00149] Scheme 1
Figure imgf000028_0001
[00150] A similar route is shown in scheme 2 whereby 0-(4-methoxybenzyl)- hydroxylamine is used to displace the 2-fluoronicotinic acid (1 ) followed by esterification with trimethylsilyl diazomethane and the like to give 13. This material can be acylated with the commercially available trichloroacetylisocyanate in the presence of a base. The
intermediate urea can be cyclized with subsequent loss of the trichloracetyl group to provide compound 14. Chloroimidate formation gives chloroimidate 15 and amine displacement as previously noted serves to provide compound 16. The 4-methoxybenzyl ether can be cleaved under acidic conditions including but not limited to the use of trifluoroacetic acid in dichloromethane to give a compound of formula l-a.
[00151] Scheme 2
Figure imgf000029_0001
microwave 12
Figure imgf000029_0002
16 (l-a)
[00152] Chloroimidate 15 can be used to provide other compounds of formula I as shown in scheme 3. In this case, an alcohol or alkoxide nucleophile can be used to form a compound of formula l-b upon removal of the PMB protecting group.
[00153] Scheme 3
Figure imgf000029_0003
[00154] Scheme 4 shows a particularly useful route whereby 2- fluoronicotonitrile (18) is reacted with the O-tert-butyl-hydroxylamine (19) to give nitrile 20. Hydrolysis of the nitrile to the corresponding acid followed by esterification with, e.g. , trimethysilyldiazomethane (TMSCHN2) serves to provide 21 . This material can be subjected to urea formation and cyclization as described above to give compound 22. Chloroimidate formation and amine displacement gives compound 24, followed by acidic deprotection serve to provide a compound of formula l-a.
[00155] Scheme 4
Figure imgf000029_0004
[00156] In a similar manner to that shown in scheme 3, the use of a thiol nucleophile can be employed with an intermediate such as 23 to give the thioether 25. This material can be deprotected under acidic conditions to give a compound of formula l-c
(scheme 5).
Figure imgf000030_0001
[00158] The use of a bromoaniline to displace the chloroimidate 23 can provide a useful intermediate for further elaboration. Bromide 27 can be subjected to cross- coupling conditions well known to one skilled in the art to provide a compound such as 29. Cross couplings may make use of boronic acid, tin or zinc coupling partners in the presence of a source of palladium (0). Deprotection as described above can serve to provide a compound of formula l-d.
Figure imgf000030_0002
(l-d)
[00160] Alternatively, method known to one skilled in the art can be used to further elaborate compounds of formula I as shown in scheme 7. Aniline analog 30, prepared using methods known to one skilled in the art, can be used to displace chloride 23. The pendant ester in 31 can be hydrolyzed under basic conditions to give the corresponding acid. This material serves as a useful intermediate to prepare amide or other derivatives which upon deprotection give a compound of formula l-e.
[00161] Scheme 7
Figure imgf000031_0001
Figure imgf000031_0002
A useful reversal of coupling partners is shown in scheme 8. In this case, the bromide 27 can be modified to provide the boronic ester or acid 34 using the Suzuki-Miyaura cross coupling. This material itself can be converted to a compound of formula I or can be further elaborated by coupling an aryl halide such as 35 under standard Suzuki conditions to provide a compound of formula l-f upon deprotection.
[00162] Scheme 8
Figure imgf000031_0003
(l-f) Intermediate 37 shown in scheme 9 can be alkylated using methods known to one skilled in the art. Particularly useful conditions involved the use of sodium hydride as a base in anhydrous solvent. THF is a useful solvent in this case and reactive electrophiles such as methyl iodide can be used. The N-alkyl intermediate 38 can be further reacted as previously described above under Suzuki conditions to provide a compound such as 40. This intermediate can be deprotected to provide a compound of formula l-g.
Figure imgf000032_0001
Chloride 33 can be used to react with secondary amines such as 41 . The subsequent intermediate 42 can be further reacted with a compound such as 43 under Suzuki conditions to provide a compound like 44. This material provides a compound of formula l-h upon deprotection (Scheme 10).
[00164] Scheme 10
Figure imgf000033_0001
(l-h)
Using similar methods to that described above, chloride 23 can be converted into a compound such as 48. This material can be subjected to raney-nickel reduction conditions to provide the corresponding amino derivative 50 which upon deprotection will give a compound of formula l-i (Scheme 1 1 ).
[00165] Scheme 1 1
Figure imgf000033_0002
(l-i)
[00166] In order that the invention described herein may be more fully understood, the following examples are set forth. It should be understood that these examples are for illustrative purposes only and are not to be construed as limiting this invention in any manner.
[00167] It will be apparent to one skilled in the art that the R1 groups on the compounds included in the examples can be made by methods known in the literature or demonstrated in the schemes to produce novel intermediates without the need for undue experimentation. It will also be apparent the the order of the chemical steps can in many instances be rearranged or the steps combined for the purpose of making a compounds of formula I . It will further be apparent that convergent or stepwise linear synthesis can be employed in many cases or may be adventitious in other examples. Examples 1 -344 are set forth below, and in Table 1 .
[00168] Example 1 : 1-hvdroxv-4-((r3-(4- morpho l)phenyl]methyl}amino)pyrido[2,3-d]pyrimidin-2(1 H)-one.
Figure imgf000034_0001
[00169] a) 2-{[(Phenylmethyl)oxy]amino}-3-pyridinecarboxylic acid.
JSL ^NHOBn
^\;O2H
[00170] A solution of 2-fluoro-3-pyridinecarboxylic acid (3.0 g, 21 .2 mmol), O- (phenylmethyl)hydroxylamine (3.4 g, 27.6 mmol) and diisopropylethylamine (7.4 ml, 42.5 mmol) was irradiated in the microwave at 120 °C. After 40 min, the reaction mixture was concentrated in vacuo and the residue purified by silica gel chromatography (0-10% MeOH- dichloromethane) to afford the title compound (3.58 g, 68.9%) as a yellow solid: 1 H NMR (400 MHz, DMSO-d6) δ ppm 8.26 (br. s. , 1 H) 8.07 (dd, J=7.62, 1 .37 Hz, 1 H) 7.42 - 7.50 (m, 2 H) 7.28 - 7.44 (m, 3 H) 6.66 - 6.85 (m, 1 H) 4.99 (s, 2 H).
[00171] b) Methyl 2-{[(phenylmethyl)oxy]amino}-3-pyridinecarboxylate.
Figure imgf000034_0002
[00172] A solution of 2-{[(phenylmethyl)oxy]amino}-3-pyridinecarboxylic acid (3.6 g, 14.7 mmol) in diethyl ether (37 ml) and methanol (37 ml) was treated with TMS- diazomethane (14.66 ml, 29.3 mmol, 2.0 M in hexane). After 5 min, AcOH was added dropwise until gas evolution ceased. The reaction mixture was concentrated in vacuo to afford the title compound (3.6 g, 96%) as an orange oil: 1 H NMR (400MHz ,CHLOROFORM- d) 5 ppm 10.04 (s, 1 H), 8.51 (dd, J = 1 .8, 4.8 Hz, 1 H), 8.17 (dd, J = 1 .9, 7.8 Hz, 1 H), 7.52 - 7.47 (m, 2 H), 7.44 - 7.33 (m, 3 H), 6.81 (dd, J = 4.8, 7.7 Hz, 1 H), 5.09 (s, 2 H), 3.85 (s, 3 H); ES+ MS: 259 (M+1 ).
[00173] c) Methyl 2-{[({[4-
(methyl mino)carbonyl][(phenylmethyl)oxy]amino}-3-pyridinecarboxylate.
Figure imgf000035_0001
[00174] A solution of methyl 2-{[(phenylmethyl)oxy]a
pyridinecarboxylate (3.1 g, 12 mmol) and 1 -(isocyanatomethyl)-4-(methyloxy)benzene (5.1 ml, 36 mmol) in 1 ,2-dichloroethane (24 ml) was irradiated in microwave at 120 °C. After 90 min, the reaction mixture was concentrated in vacuo and the residue purified by silica gel chromatography (0-100% ethyl acetate-hexanes) to afford the title compound (3.7g, 73%) as a white solid: 1 H NMR (400 MHz, CHLOROFORM-c/) δ ppm 8.58 (dd, J=4.88, 1 .76 Hz, 1 H) 8.10 (dd, J=7.80, 1 .76 Hz, 1 H) 7.37 - 7.45 (m, 2 H) 7.27 - 7.33 (m, 3 H) 7.18 - 7.24 (m, 1 H) 7.06 (d, J=8.59 Hz, 2 H) 6.76 - 6.89 (m, 2 H) 4.95 - 5.04 (m, 2 H) 4.26 (d, J=5.85 Hz, 2 H) 3.73 - 3.81 (m, 6 H);ES+ Ms: 422 (M+1 )
[00175] d) 3-{[4-(methyloxy)phenyl]methyl}-1 -[(phenylmethyl)oxy]pyrido[2,3- ,4(1 H,3H)-dione.
Figure imgf000035_0002
[00176] An ice-cooled solution of methyl 2-{[({[4-
(methyloxy)phenyl]methyl}amino)carbonyl][(phenylmethyl)oxy]amino}-3-pyridinecarboxylate (1 .0 g, 2.49 mmol) in methanol (25 ml) was treated with sodium methoxide (0.062 ml, 0.249 mmol, 25%). After 5 min, the white precipitate was filtered and washed with MeOH to afford the title compound (0.72 g, 74%): 1 H NMR (400 MHz, DMSO-d6) δ ppm 8.74 - 8.92 (m, 1 H) 8.33 - 8.53 (m, 1 H) 7.59 - 7.65 (m, 2 H) 7.42 (d, J=1 .95 Hz, 5 H) 7.29 - 7.34 (m, 2 H) 6.85 - 6.91 (m, 1 H) 5.21 (s, 2 H) 5.06 (s, 2 H) 3.72 (s, 3 H); ES + Ms: 399 (M+1 ).
[00177] e) 1 -[(Phenylmethyl)oxy]pyrido[2,3-d]pyrimidine-2,4(1 H,3H)-dione.
Figure imgf000036_0001
[00178] A suspension of methyl 2-{[({[4- (methyloxy)phenyl]methyl}amino)carbonyl][(phenylmethyl)oxy]amino}-3-pyridinecarboxylate (0.71 g, 1 .83 mmol) in Acetonitrile (16 ml.) /Water (1 .6 ml.) was treated with Cerium (IV) ammonium nitrate (5.0 g, 9.13 mmol) and heated to reflux. After 30 min, the reaction mixture was cooled, diluted with water and extracted with ethyl acetate. The combined organic layers were washed with NaHC03, brine, dried (MgS04), filtered and concentrated. The residue was purified by silica gel chromatography (0-10% MeOH/dichloromethane) to afford the title compound (0.39 g, 1 .4 mmol, 79 % yield) as a yellow solid: 1 H NMR (400MHz , DMSO-d6) δ ppm 1 1 .92 (s, 1 H), 8.79 (dd, J = 1 .7, 4.9 Hz, 1 H), 8.35 (dd, J = 1 .7, 7.8 Hz, 1 H), 7.62 (dd, J = 1 .6, 7.6 Hz, 2 H), 7.47 - 7.36 (m, 5 H), 5.17 (s, 2 H); ES+ MS: 270 (M+1 ).
[00179] f) 4-chloro-1 -[(phenylmethyl)oxy]pyrido[2,3-d]pyrimidin-2(1 H)-one.
Figure imgf000036_0002
[00180] A solution of 1 -[(phenylmethyl)oxy]pyrido[2,3-d]pyrimidine-2,4(1 H,3H)- dione (60 mg, 0.223 mmol) in diisopropylethylamine (195 μΙ, 1 .1 14 mmol) was treated with phosphorus(V)oxychloride (104 μΙ, 1 .1 14 mmol) and heated to 100 °C. After 45 min, the reaction mixture was concentrated in vacuo and the residue (62 mg, 97%) was used immediately without further purification: 1 H NMR (400 MHz, DMSO-d6) δ ppm 9.00 (dd, J=4.62, 1 .61 Hz, 1 H) 8.50 (dd, J=7.95, 1 .72 Hz, 1 H) 7.66 (dd, J=7.52, 1 .72 Hz, 2 H) 7.56 (dd, J=8.17, 4.73 Hz, 1 H) 7.42 - 7.46 (m, 3 H) 5.22 (s, 2 H) ES+ MS: 288 (M+1 ).
[00181] g) 4-({[3-(4-Morpholinylmethyl)phenyl]methyl}amino)-1 - [(phenylmethyl)oxy]pyrido[2,3-d]pyrimidin-2(1 H)-one.
Figure imgf000036_0003
[00182] A solution of 4-chloro-1 -[(phenylmethyl)oxy]pyrido[2,3-d]pyrimidin- 2(1 H)-one (50 mg, 0.174 mmol) in DMF (2.17 ml) was added {[3-(4- morpholinylmethyl)phenyl]methyl}amine (71 .7 mg, 0.348 mmol). After 2h, the reaction mixture was purified directly by reverse phase HPLC to afford the title compound (42 mg, 52.8 %): 1 H NMR (400 MHz, CHLOROFORM-c/) δ ppm 8.56 - 8.75 (m, 3 H) 7.56 - 7.70 (m, 3 H) 7.43 (d, J=7.51 Hz, 1 H) 7.29 - 7.40 (m, 3 H) 7.09 - 7.20 (m, 2 H) 5.23 (s, 2 H) 4.74 (s, 2 H) 4.08 (s, 2 H) 3.76 - 3.98 (m, 4 H) 3.29 (d, J=1 1 .72 Hz, 2 H) 2.91 (d, J=2.75 Hz, 2 H); ES+ Ms: 458 (M+1 ).
[00183] h) 1 -Hydroxy-4-({[3-(4- morpholinylmethyl)phenyl]methyl}amino)pyrido[2,3-d]pyrimidin-2(1 H)-one hydrobromide.
Figure imgf000037_0001
[00184] A solution of 4-({[3-(4-morpholinylmethyl)phenyl]methyl}amino)-1- [(phenylmethyl)oxy]pyrido[2,3-d]pyrimidin-2(1 H)-one (21 mg, 0.047 mmol) in acetic acid (0.16 ml) was treated with HBr (0.047 ml, 0.286 mmol, 33% in acetic acid) and heated to 80 °C. After 6 h, the reaction mixture was concentrated in vacuo and the residue purified by reverse phase H PLC to afford the title compound (20.1 mg, 91 %) as a white solid consisting of the TFA salt: 1H NMR (400 MHz, DMSO-d6) δ ppm 9.1 1 - 9.22 (m, 1 H) 8.68 - 8.76 (m, 1 H) 8.49 - 8.65 (m, 1 H) 7.47 (d, J=3.32 Hz, 2 H) 7.37 - 7.44 (m, 1 H) 7.26 - 7.37 (m, 1 H) 4.69 - 4.79 (m, 2 H) 4.31 - 4.38 (m, 2 H) 3.91 - 3.99 (m,2 H) 3.54 - 3.69 (m, 2 H) 3.23 - 3.34 (m, 2 H) 3.06 - 3.17 (m, 2 H) ES+ MS: 368(M+1 ).
[00185] Example 2: 1-hydroxy-4-(1 ,2,3,4-tetrahydro-1- naphthalenylamino)pyrido[2,3-d]pyrimidin-2(1 H)-one hydrobromide.
Figure imgf000037_0002
[00186] The title compound was prepared in a similar manner to example 1 to provide a white solid (20.7 mg, 88%) as a TFA salt. 1 H NMR (400 MHz, DMSO-d6) δ ppm 8.72 - 8.80 (m, 1 H) 8.65 - 8.70 (m, 1 H) 8.57 - 8.64 (m, 1 H) 7.04 - 7.27 (m, 4 H) 5.51 - 5.69 (m, 1 H) 2.74 - 2.90 (m, 2 H) 1 .94 - 2.1 1 (m, 2 H) 1 .70 - 1.94 (m, 2 H) ; ES+ MS: 310 (M+1 ).
[00187] Example 3: 4-[(cyclopropylmethyl)amino]-1-hydroxypyrido[2,3- d]pyrimidin-2(1 H)-one hydrobromide. OCT0
[00188] The title compound was prepared in a similar manner to example 1 to provide a white solid (6.12 mg, 90%) as a TFA salt. 1 H NMR (400 MHz, DMSO-d6) δ ppm 9.05 - 9.23 (m, 1 H) 8.72 (d, J=4.10 Hz, 1 H) 8.59 - 8.66 (m, 1 H) 7.27 - 7.37 (m, 1 H) 3.36 (t, J=5.86 Hz, 2 H) 1 .07 - 1 .22 (m, 1 H) 0.50 (d, J=7.04 Hz, 2 H) 0.30 (d, J=4.49 Hz, 2 H); ES+ MS: 233(M+1).
[00189] Example 4: 4-{[(4-Fluorophenyl)methyl]amino}-1 -hydroxypyrido[2,3- d]pyrimi hydrobromide.
Figure imgf000038_0001
[00190] The title compound was prepared in a similar manner to example 1 to provide a white solid (34 mg, 85%) as a TFA salt. 1H NMR (400 MHz, DMSO-d6) δ ppm 9.01 - 9.13 (m, 1 H) 8.63 - 8.73 (m, 1 H) 8.47 - 8.59 (m, 1 H) 7.36 - 7.47 (m, 2 H) 7.23 - 7.31 (m, 1 H) 7.10 - 7.19 (m, 1 H) 4.60 - 4.74 (m, 2 H) ES+ MS: 287 (M+1 ).
[00191] Example 5: 4-{[(4'-Chloro-4-biphenylyl)methyl]amino}-1 - hydroxypyrido[2,3-d]pyrimidin-2(1 H)-one hydrobromide.
Figure imgf000038_0002
[00192] The title compound was prepared in a similar manner to example 1 to provide a white solid (17.6 mg, 90%) as a TFA salt. 1 H NMR (400 MHz, DMSO-d6) δ ppm 9.07 - 9.14 (m, 1 H) 8.66 - 8.73 (m, 1 H) 8.52 - 8.60 (m, 1 H) 7.60 - 7.73 (m, 4 H) 7.46 (t, J=7.72 Hz, 4 H) 7.24 - 7.32 (m, 1 H) 4.75 (d, J=5.67 Hz, 2 H) ES+ MS: 380 (M+1 ).
[00193] Example 6: 1-Hydroxy-4-({[2- (methyl ethyl}amino)pyrido[2,3-d]pyrimidin-2(1 H)-one hydrobromide.
Figure imgf000038_0003
[00194] The title compound was prepared in a similar manner to example 1 to provide a white solid (7.1 mg, 19 %) as a TFA salt. 1 H NMR (400 MHz, DMSO-d6) δ ppm 8.88 - 8.95 (m, 1 H) 8.67 - 8.74 (m, 1 H) 8.57 - 8.65 (m, 1 H) 7.23 - 7.33 (m, 2 H) 7.14 - 7.22 (m, 1 H) 6.99 - 7.08 (m, 1 H) 6.85 - 6.94 (m, 1 H) 4.65 (br. s., 2 H) 3.86 (s, 3 H); ES+ MS: 300 (M+1 ).
[00195] Example 7: 1-Hydroxy-4-{[2-(4-morpholinyl)ethyl]amino}pyrido[2,3- d]pyrimi hydrobromide.
Figure imgf000039_0001
[00196] The title compound was prepared in a similar manner to example 1 to provide a white solid (20 mg, 36 %) as a TFA salt. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.91 - 9.06 (m, 1 H) 8.71 - 8.78 (m, 1 H) 8.46 - 8.55 (m, 1 H) 7.31 - 7.40 (m, 1 H) 3.82 (d, J=4.68 Hz, 2 H) 3.40 (br. s., 2 H) 2.90 (s, 4 H) 2.74 (s, 4 H) ; ES+ MS: 293 (M+1 ).
[00197] Example 8: 4-{[(2,4-Difluorophenyl)methyl]amino}-1 - hydroxypyrido[2,3-d]pyrimidin-2(1 H)-one hydrobromide.
Figure imgf000039_0002
[00198] The title compound was prepared in a similar manner to example 1 to provide a white solid (22 mg, 87 %) as a TFA salt. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.95 - 9.08 (m, 1 H) 8.66 - 8.74 (m, 1 H) 8.50 - 8.61 (m, 1 H) 7.42 - 7.53 (m, 1 H) 7.23 - 7.33 (m, 2 H) 7.01 - 7.12 (m, 1 H) 4.66 - 4.72 (m, 2 H) ES+ MS: 306 (M+1 ).
[00199] Example 9: 1 -Hydroxy-4-[(2-thienylmethyl)amino]pyrido[2,3- d]pyrimi hydrobromide.
Figure imgf000039_0003
[00200] The title compound was prepared in a similar manner to example 1 to provide a white solid (4.3 mg, 34 %) as a TFA salt. 1 H NMR (400 MHz, METHANOL-^) δ ppm 8.67 (d, J=3.71 Hz, 1 H) 8.37 - 8.47 (m, 1 H) 7.22 - 7.34 (m, 2 H) 7.1 1 (d, J = 2.93 Hz,
1 H) 6.93 (dd, J = 4.88, 3.71 Hz, 1 H) 4.95 (s, 2 H); ES+ MS: 276 (M+1 ). [00201] Example 10: 4-({[3'-(Aminomethyl)-4-biphenylyl]methyl}a
hydroxypyrido[2,3-d]pyrimidin-2(1H)-one.
Figure imgf000040_0001
[00202] The title compound was prepared in a similar manner to example 144 and isolated as an TFA salt. 1H NMR (300MHz, DMSO-d6) δ ppm 9.13 (m, 1H), 8.70 (d,1H), 8.58 (d, 1H), 8.15 (brs, 2H), 7.79 (s, 1H), 7.70-7.65 (m, 3H), 7.54-7.42 (m,4H), 7.30 (m, 1H), 4.75 (d, 2 H), 4.11 (s, 2H); ES+ MS: 374.0 (M + 1).
[00203] Example 11: 4-(2, 3-Dihydro-1H-inden-1-ylamino)-1- hydroxypyrido[2,3-d]pyrimidin-2(1H)-one.
Figure imgf000040_0002
[00204] The title compound was prepared in a similar manner to example 1 as a TFA salt.1H NMR (300 MHz, DMSO-d6) δ ppm 8.75-8.59 (m, 3H), 7.33-7.19 (m, 5H), 5.89 (m, 1H), 3.04-2.90 (m, 2H), 2.51 (m, 1 H), 2.08-2.04 (m, 1H); ES+ MS: 295 (M+1).
[00205] Example 12: 1-Hydroxy-4-{[(1R)-1-phenylethyl]amino}pyrido[2,3- d\ py ri m i d i n-2 ( 1 H)-o n e .
Figure imgf000040_0003
[00206] The title compound was prepared in a similar manner to example 1 as a TFA salt.1H NMR (300 MHz, CD3OD) δ ppm 8.66 (m, 2H), 7.40 (m, 2H), 7.28 (m, 3H), 7.20 (m, 1H), 5.57 (m, 2H),1.63 (d, 3H); ES+ MS: 283 (M+1).
[00207] Example 13: 1-Hydroxy-4-{[(4-methylphenyl)methyl]amino}pyrido[2,3- d\ py ri m i d i n-2 ( 1 H)-o n e .
Figure imgf000040_0004
[00208] The title compound was prepared in a similar manner to example 1 as aTFAsalt.1H NMR (300 MHz, CD3OD) δ ppm 8.59-8.57 (m, 1H), 8.37 (m, 1H), 7.21-7.18 (m, 3H), 7.05-7.02 (m, 2H), 4.66(s, 2H), 2.21(s, 3H); ES+ MS: 283 (M+1).
[00209] Example 14: 4-(Cyclopentylamino)-1-hydroxypyrido[2,3-d]pyrimidin- 2(1H)-o
Figure imgf000041_0001
[00210] The title compound was prepared in a similar manner to example 1 as a TFA salt.1H NMR (300 MHz, CD3OD) δ ppm 8.67 (m, 2H), 7.37 (m, 1 H), 4.52 (m, 1 H), 2.15 (m, 2H), 1.93-1.89 (m, 6H); ES+ MS: 247 (M+1).
[00211] Example 15: 1-Hydroxy-4-[(2-methylpropyl)amino]pyrido[2,3- d\ py ri m i d i n-2 ( 1 H)-o n e .
Figure imgf000041_0002
[00212] The title compound was prepared in a similar manner to example 1 as aTFAsalt.1H NMR (300 MHz, CD3OD) δ ppm 8.53 (d, 1H), 8.40 (d, 1H), 7.38 (dd, 1H), 3.42 (m, 2H), 2.08 (m, 1H), 1.00 (d, 6H); ES+ MS: 235 (M+1).
[00213] Example 16: 4'-{[(1-Hdroxy-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidin-4- yl)amino]methyl}-2-biphenylcarboxylic acid.
Figure imgf000041_0003
[00214] The title compound was prepared in a similar manner to example 144 and isolated as an TFA salt. 1H NMR (300MHz, DMSO-d6) δ ppm 12.70 (s, 1H), 10.37 (s, 1H), 9.11 (m, 1H), 8.69 (d,1H), 8.57 (d, 1H), 7.71 (d, 1H), 7.55 (m, 1H), 7.47-7.29 (m, 7H), 4.75 (d, 2 H); ES+ MS: 388.9 (M + 1).
[00215] Example 17: 1-Hydroxy-4-({[4- (methyloxy)phenyl]methyl}amino)pyrido[2,3-d]pyrimidin-2(1H)-one.
Figure imgf000041_0004
[00216] The title compound was prepared in a similar manner to example 1 as a TFA salt. 1 H NMR (300 MHz, CD3OD) δ ppm 8.60-8.40 (m,2H);7.26-7.24 (m,3H);6.90- 6.78 (m,2H);4.64 (m,2H);3.67 (m,3H); ES+ MS: 299 (M+1 ).
[00217] Example 18: 4-(Butylamino)-1 -hydroxypyrido[2,3-d]pyrimidin-2(1 H)- one.
Figure imgf000042_0001
[00218] The title compound was prepared in a similar manner to example 1 as a hydrobromide salt. 1 H NMR (300 MHz, CD3OD) δ ppm 8.91 (m, 1 H), 8.88 (m, 1 H), 7.56 (m, 1 H), 4.91 (m, 2H), 1 .83 (m, 2H), 1 .53 (m, 2H), 1 .06 (t, 3H); ES+ MS: 235 (M+1 ).
[00219] Example 19: 1 -Hydroxy-4-[(2-phenylethyl)amino]pyrido[2,3- d\ py ri m i d i n-2 ( 1 H)-o n e .
Figure imgf000042_0002
[00220] The title compound was prepared in a similar manner to example 1 as a TFA salt. 1 H NMR (300 MHz, CD3OD) δ ppm 8.71 (d, 1 H), 8.43 (d, 1 H), 7.37-7.20 (m, 6H), 3.85 (t, 2H), 3.04 (t,2H); ES+ MS: 283 (M+1 ).
[00221] Example 20: 1 -Hydroxy-4-[(phenylmethyl)amino]pyrido[2,3- d\ py ri m i d i n-2 ( 1 H)-o n e .
Figure imgf000042_0003
[00222] The title compound was prepared in a similar manner to example 1 as an HBr salt. 1 H NMR (300 MHz, CD3OD) δ ppm 8.91 (m, 1 H), 8.86 (m, 1 H),7.57 (m, 1 H), 7.41 -7.50 (m, 5H), 4.92 (s, 2H); ES+ MS: 269 (M+1 ).
[00223] Example 21 : 1 -Hydroxy-4-[(2-pyridinylmethyl)amino]pyrido[2,3- d\ py ri m i d i n-2 ( 1 H)-o n e .
Figure imgf000043_0001
[00224] The title compound was prepared in a similar manner to example 1 as a TFA salt.1H NMR (300 MHz, CD3OD) δ ppm 8.78-7.33 (m, 7 H), 5.12 (s, 2H),; ES+ MS: 270 (M+1).
[00225] Example 22: 1-Hydroxy-4-[(2-methylphenyl)amino]pyrido[2,3- d\ py ri m i d i n-2 ( 1 H)-o n e .
Figure imgf000043_0002
[00226] The title compound was prepared in a similar manner to example 1 as a TFA salt.1H NMR (300 MHz, CD3OD) δ ppm 8.79 (m, 1H), 8.70 (d, 1H), 7.44 (m, 1H), 7.36-7.27 (m, 4H), 2.30 (s, 3H); ES+ MS: 269 (M+1).
[00227] Example 23: 4-({[2'-(Aminomethyl)-4-biphenylyl]methyl}amino)-1- hydroxypyrido[2,3-d]pyrimidin-2(1H)-one.
Figure imgf000043_0003
[00228] The title compound was prepared in a similar manner to example 144 and isolated as an TFA salt. 1H NMR (300MHz, DMSO-d6) δ ppm 10.38 (s, 1H), 9.16 (m, 1H), 8.71 (d,1H), 8.58 (d, 1H), 8.13 (brs, 2H), 7.60 (m, 1H), 7.52-7.44 (m, 4H), 7.36-7.28 (m, 4H), 4.78 (d, 2 H), 3.98 (m, 2H); ES+ MS: 373.9 (M + 1).
[00229] Example 24: 4-(4-Biphenylylamino)-1-hydroxypyrido[2,3-d]pyrimidin- 2(1H)-o
Figure imgf000043_0004
[00230] The title compound was prepared in a similar manner to example 1 as a TFA salt.1H NMR (300 MHz, DMSO-d6) δ ppm 9.99 (s, 1 H), 8.84-8.75 (m, 2H), 7.97-7.94 (m, 2H), 7.75-7.70 (m, 4H), 7.51-7.37(m, 4H); ES+ MS: 331 (M+1).
[00231] Example 25: 4-(Cyclopropylamino)-1-hydroxypyrido[2,3-d]pyrimidin- 2(1H)-one.
Figure imgf000044_0001
[00232] The title compound was prepared in a similar manner to example 1 as a TFA salt.1H NMR (300 MHz, CD3OD) δ ppm 8.77 (d, 1H), 8.55 (d, 1H), 7.40 (m, 1H), 3.06 (m, 1H), 1.02 (m, 2H), 0.85 (m, 2H); ES+ MS: 219 (M+1).
[00233] Example 26: 1-Hydroxy-4-(1-pyrrolidinyl)pyrido[2,3-d]pyrimidin-2(1H)- one.
Figure imgf000044_0002
[00234] The title compound was prepared in a similar manner to example 1 as a TFA salt.1H NMR (300 MHz, CD3OD) δ ppm 8.71-8.74 (m, 2H), 7.40-7.42 (m, 1 H), 4.02 (m, 4H), 2.15 (m, 4H); ES+ MS: 233 (M+1).
[00235] Example 27: 4-(Cyclohexylamino)-1-hydroxypyrido[2,3-d]pyrimidin- 2(1H)-one.
Figure imgf000044_0003
[00236] The title compound was prepared in a similar manner to example 1 as a TFA salt.1H NMR (300 MHz, CD3OD) δ ppm 8.75 (d, 1H), 8.68 (d, 1H), 8.40 (dd, 1H), 4.18 (m, 1H), 2.07 (m, 2H), 1.78 (m, 2H), 1.74 (m, 1H), 1.49-1.32 (m, 5H); ES+ MS: 261 (M+1). [00237] Example 28: 1 -Hydroxy-4-[(1 S)-1 ,2,3,4-tetrahydro-1- naphthalenylamino]pyrido[2,3-d]pyrimidin-2(1 H)-one.
Figure imgf000045_0001
[00238] The title compound was prepared in a similar manner to example 1 and isolated as an HBr salt. 1 H NMR (300MHz, CD3OD) δ ppm 8.87(d, 2H), 7.52(t, 1 H), 7.29 (m, 4H), 5.52 (s, 1 H), 2.93(m, 2H), 2.05(m,4H); ES+ MS: 309 (M + 1 ).
[00239] Example 29: 1 -Hydroxy-4-[(1 R)-1 ,2,3,4-tetrahydro-1 - naphthalenylamino]pyrido[2,3-d]pyrimidin-2(1 H)-one.
Figure imgf000045_0002
[00240] The title compound was prepared in a similar manner to example 1 and isolated as an HBr salt. 1 H NMR (300MHz, CD3OD) δ ppm 8.72(d, 1 H), 8.60(d, 1 H), 7.30 (m, 5H), 5.73 (s, 1 H), 2.88(m, 2H), 2.05(m,4H); ES+ MS: 309 (M + 1 ).
[00241] Example 30: 1 -Hydroxy-4-{[2-(2-thienyl)ethyl]amino}pyrido[2,3- d\ py ri m 1 H)-o n e .
Figure imgf000045_0003
[00242] The title compound was prepared in a similar manner to example 1 and isolated as an HBr salt. 1 H NMR (300MHz, CD3OD) δ ppm 8.88(t, 1 H), 8.75(t, 1 H), 7.56 (m, 1 H), 7.30 (t, 1 H), 6.97-7.01 (m, 2H), 3.97(m, 2H), 3.38 (m,2H). ES+ MS: 289 (M + 1 )-
[00243] Example 31 : 1 -Hydroxy-4-[(4,4,4-trifluorobutyl)amino]pyrido[2,3- d\ py ri m i d i n-2 ( 1 H)-o n e .
Figure imgf000045_0004
[00244] The title compound was prepared in a similar manner to example 1 and isolated as a TFA salt. 1 H NMR (300MHz, CD3OD) δ 8.73-8.74 (m, 1 H), 8.47-8.49 (m, 1 H), 7.35-7.39 (m, 1 H), 3.66-3.71 (m, 2H), 2.28-2.37 (m, 2H), 1 .94-2.04 (m, 2H); ES+ MS: 289 (M + 1 ).
[00245] Example 32: 4-[(1 , 1 -Dimethylethyl)amino]-1 -hydroxypyrido[2,3- d\ py ri m i d i n-2 ( 1 H)-o n e .
Figure imgf000046_0001
[00246] The title compound was prepared in a similar manner to example 1 and isolated as a TFA salt. 1 H NMR (300MHz, CD3OD) δ 8.62-8.68 (m, 2H), 7.32-7.36 (m, 1 H), 1 .61 (s, 9H); ES+ MS: 235 (M + 1 ).
[00247] Example 33: 1 -Hydroxy-4-[(3-thienylmethyl)amino]pyrido[2,3- d\ py ri m i d i n-2 ( 1 H)-o n e .
Figure imgf000046_0002
[00248] The title compound was prepared in a similar manner to example 1 and isolated as an HBr salt. 1 H NMR (300MHz, CD3OD) δ 8.88 (m, 2H), 7.60 (m, 2H), 7.50 (m, 1 H), 7.23 (m, 1 H), 4.95 (s, 2H); ES+ MS: 275 (M + 1 ).
[00249] Example 34: 4-[(1 -Hydroxy-2-oxo-1 ,2-dihydropyrido[2,3-d]pyrimidin-4- yl)amino]benzonitrile.
Figure imgf000046_0003
[00250] The title compound was prepared in a similar manner to example 144 and isolated as a TFA salt. 1 H NMR (300MHz, DMSO-d6) δ 10.16 (m, 1 H), 8.82-8.77 (m, 2H), 8.12 (m, 2H), 7.87 (m, 2H), 7.42-7.38 (m, 1 H); ES+ MS: 280 (M+1 ).
[00251] Example 35: 1 -Hydroxy-4-({[5-(2-pyridinyl)-2- thienyl]methyl}amino)pyrido[2,3-d]pyrimidin-2(1 H)-one.
Figure imgf000047_0001
[00252] The title compound was prepared in a similar manner to example 1 and isolated as a TFA salt. 1 H NMR (300MHz, CD3OD) δ 8.74 (m, 1 H), 8.49-8.55 (m, 2H), 8.02-8.14 (m, 2H), 7.73 (m, 1 H), 7.54 (m, 1 H), 7.28-7.38 (m, 2H), 5.05 (d, 2H); ES+ MS: 352 (M+1 ).
[00253] Example 36: 1 -Hydroxy-4-{[3'-(4-morpholinyl)-4- biphenylyl]amino}pyrido[2,3-d]pyrimidin-2(1 H)-one.
Figure imgf000047_0002
[00254] The title compound was prepared in a similar manner to example 1 and isolated as a TFA salt. 1 H NMR (300MHz, DMSO-d6) δ 10.58 (s, 1 H), 10.01 (s, 1 H), 8.83(m, 1 H), 8.76 (m, 1 H), 7.94 (m, 2H), 7.71 (m, 2H),7.36 (m, 2H), 7.21 (s, 1 H), 7.13 (m, 1 H),6.96(m, 1 H), 3.77 (m ,4H), 3.21 (m ,4H); ES+ MS: 416 (M+1 ).
[00255] Example 37: 4-(Hexahydro-1 H-azepin-1 -yl)-1 -hydroxypyrido[2,3- d\ py ri m i d i n-2 ( 1 H)-o n e .
Figure imgf000047_0003
[00256] a) 2-[({[4-(Methyloxy)phenyl]methyl}oxy)amino]-3-pyridinecarboxyli
Figure imgf000047_0004
[00257] A mixture of 2-Fluoronicotinic acid (1 .00 g, 7.09 mmol) and 0-4- methoxybenzyl ghydroxylamine hydrochloride (1 .75 g, 9.21 mmol) in DIEA (7.0 ml, 40.1 mmol) was heated in a pW at 120 °C for 40 min. LC/MS showed about 1 : 1 starting material to product ratio based on peak areas and otherwise very clean. The mixture was resubjected to 120 C for 60 min. LC/MS showed further conversion (-75%). The mixture was heated a 3rd time at 125 °C for 60 min. The mixture was concentrated in vacuo and purified via flash chromatography (0% - 10% MeOH in DCM, gradient elution) to provide 2- [({[4-(methyloxy)phenyl]methyl}oxy)amino]-3-pyridinecarboxylic acid (2.92 g, 7.24 mmol, 102 % yield) containing DIEA as an impurtity as a yellow semisolid. Use in next step without further purification. 1 H NMR (400 MHz, CDCI3) δ ppm 1 1 .22 (br s, 1 H), 8.18-8.15 (m, 2 H), 7.34 (d, J = 8.8 Hz, 2 H), 6.83 (d, J = 8.8 Hz, 2 H), 6.59 (dd, J = 7.2, 5.6 Hz, 1 H), 4.95 (s, 2 H), 3.76 (s, 3 H); ES+ MS: 275 (M + 1 ).
[00258] b) Methyl 2-[({[4-(methyloxy)phenyl]methyl}oxy)amino]-3- pyridine
Figure imgf000048_0001
[00259] To a solution of 2-[({[4-(methyloxy)phenyl]methyl}oxy)a
pyridinecarboxylic acid (2.86 g, 7.09 mmol) (impure with DIEA from step a) in Diethyl ether (20 ml.) and Methanol (20.00 ml.) was added TMS-diazomethane (2M in hexanes) (3.55 ml_, 7.09 mmol) dropwise. The reaction was stirred for 30 minutes and only about 50% conversion was noted. An additional 2 ml. of TMS-diazomethane was added and the reaction proceeded further (TLC monitoring with 5% MeOH in DCM). An additional two 1 ml_ aliquots of TMS-diazomethane were added the reaction appeared to be nearly complete. Dilute AcOH was added to consume any excess TMS-diazomethane and the mixture was concentrated in vacuo. The residue was dissolved in DCM and Celite was added and the mixture concentrated and purified by flash chromatography on silica (25% EtOAc in hexanes, gradient elution) to provide methyl 2-[({[4-
(methyloxy)phenyl]methyl}oxy)amino]-3-pyridinecarboxylate (860 mg, 2.98 mmol, 42.1 % yield) as a yellow oil. . 1 H NMR (400 MHz, CDCI3) δ ppm 9.95 (s, 1 H), 8.45 (dd, J = 4.8, 1 .6 Hz, 1 H), 8.12 (dd, J = 7.6, 2.0 Hz, 1 H), 7.38 (d, J = 8.8 Hz, 2 H), 6.88 (d, J = 8.8 Hz, 2 H), 6.76 (dd, J = 7.6, 4.8 Hz, 1 H), 4.98 (s, 2 H), 3.82 (s, 3 H), 3.79 (s, 3 H); ES+ MS: 289 (M +
1 ).
[00260] c) 1 -({[4-(Methyloxy)phenyl]methyl}oxy)pyrido[2,3-d]pyrimidine-
2,4(1 H,3H)-dione.
Figure imgf000048_0002
[00261] A solution of methyl 2-[({[4-(methyloxy)phenyl]methyl}oxy)amino]-3- pyridinecarboxylate (520 mg, 1 .804 mmol) in 1 ,2-Dichloroethane (DCE) (25 mL) was treated with Trichloroacetyl isocyanate (0.77 M in DCE) (4.94 mL, 3.79 mmol) and stirred at ambient temperature. After 30 minutes, the mixture was about a 1 : 1 mixture of SM to trichloroacetyl urea, triethylamine (0.528 mL, 3.79 mmol) was added and the mixture stirred for 30 min. The material converted to mostly trichloroacetyl urea. The mixture was concentrated in vacuo and placed under high vacuum for 1 h. This residue was dissolved in MeOH and sodium methoxide (25 wt% in methanol) (1 .949 mL, 9.02 mmol) was added. Mixture was stirred overnight. An additional 1 mL of NaOMe was added but no change observed. The reaction mixture was concentrated in vacuo and the residue was taken up in water and EtOAc. It was acidified with 1 Λ/ HCI. Some solids formed and were filtered off. The mixture was extracted into EtOAc, washed with brine and dried over sodium sulfate. The residue was purified by flash chromatography on silica (20% EtOAc/hexanes, gradient) to provide 1- ({[4-(methyloxy)phenyl]methyl}oxy)pyrido[2,3-d]pyrimidine-2,4(1 H,3H)-dione (320 mg, 1 .069 mmol, 59.3 % yield) as a off-white solid. 1 H NMR (400 MHz, CDCI3) δ ppm 8.75 (dd, J = 4.8, 1.6 Hz, 1 H), 8.41 (dd, J = 7.6, 2.0 Hz, 1 H), 8.16 (br s, 1 H), 7.53 (d, J = 8.8 Hz, 2 H), 7.25 (dd, J = 7.6, 4.8 Hz, 1 H), 6.87 (d, J = 8.8 Hz, 2 H), 5.21 (s, 2 H), 3.79 (s, 3 H).
[00262] d) 4-(Hexahydro-1 H-azepin-1 -yl)-1 -({[4- (methyl l]methyl}oxy)pyrido[2,3-d]pyrimidin-2(1 H)-one.
