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WO1998046605A1 - 5,7-disubstituted 4-aminopyrido[2,3-d]pyrimidine compounds and their use as adenosine kinase inhibitors - Google Patents

5,7-disubstituted 4-aminopyrido[2,3-d]pyrimidine compounds and their use as adenosine kinase inhibitors Download PDF

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Publication number
WO1998046605A1
WO1998046605A1 PCT/US1998/007207 US9807207W WO9846605A1 WO 1998046605 A1 WO1998046605 A1 WO 1998046605A1 US 9807207 W US9807207 W US 9807207W WO 9846605 A1 WO9846605 A1 WO 9846605A1
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Prior art keywords
pyrido
amino
dlpyrimidine
bromophenyl
phenyl
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PCT/US1998/007207
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French (fr)
Inventor
Shripad S. Bhagwat
Chih-Hung Lee
Marlon D. Cowart
Jeffrey Mckie
Anne Laure Grillot
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Abbott Laboratories
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Abbott Laboratories
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Priority to SK1417-99A priority Critical patent/SK141799A3/en
Priority to CA002286909A priority patent/CA2286909A1/en
Priority to PL98336304A priority patent/PL336304A1/en
Priority to EP98918093A priority patent/EP0989986A1/en
Priority to IL13161898A priority patent/IL131618A0/en
Priority to JP54408898A priority patent/JP2001520655A/en
Priority to AU71083/98A priority patent/AU7108398A/en
Priority to BR9809055-0A priority patent/BR9809055A/en
Application filed by Abbott Laboratories filed Critical Abbott Laboratories
Priority to HU0001434A priority patent/HUP0001434A3/en
Publication of WO1998046605A1 publication Critical patent/WO1998046605A1/en
Priority to NO995036A priority patent/NO995036L/en
Anticipated expiration legal-status Critical
Priority to BG103842A priority patent/BG103842A/en
Ceased legal-status Critical Current

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/08—Antiepileptics; Anticonvulsants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • 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 a method of inhibiting adenosine kinase by administering 5,7-disubstirated-4-aminopyrido[2,3-d]pyri ⁇ dine compounds, to pharmaceutical compositions containing such compounds, as well as to certain 5,7- disubstituted-4-aminopyrido[2,3-d]pyrimidine compounds.
  • Adenosine kinase (ATP:adenosine 5'-phosphotransferase, EC 2.7.1.20) is a ubiquitous enzyme which catalyzes the phosphorylation of adenosine to AMP, using ATP, preferentially, as the phosphate source.
  • Adenosine kinase has broad tissue and species distribution, and has been isolated from yeast, a variety of mammalian sources and certain microorganisms. It has been found to be present in virtually every human tissue assayed including kidney, liver, brain, spleen, placenta and pancreas.
  • Adenosine kinase is a key enzyme in the control of the cellular concentrations of adenosine.
  • Adenosine is a purine nucleoside that is an intermediate in the pathways of purine nucleotide degradation and salvage. Adenosine also has many important physiologic effects, many of which are mediated through the activation of specific ectocellular receptors, termed Pl receptors (Burnstock, in Cell Membrane Receptors for Drugs and Hormones,
  • adenosine inhibits the release of certain neurotransmitters (Corradetti, et al., Eur. J. Pharmacol. 1984, 104: 19-26), stabilizes membrane potential (Rudolphi, et al., Cerebrovasc. Brain Metab. Rev. 1992, : 346-360), functions as an endogenous anticonvulsant (Dragunow, Trends Pharmacol. Sci. 1986, 7: 128- 130) and may have a role as an endogenous neuroprotective agent (Rudolphi, et al., Trends Pharmacol. Sci., 1992, 13: 439-445).
  • Adenosine may play a role in several disorders of the central nervous system such as schizophrenia, anxiety, depression and Parkinson's disease.
  • schizophrenia anxiety, depression and Parkinson's disease.
  • Parkinson's disease adenosine may play a role in several disorders of the central nervous system such as schizophrenia, anxiety, depression and Parkinson's disease.
  • Adenosine has also been implicated in modulating transmission in pain pathways in the spinal cord (Sawynok, et al., Br. J. Pharmacol., 1986, 88: 923-930), and in mediating the analgesic effects of morphine (Sweeney, et al., J. Pharmacol. Exp. Ther. 1987, 243: 657-665). In the immune system, adenosine inhibits certain neutrophil functions and exhibits anti-inflammatory effects (Cronstein, J. Appl. Physiol. 1994, 76: 5-13).
  • Adenosine also exerts a variety of effects on the cardiovascular system, including vasodilation, impairment of atrioventricular conduction and endogenous cardioprotection in myocardial ischemia and reperfusion (Mullane and Williams, in Adenosine and Adenosine Receptors, 1990 (Williams, ed.) Humana Press, New Jersey, pp. 289-334).
  • the widespread actions of adenosine also include effects on the renal, respiratory, gastrointestinal and reproductive systems, as well as on blood cells and adipocytes.
  • Adenosine via its Al receptor activation on adipocytes, plays a role in diabetes by inhibiting lipolysis [Londos, et al., Proc. Natl. Acad. Sci. USA, 1980, 77, 2551.
  • Endogenous adenosine release appears to have a role as a natural defense mechanism in various pathophysiologic conditions, including cerebral and myocardial ischemia, seizures, pain, inflammation and sepsis. While adenosine is normally present at low levels in the extracellular space, its release is locally enhanced at the site(s) of excessive cellular activity, trauma or metabolic stress. Once in the extracellular space, adenosine activates specific extracellular receptors to elicit a variety of responses which tend to restore cellular function towards normal (Bruns, Nucleosides Nucleotides, 1991, 10: 931-943; Miller and Hsu, J. Neurotrauma, 1992, 9: S563-S577). Adenosine has a half-life measured in seconds in extracellular fluids (Moser, et al., Am. J. Physiol. 1989, 25: C799-C806), and its endogenous actions are therefore highly localized.
  • adenosine kinase can result in augmentation of the local adenosine concentrations at foci of tissue injury, further enhancing cytoprotection. This effect is likely to be most pronounced at tissue sites where trauma results in increased adenosine production, thereby minimizing systemic toxicities.
  • Pharmacologic compounds directed towards adenosine kinase inhibition provide potentially effective new therapies for disorders benefited by the site- and event-specific potentiation of adenosine.
  • Disorders where such compounds may be useful include ischemic conditions such as cerebral ischemia, myocardial ischemia, angina, coronary artery bypass graft surgery (CABG), percutaneous transluminal angioplasty (PTCA), stroke, other ' thrombotic and embolic conditions, and neurological disorders such as epilepsy, anxiety, schizophrenia, nociperception including pain perception, neuropathic pain, visceral pain, as well as inflammation, arthritis, immunosuppression, sepsis, diabetes and gastrointestinal disfunctions such as abnormal gastrointestinal motility.
  • ischemic conditions such as cerebral ischemia, myocardial ischemia, angina, coronary artery bypass graft surgery (CABG), percutaneous transluminal angioplasty (PTCA), stroke, other ' thrombotic and embolic conditions
  • neurological disorders such
  • Adenosine kinase is also responsible for the activation of many pharmacologically active nucleosides (Miller, et al., J. Biol. Chem. 1979, 254: 2339-2345), including tubercidin, formycin, ribavirin, pyrazofurin and 6-(methylmercapto)purine riboside.
  • These purine nucleoside analogs represent an important group of antimetabolites which possess cytotoxic, anticancer and antiviral properties. They serve as substrates for adenosine kinase and are phosphorylated by the enzyme to generate the active form.
  • adenosine kinase activity has been implicated as a mechanism of cellular resistance to the pharmacological effects of these nucleoside analogs ⁇ e.g. Bennett, et al., Mol. Pharmacol., 1966, 2: 432-443; Caldwell, et al, Can. J. Biochem., 1967, 45: 735-744; Suttle, et al., Europ. J. Cancer, 1981, 17: 43-51).
  • Decreased cellular levels of adenosine kinase have also been associated with resistance to the toxic effects of 2'-deoxyadenosine (Hershfield and Kredich, Proc. Natl. Acad. Sci.
  • dATP deoxyadenosine triphosphate
  • Chem., 31B: 719-720 (1992) disclose 4-amino-5-(4-chlorophenyl)-7-(4- nitrophenyl)pyrido[2,3-d]pyrimidine and 4-amino-5-(4-methoxyphenyl)-7-(4- nitiOphenyl)pyrido[2,3-d]pyrimidine compounds having antibacterial activity.
  • Prakash et al, Pharmazie, 48: 221-222 (1993)) disclose 4-amino-5-phenyl-7-(4- aminophenyl)pyrido[2,3-d]pyrimidine, 4-amino-5-phenyl-7-(4-bromophenyl)pyrido[2,3- djpyrimidine, 4-ammo-5-(4-methoxyphenyl)-7-(4-aminophenyl)pyrido[2,3-d]pyrimidine, and 4-amino-5-(4-methoxyphenyl)-7-(4-bromophenyl)pyrido[2,3-d]pyrimidine compounds having antifungal activity.
  • the present invention provides for 5,7-disubstituted-4-aminopyrido[2,3- djpyrimidine compounds having utility as adenosine kinase inhibitors.
  • the present invention provides a method of inhibiting adenosine kinase by administering a compound of formula (I)
  • Ri and R ⁇ are independently selected from H, loweralkyl, Ci-CgalkoxyCi- C ⁇ alkyl, arylC ⁇ -C6alkyl, -C(O)C ⁇ -C6alkyl, -C(O)aryl, -C(O)heterocyclic or may join together with the nitrogen to which they are attached to form a 5-7 membered ring optionally containing 1-2 additional heteroatoms selected from O, N or S;
  • R3 is selected from the group consisting of loweralkyl, loweralkenyl, loweralkynyl, cycloalkyl, aryl, arylalkyl, heteroaryl, heterocyclic group, heteroarylalkyl or heterocycloalkyl wherein the heteroaryl and heterocyclic groups are linked directly or indirectly by a ring carbon;
  • R4 is selected from the group consisting of loweralkyl, loweralkenyl, loweralkynyl, cycloalkyl, aryl, arylalkyl, heteroaryl, heterocyclic group heteroarylalkyl or heterocycloalkyl; and a dashed line — indicates that a double bond is optionally present provided that proper valencies are maintained.
  • the method of inhibiting adenosine kinase comprises exposing an adenosine kinase to an effective inhibiting amount of a compound of Formula I of the present invention.
  • the adenosine kinase is located in vivo, the compound is administered to the organism.
  • the present invention provides a method of treating ischemia, neurological disorders, nociperception , inflammation, immunosuppression, gastrointestinal disfunctions, diabetes and sepsis in a mammal in need of such treatment, comprising adiTiinistering to the mammal a therapeutically effective amount of a compound of Formula I of the present invention.
  • the present invention provides a method of treating cerebral ischemia, myocardial ischemia, angina, coronary artery bypass graft surgery, percutaneous transluminal angioplasty, stroke, thrombotic and embolic conditions, epilepsy, anxiety, schizophrenia, pain perception, neuropathic pain, visceral pain, arthritis, sepsis, diabetes and abnormal gastrointestinal motility in a mammal in need of such treatment, comprising adrninistering to the mammal a therapeutically effective amount of a compound of Formula I of the present invention.
  • the present invention also contemplates the use of pharmaceutically acceptable salts and amides of compounds having Formula I.
  • the present invention provides a compound of formula (I)
  • Ri and R ⁇ are independently selected from H, loweralkyl, C ⁇ -C6alkoxyCi- C ⁇ alkyl, arylCj-C ⁇ alkyl, -C(O)C ⁇ -C6alkyl, -C(O)aryl, -C(O)heterocyclic or may join together with the nitrogen to which they are attached to form a 5-7 membered ring optionally containing 1-2 additional heteroatoms selected from O, N or S;
  • R3 is selected from the group consisting of loweralkyl, loweralkenyl, loweralkynyl, cycloalkyl, aryl, arylalkyl, heteroaryl, heterocyclic group, heteroarylalkyl or heterocycloalkyl wherein the heteroaryl and heterocyclic groups are linked directly or indirectly by a ring carbon;
  • R4 is selected from the group consisting of loweralkyl, loweralkenyl, loweralkynyl, cycloalkyl, aryl, arylalkyl, heteroaryl, heterocyclic group heteroarylalkyl or heterocycloalkyl; and a dashed line — indicates that a double bond is optionally present provided that proper valencies are maintained; with the proviso that the compound may not be selected from the group consisting of:
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula I above in combination with a pharmaceutically acceptable carrier.
  • the present invention provides a process for the preparation of adenosine kinase inhibiting compounds having the formula
  • the present invention relates to 5,7-disubstituted-4-ammopyrido[2,3-d]pyrimidine compounds that are useful in inhibiting adenosine kinase, to pharmaceutical compositions containing such compounds, to a method of using such compounds for inhibiting adenosine kinase, and to novel 5,7-disubstituted-4-aminopyrido[2,3-d]pyrimidine compounds.
  • the present invention provides 5,7-disubstituted-4-aminopyrido[2,3- d]pyrimidine compounds that are adenosine kinase inhibitors.
  • An adenosine kinase inhibitor of the present invention is a compound of the Formula I, shown above.
  • the present invention relates to a method of inhibiting adenosine kinase comprising administering a compound of formula I 98/46605
  • Ri and R2 are independently selected from H, loweralkyl, arylC ⁇ -C6alkyl, - C(O)C ⁇ -C6alkyl, -C(O)aryl, -C(O)heterocyclic or may join together with the nitrogen to which they are attached to from a 5-7 membered ring optionally containing 1-2 additional heteroatoms selected from O, N or S;
  • R3 and R ⁇ are independently selected from the group consisting of:
  • C3-C8cycloalkyl heteroarylCo-C ⁇ alkyl or substituted heteroarylCo-C ⁇ alkyl, optionally substituted cycloalkyl, arylCo-C ⁇ alkyl or substituted arylC()-C6alkyl, heteroarylC2-C6alkenyl or substituted heteroarylC2-C6 ⁇ alkenyl, arylC2-C6alkenyl or substituted arylC2-C6alkenyl, heteroarylC2-C6alkynyl or substituted heteroarylC2-C6alkynyl, arylC2-C6alkynyl or substituted arylC2-C6alkynyl wherein the 1-4 heteroaryl or aryl substituents are independently selected from halogen, oxo, CO2 ⁇ , cyanoCi-C ⁇ alkyl, heteroarylC()-C6alkyl, heterocyclicCo-C alkyl, Ci-Cgalkyloxy,
  • C6alkylacryl R 5 R 6 N(CO)NR 5 , N-formyl(heterocyclic), NO2, NR5R6C ⁇ - C ⁇ alkyl, (R 5 O)(R 6 O)-P(O)- C()-C6alkyl, wherein R ⁇ and R ⁇ are independently selected from H, C ⁇ -C6alkyl, HC(O), C ⁇ -C6alkyloxyC ⁇ -C6alkyl, C ⁇ -C6alkyloxy, C ⁇ - C6alkylC(O), CF3C(O), phthalimidoCi-
  • an adenosine kinase inhibitor of the present invention is a compound of Formula (II) above, wherein R 4 is aryl or heteroaryl and substituted versions thereof.