Figure imgf000049_0001
[00263] To a solution of 1 -({[4-(methyloxy)phenyl]methyl}oxy)pyrido[2,3- d]pyrimidine-2,4(1 H,3H)-dione (127 mg, 0.424 mmol) in DIEA (5 mL, 28.6 mmol) was added POCI3 (0.198 mL, 2.122 mmol). The mixture was a suspension that cleared at it warmed to 100 °C. After 5 minutes, black droplets formed, added 5 mL of PhH and heated for 45 min. Cooled to RT and removed solvents in vacuo. Dissolved material in 12 mL of DMF and partitioned 4 ways. One aliquot of 4-chloro-1 -({[4-(methyloxy)phenyl]methyl}oxy)pyrido[2,3- d]pyrimidin-2(1 H)-one (33.75 mg, 0.106 mmol) in N ,N-Dimethylformamide (DMF) (3 mL) was treated with hexamethyleneimine (300 mg, 3.02 mmol) and stirred at rt. After 10 minutes the reaction was complete by LC/MS. The solution was stirred for 1 h. Water and EtOAc were added and the layers separated. The organic layer was washed with brine and the aqueous layer extracted 3 times with EtOAc. The combined organics were dried over sodium sulfate, filtered and concentrated. The residue was purified by flash
chromatography on silica to provide 4-(hexahydro-1 H-azepin-1-yl)-1 -({[4- (methyloxy)phenyl]methyl}oxy)pyrido[2,3-d]pyrimidin-2(1 H)-one (35 mg, 0.092 mmol, 87 % yield) as a yellow crystalline solid. 1 H NMR (400 MHz, CDCI3) δ ppm 8.59(dd, J = 4.8, 1 .2 Hz, 1 H), 8.02 (dd, J = 8.0, 1 .2 Hz, 1 H), 7.56 (d, J = 8.4 Hz, 2 H), 7.04 (dd, J = 8.0, 4.8 Hz, 1 H), 6.84 (d, J = 8.4 Hz, 2 H), 5.19 (s, 2 H), 3.84 (m, 4 H), 3.76 (s, 3 H), 1 .91 (m, 4 H), 1 .62 (m, 4 H); ES+ MS: 381 (M + 1 ).
[00264] e) 4-(Hexahydro-1 -/-azepin-1 -yl)-1 -hydroxypyrido[2,3-d]pyrimidin- 2(1 H)-one.
Figure imgf000050_0001
[00265] To a solution of 4-(hexahydro-1 H-azepin-1 -yl)-1-({[4-
(methyloxy)phenyl]methyl}oxy)pyrido[2,3-d]pyrimidin-2(1 H)-one (35 mg, 0.092 mmol) in dichloromethane (DCM) (5 mL) was added TFA (1 mL, 12.98 mmol). The resultant solution was stirred at rt for 1 h. The mixture was concentrated in vacuo and the residue purified by preparative HPLC to give 4-(hexahydro-1 H-azepin-1 -yl)-1 -hydroxypyrido[2,3-d]pyrimidin- 2(1 H)-one (30mg, 0.080 mmol, 87 % yield) as a TFA salt. 1 H NMR (400 MHz, CDCI3) δ ppm 9.94 (br s, TFA), 8.72(d, J = 4.4 Hz, 1 H), 8.25 (d, J = 8.0 Hz, 1 H), 7.23 (m, 1 H). 3.88 (m, 4 H), 1 .92 (m, 4 H), 1 .61 (m, 4 H); ES+ MS: 261 (M + 1 ).
[00266] Example 38: 4-(4-Acetyl-1-piperazinyl)-1 -hydroxypyrido[2,3- d]pyrimidin-2(1 H)-one.
Figure imgf000050_0002
[00267] a): 1 -[(1 , 1 -Dimethylethyl)oxy]-4-(1 -piperazinyl)pyrido[2,3-d]pyrimidin-
2(1 H)-one.
Figure imgf000051_0001
[00268] To a solution of 1 -[(1 , 1 -dimethylethyl)oxy]pyrido[2,3-d]pyrimidine-
2,4(1 H ,3H)-dione (20 mg, 0.085 mmol) and DIEA (1 .485 mL, 8.50 mmol) in toluene (2ml_) was added POCI3 (0.079 mL, 0.850 mmol). The mixture was heated at 100 °C for 45 min. Concentrated to dryness in a rotary evaporator and the residue was immediately taken up in DMF (2 ml). This solution was added to a solution of piperazine (732 mg, 8.50 mmol) in DMF (10 ml) dropwise and stirred at room temperature for 15 min.
[00269] Concentrated in the rotary evaporator and purified by silica gel liquid chromatography, eluting with 0-20% methanol/dichloromethane to provide 1 -[(1 , 1 - dimethylethyl)oxy]-4-(1 -piperazinyl)pyrido[2,3-d]pyrimidin-2(1 H)-one (25 mg , 97%) as a brown oil. 1H NMR (400 MHz, CDCI3) δ ppm 8.61 (dd, J=4.6, 1 .7 Hz, 1 H), 8.00 (s, 1 H), 7.86 (dd, J=7.9, 1.7 Hz, 1 H), 7.07 (dd, J=7.9, 4.6 Hz, 1 H), 3.95 (d, J=7.0 Hz, 2 H), 3.75 (br. s., 2 H), 2.92 - 3.21 (m, 4 H), 1 .46 (s, 9 H); ES+ MS: 304 (M + 1 ).
[00270] b): 4-(4-Acetyl-1-piperazinyl)-1 -[(1 , 1 -dimethylethyl)oxy]pyrido[2,3- d]pyrimi -one.
Figure imgf000051_0002
[00271] To a solution of 1 -[(1 , 1 -dimethylethyl)oxy]-4-(1-piperazinyl)pyrido[2,3- d]pyrimidin-2(1 H)-one (23.4 mg, 0.077 mmol) in dichloromethane (2 mL) was added DIEA (0.040 mL, 0.231 mmol), followed by addition of acetyl chloride (8.22 pL, 0.1 16 mmol). Stirred at room temperature for 45 min. Concentrated and purified by silica gel liquid chromatography, eluting with 0-5% methanol/dichloromethane to provide 4-(4-acetyl-1 - piperazinyl)-1 -[(1 , 1-dimethylethyl)oxy]pyrido[2,3-d]pyrimidin-2(1 H)-one (26 mg, 98%) as a thick yellow oil. 1 H NMR (400 MHz, CDCI3) δ ppm 8.65 (dd, J=4.7, 1 .8 Hz, 1 H), 7.88 (dd, J=8.0, 1 .8 Hz, 1 H), 7.12 (dd, J=8.0, 4.7 Hz, 1 H), 3.52 - 4.12 (m, 8 H), 2.14 (s, 3 H), 1 .46 (s, 9 H); ES+ MS: 346 (M + 1 ). [00272] c): 4-(4-Acetyl-1-piperazinyl)-1 -hydroxypyrido[2,3-d]pyrimidin-2(1 H)- one.
Figure imgf000052_0001
[00273] The title compound was prepared in a similar manner to example 144 and precipitated from methanol/ethyl acetate to provide a beige solid (6.6 mg, 22%) as a trifluoroacetate salt. 1 H NMR (400 MHz, DMSO-d6) δ ppm 10.51 (br. s., 1 H), 8.74 - 8.60 (m, 1 H), 8.25 (dd, J=8.0, 1 .6 Hz, 1 H), 7.24 (dd, J=8.1 , 4.6 Hz, 1 H), 3.76 (ddd, J=18.5, 6.4, 3.8 Hz, 4 H), 3.69 - 3.56 (m, 4 H), 2.04 (s, 3 H); ES+ MS: 290 (M + 1 ); H RMS calcd for C13H 16N503: 290.1253. Found: 290.1254.
[00274] Example 39: 1 -Hydroxy-4-{[4- (trifluoromethyl)phenyl]amino}pyrido[2,3-d]pyrimidin-2(1 H)-one.
Figure imgf000052_0002
[00275] The title compound was prepared in a similar manner to example 37 and isolated as a TFA salt. 1 H NMR (300MHz, DMSO-d6) δ 8.76-8.84 (m, 2H), 8.09-8.12 (m, 2H), 7.77-7.80 (m, 2H), 7.37-7.41 (m, 1 H); ES+ MS: 323 (M + 1 ).
[00276] Example 40: 1 -Hydroxy-4-(1 -piperazinyl)pyrido[2,3-d]pyrimidin-2(1 H)- one.
Figure imgf000052_0003
[00277] a): 1 , 1 -Dimethylethyl 4-{1 -[(1 , 1-dimethylethyl)oxy]-2-oxo-1 ,2- dihydropyrido[2,3-d]pyrimidin-4-yl}-1 -piperazinecarboxylate.
Figure imgf000053_0001
[00278] To a solution of 1 -[(1 , 1 -dimethylethyl)oxy]pyrido[2,3-d]pyrimidine-
2,4(1 H ,3H)-dione (20 mg, 0.085 mmol) and DIEA (1 .485 mL, 8.50 mmol) in toluene (2 mL) was added POCI3 (0.079 mL, 0.850 mmol). The mixture was heated at 100 °C for 45 min. Concentrated to dryness in a rotary evaporator and the residue was immediately taken up DMF (1 mL). Added 1 , 1 -dimethylethyl 1 -piperazinecarboxylate (190 mg, 1 .020 mmol) and stirred at room temperature for 15 min. Concentrated and purified by reverse phase to provide 1 , 1 -dimethylethyl 4-{1 -[(1 , 1 -dimethylethyl)oxy]-2-oxo-1 ,2-dihydropyrido[2 ,3- d]pyrimidin-4-yl}-1 -piperazinecarboxylate ( 32.2 mg, 94%) as a brown foam. 1H NMR (400 MHz, CDCI3) δ ppm 8.65 - 8.76 (m, 1 H), 7.94 (dd, J=8.0, 1 .6 Hz, 1 H), 7.18 (dd, J=8.0, 4.7 Hz, 1 H), 3.47 - 4.04 (m, 8 H), 1 .47 (s, 9 H), 1 .45 (s, 9 H); ES+ MS: 404 (M + 1 ).
b): 1 -Hydroxy-4-(1-piperazinyl)pyrido[2,3-d]pyrimidin-2(1 H)-one.
Figure imgf000053_0002
[00280] The title compound was prepared in a similar manner to example 144 and precipitated from methanol/dichloromethane to provide a beige solid (10 mg, 55%) as a trifluoroacetate salt. 1 H NMR (400 MHz, DMSO-d6) δ ppm 10.61 (br. s., 1 H), 8.83 (br. s., 1 H), 8.66 (dd, J=4.6, 1 .3 Hz, 1 H), 8.32 - 8.17 (m, 1 H), 7.21 (dd, J=8.0, 4.7 Hz, 1 H), 3.80 (d, J=4.5 Hz, 4 H), 3.26 - 3.18 (m, 4 H); ES+ MS: 248 (M + 1 ); H RMS calcd for C1 1 H 14N502: 248.1 147. Found: 248.1 150.
[00281] Example 41 : 1 -Hydroxy-4-{[3-(4-pyridinyl)phenyl]amino}pyrido[2,3- d\ py ri m i d i n-2 ( 1 H)-o n e .
Figure imgf000053_0003
[00282] The title compound was prepared in a similar manner to example 1 and isolated asaTFAsalt. 1H NMR (300MHz, DMSO-d6) δ 10.60 (s, 1H), 10.07 (s, 1H), 8.80-8.68 (m, 3H), 8.20 (s, 1H), 7.98 (m, 1H), 7.72-7.58 (m.3H), 7.39 (s, 1H); ES+ MS: 332 (M + 1).
[00283] Example 42: 4-({4'-[(Dimethylamino)methyl]-3-biphenylyl}amino)-1- hydroxypyrido[2,3-d]pyrimidin-2(1H)-one.
Figure imgf000054_0001
[00284] The title compound was prepared in a similar manner to example 144 and isolated as an TFA salt. 1H NMR (300MHz, CD3OD) δ ppm 8.88 (br, 2H), 8.13-7.86 (br m, 4H), 7.63-7.46 (br m, 5H), 4.40 (s, 2H), 2.93 (s, 6H); ES+ MS: 388.0 (M + 1).
[00285] Example 43: 1-Hydroxy-4-({[3-(4- morpho hyl}amino)pyrido[2,3-d]pyrimidin-2(1H)-one.
Figure imgf000054_0002
[00286] The title compound was prepared in a similar manner to example 144 and isolated as an TFA salt. 1H NMR (300MHz, DMSO-d6) δ ppm 9.04 (s, 1 H), 8.64 (d, 1H), 8.56 (d, 1H), 7.24-7.13 (m, 2H), 6.95 (s, 1H), 6.84-6.76 (m, 2H), 4.62 (s, 2H), 3.71 (s, 4H), 3.07 (s, 4H); ES+ MS: 354.0 (M + 1).
[00287] Example 44: 1-Hydroxy-4-{[3'-(4-morpholinyl)-3- biphen [2,3-d]pyrimidin-2(1H)-one.
[00288] The title compound was prepared in a similar manner to example 1 and isolated as a TFA salt. 1H NMR (300MHz, DMSO-d6) δ 0.57 (s, 1 H), 9.98 (s, 1 H), 8.83- 8.75 (m, 2H), 8.08 (s, 1H), 7.87-7.86 (m, 1H), 7.50-7.48 (m 2H), 7.40-7.33 (m.2H), 7.20 (s, 1H), 7.13-7.10 (m,1H), 7.00-6.97 (m, 1H) 3.78 (m, 4 H), 3.21 (m, 4 H); ES+ MS: 416 (M + 1). [00289] Example 45: 3'-{[(1 -Hydroxy-2-oxo-1 ,2-dihydropyrido[2,3-d]pyrimidin- 4-yl)am rboxamide.
Figure imgf000055_0001
[00290] The title compound was prepared in a similar manner to example 144 and isolated as an TFA salt. 1 H NMR (300MHz, DMSO-d6) δ ppm 10.39 (s, 1 H), 9.10 (m, 1 H), 8.70-8.68 (m, 1 H), 8.57 (d, 1 H), 8.04-7.96 (m, 3H), 7.76-7.73 (m, 3H), 7.63 (m, 1 H), 7.49-7.7.38 (m, 3H), 7.28 (m, 1 H),4.79 (d, 2H); ES+ MS: 387.9 (M + 1 ).
[00291] Example 46: 1 -Hydroxy-4-{[2-(methyloxy)ethyl]amino}pyrido[2,3- d\ py ri m i d i n-2 ( 1 H)-o n e .
Figure imgf000055_0002
[00292] The title compound was prepared in a similar manner to example 144 and isolated as a TFA salt. 1 H NMR (400MHz, CDCI3/CD3OD) δ 8.71 (m, 1 H), 8.12 (d, J = 7.6 Hz, 1 H), 7.16 (dd, J = 8.0, 4.8 Hz, 1 H), 3.82 (t, J = 4.8 Hz, 2 H), 3.62 (t, J = 4.8 Hz, 2 H), 3.38 (s, 3 H) ; ES+ MS: 237 (M + 1 ).
[00293] Example 47: 1 -Hydroxy-4-({[4-(4- morph l]methyl}amino)pyrido[2,3-d]pyrimidin-2(1 H)-one.
Figure imgf000055_0003
[00294] The title compound was prepared in a similar manner to example 144 and isolated as an TFA salt. 1 H NMR (300MHz, DMSO-d6) δ ppm 9.07 (s, 1 H), 8.67 (s, 1 H), 8.57 (d, 1 H), 7.24 (m, 3H), 6.91 (d, 2H), 4.60 (s, 2H), 3.72 (s, 4H), 3.06 (s, 4H); ES+ MS: 354.0 (M + 1 ). [00295] Example 48: 1-Hydroxy-4-({[4-(1- piperidinylmethyl)phenyl]methyl}amino)pyrido[2,3-c|pyrimidin-2(1H)-
Figure imgf000056_0001
[00296] The title compound was prepared in a similar manner to example 1 and isolated as an HBrsalt. 1H NMR (300MHz, CD3OD) δ 8.73(m, 1H), 8.48 (m, 1H),8.13 (m, 1H),7.46-7.75(m, 3H),7.36 (m, 1H),4.93 (s,2H), 4.41-4.28 (m,2 H), 3.40 (m,2H),2.96 (m,2H),1.75-2.03 (m,5H),1.54(m,1H); ES+ MS: 366 (M + 1).
[00297] Example 49: 1-Hydroxy-4-{[4-(4-pyridinyl)phenyl]amino}pyrido[2,3- d\ py ri m n e .
Figure imgf000056_0002
[00298] The title compound was prepared in a similar manner to example 1 and isolated as an HBrsalt. 1H NMR (300MHz, DMSO-d6) δ 10.16 (s, 1H), 8.87 (m, 4H), 8.35 (m, 2H),8.15 (m, 4H), 7.41 (m, 1H), 3.17 (s, 1H); ES+ MS: 332 (M + 1).
[00299] Example 50: 3'-{[(1-Hydroxy-2-oxo-1 ,2-dihydropyrido[2,3-d]pyrimidin- 4-yl)am rboxylic acid.
Figure imgf000056_0003
[00300] The title compound was prepared in a similar manner to example 144 and isolated as an TFA salt. 1H NMR (300MHz, DMSO-d6) δ ppm 12.97 (s, 1 H), 9.11 (m, 1H), 8.68 (m, 1H), 8.56 (m, 1H), 8.03 (m, 2H), 7.81-7.76 (m, 3H), 7.64 (d, 1H), 7.51-7.41 (m, 2H), 7.28 (m, 1H), 4.79 (d, 2H); ES+ MS: 388.9 (M + 1).
[00301] Example 51: 4-[(3-Bomophenyl)amino]-1-hydroxypyrido[2,3- d\ py ri m i d i n-2 ( 1 H)-o n e .
Figure imgf000057_0001
[00302] The title compound was prepared in a similar manner to example 1 and isolated as a TFA salt. 1 H NMR (300MHz, CD3OD) δ 8.80-8.74 (m, 2 H), 8.13 (br, 1 H), 7.85 (br, 1 H), 7.46-7.33 (m, 3 H); ES+ MS: 333 (M + 1 ).
[00303] Example 52: 4'-[(1 -Hydroxy-2-oxo-1 ,2-dihydropyrido[2,3-d]pyrimidin- 4-yl)am ide.
Figure imgf000057_0002
[00304] The title compound was prepared in a similar manner to example 1 and isolated as an HBr salt. 1 H NMR (300MHz, DMSO-d6) δ 10.04 (br, 1 H), 8.84 (m, 1 H), 8.76 (m, 1 H), 8.02 (m, 1 H), 7.98 (m, 4H), 7.82 (m, 4H), 7.39 (m, 2H); ES+ MS: 374(M + 1 ).
[00305] Example 53: 4-{[3'-(Aminomethyl)-4-biphenylyl]amino}-1 - hydro (1 H)-one.
Figure imgf000057_0003
[00306] The title compound was prepared in a similar manner to example 1 and isolated as a TFA salt. 1 H NMR (300MHz, CD3OD) δ 8.81 -8.78 (m, 2H), 8.33 (s, 1 H), 7.99 (m, 2H), 7.76-7.73 (m, 4H), 7.60-7.43 (m, 3H), 4.24 (s, 2H). ; ES+ MS: 360 (M + 1 ).
[00307] Example 54: 1 -Hydroxy-4-({1 -methyl-1 -[4- (methyloxy)phenyl]ethyl}amino)pyrido[2,3-d]pyrimidin-2(1 H)-one.
[00308]
Figure imgf000058_0001
[00309] Using a modification of the methods of example 1 , 4-({1-methyl-1 -[4- (methyloxy)phenyl]ethyl}amino)-1 -[(phenylmethyl)oxy]pyrido[2,3-d]pyrimidin-2(1 H)-one (20 mg, 0.05 mmol) was subjected to Pd(OH)2/C and NH4C02H in ethanol to provide the title compound (12 mg, 77%) as a TFA salt. 1 H NMR (300MHz, CD3OD) δ 8.68-8.69 (m, 2H), 7.37-7.35 (m, 3H), 6.84 (d, 2H), 3.77 (s, 3H), 1 .90 (s, 6H); ES+ MS: 327 (M + 1 ).
[00310] Example 55: 4-[(2-Furanylmethyl)amino]-1 -hydroxypyrido[2,3- d\ py ri m i d i n-2 ( 1 H)-o n e .
Figure imgf000058_0002
[00311] The title compound was prepared in a similar manner to example 1 and isolated as a TFA salt. 1 H NMR (300MHz, CD3OD) δ 8.70 (d, 1 H), 8.49 (d, 1 H), 7.46 (s, 1 H), 7.33 (m, 1 H), 6.42-38 (d, 2H), 4.80 (s, 2H).; ES+ MS: 259 (M + 1 ).
[00312] Example 56: 4'-[(1 -Hydroxy-2-oxo-1 ,2-dihydropyrido[2,3-d]pyrimidin- 4-yl)amino]-3-biphenylcarboxamide.
Figure imgf000058_0003
[00313] The title compound was prepared in a similar manner to example 1 and isolated as a TFA salt. 1 H NMR (300MHz, DMSO-d6) δ 10.00 (br, 1 H), 8.83-8.75 (m, 2H), 8.19 (s, 1 H), 8.1 1 (s, 1 H), 7.98-7.35 (m, 7H); ES+ MS: 374 (M + 1 ).
[00314] Example 57: 1 -Hydroxy-4-{[4-(3-pyridinyl)phenyl]amino}pyrido[2,3- d\ py ri m i d i n-2 ( 1 H)-o n e .
Figure imgf000059_0001
[00315] The title compound was prepared in a similar manner to example 1 and isolated as a TFA salt. 1 H NMR (300MHz, CD3OD) δ 9.22 (s, 1 H), 8.93 (m, 1 H), 8.81 (m, 3H), 8.16 (m, 3H), 7.89 (m, 2H), 7.45(m, 1 H); ES+ MS: 332 (M + 1 ).
[00316] Example 58: 1 -Hydroxy-4-({[3-(1- piperidinylmethyl)phenyl]methyl}amino)pyrido[2,3-d]pyrimidin-2(1 H)-one.
Figure imgf000059_0002
[00317] The title compound was prepared in a similar manner to example 1 and isolated as an HBr salt. 1 H NMR (300MHz, CD3OD) δ 8.90(d, 1 H), 8.81 (d, 1 H),7.78 (s, 1 H),7.50-7.57(m, 4H),4.93 (s,2H),4.34 (s,2H),3.47 (d,2H),3.03 (t,2H), 1 .79-1.96 (m,5H), 1 .59 (m, 1 H); ES+ MS: 366 (M + 1 ).
[00318] Example 59: 4-({[3-(Aminomethyl)phenyl]methyl}amino)-1 - hydroxy in-2(1 H)-one.
Figure imgf000059_0003
[00319] The title compound was prepared in a similar manner to example 1 and isolated as an HBr salt. 1 H NMR (300MHz, CD3OD) δ 9.02(d, 1 H), 8.83 (d, 1 H),7.47- 7.67(m, 5H),4.95(s,2H),4.18(s,2H); ES+ MS: 298 (M + 1 ).
[00320] Example 60: 1 -Hydroxy-4-{[(4'-hydroxy-4- biphen [2,3-d]pyrimidin-2(1 H)-one.
Figure imgf000059_0004
[00321] The title compound was prepared in a similar manner to example 1 and isolated as an HBr salt. 1 H NMR (300MHz, DMSO-d6) δ 9.61 (m, 1 H), 8.74-8.67 (m, 2 H), 7.57-7.33 (m, 7 H), 6.83 (d, 2 H), 4.78 (m, 2 H); ES+ MS: 361 (M + 1 ). [00322] Example 61 : 4-[(4-Bromophenyl)amino]-1 -hydroxypyrido[2,3- d\ py ri m i d i n-2 ( 1 H)-o n e .
Figure imgf000060_0001
[00323] The title compound was prepared in a similar manner to example 1 and isolated as an HBr salt. 1 H NMR (300MHz, DMSO-d6) δ 10.65 (s, 1 H), 10.02 (s, 1 H), 8.83 (m, 2H), 7.90 (m, 2H), 7.65 (m, 2H), 7.41 (m, 1 H); ES+ MS: 332.9 (M + 1 ).
[00324] Example 62: 4-({[4-(Aminomethyl)phenyl]methyl}amino)-1 - hydroxypyrido[2,3-d]pyrimidin-2(1 H)-one.
Figure imgf000060_0002
[00325] The title compound was prepared in a similar manner to example 1 and isolated as an HBr salt. 1 H NMR (300MHz, CD3OD) δ 8.93 (d, 1 H), 8.84 (d, 1 H), 7.57 (m, 4H), 7.52 (m, 1 H), 4.93 (s, 2H), 4.16 (s, 2H); ES+ MS: 298 (M + 1 ).
[00326] Example 63: 1 -Hydroxy-4-(methylamino)pyrido[2,3-d]pyrimidin-2(1 H)- one.
Figure imgf000060_0003
[00327] The title compound was prepared in a similar manner to example 1 and isolated as an HBr salt. 1 H NMR (300MHz, CD3OD) δ 8.90 (d, 1 H), 8.67 (d, 1 H),7.55 (m, 1 H), 3.29 (s,3H); ES+ MS: 193 (M + 1 ).
[00328] Example 64: 1 -Hydroxy-4-{[3-(3-pyridinyl)phenyl]amino}pyrido[2,3- d\ py ri m -2 ( 1 H)-o n e .
Figure imgf000060_0004
[00329] The title compound was prepared in a similar manner to example 1 and isolated as an TFA salt. 1 H NMR (300MHz, CD3OD) δ 8.27 (s, 1 H), 8.94-8.79 (m, 4H),
8.59 (s, 1 H), 8.14 (s, 1 H), 7.79 (s, 1 H), 7.65 (s, 2H), 7.45 (s, 1 H); ES+ MS: 332.0 (M + 1 ). [00330] Example 65: 3'-[(1 -Hydroxy-2-oxo-1 ,2-dihydropyrido[2,3-d]pyrimidin- 4-yl)amino]-3-biphenylcarboxamide.
Figure imgf000061_0001
[00331] The title compound was prepared in a similar manner to example 1 and isolated as an HBr salt. 1 H NMR (300MHz, DMSO-d6) δ 8.80-8.73 (m, 2 H), 8.16 (s, 1 H), 8.04 (s, 1 H), 7.90-7.82 (m, 3 H), 7.60-7.53 (m, 3 H), 7.37 (m, 1 H).
[00332] Example 66: 4-[(3'-Amino-3-biphenylyl)amino]-1 -hydroxypyrido[2,3- d\ py ri m -2 ( 1 H)-o n e .
Figure imgf000061_0002
[00333] The title compound was prepared in a similar manner to example 1 and isolated as a TFA salt. 1 H NMR (300MHz, CD3OD) δ 8.78 (m, 2H), 8.38 (s, 1 H), 7.70 (m, 4H), 7.51 (m, 2H), 7.41 (m, 2H); ES+ MS: 346.0 (M + 1 ).
[00334] Example 67: 4-[(1 -Benzothien-2-ylmethyl)amino]-1 -hydroxypyrido[2,3- d\ py ri m i d i n-2 ( 1 H)-o n e .
Figure imgf000061_0003
[00335] The title compound was prepared in a similar manner to example 1 and isolated as a TFA salt. 1 H NMR (300MHz, CD3OD) δ 8.72 (d, 1 H), 8.49 (d, 1 H), 7.81 - 7.73 (m, 2H), 7.38-7.29 (m, 4H), 5.08 (s, 2H); ES+ MS: 325.0 (M + 1 ).
[00336] Example 68: 4-{[(4'-Fluoro-3-biphenylyl)methyl]amino}-1 - hydroxypyrido[2,3-d]pyrimidin-2(1 H)-one.
Figure imgf000061_0004
[00337] The title compound was prepared in a similar manner to example 1 and isolated as a HBr salt. 1 H NMR (300MHz, CD3OD) δ 8.92 (d, 1 H), 8.50 (d, 1 H), 7.49- 7.74 (m, 7H), 7.19 (t, 2H), 4.96 (s, 2H); ES+ MS: 363.0 (M + 1 ).
[00338] Example 69: 4-[(3-Biphenylylmethyl)amino]-1 -hydroxypyrido[2,3- d\ py ri m i d i n-2 ( 1 H)-o n e .
Figure imgf000062_0001
[00339] The title compound was prepared in a similar manner to example 1 and isolated as a TFA salt. 1 H NMR (300MHz, CD3OD) δ 8.70 (m, 1 H), 8.54 (m, 1 H), 7.52- 7.69 (m, 8H), 7.32 (m, 2H), 4.89 (s, 2H); ES+ MS: 345.0 (M + 1 ).
[00340] Example 70: 1 -Hydroxy-4-(3-pyridinylamino)pyrido[2,3-d]pyrimidin- 2(1 H)-o
Figure imgf000062_0002
[00341] The title compound was prepared in a similar manner to example 37 and isolated as a TFA salt. 1 H NMR (300MHz, CD3OD) δ 9.60 (m, 1 H), 8.84 (m, 1 H), 8.76 (m, 2H), 8.60 (m, 1 H), 8.00 (m, 1 H), 7.49 (m, 1 H); ES+ MS: 256.0 (M + 1 ).
[00342] Example 71 : 1 -Hydroxy-4-[(2-hydroxy-2- methylpropyl)amino]pyrido[2,3-d]pyrimidin-2(1 H)-one.
Figure imgf000062_0003
[00343] The title compound was prepared in a similar manner to example 37 and isolated as a TFA salt. 1 H NMR (300MHz, CD3OD) δ 8.80 (d, 1 H), 8.65 (m, 1 H), 7.45 (m, 1 H), 3.71 (s, 2H), 1 .33 (s, 6H); ES+ MS: 251.0 (M + 1 ).
[00344] Example 72: 4-[(1 -Hydroxy-2-oxo-1 ,2-dihydropyrido[2,3-d]pyrimidin-4- yl)amino]-A/-methyl-1 -piperidinecarboxamide.
Figure imgf000063_0001
[00345] The title compound was prepared in a similar manner to example 1 and isolated as a TFA salt. 1H NMR (300MHz, CD3OD) δ 8.70 (m, 1 H), 8.58 (m, 1 H), 7.34 (m, 1H),4.43 (m, 1H), 4.10 (m, 2H), 2.95 (m, 2H), 2.75 (s, 3H), 2.08 (m, 2H), 1.58 (m, 2H).; ES+ MS: 319.0 (M + 1).
[00346] Example 73: 4-{4-[(3,5-Difluorophenyl)carbonyl]-1-piperazinyl}-1- hydroxypyrido[2,3-d]pyrimidin-2(1H)-one.
Figure imgf000063_0002
[00347] The title compound was prepared in a similar manner to example 144 and isolated as a TFA salt.1H NMR (300MHz, DMSO-d6) δ 10.53 (s, 1H), 8.68 (d, 1H), 8.25 (d, 1H), 7.43-7.37 (m, 1H), 7.26-7.22 (m, 3H), 3.85-3.78 (m, 6H), 3.52-3.43 (br s, 2H); ES+ MS: 389.9 (M + 1).
[00348] Example 74: 4,4'-(1,4-Piperazinediyl)bis(1-hydroxypyrido[2,3- cf]pyrimi -one).
Figure imgf000063_0003
[00349] a): 4,4'-(1 ,4-Piperazinediyl)bis[1-[(1 ,1-dimethylethyl)oxy]pyrido[2,3- d]pyrimidin-2(1 H)-one].
Figure imgf000064_0001
[00350] To a solution of 1-[(1 ,1-dimethylethyl)oxy]pyrido[2,3-d]pyrimidine- 2,4(1 H,3H)-dione (20 mg, 0.085 mmol) and DIEA (1.485 mL, 8.50 mmol) in toluene (2ml_), was added POCI3 (0.079 mL, 0.850 mmol). The mixture was heated at 100 °C for 45 min. Concentrated to dryness in a rotary evaporator and the residue was immediately taken up in DMF (1 mL). Added piperazine (43.9 mg, 0.510 mmol) and stirred at room temperature for 15 min. Purified by reverse phase chromatography to provide 4,4'-(1,4-piperazinediyl)bis[1- [(1,1-dimethylethyl)oxy]pyrido[2,3-d]pyrimidin-2(1H)-one].
[00351] (13 mg, 59%) as an orange solid.1H NMR (400 MHz, CDCI3) δ ppm 8.64 - 8.80 (m, 2 H), 8.04 (dd, J=8.0, 1.2 Hz, 2 H), 7.17 - 7.29 (m, 2 H), 4.64 (br. s., 4 H), 4.17 (br. s., 4 H), 1.48 (s, 18 H); ES+ MS: 521 (M + 1).
[00352] b): 4,4'-(1,4-Piperazinediyl)bis(1-hydroxypyrido[2,3-d]pyrimidin-2(1H)- one).
Figure imgf000064_0002
[00353] The title compound was prepared in a similar manner to example 144 and precipitated from methanol/dichloromethane to provide a beige solid (3 mg, 25%) as a trifluoroacetate salt. 1H NMR (400 MHz, TFA-di) δ ppm 11.58 (s, 2 H), 9.13 (d, J=8.2 Hz, 2 H), 8.92 (d, J=5.7 Hz, 2 H), 7.87 (br. s., 2 H), 4.63 (br. s., 8 H); ES+ MS: 409 (M + 1); HRMS calcdforC18H17N804: 409.1374. Found: 409.1373.
[00354] Example 75: 4-{4-[(4-Fluorophenyl)carbonyl]-1-piperazinyl}-1- hydroxypyrido[2,3-d]pyrimidin-2(1H)-one. [00355] The title compound was prepared in a similar manner to example 144 and isolated asaTFAsalt.1H NMR (300MHz, DMSO-d6) δ 10.53 (s, 1H), 8.69 (d, 1H), 8.25 (d, 1H), 7.56-7.53 (m, 2H), 7.34-7.22 (m, 3H), 4.07-3.60 (m, 8H); ES+ MS: 369.9 (M + 1).
[00356] Example 76: 4-[(2,2'-Bithien-5-ylmethyl)amino]-1-hydroxypyrido[2,3- d\ py ri m i d i n-2 ( 1 H)-o n e .
Figure imgf000065_0001
[00357] The title compound was prepared in a similar manner to example 144 and isolated asaTFAsalt.1H NMR (300MHz, DMSO-d6) δ 10.42 (s, 1H), 9.17-9.20 (m, 1H), 8.69-8.70 (m, 1H), 8.49-8.52 (m, 1H), 7.47-7.48 (m, 1H), 7.23-7.30 (m, 2H), 7.05-7.15 (m, 4H), 4.82-4.84 (m, 2H); ES+ MS: 356.9 (M + 1).
[00358] Example 77: 4-[(3,5-Difluorophenyl)amino]-1-hydroxypyrido[2,3- d\ py ri m i d i n-2 ( 1 H)-o n e .
Figure imgf000065_0002
[00359] The title compound was prepared in a similar manner to example 37 and isolated as a TFA salt.1H NMR (300MHz, DMSO-d6) δ 10.08 (s, 1 H), 8.77-8.79 (m, 2H), 7.73-7.76 (m, 2H), 7.39-7.43(m, 1H), 7.01-7.07(m, 1H); ES+ MS: 290.9 (M + 1).
[00360] Example 78: 4-{4-[(2,4-Dichlorophenyl)carbonyl]-1-piperazinyl}-1- hydroxypyrido[2,3-d]pyrimidin-2(1H)-one.
Figure imgf000065_0003
[00361] The title compound was prepared in a similar manner to example 144 and isolated as an TFA salt. 1H NMR (300MHz, DMSO-d6) δ 10.55 (s, 1 H), 8.69-8.68 (m, 1H), 8.27-8.24 (m, 1H), 7.78-7.77 (m, 1H), 7.58-7.49 (m, 2H), 7.26-7.22 (m, 1H), 3.84 (s, 4H), 3.72 (s, 2H), 3.36 (s, 2H); ES+ MS: 419.8 (M+ 1). [00362] Example 79: 1 -Hydroxy-4-[4-(2-thienylmethyl)-1- piperazinyl]pyrido[2,3-d]pyrimidin-2(1 H)-one.
Figure imgf000066_0001
a): 1 , 1 -Dimethylethyl 4-(2-thienylmethyl)-1 -piperazinecarboxylate.
Figure imgf000066_0002
[00364] To a solution of 1 , 1 -dimethylethyl 1-piperazinecarboxylate (700 mg, 3.76 mmol), in 1 ,2-dichloroethane (10 ml.) was added 2-thiophenecarbaldehyde (0.345 mL, 3.76 mmol). Cooled to 0 °C in an ice bath and added sodium triacetoxyborohydride (1 .274 g, 6.01 mmol) in several portions. The mixture was stirred at 0 °C for 3 h. Quenched with a saturated solution of NaHC03. Layers were separated and organic layer was washed with NaHC03 and brine. Dried over Na2S04, filtered and concentrated. Purified by silica gel liquid chromatography eluting with 0-20% ethyl acetate/hexanes to provide 1 , 1 -dimethylethyl 4-(2-thienylmethyl)-1 -piperazinecarboxylate (830 mg, 78%) as a yellow oil. 1 H NMR (400 MHz, CDCI3) δ ppm 7.20 - 7.27 (m, 1 H), 6.87 - 6.98 (m, 2 H), 3.73 (s, 2 H), 3.38 - 3.51 (m, 4 H), 2.43 (br. s., 4 H), 1 .45 (s, 9 H); ES+ MS: 283 (M + 1 ). b): 1 -(2-Thienylmethyl)piperazine.
Figure imgf000066_0003
[00366] To a solution of 1 , 1 -dimethylethyl 4-(2-thienylmethyl)-1- piperazinecarboxylate (830 mg, 2.94 mmol) in dichloromethane (2 mL) was added trifluoroacetic acid (2 mL). Stirred at room temperature for 3 h. Concentrated, and precipitated from diethyl ether to provide 1 -(2-thienylmethyl)piperazine ditrifluoroacetate salt (1 .14 g, 95%) as a white solid. 1 H NMR (400 MHz, DMSO-d6) δ ppm 8.87 (br. s, 1 H), 7.57 (d, J=4.7 Hz, 1 H), 7.13 (br. s., 1 H), 7.05 (dd, J=4.9, 3.5 Hz, 1 H), 4.09 (br. s., 2 H), 3.20 (br. s., 4 H), 2.87 (br. s., 4 H).
[00367] c): 1 -Hydroxy-4-[4-(2-thienylmethyl)-1 -piperazinyl]pyrido[2,3- d\ py ri m i d i n-2 ( 1 H)-o n e .
Figure imgf000067_0001
[00368] The title compound was prepared in a similar manner to example 144 and precipitated from hexanes to provide a tan solid (26 mg, 43%) as a trifluoroacetate salt. 1H NMR (400 MHz, DMSO-d6) δ ppm 10.23 (br. s., 1 H), 8.77 - 8.67 (m, 1 H), 8.39 - 8.20 (m, 1 H), 7.76 (br. s. , 1 H), 7.39 - 7.29 (m, 1 H), 7.26 (dd, J=8.0, 4.5 Hz, 1 H), 7.22 - 7.12 (m, 1 H), 4.64 (br. s., 2 H), 4.33 (br. s., 2 H), 3.50 (d, J=17.6 Hz, 4 H), 3.15 - 3.36 (m, 2 H); ES+ MS: 344 (M + 1 ); HRMS calcd for C16H 18N502S: 344.1 181 . Found: 344.1 179.
[00369] Example 80: 4-{4-[(2-Fluorophenyl)carbonyl]-1 -piperazinyl}-1 - hydroxypyrido[2,3-d]pyrimidin-2(1 H)-one.
Figure imgf000067_0002
[00370] The title compound was prepared in a similar manner to example 144 and isolated as an TFA salt. 1 H NMR (300MHz, CD3OD) δ 8.76 (d, 1 H), 8.44 (d, 1 H), 7.64- 7.51 (m, 2H), 7.41-7.28 (m, 3H), 4.10-3.96 (m, 6H), 3.65 (br, 2H). ES+ MS: 370 (M + 1 ).
[00371] Example 81 : 1 -Hydroxy-4-(4-{[2-(methyloxy)-3-pyridinyl]carbonyl}-1 - piperazinyl)pyrido[2,3-cf]pyrimidin-2(1 H)-one.
Figure imgf000067_0003
[00372] The title compound was prepared in a similar manner to example 144 and isolated as an TFA salt. 1H NMR (300MHz, CD3OD) δ 8.76 (d, 1 H), 8.45 (d, 1H), 8.35- 8.32 (m, 1H), 7.81-7.77 (m, 1H), 7.43-7.37 (m, 1H), 7.17-7.12 (m, 1H), 4.11-3.96 (m, 9H), 3.57 (br, 2H); ES+ MS: 383 (M + 1).
[00373] Example 82: 4-{4-[(3-Chlorophenyl)carbonyl]-1-piperazinyl}-1- hydroxypyrido[2,3-d]pyrimidin-2(1H)-one.
Figure imgf000068_0001
[00374] The title compound was prepared in a similar manner to example 144 and isolated as an TFA salt. 1H NMR (300MHz, CD3OD) δ 8.92(s, 1H), 8.57 (s, 1H), 7.58- 7.50 (m, 5H), 4.03-3.76 (m, 8H); ES+ MS: 385.9 (M + 1).
[00375] Example 83: 1-Hydroxy-4-{[2-(4-morpholinyl)phenyl]amino}pyrido[2,3- d\ py ri m i d i n-2 ( 1 H)-o n e .
Figure imgf000068_0002
[00376] The title compound was prepared in a similar manner to example 37 and isolated as an TFA salt. 1H NMR (300MHz, CD3OD) δ 10.52 (s, 1H), 9.62 (s, 1H), 8.75 (m, 1H), 8.64 (m, 1H), 7.91 (m, 1H), 7.39 (m, 1H), 7.27-7.19 (m, 3H), 3.68 (m, 4H), 2.86 (m, 4H); ES+ MS: 340.0 (M + 1).
[00377] Example 84: 1-Hydroxy-4-(2-pyridinylamino)pyrido[2,3-d]pyrimidin-
2(1H)-o
Figure imgf000068_0003
[00378] The title compound was prepared in a similar manner to example 37 and isolated as an TFA salt. 1H NMR (300MHz, CD3OD/CDCI3) δ 8.82 (d, 1 H), 8.74 (d, 1 H), 8.45 (d, 1H), 7.96 (m, 1H), 7.64 (m, 1H), 7.30 (m, 1H), 7.27 (m, 1H); ES+ MS: 256.0 (M + 1). [00379] Example 85: 1 -Hydroxy-4-(4-{[4-(methyloxy)phenyl]methyl}-1 - piperazinyl)pyrido[2,3-c ]pyrimidin-2(1 H)-one.