  • an adenosine kinase inhibitor of the present invention is a compound of Formula (II) above, wherein R 4 is aryl or heteroaryl and substituted versions thereof and R 3 is loweralkyl, aryl, arylalkyl or heteroaryl and substituted versions thereof wherein the substituents are as identified above.
  • an adenosine kinase inhibitor of the present invention is a compound of Formula (I) above, wherein R 4 is selected from the group consisting of: phenyl; thiophene-2-yl; 3-methyl-2-oxobenzoxazolin-6-yl; 2-(dimethylamino)- 5-pyrimidinyl; 2-(N-formyl-N-methyl amino)-5-pyrimidinyl; 2-(N-methoxyethyl-N-methyl amino)-5-pyrimidinyl; 2-(N-methylamino)-5-pyrimidinyl; 2-(l-mo holinyl)-5-pyrimidinyl; 2-(l-pyrrolidinyl)-5-pyrimidinyl; 2-dimethylamino-5-pyrimidinyl; 2-furanyl; 2- oxobenzoxazolin-6-yl; 2-pyridyl; 3-(dimethylamino)phenyl; 3-
  • an adenosine kinase inhibitor of the present invention is a compound of Formula (I) above, wherein R 3 is selected from the group consisting of: (thiophene-2-yl)methyl; (thiophene-3-yl)methyl; butyl; cycloheptyl; pentyl; thiophene-2-yl; l-(3-bromophenyl)ethyl; 2-(N-phenylmethoxycarbonyl)aminophenyl; 2-(3- bromophenyl)ethyl; 2-(3-cyanophenyl)methyl; 2-(4-bromophenyl)ethyl; 2-(5-chloro-2- (thiophen-3-yl)phenyl; 2-bromophenyl; 2-furanyl; 2-methylpropyl; 2-phenylethyl; phenylmethyl; 2,3-dimethoxyphenyl; 2,3-methylenedioxypheny
  • Exemplary and preferred adenosine kinase inhibitor compounds of the invention utilized in the method recited herein include the compounds listed below wherein Rl and R ⁇ in a compound of formula II are selected from H, the groups identified at the 5-position are included within R3 and the groups identified at the 7-position are included within R ⁇ , R5- R8 are as described in the specific compound: 4-arnino-5-(4-dime ylaminophenyl)-7-(4-bromophenyl)pyrido[2,3-d]pyrirnidine;
  • 4-amino-5-(3-bromophenyl)-7-(6-(N-(2-hydroxyethoxyethyl)-N-formylamino)-3 pyridyl)pyrido[2,3-dlpyrimidine; 4-amino-5-(3-bromophenyl)-7-(6-(N-(2-hydroxyethoxyethyl)-3-pyridyl-N- oxide)pyrido[2,3-d]pyrimidine;
  • the partially hydrogenated or fully hydrogenated versions wherein the 5,6 and/or the 7,8 double bonds are hydrogenated of the compounds identified above are also included within the scope of the invention.
  • the preferred substitution pattern on the R3 group when it is selected from, for example, a substituted aryl group is having at least one substituent at the meta position.
  • the preferred substitution pattern on the R ⁇ position when it is selected from, for example, a substituted heteroaryl group is having at least one substituent at the para position.
  • the present invention is therefore directed to compounds of formula I or II with the variables recited as above wherein, in the case of R selected from substituted aryl or heteroaryl groups and R ⁇ selected from substituted aryl or heteroaryl groups, the substiuents on the R group are meta and the substituents on the R ⁇ group are para.
  • the present invention encompasses pro-drugs of the above compounds which may be active in their own right or are metabolized or converted to the non pro-drug form as exemplified above.
  • the invention is not limited to synthetic versions of the claimed compounds and includes the compounds-per-se or pro-drugs or metabolites thereof regardless of how or where they are manufactured or made.
  • acyl refers to a moiety attached by a carbonyl linkage, as for example, loweralkyl-carbonyl or aryl-carbonyl, wherein loweralkyl and aryl are as defined herein.
  • acyl include, for example, acetyl, propionyl, hexanoyl, trifluoroacetyl, benzoyl, 4-methylbenzoyl, methoxyacetyl, pentanoyl, N- Bocglycylimidazoyl, N-phthalimidylglycyl and the like or others as specified herein.
  • aryl or “substituted aryl” as used herein, refers to a carbocyclic aromatic radical, including, for example, phenyl and 1- or 2-naphthyl, which may be unsubstituted or substituted respectively by independent replacement of one, two or three of the hydrogen atoms thereon with Cl, Br, F, I, cyano, carboxamido, hydroxy, loweralkoxy, loweralkyl, loweralkenyl, loweralkynyl, amino, loweralkylamino, di(loweralkylamino), N-loweralkyl- N-loweralkoxyamino, trifluoromethyl or methoxymethyl groups.
  • aryl refers to a phenyl group substituted with one ureido, methylsulfonyl, pyrimidinyl, pyridinyl, pyridazinyl, mo ⁇ holinyl, phenyl-loweralkoxy, phenyl-loweralkenyl or cycloalkyl-loweralkyl group.
  • aryl radicals include, but are not limited to, 3- bromophenyl, 3-chlorophenyl, 4-chlorophenyl, 3-methoxyphenyl, 3-(2-propyl)phenyl, 3,4- dimethoxyphenyl, 3-trifluromethylphenyl, 3-trifluoro-4-fluorophenyl, 4-(N-methyl-N- methoxyl)ethylaminophenyl, 4-dimethylaminophenyl, 3-fluoro-4-methylphenyl, 4- methylphenyl, 4-cyanophenyl, 4-propylmethyl, 3,5-dichlorophenyl, 3,4- methylenedioxyphenyl, 3-cyanopropylphenyl, 4-ureidophenyl, 3-methylsulfonylphenyl, 3- carboxamidopropylphenyl.
  • arylalkyl refers to a loweralkyl radical having appended thereto an aryl group, as defined above, as for example benzyl and phenylethyl.
  • aryloxy refers to a aryl radical which is appended to the molecule via an ether linkage ⁇ i.e., through an oxygen atom), as for example phenoxy, naphthyloxy, 4- chlorophenoxy, 4-methylphenoxy, 3,5-dimethoxypehenoxy, and the like.
  • cycloalkyl refers to a cyclic saturated hydrocarbon radical having from 3 to 7 ring atoms.
  • examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl. Cycloalkyl is also described as C3-C8cycloalkyl.
  • cycloalkyl-loweralkyl refers to a loweralkyl radical as defined below substituted with a cycloalkyl group as defined above by replacement of one hydrogen atom.
  • examples of cycloalkyl-loweralkyl include cyclopropylmethyl, cyclobutylethyl, cyclopentylmethyl, cyclohexylmethyl and cycloheptylbutyl, and the like.
  • heteroaryl or “substituted heteroaryl” refers to a monocyclic aromatic radical having from five to seven ring atoms of which one ring atom is nitrogen, oxygen or sulfur; zero, one or two ring atoms are additional heteroatoms independently selected from S, O and N; and the remaining ring atoms are carbon, the radical being joined to the rest of the molecule via any of the ring atoms.
  • a heteroaryl group may be unsubstituted or substituted by independent replacement of one, two or three of the hydrogen atoms thereon with Cl, Br, F, I, cyano, carboxamido, hydroxy, loweralkoxy, loweralkyl, loweralkenyl, loweralkynyl, amino, loweralkylamino, di(loweralkylarnino), N-loweralkyl-N- loweralkoxyamino, trifluoromethyl or methoxymethyl groups.
  • heteroaryl refers to a heteroaryl group substituted with one ureido, methylsulfonyl, pyrimidinyl, pyridinyl, pyridazinyl, mo ⁇ holinyl, phenyl-loweralkoxy. phenyl-loweralkenyl or cycloalkyl-loweralkyl group.
  • a heteroaryl group may be substituted by replacement of any two adjacent hydrogen atoms with a grouping of atoms to form a fused benzene ring, e.g., benz derivatives such as indole, benzoxazole and the like.
  • heteroaryl examples include pyridinyl, pyrazinyl, pyrimidinyl, pyrrolyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, isoxazolyl, thiadiazolyl, oxadiazolyl, furanyl, thiophenyl, 5- methylthiophene-2-yl, 5-nitrothiophene-2-yl, 5-methylfuranyl, benzofuranyl, benzothiophenyl, and the like and those additionally described herein.
  • heterocyclic refers to a saturated or unsaturated monocyclic ring system radical having from four to seven ring atoms of which one is nitrogen or oxygen; zero, one or two ring atoms are additional heteroatoms independently selected from S, O and N; and the remainder are carbon, the radical being joined to the rest of the molecule via any of the ring carbon atoms and being optionally substituted, either on a nitrogen or a carbon atom, by an additional radical selected from among aryl(loweralkyl), alkoxycarbonyl, loweralkyl, halo(loweralkyl), amino (loweralkyl), hydroxy-substituted loweralkyl, hydroxy, loweralkoxy, halogen, amino, loweralkylamino, and amino, (loweralkyl)amino or alkanoylamino of from one to eight carbon atoms in which the amino group may be further substituted with alkanoyl of from one to eight carbons, an alpha-amin
  • heterocyclic examples include pyrrolidine, tetrahydrofuran, dihydropyrrole, isoxazolidine, oxazolidine, tetrahydropyridine, piperidine, piperazine, mo ⁇ holine, thiomo ⁇ holine, aziridine and azetidine or those additionally described herein.
  • heterocyclic-loweralkyl refers to a loweralkyl radical as defined below substituted with a heterocyclic-group as defined above by replacement of one hydrogen atom.
  • examples of cycloalkyl-loweralkyl include pyrrolidinylmethyl, piperidinylethyl, and the like.
  • loweralkyl refers to saturated, straight- or branched- chain hydrocarbon radicals containing from one to six carbon atoms including, which may be unsubstituted or substituted by independent replacement of one, two or three of the hydrogen atoms thereon with Cl, Br, F, I. cyano, carboxamido, hydroxy, loweralkoxy, amino, loweralkylamino, iminoloweralkylamino,di(loweralkylamino) or N-loweralkyl-N- loweralkoxyamino groups.
  • loweralkyl examples include, but are not limited to, methyl, ethyl, propyl, isopropyl, ⁇ -butyl, tert-butyl. neopentyl, n-hexyl, hydroxyethyl, methoxymethyl, trifluoromethyl, 3-cyanopropyl, 3-carboxamidopropyi, and the like.
  • the group "C ⁇ -C6alkyl” is described and has a similar meaning as above for loweralkyl but is more specifically recited.
  • the term "Co-C6alkyl” indicates the carbon atoms which may be present in the alkyl chain including zero. These terms are also provided adjacent to aryl or heteroaryl or other generic group and represent or have the same meaning as, for example, “arylalkyl” or “heteroarylalkyl”.
  • loweralkenyl refers to mono-unsaturated straight- or branched-chain hydrocarbon radicals containing from two to six carbon atoms including, but not limited to, vinyl, propenyl, n-butenyl, -butenyl, n-pentenyl, and n-hexenyl. These variables are also recited as, for example, C2-C6alkenyl.
  • loweralkoxy refers to a loweralkyl radical which is appended to the molecule via an ether linkage ⁇ i.e., through an oxygen atom), as for example methoxy, ethoxy, propoxy, 2-propoxy, 2-methyl-2-propoxy, tert-butoxy, pentyloxy, hexyloxy, isomeric forms thereof and the like. This term is also described as Ci-C6alkyloxy.
  • loweralkynyl refers to straight- or branched-chain hydrocarbon radicals possessing a single triple bond and containing from two to six carbon atoms including, but not limited to, ethynyl, propynyl, n-butynyl, n-pentynyl, and n- hexynyl. This term is also described as C2-C6alkynyl.
  • compositions which comprise a compound of the present invention in combination with a pharmaceutically acceptable carrier.
  • the present invention includes one or more compounds, as set forth above, formulated into compositions together with one or more non-toxic physiologically tolerable or acceptable diluents, carriers, adjuvants or vehicles that are collectively referred to herein as diluents, for parenteral injection, for oral administration in solid or liquid form, for rectal or topical administration, or the like.
  • diluents for parenteral injection, for oral administration in solid or liquid form, for rectal or topical administration, or the like.
  • a compound of the present invention can exist in a variety of forms including pharmaceutically-acceptable salts, amides and the like.
  • Compositions may be prepared that will deliver the correct amount of a compound or compounds of the invention.
  • the following dosages are thought to provide the optimal therapy: iv infusions: 0.1- 250 nmol/kg/minute, preferably from 1-50 nmol/kg/minute; oral: 0.01-250 ⁇ Mol/kg/day, preferably from about 0.1-50 ⁇ Mol/kg/day; these oral molar dosage ranges correspond to 0.005-125 mg/kg/day, preferably 0.05-25 mg/kg/day.
  • the preferred route of administration is intravenous; the preferred method of treating chronic disorders is orally by means of a tablet or sustained release formulation.
  • “Pharmaceutically-acceptable amide” refers to the pharmaceutically-acceptable, nontoxic amides of the compounds of the present invention which include amides formed with suitable organic acids or with amino acids, including short peptides consisting of from l-to-6 amino acids joined by amide linkages which may be branched or linear, wherein the amino acids are selected independently from naturally-occurring amino acids, such as for example, glycine, alanine, leucine, valine, phenylalanine, proline, methionine, tryptophan, asparagine, aspartic acid, glutamic acid, glutamine, serine, threonine, lysine, arginine, tyrosine, histidine, ornithine, and the like.
  • “Pharmaceutically-acceptable salts” refers to the pharmaceutically-acceptable, nontoxic, inorganic or organic acid addition salts of the compounds of the present invention, as described in greater detail below.
  • the compounds of the present invention can be used in the form of pharmaceutically-acceptable salts derived from inorganic or organic acids.