Figure imgf000069_0001
[00380] The title compound was prepared in a similar manner to example 144 and precipitated from diethyl ether to provide a tan solid (30 mg, 63%) as a trifluoroacetate salt. 1 H NMR (400 MHz, DMSO-d6) δ ppm 9.90 (br. s., 1 H), 8.72 (d, J=4.3 Hz, 1 H), 8.35 - 8.21 (m, 1 H), 7.42 (br. s., 2 H), 7.33 - 7.22 (m, 1 H), 7.05 (d, J=8.2 Hz, 2 H), 4.32 (br. s., 4 H), 3.79 (s, 3 H), 3.59 - 3.10 (m, 6 H); ES+ MS: 368 (M + 1 ); HRMS calcd for C19H22N503: 368.1723. Found: 368.1724.
[00381] Example 86: Methyl 4-[(1 -hydroxy-2-oxo-1 ,2-dihydropyrido[2,3- cf]pyrimidin-4-yl)amino]-1-piperidinecarboxylate.
Figure imgf000069_0002
[00382] The title compound was prepared in a similar manner to example 144 and isolated as an TFA salt. 1 H NMR (300MHz, CD3OD) δ 8.77-8.75(d, 1 H), 8.68-8.66(s, 1 H), 7.41 (s, 1 H), 4.44(s, 1 H), 4.27-4.23(d, 2H), 3.76(s, 3H), 3.04(m, 2H), 2.14-2.1 1 (d, 2H), 1.68-1 .64(d, 2H); ES+ MS: 320.0 (M+ 1 ).
[00383] Example 87: 4-(4-Glycyl-1 -piperazinyl)-1 -hydroxypyrido[2,3- d\ py ri m i d i n-2 ( 1 H)-o n e .
Figure imgf000069_0003
[00384] The title compound was prepared in a similar manner to example 1 and isolated as an TFA salt. 1 H NMR (300MHz, CD3OD) δ 8.75 (s, 1 H), 8.43 (s, 1 H), 7.40 (s, 1 H), 4.22-3.48 (m, 12H); ES+ MS: 305 (M + 1 ). [00385] Example 88: 4-[(1 -Glycyl-4-piperidinyl)amino]-1-hydroxypyrido[2,3- d\ py ri m i d i n-2 ( 1 H)-o n e .
Figure imgf000070_0001
[00386] The title compound was prepared in a similar manner to example 144 and isolated as an TFA salt. 1 H NMR (300MHz, CD3OD) δ 8.68-8.69 (m, 1 H), 8.50-8.53 (m, 1 H), 7.30-7.34 (m, 1 H),4.45-4.61 (m, 2H), 3.98 (s, 2H), 3.79-3.82 (m, 1 H), 2.88-2.96 (m, 1 H), 2.10-2.18 (m, 2H), 1 .59-1 .63 (m, 2H); ES+ MS: 319.0 (M+ 1 ). (missing 1 hydrogen, presumably under the NMR solvent peaks)
[00387] Example 89: 4-[(1 -Hydroxy-2-oxo-1 ,2-dihydropyrido[2,3-d]pyrimidin-4- yl)amino]-1-piperidinecarboxamide.
Figure imgf000070_0002
[00388] The title compound was prepared in a similar manner to example 144 and isolated as an TFA salt. 1 H NMR (300MHz, DMSO-d6) δ 10.37 (s, 1 H), 8.68-8.56 (m, 2H), 8.20-8.17 (m, 1 H), 7.29-7.27 (m, 1 H), 5.99 (s, 2H), 4.28 (s, 1 H), 4.03-3.99 (m, 2H), 2.85-2.77 (m, 2H), 1 .88-1 .84 (m, 2H), 1.49-1 .46 (m, 2H); ES+ MS: 305.0 (M+ 1 ).
[00389] Example 90: 4-(1 -Hydroxy-2-oxo-1 ,2-dihydropyrido[2,3-d]pyrimidin-4- yl)-1 -piperazinecarboxamide.
Figure imgf000070_0003
[00390] The title compound was prepared in a similar manner to example 1 and isolated as an TFA salt. 1 H NMR (300MHz, DMSO-d6) δ 8.67-8.66 (m, 1 H), 8.27-8.24 (m, 1 H), 7.25-7.21 (m, 1 H), 3.72 (s, 6H), 3.48 (s, 4H); ES+ MS: 291 .0 (M + 1 ).
[00391] Example 91 : 1 -Hydroxy-4-[4-(phenylsulfonyl)-1-piperazinyl]pyrido[2,3- d\ py ri m i d i n-2 ( 1 H)-o n e .
Figure imgf000071_0001
[00392] The title compound was prepared in a similar manner to example 144 and isolated as an TFA salt. 1H NMR (300MHz, CD3OD) δ 8.72-8.71 (m, 1 H), 8.33-8.30 (m, 1H), 7.89-7.86 (m, 2H), 7.77-7.66 (m, 3H), 7.37-7.33 (m, 1H), 4.02-3.99 (m, 4H), 3.28-3.25 (m, 4H).; ES+ MS: 291.0 (M + 1); ES+ MS: 387.9 (M + 1).
[00393] Example 92: 1-Hydroxy-4-[4-(2-pyridinylcarbonyl)-1- piperazinyl]pyrido[2,3-d]pyrimidin-2(1H)-one.
Figure imgf000071_0002
[00394] The title compound was prepared in a similar manner to example 144 and isolated as an TFA salt. 1H NMR (300MHz, CD3OD) δ 8.72 (d, 2H), 8.45 (s, 1 H), 8.06 (s, 1H), 7.76 (d, 2H), 7.60 (s, 1H), 7.39 (s, 1H), 4.21-4.02 (m, 6H), 3.82 (s, 2H); ES+ MS: 353 (M + 1).
[00395] Example 93: 1-Hydroxy-4-[4-(3-pyridinylcarbonyl)-1- piperazinyl]pyrido[2,3-d]pyrimidin-2(1H)-one.
Figure imgf000071_0003
[00396] The title compound was prepared in a similar manner to example 144 and isolated as an TFA salt. 1H NMR (300MHz, CD3OD) δ 8.75 (br, 2H), 8.57 (s, 1H), 8.31 (br, 2H), 7.81 (s, 1H), 7.23 (s, 1H),4.04-3.49 (m, 8H); ES+ MS: 353 (M + 1).
[00397] Example 94: 1-Hydroxy-4-[4-(methylsulfonyl)-1-piperazinyl]pyrido[2,3- d\ py ri m i d i n-2 ( 1 H)-o n e .
Figure imgf000072_0001
[00398] The title compound was prepared in a similar manner to example 144 and isolated as an TFA salt. 1H NMR (300MHz, CD3OD) δ 8.85 (s, 1 H),8.47 (d, 1 H), 7.422 (s, 1H), 4.03 (s, 4H), 3.42 (m, 4H), 2.96 (s, 3H); ES+ MS: 326.0 (M + 1).
[00399] Example 95: Ethyl 4-(1-hydroxy-2-oxo-1 ,2-dihydropyrido[2,3- cf]pyrimidin-4-yl)-1-piperazinecarboxylate.
Figure imgf000072_0002
[00400] The title compound was prepared in a similar manner to example 144 and isolated as an TFA salt. 1H NMR (300MHz, CD3OD) δ 8.75 (d, 1 H),8.43 (d, 1 H), 7.41 (m, 1H),4.28-4.21 (m, 2H), 4.00 (m, 4H), 3.74 (s, 4H),1.35 (m,3H); ES+ MS: 330.0 (M + 1).
[00401] Example 96: 1-Hydroxy-4-({1-[(methyloxy)acetyl]-4- piperidinyl}amino)pyrido[2,3-d]pyrimidin-2(1H)-one.
Figure imgf000072_0003
[00402] The title compound was prepared in a similar manner to example 144 and isolated as an TFA salt. 1H NMR (300MHz, CD3OD) δ 8.76 (m, 1 H), 8.62 (m, 1 H), 7.40 (m, 1H), 4.67-4.50 (m, 2H), 4.33-4.18 (m, 2H), 4.03 (m, 1H), 3.48 (s, 3H), 3.30 (m, 1H), 2.90 (m, 1H), 2.24-2.15 (m, 2H), 1.69-1.63 (m, 2H); ES+ MS: 334.0 (M+ 1).
[00403] Example 97: 1-Hydroxy-4-(4-piperidinylamino)pyrido[2,3-c]pyrimidin-
2(1H)-one.
Figure imgf000072_0004
[00404] The title compound was prepared in a similar manner to example 144 and isolated as an TFA salt. 1 H NMR (300MHz, DMSO-d6) δ 10.39 (br, 1 H), 8.68-8.31 (m, 4H), 7.26 (m, 1 H), 4.33 (s, 1 H), 3.40-3.09 (m. 4H), 2.10-2.06 (m,2H), 1 .79-1.75 (m, 2H); ES+ MS: 262.1 (M + 1 ).
[00405] Example 98: 1 -Hydroxy-4-[4-(4-pyridinylcarbonyl)-1 - piperazinyl]pyrido[2,3-d]pyrimidin-2(1 H)-one.
Figure imgf000073_0001
[00406] The title compound was prepared in a similar manner to example 144 and isolated as an TFA salt. 1 H NMR (300MHz, CD3OD) δ 8.87 (m, 2H), 8.77 (m, 1 H), 8.44 (m, 1 H), 7.87 (m, 2H), 7.40 (m, 1 H), 4.13 (m, 2H), 4.03 (m, 4H), 3.68 (m, 2H); ES+ MS: 353.0 (M + 1 ).
[00407] Example 99: 1 -Hydroxy-4-[4-(phenylmethyl)-1 -piperazinyl]pyrido[2,3- d\ py ri m i d i n-2 ( 1 H)-o n e .
Figure imgf000073_0002
[00408] The title compound was prepared in a similar manner to example 144 and precipitated from diethyl ether to provide a brown solid (1 1 .2 mg, 15%) as a
trifluoroacetate salt. 1 H NMR (400 MHz, DMSO-d6) δ ppm 9.99 (br. s., 1 H), 8.70 (d, J=3.3 Hz, 1 H), 8.32 - 8.19 (m, 1 H), 7.49 (br. s., 5 H), 7.32 - 7.13 (m, 1 H), 4.38 (br. s., 4 H), 3.57 - 3.17 (m, 6 H); ES+ MS: 338 (M + 1 ); HRMS calcd for C18H20N5O2: 338.1617. Found: 338.1619.
[00409] Example 100: 1 -Hydroxy-4-[(2R)-2-methyl-4-(phenylsulfonyl)-1 - piperazinyl]pyrido[2,3-d]pyrimidin-2(1 H)-one.
Figure imgf000074_0001
[00410] The title compound was prepared in a similar manner to example 144 and precipitated from diethyl ether to provide a beige solid (27 mg, 69%) as a
trifluoroacetate salt. 1 H NMR (400 MHz, DMSO-d6) δ ppm 8.62 (dd, J=4.7, 1 .6 Hz, 1 H), 8.08 (dd, J=8.1 , 1 .5 Hz, 1 H), 7.73 - 7.70 (m, 3 H), 7.66 - 7.62 (m, 2 H), 7.18 (dd, J=8.0, 4.7 Hz, 1 H), 4.70 - 4.55 (m, 1 H), 4.07 (d, J=13.9 Hz, 1 H), 3.65 (d, J=1 1.7 Hz, 1 H), 3.60 - 3.50 (m, 1 H), 3.48 - 3.40 (m, 1 H), 2.55 (dd, J=1 1 .7, 3.3 Hz, 1 H), 2.45 - 2.34 (m, 1 H), 1 .38 (d, J=6.8 Hz, 3 H); ES+ MS: 402 (M + 1 ); HRMS calcd for C18H20N5O4S: 402.1236. Found: 402.1235; HPLC: one major peak at 2.331 min., 95.77% pure; Anal, calcd for
C18H 19N504S with 1 .1 mol of TFA (C2HF302): C, 46.05; H , 3.85; N, 13.29; S, 6.09. Found: C, 46.09; H, 4.20; N, 13.16; S, 6.01 .
[00411] Example 101 : 1-Hydroxy-4-[(1 -methyl-4-piperidinyl)amino]pyrido[2,3- d\ py ri m i d i n-2 ( 1 H)-o n e .
Figure imgf000074_0002
[00412] The title compound was prepared in a similar manner to example 144 and isolated as an TFA salt. 1 H NMR (300MHz, CD3OD) δ 8.76 (s, 1 H), 8.65 (s, 1 H), 7.40 (s, 1 H), 4.49 (s, 1 H), 3.70 (d, 2H), 3.38-3.31 (m, 2H), 2.99 (s, 3H), 2.41 (br, 2H), 2.08 (br, 2H); ES+ MS: 276 (M + 1 ).
[00413] Example 102: 4-{[1-(2,2-Dimethylpropanoyl)-4-piperidinyl]amino}-1 - hydroxypyrido[2,3-d]pyrimidin-2(1 H)-one.
Figure imgf000074_0003
[00414] The title compound was prepared in a similar manner to example 144 and isolated as an TFA salt. 1H NMR (300MHz, CD3OD) δ 8.77 (m, 1 H), 8.76 (m, 1 H), 7.41 (m, 1H), 4.60 (m, 1H), 4.56 (m, 2H), 3.13 (m, 2H), 2.17 (m, 2H), 1.67 (m, 2H), 1.37 (s, 9H); ES+ MS: 346.1 (M + 1).
[00415] Example 103: 4-(7,8-Dihydro-1,6-naphthyridin-6(5H)-yl)-1- hydroxypyrido[2,3-d]pyrimidin-2(1H)-one.
Figure imgf000075_0001
[00416] The title compound was prepared in a similar manner to example 144 and isolated as an TFA salt. 1H NMR (300MHz, DMSO-d6) δ 11.80 (s, 1 H), 8.70 (d, 1 H), 8.90 (m, 1H), 8.32 (m, 1H), 8.03 (m, 1H), 7.56 (m, 1H), 7.29 (m, 1H), 4.98 (s, 2H), 4.05 (m, 2H), 3.27 (m, 2H); ES+ MS: 296.0 (M + 1).
[00417] Example 104: 1-Hydroxy-4-{(2R)-2-methyl-4-[(1S)-1-(2,3,5- trifluoro ]-1-piperazinyl}pyrido[2,3-d]pyrimidin-2(1H)-one.
Figure imgf000075_0002
[00418] The title compound was prepared in a similar manner to example 144 and precipitated from diethyl ether to provide a tan solid (27 mg, 50%) as a trifluoroacetate salt. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.66 (br. s., 1 H), 8.12 (br. s., 1 H), 7.74 - 7.40 (m, 1 H), 7.36 - 7.30 (m, 2 H), 4.61 (br. s., 2 H), 4.13 (br. s., 1 H), 3.58 (br. s., 3 H), 3.29 - 2.93 (m, 1 H), 2.32 - 2.05 (m, 1 H), 1.38 (br. s., 6 H); ES+ MS: 420 (M + 1 ); HRMS calcd for C20H21F3N5O2: 420.1647. Found: 420.1649; Anal, calcd for C20H20F3N5O2 with 2.1 mol of TFA (C2HF302): C, 44.12; H, 3.38; N, 10.63. Found: C, 44.16; H, 3.75; N, 10.95.
[00419] Example 105: 1-Hydroxy-4-{(2R)-4-[(1S)-2-hydroxy-1-phenylethyl]-2- methyl-1-piperazinyl}pyrido[2,3-d]pyrimidin-2(1H)-one.
Figure imgf000076_0001
[00420] The title compound was prepared in a similar manner to example 144 and precipitated from ethyl acetate/hexanes to provide a tan solid (9.5 mg, 40%) as a trifluoroacetate salt. 1 H NMR (400 MHz, DMSO-d6) δ ppm 10.59 (br. s., 1 H), 8.82 - 8.56 (m, 1 H), 8.01 - 8.21 (m, 1 H), 7.69 - 7.07 (m, 6 H), 4.79 (br. s., 1 H), 3.19 - 4.68 (m, 10 H), 1.40 - 1 .63 (m, 3 H); ES+ MS: 382 (M + 1 ); H RMS calcd for C20H24N5O3: 382.1879.
Found: 382.1881 .
[00421] Example 106: 1-hydroxy-4-{[1 -(phenylacetyl)-4- piperidinyl]amino}pyrido[2,3-d]pyrimidin-2(1 H)-one.
Figure imgf000076_0002
[00422] The title compound was prepared in a similar manner to example 144 and isolated as an TFA salt. 1 H NMR (300MHz, CD3OD) δ 8.71 (m, 1 H), 8.57 (m, 1 H), 7.33 (m, 6H),4.69 (m, 1 H), 4.44 (m, 1 H), 4.15 (m, 1 H), 3.83 (m, 2H), 3.16(m, 1 H), 2.84 (m, 1 H), 2.07-1 .31 (m, 4H); ES+ MS: 380.0 (M + 1 ).
[00423] Example 107: 1-Hydroxy-4-{(2R)-2-methyl-4-[(2,3,5- trifluorophenyl)methyl]-1 -piperazinyl}pyrido[2,3-d]pyrimidin-2(1 H)-one.
Figure imgf000076_0003
[00424] a): (3R)-3-Methyl-1 -[(2,3,5-trifluorophenyl)methyl]piperazine.
Figure imgf000077_0001
[00425] To a solution of (2R)-2-methylpiperazine (3 g, 30.0 mmol) in ethanol (60 mL) was added 1 -(bromomethyl)-2,3,5-trifluorobenzene (3.92 mL, 30.0 mmol), followed by addition of sodium bicarbonate (7.55 g, 90 mmol). The resulting suspension was heated to reflux for 4h. Concentrated and diluted with dichloromethane and water. The product was extracted twice from the dichloromethane layer with 1 N HCI. The acidic layers were combined, made basic with 4M NaOH and extracted with dichloromethane. Dried over Na2S04, filtered and concentrated. Purified by silica gel liquid chromatography, eluting with 0-10% methanol/dichloromethane to provide (3R)-3-methyl-1 -[(2,3,5- trifluorophenyl)methyl]piperazine(3.3 g, 45%) as a light yellow oil. 1 H NMR (400 MHz, CDCI3) δ ppm 6.88 - 6.98 (m, 1 H), 6.74 - 6.86 (m, 1 H), 3.51 - 3.54 (s, 2 H), 2.80 - 3.03 (m, 3 H), 2.10 (td, J=1 1 .0, 3.5 Hz, 1 H), 1.76 (t, J=10.5 Hz, 2 H), 0.99 - 1 .06 (m, 3 H).
[00426] b): 1 -Hydroxy-4-{(2R)-2-methyl-4-[(2,3,5-trifluorophenyl)methyl]-1- piperazinyl}pyrido[2,3-d]pyrimidin-2(1 H)-one.
Figure imgf000077_0002
[00427] The title compound was prepared in a similar manner to example 144 and precipitated from diethyl ether to provide a tan solid (36 mg, 59%) as a trifluoroacetate salt. 1 H NMR (400 MHz, DMSO-d6) δ ppm 10.51 (br. s. , 1 H), 8.78 - 8.59 (m, 1 H), 8.14 (d, J=7.8 Hz, 1 H), 7.63 (br. s., 1 H), 7.45 - 7.28 (m, 1 H), 7.24 (dd, J=7.6, 4.7 Hz, 1 H), 4.71 (br. s., 2 H), 4.42 - 2.98 (br.s. , 7 H), 1 .45 (br. s., 3 H); ES+ MS: 406 (M + 1 ); HRMS calcd for C19H 19F3N502: 406.1491 . Found: 406.1491 ; Anal, calcd for C19H 18F3N502 with 1 .75 mol of TFA (C2HF302): C, 44.68; H, 3.29; N , 1 1 .58. Found: C, 44.29; H, 3.69; N, 1 1 .77.
[00428] Example 108: 4-(Hexahydro-1 (2H)-azocinyl)-1-hydroxypyrido[2,3- d\ py ri m i d i n-2 ( 1 H)-o n e .
Figure imgf000078_0001
[00429] The title compound was prepared in a similar manner to example 37 to provide a white solid (29.5 mg, 81%) as a trifluoroacetate salt. 1H NMR (400 MHz, CDCI3) δ ppm 9.08 (br, 4 H, TFA), 8.79 (d, J = 4.4. Hz, 1 H), 8.32 (d, J = 8.0 Hz, 1 H), 7.32 (dd, J= 8.0, 4.4 Hz, 1 H), 3.91 (m, 4 H), 1.96 (m, 4 H), 1.66-1.58 (m, 6 H); ES+ MS: 275 (M + 1).
[00430] Example 109: 4-[(1-Acetyl-4-piperidinyl)amino]-1-hydroxypyrido[2,3- cflpyrimi
Figure imgf000078_0002
[00431] The title compound was prepared in a similar manner to example 144 and precipitated from ethyl acetate to provide a beige solid (7 mg, 43%) as a trifluoroacetate salt. 1H NMR (400 MHz, DMSO-d6) δ ppm 10.35 (br. s., 1 H), 8.66 (dd, J=4.6, 1.5 Hz, 1 H), 8.54 (dd, J=8.0, 1.6 Hz, 1 H), 8.23- 8.12 (m, 1 H), 7.31 -7.17(m, 1 H), 4.40 (d, J=13.5 Hz, 1 H), 4.31 (dd, J=11.2, 4.0 Hz, 1 H), 3.85 (br. s., 1 H), 3.23- 3.06 (m, 1 H), 2.74-2.58 (m, 1 H), 2.02 (s, 3 H), 1.80- 1.98 (m, 2 H), 1.59- 1.31 (m, 2 H); ES+ MS: 304 (M + 1); HRMS calcdforC14H18F3N503: 304.1410. Found: 304.1411.
[00432] Example 110: 1-Hydroxy-4-(methyloxy)pyrido[2,3-d]pyrimidin-2(1H)- one.
Figure imgf000078_0003
[00433] (a): 1-[(1,1-Dimethylethyl)oxy]-4-(methyloxy)pyrido[2,3-d]pyrimidin-
2(1H)-o
Figure imgf000078_0004
[00434] To a suspension of 1 -[(1 , 1 -dimethylethyl)oxy]pyrido[2,3-d]pyrimidine- 2,4(1 H,3H)-dione (0.2 g, 0.85 mmol) in DIEA (7.42 mL, 42.5 mmol) was added POCI3 (0.79 mL, 8.5 mmol) and toluene (2 mL) and the mixture was stirred at 100°C for 1 h. The mixture was concentrated, co-evaporated with toluene, dissolved in MeOH (2 mL), cooled to 0°C and 25% NaOMe/MeOH (1 mL, 4.6 mmol) was added. After 15 min the mixture was partitioned between EtOAc and water/brine (1 : 1 ). The organic phase was dried over Na2S04, concentrated, and purified by flash chromatography on silica (0-100% EtOAc in hexanes) to provide 1 -[(1 , 1 -dimethylethyl)oxy]-4-(methyloxy)pyrido[2,3-d]pyrimidin-2(1 H)- one (0.15 g, 0.59 mmol, 69% yield) as a tan solid. 1 H NMR (400 MHz, CDCI3) ppm 8.74 (dd, J = 4.7, 2 Hz, 1 H), 8.20 (dd, J = 7.8, 2 Hz, 1 H), 7.20 (dd, J = 7.8, 4.7 Hz, 1 H), 4.16 (s, 3 H), 1 .49 (s, 9 H). ES+ MS: m/z = 250.4 (M+1 ). HRMS calcd for Ci2H15N303Na: 272.101 1 . Found: 272.1012.
(b): 1 -Hydroxy-4-(methyloxy)pyrido[2,3-d]pyrimidin-2(1 H)-one.
Figure imgf000079_0001
[00436] The title compound was prepared in a similar manner to example 144 to provide a tan solid as a TFA salt. 1 H NMR (400 MHz, DMSO-D6) δ ppm 10.91 (broad s, 1 H), 8.80 (dd, J = 4.7, 1 .7 Hz, 1 H), 8.30 (dd, J = 7.8, 1 .7 Hz, 1 H), 7.33 (dd, J = 7.8, 4.7 Hz, 1 H), 4.04 (s, 3H). ES+ MS: m/z = 194.29 (M + 1 ). HRMS calcd. for C8H7N3O3: 194.0566. Found: 194.0565.
[00437] Example 1 1 1 : 1 -Hydroxy-4-(4-methyl-1-piperazinyl)pyrido[2,3- d\ py ri m i d i n-2 ( 1 H)-o n e .
Figure imgf000079_0002
[00438] The title compound was prepared in a similar manner to example 144 and precipitated from methanol/ethyl acetate to provide an off white solid (18 mg, 33%) as a trifluoroacetate salt. 1 H NMR (400 MHz, DMSO-d6) δ ppm 9.85 (br. s., 1 H), 8.71 (dd, J=4.7, 1 .6 Hz, 1 H), 8.27 (dd, J=8.0, 1.6 Hz, 1 H), 7.27 (dd, J=8.0, 4.7 Hz, 1 H), 4.32 (br. s., 2 H), 3.62 - 3.41 (m, 4 H), 3.27 - 3.15 (m, 2 H), 2.84 (br. s., 3 H); ES+ MS: 262 (M + 1 ); HRMS calcd for C12H 16N502: 262.1304. Found: 262.1303; Anal, calcd for C12H 15N502 with 1 mol of TFA (C2HF302): C, 44.80; H , 4.30; N, 18.66 Found: C, 44.75; H, 4.33; N , 18.74.
Example 1 12: 1 -Hydroxypyrido[2,3-d]pyrimidine-2,4(1 -/,3H)-dione.
Figure imgf000080_0001
[00440] The title compound was prepared in a similar manner to example 37 and as a TFA salt. 1H NMR (400 MHz, DMSO-d6) δ ppm 1 1 .79 (s, 1 H), 10.77 (s, 1 H), 8.71 (dd, J = 4.8, 2.0 Hz, 1 H), 8.30 (dd, J = 8.0, 2.0 Hz, 1 H), 7.31 (dd, J = 8.0, 4.8 Hz, 1 H).
[00441] Example 1 13: 1 -Hydroxy-4-[methyl(phenylmethyl)amino]pyrido[2,3- d\ py ri m i d i n-2 ( 1 H)-o n e .
Figure imgf000080_0002
[00442] The title compound was prepared in a similar manner to example 37 to provide the desired product (33 mg, 70%) as a trifluoroacetate salt. 1 H NMR (400 MHz, CDCI3) δ ppm 9.45 (br s, 1 H), 8.72 (br, TFA), 8.06 (m, 1 H), 7.43-7.30 (m, 5 H), 7.08 (m, 1 H), 4.95 (s, 2 H), 3.31 (s, 3 H).
[00443] Example 1 14: Ethyl 3'-{[(1 -hydroxy-2-oxo-1 ,2-dihydropyrido[2,3- cf]pyrimidin-4-yl)amino]methyl}-3-biphenylcarboxylate.
Figure imgf000080_0003
[00444] The title compound was prepared in a similar manner to example 144 and isolated as an TFA salt. 1 H NMR (300MHz, DMSO-d6) δ ppm 10.37 (s, 1 H), 9.1 1 (m, 1 H), 8.69 (d, 1 H), 8.57 (d, 1 H), 8.19 (s, 1 H), 7.98-7.93 (m, 2H), 7.72-7.61 (m, 3H), 7.51 - 7.40 (m, 2H), 7.28 (m, 1 H), 4.80 (d, 2H), 4.35 (m, 2H), 1 .33 (m, 3H); ES+ MS: 416.9 (M +
1 ).
[00445] Example 1 15: 3'-[(1 -Hydroxy-2-oxo-1 ,2-dihydropyrido[2,3-d]pyrimidin- 4-yl)amino]-4-biphenylcarboxamide.
Figure imgf000081_0001
[00446] The title compound was prepared in a similar manner to example 144 and isolated asanTFAsalt. 1H NMR (300MHz, DMSO-d6) δ 10.57 (s, 1H), 10.02 (s, 1H), 8.81-8.75 (m, 2H), 8.14-7.94 (m, 5H), 7.78-7.75 (m, 2H), 7.55 (s, 2H), 7.40 (s, 2H); ES+ MS: 374 (M + 1).
[00447] Example 116: 1-Hydroxy-4-{[4'-(1-piperazinylcarbonyl)-3- biphenylyl]amino}pyrido[2,3-d]pyrimidin-2(1H)-one.
Figure imgf000081_0002
[00448] The title compound was prepared in a similar manner to example 144 and isolated asanTFAsalt. 1H NMR (300MHz, DMSO-d6) δ 10.56 (s, 1H), 10.03(s, 1H), 8.83 -8.75 (m, 3H), 8.19 (s, 1H), 7.83-7.76 (m, 3H), 7.61(d, 2H), 7.57 (d, 2H), 7.41-7.36 (m, 1H), 3.73 (br, 4H), 3.20 (br, 4H); ES+ MS: 443 (M + 1).
[00449] Example 117: 3'-[(1-Hydroxy-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidin- 4-yl)amino]-A/-methyl-4-biphenylcarboxamide.
Figure imgf000081_0003
[00450] The title compound was prepared in a similar manner to example 144 and isolated asanTFAsalt. 1H NMR (300MHz, DMSO-d6) δ 10.58 (s, 1H), 10.03 (s, 1H), 8.84-8.76 (m, 2H), 8.52-8.51 (d, 1H), 8.14 (s, 1H), 8.00-7.96 (m, 3H), 7.79-7.77 (m, 2H), 7.56-7.54 (m, 2H), 7.41-7.37 (m, 1H), 2.83-2.81 (s, 3H); ES+ MS: 388.0 (M + 1).
[00451] Example 118: 4-{4-[(3,4-Dichlorophenyl)carbonyl]-1-piperazinyl}-1- hydroxypyrido[2,3-d]pyrimidin-2(1H)-one.
Figure imgf000082_0001
[00452] The title compound was prepared in a similar manner to example 144 and isolated as an TFA salt. 1 H NMR (300MHz, CD3OD) δ 8.73 (s, 1 H), 8.41 (s, 1 H), 7.74- 7.69 (m, 2H), 7.48-7.37 (m, 2H), 4.15-3.67 (m, 8H); ES+ MS: 420.1 (M + 1 ).
[00453] Example 1 19: 1-Hydroxy-4-[2-(phenylmethyl)-1 -piperidinyl]pyrido[2,3- d]pyrim ne.
Figure imgf000082_0002
[00454] The title compound was prepared in a similar manner to example 144 to provide a yellow solid (13 mg, 16.1 % yield) as a trifluoroacetate salt. 1 H NMR (400 MHz, CD3OD) δ ppm 8.54 (d, J = 4.8 Hz, 1 H), 8.03 (d, J = 8.0 Hz, 1 H), 7.20 (dd, J = 4.8, 8.0 Hz,
1 H), 7.02-7.07 (m, 5 H), 4.09 (d, J = 13.6 Hz, 1 H), 3.60 (t, J = 12.0 Hz, 1 H), 3.25-3.31 (m,
2 H), 2.83 (dd, J = 5.6, 13.6 Hz, 1 H), 1 .63-1 .97 (m, 6 H); ES+ MS: 337 (M + 1 ).
[00455] Example 120: 4-(1 ,4'-Bipiperidin-1 '-yl)-1 -hydroxypyrido[2,3- d]pyrimidin-2(1 H)-one.
Figure imgf000082_0003
[00456] The title compound was prepared in a similar manner to example 144 to provide a yellow solid (5 mg, 8.5 % yield) as a trifluoroacetate salt. 1 H NMR (400 MHz, CD3OD) δ ppm 8.65 (d, J = 4.8 Hz, 1 H), 8.30 (d, J = 8.0 Hz, 1 H), 7.30 (dd, J = 4.8, 8.0 Hz, 1 H), 4.57 (d, J = 13.2 Hz, 1 H), 3.55 (m, 4 H), 3.28 (m, 2 H), 3.05 (m, 4 H), 1 .97 (m, 4 H), 1.80 (m, 4 H); ES+ MS: 330 (M + 1 ).
[00457] Example 121 : 1 -Hydroxy-4-{4-[2-(methyloxy)ethyl]-1 - piperazinyl}pyrido[2,3-d]pyrimidin-2(1 H)-one.
Figure imgf000083_0001
[00458] The title compound was prepared in a similar manner to example 144 to provide a yellow solid (5.2 mg, 9.5 % yield) as a trifluoroacetate salt.1H NMR (400 MHz, CD3OD) δ ppm 8.70 (d, J = 4.8 Hz, 1 H), 8.33 (d, J = 8.0 Hz, 1 H), 7.33 (d, J = 4.8, 8.0 Hz, 1 H), 3.73 (m, 2 H), 3.69 (m, 2 H), 3.49 (m, 4 H), 3.40 (s, 3 H), 3.28 (m, 4 H); ES+ MS: 306 (M + 1).
[00459] Example 122: 1-Hydroxy-4-{[4'-(1-pyrrolidinylcarbonyl)-4- biphenylyl]amino}pyrido[2,3-d]pyrimidin-2(1H)-one.
Figure imgf000083_0002
[00460] The title compound was prepared in a similar manner to example 144 and isolated asanTFAsalt. 1H NMR (300MHz, DMSO-d6) δ 10.59 (s, 1H), 10.01 (s, 1H), 8.83 (d, 1H), 8.75 (d, 1H), 7.99 (d, 2H), 7.80-7.76 (m, 4H), 7.62 (d, 2H), 7.40-7.36 (m, 1H), 3.49-3.46 (m, 4H), 1.89-1.84 (m, 4H); ES+ MS: 428.2 (M + 1).
[00461] Example 123: 1-Hydroxy-4-({[4'-(trifluoromethyl)-4- biphenylyl]methyl}amino)pyrido[2,3-d]pyrimidin-2(1H)-one.
Figure imgf000083_0003
[00462] The title compound was prepared in a similar manner to example 144 and isolated asaTFAsalt. 1H NMR (300MHz, DMSO-d6) δ 10.37 (s, 1H), 9.11 (m, 1H), 8.68 (d, 1H), 8.56 (d, 1H), 7.86-7.70 (m, 5H), 7.48 (m, 2H), 7.35-7.26 (m, 2H), 4.75 (m, 2H); ES+ MS: 413.2 (M + 1).
[00463] Example 124: Ethyl 3'-{[(1-hydroxy-2-oxo-1 ,2-dihydropyrido[2,3- cf]pyrimidin-4-yl)amino]methyl}-4-biphenylcarboxylate.
Figure imgf000084_0001
[00464] The title compound was prepared in a similar manner to example 144 and isolated as an TFA salt. H NMR (300MHz, DMSO-d6) δ ppm 10.38 (s, 1 H), 9.10 (m, 1 H), 8.69 (m, 1 H), 8.57 (d, 1 H), 8.06-8.03 (m, 2H), 7.84-7.81 (m, 2H), 7.77 (s, 1 H), 7.65 (d, 1 H), 7.51-7.41 (m, 2H), 7.28 (m, 1 H), 4.79 (d, 2H), 4.35 (m, 2H), 1 .35 (m, 3H); ES+ MS: 416.9 (M + 1 ).
[00465] Example 125: V-[2-(Dimethylamino)ethyl]-4'-[(1-hydroxy-2-oxo-1 ,2- dihydropyrido[2,3-d]pyrimidin-4-yl)amino]-4-biphenylcarboxamide.
Figure imgf000084_0002
[00466] The title compound was prepared in a similar manner to example 144 and isolated as an TFA salt. H NMR (300MHz, DMSO-d6) δ 8.80 (m, 2H), 7.99 (m, 4H), 7.79 (m, 4H), 7.46 (m, 1 H),3.85 (m, 2H), 3.06 (m, 8H); ES+ MS: 445.2 (M + 1 ).
[00467] Example 126: 4-{[3'-(Aminomethyl)-3-biphenylyl]amino}-1 - hydro idin-2(1 H)-one.
Figure imgf000084_0003
[00468] The title compound was prepared in a similar manner to example 144 and isolated as an TFA salt. H NMR (300MHz, CD3OD) δ 8.76 (m, 2H), 8.29 (m, 1 H), 7.83 (m, 1 H), 7.70 (m, 2H), 7.48 (m, 5H), 4.24 (s, 2H); ES+ MS: 360.2 (M + 1 ).
[00469] Example 127: N-(4-chlorophenyl)-1 -(1 -hydroxy-2-oxo-1 ,2- dihydropyrido[2,3-d]pyrimidin-4-yl)-3-piperidinecarboxamide.
Figure imgf000085_0001
[00470] The title compound was prepared in a similar manner to example 144 to provide a yellow solid (9.8 mg, 10.6% yield) as a trifluoroacetate salt. H NMR (400 MHz, CD3OD) δ ppm 8.62 (d, J = 4.8 Hz, 1 H), 8.33 (d, J = 8.0 Hz, 1 H), 7.53 (d, J = 8.0 Hz, 2 H), 7.29 (dd, J = 4.8, 8.0 Hz, 1 H), 7.25 (d, J = 8.0 Hz, 2 H), 4.51 (d, J = 12.8 Hz, 1 H), 4.28 (d, J = 12.8 Hz, 1 H), 3.48 (m, 2 H), 2.84 (m, 1 H), 2.06 (m, 1 H), 1 .95 (m, 1 H), 1 .86 (m, 1 H), 1.70 (m, 1 H); ES+ MS: 400 (M + 1 ).
[00471] Example 128: Phenylmethyl {[(2R)-1 -(1-hydroxy-2-oxo-1 ,2- dihydropyrido[2,3-d]pyrimidin-4-yl)-2-pyrrolidinyl]methyl}carbamate.
Figure imgf000085_0002
[00472] The title compound was prepared in a similar manner to example 144 to provide a yellow solid (25 mg, 54.8 % yield) as a trifluoroacetate salt. H NMR (400 MHz, CD3OD) δ ppm 8.60 (d, J = 4.8 Hz, 1 H), 8.42 (m, 1 H), 7.26 (m, 1 H), 7.25 (m, 5 H), 4.96 (m, 2 H), 4.68 (m, 1 H), 3.91 (m, 2 H), 3.60 (m, 1 H), 3.32 (m, 2 H), 2.08 (m, 2 H), 1 .94 (m, 1 H); ES+ MS: 396 (M + 1 ).
[00473] Example 129: N-(4-chlorophenyl)-3-{[4-(1 -hydroxy-2-oxo-1 ,2- dihydropyrido[2,3-d]pyrimidin-4-yl)-1 -piperazinyl]methyl}benzamide.
Figure imgf000085_0003
[00474] The title compound was prepared in a similar manner to example 144 to provide a yellow solid (45 mg, 41 .5 % yield) as a trifluoroacetate salt. H NMR (400 MHz, CD3OD) δ ppm 8.62 (d, J = 4.8 Hz, 1 H), 8.26 (d, J = 8.0 Hz, 1 H), 8.06 (s, 1 H), 7.97 (d, J = 8.0 Hz, 1 H), 7.71 (d, J = 7.2 Hz, 1 H), 7.62 (d, J = 8.0 Hz, 2 H), 7.60 (t, J = 8.0 Hz, 1 H), 7.57 (t, J = 8.0 Hz, 1 H), 7.26 (d, J = 8.0 Hz, 3 H), 5.14 (m, 4 H), 4.49 (m, 2 H), 4.51 (m, 4 H); ES+ MS: 491 (M + 1 ).
[00475] Example 130: 4'-[(1 -Hydroxy-2-oxo-1 ,2-dihydropyrido[2,3-d]pyrimidin- 4-yl)amino]- V-[2-(methyloxy)ethyl]-4-biphenylcarboxamide.
Figure imgf000086_0001
[00476] The title compound was prepared in a similar manner to example 144 and isolated as an TFA salt. H NMR (300MHz, DMSO-d6) δ 10.60 (s, 1 H), 10.02 (s, 1 H), 8.83 (d, 2H), 8.76 (d, 1 H), 8.58 (d, 1 H), 7.98 (mt, 4H), 7.81 (mt, 4H), 7.40-7.35 (m, 1 H), 3.48 (br m, 4H), 3.17(s, 3H); ES+ MS: 432 (M + 1 ).
[00477] Example 131 : 1 -Hydroxy-4-{[4'-(1 -piperazinylcarbonyl)-4- biphenylyl]amino}pyrido[2,3-d]pyrimidin-2(1 H)-one.
Figure imgf000086_0002
[00478] The title compound was prepared in a similar manner to example 144 and isolated as an TFA salt. H NMR (300MHz, DMSO-d6) δ 10.04 (s, 1 H), 8.83 (br, 2H), 8.76 (d, 1 H), 8.00 (d, 2H), 7.82-7.80 (m, 4H), 7.56 (d, 2H), 7.38 (s, 1 H), 3.69 (br, 4H), 3.13 (br, 4H); ES+ MS: 432 (M + 1 ).
[00479] Example 132: 1 -Hydroxy-4-({4'-[(4-methyl-1 -piperazinyl)carbonyl]-4- biphenylyl}amino)pyrido[2,3-d]pyrimidin-2(1 H)-one.
Figure imgf000087_0001
[00480] The title compound was prepared in a similar manner to example 144 and isolated as an TFA salt. H NMR (300MHz, DMSO-d6) δ 10.60 (s, 1 H), 10.04 (s, 1 H), 8.84 (m, 1H), 8.76 (m, 1H), 7.99 (m, 2H), 7.83-7.78 (m, 4H), 7.56 (m, 2H), 7.38 (m, 1H), 3.34-3.17 (m, 8H), 2.77-2.73 (m, 3H); ES+ MS: 457.3 (M + 1).
[00481] Example 133: 1-Hydroxy-4-[4-(phenylacetyl)-1-piperazinyl]pyrido[2,3- d\ py ri m i d i n-2 ( 1 H)-o n e .
Figure imgf000087_0002
[00482] The title compound was prepared in a similar manner to example 144 and isolated as an TFA salt. H NMR (300MHz, CD3OD) δ 8.56 (m,1H), 8.22 (m, 1H), 7.22- 7.13 (m, 6H), 3.81(m,2H), 3.74-3.70 (m,8H); ES+ MS: 366.2 (M + 1).
[00483] Example 134: 1-Hydroxy-4-[4-(phenylcarbonyl)-1- piperazinyl]pyrido[2,3-d]pyrimidin-2(1H)-one.
Figure imgf000087_0003
[00484] The title compound was prepared in a similar manner to example 144 and isolated as an TFA salt. H NMR (300MHz, CD3OD) δ 8.59 (m,1H), 8.27 (m, 1H), 7.40 (m, 5H), 7.23 (m,1H), 3.94(m,2H), 3.84 (m,4H), 3.60 (m, 2H); ES+ MS: 352.2 (M + 1).
[00485] Example 135: 1-Hydroxy-4-[((1R)-2-hydroxy-1- {[(phenylmethyl)oxy]methyl}ethyl)amino]pyrido[2,3-d]pyrimidin-2(1H)-one.
Figure imgf000088_0001
[00486] The title compound was prepared in a similar manner to example 144 to provide a yellow solid (20 mg, 24.5 % yield) as a trifluoroacetate salt. H NMR (400 MHz, CD3OD) δ ppm 8.64 (d, J = 4.8 Hz, 1 H), 8.54 (d, J = 8.0 Hz, 1 H), 7.29 (dd, J = 4.8, 8.0 Hz, 1 H), 7.25 - 7.18 (m, 5 H), 4.51 (m, 1 H), 3.79 (d, J = 5.6 Hz, 2 H), 3.73 (d, J = 5.6 Hz, 2 H); ES+ MS: 343 (M + 1 ).
[00487] Example 136: 1 -Hydroxy-4-{[(2R)-2- pyrrolidinylmethyl]amino}pyrido[2,3-d]pyrimidin-2(1 H)-one.
Figure imgf000088_0002
[00488] The title compound was prepared in a similar manner to example 144 to provide a yellow solid (10 mg, 14.9 % yield) as a trifluoroacetate salt. H NMR (400 MHz, CD3OD) δ ppm 8.66 (d, J = 4.0 Hz, 1 H), 8.42 (d, J = 8.0 Hz, 1 H), 7.31 (dd, J = 4.0, 8.0 Hz, 1 H), 3.85 (m, 2 H), 3.42 (m, 1 H), 3.28 (m, 2 H), 2.24 (m, 1 H), 2.07 (m, 2 H), 1 .84 (m, 1 H); ES+ MS: 262 (M + 1 ).
[00489] Example 137: 4-(4-{[4-(Aminomethyl)phenyl]carbonyl}-1 -piperazinyl)- 1-hydroxypyrido[2,3-d]pyrimidin-2(1 H)-one.
Figure imgf000088_0003
[00490] The title compound was prepared in a similar manner to example 144 and isolated as an TFA salt. H NMR (300MHz, CD3OD) δ 8.74 (m, 1 H), 8.42 (m, 1 H), 7.62 (m, 4H), 7.38 (m, 1 H), 4.24 (s, 2H), 4.15-3.98 (m, 6H), 3.71 (m, 2H); ES+ MS: 381 .2 (M + 1 ).
[00491] Example 138: 4'-[(1 -Hydroxy-2-oxo-1 ,2-dihydropyrido[2,3-d]pyrimidin- 4-yl)amino]- V, V-dimethyl-4-biphenylcarboxamide.
Figure imgf000089_0001
[00492] The title compound was prepared in a similar manner to example 144 and isolated as an TFA salt. H NMR (300MHz, DMSO-d6) δ 10.60 (s, 1 H), 10.01 (s, 1 H), 8.83 (d, 1 H), 8.76 (d, 1 H), 7.98 (d, 2H), 7.80-7.76 (m, 4H), 7.50 (d, 2H), 7.40-7.36 (m, 1 H), 2.99 (s, 6H); ES+ MS: 402.2 (M + 1 ).
[00493] Example 139: 1 -Hydroxy-4-{[4'-(4-morpholinylcarbonyl)-4- biphenylyl]amino}pyrido[2,3-d]pyrimidin-2(1 H)-one.
Figure imgf000089_0002
[00494] The title compound was prepared in a similar manner to example 144 and isolated as an TFA salt. H NMR (300MHz, DMSO-d6) δ 10.60 (s, 1 H), 10.02 (s, 1 H), 8.83 (m, 1 H), 8.77 (m, 1 H), 7.99 (m, 2H), 7.81-7.77 (m, 4H), 7.54-7.51 (m, 2H), 7.39 (m, 1 H), 3.63 (m, 8H); ES+ MS: 444.2 (M + 1 ).
[00495] Example 140: 4-{4-[(2,5-Difluorophenyl)carbonyl]-1 -piperazinyl}-1 - hydroxypyrido[2,3-d]pyrimidin-2(1 H)-one.
Figure imgf000089_0003
[00496] The title compound was prepared in a similar manner to example 144 and isolated as an TFA salt. H NMR (300MHz, DMSO-d6) δ 8.69 (m, 1 H), 8.27 (m, 1 H), 7.43-7.39 (m, 3H), 7.24 (m, 1 H), 7.84-7.41 (m, 6H), 3.47 (m, 2H); ES+ MS: 388.1 (M + 1 ).
[00497] Example 141 : 1 -Hydroxy-4-{[4'-(1 -piperidinylcarbonyl)-4- biphenylyl]amino}pyrido[2,3-d]pyrimidin-2(1 H)-one.
Figure imgf000090_0001
[00498] The title compound was prepared in a similar manner to example 144 and isolated as an TFA salt. H NMR (300MHz, CD3OD) δ 8.82 (m, 1 H), 8.77 (m, 1 H), 8.00- 7.97 (d, 2H), 7.80-7.77 (m, 4H), 7.49-7.39 (m, 3H), 3.58 (m, 4H), 1 .64-1 .54 (m, 6H); ES+ MS: 442.2 (M + 1 ).
[00499] Example 142: 1-Hydroxy-4-[(1 .S-thiazol^-ylmethy aminolpyridop.S- cf] py ri m i d i n-2 ( 1 H)-o n e .
Figure imgf000090_0002
[00500] The title compound was prepared in a similar manner to example 144 and isolated as an TFA salt. H NMR (300MHz, CD3OD) δ 8.84 (s, 1 H), 8.56 (s, 1 H), 7.76 (s, 1 H), 7.55 (s, 1 H), 7.39 (s, 1 H), 5.14 (s, 2H); ES+ MS: 276.1 (M + 1 ).
[00501] Example 143: 4-(3-Fluoro-1 -piperidinyl)-1-hydroxypyrido[2,3- d]pyrimidin-2 1 H -one.
Figure imgf000090_0003
[00502] The title compound was prepared in a similar manner to example 144 to provide a yellow solid (40.6 mg, 72.4 % yield) as a trifluoroacetate salt. H NMR (400 MHz, CD3OD) δ ppm 8.62 (d, J = 4.0 Hz, 1 H), 8.32 (d, J = 8.0 Hz, 1 H), 7.29 (dd, J = 4.0, 8.0 Hz, 1 H), 4.77 (m, 1 H), 4.22 (m, 2 H), 3.78 (m, 2 H), 3.45 (m, 2 H), 2.02 (m, 2 H); ES+ MS: 265 (M + 1 ).
[00503] Example 144: 4-(4,4-Difluoro-1-piperidinyl)-1-hydroxypyrido[2,3- d]pyrimidin-2(1 H)-one. a) 2-(Tert-butoxyamino)nicotinonitrile.
Figure imgf000091_0001
[00505] A mixture of 3-Cyano-2-fluoropyridine (9.0 g, 73.71 mmol), O-tert- butylhydroxylamine hydrochloride (10.17g, 81 .0 mmol) and DIEA (28.32 ml_, 162.3 mmol) was heated in a microwave at 120 °C for 9 h. LCMS showed complete consumption of the starting material. The mixture was dissolved in EtOAc and small amount of water, and washed with brine, and the aqueous layer was washed for further 3 times with EtOAc. The organic phases was combined and dried (Na2S04), concentrated to provide crude 2-(Tert- butoxyamino)nicotinonitrile (13.1 1 g, 93 % yield) as dark red oil which was crystallized under reduced pressure, which can be used without purification. H NMR (400 MHz, CDCI3): 8.34 (dd, J = 1 .6, 5.2 Hz, 1 H), 8.82 (dd, J = 1 .6, 7.6 Hz, 1 H), 7.44 (s, 1 H), 6.85 (dd, J = 5.2, 7.6 Hz, 1 H), 1.39 (s, 9 H); ES+ MS: m/z = 192.3 (M+1 ).
b) 2-(Tert-butoxyamino)-3-pyridinecarboxylic acid.
Figure imgf000091_0002
[00507] To a solution of 2-(Tert-butoxyamino)nicotinonitrile (9.00 g, 47.1 mmol) in Methanol was added a solution of NaOH (8.69g, 141 .0 mmol) in Water (50.0 ml_), and the mixture was heated at 100 °C for 13 h. Reaction was monitored by LCMS and HPLC (LCMS showed only one peak: ES+ (M+H)+ = 21 1 , ES" (M-H) " = 209; and H PLC showed only one main peak at 4.047 min). So the mixture was cooled to RT and acidified to pH = 3-4 with 1 M HCI, and evaporated under decreased pressure. MeCN was added 3 times to azeotrope water. Adsorbed on celite and purified by flash chromatography on silica gel (0-20% MeOH in DCM) to afford 2-(Tert-butoxyamino)-3-pyridinecarboxylic acid (8.76 g, 79 % yield) as a yellow solid. H NMR (400 MHz, CDCI3): 8.50 (d, J = 6.8 Hz, 1 H), 8.32 (d, J = 6.8 Hz, 1 H), 6.72 (t, J = 6.8 Hz, 1 H), 1 .41 (s, 9 H); ES+ MS: m/z = 21 1 .2 (M+1 ).
[00508] c) Methyl 2-(tert-butoxyamino)-3-pyridinecarboxylate.
Figure imgf000091_0003
[00509] To a solution of 2-(Tert-butoxyamino)-3-pyridinecarboxylic acid (4.06 g, 19.31 mmol) in Diethyl ether (54.6 ml.) and Methanol (54.6 ml_), was added TMS- diazomethane (2M in hexanes) (9.66 ml_, 19.31 mmol) dropwise over 5 min. The reaction was stirred for 5 min and monitored by LCMS. It showed 51 % of SM left. Therefore, another 10 ml. of TMS-diazomethane was added. 5 min later, LCMS showed completion of the reaction. 99.7% AcOH was added to the mixture dropwise to consume any excess TMS- diazomethane, and the mixture was concentrated in vacuo. The residue was dissolved in DCM and Celite was added, and the mixture was concentrated and purified by flash chromatography on silica gel (25% EtOAc in hexanes) to provide Methyl 2-(tert- butoxyamino)-3-pyridinecarboxylate (4.18 g, 97 % yield) as yellow oil. H NMR (400 MHz, CDCI3): 9.85 (s, 1 H), 8.42 (dd, J = 2.0, 4.8 Hz, 1 H), 8.13 (dd, J = 2.0, 7.6 Hz, 1 H), 6.68 (dd, J = 4.8, 7.6 Hz, 1 H), 3.87 (s, 3 H), 1 .34 (s, 9 H); ES+ MS: m/z = 225.3 (M+1 ).
d) 1 -(Tert-butoxy)pyrido[2,3-d]pyrimidine-2,4(1 H,3H)-dione.
Figure imgf000092_0001
[00511] A solution of Methyl 2-(tert-butoxyamino)-3-pyridinecarboxylate (4.18 g, 18.64 mmol) in 1 ,2-Dichloroethane (DCE) (240 mL) was treated with Trichloroacetyl isocyanate (4.93 mL, 41 .6 mmol) dropwise. The color of the solution changed from dark brown to light yellow. After stirring at RT for 45 min the mixture was sent for LCMS, and it showed 66% of intermediate appeared with a MS+ (M+H)+ =41 1 .8, 413.8 and 415.8. TEA (5.39 mL, 38.9 mmol) was added and it was stirred at RT for 1 h and the solution became dark brown. Reaction was followed by LCMS and after 1 h the Trichloroacetyl urea was almost converted to a more polar intermediate. Solvent was evaporated, then Methanol (240 mL) was added, followed by Sodium methoxide (20.14 mL, 93 mmol) (25% by weight in MeOH). Stirred at RT for 45 min. LCMS showed 87% of product was obtained. Evaporated solvent and EtOAc and a small amount of water was added to the residue. Acidified to pH 5 by addition of 42 mL of 1 N HCI and followed by 85 mL of 0.1 N HCI. Separated layers and extracted the water layer with EtOAc, organic layers were combined, washed with brine, dried over Na2S04, filtered and concentrated. Purified by flash chromatography on a silica gel column (0-30% EtOAc in hexanes) to afford 1-(Tert-butoxy)pyrido[2,3-d]pyrimidine- 2,4(1 H ,3H)-dione (3.27 g, 74.6 % yield) as a light yellow solid. H NMR (400 MHz, CDCI3): 9.29 (s, 1 H), 8.71 (dd, J = 2.0, 4.8 Hz, 1 H), 8.44 (dd, J = 2.0, 7.6 Hz, 1 H), 7.25 (dd, J = 4.8, 7.6 Hz, 1 H), 1 .48 (s, 9 H); ES+ MS: m/z = 236.4 (M+1 ). e) 4-Chloro-1 -(tert-butoxy)pyrido[2,3-d]pyrimidin-2(1 H)-one.
Figure imgf000093_0001
[00513] To a solution of 1 -(Tert-butoxy)pyrido[2,3-d]pyrimidine-2,4(1 H,3H)- dione (42 mg, 0.177 mmol) in toluene (3 mL) was added DIEA (0.16 mL, 0.89 mmol) and POCI3 (0.04 mL, 0.44 mmol). The color of the solution changed from colorless to brown, and the mixture was heated at 100 °C for 1 h. Then the solvent was evaporated under decreased pressure to afford the desired product, which will be used in the next step without purification.
[00514] f) 4-(4,4-Difluoro-1 -piperidinyl)-1 -(tert-butoxy)pyrido[2,3-d]pyrimidin-
2(1 H)-o
Figure imgf000093_0002
[00515] To a solution of 4-Chloro-1 -(tert-butoxy)pyrido[2,3-d]pyrimidin-2(1 H)- one (45 mg, 0.177 mmol) in N,N-Dimethylformamide (DMF) (5 mL), was added 4,4- difluoropiperidine (335 mg, 2.129 mmol) and stirred at RT for 15 min. LCMS showed conversion to desired product. The mixture was diluted by EtOAc, and washed with water and brine, dried over Na2S04 and evaporated to dry. It was put in vacuo over night. Then it was purified by flash chromatography on silica (0-5% MeOH in DCM) to provide 4-(4,4- Difluoro-1 -piperidinyl)-1-(tert-butoxy)pyrido[2,3-d]pyrimidin-2(1 H)-one (48.9 mg, 0.145 mmol, 81 % yield) as brown oil. H NMR (400 MHz, CDCI3): 8.60 (d, J = 4.8 Hz, 1 H), 7.85 (d, J = 8.0 Hz, 1 H), 7.10 (dd, J = 4.8, 8.0 Hz, 1 H), 8.88 (m, 4 H), 2.12 (m, 4 H), 1.42 (s, 9 H); ES+ MS: m/z = 339.4 (M+1 ).
[00516] g) 4-(4,4-Difluoro-1-piperidinyl)-1 -hydroxypyrido[2,3-d]pyrimidin- 2(1 H)-o
Figure imgf000093_0003
[00517] To a solution of 4-(4,4-Difluoro-1 -piperidinyl)-1-(tert-butoxy)pyrido[2,3- d]pyrimidin-2(1 H)-one (48.9 mg, 0.145 mmol) in Dichloromethane (DCM) (10 ml_), was added Trifluoroacetic acid (TFA) (1 .000 ml_). The reaction was monitored by LCMS to complete. Then the solvent was evaporated under decreased pressure. The product was crystallized by MeOH, DCM, ether and hexanes to afford 4-(4,4-difluoro-1 -piperidinyl)-1 - hydroxypyrido[2,3-d]pyrimidin-2(1 H)-one as a yellow solid as its TFA salt form (37.8 mg, 65.3% yield) as a brown solid. H NMR (400 MHz, CD3OD): 8.65 (dd, J = 1 .2, 4.8 Hz, 1 H), 8.30 (dd, J = 1.2, 8.0 Hz, 1 H), 7.30 (dd, J = 4.8, 8.0 Hz, 1 H), 3.93 (m, 2 H), 3.28 (m, 2 H), 2.16 (m, 4 H). ES+ MS: m/z = 282.9 (M+1 ).
[00518] Example 145: 4-(4-Fluoro-1 -piperidinyl)-1-hydroxypyrido[2,3- d]pyrimidin-2 1 H -one.
Figure imgf000094_0001
[00519] The title compound was prepared in a similar manner to example 144 to provide a yellow solid (25.8 mg, 62.0 % yield) as a trifluoroacetate salt. H NMR (400 MHz, CD3OD) δ ppm 8.64 (dd, J = 1 .2, 4.8 Hz, 1 H), 8.28 (dd, J = 1 .2, 8.0 Hz, 1 H), 7.28 (dd, J = 4.8, 8.0 Hz, 1 H), 4.98 (m, 1 H), 3.91 (m, 4 H), 2.03 (m, 4 H); ES+ MS: 265 (M + 1 ).
[00520] Example 146: 1 -Hydroxy-4-(4-thiomorpholinyl)pyrido[2,3-d]pyrimidin- 2(1 H)-o
Figure imgf000094_0002
[00521] The title compound was prepared in a similar manner to example 144 to provide a yellow solid (19.6 mg, 28.9 % yield) as a trifluoroacetate salt. H NMR (400 MHz, CD3OD) δ ppm 8.64 (dd, J = 1.2 Hz, 1 H), 8.24 (d, J = 8.0 Hz, 1 H), 7.29 (dd, J = 1.2, 8.0 Hz, 1 H), 4.08 (m, 4 H), 2.82 (m, 4 H); ES+ MS: 265 (M + 1 ).
[00522] Example 147: 1 -Hydroxy-4-[4-(1 H-imidazol-2-ylmethyl)-1 - piperazinyl]pyrido[2,3-d]pyrimidin-2(1 H)-one.
Figure imgf000095_0001
[00523] The title compound was prepared in a similar manner to example 144 to provide a brown thick oil (29 mg, 50%) as a trifluoroacetate salt. H NMR (400 MHz, DMSO-d6) δ ppm 1 1 .80 (s, 1 H), 10.58 (s, 1 H), 8.73 - 8.65 (m, 1 H), 8.20 (dd, J=8.1 , 1 .5 Hz, 1 H), 7.67 - 7.59 (m, 2 H), 7.23 (dd, J=8.0, 4.7 Hz, 1 H), 4.01 - 3.85 (m, 2 H), 3.77 (br. s., 2 H), 3.17 - 3.07 (m, 2 H), 2.76 - 2.56 (m, 4 H); ES+ MS: 328 (M + 1 ); HRMS calcd for C15H 18N702: 328.1522. Found: 328.1525.
[00524] Example 148: 4-(1 , 1 -Dioxido-4-thiomorpholinyl)-1 -hydroxypyrido[2,3- d]pyrimi H)-one.
Figure imgf000095_0002
[00525] The title compound was prepared in a similar manner to example 144 to provide a yellow solid (13.5 mg, 13.9 % yield) as a trifluoroacetate salt. H NMR (400 MHz, DMSO-d6) δ ppm 10.67 (s, 1 H), 8.70 (d, J = 4.0 Hz, 1 H), 8.25 (d, J = 8.0 Hz, 1 H), 7.26 (dd, J = 4.0, 8.0 Hz, 1 H), 4.07 (s, 4 H), 3.37 (s, 4 H); ES+ MS: 297 (M + 1 ).
[00526] Example 149: 1 -Hydroxy-4-(4-morpholinyl)pyrido[2,3-d]pyrimidin-
2(1 H)-one.
Figure imgf000095_0003
[00527] The title compound was prepared in a similar manner to example 144 to provide an off-white solid (6.8 mg, 10.5 % yield) as a trifluoroacetate salt. H NMR (400 MHz, DMSO-d6) δ ppm 10.50 (s, 1 H), 8.66 (dd, J = 1 .2, 4.8 Hz, 1 H), 8.24 (dd, J = 1 .2, 8.0 Hz, 1 H), 7.22 (dd, J = 4.8, 8.0 Hz, 1 H), 3.73 (s, 4 H), 3.33 (s, 2 H), 3.16 (d, J = 5.2 Hz, 2 H); ES+ MS: 249 (M + 1 ). [00528] Example 150a: 4-{[2-(Aminomethyl)phenyl]amino}-1 - hydroxypyrido[2,3-d]pyrimidin-2(1 H)-one and Example 150b: 4-{[(2- aminop
Figure imgf000096_0001
[00529] The title compounds were prepared in a similar manner to example 144 and isolated as a mixture each as a TFA salt. ES+ MS: 284.0 (M + 1 ).
[00530] Example 151 : 4-{4-[(3-Fluorophenyl)carbonyl]-1 -piperazinyl}-1 - hydroxypyrido[2,3-d]pyrimidin-2(1 H)-one.
Figure imgf000096_0002
[00531] The title compound was prepared in a similar manner to example 144 and isolated as an TFA salt. H NMR (300MHz, DMSO-d6) δ 10.53 (s, 1 H), 8.69 (m, 1 H), 8.25 (m, 1 H), 7.53 (m, 1 H), 7.36-7.22 (m, 4H), 3.80-3.55 (m, 8H); ES+ MS: 370.0 (M + 1 ).
[00532] Example 152: 1-Hydroxy-4-[(phenylmethyl)thio]pyrido[2,3-d]pyrimidin- 2(1 H)-o
Figure imgf000096_0003
[00533] The title compound was prepared in a similar manner to example 144 and precipitated from ethyl acetate to provide a yellow solid (15.3 mg, 42%) as a trifluoroacetate salt. H NMR (400 MHz, DMSO-d6) δ ppm 10.78 (s, 1 H), 8.89 - 8.79 (m, 1 H), 8.42 - 8.27 (m, 1 H), 7.48 (d, J=7.2 Hz, 2 H), 7.42 - 7.22 (m, 4 H), 4.56 (s, 2 H); ES+ MS: 286 (M + 1 ); HRMS calcd for C14H 12N3 02S: 286.0550. Found: 286.0648.
[00534] Example 153: 4-{4-[(4-Hexylphenyl)carbonyl]-1 -piperazinyl}-1 - hydroxypyrido[2,3-d]pyrimidin-2(1 H)-one.
Figure imgf000097_0001
[00535] The title compound was prepared in a similar manner to example 144 and isolated as an TFA salt. H NMR (300MHz, DMSO-d6) δ 8.68 (m, 1 H), 8.25 (m, 1 H), 7.39 (m, 2H), 7.30-7.21 (m, 3H), 3.81 (m, 8H), 2.65-2.60 (m, 2H), 1 .59 (m, 2H), 1 .30 (m, 6H), 0.88 (m, 3H); ES+ MS: 436.0 (M + 1 ).
[00536] Example 154: 1 -Hydroxy-4-{[4'-(4-morpholinylcarbonyl)-3- biphenylyl]amino}pyrido[2,3-d]pyrimidin-2(1 H)-one.
Figure imgf000097_0002
[00537] The title compound was prepared in a similar manner to example 144 and isolated as an TFA salt. H NMR (300MHz, DMSO-d6) δ 10.57 (s, 1 H), 10.02 (s, 1 H), 8.83-8.75 (m, 2H), 8.14 (s, 1 H), 7.90(m, 1 H), 7.77-7.74 (m, 2H), 7.56-7.53 (m, 4H), 7.40- 7.36 (m, 1 H), 3.62 (m, 4H), 3.35 (m, 4H); ES+ MS: 444.2 (M + 1 ).
[00538] Example 155: 1 -Hydroxy-4-{[4'-(1-pyrrolidinylcarbonyl)-3- biphenylyl]amino}pyrido[2,3-d]pyrimidin-2(1 H)-one.
Figure imgf000097_0003
[00539] The title compound was prepared in a similar manner to example 144 and isolated as an TFA salt. H NMR (300MHz, DMSO-d6) δ 10.58 (s, 1 H), 10.01 (s, 1 H), 8.83 (d, 1 H), 8.77 (d, 1 H), 8.14 (d, 1 H), 7.92 (d, 1 H), 7.76-7.74 (m, 2H), 7.68-7.65 (m, 2H), 7.55-7.54 (m, 2H), 7.41-7.37 (m, 1H), 3.60-3.44 (m, 4H), 1.64-1.55 (d, 4H); ES+ MS: 428.2 (M + 1).
[00540] Example 156: 1-Hydroxy-4-{[4'-(1-piperidinylcarbonyl)-3- biphenylyl]amino}pyrido[2,3-d]pyrimidin-2(1H)-one.
Figure imgf000098_0001
[00541] The title compound was prepared in a similar manner to example 144 and isolated as an TFA salt. H NMR (300MHz, DMSO-d6) δ 10.58 (s, 1 H), 10.01 (s, 1 H), 8.83 (d, 1H), 8.77 (d, 1H), 8.14 (d, 1H), 7.92 (d, 1H), 7.76-7.74 (m, 1H), 7.68-7.65 (m, 4H), 7.55-7.54 (m, 2H), 7.41-7.37 (m, 1H), 3.60-3.44 (m, 4H), 1.64-1.55 (d, 6H); ES+ MS: 442.3 (M + 1).
[00542] Example 157: 4'-[(1-Hydroxy-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidin- 4-yl)amino]-4-biphenylcarboxylic acid.
Figure imgf000098_0002
[00543] The title compound was prepared in a similar manner to example 144 and isolated as an TFA salt. H NMR (300MHz, DMSO-d6) δ 12.90 (brs, 1H), 10.60 (brs, 1H, ) 10.02 (s, 1H), 8.82-8.75 (m, 2H), 8.04- 7.99 (m, 4H), 7.86-7.81 (m, 4H), 7.39 (m, 1H); ES+ MS: 375.2 (M + 1).
[00544] Example 158: 1-Hydroxy-4-{[4'-(4-morpholinyl)-3- biphenylyl]amino}pyrido[2,3-d]pyrimidin-2(1H)-one.
Figure imgf000098_0003
[00545] The title compound was prepared in a similar manner to example 1 and isolated as an HBrsalt. H NMR (300MHz, DMSO-d6) δ 10.56 (s, 1H), 9.96 (s, 1H), 8.84-8.76 (m, 2H), 8.03 (s, 1H), 7.82-7.80 (m, 1H), 7.60-7.57 (m, 2H), 7.47-7.39 (m, 3H), 7.09-7.06 (m, 2H), 3.79-3.76 (m, 4H), 3.20-3.17 (m, 4H); ES+ MS: 416.2 (M + 1). [00546] Example 159: 4'-[(1-Hydroxy-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidin- 4-yl)amino]-3-biphenylcarboxylic acid.
Figure imgf000099_0001
[00547] The title compound was prepared in a similar manner to example 144 and isolated asanTFAsalt. H NMR (300MHz, DMSO-d6) δ 13.10 (brs, 1H), 10.60 (s, 1H), 10.03 (s, 1H), 8.86- 8.24 (m, 2H), 8.24(s, 1H), 8.02-7.99 (m, 4H),7.81-7.78 (m, 2H), 7.65- 7.60 (m,1H), 7.41-7.37 (m, 1H); ES+ MS: 375.2 (M + 1).
[00548] Example 160: 1-Hydroxy-4-{[4'-(4-morpholinyl)-4- biphen yrimidin-2(1H)-one.
Figure imgf000099_0002
[00549] The title compound was prepared in a similar manner to example 37 and isolated as an TFA salt. H NMR (300MHz, DMSO-d6) δ 9.96 (s, 1 H), 8.84-8.75 (m, 2H), 7.89 (d, 2H), 7.68 (d, 2H), 7.61 (d, 2H), 7.40-7.35 (m, 1H), 7.05 (d, 2H), 3.78-3.76 (m, 4H), 3.19-3.17 (m,4H); ES+ MS: 416.2 (M + 1).
[00550] Example 161: 1-Hydroxy-4-{[3'-(trifluoromethyl)-4- biphen d]pyrimidin-2(1H)-one.
Figure imgf000099_0003
[00551] The title compound was prepared in a similar manner to example 37 and isolated as an TFA salt. H NMR (300MHz, DMSO-d6) δ 10.60 (s, 1 H), 10.02 (s, 1 H), 8.85-8.75 (m, 2H), 8.02 (m, 4H), 7.85-7.83 (m, 2H), 7.73-7.72 (m, 2H), 7.38 (m, 1H); ES+ MS: 399.1 (M + 1).
[00552] Example 162: 4-[(3',5'-Dichloro-4-biphenylyl)amino]-1- hydroxypyrido[2,3-d]pyrimidin-2(1H)-one.
Figure imgf000100_0001
[00553] The title compound was prepared in a similar manner to example 37 and isolated as an TFA salt. H NMR (300MHz, DMSO-d6) 5 10.61 (s, 1 H), 10.02 (s, 1 H), 8.84-8.77 (m, 2H), 8.02-7.99 (m, 2H), 7.85-7.80 (m, 4H), 7.60 (s, 1 H), 7.38 (m, 1 H); ES+ MS: 399.1 (M + 1 ).
[00554] Example 163: 1 -Hydroxy-4-{[3'-(methyloxy)-4- biphenylyl]amino}pyrido[2,3-d]pyrimidin-2(1 H)-one.
Figure imgf000100_0002
[00555] The title compound was prepared in a similar manner to example 37 and isolated as an TFA salt. H NMR (300MHz, DMSO-d6) δ 10.58 (s, 1 H), 10.01 (s, 1 H), 8.83 (d, 1 H), 8.75 (d, 1 H), 7.94 (d, 2H), 7.74 (d, 2H), 7.41-7.36 (m, 2H), 7.29-7.26 (m, 2H), 6.95-6.92 (m, 1 H), 3.84 (s, 3H); ES+ MS: 361 .2 (M + 1 ).
[00556] Example 164: 4-[(4'-Amino-4-biphenylyl)amino]-1 -hydroxypyrido[2,3- d\ py ri m i d i n-2 ( 1 H)-o n e .
Figure imgf000100_0003
[00557] The title compound was prepared in a similar manner to example 144 and isolated as an TFA salt. H NMR (300MHz, DMSO-d6) δ 10.55 (s, 1 H), 9.94 (s, 1 H), 8.82-8.74 (m, 2H), 7.84 (s, 2H), 7.61 (s, 2H), 7.44-7.36 (m, 3H), 6.73-6.71 (m, 2H), 5.82 (br s, 2H); ES+ MS: 346.2 (M + 1 ).
[00558] Example 165: 1 -Hydroxy-4-(4-{[4-methyl-3,5- bis(methyloxy)phenyl]carbonyl}-1 -piperazinyl)pyrido[2,3-d]pyrimidin-2(1 H)-one.
Figure imgf000101_0001
[00559] The title compound was prepared in a similar manner to example 144 and isolated as an TFA salt. H NMR (300MHz, DMSO-d6) 5 10.51 (s, 1 H), 8.68-8.67 (m, 1 H), 8.26-8.24 (m, 1 H), 7.26-7.22 (m, 1 H), 6.69 (s, 2H), 3.80-3.61 (m, 14H), 2.02 (s, 3H); ES+ MS: 426.2 (M + 1 ).
[00560] Example 166: 4-[(3'-Chloro-4-biphenylyl)amino]-1 -hydroxypyrido[2,3- d\ py ri m i d i n-2 ( 1 H)-o n e .
Figure imgf000101_0002
[00561] The title compound was prepared in a similar manner to example 37 and isolated as an TFA salt. H NMR (300MHz, DMSO-d6) δ 10.00 (s, 1 H), 8.83-8.75 (m, 2H),7.97 (m, 2H), 7.79-7.76 (m, 3H), 7.69 (m, 1 H), 7.53-7.35 (m, 3H); ES+ MS: 365.1 (M + 1 ).
[00562] Example 167: 1-Hydroxy-4-[(3'-methyl-4-biphenylyl)amino]pyrido[2,3- d\ py ri m i d i n-2 ( 1 H)-o n e .
Figure imgf000101_0003
[00563] The title compound was prepared in a similar manner to example 37 and isolated as an TFA salt. H NMR (300MHz, DMSO-d6) δ 9.99 (s, 1 H), 8.83-8.75 (m, 2H), 7.93 (m, 2H), 7.73 (m, 2H),7.52 (m, 2H), 7.36 (m, 2H), 7.19 (m, 1 H), 2.39 (s, 3H); ES+ MS: 345.1 (M + 1 ).
[00564] Example 168: ethyl 3'-[(1 -Hydroxy-2-oxo-1 ,2-dihydropyrido[2,3- cf]pyrimidin-4-yl)amino]-3-biphenylcarboxylate.
Figure imgf000102_0001
[00565] The title compound was prepared in a similar manner to example 37 and isolated as an TFA salt. H NMR (300MHz, DMSO-d6) δ 10.57 (s, 1 H), 10.02 (s, 1 H), 8.83-8.75 (m, 2H), 8.23 (s, 1H), 8.10 (s, 1H), 8.01-7.96 (m,3H), 7.67 (m, 1H), 7.56-7.53 (m, 2H), 7.38 (m, 1H), 4.37 (m, 2H), 1.35 (m, 3H); ES+ MS: 403.2 (M + 1).
[00566] Example 169: ethyl 4'-[(1-Hydroxy-2-oxo-1,2-dihydropyrido[2,3- cf]pyrimidin-4-yl)amino]-3-biphenylcarboxylate.
Figure imgf000102_0002
[00567] The title compound was prepared in a similar manner to example 37 and isolated as an TFA salt. H NMR (300MHz, DMSO-d6) δ 10.59 (m, 1H), 10.02 (s, 1H), 8.84-8.75 (m, 2H), 8.23 (s, 1H),8.01-7.94 (m,4H), 7.78 (m, 2H), 7.64 (m, 1H), 7.40-7.35 (m, 1H), 4.40-4.33 (m, 2H), 1.38-1.34 (m, 3H); ES+ MS: 403.2 (M + 1).
[00568] Example 170: 4'-[(1-Hydroxy-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidin- 4-yl)amino]-3-biphenylcarbonitrile.
Figure imgf000102_0003
[00569] The title compound was prepared in a similar manner to example 37 and isolated as an TFA salt. H NMR (300MHz, DMSO-d6) δ 10.59 (s, 1 H), 10.00 (s, 1 H), 8.83 (d, 1H), 8.76 (m, 1H), 8.20 (s, 1H), 8.09-7.99 (m, 3H), 7.85-7.81(m, 3H), 7.68 (m, 1H), 7.38 (m, 1H); ES+ MS: 356.2 (M + 1).
[00570] Example 171: 3'-[(1-Hydroxy-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidin- 4-yl)amino]-A/-phenyl-4-biphenylcarboxamide.
Figure imgf000102_0004
[00571] The title compound was prepared in a similar manner to example 37 and isolated asanTFAsalt. H NMR (300MHz, DMSO-d6) δ 10.31 (s, 1H), 10.04 (s,1H), 8.83-8.75 (m, 2H), 8.18-7.92 (m, 3H), 7.98-7.79 (m, 5H), 7.58-7.53 (m, 2H), 7.39-7.34 (m, 3H), 7.11 (m, 1H); ES+ MS: 450.2 (M + 1).
[00572] Example 172: 4'-[(1-Hydroxy-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidin- 4-yl)amino]-A/-phenyl-4-biphenylcarboxamide.
Figure imgf000103_0001
[00573] The title compound was prepared in a similar manner to example 37 and isolated asanTFAsalt. H NMR (300MHz, DMSO-d6) δ 10.60 (m, 1H), 10.28 (s, 1H), 10.04(m, 1H), 8.86-8.75 (m, 2H), 8.08-7.99 (m, 4H),7.90-7.79 (m,6H), 7.39-7.34 (m, 3H), 7.11 (m, 1H); ES+ MS: 450.2 (M + 1).
[00574] Example 173: A/-{4'-[(1-Hydroxy-2-oxo-1,2-dihydropyrido[2,3- cf]pyrimidin-4-yl)amino]-4-biphenylyl}acetamide.
Figure imgf000103_0002
[00575] The title compound was prepared in a similar manner to example 37 and isolated as an TFA salt. H NMR (300MHz, DMSO-d6) δ 10.56 (s, 1 H), 10.03 (s, 1 H), 9.97 (s, 1H), 8.77 (d, 2H), 7.92 (d, 2H), 7.67 (m, 6H), 7.37 (br, 1H), 2.07 (s, 3H); ES+ MS: 388.2 (M + 1).
[00576] Example 174: 1-Hydroxy-4-[(4'-methyl-4-biphenylyl)amino]pyrido[2,3- d\ py ri m n e .
Figure imgf000103_0003
[00577] The title compound was prepared in a similar manner to example 37 and isolated as an TFA salt. H NMR (300MHz, DMSO-d6) δ 10.00 (s, 1 H), 8.83-8.74 (m, 2H),7.93-7.90 (m, 2H), 7.72-7.69 (m, 2H), 7.62-7.59 (m, 2H), 7.39-7.35 (m, 1 H), 7.29-7.27 (m, 2H), 2.35 (s, 3H); ES+ MS: 345.2 (M + 1 ).
[00578] Example 175: 1 -Hydroxy-4-{[3'-(trifluoromethyl)-3- biphenylyl]amino}pyrido[2,3-d]pyrimidin-2(1 H)-one.
Figure imgf000104_0001
[00579] The title compound was prepared in a similar manner to example 144 and isolated as a TFA salt. H NMR (300MHz, DMSO-d6) δ 10.58 (s, 1 H), 10.02 (s, 1 H), 8.83-8..75 (m, 2H), 8.13 (s, 1 H), 8.01 -7.93 (m, 3H), 7.77-7.52 (m, 2H), 7.58-7.53 (m, 2H), 7.38 (m, 1 H); ES+ MS: 399.1 (M + 1 ).
[00580] Example 176: 4-[(3',5'-Dichloro-3-biphenylyl)amino]-1 - hydroxypyrido[2,3-d]pyrimidin-2(1 H)-one.
Figure imgf000104_0002
[00581] The title compound was prepared in a similar manner to example 144 and isolated as an TFA salt. H NMR (300MHz, DMSO-d6) δ 10.58 (s, 1 H), 9.99 (s, 1 H), 8.81 -8.75 (m, 2H), 8.10 (s, 1 H), 8.00 (m, 1 H), 7.74-7.51 (m, 5H), 7.38 (m, 1 H); ES+ MS: 399.1 (M + 1 ).
[00582] Example 177: 4-[(3'-Chloro-3-biphenylyl)amino]-1 -hydroxypyrido[2,3- d\ py ri m i d i n-2 ( 1 H)-o n e .
Figure imgf000104_0003
[00583] The title compound was prepared in a similar manner to example 144 and isolated as an TFA salt. H NMR (300MHz, DMSO-d6) δ 10.58 (s, 1 H), 10.00 (s, 1 H), 8.82-8.75 (m, 2H), 8.09 (s, 1 H), 7.96 (m, 1 H), 7.72-7.65 (m, 2H), 7.57-7.46 (m, 4H), 7.38 (m, 1 H); ES+ MS: 365.1 (M + 1 ). [00584] Example 178: 1-Hydroxy-4-[(3'-methyl-3-biphenylyl)amino]pyrido[2,3- d\ py ri m i d i n-2 ( 1 H)-o n e .
Figure imgf000105_0001
[00585] The title compound was prepared in a similar manner to example 144 and isolated as an TFA salt. H NMR (300MHz, DMSO-d6) δ 10.56 (s, 1H), 9.98 (s, 1H), 8.83-8.75 (m, 2H), 8.04 (s, 1H), 7.91 (m, 1H), 7.53-7.36 (m, 6H), 7.22 (m, 1H), 2.40 (s, 3H); ES+ MS: 345.2 (M + 1).
[00586] Example 179: 1-Hydroxy-4-{[3'-(1-piperidinylcarbonyl)-3- biphen yrimidin-2(1H)-one.
Figure imgf000105_0002
[00587] The title compound was prepared in a similar manner to example 37 and isolated as an TFA salt. H NMR (300MHz, DMSO-d6) δ 10.57 (s, 1H), 9.98 (s, 1H), 8.82-8.75 (m, 2H), 8.11 (s, 1H), 7.95 (m, 1H), 7.77-7.75 (m, 1H), 7.75-7.51 (m, 4H), 7.39- 7.35 (m, 2H), 3.61 (m, 2H), 3.32(m, 2H), 1.61-1.40 (m,6H); ES+ MS: 442.2 (M + 1).
[00588] Example 180: 1-Hydroxy-4-{[3'-(1-pyrrolidinylcarbonyl)-3- biphen yrimidin-2(1H)-one.
Figure imgf000105_0003
[00589] The title compound was prepared in a similar manner to example 37 and isolated as an TFA salt. H NMR (300MHz, CD3OD) δ 8.80 (m, 2H), 8.13 (m, 1H), 7.87 (m, 3H), 7.58-7.46 (m, 5H), 3.68-3.36 (m, 4H), 2.07-1.98(m, 4H); ES+ MS: 428.2 (M + 1).
[00590] Example 181: 1-Hydroxy-4-{[4'-(methylamino)-3- biphenylyl]amino}pyrido[2,3-d]pyrimidin-2(1H)-one.
Figure imgf000105_0004
[00591] The title compound was prepared in a similar manner to example 144 and isolated as an TFA salt. H NMR (300MHz, DMSO-d6) δ 9.94 (s, 1H), 8.80 (d, 1H), 8.74 (d, 1H), 7.94 (s, 1H), 7.74 (d, 1H), 7.49-7.34 (m, 5H), 6.70 (d, 2H), 2.74 (s, 3H); ES+ MS: 360.2 (M + 1).
[00592] Example 182: 3'-[(1-Hydroxy-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidin- 4-yl)amino]-3-biphenylcarboxylic acid.
Figure imgf000106_0001
[00593] The title compound was prepared in a similar manner to example 37 and isolated as an TFA salt. H NMR (300MHz, DMSO-d6) δ 13.11 (brs, 1H), 10.58 (s, 1H), 10.02 (brs,1H), 8.81-8.75 (m, 2H), 8.24 (s,1H), 8.08-7.94 (m, 4H), 7.64 (t, 1H), 7.58-7.53 (m, 2H), 7.38 (m, 1H); ES+ MS: 375.2 (M + 1).
[00594] Example 183: 3'-[(1-Hydroxy-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidin- 4-yl)ami biphenylcarboxamide.
Figure imgf000106_0002
[00595] The title compound was prepared in a similar manner to example 144 and isolated as an TFA salt. H NMR (300MHz, DMSO-d6) 510.01 (s, 1 H), 8.83-8.76 (m, 2H), 8.13 (s, 1H), 7.97 (m, 1 H),7.76-7.13 (m, 2H), 7.57-7.53 (m, 4H), 7.41-7.37 (m, 1H), 3.00 (s, 6H); ES+ MS: 402.2 (M + 1).
[00596] Example 184: 1-Hydroxy-4-({3'-[(4-methyl-1-piperazinyl)carbonyl]-4- biphenylyl}amino)pyrido[2,3-d]pyrimidin-2(1H)-one.