  • These salts include, but are not limited to, the following: acetate, adipate, alginate, aspartate, benzoate, benzenesulf onate, bisulfate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, flavianate, fumarate, glucoheptonate, glycerophosphate, hemisulfate, heptonate, hexonoate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxy-ethanesulfonate, lactate, maleate, methanesulfonate, nicotinate, 2-naphthalenesulfonate, oxalate, palmoate, pectinate
  • Appropriate cationic salts are also readily prepared by conventional procedures such as treating an acid of Formula I with an appropriate amount of base, such as an alkali or alkaline earth metal hydroxide, e.g., sodium, potassium, lithium, calcium, or magnesium, or an organic base such as an amine, e.g., dibenzylethylenediamine, cyclohexylamine, dicyclohexylamine, triethylamine, piperidine, pyrrolidine, benzylamine, and the like, or a quaternary ammonium hydroxide such as tetramethylammonium hydroxide and the like.
  • base such as an alkali or alkaline earth metal hydroxide, e.g., sodium, potassium, lithium, calcium, or magnesium
  • an organic base such as an amine, e.g., dibenzylethylenediamine, cyclohexylamine, dicyclohexylamine, triethylamine, piperidine,
  • the basic nitrogen-containing groups can be quaternized with such agents as loweralkyl halides, such as methyl, ethyl, propyl, and butyl chlorides, bromides, and iodides; dialkyl sulfates; long chain halides such as decyl, lauryl, myristyl, and stearyl chlorides, bromides and iodides; arylalkyl halides like benzyl and phenethyl bromides, and others. Water or oil-soluble or dispersible products are thereby obtained.
  • loweralkyl halides such as methyl, ethyl, propyl, and butyl chlorides, bromides, and iodides
  • dialkyl sulfates long chain halides such as decyl, lauryl, myristyl, and stearyl chlorides, bromides and iodides
  • arylalkyl halides like benzy
  • compositions suitable for parenteral injection may comprise pharmaceutically acceptable sterile aqueous or nonaqueous solutions, dispersions, suspensions or emulsions and sterile powders for reconstitution into sterile injectable solutions or dispersions.
  • aqueous and nonaqueous carriers, diluents, solvents or vehicles examples include water, ethanol, polyols (propylene glycol, polyethylene glycol, glycerol, and the like), suitable mixtures thereof, vegetable oils (such as olive oil) and injectable organic esters such as ethyl oleate.
  • a coating such as lecithin
  • surfactants for example, by the use of surfactants.
  • compositions may also contain adjuvants such as preserving, wetting, emulsifying, and dispersing agents. Prevention of the action of microorganisms may be ensured by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, and the like. It may also be desirable to include isotonic agents, for example, sugars, sodium chloride and the like. Prolonged abso ⁇ tion of the injectable pharmaceutical form may be brought about by the use of agents delaying abso ⁇ tion, for example, aluminum monostearate and gelatin.
  • the compounds may be inco ⁇ orated into slow-release or targeted-delivery systems, such as polymer matrices, liposomes, and microspheres. They may be sterilized, for example, by filtration through a bacteria-retaining filter, or by inco ⁇ orating sterilizing agents in the form of sterile solid compositions, which may be dissolved in sterile water, or some other sterile injectable medium immediately before use.
  • Solid dosage forms for oral administration may include capsules, tablets, pills, powders, and granules.
  • the active compound is admixed with at least one inert customary excipient (or carrier), such as sodium citrate or dicalcium phosphate, and additionally (a) fillers or extenders, as for example, starches, lactose, sucrose, glucose, mannitol and silicic acid; (b) binders, as for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and acacia; (c) humectants, as for example, glycerol; (d) disintegrating agents, as for example, agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates and sodium carbonate; (e) solution retarders, as for example paraffin; (f) abso ⁇ tion accelerators, as for example, quaternary ammonium compounds; (g) fillers
  • compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules, using such excipients as lactose or milk sugar, as well as high molecular weight polyethylene glycols, and the like.
  • Solid dosage forms such as tablets, dragees, capsules, pills and granules may be prepared with coatings and shells, such as enteric coatings and others well known in this art. They may contain pacifying agents, and may also be of such composition that they release the active compound or compounds in a certain part of the intestinal tract in a delayed manner. Examples of embedding compositions which may be used are polymeric substances and waxes.
  • the active compounds may also be in micro-encapsulated form, if appropriate, with one or more of the above-mentioned excipients.
  • Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups and elixirs.
  • the liquid dosage forms may contain inert diluents commonly used in the art, such as water or other solvents, solubilizing agents and emulsifiers, as for example, ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils, in particular, cottonseed oil, groundnut oil, com germ oil, olive oil, castor oil and sesame oil, glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan or mixtures of these substances, and the like.
  • inert diluents commonly used in the art, such as water or other solvents, solubilizing agents and emulsifiers, as for example, ethyl alcohol, isopropyl alcohol, ethyl carbonate, eth
  • these liquid dosage forms may also include adjuvants, such as wetting agents, emulsifying and suspending agents, sweetening, flavoring and perfuming agents.
  • adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring and perfuming agents.
  • Suspensions in addition to the active compounds, may contain suspending agents, as for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, or mixtures of these substances, and the like.
  • suspending agents as for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, or mixtures of these substances, and the like.
  • compositions for rectal or vaginal administrations are preferably suppositories which can be prepared by mixing the compounds of this invention with suitable non- irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax, which are solid at ordinary temperatures but liquid at body temperature and therefore, melt in the rectum or vaginal cavity and release the active component.
  • suitable non- irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax, which are solid at ordinary temperatures but liquid at body temperature and therefore, melt in the rectum or vaginal cavity and release the active component.
  • Dosage forms for topical or transdermal administration of a compound of this invention further include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants or transdermal patches.
  • Transdermal administration via a transdermal patch is a particularly effective and preferred dosage form of the present invention.
  • the active component is admixed under sterile conditions with a pharmaceutically acceptable carrier and any needed preservative, buffers or propellants as may be required. It is known that some agents may require special handling in the preparation of transdermal patch formulations. For example, compounds that are volatile in nature may require admixture with special formulating agents or with special packaging materials to assure proper dosage delivery. In addition, compounds which are very rapidly absorbed through the skin may require formulation with abso ⁇ tion-retarding agents or barriers. Ophthalmic formulations, eye ointments, powders and solutions are also contemplated as being within the scope of this invention.
  • the present compounds may also be administered in the form of liposomes.
  • liposomes are generally derived from phospholipids or other lipid substances. Liposomes are formed by mono- or multi-lamellar hydrated liquid crystals that are dispersed in an aqueous medium. Any non-toxic, physiologically acceptable and metabolizable lipid capable of forming liposomes may be used.
  • the present compositions in liposome form may contain, in addition to the compounds of the present invention, stabilizers, preservatives, excipients, and the like.
  • the preferred lipids are the phospholipids and the phosphatidyl cholines (lecithins), both natural and synthetic. Methods to form liposomes are known in the art. See, for example, Prescott, Ed., Methods in Cell Biology, Volume XIV, Academic Press, New York, N. Y., (1976), p 33 et seq.
  • the compounds of the present invention may be synthesized by methods illustrated in Schemes 1 and 2.
  • the 5,7-disubstituted compounds wherein R 4 and R 3 are aryl, heteroaryl, or a heterocyclic group may be prepared by a modification of a method of Kambe et al, Synthesis, 1980, 366-368.
  • Suitable aprotic solvents include benzene, toluene, methylene chloride, DMF, THF, dioxane, and the like.