Figure imgf000106_0003
[00597] The title compound was prepared in a similar manner to example 37 and isolated as an TFA salt. H NMR (300MHz, DMSO-d6) δ 10.58 (s, 1 H), 10.03 (s, 1 H), 8.84-8.75 (m, 2H), 8.00-7.97 (m, 2H), 7.86-7.76 (m, 4H), 7.62-7.57 (m, 1 H), 7.45-7.36 (m, 2H), 3.34 (s, 8H), 2.83 (s, 3H); ES+ MS: 457.3 (M + 1 ).
[00598] Example 185: 1 -Hydroxy-4-{[3'-(4-morpholinylcarbonyl)-4- biphenylyl]amino}pyrido[2,3-d]pyrimidin-2(1 H)-one.
Figure imgf000107_0001
[00599] The title compound was prepared in a similar manner to example 37 and isolated as an TFA salt. H NMR (300MHz, DMSO-d6) δ 10.58 (s, 1 H), 10.01 (s, 1 H), 8.77-8.75 (m, 2H), 7.99-7.97 (m, 2H), 7.82-7.72 (m, 4H), 7.56 (m, 1 H), 7.40-7.38 (m, 2H), 3.63 (s, 4H), 3.33 (s, 4H); ES+ MS: 444.2 (M + 1 ).
[00600] Example 186: 1 -Hydroxy-4-{[3'-(1 -piperazinylcarbonyl)-3- biphenylyl]amino}pyrido[2,3-d]pyrimidin-2(1 H)-one.
Figure imgf000107_0002
[00601] The title compound was prepared in a similar manner to example 37 and isolated as an TFA salt. H NMR (300MHz, DMSO-d6) δ 10.58 (br s, 1 H), 10.03 (s, 1 H), 8.83-8.76 (m, 3H), 8.18 (s, 1 H), 7.88-7.75 (m, 3H), 7.64-7.48 (m, 4H), 7.41 -7.37 (m, 1 H), 3.71 (m, 4H), 3.19(m, 4H); ES+ MS: 433.3 (M + 1 ).
[00602] Example 187: 3'-[(1 -Hydroxy-2-oxo-1 ,2-dihydropyrido[2,3-d]pyrimidin- 4-yl)am biphenylcarboxamide.
Figure imgf000107_0003
[00603] The title compound was prepared in a similar manner to example 144 and isolated as an TFA salt. H NMR (300MHz, DMSO-d6) δ 10.57 (s, 1 H), 10.02 (s, 1 H), 8.82 (d, 1 H), 8.76 (d, 1 H), 8.59 (s, 1 H), 8.14 (s, 1 H), 8.00-7.97 (m, 3H), 7.79 (d, 2H), 7.56- 7.53 (m, 2H), 7.41-7.36 (m, 1 H), 3.48 (m, 4H), 3.29 (s, 3H); ES+ MS: 432.3 (M + 1 ). [00604] Example 188: 4-{[4'-(Dimethylamino)-3-biphenylyl]a hydroxypyrido[2,3-d]pyrimidin-2(1H)-one.
Figure imgf000108_0001
[00605] The title compound was prepared in a similar manner to example 144 and isolated as an TFA salt. H NMR (300MHz, DMSO-d6) δ 10.54 (s, 1H), 9.94 (s, 1H), 8.81 (d, 1H), 8.75 (d, 1H), 7.99 (s, 1H), 7.77 (d, 1H), 7.54 (d, 2H), 7.44-7.34 (m, 3H), 6.84 (d, 2H), 2.96 (s, 6H); ES+ MS: 374.2 (M + 1).
[00606] Example 189: 4-[(4'-Chloro-3-biphenylyl)amino]-1-hydroxypyrido[2,3- d] py ri m i d i n-2 (1H)-o n e .
Figure imgf000108_0002
[00607] The title compound was prepared in a similar manner to example 144 and isolated as an TFA salt. H NMR (300MHz, DMSO-d6) δ 10.57 (s, 1 H), 10.01 (s, 1 H), 8.81 (d, 1H), 8.76 (d, 1H), 8.08 (s, 1H), 7.92 (d, 1H), 7.71 (d, 2H), 7.59-7.51 (m, 4H), 7.41- 7.36 (m, 1H); ES+ MS: 365.1 (M + 1).
[00608] Example 190: 1-Hydroxy-4-{[4'-(methyloxy)-3- biphenylyl]amino}pyrido[2,3-d]pyrimidin-2(1H)-one.
Figure imgf000108_0003
[00609] The title compound was prepared in a similar manner to example 144 and isolated as an TFA salt. H NMR (300MHz, DMSO-d6) δ 10.55 (s, 1H), 9.97 (s, 1H), 8.78 (d, 1H), 8.75 (d, 1H), 8.02 (s, 1H), 7.85 (d, 1H), 7.62 (d, 2H), 7.48-7.32 (m, 3H), 7.07 (d, 2H), 3.82 (s, 3H); ES+ MS: 361.2 (M + 1).
[00610] Example 191: 1-Hydroxy-4-{[3'-(methyloxy)-3- biphenylyl]amino}pyrido[2,3-d]pyrimidin-2(1H)-one.
Figure imgf000109_0001
[00611] The title compound was prepared in a similar manner to example 144 and isolated as an TFA salt. H NMR (300MHz, DMSO-d6) δ 10.57 (s, 1H), 9.98 (s, 1H), 8.82-8.73 (m, 2H), 8.09 (s, 1H), 7.90-7.86 (m, 1H), 7.53-7.49 (m, 2H), 7.44-7.35 (m, 2H), 7.26-7.20 (m, 2H), 6.99-6.95 (m, 1H), 3.84 (s, 3H); ES+ MS: 361.2 (M + 1).
[00612] Example 192: N-[2-(Dimethylamino)ethyl]-3'-[(1-hydroxy-2-oxo-1,2- dihydropyrido[2,3-d]pyrimidin-4-yl)amino]-3-biphenylcarboxamide.
Figure imgf000109_0002
[00613] The title compound was prepared in a similar manner to example 37 and isolated as an TFA salt. H NMR (300MHz, DMSO-d6) δ 10.05 (br. s., 1H), 8.95 (m, 2H), 8.75 (s, 1H), 8.22-8.15 (m, 2H), 7.93-7.85 (m, 3H), 7.64-7.54 (m, 3H), 7.39 (m, 1H), 3.66 (m, 2H), 3.30 (m, 2H), 2.84 (s, 6H); ES+ MS: 445.2 (M + 1).
[00614] Example 193: 1-Hydroxy-4-[(3'-hydroxy-3- biphenylyl)amino]pyrido[2,3-d]pyrimidin-2(1H)-one.
Figure imgf000109_0003
[00615] The title compound was prepared in a similar manner to example 37 and isolated as an TFA salt. H NMR (300MHz, DMSO-d6) δ 10.56 (s, 1H), 9.97 (s, 1H), 9.57 (s, 1H), 8.82-8.74 (m, 2H), 8.02-7.99 (m, 1H), 7.90-7.87 (m, 1H), 7.51-7.26 (m, 4H),7.09-7.04 (m, 2H), 6.81-6.78 (m, 1H); ES+ MS: 347.2 (M + 1).
[00616] Example 194: 3'-[(1-Hydroxy-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidin- 4-yl)amino]-3-biphenylcarbonitrile.
Figure imgf000109_0004
[00617] The title compound was prepared in a similar manner to example 37 and isolated as an TFA salt. H NMR (300MHz, DMSO-d6) δ 10.03 (s, 1 H), 8.82-8.75 (m, 2H), 8.14 (d, 2H), 8.03 (m, 1 H),7.94 (m, 1 H),7.87 (m, 1 H), 7.86-7.70 (m, 1 H), 7.57-7.55 (m, 2H), 7.38 (m, 1 H); ES+ MS: 356.1 (M + 1 ).
[00618] Example 195: 3'-[(1 -Hydroxy-2-oxo-1 ,2-dihydropyrido[2,3-d]pyrimidin- 4-yl)amino]-4-biphenylcarboxylic acid.
Figure imgf000110_0001
[00619] The title compound was prepared in a similar manner to example 144 and isolated as an TFA salt. H NMR (300MHz, DMSO-d6) δ 12.98 (s, 1 H), 10.57 (s, 1 H), 10.03 (s, 1 H), 8.83-8.75 (m, 2H), 8.13 (s, 1 H), 8.08-8.05 (d, 2H), 7.96 (s, 1 H), 7.83-7.80 (d, 2H), 7.57-7.55 (d, 2H), 7.40-7.36 (m, 1 H); ES+ MS: 375.1 (M + 1 ).
[00620] Example 196: 1-Hydroxy-4-[(4'-methyl-3-biphenylyl)amino]pyrido[2,3- d\ py ri m i d i n-2 ( 1 H)-o n e .
Figure imgf000110_0002
[00621] The title compound was prepared in a similar manner to example 144 and isolated as an TFA salt. H NMR (300MHz, DMSO-d6) δ 9.97 (s, 1 H), 8.82-8.74 (m, 2H), 8.04 (s, 1 H), 7.86 (m, 1 H),7.58-7.46 (m, 4H), 7.39-7.29 (m, 3H), 2.36 (s, 3H); ES+ MS: 345.2 (M + 1 ).
[00622] Example 197: 4-(3-Biphenylylamino)-1 -hydroxypyrido[2,3-d]pyrimidin- 2(1 H)-o
Figure imgf000110_0003
[00623] The title compound was prepared in a similar manner to example 144 and isolated as an TFA salt. H NMR (300MHz, DMSO-d6) δ 10.54 (s, 1 H), 9.97 (s, 1 H), 8.81 -8.72 (m, 2H), 8.06 (s, 1 H), 7.88-7.76 (d, 1 H), 7.67-7.65 (m, 2H), 7.51 -7.46 (m, 4H), 7.40-7.34 (m, 2H); ES+ MS: 331 .2 (M + 1 ). [00624] Example 198: 1 -Hydroxy-4-{[4'-(methyloxy)-4- biphenylyl]amino}pyrido[2,3-d]pyrimidin-2(1 H)-one.
Figure imgf000111_0001
[00625] The title compound was prepared in a similar manner to example 37 and isolated as an TFA salt. H NMR (300MHz, DMSO-d6) δ 9.99 (s, 1 H), 8.82 (d, 1 H), 8.75 (d, 1 H), 7.90 (d, 2H), 7.66 (t, 4H), 7.39-7.34 (m, 1 H), 7.04 (d, 2H), 3.81 (s, 3H); ES+ MS: 361 .1 (M + 1 ).
[00626] Example 199: 3-[(1-Hydroxy-2-oxo-1 ,2-dihydropyrido[2,3-d]pyrimidin- 4-yl)amino]benzonitrile.
[00627] The title compound was prepared in a similar manner to example 37 and isolated as an TFA salt. H NMR (300MHz, DMSO-d6) δ 10.67 (s, 1 H), 10.12 (s, 1 H), 8.80-8.77 (m, 2H), 8.40 (s, 1 H), 8.12 (br, 1 H), 7.65 (d, 2H), 7.42-7.38 (m, 1 H); ES+ MS: 280.1 (M + 1 ).
[00628] Example 200: 4-[(3'-amino-3-biphenylyl)amino]-1 -hydroxypyrido[2,3- d]pyrimi
Figure imgf000111_0003
[00629] The title compound was prepared in a similar manner to example 219 to provide a yellow solid (29.5 mg, 37.4 % yield) as a trifluoroacetate salt. H NMR (400 MHz, DMSO-d6) δ ppm 10.60 (br, 1 H), 10.01 (s, 1 H), 8.80 (d, J = 8.0 Hz, 1 H), 8.75 (dd, J = 1 .2, 4.8 Hz, 1 H), 8.02 (s, 1 H), 7.85 (d, J = 8.0 Hz, 1 H), 7.51 (t, J = 8.0 Hz, 1 H), 7.41 (d, J = 8.0 Hz, 1 H), 7.39 (dd, J = 4.8, 8.0 Hz, 1 H), 7.36 (t, J = 8.0 Hz, 1 H), 7.22 (d, J = 8.0 Hz, 1 H), 7.20 (s, 1 H), 6.96 (d, J = 8.0 Hz, 1 H); ES+ MS: 346 (M + 1 ).
[00630] Example 201 : 1 -Hydroxy-4-{[3-(3-pyridinyl)phenyl]amino}pyrido[2,3- d]pyrimidin-2(1 H)-one.
Figure imgf000112_0001
[00631] The title compound was prepared in a similar manner to example 219 to provide a yellow solid (41 .5 mg, 53.8 % yield) as a trifluoroacetate salt. H NMR (400 MHz, DMSO-d6) δ ppm 10.09 (s, 1 H), 9.04 (d, J = 1.6 Hz, 1 H), 8.80 (d, J = 8.0 Hz, 1 H), 8.76 (dd, J = 1.2, 4.8 Hz, 1 H), 8.74 (d, J = 8.0 Hz, 1 H), 8.39 (d, J = 8.0 Hz, 1 H), 8.18 (s, 1 H), 7.93 (d, J = 8.0 Hz, 1 H), 7.79 (dd, J = 5.2, 8.0 Hz, 1 H), 7.60 (m, 2 H), 7.38 (dd, J = 4.8, 8.0 Hz, 1 H); ES+ MS: 332 (M + 1 ).
[00632] Example 202: 1 -Hydroxy-4-{[4'-(trifluoromethyl)-3- biphenylyl]amino}pyrido[2,3-d]pyrimidin-2(1 H)-one.
Figure imgf000112_0002
[00633] The title compound was prepared in a similar manner to example 144 and isolated as an TFA salt. H NMR (300MHz, DMSO-d6) δ 10.02 (s, 1 H), 8.83-8.76 (m, 2H), 8.16 (s, 1 H), 7.97-7.86 (m, 5H), 7.58-7.56 (m, 2H), 7.40-7.36 (m, 1 H); ES+ MS: 399.2 (M + 1 ).
[00634] Example 203: 4-{[(4-Bromophenyl)methyl]amino}-1 - hydroxy d]pyrimidin-2(1 H)-one.
Figure imgf000112_0003
[00635] The title compound was prepared in a similar manner to example 144 and isolated as an TFA salt. H NMR (300MHz, DMSO-d6) δ 9.03 (m, 1 H), 8.70-8.68 (d, 1 H), 8.55-8.52 (d, 1 H), 7.55-7.52 (d, 2H), 7.34-7.25 (m, 3H), 4.68-4.67 (m, 2H); ES+ MS: 347.0 (M + 1 ).
[00636] Example 204: 1 -Hydroxy-4-{[3'-(methylamino)-3- biphenylyl]amino}pyrido[2,3-d]pyrimidin-2(1 H)-one.
I l l
Figure imgf000113_0001
[00637] The title compound was prepared in a similar manner to example 144 and isolated as an TFA salt. H NMR (300MHz, DMSO-d6) δ 10.00 (s, 1 H), 8.83-8.75 (m, 2H), 8.03 (s, 1H), 7.87-7.85 (m, 1 H),7.53-7.27 (m, 5H), 7.02-6.98 (m, 2H), 6.77-6.74 (m, 1H), 2.81 (s, 3H); ES+ MS: 360.2 (M + 1).
[00638] Example 205: 1-Hydroxy-4-{[3'-(1-piperidinylcarbonyl)-4- biphenylyl]amino}pyrido[2,3-d]pyrimidin-2(1H)-one.
Figure imgf000113_0002
[00639] The title compound was prepared in a similar manner to example 144 and isolated as an TFA salt. H NMR (300MHz, DMSO-d6) δ 10.57 (s, 1H), 9.98 (s, 1H), 8.82-8.72 (m, 2H), 7.96-7.94 (m, 2H), 7.76-7.73 (m, 3H), 7.64 (s, 1H), 7.54-7.49 (m, 1H), 7.37-7.30 (m, 2H), 3.59-3.30 (m, 4H), 1.60 (m, 6H); ES+ MS: 442.2 (M + 1).
[00640] Example 206: 1-Hydroxy-4-{[4-(2- naphthalenyl)phenyl]amino}pyrido[2,3-c]pyrimidin-2(1H)-one.
Figure imgf000113_0003
[00641] The title compound was prepared in a similar manner to example 37 and isolated as an TFA salt. H NMR (300MHz, DMSO-d6) δ 10.56 (s, 1H), 10.00 (s, 1H), 8.03 (d, 1H), 8.00 (d, 1H), 7.98 (s, 1H), 7.90-7.86 (m, 8H), 7.58-7.50 (m, 2H), 7.36-7.30 (m, 1H); ES+ MS: 381.1 (M + 1).
[00642] Example 207: 4'-[(1-Hydroxy-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidin- 4-yl)amino]-V-[2-(methyloxy)ethyl]-3-biphenylcarboxamide.
Figure imgf000114_0001
[00643] The title compound was prepared in a similar manner to example 37 and isolated as an TFA salt. H NMR (300MHz, DMSO-d6) δ 10.56 (s, 1 H), 10.00 (s, 1 H), 8.82-8.65 (m, 3H), 8.15 (s, 1 H), 7.97-7.94 (d, 2H), 7.85-7.77 (m, 4H), 7.53 (m, 1 H), 7.35 (m, 1 H), 3.46 (s, 4H), 3.26 (s, 3H); ES+ MS: 432.2 (M + 1 ).
[00644] Example 208: 1 -Hydroxy-4-({3'-[(4-methyl-1 -piperazinyl)carbonyl]-4- biphen midin-2(1 H)-one.
Figure imgf000114_0002
[00645] The title compound was prepared in a similar manner to example 37 and isolated as an TFA salt. H NMR (300MHz, DMSO-d6) δ 8.81 -8.78 (m, 2H), 8.42 (s, 1 H), 7.88-7.85 (m, 2H), 7.65-7.60 (m, 2H), 7.53 (m, 3H), 7.47-7.42 (m, 1 H), 3.56-3.32 (m, 8H), 3.01 (s, 3H); ES+ MS: 457.3 (M + 1 ).
[00646] Example 209: 1 -Hydroxy-4-{[3'-(1-pyrrolidinylcarbonyl)-4- biphenylyl]amino}pyrido[2,3-d]pyrimidin-2(1 H)-one.
Figure imgf000114_0003
[00647] The title compound was prepared in a similar manner to example 37 and isolated as an TFA salt. H NMR (300MHz, DMSO-d6) δ 10.57 (s, 1 H), 9.99 (s, 1 H), 8.83-8.73 (m, 2H), 7.97-7.94 (m, 2H), 7.79-7.75 (m, 4H), 7.55-7.45 (m, 2H), 7.38-7.34 (m, 1 H), 3.51-3.41 (m, 4H), 1 .90-1 .82 (m, 4H); ES+ MS: 428.2 (M + 1 ).
[00648] Example 210: 1 -Hydroxy-4-{[4'-(trifluoromethyl)-4- biphenylyl]amino}pyrido[2,3-d]pyrimidin-2(1 H)-one.
Figure imgf000115_0001
[00649] The title compound was prepared in a similar manner to example 144 and isolated as an TFA salt. H NMR (300MHz, DMSO-d6) δ 10.02 (s, 1 H), 8.82 (d, 1 H), 8.75 (d, 1 H), 8.03-7.93 (m, 4H), 7.84-7.81 (m, 4H), 7.37 (m, 1 H); ES+ MS: 399.0 (M + 1 ).
[00650] Example 21 1 : 4'-[(1 -Hydroxy-2-oxo-1 ,2-dihydropyrido[2,3-d]pyrimidin- 4-yl)am itrile.
Figure imgf000115_0002
[00651] The title compound was prepared in a similar manner to example 144 and isolated as an TFA salt. H NMR (300MHz, DMSO-d6) δ 10.60 (s, 1 H), 10.25 (s, 1 H), 8.82 (d, 1 H), 8.75 (d, 1 H), 8.02 (d, 2H), 7.93 (m, 4H), 7.83 (d, 2H), 7.40-7.35 (m, 1 H); ES+ MS: 356.1 (M + 1 ).
Exampl 4-{[4-(3-quinolinyl)phenyl]amino}pyrido[2,3-d]pyrimidin-2(1 H)-one.
Figure imgf000115_0003
[00652] The title compound was prepared in a similar manner to example 216 to provide a yellow solid (13.9 mg, 16.4 % yield) as a trifluoroacetate salt. H NMR (400 MHz, DMSO-d6) δ ppm 10.08 (s, 1 H), 9.40 (d, J = 1 .2 Hz, 1 H), 8.85 (s, 1 H), 8.84 (d, J = 8.0 Hz, 1 H), 8.76 (dd, J = 1 .2, 4.8 Hz, 1 H), 8.13 (d, J = 8.8 Hz, 2 H), 8.08 (m, 2 H), 8.00 (d, J = 8.8 Hz, 2 H), 7.85 (t, J = 7.2 Hz, 1 H), 7.72 (t, J = 7.2 Hz, 1 H), 7.39 (dd, J = 4.8, 8.0 Hz, 1 H); ES+ MS: 382 (M + 1 ).
[00653] Example 213: 1-Hydroxy-4-{[3-(3-quinolinyl)phenyl]amino}pyrido[2,3- d]pyrimidin-2(1 H)-one.
Figure imgf000116_0001
[00654] The title compound was prepared in a similar manner to example 219 to provide a yellow solid (8.5 mg, 10.0% yield) as a trifluoroacetate salt. H NMR (400 MHz, DMSO-d6) δ ppm 10.60 (br, 1 H), 10.1 1 (s, 1 H), 9.30 (d, J = 1.2 Hz, 1 H), 8.83 (d, J = 8.0 Hz, 1 H), 8.76 (d, J = 4.8 Hz, 1 H), 8.73 (d, J = 2.0 Hz, 1 H), 8.26 (s, 1 H), 8.1 1 (d, J = 3.2 Hz, 1 H), 8.10 (d, J = 4.0 Hz, 1 H), 8.00 (d, J = 8.0 Hz, 1 H), 7.83 (t, J = 7.2 Hz, 1 H), 7.73 (d, J = 8.0 Hz, 1 H), 7.70 (t, J = 7.2 Hz, 1 H), 7.62 (t, J = 8.0 Hz, 1 H), 7.39 (dd, J = 4.8, 8.0 Hz, 1 H); ES+ MS: 382 (M + 1 ).
[00655] Example 214: 1 -Hydroxy-4-({4-[6-(methyloxy)-3- pyridinyl]phenyl}amino)pyrido[2,3-d]pyrimidin-2(1 H)-one.
Figure imgf000116_0002
[00656] The title compound was prepared in a similar manner to example 216 to provide a yellow solid (32.6 mg, 40.0 % yield) as a trifluoroacetate salt. H NMR (400 MHz, DMSO-d6) δ ppm 10.60 (br, 1 H), 10.00 (s, 1 H), 8.81 (d, J = 8.0 Hz, 1 H), 8.75 (d, J = 4.8 Hz, 1 H), 8.53 (d, J = 2.4 Hz, 1 H), 8.05 (dd, J = 2.4, 8.8 Hz, 1 H), 7.93 (d, J = 8.0 Hz, 2 H), 7.72 (d, J = 8.0 Hz, 2 H), 7.37 (dd, J = 4.8, 8.0 Hz, 1 H), 6.92 (dd, J = 8.8 Hz, 1 H), 3.90 (s, 3 H); ES+ MS: 362 (M + 1 ).
[00657] Example 215: 1 -Hydroxy-4-({4-[5-(methyloxy)-3- pyridinyl]phenyl}amino)pyrido[2,3-d]pyrimidin-2(1 H)-one.
Figure imgf000116_0003
[00658] The title compound was prepared in a similar manner to example 216 to provide a yellow solid (32.6 mg, 40.0 % yield) as a trifluoroacetate salt. H NMR (400 MHz, DMSO-d6) δ ppm 10.61 (br, 1 H), 10.04 (s, 1 H), 8.82 (d, J = 8.0 Hz, 1 H), 8.76 (d, J = 4.8 Hz, 1 H), 8.57 (d, J = 2.0 Hz, 1 H), 8.32 (d, J = 3.2 Hz, 1 H), 8.00 (d, J = 8.4 Hz, 2 H), 7.84 (d, J = 8.4 Hz, 2 H), 7.74 (t, J = 2.0Hz, 1 H), 7.38 (dd, J = 4.8, 8.0 Hz, 1 H), 3.94 (s, 3 H); ES+ MS: 362 (M + 1 ).
[00659] Example 216: 4-{[4-(6-Fluoro-3-pyridinyl)phenyl]amino}-1 - hydroxypyrido[2,3-d]pyrimidin-2(1 H)-one.
Figure imgf000117_0003
[00660] a) 4-[(4-Bromophenyl)amino]-1-(tert-butoxy)pyrido[2,3-d]pyrimidin-
2(1 H)-o
Figure imgf000117_0001
[00661] The title compound was prepared in a similar manner to example 144 to provide a yellow solid 4-[(4-bromophenyl)amino]-1-(tert-butoxy)pyrido[2,3-d]pyrimidin- 2(1 H)-one (2.78g, 74 % yield). H NMR (400 MHz, CDCI3): δ ppm 9.95 (s, 1 H), 8.74 (d, J = 8.0 Hz, 1 H), 8.62 (d, J = 4.0 Hz, 1 H), 7.79 (d, J = 8.4 Hz, 2 H), 7.41 (d, J = 7.4 Hz, 2 H), 7.20 (d, J = 4.4, 8.0 Hz, 1 H), 1 .36 (s, 9 H); ES+ MS: m/z = 389, 401 (M+1 ).
[00662] b) 1 -(Tert-butoxy)-4-{[4-(6-fluoro-3-pyridinyl)phenyl]amino}pyrido[2,3- d\ py ri m i d i n-2 ( 1 H)-o n e .
Figure imgf000117_0002
[00663] To a flask was added 4-[(4-bromophenyl)amino]-1 -(tert- butoxy)pyrido[2,3-d]pyrimidin-2(1 H)-one (27.2 mg, 0.193 mmol), Na2C03 (61 .3 mg, 0.578 mmol) and tetrakis(triphenylphosphine)palladium(0) (1 1 .13 mg, 9.63 μmol). Then water (1 mL) and 1 ,4-dioxane (4.00 mL) was added. The reaction was heated to 90 °C for 5 h. The mixture was dilute with EtOAc, washed with water and brine. Dried, filtered and evaporated The residue was purified by flash chromatography on silica (0-5% MeOH in DCM) to provide brown oil (42.3 mg, 54.1 % yield). H NMR (400 MHz, CDCI3): δ ppm 8.61 (d, J = 4.4 Hz, 1 H), 8.58 (d, J = 8.0 Hz, 1 H), 8.30 (d, J = 2.0 Hz, 1 H), 7.99 (dt, J = 2.4, 8.0 Hz, 1 H), 7.92 (d, J = 7.2 Hz, 2 H), 7.49 (d, J = 8.4 Hz, 2 H), 7.23 (dd, J = 4.8, 8.0 Hz, 1 H), 7.01 (dd, J = 2.4, 8.4 Hz, 1 H), 1 .40 (s, 9 H); ES+ MS: m/z = 406 (M+1 ).
[00664] c) 4-{[4-(6-Fluoro-3-pyridinyl)phenyl]amino}-1 -hydroxypyrido[2,3- d]pyrimidin-2(1 H)-one.
Figure imgf000118_0001
[00665] To a solution of 1 -(tert-butoxy)-4-{[4-(6-fluoro-3- pyridinyl)phenyl]amino}pyrido[2,3-d]pyrimidin-2(1 H)-one in dichloromethane (DCM) (10 ml.) was added trifluoroacetic acid (TFA) (1 .000 ml_). The reaction was monitored by LCMS. Then solvent was evaporated under decreased pressure and the mixture was crystallized by MeOH, DCM, ether and hexanes to afford a yellow solid 4-{[4-(6-fluoro-3- pyridinyl)phenyl]amino}-1 -hydroxypyrido[2,3-d]pyrimidin-2(1 H)-one (44.0 mg, 90 % yield) as a trifluoroacetate salt. H NMR (400 MHz, DMSO-d6) δ ppm 10.60 (br, 1 H), 10.02 (s, 1 H), 8.82 (d, J = 8.0 Hz, 1 H), 8.75 (d, J = 4.8 Hz, 1 H), 8.60 (d, J = 2.4 Hz, 1 H), 8.32 (dt, J = 2.4, 8.0 Hz, 1 H), 7.99 (d, J = 8.0 Hz, 2 H), 7.80 (d, J = 8.0 Hz, 2 H), 7.37 (dd, J = 4.8, 8.0 Hz, 1 H), 7.30 (dd, J = 2.4, 8.0 Hz, 1 H); ES+ MS: 350 (M + 1 ).
[00666] Example 217: 1 -Hydroxy-4-({3-[6-(methyloxy)-3- pyridinyl]phenyl}amino)pyrido[2,3-d]pyrimidin-2(1 H)-one.
Figure imgf000118_0002
[00667] The title compound was prepared in a similar manner to example 219 to provide a yellow solid (35.3 mg, 56.7 % yield) as a trifluoroacetate salt. H NMR (400 MHz, DMSO-d6) δ ppm 8.80 (d, J = 8.0 Hz, 1 H), 8.75 (d, J = 4.0 Hz, 1 H), 8.49 (d, J = 4.0 Hz, 1 H), 8.06 (s, 1 H), 8.01 (dd, J = 2.4, 8.0 Hz, 1 H), 7.84 (d, J = 4.8 Hz, 1 H), 7.51 (t, J = 8.0 Hz, 1 H), 7.49 (s, 1 H), 7.38 (dd, J = 4.8, 8.0 Hz, 1 H), 6.96 (d, J = 8.0 Hz, 1 H), 3.91 (s, 3 H); ES+ MS: 362 (M + 1 ). [00668] Example 218: 1 -Hydroxy-4-({3-[5-(methyloxy)-3- pyridinyl]phenyl}amino)pyrido[2,3-d]pyrimidin-2(1 H)-one.
Figure imgf000119_0001
[00669] The title compound was prepared in a similar manner to example 219 to provide a yellow solid (1 1 .8 mg, 18.1 % yield) as a trifluoroacetate salt. H NMR (400 MHz, DMSO-d6) δ ppm 10.05 (br, 1 H), 8.80 (d, J = 8.0 Hz, 1 H), 8.76 (dd, J = 1 .2, 4.8 Hz, 1 H), 8.58 (d, J = 1 .6 Hz, 1 H), 8.42 (d, J = 2.4 Hz, 1 H), 8.17 (s, 1 H), 7.91 (d, J = 8.0 Hz, 1 H), 7.81 (s, 1 H), 7.61 (d, J = 8.0 Hz, 1 H), 7.57 (t, J = 8.0 Hz, 1 H), 7.38 (dd, J = 4.8, 8.0 Hz, 1 H), 3.96 (s, 3 H); ES+ MS: 362 (M + 1 ).
[00670] Example 219: 4-{[3-(6-Fluoro-3-pyridinyl)phenyl]amino}-1- hydroxypyrido[2,3-d]pyrimidin-2(1 H)-one.
Figure imgf000119_0002
[00671] a): 4-[(3-Bromophenyl)amino]-1 -(tert-butoxy)pyrido[2,3-d]pyrimidin- 2(1 H)-o
Figure imgf000119_0003
[00672] The title compound was prepared in a similar manner to example 144 to provide a yellow solid (2.73 g, 73 % yield). H NMR (400 MHz, CDCI3): 8.62 (dd, J = 1 .6, 4.8 Hz, 1 H), 8.54 (dd, J = 1 .6, 8.0 Hz, 1 H), 7.29 (s, 1 H), 7.28 (d, J = 8.0 Hz, 1 H), 7.22 (dd, J = 4.8, 8.0 Hz, 1 H), 7.12 (m, 1 H), 6.87 (d, J = 8.0 Hz, 1 H), 1 .47 (s, 9 H); ES+ MS: m/z = 389 (M+1 ).
[00673] b): 1-(Tert-butoxy)-4-{[3-(6-fluoro-3-pyridinyl)phenyl]amino}pyrido[2,3- d]pyrimidin-2(1 H)-one.
Figure imgf000120_0001
[00674] To a flask was added 4-[(3-Bromophenyl)amino]-1 -(tert- butoxy)pyrido[2,3-d]pyrimidin-2(1 H)-one (27.2 mg, 0.193 mmol), Na2C03 (61 .3 mg, 0.578 mmol) and tetrakis(triphenylphosphine)palladium(0) (1 1 .13 mg, 9.63 μηηοΙ). Then added Water (1 mL) and 1 ,4-Dioxane (4.00 mL). The reaction was heated to 90 °C for 5 h. The mixture was dilute with EtOAc, washed with water and brine. Dried, filtered and evaporated. The residue was purified by flash chromatography on silica (0-5% MeOH in DCM) to provide brown oil (52.7 mg, 67 % yield). H NMR (400 MHz, CDCI3): 10.05 (s, 1 H), 8.80 (d, J = 8.0 Hz, 1 H), 8.75 (d, J = 3.6 Hz, 1 H), 8.55 (d, J = 2.0 Hz, 1 H), 8.28 (dt, J = 3.2, 3.6 Hz, 1 H), 8.10 (s, 1 H), 7.90 (s, 1 H), 7.55 (d, J = 8.0 Hz, 1 H), 7.54 (s, 1 H), 7.38 (dd, J = 4.8, 8.0 Hz, 1 H), 7.34 (dd, J = 6.8, 8.8 Hz, 1 H), 1 .37 (s, 9 H); ES+ MS: m/z = 406 (M+1 ).
[00675] c): 4-{[3-(6-Fluoro-3-pyridinyl)phenyl]amino}-1 -hydroxypyrido[2,3- d]pyrimidin-2(1 H)-one.
Figure imgf000120_0002
[00676] To a solution of 1 -(Tert-butoxy)-4-{[3-(6-fluoro-3- pyridinyl)phenyl]amino}pyrido[2,3-d]pyrimidin-2(1 H)-one in Dichloromethane (DCM) (10 mL), was added Trifluoroacetic acid (TFA) (1 .000 mL). The reaction was monitored by LCMS. Then solvent was evaporated under decreased pressure and the mixture was crystallized by MeOH, DCM, ether and hexanes to afford a yellow solid (41.2 mg, 90 % yield). H NMR (400 MHz, DMSO-d6): 10.05 (s, 1 H), 8.80 (d, J = 8.0 Hz, 1 H), 8.75 (d, J = 3.6 Hz, 1 H), 8.55 (d, J = 2.0 Hz, 1 H), 8.28 (dt, J = 3.2, 3.6 Hz, 1 H), 8.10 (s, 1 H), 7.90 (s, 1 H), 7.55 (d, J = 8.0 Hz, 1 H), 7.54 (s, 1 H), 7.38 (dd, J = 4.8, 8.0 Hz, 1 H), 7.34 (dd, J = 6.8, 8.8 Hz, 1 H); ES+ MS: m/z = 350 (M+1 ).
[00677] Example 220: 4'-[(1 -Hydroxy-2-oxo-1 ,2-dihydropyrido[2,3-d]pyrimidin- 4-yl)amino]-A/,A/-dimethyl-3-biphenylcarboxamide.
Figure imgf000121_0001
[00678] The title compound was prepared in a similar manner to example 37 and isolated as an TFA salt. H NMR (300MHz, DMSO-d6) δ 10.57 (s, 1 H), 9.99 (s, 1 H), 8.83-8.74 (m, 2H), 7.98-7.95 (m, 2H), 7.78-7.69 (m, 4H), 7.55-7.50 (m, 1 H), 7.38-7.36 (m, 2H), 3.01-2.96 (d, 6H); ES+ MS: 402.2 (M + 1 ).
[00679] Example 221 : 4'-[(1 -Hydroxy-2-oxo-1 ,2-dihydropyrido[2,3-d]pyrimidin- 4-yl)amino]-A/-methyl-3-biphenylcarboxamide.
Figure imgf000121_0002
[00680] The title compound was prepared in a similar manner to example 37 and isolated as an TFA salt. H NMR (300MHz, DMSO-d6) δ 10.58 (s, 1 H), 10.01 (s, 1 H), 8.83-8.74 (m, 2H), 8.56-8.54 (m, 1 H), 8.14 (s, 1 H), 7.99-7.96 (m, 2H), 7.86-7.78 (m, 4H), 7.58-7.53 (m, 1 H), 7.39-7.35 (m, 1 H), 2.82 (s, 3H); ES+ MS: 388.2 (M + 1 ).
[00681] Example 222: 1 -Hydroxy-4-{[3'-(4-morpholinylcarbonyl)-3- biphen -d]pyrimidin-2(1 H)-one.
Figure imgf000121_0003
[00682] The title compound was prepared in a similar manner to example 144 and isolated as an TFA salt. H NMR (300MHz, DMSO-d6) δ 10.56 (s, 1 H), 9.98 (s, 1 H), 8.82-8.74 (m, 2H), 8.14 (s, 1 H), 7.92 (m, 1 H), 7.77 (m, 1 H), 7.68 (s, 1 H), 7.60-7.51 (m, 3H), 7.44-7.35 (m, 2H), 3.61 (s, 4H), 3.31 (s, 4H); ES+ MS: 444.2 (M + 1 ).
[00683] Example 223: 1-Hydroxy-4-[(3'-hydroxy-4- biphenylyl)amino]pyrido[2,3-d]pyrimidin-2(1 H)-one.
Figure imgf000122_0001
[00684] The title compound was prepared in a similar manner to example 37 and isolated as an TFA salt. H NMR (300MHz, DMSO-d6) δ 8.82-8.80 (m, 2H), 7.98 (m, 2H), 7.72-7.69 (m, 2H), 7.40 (m, 1 H), 7.31 (m, 1 H), 7.19-7.1 1 (m, 2H), 6.83 (m, 1 H); ES+ MS: 347.1 (M + 1 ).
[00685] Example 224: (3R)-N-(4-chlorophenyl)-1-(1 -hydroxy-2-oxo-1 ,2- dihydropyrido[2,3-d]pyrimidin-4-yl)-3-piperidinecarboxamide.
Figure imgf000122_0002
[00686] The title compound was prepared in a similar manner to example 144 to provide a yellow solid (34 mg, 47.4 % yield) as a trifluoroacetate salt. H NMR (400 MHz, CD3OD) δ ppm 8.61 (d, J = 4.8 Hz, 1 H), 8.29 (d, J = 8.0 Hz, 1 H), 7.51 (d, J = 8.0 Hz, 2 H), 7.27 (dd, J = 4.8, 8.0 Hz, 1 H), 7.22 (d, J = 8.0 Hz, 2 H), 4.49 (d, J = 12.8 Hz, 1 H), 4.26 (d, J = 12.8 Hz, 1 H), 3.45 (m, 2 H), 2.83 (m, 1 H), 2.05 (m, 1 H), 1 .91 (m, 1 H), 1 .85 (m, 1 H), 1.68 (m, 1 H); ES+ MS: 400 (M + 1 ).
[00687] Example 225: (3S)-N-(4-chlorophenyl)-1 -(1 -hydroxy-2-oxo-1 ,2- dihydropyrido[2,3-d]pyrimidin-4-yl)-3-piperidinecarboxamide.
Figure imgf000122_0003
I
[00688] The title compound was prepared in a similar manner to example 144 to provide a yellow solid (52 mg, 72.5 % yield) as a trifluoroacetate salt. H NMR (400 MHz, CD3OD) δ ppm 8.60 (d, J = 4.8 Hz, 1 H), 8.28 (d, J = 8.0 Hz, 1 H), 7.51 (d, J = 8.0 Hz, 2 H), 7.24 (dd, J = 4.8, 8.0 Hz, 1 H), 7.22 (d, J = 8.0 Hz, 2 H), 4.48 (d, J = 12.8 Hz, 1 H), 4.26 (d, J = 12.8 Hz, 1 H), 3.43 (m, 2 H), 2.82 (m, 1 H), 2.05 (m, 1 H), 1 .91 (m, 1 H), 1 .84 (m, 1 H), 1.67 (m, 1 H); ES+ MS: 400 (M + 1 ).
[00689] Example 226: 4-[(4'-Chloro-4-biphenylyl)amino]-1 -hydroxypyrido[2,3- d\ py ri m i d i n-2 ( 1 H)-o n e .
Figure imgf000123_0001
[00690] The title compound was prepared in a similar manner to example 37 and isolated as an TFA salt. H NMR (300MHz, DMSO-d6) δ 10.60 (s, 1 H), 10.00 (s, 1 H), 8.82 (d, 1 H), 8.75 (d, 1 H), 7.96 (s, 2H), 7.74 (d, 4H), 7.52 (d, 2H), 7.37 (m, 1 H); ES+ MS: 365.0 (M + 1 ).
[00691] Example 227: 1 -Hydroxy-4-{[3'-(1 -piperazinylcarbonyl)-4- biphenylyl]amino}pyrido[2,3-d]pyrimidin-2(1 H)-one.
Figure imgf000123_0002
[00692] The title compound was prepared in a similar manner to example 37 and isolated as an TFA salt. H NMR (300MHz, DMSO-d6) δ 10.57 (s, 1 H), 10.01 (s, 1 H), 8.85-8.75 (m, 3H), 7.99-7.96 (m, 2H), 7.81 -7.76 (m, 4H), 7.57 (m, 1 H), 7.45 (m, 2H), 3.56 (m, 4H), 3.17 (s, 4H); ES+ MS: 443.2 (M + 1 ).
[00693] Example 228: 1-Hydroxy-4-{[4-(1 - naphthalenyl)phenyl]amino}pyrido[2,3-c ]pyrimidin-2(1 H)-one.
Figure imgf000123_0003
[00694] The title compound was prepared in a similar manner to example 37 and isolated as an TFA salt. H NMR (300MHz, DMSO-d6) δ 10.59 (s, 1 H), 10.06 (s, 1 H), 8.87-8.76 (m, 2H), 8.03-7.88 (m, 5H), 7.60-7.39 (m, 7H); ES+ MS: 381.1 (M + 1 ). [00695] Example 229: 4-{[3'-(Dimethylamino)-3-biphenylyl]a hydroxypyrido[2,3-d]pyrimidin-2(1 H)-one.
Figure imgf000124_0001
[00696] The title compound was prepared in a similar manner to example 144 and isolated as an TFA salt. H NMR (300MHz, DMSO-d6) δ 10.57 (s, 1 H), 9.98 (s, 1 H), 8.82-8.73 (m, 2H), 8.09 (s, 1 H), 7.90-7.86 (m, 1 H), 7.49-7.27 (m, 4H), 6.96-6.94 (m, 2H), 6.79-6.75 (m, 1 H), 2.98 (s, 6H); ES+ MS: 374.2 (M + 1 ).