  • the reaction may be performed at from about 40 °C to about 200 °C, and preferably at the reflux temperature of the solvent, for from about 1 hour to about 24 hours, preferably about 4 hours to 8 hours.
  • the product (3) is preferably purified by chromatography after isolation from the reaction mixture.
  • the above reaction may also proceed by contacting the aldehyde (2) with malononitrile and isolating the resulting dicyano R3substituted alkene which is then reacted with the ketone (1) to form, upon addition of ammonium and cyclization, compound (3).
  • Aliphatic aldehydes do not work effectively by this route.
  • the ketone (1) may, however, include R ⁇ as alkyl groups.
  • the acetophenone starting materials (1) may be obtained commercially, or prepared easily by Friedel-Craft acylation of a suitable aromatic substrate, for example.
  • the appropriate aldehyde starting materials (2) also may be obtained commercially, or may be prepared easily, for example by reductions of esters or acids with DIBAL or another suitable hydride reducing agent, or oxidation of alcohols under Swem conditions, for example.
  • Compound (3) is then treated with excess formamide by heating at reflux. The formation of product is monitored by TLC, and when the reaction is complete (after about 1 to about 8 hours) the reaction mixture is cooled to room temperature.
  • the 5,7-disubstituted pyrido[2,3-d]pyrimidine product (I) is then removed by filtration and purified by column chromatography.
  • This compound may then be partially or fully reduced by catalytic hydrogenation to the partially saturated or fully saturated version(s) (on the right side of the molecule) of the compounds shown in Scheme 1 or of Formula I.
  • Stereoisomers produced during these reduction steps are included within the scope of the invention.
  • the present invention also contemplates reductions which produce single bonds between the 5,6 and 7,8 positions and a double bond between the 6,7 carbons.
  • the stereoisomers may be isolated and purified by conventional means.
  • R 4 is preferrably an aryl, heteroaryl or heterocyclic group
  • R 3 is loweralkyl, loweralkenyl, loweralkynyl, or an arylalkyl group.
  • R ⁇ may be selected from those additional groups listed in R3.
  • Compound (4, the "R 3 Reagent”) may be obtained commercially or prepared from the precursor ester (5) or alcohol (5) by suitable reactions.
  • Compound (5) may be reduced with a suitable reducing agent, such as for example, diisobutylaluminum hydride or another similar alkylaluminum hydride, under conditions well known to the art.
  • Compound (6) may be oxidized to the aldehyde (4) Swem oxidation conditions, or other reactions known to those skilled in the art.
  • the desired compound (4) is freshly prepared before its use in the reaction described below.
  • Compound (9), the "R 4 Reagent”)) may be prepared from the precursor alpha-bromo ketone (7) by a two-step procedure.
  • Compound (7) is treated with triphenylphosphine in the presence of a base, such as for example, triethyl amine, to give compound (8).
  • Compound (8) is then treated with an alkali metal base, such as NaOH or the like, to give compound (9).
  • the procedure is normally accomplished by vigorous mixing of a solution of (8) in an organic solvent with an aqueous solution of base.
  • the reaction mixture is cooled and added to a mixture of ammonia in ethanol.
  • the mixture is stirred for about 12 to 24 hours at 25 °C, then at reflux for from one to 4 hours, and the solvent is removed in vacuo.
  • the residue is purified by trituration with chloroform/ethyl acetate, and the product may be converted to a hydrochloride salt by suspension in 3M HCl, followed by lyophilization.
  • Scheme 3 illustrates an alternate method for preparing the compounds (I) of the invention.
  • Compounds (1), prepared as described above, are reacted with a dicyanoalkene compound (12) by heating with a suitable ammonium salt, such as for example, ammonium acetate, ammonium propionate, ammonium iodide, or the like, at reflux in an alcoholic or aprotic solvent to give the compound (I).
  • a suitable ammonium salt such as for example, ammonium acetate, ammonium propionate, ammonium iodide, or the like
  • Suitable solvents for the reaction may be easily determined by those skilled in the art, without undue trial and error, and may include, for example, ethanol, propanol, isopropanol, t-butanol, n-butanol, 1,2-dichloroethane, benzene, chloroform, carbon tetrachloride, toluene, dioxane, dimethoxyethane, and the like.
  • a preferred solvent is 1,2-dichloroethane.
  • the dicyano compounds (12) may be prepared from the precursor aldehyde (4) by treatment with malononitrile in 1 : 1 H2 ⁇ :EtOH in the presence of a catalytic amount of glycine according to the method of Bastus ⁇ Tetrahedron Lett. , 1963: 955), or alternately MgO in dichloromethane or a similar aprotic solvent (cf. Broekhuis, et al., Reel. J. R. Neth. Chem. Soc, 99: 6-12 (1980); Moison, et al. Tetrahedron (1987), 43:537-542).
  • R 1 and R 2 are not both hydrogen atoms
  • R 1 or R 2 is loweralkyl this may be accomplished by reaction of the free amino group with the appropriate alkylating reagent, such as an alkyl halide, an alkyl mesylate or an alkyl tosylate, for example, in the presence of a base such as triethylamine or potassium carbonate in a suitable solvent, such as for example, methylene chloride or THF.
  • the appropriate alkylating reagent such as an alkyl halide, an alkyl mesylate or an alkyl tosylate, for example, in the presence of a base such as triethylamine or potassium carbonate in a suitable solvent, such as for example, methylene chloride or THF.
  • R 1 or R 2 is arylalkyl this may be accomplished by reaction of the free amino group with the appropriate arylalkyl halide, an alkyl mesylate or an alkyl tosylate, for example, in the presence of a base such as triemylamine or potassium carbonate in a suitable solvent, such as for example, methylene chloride or THF.
  • a base such as triemylamine or potassium carbonate in a suitable solvent, such as for example, methylene chloride or THF.
  • R 1 or R 2 is acyl this may be accomplished by reaction of the free amino group with the appropriate acid anhydride, acyl chloride or activated acyl group, in the presence of a base such as triethylamine or potassium carbonate in a suitable solvent, such as for example, methylene chloride or THF.
  • the compound may be prepared by reacting a precursor compound having a halogen atom in place of the amino group at the 4-position with a 5-7 membered ring compound optionally containing an additional oxygen or nitrogen atom.
  • a precursor compound having a halogen atom in place of the amino group at the 4-position with a 5-7 membered ring compound optionally containing an additional oxygen or nitrogen atom.
  • examples of such compounds include, but are not limited to, mo ⁇ holine, piperidine, pyrrolidine, piperazine, thiomo ⁇ holine, and the like.
  • this alternate procedure may be used to prepare alkyl substituted amino compounds, for example by reacting the chloro compound with a mono- or disubstituted amine, such as for example, diethylamine, allyl amine, dibutylamine.
  • a mono- or disubstituted amine such as for example, diethylamine, allyl amine, dibutylamine.
  • This reaction takes place readily in a solvent such as methylene chloride, for example, in the presence of a tertiary amine.
  • the precursor compound having a halogen atom in place of the amino group at the 4-position may be prepared by substitution of triethyl orthoformate for the formamide followed by chlorination of the ring by treatment with phosphorous oxychloride or thionyl chloride in the presence of DMF in Scheme 1 wherein compound (3) is converted to compound (I).
  • a process of inhibiting adenosine kinase is disclosed.
  • an adenosine kinase enzyme is exposed to an effective inhibiting amount of an adenosine kinase inhibitor compound of the present invention.
  • Preferred such compounds for use in the process are the same as set forth above.
  • Means for determining an effective inhibiting amount are well known in the art.
  • the adenosine kinase to be inhibited can be located in vitro, in situ or in vivo. Where the adenosine kinase is located in vitro, adenosine kinase is contacted with the inhibitor compound, typically by adding the compound to an aqueous solution containing the enzyme, radiolabeled substrate adenosine, magnesium chloride and ATP.
  • the enzyme can exist in intact cells or in isolated subcellular fractions containing the enzyme. The enzyme is then maintained in the presence of the inhibitor for a period of time and under suitable physiological conditions. Means for determining maintenance times are well known in the art and depend inter aha on the concentrations of enzyme and the physiological conditions.
  • Suitable physiological conditions are those necessary to maintain adenosine kinase viability and include temperature, acidity, tonicity and the like. Inhibition of adenosine kinase can be performed, by example, according to standard procedures well known in the art (Yamada, et al, Comp. Biochem. Physiol. 1982, 71B: 367-372).
  • adenosine kinase is located in situ or in vivo, is typically administered to a fluid perfusing the tissue containing the enzyme.
  • That fluid can be a naturally occuring fluid such as blood or plasma or an artificial fluid such as saline, Ringer's solution and the like.
  • a method of inhibiting adenosine kinase in vivo is particularly useful in mammals such as humans.
  • Administering an inhibitor compound is typically accomplished by the parenteral ⁇ e.g., intravenous injection or oral) administration of the compound. The amount administered is an effective inhibiting or therapeutic amount.
  • a “therapeutically-effective amount” of the compound of the invention is meant a sufficient amount of the compound to treat adenosine kinase related disorders or those conditions or diseases which are ameliorated or modified by local inhibition of the enzyme which results in an increase in the concentration of adenosine. It will be understood, however, that the total daily usage of the compounds and compositions of the present invention is to be decided by the attending physician within the scope of sound medical judgment.
  • the specific therapeutically-effective dose level for any particular patient will depend upon a variety of factors including the disorder being treated and the severity of the disorder; activity of the specific compound employed; the specific composition employed; the age, body weight, general health, gender and diet of the patient; the time of administration, route of administration, and rate of excretion of the specific compound employed; the duration of the treatment; drugs used in combination or coincidental with specific compound employed; and the like factors well known in the medical arts and well within the capabilities of attending physicians.
  • Compounds of the present invention inhibit adenosine kinase activity in vitro and in vivo. In vitro adenosine kinase activity can be measured using any of the standard procedures well known in the art.
  • cells containing adenosine kinase are cultured in the presence and absence of an inhibitor. Inhibition is measured as the ability to inhibit phosphorylation of endogenous or externally applied ⁇ C-adenosine by these cells.
  • the cells can be intact or broken.
  • the specificity of adenosine kinase inhibitory activity is determined by studying the effects of inhibitors on adenosine Al and A2 ⁇ receptor binding, adenosine deaminase activity and adenosine transport.
  • adenosine kinase inhibitors have been reported to protect rodents ⁇ e.g., mice and rats) from seizures induced by the subcutaneous administration of pentylenetetrazol (PTZ).
  • PTZ pentylenetetrazol
  • the rodents are injected with various doses of a given inhibitor followed at various times by the subcutaneous administration of from about 10 to about 500 milligrams per kilogram of PTZ, The injected animals are then observed for the onset of seizures.
  • the compounds of the invention were tested in vivo in the hot plate test of analgesia in mammals such as mice.
  • the compounds of examples 6, 79, 104, 130, 133, 134, 137, 205, 246 and 256 in the procedure described directly below were tested thirty minutes after pretreatment with the drugs (30 ⁇ mol/kg i.p.) for latency to 10th jump (in seconds). The longer the number of seconds, the more effective the drug at masking the pain felt from the hot plate.
  • Compound 6 resulted in 152 seconds relative to the vehicle alone of 72.8 ⁇ 10.5 seconds (average ⁇ standard deviation); compound 79 resulted in 143 seconds; compound 104 resulted in 180 seconds; compound 130 resulted in 158 seconds; compound 133 resulted in 131 seconds; compound 134 resulted in 137 seconds; compound 137 resulted in 159 seconds; compound 205 resulted in 158 seconds, compound 246 resulted in 160 seconds and compound 256 resulted in 143 seconds.
  • Compounds of the invention are therefore potent pain relievers as demonstrated in this animal model.
  • mice Male CF1 mice (Charles River) of approximately 25-30 g body weight are pretreated with 10 ml/kg of the test compounds, i.p. or p.o, in groups of 8 animals per dose. At the end of the pretreatment period, the mice are placed in an Omnitech Electronics Automated 16 Animal Hot Plate Analgesia Monitor (Columbus, OH; Model AHP16AN) in individual, 9.8 x 7.2 x 15.3 cm (1 x w x h) plastic enclosures on top of a copper plate warmed to 55°C. Infared sensors located near the top of each enclosure record beam crossings that occur as the mice jump off of the heated surface.
  • Omnitech Electronics Automated 16 Animal Hot Plate Analgesia Monitor Coldbus, OH; Model AHP16AN
  • Latency times for each jump are automatically recorded, and latency to both the first and tenth jumps are used for data analysis. Mice that do not reach the criteria of 10 jumps by 180 seconds are immediately removed from the hotplate to avoid tissue damage, and they are assigned the maximum value of 180 seconds as their latency to tenth jump. Numerous other animal models of adenosine kinase activity have been described
  • Nociperception Nociperception (Nociception) (Pain)
  • Inflammation including conditions such as Septic Shock due to Sepsis Infection
  • a method of treating cerebral ischemia, epilepsy, nociperception or nociception, inflammation including conditions such as septic shock due to sepsis infection in a human or lower mammal comprising administering to the mammal a therapeutically effective amount of a compound of formula I with R -R° as defined herein.
  • the preferred compounds are those of formula II with the R variables as defined previously.
  • the present invention relates to a method of treating the above disorders comprising administering a compound of formula II wherein R3 is a substituted aryl or heteroaryl moiety wherein the substituent (preferrably halogen) is at the meta position relative to the ring attachment and R ⁇ is a substituted heteroaryl or aryl moiety wherein the substituent is at the para position relative to the ring attachment.
  • R3 is a substituted aryl or heteroaryl moiety wherein the substituent (preferrably halogen) is at the meta position relative to the ring attachment and R ⁇ is a substituted heteroaryl or aryl moiety wherein the substituent is at the para position relative to the ring attachment.
  • R ⁇ is a substituted heteroaryl or aryl moiety wherein the substituent is at the para position relative to the ring attachment.
  • Adenosine kinase activity was found to be decreased, relative to normal liver, in a variety of rat hepatomas: activity of the enzyme giving a negative correlation with tumor growth rate (Jackson, et al, Br. J. Cancer, 1978, 37: 701-713). Adenosine kinase activity was also diminished in regenerating Uver after partial hepatectomy in experimental animals (Jackson, et al, Br. J. Cancer, 1978, 37: 701-713).