[00697] Example 230: 3'-[(1-Hydroxy-2-oxo-1 ,2-dihydropyrido[2,3-d]pyrimidin- 4-yl)amino]-A/-phenyl-3-biphenylcarboxamide.
Figure imgf000124_0002
[00698] The title compound was prepared in a similar manner to example 37 and isolated as an TFA salt. H NMR (300MHz, DMSO-d6) δ 10.36 (s, 1 H), 10.03 (s, 1 H), 8.82-8.74 (m, 2H), 8.23 (s, 1 H),8.09 (m, 1 H), 7.98-7.88 (m, 3H), 7.83-7.74 (m, 2H), 7.69-7.56 (m, 3H), 7.39-7.33 (m, 3H), 7.1 1 (m, 1 H); ES+ MS: 450.1 (M + 1 ).
[00699] Example 231 : 3'-[(1-Hydroxy-2-oxo-1 ,2-dihydropyrido[2,3-d]pyrimidin- 4-yl)amino]- V-[2-(methyloxy)ethyl]-3-biphenylcarboxamide.
Figure imgf000124_0003
[00700] The title compound was prepared in a similar manner to example 37 and isolated as an TFA salt. H NMR (300MHz, DMSO-d6) δ 10.55 (s, 1 H), 10.02 (s, 1 H), 8.82-8.74 (m, 2H), 8.65 (m, 1 H), 8.16 (s, 1 H), 8.06 (s, 1 H), 7.98-7.94(m, 1 H), 7.88-7.81 (m, 2H), 7.61-7.53 (m, 3H), 7.39-7.35 (m, 1 H), 3.47 (m, 4H), 3.27 (s, 3H); ES+ MS: 432.2 (M + 1 ).
[00701] Example 232: 4-{[(3-Bromophenyl)methyl]amino}-1 - hydroxypyrido[2,3-d]pyrimidin-2(1 H)-one.
Figure imgf000125_0001
[00702] The title compound was prepared in a similar manner to example 144 and isolated asanTFAsalt. H NMR (300MHz, DMSO-d6) δ 9.46 (br. s., 1H), 8.74 (d, 1H), 8.64 (d, 1H), 7.60 (s, 1H), 7.48 (d, 1H), 7.40-7.28 (m, 3H), 4.73 (d, 2H); ES+ MS: 347.0 (M + 1).
[00703] Example 233: 3'-[(1-Hydroxy-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidin- 4-yl)amino]-A/,A/-dimethyl-3-biphenylcarboxamide.
Figure imgf000125_0002
[00704] The title compound was prepared in a similar manner to example 37 and isolated asanTFAsalt. H NMR (300MHz, DMSO-d6) δ 10.58 (brs, 1H), 9.97 (s, 1H), 8.81-8.74 (m, 2H), 8.11 (s, 1H), 7.94 (m, 1H), 7.76-7.74 (m, 1H), 7.66 (s, 1 H),7.58-7.51 (m, 3H), 7.42-7.34 (m, 2H), 2.98 (d, 6H); ES+ MS: 402.2 (M + 1).
[00705] Example 234: 3'-[(1-Hydroxy-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidin- 4-yl)amino]-A/-methyl-3-biphenylcarboxamide.
Figure imgf000125_0003
[00706] The title compound was prepared in a similar manner to example 37 and isolated as an TFA salt. H NMR (300MHz, DMSO-d6) δ 10.78 (br s, 1 H), 10.02 (s, 1 H), 8.82-8.75 (m, 2H), 8.56 (m, 1H), 8.14 (s, 1H), 8.06 (s, 1H), 7.96 (m, 1H), 7.86-7.81(m, 2H), 7.61-7.54 (m, 3H), 7.40-7.35 (m, 1H), 2.82 (d, 3H); ES+ MS: 388.2 (M + 1).
[00707] Example 235: 1-Hydroxy-4-({4'-[(4-methyl-1-piperazinyl)carbonyl]-3- biphenylyl}amino)pyrido[2,3-d]pyrimidin-2(1H)-one.
Figure imgf000125_0004
[00708] The title compound was prepared in a similar manner to example 144 and isolated as an TFA salt. H NMR (300MHz, DMSO-d6) δ 10.58 (s, 1 H), 10.07 (s, 1 H), 8.84-8.76 (m, 2H), 8.20 (s, 1 H), 7.87-7.77 (m, 3H), 7.60-7.53 (m, 4H), 7.38 (m, 1 H), 3.34 (m, 8H), 2.76-2.67 (m, 3H); ES+ MS: 457.2 (M + 1 ).
[00709] Example 236: 4'-{[(1 -Hydroxy-2-oxo-1 ,2-dihydropyrido[2,3- cf]pyrimidin-4-yl)amino]methyl}- V-phenyl-4-biphenylcarboxamide.
Figure imgf000126_0001
[00710] The title compound was prepared in a similar manner to example 144 and isolated as an TFA salt. H NMR (300MHz, DMSO-d6) δ ppm 10.38 (s, 1 H), 10.28 (s, 1 H), 9.13 (m, 1 H), 8.70 (d, 1 H), 8.58 (d, 1 H), 8.04 (d, 2H), 7.85-7.73 (m, 6H), 7.50 (d, 2H), 7.39-7.29 (m, 3H), 7.1 1 (m, 1 H), 4.77 (d, 2H); ES+ MS: 463.9 (M + 1 ).
[00711] Example 237: V-[2-(Dimethylamino)ethyl]-3'-[(1 -hydroxy-2-oxo-1 ,2- dihydropyrido[2,3-d]pyrimidin-4-yl)amino]-4-biphenylcarboxamide.
Figure imgf000126_0002
[00712] The title compound was prepared in a similar manner to example 37 and isolated as an TFA salt. H NMR (300MHz, DMSO-d6) δ 10.58 (s, 1 H), 10.04 (s, 1 H), 8.82 (d, 1 H), 8.76 (d, 1 H), 8.19 (s, 1 H), 8.00-7.82 (m, 5H), 7.55 (d, 2H), 7.41 -7.36 (m, 1 H), 3.61 ( br, 2H), 3.22 (br, 2H), 2.80 (s, 6H); ES+ MS: 445.2 (M + 1 ).
[00713] Example 238: 5-{3-[(1 -Hydroxy-2-oxo-1 ,2-dihydropyrido[2,3- d]pyrimidin-4-yl)amino]phenyl}-2-pyridinecarbonitrile.
Figure imgf000126_0003
[00714] a ) [3-({1 -(Tert-butoxyamino)-2-oxo-1 ,2-dihydropyrido[2,3-d]pyrimidin- 4-yl}amino)phenyl]boronic acid.
Figure imgf000127_0001
[00715] To a flask was added 4-[(3-bromophenyl)amino]-1 -(tert- butoxy)pyrido[2,3-d]pyrimidin-2(1 H)-on, 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi-1 ,3,2- dioxaborolane (161 mg, 0.636 mmol), 1 , 1 '-bis(diphenylphosphino)ferrocene- palladium(ll)dichloride dichloromethane complex (14.16 mg, 0.017 mmol) and potassium acetate (56.7 mg, 0.578 mmol). Then 1 ,4-Dioxane (3 ml.) and Dimethyl Sulfoxide (DMSO) (0.300 ml.) was added. The mixture was heated to 100 °C for 3 h and monitored by LCMS. The mixture was then extracted by EtOAc and water, and the organic layer was washed with brine, dried, filtered and evaporated to afford black oil. The crude product was purified by flash column on silica gel (0-50% EtOAc in hexanes) to afford the title compound, which exist as the boronic acid and boronic ester. However, it can be used without further purification. H NMR (400 MHz, DMSO-d6) δ ppm 10.52 (br, 1 H), 9.95 (s, 1 H), 8.80 (d, J = 8.0 Hz, 1 H), 8.73 (d, J = 4.0 Hz, 1 H), 8.1 1 (br, 2 H), 7.95 (s, 1 H), 7.93 (d, J = 8.0 Hz, 1 H), 7.63 (d, J = 8.0 Hz, 1 H), 7.39 (t, J = 8.0 Hz, 1 H), 7.34 (dd, J = 4.0, 8.0 Hz, 1 H), 1 .40 (s, 9 H); ES+ MS: 355 (M+1 ).
[00716] b) 5-[3-({1 -(Tert-butoxyamino)-2-oxo-1 ,2-dihydropyrido[2,3- cf]pyrimidin-4-yl}amino)phenyl]-2-pyridinecarbonitrile.
Figure imgf000127_0002
[00717] To a flask was added [3-({1 -(tert-butoxyamino)-2-oxo-1 ,2- dihydropyrido[2,3-d]pyrimidin-4-yl}amino)phenyl]boronic acid, Na2C03 (60.2 mg, 0.568 mmol), tetrakis(triphenylphosphine)palladium(0) (10.93 mg, 9.46 μηηοΙ), and
pyridinecarbonitrile (34.6 mg, 0.189 mmol). Then Water (1 ml.) and 1 ,4-Dioxane (4.00 ml.) was added. The reaction was heated to 90 °C over night. The mixture was dilute with EtOAc, washed with water and brine. Dried, filtered and evaporated to give desired product (13.7 mg, 17.6 % yield) as yellow foam. H NMR (400 MHz, DMSO-d6) δ ppm 10.60 (br, 1 H), 10.10 (s, 1 H), 9.10 (d, J = 8.0 Hz, 1 H), 8.80 (d, J = 4.8 Hz, 1 H), 8.76 (s, 1 H), 8.34 (d, J = 8.0 Hz, 1 H), 8.22 (s, 1 H), 8.20 (d, J = 8.0 Hz, 1 H), 7.98 (d, J = 8.0 Hz, 1 H), 7.65 (d, J = 8.0 Hz, 1 H), 7.61 (t, J = 8.0 Hz, 1 H), 7.39 (dd, J = 4.8, 8.0 Hz, 1 H), 1 .39 (s, 9 H); ES+ MS: 413 (M+1 ).
[00718] c) 5-{3-[(1 -Hydroxy-2-oxo-1 ,2-dihydropyrido[2,3-d]pyrimidin-4- yl)amino]phenyl}-2-pyridinecarbonitrile
Figure imgf000128_0001
[00719] To a solution of 5-[3-({1 -(Tert-butoxyamino)-2-oxo-1 ,2- dihydropyrido[2,3-c |pyrimidin-4-yl}amino)phenyl]-2-pyridinecarbonitrile (13.7 mg, 0.03 mmol) in dichloromethane (DCM) (10 mL) was added trifluoroacetic acid (TFA) (1 .000 mL). The reaction was monitored by LCMS to complete. Then the solvent was evaporated under decreased pressure. The product was crystallized by MeOH, DCM, ether and hexanes to afford a yellow solid (9.6 mg, 60 % yield) as a trifluoroacetate salt. H NMR (400 MHz, DMSO-d6) δ ppm 10.60 (br, 1 H), 10.10 (s, 1 H), 9.10 (d, J = 8.0 Hz, 1 H), 8.80 (d, J = 4.8 Hz, 1 H), 8.76 (s, 1 H), 8.34 (d, J = 8.0 Hz, 1 H), 8.22 (s, 1 H), 8.20 (d, J = 8.0 Hz, 1 H), 7.98 (d, J = 8.0 Hz, 1 H), 7.65 (d, J = 8.0 Hz, 1 H), 7.61 (t, J = 8.0 Hz, 1 H), 7.39 (dd, J = 4.8, 8.0 Hz, 1 H); ES+ MS: 357 (M+1 ).
[00720] Example 239: 5-{3-[(1 -Hydroxy-2-oxo-1 ,2-dihydropyrido[2,3- d]pyrimidin-4-yl)amino]phenyl}-3-pyridinecarbonitrile.
Figure imgf000128_0002
[00721] The title compound was prepared in a similar manner to example 238 to provide a yellow solid (20.2 mg, 25.1 % yield) as a trifluoroacetate salt. H NMR (400 MHz, DMSO-d6) δ ppm 10.08 (br, 1 H), 9.18 (s, 1 H), 9.05 (s, 1 H), 8.80 (d, J = 6.4 Hz, 1 H), 8.76 (d, J = 4.8 Hz, 1 H), 8.64 (s, 1 H), 8.18 (s, 1 H), 7.95 (d, J = 6.4 Hz, 1 H), 7.65 (d, J = 8.0 Hz, 1 H), 7.59 (t, J = 6.4 Hz, 1 H), 7.38 (dd, J = 4.8, 8.0 Hz, 1 H); ES+ MS: 357 (M+1 ).
[00722] Example 240: 4-{[3-(5-Fluoro-3-pyridinyl)phenyl]amino}-1 - hydroxypyrido[2,3-d]pyrimidin-2(1 H)-one.
Figure imgf000129_0001
[00723] The title compound was prepared in a similar manner to example 238 to provide a yellow solid (30.2 mg, 38.0 % yield) as a trifluoroacetate salt. H NMR (400 MHz, DMSO-d6) δ ppm 10.06 (br, 1 H), 8.80 (d, J = 8.0 Hz, 1 H), 8.76 (d, J = 4.8 Hz, 1 H), 8.62 (d, J = 2.8 Hz, 1 H), 8.17 (s, 1 H), 8.06 (d, J = 8.0 Hz, 1 H), 7.93 (d, J = 2.8 Hz, 1 H), 7.62 (t, J = 8.0 Hz, 1 H), 7.59 (t, J = 8.0 Hz, 1 H), 7.56 (s, 1 H), 7.38 (dd, J = 4.8, 8.0 Hz, 1 H); ES+ MS: 350 (M+1 ).
[00724] Example 241 : 1 -Hydroxy-4-({4-[2-(methyloxy)-4- pyridinyl]phenyl}amino)pyrido[2,3-d]pyrimidin-2(1 H)-one.
Figure imgf000129_0002
[00725] The title compound was prepared in a similar manner to example 216 to provide a yellow solid (23.4 mg, 37.4 % yield) as a trifluoroacetate salt. H NMR (400 MHz, DMSO-d6) δ ppm 10.62 (s, 1 H), 10.04 (s, 1 H), 8.82 (d, J = 8.0 Hz, 1 H), 8.76 (d, J = 4.0 Hz, 1 H), 8.23 (d, J = 5.6 Hz, 1 H), 8.01 (d, J = 8.8 Hz, 2 H), 7.87 (d, J = 8.8 Hz, 2 H), 7.38 (dd, J = 4.8, 8.0 Hz, 1 H), 7.36 (dd, J = 1 .2, 5.6 Hz, 1 H), 7.15 (s, 1 H), 3.90 (s, 3 H). ES+ MS: 362 (M+1 ).
[00726] Example 242: 1 -Hydroxy-4-({3-[2-(methyloxy)-4- pyridinyl]phenyl}amino)pyrido[2,3-d]pyrimidin-2(1 H)-one.
Figure imgf000129_0003
[00727] The title compound was prepared in a similar manner to example 219 to provide a yellow solid (33.1 mg, 53.2 % yield) as a trifluoroacetate salt. H NMR (400 MHz, DMSO-d6) δ ppm 10.05 (s, 1 H), 8.80 (d, J = 8.0 Hz, 1 H), 8.75 (dd, J = 1 .2, 4.8 Hz, 1 H), 8.27 (d, J = 4.8 Hz, 1 H), 8.17 (s, 1 H), 7.96 (d, J = 8.0 Hz, 1 H), 7.59 (t, J = 8.0 Hz, 1 H), 7.55 (t, J = 8.0 Hz, 1 H), 7.38 (dd, J = 4.8, 8.0 Hz, 1 H), 7.31 (dd, J = 1 .2, 4.8 Hz, 1 H), 7.10 (s, 1 H), 3.91 (s, 3 H); ES+ MS: 362 (M+1 ).
[00728] Example 243: 1 -Hydroxy-4-{[4-(2-pyridinyl)phenyl]amino}pyrido[2,3- d]pyrimidin-2(1 H)-one.
Figure imgf000130_0001
[00729] a) 1 -(Tert-butoxyamino)-4-{[4-(2-pyridinyl)phenyl]amino}pyrido[2,3- d\ py ri m i d i n-2 ( 1 H)-o n e .
Figure imgf000130_0002
[00730] To a solution of 4-[(4-bromophenyl)amino]-1 -[(1 , 1 - dimethylethyl)oxy]pyrido[2,3-d]pyrimidin-2(1 H)-one (50 mg, 0.128 mmol) in N,N- Dimethylformamide (DMF) (1 .5 ml.) was added bromo(2-pyridinyl)zinc (2.055 ml_, 1 .028 mmol) and tetrakis(triphenylphosphine)palladium(0) (14.84 mg, 0.013 mmol). The mixture was irradiated in the microwave at 100 °C for 20 min. LCMS showed complete conversion to desired product and complete consumption of starting material. The mixture was washed with brine, dried, filtered and evaporated. Then purified by flash column (0-5% MeOH in DCM) to afford the product as a yellow foam (45.4 mg, 92 % yield). H NMR (400 MHz, CDCI3): δ ppm 10.10 (s, 1 H), 8.85 (d, J = 8.8 Hz, 2 H), 8.78 (dd, J = 1 .2, 4.8 Hz, 1 H), 8.72 (d, J = 4.0 Hz, 1 H), 8.16 (d, J = 8.8 Hz, 2 H), 8.08 (d, J = 8.0 Hz, 1 H), 8.04 (m, 2 H), 7.46 (m, 1 H), 7.40 (dd, J = 4.8, 8.0 Hz, 1 H), 1 .40 (s, 9 H); ES+ MS: 388 (M+1 ).
[00731] b) 1 -Hydroxy-4-{[4-(2-pyridinyl)phenyl]amino}pyrido[2,3-d]pyrimidin- 2(1 H)-o
Figure imgf000130_0003
[00732] To a solution of 1 -(tert-butoxyamino)-4-{[4-(2- pyridinyl)phenyl]amino}pyrido[2,3-d]pyrimidin-2(1 H)-one (45.4 mg, 0.1 18 mmol) in dichloromethane (DCM) (10 ml.) was added trifluoroacetic acid (TFA) (1 .000 ml_). The reaction was monitored by LCMS to complete. Then the solvent was evaporated under decreased pressure. The product was crystallized by MeOH, DCM, ether and hexanes to afford a yellow solid 1 -hydroxy-4-{[4-(2-pyridinyl)phenyl]amino}pyrido[2,3-d]pyrimidin-2(1 H)- one (30 mg, 56.8 % yield) as TFA salt. H NMR (400 MHz, DMSO-d6) δ ppm 10.10 (s, 1 H), 8.85 (d, J = 8.8 Hz, 2 H), 8.78 (dd, J = 1 .2, 4.8 Hz, 1 H), 8.72 (d, J = 4.0 Hz, 1 H), 8.16 (d, J = 8.8 Hz, 2 H), 8.08 (d, J = 8.0 Hz, 1 H), 8.04 (m, 2 H), 7.46 (m, 1 H), 7.40 (dd, J = 4.8, 8.0 Hz, 1 H). ES+ MS: 332 (M+1 ).
[00733] Example 244: 1 -Hydroxy-4-{[3-(2-pyridinyl)phenyl]amino}pyrido[2,3- d]pyrimidin-2(1 H)-one.
Figure imgf000131_0001
[00734] The title compound was prepared in a similar manner to example 243 to provide a yellow solid (47.5 mg, 82 % yield) as a trifluoroacetate salt. H NMR (400 MHz, DMSO-d6) δ ppm 10.60 (br, 1 H), 10.10 (s, 1 H), 8.86 (d, J = 4.8 Hz, 1 H), 8.76 (dd, J = 1 .2, 4.8 Hz, 1 H), 8.72 (d, J = 4.0 Hz, 1 H), 8.46 (s, 1 H), 8.05 (d, J = 8.0 Hz, 1 H), 7.92-8.00 (m, 2 H), 7.90 (d, J = 8.0 Hz, 1 H), 7.56 (t, J = 8.0 Hz, 1 H), 7.41 (m, 1 H), 7.38 (dd, J = 4.8, 8.0 Hz, 1 H); ES+ MS: 332 (M+1 ).
[00735] Example 245: 3-{4-[(1 -Hydroxy-2-oxo-1 ,2-dihydropyrido[2,3- d]pyrimidin-4-yl)amino]phenyl}-4-pyridinecarboxamide.
Figure imgf000131_0002
[00736] The title compound was prepared in a similar manner to example 216 to provide a yellow solid (10 mg, 1 1 .7 % yield) as a trifluoroacetate salt. H NMR (400 MHz, DMSO-d6) δ ppm 10.02 (s, 1 H), 8.81 (d, J = 8.0 Hz, 2 H), 8.76 (d, J = 4.8 Hz, 1 H), 8.71 (s, 1 H), 8.65 (d, J = 4.8 Hz, 1 H), 7.98 (s, 1 H), 7.92 (d, J = 8.0 Hz, 1 H), 7.67 (s, 1 H), 7.54 (d, J = 8.0 Hz, 2 H), 7.47 (d, J = 4.8 Hz, 1 H), 7.38 (dd, J = 4.8, 8.0 Hz, 1 H). ES+ MS: 375 (M+1 ).
[00737] Example 246: 3-{4-[(1 -Hydroxy-2-oxo-1 ,2-dihydropyrido[2,3- d]pyrimidin-4-yl)amino]phenyl}-4-pyridinecarbonitrile.
Figure imgf000132_0001
[00738] The title compound was prepared in a similar manner to example 216 to provide a yellow solid (7.4 mg, 9.4 % yield) as a trifluoroacetate salt. H NMR (400 MHz, DMSO-d6) δ ppm 10.60 (br, 1 H), 10.05 (s, 1 H), 8.97 (d, J = 4.8 Hz, 1 H), 8.82 (d, J = 4.8 Hz, 1 H), 8.81 (s, 1 H), 8.76 (d, J = 4.8 Hz, 1 H),8.08 (d, J = 8.0 Hz, 2 H), 7.75 (d, J = 8.0 Hz, 3 H), 7.39 (dd, J = 4.8, 8.0 Hz, 1 H); ES+ MS: 357 (M+1 ).
[00739] Example 247: 3-{3-[(1 -Hydroxy-2-oxo-1 ,2-dihydropyrido[2,3- d]pyrimidin-4-yl)amino]phenyl}-4-pyridinecarboxamide.
Figure imgf000132_0002
[00740] The title compound was prepared in a similar manner to example 219 to provide a yellow solid (1 1 mg, 12.9 % yield) as a trifluoroacetate salt. H NMR (400 MHz, DMSO-d6) δ ppm 10.60 (br, 1 H), 10.04 (s, 1 H), 8.81 (d, J = 8.0 Hz, 1 H), 8.75 (d, J = 4.8 Hz, 1 H), 8.67 (s, 1 H), 8.66 (d, J = 4.8 Hz, 1 H), 7.98 (d, J = 13.2 Hz, 2 H), 7.87 (d, J = 8.0 Hz, 1 H), 7.67 (s, 1 H), 7.49 (t, J = 8.0 Hz, 1 H), 7.46 (d, J = 4.8 Hz, 1 H), 7.38 (dd, J = 4.8, 8.0 Hz, 1 H), 7.30 (d, J = 8.0 Hz, 1 H); ES+ MS: 375 (M+1 ).
[00741] Example 248: 3-{3-[(1 -Hydroxy-2-oxo-1 ,2-dihydropyrido[2,3- d]pyrimidin-4-yl)amino]phenyl}-4-pyridinecarbonitrile.
Figure imgf000132_0003
[00742] The title compound was prepared in a similar manner to example 219 to provide a yellow solid (6.2 mg, 10.0 % yield) as a trifluoroacetate salt. H NMR (400 MHz, DMSO-d6) δ ppm 10.60 (br, 1 H), 10.10 (s, 1 H), 8.94 (s, 1 H), 8.87 (d, J = 4.8 Hz, 1 H), 8.82 (d, J = 8.0 Hz, 1 H), 8.76 (d, J = 4.0 Hz, 1 H), 8.1 1 (s, 1 H), 8.06 (d, J = 8.0 Hz, 1 H), 8.03 (d, J = 4.0 Hz, 1 H), 7.63 (t, J = 8.0 Hz, 1 H), 7.49 (d, J = 8.0 Hz, 1 H), 7.38 (dd, J = 4.8, 8.0 Hz, 1 H); ES+ MS: 357 (M + 1 ).
[00743] Example 249: 1 -Hydroxy-4-({4-[4-(methyloxy)-3- pyridinyl]phenyl}amino)pyrido[2,3-d]pyrimidin-2(1 H)-one.
Figure imgf000133_0001
[00744] The title compound was prepared in a similar manner to example 216 to provide a yellow solid (27.7 mg, 33.9 % yield) as a trifluoroacetate salt. H NMR (400 MHz, DMSO-d6) δ ppm 10.60 (br, 1 H), 10.07 (s, 1 H), 8.82 (d, J = 8.0 Hz, 1 H), 8.76 (d, J = 6.4 Hz, 2 H), 8.74 (s, 1 H), 7.97 (d, J = 8.0 Hz, 2 H), 7.65 (d, J = 8.0 Hz, 2 H), 7.64 (d, J = 6.4 Hz, 1 H), 7.38 (dd, J = 4.8, 8.0 Hz, 1 H), 4.09 (s, 3 H); ES+ MS: 362 (M+1 ).
[00745] Example 250: 1 -Hydroxy-4-({3-[4-(methyloxy)-3- pyridinyl]phenyl}amino)pyrido[2,3-d]pyrimidin-2(1 H)-one.
Figure imgf000133_0002
[00746] The title compound was prepared in a similar manner to example 219 to provide a yellow solid (29.4 mg, 35.6 % yield) as a trifluoroacetate salt. H NMR (400 MHz, DMSO-d6) δ ppm 10.60 (br, 1 H), 10.06 (s, 1 H), 8.80 (d, J = 6.8 Hz, 1 H), 8.78 (d, J = 6.8 Hz, 1 H), 8.76 (dd, J = 4.8, 8.0 Hz, 1 H), 8.71 (s, 1 H), 8.07 (s, 1 H), 7.85 (d, J = 8.0 Hz, 1 H), 7.64 (d, J = 6.8 Hz, 1 H), 7.56 (t, J = 8.0 Hz, 1 H), 7.38 (d, J = 8.0 Hz, 1 H), 7.37 (d, J = 8.0 Hz, 1 H), 4.10 (s, 3 H); ES+ MS: 362 (M+1 ).
[00747] Example 251 : 1 -Hydroxy-4-{[(3-nitrophenyl)methyl]amino}pyrido[2,3- d\ py ri m i d i n-2 ( 1 H)-o n e .
Figure imgf000134_0001
[00748] The title compound was prepared in a similar manner to example 144 and isolated asanTFAsalt. H NMR(300 MHz, DMSO-d6) δ 10.39 (s, 1H), 9.18 (s, 1H), 8.71 (d, 1H), 8.54 (s, 1H), 8.24 (s, 1H), 8.15 (d, 1H), 7.84 (d, 1H), 7.65 (t, 1H), 7.30 (dd, 1H), 4.82 (d, 2H); ES+ MS: 314.1 (M + 1).
[00749] Example 252: 4-{[(2-Bromophenyl)methyl]amino}-1- hydroxy d]pyrimidin-2(1H)-one.
Figure imgf000134_0002
[00750] The title compound was prepared in a similar manner to example 144 and isolated as an TFA salt. H NMR (300MHz, DMSO-d6) δ 10.39 (s, 1 H), 9.04 (s, 1 H), 8.71 (m, 1H), 8.60 (m, 1H), 7.67 (m, 1H), 7.36-7.25 (m, 4H), 4.71-4.70 (m, 2H); ES+ MS: 347.1 (M + 1).
[00751] Example 253: V-[2-(Dimethylamino)ethyl]-4'-[(1-hydroxy-2-oxo-1 ,2- dihydropyrido[2,3-d]pyrimidin-4-yl)amino]-3-biphenylcarboxamide.
Figure imgf000134_0003
[00752] The title compound was prepared in a similar manner to example 144 and isolated as an TFA salt. H NMR (300 MHz, DMSO-d6) δ 8.76 (d, 2H), 8.16 (s, 1H), 7.94-7.83 (m, 4H), 7.73(d, 2H), 7.71(m, 2H), 3.83 (s, 2H), 3.45-3.37 (m, 2H), 3.05 (s, 6H); ES+ MS: 445.2 (M + 1).
[00753] Example 254: 1-Hydroxy-4-{[1-(A/-methylglycyl)-4- piperidinyl]amino}pyrido[2,3-c/]pyrimidin-2(1H)-one.
Figure imgf000135_0001
[00754] The title compound was prepared in a similar manner to example 144 and isolated as a TFA salt. H NMR (300MHz, DMSO-d6) δ 10.36 (s, 1 H), 8.67 (d, 2H), 8.57 (d, 1H), 8.21 (d, 1H), 7.26 (dd, 1H), 4.41-4.37 (m, 2H), 4.18-4.01 (m, 2H), 3.73-3.68 (m, 1H), 3.24-3.16 (m, 1H), 2.92-2.84 (m, 1H), 2.57 (s, 3H), 2.01-1.98 (m, 2H), 1.58-1.44 (m, 2H); ES+ MS: 333.2 (M + 1).
[00755] Example 255: 3'-[(1-Hydroxy-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidin- 4-yl)amino]-4-biphenylcarbonitrile.
Figure imgf000135_0002
[00756] The title compound was prepared in a similar manner to example 144 and isolated as an TFA salt. H NMR (300 MHz, DMSO-d6) δ 10.03 (s, 1H), 8.81-8.75 (m, 2H), 8.15 (s, 1H), 7.98-7.86 (m, 5H), 7.56 (s, 2H), 7.37 (dd, 1H); ES+ MS: 356.2 (M + 1).
[00757] Example 256: 1-Hydroxy-4-[(3-pyridinylmethyl)amino]pyrido[2,3- d\ py ri m i d i n-2 ( 1 H)-o n e .
Figure imgf000135_0003
[00758] The title compound was prepared in a similar manner to example 144 and isolated as an TFA salt. H NMR (300 MHz, DMSO-d6) δ 9.09 (s, 1H), 8.76 (s, 1H), 8.71 (d, 1H), 8.63 (s, 1H), 8.52 (dd, 1H), 8.11 (m, 1H), 7.67 (m, 1H), 7.30 (dd, 1H), 4.77 (d, 2H); ES+ MS: 270.2 (M + 1).
[00759] Example 257:1-Hdroxy-4-[(4'-hydroxy-3-biphenylyl)amino]pyrido[2,3- d\ py ri m i d i n-2 ( 1 H)-o n e .
Figure imgf000136_0001
[00760] The title compound was prepared in a similar manner to example 37 and isolated as an TFA salt. H NMR (300 MHz, DMSO-d6) δ 10.58 (s, 1H), 9.92 (s, 1H), 9.53 (s, 1H), 8.80-8.75 (m, 2H), 7.98 (s, 1H), 7.83-7.80 (m, 1H), 7.52-7.35 (m, 5H), 6.90- 6.87 (m, 2H); ES+ MS: 347.1 (M + 1).
[00761] Example 258: 4-[(3'-Amino-4-biphenylyl)amino]-1-hydroxypyrido[2,3- d\ py ri m i d i n-2 ( 1 H)-o n e .
Figure imgf000136_0002
[00762] The title compound was prepared in a similar manner to example 37 and isolated as an TFA salt. H NMR (300 MHz, CD3OD) δ 8.78 (d, 2H), 7.98 (d, 2H), 7.71- 7.49 (m, 7H), 7.22-7.19 (m, 1H); ES+ MS: 346.1 (M + 1).
[00763] Example 259: 3-{[(1-Hydroxy-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidin- 4-yl)amino]methyl}benzonitrile.
Figure imgf000136_0003
[00764] The title compound was prepared in a similar manner to example 144 and isolated as an TFA salt. H NMR (300MHz, DMSO-d6) δ 10.37 (s, 1H), 9.08 (s, 1H), 8.69 (d, 1H), 8.53 (d, 1H), 7.83 (s, 1H), 7.76-7.70 (m, 2H), 7.60-7.54 (m, 1H), 7.28 (dd, 1H), 4.74 (d, 2H); ES+ MS: 294.2 (M + 1).
[00765] Example 260: 1-Hydroxy-4-{[3- (trifluoromethyl)phenyl]amino}pyrido[2,3-d]pyrimidin-2(1H)-one.
Figure imgf000137_0001
[00766] The title compound was prepared in a similar manner to example 144 and isolated as an TFA salt. H NMR (300MHz, CD3OD) δ ppm 8.74 (d, 1H), 8.69 (d, 1 H), 8.14 (d, 1H), 7.98 (s, 1H), 7.56-7.45 (m, 2H), 7.44 (d, 1H), 7.34 (dd, 1H); ES+ MS: 322.9 (M + 1).
[00767] Example 261 : 3'-{[(1-Hydroxy-2-oxo-1 ,2-dihydropyrido[2,3- cf]pyrimidin-4-yl)amino]methyl}-3-biphenylcarboxamide.
Figure imgf000137_0002
[00768] The title compound was prepared in a similar manner to example 144 and isolated as an TFA salt. H NMR (300MHz, DMSO-d6) δ ppm 9.15 (m, 1H), 8.70-8.68 (m, 1H), 8.60-8.8.57 (d, 1H), 8.17-8.12 (d, 2H), 7.88-7.76 (m, 3H), 7.66-7.38 (m, 5H), 7.31- 7.27 (m, 1H),4.81-4.79 (d, 2H); ES+ MS: 387.9 (M + 1).
[00769] Example 262: 4'-{[(1-Hydroxy-2-oxo-1 ,2-dihydropyrido[2,3- cf]pyrimidin-4-yl)amino]methyl}-4-biphenylcarboxylic acid.
Figure imgf000137_0004
[00770] The title compound was prepared in a similar manner to example 144 and isolated as an TFA salt. H NMR (300MHz, DMSO-d6) δ ppm 13.00 (brs, 1H),10.39 (s, 1H), 9.14 (m, 1H), 8.70 (d, 1H), 8.59 (m, 1H), 8.02 (d, 2H), 7.78-7.71(m, 4H), 7.49(d, 2H), 7.30 (m, 1H), 4.77 (s, 2H); ES+ MS: 388.9 (M + 1).
[00771] Example 263: A/-(4-{[(1-Hydroxy-2-oxo-1 ,2-dihydropyrido[2,3- cf]pyrimidin-4-yl)amino]methyl}phenyl)-2-phenylacetamide.
Figure imgf000137_0003
[00772] The title compound was prepared in a similar manner to example 144 and isolated as an TFA salt. H NMR (300MHz, CD3OD) δ ppm 8.72 (d, 1 H), 8.52 (m, 1 H),7.57-7.53 (m, 2H), 7.40-7.33 (m, 8H), 4.77 (s, 2H), 3.69 (s, 2H); ES+ MS: 402.0 (M + 1 ).
[00773] Example 264: 1 -Hydroxy-4-{[3'-(hydroxymethyl)-3- biphenylyl]amino}pyrido[2,3-d]pyrimidin-2(1 H)-one.
Figure imgf000138_0001
[00774] The title compound was prepared in a similar manner to example 144 and isolated as an TFA salt. H NMR (300MHz, DMSO-d6) δ ppm 8.83-8.75 (m, 2H), 8.03- 7.94 (m, 2H), 7.64-7.34 (m, 7H), 5.27 (s, 1 H), 4.60 (s, 2H); ES+ MS: 360.9 (M + 1 ).
[00775] Example 265: A/-(4-{[(1-Hydroxy-2-oxo-1 ,2-dihydropyrido[2,3- d]pyrimidin-4-yl)amino]methyl}phenyl)benzamide.
Figure imgf000138_0002
[00776] The title compound was prepared in a similar manner to example 144 and isolated as an TFA salt. H NMR (300MHz, DMSO-d6) δ ppm 10.36 (s, 1 H), 10.25 (s, 1 H), 9.04 (m, 1 H), 8.69 (d, 1 H), 8.57 (m, 1 H),7.97-7.94 (m, 2H), 7.76-7.74 (m, 2H), 7.60- 7.53 (m, 3H), 7.36-7.26 (, 3H), 4.70-4.68 (d, 2H); ES+ MS: 387.9 (M + 1 ).
[00777] Example 266: 4-{[4'-(Aminomethyl)-3-biphenylyl]amino}-1 - hydroxypyrido[2,3-d]pyrimidin-2(1 H)-one.
Figure imgf000138_0003
[00778] The title compound was prepared in a similar manner to example 144 and isolated as an TFA salt. H NMR (300MHz, DMSO-d6) δ ppm 8.86 (d, 1 H), 8.76 (d, 1 H), 8.31 (br, 3H), 8.16 (s, 1 H), 7.85 (m, 1 H), 7.75 (d, 2H), 7.59 (d, 2H), 7.52-7.49 (m, 2H), 7.40 (m, 1 H), 4.1 1 (m, 2H); ES+ MS: 359.9 (M + 1 ).
[00779] Example 267: Ethyl 4'-{[(1 -hydroxy-2-oxo-1 ,2-dihydropyrido[2,3- cf]pyrimidin-4-yl)amino]methyl}-4-biphenylcarboxylate.
Figure imgf000139_0001
[00780] The title compound was prepared in a similar manner to example 144 and isolated as an TFA salt. H NMR (300MHz, DMSO-d6) δ ppm 10.37 (s, 1 H), 9.12 (m, 1 H), 8.70 (m, 1 H), 8.58 (m, 1 H), 8.02 (m, 2H), 7.89 (d, 2H), 7.73 (d, 2H),7.49 (d, 2H), 7.29 (m, 1 H), 4.76 (d, 2H), 4.34 (q, 2H), 1 .35 (t, 3H); ES+ MS: 416.9 (M + 1 ).
[00781] Example 268: Ethyl 4'-{[(1 -hydroxy-2-oxo-1 ,2-dihydropyrido[2,3- cf]pyrimidin-4-yl)amino]methyl}-3-biphenylcarboxylate.
Figure imgf000139_0004
[00782] The title compound was prepared in a similar manner to example 144 and isolated as an TFA salt. H NMR (300MHz, DMSO-d6) δ ppm 10.38 (s, 1 H), 9.12 (m, 1 H), 8.70 (m, 1 H), 8.58 (m, 1 H), 8.17 (m, 1 H), 7.94 (m, 2H), 7.70-7.60 (m, 3H),7.49 (m, 2H), 7.30 (m, 1 H), 4.77 (d, 2H), 4.36 (q, 2H), 1 .35 (t, 3H); ES+ MS: 416.9 (M + 1 ).
[00783] Example 269: 1 -Hydroxy-4-[(4-pyridinylmethyl)amino]pyrido[2,3- d\ py ri m i d i n-2 ( 1 H)-o n e .
Figure imgf000139_0002
[00785] The title compound was prepared in a similar manner to example 144 and isolated as an TFA salt. H NMR (300MHz, DMSO-d6) δ ppm 9.25 (s, 1 H), 8.73-8.70 (m, 3H), 8.56 (d, 1 H), 7.74 (m, 2H), 7.32 (dd, 1 H), 4.86 (s, 2H); ES+ MS: 270.2 (M + 1 ).
[00786] Example 270: 4-{[4-(Dimethylamino)phenyl]amino}-1 - hydroxypyrido[2,3-d]pyrimidin-2(1 H)-one.
Figure imgf000139_0003
[00787] The title compound was prepared in a similar manner to example 144 and isolated as an TFA salt. H NMR (300MHz, DMSO-d6) δ ppm 10.41 (br, 1 H), 9.77 (s, 1H), 8.75 (m, 1H), 8.71-8.70 (m, 1H), 7.56 (d, 2H), 7.31 (dd, 1H), 6.78 (d, 2H), 2.92 (s, 6H); ES+ MS: 298.1 (M + 1).
[00788] Example 271: 4-{[(1-Hydroxy-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidin- 4-yl)amino]methyl}benzonitrile.
Figure imgf000140_0001
[00789] The title compound was prepared in a similar manner to example 144 and isolated as an TFA salt. H NMR (300MHz, DMSO-d6) δ ppm 10.38 (s, 1H), 9.15 (m, 1H), 8.70 (d, 1H), 8.54 (d, 1H), 7.81 (d, 2H), 7.54 (d, 2H), 7.30 (dd, 1H), 4.78 (d, 2H); ES+ MS: 293.9 (M + 1).
[00790] Example 272: 1-Hydroxy-4-[(1-naphthalenylmethyl)amino]pyrido[2,3- d\ py ri m i d i n-2 ( 1 H)-o n e .
Figure imgf000140_0002
[00791] The title compound was prepared in a similar manner to example 144 and isolated as an TFA salt. H NMR (300MHz, DMSO-d6) δ ppm 10.42 (s, 1 H), 9.09 (s, 1H), 8.70 (d, 1H), 8.62 (d, 1H), 8.17 (d, 1H), 7.80-7.61 (m, 2H), 7.60-7.44 (m, 4H), 7.29-7.24 (m, 1H), 5.16 (s, 2H); ES+ MS: 319.0 (M + 1).
[00792] Example 273: A/-(4-{[(1-Hydroxy-2-oxo-1 ,2-dihydropyrido[2,3- cf]pyrimidin-4- l amino meth l}phenyl)-2-pyridinecarboxamide.
Figure imgf000140_0003
[00793] The title compound was prepared in a similar manner to example 144 and isolated as an TFA salt. H NMR (300MHz, DMSO-d6) δ ppm 10.64 (s, 1 H), 10.36 (s, 1H), 9.04 (s, 1H), 8.76-8.68 (m, 2H), 8.58-8.55 (m, 1 H),8.18-8.08 (m, 2H), 7.89-7.87 (m, 2H), 7.71-7.68 (m, 1H), 7.39-7.35 (m, 2H), 7.30-7.25 (m, 1H), 4.70-4.68 (d, 2H); ES+ MS: 388.9 (M + 1).
[00794] Example 274: 1-Hydroxy-4-{[3-(4- morpholinyl)phenyl]amino}pyrido[2,3-d]pyrimidin-2(1H)-one.
Figure imgf000141_0001
[00795] The title compound was prepared in a similar manner to example 144 and isolated as an TFA salt. H NMR (300MHz, DMSO-d6) δ ppm 9.90 (br, 1 H), 8.74 (br, 2H), 7.36-7.26 (m, 4H), 6.80 (d, 1 H), 3.78 (br, 4H), 3.13 (br, 4H); ES+ MS: 340.0 (M + 1 ).
[00796] Example 275: 4'-{[(1 -Hydroxy-2-oxo-1 ,2-dihydropyrido[2,3- d]pyrimidin-4-yl)amino]methyl}-3-biphenylcarboxamide.
Figure imgf000141_0002
[00797] The title compound was prepared in a similar manner to example 144 and isolated as an TFA salt. H NMR (300MHz, DMSO-d6) δ ppm 9.14 (m, 1 H), 8.71-8.69 (m, 1 H), 8.60-8.57 (d, 1 H), 8.15-8.10 (d, 2H), 7.87-7.79 (m, 2H), 7.73-7.70 (d, 2H), 7.57- 7.44 (m, 4H), 7.31 (m, 1 H), 4.76 (d, 2H); ES+ MS: 387.9 (M + 1 ).
[00798] Example 276: 4'-{[(1 -Hydroxy-2-oxo-1 ,2-dihydropyrido[2,3- cf]pyrimidin-4-yl)amino]methyl}-4-biphenylcarboxamide.
Figure imgf000141_0003
[00799] The title compound was prepared in a similar manner to example 144 and isolated as an TFA salt. H NMR (300MHz, DMSO-d6) δ ppm 9.14 (m, 1 H), 8.71 (m, 1 H), 8.58 (d, 1 H), 8.03-7.95 (m, 3H), 7.76-7.70 (m, 4H), 7.49-7.46 (d, 2H), 7.40 (s, 1 H), 7.31 (m, 1 H), 4.76 (d, 2H); ES+ MS: 388.0 (M + 1 ).
[00800] Example 277: 1 -Hydroxy-4-{[(4-nitrophenyl)methyl]amino}pyrido[2,3- d]pyrimidin-2(1 H)-one.
Figure imgf000141_0004
[00801] The title compound was prepared in a similar manner to example 144 and isolated as an TFA salt. H NMR (300MHz, DMSO-d6) δ ppm 10.39 (s, 1 H), 9.20 (s, 1 H), 8.71 (m, 1 H), 8.55 (m, 1 H), 8.23-8.20 (m, 2H), 7.64-7.61 (m, 2H), 7.33-7.29 (m, 1 H), 4.82 (d, 2H); ES+ MS: 314.1 (M + 1 ). [00802] Example 278: 4-{[(4-Aminophenyl)methyl]amino}-1 -hydroxypyrido[2,3- d\ py ri m i d i n-2 ( 1 H)-o n e .
Figure imgf000142_0001
[00803] The title compound was prepared in a similar manner to example 144 and isolated as an TFA salt. H NMR (300MHz, DMSO-d6) δ ppm 9.02 (s, 1 H), 8.69 (m, 1 H), 8.55 (m, 1 H), 7.30-7.26 (m, 3H), 7.00-6.97 (m, 2H), 4.63 (d, 2H); ES+ MS: 284.2 (M + 1 ).
[00804] Example 279: A/-(4-{[(1-Hydroxy-2-oxo-1 ,2-dihydropyrido[2,3- cf]pyrimidin-4-yl)amino]methyl}phenyl)-3-pyridinecarboxamide.
Figure imgf000142_0002
[00805] The title compound was prepared in a similar manner to example 144 and isolated as an TFA salt. H NMR (300MHz, DMSO-d6) δ ppm 10.46 (s, 1 H), 9.13-9.08 (m, 2H), 8.78-8.59 (m, 2H), 8.69-8.56 (m, 1 H), 8.33 (m, 1 H), 7.76-7.73 (d, 2H), 7.62-7.59 (m, 1 H), 7.39-7.36 (m, 2H), 7.31 -7.27 (m, 1 H), 4.71 -4.69 (d, 2H); ES+ MS: 389.2 (M + 1 ).
[00806] Example 280: 4-{[(3-Aminophenyl)methyl]amino}-1 -hydroxypyrido[2,3- d\ py ri m i d i n-2 ( 1 H)-o n e .
Figure imgf000142_0003
[00807] The title compound was prepared in a similar manner to example 144 and isolated as an TFA salt. H NMR (300MHz, DMSO-d6) δ ppm 9.08 (s, 1 H), 8.70 (d, 1 H), 8.57 (d, 1 H), 7.30 (m, 1 H), 7.21 (t, 1 H), 6.95-6.80 (m, 3H), 4.66 (d, 2H); ES+ MS: 284.2 (M + 1 ).
[00808] Example 281 : 1 -Hydroxy-4-{[3'-(hydroxymethyl)-4- biphenylyl]amino}pyrido[2,3-d]pyrimidin-2(1 H)-one.
Figure imgf000142_0004
[00809] The title compound was prepared in a similar manner to example 144 and isolated as an TFA salt. H NMR (300MHz, DMSO-d6) δ ppm 10.58 (s,1H), 10.02 (s,1H), 8.85-8.75 (m, 2H), 7.97-7.95 (m, 2H), 7.75-7.57 (m, 4H), 7.46-7.31 (m, 3H), 5.25 (m, 1H), 4.59 (m, 2H).; ES+ MS: 361.1 (M + 1).
[00810] Example 282: 4-({4'-[(Dimethylamino)methyl]-4-biphenylyl}amino)-1- hydroxypyrido[2,3-d]pyrimidin-2(1H)-one.
Figure imgf000143_0001
[00811] The title compound was prepared in a similar manner to example 144 and isolated as an TFA salt. H NMR (300MHz, DMSO-d6) δ ppm 8.79-8.77 (m, 2H), 8.00- 7.97 (m, 2H), 7.83-7.73 (m, 4H), 7.62 (s, 2H),7.46-7.42 (m, 1H), 4.39 (s, 2H), 2.92 (s, 6H); ES+ MS: 388.2 (M + 1).
[00812] Example 283: 1-Hydroxy-4-{[1-(phenylcarbonyl)-4- piperidinyl]amino}pyrido[2,3-d]pyrimidin-2(1H)-one.
Figure imgf000143_0002
[00813] The title compound was prepared in a similar manner to example 144 and isolated as an TFA salt. H NMR (300MHz, CD3OD) δ ppm 8.70 (m,1H), 8.57 (s,1H), 7.51-7.44 (m, 5H), 7.34 (s, 1H), 4.72 (m, 1H), 4.53 (m, 1H), 3.81 (m, 1H), 3.32-3.06 (m, 2H), 2.19-2.06 (m, 2H), 1.70-1.63 (m, 2H); ES+ MS: 366.2 (M + 1).
[00814] Example 284: 4'-{[(1-Hydroxy-2-oxo-1 ,2-dihydropyrido[2,3- cf]pyrimidin-4-yl)amino]methyl}-3-biphenylcarboxylic acid.
Figure imgf000143_0003
[00815] The title compound was prepared in a similar manner to example 144 and isolated as an TFA salt. H NMR (300MHz, DMSO-d6) δ ppm 10.40 (br, 1H),9.13 (m, 1H), 8.70 (d, 1H), 8.58 (d, 1H), 8.17 (s, 1H), 7.92 (m, 2H),7.69 (d, 2H), 7.60 (m, 1H), 7.48 (d, 2H), 7.31-7.27 (m, 1H) 4.77 (d, 2H); ES+ MS: 388.9 (M + 1).
[00816] Example 285: 1-Hydroxy-4-{[4'-(hydroxymethyl)-3- biphenylyl]amino}pyrido[2,3-d]pyrimidin-2(1H)-one.
Figure imgf000144_0001
[00817] The title compound was prepared in a similar manner to example 144 and isolated as an TFA salt. H NMR (300MHz, DMSO-d6) δ ppm 8.81-8.74 (m, 2H), 8.05 (s, 1H), 7.88 (s, 1H), 7.66-7.64 (m, 2H), 7.51-7.38 (m, 5H), 5.24 (s, 1H), 4.56 (s, 2H); ES+ MS: 360.9 (M + 1).
[00818] Example 286: 4'-{[(1-Hydroxy-2-oxo-1 ,2-dihydropyrido[2,3- cf]pyrimidin-4-yl)amino]methyl}-2-biphenylcarbonitrile.
Figure imgf000144_0002
[00819] The title compound was prepared in a similar manner to example 144 and isolated as an TFA salt. H NMR (300MHz, DMSO-d6) δ ppm 10.37 (s, 1H), 9.14 (m, 1H), 8.69 (d,1H), 8.57 (d, 1H), 7.94 (d, 1H), 7.79 (m, 1H), 7.63-7.49 (m, 6H), 7.28 (m, 1H), 4.79 (d, 2H); ES+ MS: 370.0 (M + 1).
[00820] Example 287: 4-({[4'-(Aminomethyl)-4-biphenylyl]methyl}amino)-1- hydroxypyrido[2,3-d]pyrimidin-2(1H)-one.
Figure imgf000144_0003
[00821] The title compound was prepared in a similar manner to example 144 and isolated as an TFA salt. H NMR (300MHz, DMSO-d6) δ ppm 10.37 (br s, 1H), 9.13 (m, 1H), 8.69 (d,1H), 8.56 (d, 1H), 8.16 (brs, 2H), 7.73-7.64 (m, 4H), 7.54-7.44 (m, 4H), 7.28 (m, 1H), 4.73 (d, 2H), 4.07 (s, 2H); ES+ MS: 374.0 (M + 1).
[00822] Example 2884-({[2'-(aminomethyl)-3-biphenylyl]methyl}amino)-1- hydroxypyrido[2,3-d]pyrimidin-2(1H)-one.
Figure imgf000145_0001
[00823] The title compound was prepared in a similar manner to example 144 and isolated as an TFA salt. H NMR (300MHz, DMSO-d6) δ ppm 10.47 (br s, 1 H), 9.30 (s, 1 H), 8.70 (m, 1 H), 8.58 (m, 1 H), 8.37 (s, 2H), 7.64 (m, 1 H), 7.52-7.41 (m, 5H), 7.35-7.26 (m, 3H), 4.73 (d, 2H), 3.98 (s, 2H); ES+ MS: 374.0 (M + 1 ).
[00824] Example 289 4-({[4'-(Aminomethyl)-3-biphenylyl]methyl}amino)-1- hydroxypyrido[2,3-d]pyrimidin-2(1 H)-one.
Figure imgf000145_0002
[00825] The title compound was prepared in a similar manner to example 144 and isolated as an TFA salt. H NMR (300MHz, DMSO-d6) δ ppm 9.12 (t, 1 H), 8.69 (m, 1 H), 8.57 (m, 1 H), 8.17 (s, 2H), 7.73-7.71 (m, 3H), 7.60-7.53 (m, 3H), 7.45 (m, 1 H), 7.37 (m, 1 H), 7.28 (m, 1 H), 4.77 (d, 2H), 4.08 (d, 2H); ES+ MS: 374.0 (M + 1 ).
[00826] Example 290 4-({[3'-(Aminomethyl)-3-biphenylyl]methyl}amino)-1- hydroxypyrido[2,3-d]pyrimidin-2(1 H)-one.
Figure imgf000145_0003
[00827] The title compound was prepared in a similar manner to example 144 and isolated as an TFA salt. H NMR (300MHz, DMSO-d6) δ ppm 10.38 (br, s, 1 H), 9.12 (s, 1 H), 8.69 (d, 1 H), 8.57 (d, 1 H), 8.18 (s, 2H), 7.79 (s, 1 H), 7.71 -7.66 (m, 2H), 7.59-7.37 (m, 5H), 7.28 (m, 1 H), 4.77 (d, 2H), 4.1 1 (d, 2H); ES+ MS: 374.0 (M + 1 ).
[00828] Example 291 : 4'-{[(1 -Hydroxy-2-oxo-1 ,2-dihydropyrido[2,3- cf]pyrimidin-4-yl)amino]methyl}-3-biphenylcarbonitrile.
Figure imgf000145_0004
[00829] The title compound was prepared in a similar manner to example 144 and isolated as an TFA salt. H NMR (300MHz, DMSO-d6) δ ppm 10.36 (s, 1H), 9.11 (m, 1H), 8.69 (d,1H), 8.56 (d, 1H), 8.14 (s, 1H), 8.01 (d, 1H), 7.82 (d, 1H), 7.74-7.63 (m, 3H), 7.48 (d, 2H), 7.28 (m, 1H), 4.75 (d, 2H); ES+ MS: 369.9 (M + 1).
[00830] Example 292: Ethyl 3'-[(1-hydroxy-2-oxo-1 ,2-dihydropyrido[2,3- cf]pyrimidin-4-yl)amino]-4-biphenylcarboxylate.
Figure imgf000146_0001
[00831] The title compound was prepared in a similar manner to example 144 and isolated as an TFA salt. H NMR (300MHz, DMSO-d6) δ ppm 10.59 (s, 1 H), 10.04 (s, 1H), 8.81 (d, 1H), 8.76 (d, 1H), 8.13 (s, 1H), 8.08 (d, 2H), 7.98 (m, 1H), 7.84 (d, 2H), 7.56 (d, 2H), 7.38 (dd, 1H), 4.35 (q, 2H), 1.35 (t, 3H); ES+ MS: 403.0 (M + 1).
[00832] Example 293: A/-(3-{[(1-Hydroxy-2-oxo-1 ,2-dihydropyrido[2,3- cf]pyrimidin-4-yl)amino]methyl}phenyl)-2-phenylacetamide.
Figure imgf000146_0002
[00833] The title compound was prepared in a similar manner to example 144 and isolated as an TFA salt. H NMR (300MHz, DMSO-d6) δ ppm 10.15 (s, 1H), 9.11 (br, 1H), 8.69 (d, 1H), 8.56 (d, 1H), 7.56 (d, 1H), 7.50 (s, 1H), 7.31-7.22 (m, 7H), 7.03 (d, 1H), 4.67 (d, 2H), 3.60 (s, 2H); ES+ MS: 401.9 (M + 1).
[00834] Example 294: A/-(3-{[(1-Hydroxy-2-oxo-1 ,2-dihydropyrido[2,3- d]pyrimidin-4-yl)amino]methyl}phenyl)-2-pyridinecarboxamide.
Figure imgf000146_0003
[00835] The title compound was prepared in a similar manner to example 144 and isolated as an TFA salt. H NMR (300MHz, DMSO-d6) δ ppm 10.62 (s, 1H), 9.13 (t, 1H), 8.71 (t, 2H), 8.58 (d, 1H), 8.14 (d, 1H), 8.06 (m, 1H), 7.89-7.82 (m, 2H), 7.67 (m, 1H), 7.36-7.27 (m, 2H), 7.12 (d, 1H), 4.73 (d, 2H); ES+ MS: 388.9 (M + 1). [00836] Example 295: 4'-[(1-Hydroxy-2-oxo-1 ,2-dihydropyrido[2,3-d]pyrimidin- 4-yl)amino]-N-methyl-4-biphenylcarboxamide.
Figure imgf000147_0001
[00837] The title compound was prepared in a similar manner to example 144 and isolated as an TFA salt. H NMR (300MHz, DMSO-d6) δ ppm 10.02 (s, 1H), 8.84 (m, 1H), 8.76 (m, 1H), 8.49 (m, 1H), 8.00-7.92 (m, 4H), 7.81(d, 4H), 7.38 (m, 1H), 2.81 (d, 3H); ES+ MS: 387.9 (M + 1).
[00838] Example 296: 1-Hydroxy-4-[(4'-hydroxy-4- biphenylyl)amino]pyrido[2,3-d]pyrimidin-2(1H)-one.
Figure imgf000147_0002
[00839] The title compound was prepared in a similar manner to example 144 and isolated as an TFA salt. H NMR (300MHz, DMSO-d6) δ ppm 10.55 (s, 1 H), 9.95 (s, 1H), 9.54 (s, 1H), 8.81 (d, 1H), 8.74 (d, 1H), 7.87 (d, 2H), 7.63 (d, 2H), 7.53 (d, 2H), 7.36 (dd, 1H), 6.86 (d, 2H); ES+ MS: 347.0 (M + 1).
[00840] Example 297: 4-{[(3'-Chloro-4-biphenylyl)methyl]amino}-1- hydroxypyrido[2,3-d]pyrimidin-2(1H)-one.
Figure imgf000147_0003
[00841] The title compound was prepared in a similar manner to example 144 and isolated as an TFA salt. H NMR (300MHz, DMSO-d6) δ ppm 10.40 (s, 1H), 9.11 (m, 1H), 8.69 (m, 1H), 8.57 (d, 1H), 7.70-7.61 (m, 4H), 7.51-7.40 (m, 4H), 7.28 (m, 1H), 4.75 (d, 2H); ES+ MS: 378.9 (M + 1).
[00842] Example 298: 4'-{[(1-Hydroxy-2-oxo-1 ,2-dihydropyrido[2,3- cf]pyrimidin-4-yl)amino]methyl}-4-biphenylcarbonitrile.
Figure imgf000148_0001
[00843] The title compound was prepared in a similar manner to example 144 and isolated as an TFA salt. H NMR (300MHz, DMSO-d6) δ ppm 10.37 (s, 1H), 9.12 (m, 1H), 8.69 (m, 1H), 8.56 (m, 1H), 7.94-7.85 (m, 4H), 7.73 (d, 2H), 7.49 (d, 2H), 7.28 (m, 1H), 4.76 (d, 2H); ES+ MS: 369.9 (M + 1).
[00844] Example 299: 1-Hydroxy-4-({[4-(4- pyridinyl)phenyl]methyl}amino)pyrido[2,3-d]pyrimidin-2(1H)-one.
Figure imgf000148_0002
[00845] The title compound was prepared in a similar manner to example 144 and isolated as an TFA salt. H NMR (300MHz, DMSO-d6) δ ppm 9.17 (m, 1H), 8.80 (m, 1H), 8.70 (d, 1H), 8.57 (d, 1H), 8.07 (d, 2H), 7.91 (d, 2H), 7.56 (d, 2H), 7.30 (m, 1H), 4.78(d, 2H); ES+ MS: 346.0 (M + 1).
[00846] Example 300: 4'-[(1-Hydroxy-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidin- 4-yl)(methyl)amino]-4-biphenylcarboxamide.
Figure imgf000148_0003
[00847] The title compound was prepared in a similar manner to example 144 and isolated as an TFA salt. H NMR (300MHz, DMSO-d6) δ ppm 10.63 (s, 1H), 8.55 (m, 1H), 8.04 (s, 1H), 7.98 (d, 2H), 7.86-7.81 (m, 4H), 7.48 (d, 2H), 7.41 (s, 1H), 7.17 (m, 1H), 6.90 (m, 1H), 3.51 (s, 3H); ES+ MS: 387.9 (M + 1).
[00848] Example 301 : 3'-{[(1-Hydroxy-2-oxo-1 ,2-dihydropyrido[2,3- cf]pyrimidin-4-yl)amino]methyl}-3-biphenylcarbonitrile.
Figure imgf000148_0004
[00849] The title compound was prepared in a similar manner to example 144 and isolated as an TFA salt. H NMR (300MHz, DMSO-d6) δ ppm 10.36 (s, 1 H), 9.07 (t, 1 H), 8.68 (d, 1 H), 8.57 (d, 1 H), 8.15 (s, 1 H), 8.01 (d, 1 H), 7.84 (d, 1 H), 7.78 (s, 1 H), 7.70- 7.65 (m, 2H), 7.50-7.40 (m, 2H), 7.27 (m, 1 H); ES+ MS: 370.0 (M + 1 ).
[00850] Example 302: 4-{[4'-(Aminomethyl)-4-biphenylyl]amino}-1 - hydroxypyrido[2,3-d]pyrimidin-2(1 H)-one.
Figure imgf000149_0001
[00851] The title compound was prepared in a similar manner to example 144 and isolated as an TFA salt. H NMR (300MHz, DMSO-d6) δ ppm 10.04 (s, 1 H), 8.82 (d, 1 H), 8.76 (d, 1 H), 7.95 (d, 2H), 7.80-7.75 (m, 4H), 7.56 (d, 2H), 7.38 (dd, 1 H), 4.09 (s, 2H); ES+ MS: 360.0 (M + 1 ).
[00852] Example 303: 3'-{[(1 -Hydroxy-2-oxo-1 ,2-dihydropyrido[2,3- cf]pyrimidin-4-yl)amino]methyl}-2-biphenylcarbonitrile.
Figure imgf000149_0002
[00853] The title compound was prepared in a similar manner to example 144 and isolated as an TFA salt. H NMR (300MHz, DMSO-d6) δ ppm 9.16 (m, 1 H), 8.70 (d, 1 H), 8.58 (d, 1 H), 7.96 (d, 1 H), 7.82 (m, 1 H), 7.66-7.53 (m, 6H), 7.29 (m, 1 H), 4.82 (d, 2H); ES+ MS: 369.9 (M + 1 ).
[00854] Example 304: 3'-{[(1 -Hydroxy-2-oxo-1 ,2-dihydropyrido[2,3- cf]pyrimidin-4-yl)amino]methyl}-4-biphenylcarbonitrile.
Figure imgf000149_0003
[00855] The title compound was prepared in a similar manner to example 144 and isolated as an TFA salt. H NMR (300MHz, DMSO-d6) δ ppm 10.38 (s, 1 H), 9.09 (t, 1H), 8.68 (d, 1H), 8.56 (d, 1H), 7.94 (d, 2H), 7.87 (d, 2H), 7.77 (s, 1H), 7.66 (d, 1H), 7.51- 7.42 (m, 2H), 7.27 (m, 1H), 4.78 (d, 2H); ES+ MS: 370.0 (M + 1).
[00856] Example 305: 4'-[(1-Hydroxy-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidin- 4-yl)(methyl)amino]-3-biphenylcarboxylic acid.
Figure imgf000150_0001
[00857] The title compound was prepared in a similar manner to example 144 and isolated asanTFAsalt. H NMR (300MHz, DMSO-d6) δ ppm 13.15 (br., s, 1H), 10.68 (br., s, 1H), 8.54 (d, 1H), 8.21 (s, 1H), 7.99-7.94 (m, 2H), 7.80 (d, 2H), 7.61 (m, 1H), 7.48 (d, 2H), 7.15 (d, 1H), 6.89 (m, 1H), 3.51 (s, 3H); ES+ MS: 388.9 (M + 1).
[00858] Example 306: V-[2-(Dimethylamino)ethyl]-4'-{[(1-hydroxy-2-oxo-1 ,2- dihydropyrido[2,3-d]pyrimidin-4-yl)amino]methyl}-3-biphenylcarboxamide.
Figure imgf000150_0002
[00859] The title compound was prepared in a similar manner to example 144 and isolated as an TFA salt. H NMR (300MHz, DMSO-d6) δ ppm 10.39 (s, 1H), 9.17 (m, 1H), 8.70 (d, 1H), 8.58 (d, 1H), 8.14 (m, 1H), 7.85 (m, 2H), 7.70-7.50 (m, 5H), 7.32-7.28 (m, 1H), 4.76 (d, 2H), 3.64 (m, 2H), 3.41(m, 2H), 2.85 (m, 6H); ES+ MS: 458.9 (M + 1).
[00860] Example 307: N-[2-(Dimethylamino)ethyl]-4'-{[(1-hydroxy-2-oxo-1,2- dihydropyrido[2,3-d]pyrimidin-4-yl)amino]methyl}-4-biphenylcarboxamide.
Figure imgf000150_0003
[00861] The title compound was prepared in a similar manner to example 144 and isolated as an TFA salt. H NMR (300MHz, DMSO-d6) δ ppm 10.39 (s, 1H), 9.16 (m, 1H), 8.70 (d, 1H), 8.58 (d, 1H), 8.04 (d, 1H), 7.96 (m, 1H), 7.80-7.71 (m, 4H), 7.48 (d, 2H), 7.32-7.28 (m, 1H), 4.76 (d, 2H), 3.62 (m, 2H), 2.82 (m, 6H); ES+ MS: 459.0 (M + 1).
[00862] Example 308: 4-{[(3',5'-Dichloro-4-biphenylyl)methyl]amino}-1- hydroxypyrido[2,3-d]pyrimidin-2(1H)-one.
Figure imgf000151_0001
[00863] The title compound was prepared in a similar manner to example 144 and isolated as an TFA salt. H NMR (300MHz, DMSO-d6) δ ppm 10.38 (s, 1H), 9.13 (m, 1H), 8.70 (m, 1H), 8.57 (m, 1H), 773 (m, 4H), 7.60 (s, 1H), 7.47 (m, 2H), 7.30 (m, 1H), 4.76 (d, 2H); ES+ MS: 412.8 (M + 1).
[00864] Example 309: 4-[(4-Biphenylylmethyl)amino]-1-hydroxypyrido[2,3- d\ py ri m i d i n-2 ( 1 H)-o n e .
Figure imgf000151_0002
[00865] The title compound was prepared in a similar manner to example 144 and isolated as an TFA salt. H NMR (300MHz, DMSO-d6) δ ppm 10.36 (s, 1H), 9.10 (s, 1H), 8.70-8.68 (m, 1H), 8.58-8.56 (d, 1H), 7.66-7.62 (m, 4H), 7.48-7.26 (m, 6H), 4.75-4.74 (d, 2H); ES+ MS: 344.9 (M + 1).
[00866] Example 310: 3'-{[(1-Hydroxy-2-oxo-1,2-dihydropyrido[2,3- cf]pyrimidin-4-yl)amino]methyl}-V-phenyl-3-biphenylcarboxamide.
Figure imgf000151_0003
[00867] The title compound was prepared in a similar manner to example 144 and isolated as an TFA salt. H NMR (300MHz, DMSO-d6) δ ppm 10.36 (s, 1H), 9.14 (m, 1H), 8.70-8.69 (m, 1H), 8.60-8.58 (d, 1H), 8.21 (s, 1H), 7.95-7.78 (m, 5H), 7.70-7.61 (m, 2H), 7.52-7.26 (m, 5H), 7.15-7.10 (m, 1H), 4.82-4.80 (d, 2H); ES+ MS: 463.9 (M + 1).
[00868] Example 311 : V-[2-(Dimethylamino)ethyl]-3'-{[(1-hydroxy-2-oxo-1 ,2- dihydropyrido[2,3-d]pyrimidin-4-yl)amino]methyl}-3-biphenylcarboxamide.
Figure imgf000151_0004
[00869] The title compound was prepared in a similar manner to example 144 and isolated as an TFA salt. H NMR (300MHz, DMSO-d6) δ ppm 9.40 (s, 1H), 9.18 (m, 1 H), 8.83 (s, 1 H), 8.70 (m, 1 H), 8.58 (d, 1 H), 8.14 (s, 1 H), 7.86-7.78 (m, 3H), 7.63-7.39 (m, 4H), 7.30 (m, 1 H), 4.79 (d, 2H), 3.66 (m, 2H), 3.32 (m, 2H), 2.88 (s, 6H); ES+ MS: 458.9 (M + 1 ).
[00870] Example 312: 1-Hydroxy-4-[(2-naphthalenylmethyl)amino]pyrido[2,3- d]pyrimi
Figure imgf000152_0001
[00871] The title compound was prepared in a similar manner to example 144 and isolated as an TFA salt. H NMR (300MHz, DMSO-d6) δ ppm 10.40 (s, 1 H), 9.18 (s, 1 H), 8.72 (d, 1 H), 8.62 (d, 1 H), 7.93-7.85 (m, 4H), 7.57-7.49 (m, 3H), 7.33-7.28 (m, 1 H), 4.90 (d, 2H); ES+ MS: 319.0 (M + 1 ).
[00872] Example 313: 1-Hydroxy-4-({[3'-(trifluoromethyl)-4- biphenylyl]methyl}amino)pyrido[2,3-d]pyrimidin-2(1 H)-one.
Figure imgf000152_0002
[00873] The title compound was prepared in a similar manner to example 144 and isolated as an TFA salt. H NMR (300MHz, DMSO-d6) δ ppm 10.20 (br s, 1 H), 9.14 (m, 1 H), 8.70 (m, 1 H), 8.58 (m, 1 H), 7.97 (m, 2H), 7.72 (m, 4H), 7.49 (m, 2H), 7.32-7.27 (m, 1 H), 4.77 (d, 2H); ES+ MS: 412.9 (M + 1 ).
[00874] Example 314: 1-Hydroxy-4-[(4-{[2-
(methyloxy)ethyl]amino}phenyl)amino]pyrido[2,3-d]pyrimidin-2(1 H)-one.
Figure imgf000152_0003
[00875] The title compound was prepared in a similar manner to example 144 and isolated as an TFA salt. H NMR (300MHz, DMSO-d6) δ ppm 10.45 (s, 1 H), 9.73 (s, 1 H), 8.73-8.69 (m, 2H), 7.43 (d, 2H), 7.31 (m, 1 H), 6.64 (d, 2H), 3.51 (t, 2H), 3.30 (s, 3H), 3.23 (t, 2H); ES+ MS: 328.0 (M + 1 ). [00876] Example 315: 4'-[(1-Hydroxy-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidin- 4-yl)amino]-A/-phenyl-3-biphenylcarboxamide.
Figure imgf000153_0001
[00877] The title compound was prepared in a similar manner to example 144 and isolated as an TFA salt. H NMR (300MHz, DMSO-d6) δ ppm 10.62 (s, 1 H), 10.37 (s, 1H), 10.05 (s, 1H), 8.84 (m, 1H), 8.77-8.76 (m, 1H), 8.27 (s, 1H), 8.02-7.80 (m, 8H), 7.64 (m, 1H), 7.41-7.36 (m, 3H), 7.14 (m, 1H); ES+ MS: 449.9 (M + 1).
[00878] Example 316: 1-Hydroxy-4-({[3-(3- pyridinyl)phenyl]methyl}amino)pyrido[2,3-d]pyrimidin-2(1H)-one.
Figure imgf000153_0002
[00879] The title compound was prepared in a similar manner to example 144 and isolated as an TFA salt. H NMR (300MHz, DMSO-d6) δ ppm 9.18 (s, 1H), 9.08 (s, 1H), 8.76 (m, 1H), 8.70 (m, 1H), 8.59 (m, 1H), 8.50 (m, 1H), 7.86-7.83 (m, 2H), 7.72 (m, 1H), 7.56-7.47 (m, 2H), 7.30 (m, 1H) 4.81 (s, 2H); ES+ MS: 346.0 (M + 1).
[00880] Example 317: 1-Hydroxy-4-({[3-(4- pyridinyl)phenyl]methyl}amino)pyrido[2,3-d]pyrimidin-2(1H)-one.
Figure imgf000153_0003
[00881] The title compound was prepared in a similar manner to example 144 and isolated as an TFA salt. H NMR (300MHz, DMSO-d6) δ ppm 9.17 (s, 1H), 8.86 (s, 2H), 8.70 (m, 1H), 8.59-8.57 (m, 1H), 8.16-8.15 (m, 2H), 7.97 (s, 1H), 7.86 (s, 1H), 7.58-7.57 (m, 2H), 7.30 (m, 1H), 4.82 (s, 2H); ES+ MS: 346.0 (M + 1).
[00882] Example 318: 1-Hydroxy-4-({[4-(3- pyridinyl)phenyl]methyl}amino)pyrido[2,3-d]pyrimidin-2(1H)-one.
Figure imgf000154_0001
[00883] The title compound was prepared in a similar manner to example 144 and isolated as an TFA salt. H NMR (300MHz, DMSO-d6) δ ppm 9.18 (brs, 1H), 9.03 (s, 1H), 8.70 (m, 2H), 8.58 (m, 1H), 8.36 (m, 1H), 7.78-7.69 (m, 3H), 7.51 (m, 2H), 7.30 (m, 1H), 4.77 (d, 2H); ES+ MS: 346.0 (M + 1).
[00884] Example 319: V-[2-(Dimethylamino)ethyl]-3'-{[(1-hydroxy-2-oxo-1,2- dihydropyrido[2,3-d]pyrimidin-4-yl)amino]methyl}-4-biphenylcarboxamide.
Figure imgf000154_0002
[00885] The title compound was prepared in a similar manner to example 144 and isolated as an TFA salt. H NMR (300MHz, DMSO-d6) δ ppm 9.35 (s, 1H), 9.14 (m, 1H), 8.76-8.69 (m, 2H), 8.57 (d, 1H), 7.98-7.95 (m, 2H), 7.82-7.77 (m, 3H), 7.64 (d, 1H), 7.50-7.39 (m, 2H), 7.29 (m, 1H), 4.78 (d, 2H), 3.63 (m, 2H), 3.29 (m, 2H), 2.87 (m, 6H); ES+ MS: 458.9 (M + 1).
[00886] Example 320: 3'-{[(1-Hydroxy-2-oxo-1 ,2-dihydropyrido[2,3- d]pyrimidin-4-yl)amino]methyl}-N-phenyl-4-biphenylcarboxamide.
Figure imgf000154_0003
[00887] The title compound was prepared in a similar manner to example 144 and isolated as an TFA salt. H NMR (300MHz, DMSO-d6) δ ppm 10.40 (s, 1 H), 10.30 (s, 1H), 9.12 (m, 1H), 8.69 (m, 1H), 8.59 (d, 1H), 8.08-8.05 (d, 2H), 7.85-7.79 (m, 5H), 7.67 (d, 1H), 7.51-7.27 (m, 5H), 7.11 (m, 1H), 4.80 (d, 2H); ES+ MS: 463.8 (M + 1).
[00888] Example 321 : 4'-{[(1-Hydroxy-2-oxo-1 ,2-dihydropyrido[2,3- cf]pyrimidin-4-yl)amino]methyl}-V-phenyl-3-biphenylcarboxamide.
Figure imgf000155_0001
[00889] The title compound was prepared in a similar manner to example 144 and isolated as an TFA salt. H NMR (300MHz, DMSO-d6) δ ppm 10.36 (m, 2H), 9.14 (m, 1H), 8.70 (d, 1H), 8.58 (d, 1H), 8.20 (s, 1H), 7.94-7.74 (m, 6H), 7.65-7.49 (m, 3H), 7.40-7.27 (m, 3H), 7.12 (m, 1H), 4.77 (d, 2H); ES+ MS: 463.9 (M + 1).
[00890] Example 322: 1-Hydroxy-4-({[4'-(trifluoromethyl)-3- biphenylyl]methyl}amino)pyrido[2,3-d]pyrimidin-2(1H)-one.
Figure imgf000155_0002
[00891] The title compound was prepared in a similar manner to example 144 and isolated as an TFA salt. H NMR (300MHz, DMSO-d6) δ ppm 10.39 (s, 1H), 9.11 (s, 1H), 8.79 (m, 1H), 8.58 (m, 1H), 7.90-7.81 (m, 4H), 7.76 (s, 1H), 7.65 (m, 1H), 7.52-7.42 (m, 2H), 7.28 (m, 1H), 4.80 (m, 2H); ES+ MS: 412.9 (M + 1).
[00892] Example 323: 4'-[(1-Hydroxy-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidin- 4-yl)(methyl)amino]-3-biphenylcarboxamide.
Figure imgf000155_0003
[00893] The title compound was prepared in a similar manner to example 144 and isolated as an TFA salt. H NMR (300MHz, DMSO-d6) δ ppm 8.55 (m, 1 H), 8.22 (s, 1H), 8.13 (s, 1H), 7.91-7.84 (m, 4H), 7.60-7.46 (m, 4H), 7.17 (m, 1H), 6.90 (m, 1H), 3.52 (s, 3H); ES+ MS: 387.9 (M + 1).
[00894] Example 324: 4-{[(4'-Chloro-3-biphenylyl)methyl]amino}-1- hydroxypyrido[2,3-d]pyrimidin-2(1H)-one.
Figure imgf000155_0004
[00895] The title compound was prepared in a similar manner to example 144 and isolated as an TFA salt. H NMR (300MHz, DMSO-d6) δ ppm 9.09 (m, 1 H), 8.69 (m, 1 H), 8.57 (m, 1 H), 7.70-7.68 (m, 3H), 7.59-7.37 (m, 5H), 7.28 (m, 1 H), 4.78 (m, 2H); ES+ MS: 378.9 (M + 1 ).
[00896] Example 325: A/-(3-{[(1-Hydroxy-2-oxo-1 ,2-dihydropyrido[2,3- cf]pyrimidin-4-yl)amino]methyl}phenyl)benzamide.
Figure imgf000156_0001
[00897] The title compound was prepared in a similar manner to example 144 and isolated as an TFA salt. H NMR (300MHz, DMSO-d6) δ ppm 10.38 (s, 1 H), 10.26 (s, 1 H), 9.12 (s, 1 H), 8.70 (d, 1 H), 8.58 (s, 1 H),7.94-7.92 (m, 2H), 7.75-7.23 (m, 2H), 7.56-7.52 (m, 3H), 7.35-7.30 (m, 2H), 7.1 1 (m, 1 H), 4.73 (s, 2H); ES+ MS: 387.9 (M + 1 ).
[00898] Example 326: N-(3-{[(1 -Hydroxy-2-oxo-1 ,2-dihydropyrido[2,3- d]pyrimidin-4-yl)amino]methyl}phenyl)-3-pyridinecarboxamide.
Figure imgf000156_0002
[00899] The title compound was prepared in a similar manner to example 144 and isolated as an TFA salt. H NMR (300MHz, DMSO-d6) δ ppm 10.49 (s, 1 H), 9.20-9.1 1 (m, 2H), 8.79 (m, 1 H), 8.71 (m, 1 H), 8.59 (m, 1 H),8.33 (m, 1 H), 7.74-7.72 (m, 2H), 7.63 (m, 1 H), 7.36-7.29 (m, 2H), 7.14 (m, 1 H), 4.74 (d,2H); ES+ MS: 388.9 (M + 1 ).
[00900] Example 327: 4-{[(3',5'-Dichloro-3-biphenylyl)methyl]amino}-1 - hydroxypyrido[2,3-d]pyrimidin-2(1 H)-one.
Figure imgf000156_0003
[00901] The title compound was prepared in a similar manner to example 144 and isolated as an TFA salt. H NMR (300MHz, DMSO-d6) δ ppm 10.39 (s, 1 H), 9.07 (m, 1 H), 8.69 (m, 1 H), 8.57 (d, 1 H), 7.79-7.74 (m, 3H), 7.67-7.62 (m, 2H), 7.49-7.40 (m, 2H), 7.28 (m, 1 H), 4.77 (d, 2H); ES+ MS: 412.9 (M + 1 ). [00902] Example 328: 1-Hydroxy-4-{[(4-{[2-
(methyloxy)ethyl]amino}phenyl)methyl]amino}pyrido[2,3-c |pyrimidin-2(1 H)-
Figure imgf000157_0003
[00903] The title compound was prepared in a similar manner to example 144 and isolated as an TFA salt. H NMR (300MHz, DMSO-d6) δ ppm 10.33 (s, 1 H), 8.88 (br, 1 H), 8.66 (d, 1 H), 8.54 (d, 1 H), 7.24 (dd, 1 H), 7.09 (d, 2H), 6.56 (d, 2H), 5.52 (s, 1 H), 4.53 (d, 2H), 3.47 (t, 2H), 3.27 (s, 3H), 3.20-3.10 (m, 2H); ES+ MS: 342.0 (M + 1 ).
[00904] Example 329: 1-Hydroxy-4-[(3-{[2-
(methyloxy)ethyl]amino}phenyl)amino]pyrido[2,3-d]pyrimidin-2(1 H)-one.
Figure imgf000157_0001
[00905] The title compound was prepared in a similar manner to example 144 and isolated as an TFA salt. H NMR (300MHz, DMSO-d6) δ ppm 10.51 (s, 1 H), 9.71 (s, 1 H), 8.79-8.72 (m, 2H), 7.34 (m, 1 H), 7.12-7.00 (m, 3H), 6.45 (m, 1 H), 3.52 (m, 2H), 3.30 (s, 3H), 3.20 (m, 2H); ES+ MS: 328.0 (M + 1 ).
[00906] Example 330: 1-Hydroxy-4-{[4-(4- morpholinyl)phenyl]amino}pyrido[2,3-d]pyrimidin-2(1 H)-one.
Figure imgf000157_0002
[00907] The title compound was prepared in a similar manner to example 144 and isolated as an TFA salt. H NMR (300MHz, DMSO-d6) δ ppm 9.82 (s, 1 H), 8.76-8.71 (m, 2H), 7.65-7.62 (m, 2H), 7.34 (m, 1 H), 7.02-6.99 (m, 2H), 3.78-3.75 (m, 4H), 3.14-3.1 1 (m, 4H); ES+ MS: 339.9 (M + 1 ).
[00908] Example 331 : 3'-{[(1 -Hydroxy-2-oxo-1 ,2-dihydropyrido[2,3- cf]pyrimidin-4-yl)amino]methyl}-3-biphenylcarboxylic acid.
Figure imgf000158_0001
[00909] The title compound was prepared in a similar manner to example 144 and isolated as an TFA salt. H NMR (300MHz, DMSO-d6) δ ppm 13.1 1 (s, 1 H), 9.12 (m, 1 H), 8.69 (m, 1 H), 8.58 (m, 1 H), 8.20 (s, 1 H), 8.00-7.90 (m, 2H), 7.73 (s, 1 H), 7.64-7.58 (m, 2H), 7.50-7.39 (m, 2H), 7.28 (m, 1 H), 4.80 (d, 2H); ES+ MS: 388.9 (M + 1 ).
[00910] Example 332: 1 -Hydroxy-4-{[3-(1 -methyl-1 H-pyrazol-4- yl)phenyl]amino}pyrido[2,3-d]pyrimidin-2(1 H)-one
Figure imgf000158_0002
[00911] The title compound was prepared in a similar manner to example 238 to provide a yellow solid (3.8 mg, 6.0 % yield). H NMR (400 MHz, DMSO-d6) δ ppm 10.60 (s, 1 H), 9.96 (s, 1 H), 8.78 (d, J = 8.0 Hz, 1 H), 8.74 (t, J = 4.8 Hz, 1 H), 8.1 1 (s, 1 H), 7.82 (s, 1 H), 7.80 (d, J = 8.0 Hz, 1 H), 7.42 (t, J = 8.0 Hz, 1 H), 7.39 (d, J = 8.0 Hz, 1 H), 7.39 (s, 1 H), 7.36 (dd, J = 4.8, 8.0 Hz, 1 H), 3.88 (s, 3 H); ES+ MS: 335 (M+1 ); HRMS (ES+) calcd for C17H15N602 (M + 1 ): 335.1256. Found: 335.1258.
[00912] Example 333: 1 -Hydroxy-4-{[4-(5-pyrimidinyl)phenyl]amino}pyrido[2,3- d\ py ri m i d i n-2 ( 1 H)-o n e .
Figure imgf000158_0003
[00913] The title compound was prepared in a similar manner to example 238 to provide a yellow solid (8.5 mg, 10.3 % yield) as a trifluoroacetate salt. H NMR (400 MHz, DMSO-d6) δ ppm 10.62 (s, 1 H), 10.05 (s, 1 H), 9.19 (s, 2 H), 9.18 (s, 1 H), 8.82 (d, J = 8.0 Hz, 1 H), 8.76 (d, J = 4.8 Hz, 1 H), 8.04 (d, J = 8.0 Hz, 2 H), 7.90 (d, J = 8.0 Hz, 2 H), 7.38 (dd, J = 4.8, 8.0 Hz, 1 H); ES+ MS: 333 (M+1 ); HRMS (ES+) calcd for C17H13N602 (M + 1 ): 333.1 100. Found: 333.1098.
[00914] Example 334: 1 -Hydroxy-4-{[4-(1 -methyl-1 H-imidazol-2- yl)phenyl]amino}pyrido[2,3-c/]pyrimidin-2(1 H)-one.
Figure imgf000159_0001
[00915] The title compound was prepared in a similar manner to example 238 to provide a yellow solid (1 .1 mg, 1 .3 % yield) as a trifluoroacetate salt. H NMR (400 MHz, CD3OD) δ ppm 8.76 (d, J = 4.8 Hz, 1 H), 8.76 (d, J = 8.0 Hz, 1 H), 8.23 (d, J = 8.0 Hz, 2 H), 7.76 (d, J = 8.0 Hz, 2 H), 7.63 (s, 1 H), 7.60 (s, 1 H), 7.42 (dd, J = 4.8, 8.0 Hz, 1 H), 3.93 (s, 3 H); ES+ MS: 335 (M+1 ); H RMS (ES+) calcd for C17H15N602 (M + 1 ): 335.1256. Found: 335.1257.
[00916] Example 335: 1 -Hydroxy-4-{[4-(1 -methyl-1 H-pyrazol-4- yl)phenyl]amino}pyrido[2,3-d]pyrimidin-2(1 H)-one.
Figure imgf000159_0002
[00917] The title compound was prepared in a similar manner to example 238 to provide a yellow solid (5.0 mg, 6.0 % yield) as a trifluoroacetate salt. H NMR (400 MHz, DMSO-d6) δ ppm 10.55 (s, 1 H), 9.92 (s, 1 H), 8.79 (d, J = 8.0 Hz, 1 H), 8.74 (d, J = 4.8 Hz, 1 H), 8.13 (s, 1 H), 7.87 (s, 1 H), 7.80 (d, J = 8.0 Hz, 2 H), 7.60 (d, J = 8.0 Hz, 2 H), 7.35 (dd, J = 4.8, 8.0 Hz, 1 H), 3.87 (s, 3 H); ES+ MS: 335 (M+1 ); HRMS (ES+) calcd for
C17H15N602 (M + 1 ): 335.1256. Found: 335.1255.
[00918] Example 336: 1 -Hydroxy-4-{[3-(1 -methyl-1 H-imidazol-2- yl)phenyl]amino}pyrido[2,3-d]pyrimidin-2(1 H)-one.
Figure imgf000159_0003
[00919] The title compound was prepared in a similar manner to example 238 to provide a yellow solid (4.0 mg, 4.5 % yield) as a trifluoroacetate salt. H NMR (400 MHz, DMSO-d6) δ ppm 10.66 (s, 1 H), 10.22 (s, 1 H), 8.81 (d, J = 8.0 Hz, 1 H), 8.78 (d, J = 4.8 Hz, 1 H), 8.42 (s, 1 H), 7.98 (d, J = 8.0 Hz, 1 H), 7.80 (s, 1 H), 7.72 (s, 1 H), 7.69 (t, J = 8.0 Hz, 1 H), 7.56 (d, J = 8.0 Hz, 1 H), 7.40 (dd, J = 4.8, 8.0 Hz, 1 H), 3.94 (s, 3 H); ES+ MS: 335 (M+1 ); HRMS (ES+) calcd for C17H15N602 (M + 1 ): 335.1256. Found: 335.1256.
[00920] Example 337: {4-[(1-Hydroxy-2-oxo-1 ,2-dihydropyrido[2,3-d]pyrimidin- 4-yl)amino]phenyl}boronic acid.
OH
Figure imgf000160_0001
[00921] The title compound was prepared in a similar manner to example 238 to provide a yellow solid (15.0 mg, 15.2 % yield) as a hydrochloride salt. H NMR (400 MHz, DMSO-c 6) δ ppm 10.64 (br, 1 H), 9.98 (s, 1 H), 8.85 (d, J = 8.0 Hz, 1 H), 8.76 (d, J = 4.0 Hz, 1 H), 7.94 (d, J = 8.0 Hz, 2 H), 7.72 (d, J = 8.0 Hz, 2 H), 7.38 (dd, J = 4.0, 8.0 Hz, 1 H); ES+ MS: 299 (M+1 ). ES+ MS: 299 (M+1 ); HRMS (ES+) calcd for C13H12N4O4B (M + 1 ): 299.0952. Found: 299.0952.
[00922] Example 338: {3-[(1-Hydroxy-2-oxo-1 ,2-dihydropyrido[2,3-d]pyrimidin- 4-yl)amino]phenyl}boronic acid.
OH
Figure imgf000160_0002
[00923] The title compound was prepared in a similar manner to example 238 to provide a yellow solid (20.0 mg, 20.3 % yield) as a trifluoroacetate salt. H NMR (400 MHz, DMSO-c 6) δ ppm 10.52 (br, 1 H), 9.95 (s, 1 H), 8.80 (d, J = 8.0 Hz, 1 H), 8.73 (d, J = 4.0 Hz, 1 H), 8.1 1 (br, 2 H), 7.95 (s, 1 H), 7.93 (d, J = 8.0 Hz, 1 H), 7.63 (d, J = 8.0 Hz, 1 H), 7.39 (t, J = 8.0 Hz, 1 H), 7.34 (dd, J = 4.0, 8.0 Hz, 1 H); ES+ MS: 299 (M+1 ); H RMS (ES+) calcd for C13H12N4O4B (M + 1 ): 299.0952. Found: 299.0953.
[00924] Example 339: 5-{4-[(1 -Hydroxy-2-oxo-1 ,2-dihydropyrido[2,3- c ]pyrimidin-4-yl)amino]phenyl}-2-pyridinecarbonitrile.
Figure imgf000160_0003
[00925] The title compound was prepared in a similar manner to example 238 to provide a yellow solid (10.0 mg, 14.8 % yield) as a trifluoroacetate salt. H NMR (400 MHz, DMSO-d6) δ ppm 10.63 (s, 1 H), 10.10 (br, 1 H), 9.16 (d, J = 4.0 Hz, 1 H), 8.98 (d, J = 1.6 Hz, 1 H), 8.76 (s, 1 H), 8.13 (d, J = 4.8 Hz, 1 H), 8.06 (d, J = 8.8 Hz, 2 H), 7.95 (d, J = 8.8 Hz, 2 H), 7.88 (d, J = 4.8 Hz, 1 H), 7.39 (dd, J = 3.2, 8.0 Hz, 1 H); ES+ MS: 357 (M+1 ).
[00926] Example 340: 5-{4-[(1 -Hydroxy-2-oxo-1 ,2-dihydropyrido[2,3- c ]pyrimidin-4-yl)amino]phenyl}-3-pyridinecarbonitrile.
Figure imgf000161_0001
[00927] The title compound was prepared in a similar manner to example 238 to provide a yellow solid (20.0 mg, 29.6 % yield) as a trifluoroacetate salt. H NMR (400 MHz, DMSO-d6) δ ppm 10.62 (br, 1 H), 10.04 (s, 1 H), 9.25 (d, J = 4.0 Hz, 1 H), 9.00 (d, J = 1.6 Hz, 1 H), 8.82 (d, J = 8.0 Hz, 1 H), 8.76 (d, J = 4.8 Hz, 1 H), 8.70 (m, 1 H), 8.04 (d, J = 8.8 Hz, 2 H), 7.91 (d, J = 8.8 Hz, 2 H), 7.38 (dd, J = 3.2, 8.0 Hz, 1 H); ES+ MS: 357 (M+1 ).
[00928] Example 341 : 4-{[4-(5-Fluoro-3-pyridinyl)phenyl]amino}-1 - hydroxypyrido[2,3-c |pyrimidin-2(1 H)-one.
Figure imgf000161_0002
[00929] The title compound was prepared in a similar manner to example 238 to provide a yellow solid (33.0 mg, 49.7 % yield) as a trifluoroacetate salt. H NMR (400 MHz, DMSO-d6) δ ppm 10.61 (br, 1 H), 10.03 (s, 1 H), 8.86 (s, 1 H), 8.82 (d, J = 8.0 Hz, 1 H), 8.76 (d, J = 4.0 Hz, 1 H), 8.76 (d, J = 2.4 Hz, 1 H), 8.02 (d, J = 8.8 Hz, 2 H), 7.87 (d, J = 8.8 Hz, 2 H), 7.38 (dd, J = 4.8, 8.0 Hz, 1 H), 6.79 (d, J = 8.8 Hz, 1 H); ES+ MS: 350 (M+1 ).
[00930] Example 342: 1 -Hydroxy-4-{[3-(5-pyrimidinyl)phenyl]amino}pyrido[2,3- d\ py ri m i d i n-2 ( 1 H)-o n e .
Figure imgf000162_0001
[00931] The title compound was prepared in a similar manner to example 238 to provide a yellow solid (8.6 mg, 10.0 % yield) as a trifluoroacetate salt. H NMR (400 MHz, DMSO-d6) δ ppm 10.61 (s, 1 H), 10.09 (s, 1 H), 9.23 (s, 1 H), 9.15 (s, 1 H), 9.14 (s, 1 H), 8.81 (d, J = 4.8 Hz, 1 H), 8.76 (d, J = 8.0 Hz, 1 H), 8.20 (s, 1 H), 7.96 (d, J = 4.8 Hz, 1 H), 7.63 (d, J = 4.8 Hz, 1 H), 7.60 (t, J = 4.8 Hz, 1 H), 7.38 (dd, J = 4.8, 8.0 Hz, 1 H); ES+ MS: 333 (M+1 ); HRMS (ES+) calcd for C17H13N602 (M + 1 ): 333.1 100. Found: 333.1 102.
[00932] Example 343: A/-{4'-[(1 -hydroxy-2-oxo-1 ,2-dihydropyrido[2,3- <^pyrimidin-4-yl)amino]-4-biphenylyl}-ATmethylurea.
Figure imgf000162_0002
[00933] The title compound was prepared in a similar manner to example 216 to provide a brown solid (89.5 mg, 93.5 % yield) as a trifluoroacetate salt. H NMR (400 MHz, DMSO-d6) δ ppm 10.36 (s, 1 H), 9.24 (d, J = 4.4 Hz, 1 H), 9.12 (d, J = 8.0 Hz, 1 H), 8.72 (s, 1 H), 7.96 (d, J = 8.4 Hz, 2 H), 7.65 (d, J = 8.4 Hz, 2 H), 7.56 (d, J = 8.8 Hz, 2 H), 7.50 (d, J = 8.8 Hz, 2 H), 7.34 (dd, J = 4.8, 8.0 Hz, 1 H), 6.49 (d, J = 4.4 Hz, 1 H), 2.64 (d, J = 4.4 Hz, 3 H); ES+ MS: 403 (M+1 ). HRMS (ES+) calcd for C2i H19N603 (M + 1 ): 403.1519. Found: 403.1516.
[00934] Example 344: A/-{3'-[(1 -hydroxy-2-oxo-1 ,2-dihydropyrido[2,3- <^pyrimidin-4-yl)amino]-4-biphenylyl}-ATmethylurea.
Figure imgf000162_0003
[00935] The title compound was prepared in a similar manner to example 238 to provide a yellow solid (49.4 mg, 51 .6 % yield) as a trifluoroacetate salt. H NMR (400 MHz, DMSO-d6) δ ppm 9.98 (s, 1 H), 8.81 (d, J = 8.0 Hz, 1 H), 8.75 (d, J = 4.4 Hz, 1 H),
8.64 (s, 1 H), 7.99 (s, 1 H), 7.81 (d, J = 7.2 Hz, 1 H), 7.55 (d, J = 8.8 Hz, 2 H), 7.51 (d, J = 8.8 Hz, 2 H), 7.46 (d, J = 7.2 Hz, 1 H), 7.45 (t, J = 7.2 Hz, 1 H), 7.38 (dd, J = 4.8, 8.0 Hz, 1 H), 6.06 (d, J = 4.4 Hz, 1 H), 2.66 (d, J = 4.8 Hz, 3 H); ES+ MS: 403 (M+1 ). H RMS (ES+) calcd for C2i H19N603 (M + 1 ): 403.1519. Found: 403.1519.
[00936] Examples 345-644 (Table 2) were made in a similar manner to those methods described above or in combination with methods known to one skilled in the art.
[00937] Example 645: RNase H biochemical assay.
[00938] Compounds of the present invention were tested against the
Ribonuclease H (RNase H) activity of HIV-1 reverse transcriptase (RT) in a fluorescence resonance energy transfer (FRET) assay. This FRET assay employs a hybridized
RNA/DNA substrate, consisting of a 40mer RNA that is covalently linked at the 3' end to a Cy3 fluorophore (GE Healthcare Bio-Sciences Corp., Piscataway, NJ) and a 40mer DNA that is covalently linked at the 5' end to a Blackhole Quencher 2 (BHQ2; Biosearch
Technologies, Inc., Novato, CA) molecule. After initial binding to the 5' end of the substrate's RNA, H IV-1 RT sequentially cuts endonucleolytically from 5' to 3' with the eventual release of the Cy3 fluorophore, resulting in a fluorescent, unquenched signal that is detected at 580 nm. Recombinant HIV-1 RT that had been expressed in E. coli was used for these experiments. The RNA and DNA were synthesized by TriLink BioTechnologies, Inc. and were annealed by sequential incubations of 6 - 20 seconds from 95°C to 30°C in a BioRad Dyad Thermal Cycler.
[00939] In preparation for the assay, test compounds were serially diluted in DMSO and plated (0.1 μΙ_) in low volume, black 384-well plates. High and low control wells contained 0.1 μΙ_ of DMSO alone. To start the assay, 5μΙ_ of 2X enzyme solution (4 nM HIV- 1 RT in 50 mM Tris pH 8, 80 mM KCI, 10 mM MgCI2, 0.02% N P40, 5 mM DTT, DNase and RNase-free dH20) were dispensed to each well, and the enzyme was allowed to incubate with the test compounds for 30 minutes at room temperature. During this time, 5μΙ_ of Quench Buffer (50 mM Tris pH 8, 80 mM KCI, 100 mM EDTA, 0.02% NP40, DNase and RNase-free dH20) were added to the low control wells. The assay was initiated by the addition of 5μΙ_ of 2X substrate (10 nM Cy3-RNA/BHQ2-DNA hybrid in 50 mM Tris pH 8, 80 mM KCI, 10 mM MgCI2, 0.02% N P40, 5 mM DTT, DNase and RNase-free dH20) to each well. The final assay composition was 50 mM Tris pH 8, 80 mM KCI, 10 mM MgCI2, 0.02% NP40, 5 mM DTT, 5 nM Cy3-RNA/BHQ2-DNA, 2 nM H IV-1 RT, 1 % DMSO and 0.169 nM - 10 μΜ test compound.
[00940] After incubating for 40 minutes, the reaction was stopped via the addition of 5μΙ of Quench Buffer to all wells, excluding the low control wells. The plates were then incubated for 1 hour before the Cy3 fluorescence was read on a Molecular Devices Analyst GT with excitation at 530 nm and emission at 580 nm, using a 561 nm dichroic.
[00941] The data for dose responses were plotted as % Inhibition versus compound concentration following normalization using the formula 100*((U-C1 )/(C2-C1 )), where U was the unknown value, C1 was the average of the high (0% Inhibition) control wells and C2 was the average of the low (100% Inhibition) control wells. Curve fitting was performed with the equation y=A+((B-A)/(1 +(10 /10c)D)), where A was the minimum response, B was the maximum response, C was the log(XC50) and D was the Hill slope. The results for each test compound were recorded as plC50 values (-C in the above equation).
[00942] Example 646: Integrase strand transfer assay.
Preparation of Biotinylated Donor DNA Oligo Stocks.
Oligo A: 5'-Bio-ACCCTTTTAGTCAGTGTGGAAAATCTCTAGCAGT-3' SEQ ID NO: 1 Oligo B: 3 -GAAAATCAGTCACACCTTTTAGAGATCGTCA-5' SEQ ID NO: 2
[00943] Prepare a 500μΜ stock solution of each oligo in annealing buffer (50mM MOPS pH 7.2, 50mM NaCI, 10mM MgCI2). To anneal Oligos A and B to an eppendorf tube add: 52.8μΙ_ of 500μΜ Oligo A stock + 52.8μΙ_ of 500μΜ Oligo B stock + 422.4μΙ_ of annealing buffer. Place eppendorf tube in 95°C heat block to denature for 5 minutes, turn off heat block and cool to room temp use or snap freeze and store at -20°C.
Conjugation of Annealed Donor DNA to LEADseeker Beads
[00944] Components 20mg/mL LEADseeker beads (Amersham RPNQ0261 ) in bead storage buffer (25mM MOPS pH 7.2) and annealed donor DNA. Guidelines for DNA-conjugated beads: Mix 3ml_ of LEADseeker beads and 132μί of 50μΜ (ρηηοΐεβ/μί) solution of annealed donor DNA in a tube. Nutate for 80 minutes, spin at 1500 RPM for 10 minutes, discard supernatant, wash with 3ml_ of annealing buffer (50mM MOPS pH 7.2, 50mM NaCI, 10mM MgCI2), spin again, discard supernatant, and add 1 .5ml of annealing buffer to conical tube for a final concentration of 40mg/ml. Store at 4°C for 3-4 months, use as needed.
[00945] Note he calculated DNA capacity for the LEADseeker beads is 3200pmoles/mL based on 160pmoles per mg of Streptavidin. The optimal DNA capacity for this assay determined experimentally is 2200pmoles/mL.
Reagent 3H-Target DNA:
AAAAAAAT G ACC AAG G G CTAATTC ACTTTTTTTT SEQ ID NO: 3 TTTTTTTACTG GTTCCC GATTAAGTG AAAAAAAA SEQ ID NO: 4
[00946] Supplied as ds-annealed 389nM solution, 1333Ci/mmol, 0.5mCi/mL Store at -70° C. Source is custom synthesis from PerkinElmer.
[00947] c) Prepare a sufficient volume of reagent to pipet into desired 96-well plates. The following are final concentrations of each reagent in the reaction tube:
LEADseeker beads complexed with DNA = 5.2mg/ml
Assay Buffer = 25mM MOPS pH 7.2, 23mM NaCI, 10mM MgCI2
DMSO = 10%
DTT = 10mM
Integrase Enzyme = 2.77uM (add last)
[00948] Invert tube to mix and incubate tube at 37°C for 8 minutes using a heat block. While the tube is incubating in heat block, prepare assay plate as follows:
[00949] To a thawed assay plate (we use 96-well Corning round bottom plate with 1 ul compound/well), dispense 1 μΙ_Λ/νβΙΙ of 400μΜ GSK501015A to column 12 only (column 1 1 had DMSO only). Set plate aside until bead/DNA/enzyme slurry is prepared. After incubation, spin the reaction tube in a microfuge at 12000 RPM for 2 minutes, remove supernatant using a pipet and discard it, resuspend pellet with of 1 X assay buffer, mix gently, spin the eppendorf tube in a microfuge at 12000 RPM for 2 minutes, remove supernatant using a pipet and discard it. Resuspend pellet in 1X assay buffer and add 14ul/well to assay plates. Incubate 1 hr at 37°C covered. After incubation, add 5ul/well of 3H-Target DNA substrate (diluted in 1X assay buffer) for a 7nM final concentration/well. Quick spin plate and incubate at 37°C for 35 minutes. Add 60μΙ_Λ/νβΙΙ stop solution (25mM HEPES pH 7.0, 50mM EDTA, 500mM NaCI), seal plate, spin 30 sec 1500rpm and incubate 3hrs to overnight in the dark. Read plate on Viewlux Imager.
[00950] Example 647: Pseudo-typed H IV antiviral assay.
[00951] Overview of PHIV Assay. Pseudo HIV is an H IV-based vector system. The vector incorporates a number of safety features to prevent replication and to inhibit the pathogenicity of the virus. The vector also incorporates a luciferase reporter gene for easy readout. With this system, events of the HIV life cycle after entry and through integration can be easily assayed in a BSL-2 environment. The screen will detect inhibitors of uncoating, reverse transcription, RNase H , and integration.
[00952] Cells. The assay is typically run using CIP4 and CI P4-Luci cells in parallel. CIP4 cells are derived from 293 cells which are human embryonal kidney cells transformed with sheared Adenovirus type 5 DNA. 293T cells have been modified by transfection of SV40 T antigen. 293 TAg/hsr-A pCIP4 or "CIP4" cells have been further modified by transfection with a macrophage attachment factor to improve adherence to plastic. The CIP4 cells can be acutely infected with pseudotyped HIV virus and are used to measure the antiviral response. CIP4-Luci cells are chronically infected with pseudotyped HIV virus (i.e. they carry the integrated provirus) and are used to measure non-specific toxicity. Both cell lines are maintained in DMEM/F12 (Invitrogen cat. No.13330-032) medium with 10% FBS.
[00953] Pseudotyped H IV. PH IV is a VSV-G pseudotyped, replication defective H IV vector that expresses a luciferase reporter. The PHIV assay detects HIV inhibitors acting after entry and through integration (e.g. uncoating, RT, RNase H, and integrase inhibitors). It will not detect HIV entry inhibitors, or inhibitors acting from gene expression through virus maturation (e.g. CCR5, tat, rev, or protease inhibitors). An H IV NIB vector was constructed with tat, vif, vpu, vpr, nef, and env deletions. A CMV promotor replaces 5' LTR U3 and a deletion within 3' LTR U3 exists. A luciferase reporter is incorporated and is driven by the SFFV promoter. The construct is packaged by co- transfecting with a VSVg expression vector.
[00954] Compound Titration. Antiviral compounds are diluted to 5 mM in 100% DMSO. Starting at 5 mM, the compounds are serially diluted by a factor of 4 across 10 wells of a 96 well plate. Two ul from each well is spotted onto each of 4 assay plates. The final assay volume is 200 ul, so the final concentration in the first well of the plate is 50 uM. Pseudovirus infected cells are plated at a concentration of 2 x 104 cells per well.
Typically, assays are run on duplicate assay plates. The plates are incubated at 37°C, 5% C02 for 48 hours, the medium is aspirated and SteadyGlo luciferase reagent (Promega, catalog number E2550) is added. Luminescense is read in a Packard Topcount plate reader, and a dose response curve is generated.
[00955] Example 648: Peripheral blood mononuclear cells PBMC antiviral assay.
Preparation of cells for the PBMC assay
[00956] Normal donor peripheral blood mononuclear cells (PBMCs) were isolated from random buffy coats (35 to 40 ml. of elutriated whole blood in anticoagulant from HIV-negative donors) received from Gulf Coast Regional Blood Center (Houston, Tx). PBMCs were isolated by density gradient centrifugation over lymphocyte separation medium (Mediatech, # 25-072-CL) and stimulated for 24 to 48 hr in 150 ml. stimulation media; RPMI 1640 (GibcoBRL # 22400-089) containing 20% fetal calf serum (FCS, Hyclone # SH30070.03), 10% IL-2 (Zeptometrix, # 0801017), 10 μg/nnL gentamicin (GibcoBRL # 15750-060), and 5 μ9/ηηΙ_ phytohemagglutinin (PHA, Sigma # L9017).
[00957] Preparation of Virus for the PBMC assay
[00958] High titer CCR5-tropic H IV-1 Ba-L was purchased from Advanced Biotechnologies (Columbia, MD) and expanded in PHA-stimulated PBMCs. The cell culture media was the same as stimulation media (see above) except without PHA. Cell-free supernatants were monitored daily for reverse transcriptase (RT) activity (see below for details). The culture was considered mature when RT counts remained unchanged for two consecutive days. Mature cultures were harvested by centrifugation at 250 x g for 15 min, the supernatants were passed through 0.2 micron filter units, aliquoted into 1 ml_ portions and frozen at -80°C. An aliquot of the PBMC-expanded virus was titrated into cell culture media and assayed under standard conditions except test compounds were not present. Viral input was determined by selecting a dilution that gave a signal within the linear range of the assay and a signal-to-background ratio of 75 to 100.
[00959] Assaying of compounds in PBMCs
[00960] HIV-1 Ba-L replication in PBMCs was quantitated by measuring reverse transcriptase activity present in the supernatant from compound-treated infections. PHA-stimulated PBMCs were centrifuged at 260 x g for 15 min, washed once with sterile phosphate buffered saline, centrifuged as before, resuspended in culture media to a density of 2.6 x 10s cells/mL and 150 μΙ_ were distributed to 96-well tissue culture plates. Test compounds were dissolved and titrated into DMSO at 100 times the final assay
concentration. Two microliters of titrated test compounds were added to the cells in duplicate and the plates were placed in a humidified incubator at 37°C, 5% C02 for 1 h. H IV-
1 Ba-L was diluted into culture media to the desired input and 50 μΙ_ was added to the PBMC/compound mixture. Infection proceeded in a humidified incubator at 37°C, 5% C02 for seven days. Fifty μΙ_ of cell free culture supernatant was transferred to a new 96-well plate. Ten μΙ_ of RT extraction buffer (500 mM KCI, 50 mM DTT, 0.5% NP40) was added and mixed, followed by 40 μΙ_ of RT assay buffer (1 .25 mM EGTA, 125 mM Tris/HCI, 12.5 mM MgCI2, 68 Ci/mmole methyl-3H deoxythymidine-5'-triphosphate, 0.62 O.D. units/mL poly(rA) p(dT)12-18 ). The plates were placed in a humidified incubator at 37°C, 5% C02 for
2 hr. Radioactivity was captured by transferring the entire reaction onto Unifilter® DE-81 96- well plates (Whatman # 7700-4313) which were then placed on a Univac® vacuum manifold (Whatman # 7705-102). Vacuum was applied and the reaction was allowed to seep through the Unifilter® plates. Wells were washed a total of three times under full vacuum: the first wash consisted of 5% Na2HP04 in distilled water, followed by distilled water, and a final wash of 95% ethanol. The plates were allowed to dry at room temperature for at least 30 min, bottom-sealed with sealers provided with the Unifilter® plates and 50 μΙ_ of scintillation media (PerkinElmer # 6013329) was added. The plates were top-sealed and read in a Topcount luminometer (PerkinElmer) at 10 seconds per well.
[00961] Data analysis for the PBMC assay
[00962] Raw data were normalized according to the following equation:
[ Log10(raw) - Log10(PC) ] ÷ [ Log10(NC) - Log10(PC) ] ...[1 ]
Where:
PC = geometric mean of Positive Controls = mock infected wells in column 12 on each assay plate = minimum signal
NC = geometric mean of Negative Controls = untreated but infected wells in column 1 1 on each assay plate = maximum signal
[00963] Normalized response data were fit to an unconstrained four parameter logistic equation, defined as:
y = Vmax{1 - [xn ÷ (Kn + xn) ] } + Y2 ...[2]
Where:
x = compound concentration
y = normalized response data
Vmax = upper bound of response
K = IC50
Y2 = lower bound or baseline of response
n = hill coefficient
[00964] IC50 values were then derived from the following back calculation using parameter estimates from [2]:
IC50 = K [ (Vmax + Y2 - Y.50) ÷ (Y.50 - Y2) n ] ...[3]
Where:
Y.50 = log[ 0.5 (geomean PC + geomean NC) ]
[00965] Example 649: Biological Activity
MT4 Cell Assay: Experimental Procedure
[00966] Antiviral HIV activity and compound-induced cytotoxicity were measured in parallel by means of a propidium iodide based procedure in the human T-cell lymphotropic virus transformed cell line MT4. Aliquots of the test compounds were serially diluted in medium (RPMI 1640, 10% fetal calf serum (FCS), and gentamycin) in 96-well plates (Costar 3598) using a Cetus Pro/Pette. Exponentially growing MT4 cells were harvested and centrifuged at 1000 rpm for 10 min in a Jouan centrifuge (model CR 4 12). Cell pellets were resuspended in fresh medium (RPMI 1640, 20% FCS, 20% IL-2, and gentamycin) to a density of 5 x 105 cells/ml. Cell aliquots were infected by the addition of HIV-1 (strain 1MB) diluted to give a viral multiplicity of infection of 100 x TCID50. A similar cell aliquot was diluted with medium to provide a mock-infected control. Cell infection was allowed to proceed for 1 hr at 37°C in a tissue culture incubator with humidified 5% C02 atmosphere. After the 1 hr incubation the virus/cell suspensions were diluted 6-fold with fresh medium, and 125 μΙ of the cell suspension was added to each well of the plate containing pre-diluted compound. Plates were then placed in a tissue culture incubator with humidified 5% C02 for 5 days. At the end of the incubation period, cell number and hence HIV-induced cytopathy was estimated by either (A) propidium iodide staining, or by an (B) MTS tetrazolium staining method (ref. 5).
[00967] For propidium iodide readout, 27 μΙ of 5% Nonidet-40 was added to each well of the incubation plate. After thorough mixing with a Costar multitip pipetter, 60 μΙ of the mixture was transferred to filter-bottomed 96-well plates. The plates were analyzed in an automated assay instrument (Screen Machine, Idexx Laboratories). The control and standard used was 3'-azido-3'-deoxythymidine tested over a concentration range of 0.01 to 1 μΜ in every assay. The expected range of IC50 values for 3'-azido-3'-deoxythymidine is 0.04 to 0.12 μΜ. The assay makes use of a propidium iodide dye to estimate the DNA content of each well.
[00968] For MTS readout, 20 μl CellTiter 96 AQ One Solution reagent (Promega #G3582) was added to each well. At 75 minutes following the addition of MTS reagent, absobance was read at 492 nM using a Tecan Sunrise 96-well plate reader.
[00969] Analysis
The antiviral effect of a test compound is reported as an IC50, i.e. the inhibitory concentration that would produce a 50% decrease in the HIV-induced cytopathic effect. This effect is measured by the amount of test compound required to restore 50% of the cell growth of HIV-infected MT4 cells, compared to uninfected MT4 cell controls. IC50 was calculated by RoboSage, Automated Curve Fitting Program, version 5.00, 10-Jul-1995.
[00970] For each assay plate, the results (relative fluorescence units, rfU , or OD values) of wells containing uninfected cells or infected cells with no compound were averaged, respectively. For measurements of compound-induced cytotoxicty, results from wells containing various compound concentrations and uninfected cells were compared to the average of uninfected cells without compound treatment. Percent of cells remaining is determined by the following formula:
[00971] Percent of cells remaining = (compound-treated uninfected cells, rfU, or OD values / untreated uninfected cells) x 100.
[00972] A level of percent of cells remaining of 79% or less indicates a significant level of direct compound-induced cytotoxicity for the compound at that concentration. When this condition occurs the results from the compound-treated infected wells at this concentration are not included in the calculation of IC50.
[00973] For measurements of compound antiviral activity, results from wells containing various compound concentrations and infected cells are compared to the average of uninfected and infected cells without compound treatment. Percent inhibition of virus is determined by the following formula:
[00974] Percent inhibition of virus = (1 -((ave. untreated uninfected cells - treated infected cells) / (ave. untreated uninfected cells - ave. untreated infected cells)))x 100.
[00975] Results
Compounds of the present invention have anti-HIV activity in the range IC50 = 0.001 to 50 μΜ.
[00976] The embodiments of the invention described above are intended to be merely exemplary; numerous variations and modifications will be apparent to those skilled in the art. All such variations and modifications are intended to be within the scope of the present invention as defined in any appended claims.
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Claims

What is claimed is:
1. A compound of formula (I):
wherein:
Figure imgf000316_0001
R is hydrogen, halogen, -NR2R3, nitrogen-containing heterocycle connected via the nitrogen, HetZ, -OR2, -SR2;
R2 and R3 are independently selected from the group consisting of
-(R4)p(R5)q, R2 and R3 may be taken together along with the nitrogen atom to form a 4-10 membered heterocyclic ring;
R4 is selected from -(C(R 4)(R 5))j-, ArylA, heteroarylA;
R5 is independently selected from hydrogen, halogen, -(C(R 6)(R 7))j-, arylB, heteroarylB, heterocycle, Rz, two independent R5 groups may be taken together to form a 4- 10 membered ring;
Rz is selected from halogen, C1-8alkyl, CrC8haloalkyl, C3-10cycloalkyl, -CN, -NR6R7, - OR6, -C(0)OR6, -C(0)R6, -C(0)NR6R7, -C(0)HetY, -NR6C(0)R7, -NR6C(0)OR7, - NR6C(0)NR7R8, -NR6C(0)HetY, -OC(0)R7, -OC(0)OR7, -OC(0)NR7R8, -OC(0)HetY, - C(S)OR6, -C(S)R6, -C(S)NR6R7, -C(S)HetY, -NR6C(S)R7, -NR6C(S)OR7, -NR6C(S)NR7R8, - NR6C(S)HetY, -OC(S)R7, -OC(S)OR7, -OC(S)NR7R8, -OC(S)HetY, -C(NR8)OR6, -C(NR8)R6, -C(NR8)NR6R7, -C(NR8)HetY, -NR6C(NR8)R7, -NR6C(NR8)OR7, -NR6C(NR8)NR7R8, - NR6C(NR8)HetY, -OC(NR8)R7, -OC(NR8)OR7, -OC(NR8)NR7R8, -OC(NR8)HetY, -S(0)nOR6, - S(0)nR6, -S(0)nNR6R7, -S(0)nHetY, -NR6S(0)nR7, -NR6S(0)nOR7, -NR6S(0)nNR7R8, - NR6S(0)nHetY, -N3, -N02;
R6, R7 and R8 are independently selected from hydrogen, C1-8alkyl, C3-10cycloalkyl, arylB, heteroarylB, heterocycle, any two of the R6, R7 and R8 may be taken together to form a 4-10 membered heterocyclic or heteroaryl ring;
HetY is a 4-8 membered heterocyclic ring containing one or more optionally substituted heteroatoms;
wherein alkyl, cycloalkyi, heterocycle, arylA, heteroarylA may be optionally substituted with 1-4 substituents independently selected from the group consisting of hydrogen, halogen, -CF3, CrCshaloalkyl, -(R9)p(R 0)q, heterocycle optionally substituted with oxo, Rz; wherein two independent substituents may be taken together to form a 4-10 membered ring; and wherein arylB, heteroarylB may be optionally substituted with 1-4 substituents independently selected from the group consisting of hydrogen, halogen, -CF3, d-C8haloalkyl, -(R9)p(R )q, heterocycle;
R9 is selected from -(C(R 2)(R 3))j-
R-io is H, C1-8haloalkyl, heterocycle, arylB, heteroarylB, -Rz; wherein two independent substituents may be taken together to form a 4-10 membered ring;
R-i -i is H, halogen, C1-8haloalkyl, heterocycle, arylC, heteroarylC, -Rz;
wherein arylC, heteroarylC may be optionally substituted with 1-4 substituents
independently selected from the group consisting of hydrogen, halogen, -d-C8haloalkyl, heterocycle, -Rz; wherein two independent substituents may be taken together to form a 4- 10 membered ring;
HetZ is selected from
Figure imgf000317_0001
wherein T, U, V, X, Y, Z are chosen from O, -N(R12)-, S(0)n, and
-C(R 2)(R13)- optionally substituted with oxo to form a saturated, partially unsaturated or aryl ring fused to ring A which is a 5 or 6 membered arylA or heteroarylA ring;
R 2 and R 3 are independently selected from hydrogen, halogen, -NR6R7, -OR6, d. 8alkyl, d-C8haloalkyl, C3-iocycloalkyl, C2-8alkenyl, C3-8cycloalkenyl, C3-8alkynyl, and -Rz, R 2 and R 3 substituents may be combined to form a 3-8 membered ring, form a double bond, or form an oxo (=0) as the valence allows;
R 4 and R 5 are independently selected from hydrogen, halogen, -NR6R7, -OR6, d. 8alkyl, d-Cehaloalkyl, C3-10cycloalkyl, C2-8alkenyl, C3-8cycloalkenyl, C3-8alkynyl, and -Rz, R 4 and R 5 substituents may be combined to form a 3-8 membered ring, form a double bond, form a triple bond, or form an oxo (=0) as the valence allows;
R 6 and R 7 are independently selected from hydrogen, halogen, -NR6R7, -OR6, d. 8alkyl, Ci-C8haloalkyl, C3-i0cycloalkyl, C2-8alkenyl, C3-8cycloalkenyl, C3-8alkynyl, and -Rz, R 6 and R 7 substituents may be combined to form a 3-8 membered ring, form a double bond, form a triple bond, or form an oxo (=0) as the valence allows;
n is 0, 1 , or 2; P is 0 or 1 ;
Q is 1 , 2 or 3;
J is 1-8;
or a solvate, hydrate or pharmaceutically acceptable salt thereof.
2. A compound according to claim 1 , wherein R is hydrogen or halogen.
3. A compound according to claim 1 , wherein R is -NR2R3, -OR2 or -SR2.
4. A compound according to claim 1 , wherein the compound of formula (1 ) is a compound described by Examples 1-644, as set forth in Table 1 or Table 2.
5. A pharmaceutical composition comprising a therapeutically effective amount of a compound as described in any of claims 1-4, or a pharmaceutically acceptable salt, solvate or hydrate thereof and one or more agent selected from a pharmaceutically acceptable carrier, a diluent and an excipient.
6. A method of treating a mammal infected with a virus susceptible to HIV reverse transcriptase inhibition, comprising administering to said mammal a therapeutically effective amount of a compound according to any of claims 1-4, or a pharmaceutically acceptable salt, solvate or hydrate thereof.
7. A method of inhibiting HIV-related reverse transcriptase in a mammal, comprising administering to said mammal a therapeutically effective amount of a compound according to any of claims 1-4, or a pharmaceutically acceptable salt, solvate or hydrate thereof.
8. A method of treating reverse transcriptase inhibitor-resistant HIV in a mammal, comprising administering to said mammal a therapeutically effective amount of a compound according to any of claims 1-4, or a pharmaceutically acceptable salt, solvate or hydrate thereof, wherein the reverse transcriptase inhibitor against which HIV resistance is treated is not a reverse transcriptase inhibitor of formula 1.
9. A method of preventing development of reverse transcriptase inhibitor-resistant HIV in a mammal, comprising administering to said mammal a therapeutically effective amount of a compound according to any of claims 1-4, or a pharmaceutically acceptable salt, solvate or hydrate thereof, wherein the reverse transcriptase inhibitor against which HIV resistance is prevented is not a reverse transcriptase inhibitor of formula 1.
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Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102627657A (en) * 2012-03-09 2012-08-08 苏州施亚生物科技有限公司 Synthetic method of 3-(4-methoxy-benzyl)-1H-pyrimidine-2,4-dione derivative
WO2013115265A1 (en) * 2012-01-31 2013-08-08 富山化学工業株式会社 Heterocyclic compound having anti-hiv activity
US20150148352A1 (en) * 2012-08-14 2015-05-28 Cellixbio Private Limited Compositions and methods for the treatment angina and cardiovascular conditions
CN105418609A (en) * 2015-12-31 2016-03-23 山东大学 4-(1,2,3-triazole substituted anilino)-pyridinopyrimidinones derivative and preparation method and application thereof
JP2019031476A (en) * 2017-05-22 2019-02-28 アムジエン・インコーポレーテツド Kras g12c inhibitor and application method thereof
WO2021107066A1 (en) 2019-11-28 2021-06-03 塩野義製薬株式会社 Prophylactic and therapeutic pharmaceutical agent for hiv infectious diseases characterized by comprising combination of integrase inhibitor and anti-hiv agent
WO2023165509A1 (en) * 2022-03-01 2023-09-07 Insilico Medicine Ip Limited Diacylglycerol kinase (dgk) alpha inhibitors and uses thereof

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7273859B2 (en) * 2004-05-12 2007-09-25 Bristol-Myers Squibb Company HIV integrase inhibitors: cyclic pyrimidinone compounds
US20080306053A1 (en) * 2007-06-08 2008-12-11 Senomyx, Inc. Modulation of chemosensory receptors and ligands associated therewith
US20090012046A1 (en) * 2006-02-03 2009-01-08 Dirk Edward Desire Jochmans Methods of Treating Mutated Hiv
US20090131414A1 (en) * 2005-06-24 2009-05-21 Gilead Sciences, Inc. Pyrido(3,2-d)pyrimidines and pharmaceutical compositions useful for treating hepatitis c

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7273859B2 (en) * 2004-05-12 2007-09-25 Bristol-Myers Squibb Company HIV integrase inhibitors: cyclic pyrimidinone compounds
US20090131414A1 (en) * 2005-06-24 2009-05-21 Gilead Sciences, Inc. Pyrido(3,2-d)pyrimidines and pharmaceutical compositions useful for treating hepatitis c
US20090012046A1 (en) * 2006-02-03 2009-01-08 Dirk Edward Desire Jochmans Methods of Treating Mutated Hiv
US20080306053A1 (en) * 2007-06-08 2008-12-11 Senomyx, Inc. Modulation of chemosensory receptors and ligands associated therewith

Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2013115265A1 (en) * 2012-01-31 2013-08-08 富山化学工業株式会社 Heterocyclic compound having anti-hiv activity
CN102627657A (en) * 2012-03-09 2012-08-08 苏州施亚生物科技有限公司 Synthetic method of 3-(4-methoxy-benzyl)-1H-pyrimidine-2,4-dione derivative
US20150148352A1 (en) * 2012-08-14 2015-05-28 Cellixbio Private Limited Compositions and methods for the treatment angina and cardiovascular conditions
CN105418609A (en) * 2015-12-31 2016-03-23 山东大学 4-(1,2,3-triazole substituted anilino)-pyridinopyrimidinones derivative and preparation method and application thereof
JP2019031476A (en) * 2017-05-22 2019-02-28 アムジエン・インコーポレーテツド Kras g12c inhibitor and application method thereof
CN110997668A (en) * 2017-05-22 2020-04-10 美国安进公司 KRAS G12C inhibitors and methods of use thereof
CN110997668B (en) * 2017-05-22 2022-11-01 美国安进公司 KRAS G12C inhibitors and methods of use thereof
CN115626923A (en) * 2017-05-22 2023-01-20 美国安进公司 KRAS G12C inhibitors and methods of use thereof
WO2021107066A1 (en) 2019-11-28 2021-06-03 塩野義製薬株式会社 Prophylactic and therapeutic pharmaceutical agent for hiv infectious diseases characterized by comprising combination of integrase inhibitor and anti-hiv agent
WO2023165509A1 (en) * 2022-03-01 2023-09-07 Insilico Medicine Ip Limited Diacylglycerol kinase (dgk) alpha inhibitors and uses thereof

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