  • Erythrocyte Adenosine kinase activity was found to be diminished in patients with gout (Nishizawa, et al, Clin. Chim. Acta 1976, 67: 15-20). Lymphocyte adenosine kinase activity was decreased in patients infected with the human immunodeficiency virus (HIV) exhibiting symptoms of AIDS, and increased in asymptomatic HIY-seropositive and HTV-seronegative high-risk subjects, compared to normal healthy controls (Renouf, et al, Clin. Chem. 1989, 35: 1478-1481).
  • HIV human immunodeficiency virus
  • adenosine kinase activity may prove useful in monitoring the clinical progress of patients with HIV infection (Renouf, et al, Clin. Chem. 1989, 35: 1478-1481).
  • Sepsis infection may lead to a systemic inflammatory syndrome (SIRS), characterized by an increase in cytokine production, neutrophil accumulation, hemodynamic effects, and tissue damage or death.
  • SIRS systemic inflammatory syndrome
  • the ability of adenosine kinase inhibitor to elevate adenosine levels in tissues has been demonstrated to ameliorate syndrome symptoms, due to the known anti-inflammatory effects of adenosine. (Firestein, et al., J. of Immunology, 1994: 5853-5859).
  • adenosine kinase inhibitors to elevate adenosine levels is expected to alleviate pain states, since it has been demonstrated that administration of adenosine or its analogs results in antinociception or antinociperception. (Swaynok, et al, Neuroscience, 1989, 32:557-569).
  • Examples 2-156 Following the procedures of Example 1, except substituting the appropriate reagents for R 4 and R 3 as indicated in Table 2 below, compounds of Examples 2-156 were prepared. Table 2 Examples 2-156
  • step 157a preparation of 3-bromophenylacetaldehyde (the "R 3 reagent")
  • step 157b preparation of ⁇ -(triphenylphosphonium)-4-(dimethylamino)phenylethan-l-one chloride
  • the ⁇ -bromo-(4-dimethylaminophenyl)ethan-l-one was prepared by bromination with bromine in hydrobromic acid according to the method of Suzuki et al (J. Pharm. Soc. Japan, (1955), 75:54. Removal of solvent and recrystallization from methanol/ethyl acetate/toluene gave the title product as a white powder.
  • step 157c preparation of l-(4-(dimethylamino ' )phenyl)-4-(3-bromophenyl)-but-2-en-l-one 20 g of ⁇ -(triphenylphosphonium)-4-(dimethylamino)phenylethan-l-one chloride
  • step b was partitioned between dichloromethane and 50 mL of 2N NaOH. The organic phase was dried over sodium sulfate and concentrated in vacuo. The residue was mixed with 3-bromophenylacetaldehyde (from step a) for 24 hours at 25 °C. The mixture was purified by chromatography to give 8.35 g (61%) of a cis/trans mixture of the title compound. The cis/trans mixture was taken to the next step without separation of the isomers.
  • step 157d preparation of 3-cvano-4-(3-bromophenyl)methyl-6- (4- fdimethyl)am ophenyl)pyridine-2-amine
  • Examples 158-174 Following the procedures of Example 157, except substituting the appropriate reagents for the R 4 and R 3 reagents of Example 157 as indicated in Table 3 below, compounds of Examples 158-174 were prepared. The treatment with aqueous HCl was omitted, and the free bases were obtained except as indicated.
  • Examples 167-174 the formamide or formamidine acetate (added periodically until the reaction was complete) treatment was replaced by treatment with triethyl orthoformate at reflux in the presence of a catalytic amount of ammonium sulfate, followed by cooling to 25 °C and addition of excess ammonia in ethanol. After 24 hours, the precipitated amidine compound was filtered and washed with hexanes, then dried under vacuum. The amidine compound was then heated in 1,2-dichloro benzene at 120-180 °C for 1-8 hours. The reaction mixture was cooled to room temperatureand purified by chromatography, and the product was recrystallized if necessary (chloroform in methanol). Table 3 Examples 158-187
  • Examples 190-198 Following the procedures of Example 189, except substituting the appropriate acylating reagent for the acetic anhydride of Example 189 as indicated in Table 5 below, compounds of Examples 190-198 were prepared.
  • the product was prepared by treating a solution of 4-chloro-5-(p- dimethylaminophenyl)-7-(p-bromophenyl)pyrido[2,3-d]pyrimidine in CH2 2-TEA with allylamine and heating the resulting mixture at reflux for 1 hour. The volatiles were removed under reduced pressure, and the residue was purified by flash chromatography (Si ⁇ 2, EtOAc/hexanes) to provide the title compound IR (KBr) 3437, 1564, 1355, 1195; MS mlz 460/462 (M+H)+.
  • the 4-chloro-5-(p-dimethylaminophenyl)-7-(p-bromophenyl)pyrido [2,3- dlpyrimidine was prepared as follows. A sample of 4-(4-bromophenyl)-3-cyano-6-(4-(dimethylamino)phenyl)pyridine-2- amine (from Example 1, 5.0 g, 12.7 mmol) in 20 mL of H2SO4 was heated at 80 °C for 30 minutes. Ice was added, and the reaction mixture was neutralized with aqueous NaOH. The resulting crude 3-carboxamide was collected by filtration, triturated with EtOAc- hexanes, then dried under reduced pressure (4.95 g, 95% theoretical).
  • the POCl 3 was removed under reduced pressure to provide crude 4-chloro-5-(p-dimethyla ⁇ nophenyl)-7-(p-bromophenyl)pyrido[2,3-d]pyrimidine.
  • the invention therefore relates to intermediate compounds of formula HI wherein X is selected from hydroxyl or halogen and the remaining variables are the same as in formula I or II.
  • Example 200 4-(2-(N.N-dimemylamino)ethylamino)-5-(4-bromophenyl)-7-(4-dimethylaminophenyl) pyrido r2,3-dl pyrimidine trihvdrochloride
  • the product was prepared by treating a solution of 4-chloro-5-(p- dimethylaminophenyl)-7-(p-bromophenyl)pyrido[2,3-d]pyrimidine (prepared as in Example 199) in CH2CI2-TEA with the 2-(dimethylamino)ethylamine and heating the resulting mixture at reflux for 1 hour.
  • Example 201 4-(4-(N.N-dimethylamino)butylamino)-5-(3-bromophenyl)-7-(4- dimethylaminophenyl) pyrido [2.3-dl pyrimidine tetrahvdrochlori.de
  • the product was prepared by treating a solution of 4-amino-5-(p- dimethylaminophenyl)-7-(p-bromophenyl)pyrido[2,3-dlpyrimidine in CH2CI2-TEA with the 4-(dimethylamino)butylamine and heating the resulting mixture at reflux for 1 hour. The volatiles were removed under reduced pressure, and the residue was purified by flash chromatography (Si ⁇ 2, EtOAc/hexanes).
  • the 5-aminopyridine-2-carboxaldehyde starting material was prepared as follows: 204a. 5-amino-2-bromopyridine
  • Hg(O2CCF3)2 (11.1 g, 26 mmol) and H2SO4 (72 mmol) were added to the reaction mixture, and the solution was heated at reflux for 2 hours.
  • the reaction mixture was cooled to 25 °C and neutralized with saturated aqueous sodium carbonate.
  • Example 205 4-am o-5-(3-bromophenyl)-7-(5-dimemylamino-2-pyridyl)pyridor2,3-dlpyrirrudine trihvdrochloride salt
  • the 5-dimethylammopyridine-2-carboxaldehyde starting material was prepared as follows:
  • Example 206 4-am o-5-(3-bromophenyl)-7-(5-dimethylamino-2-pyrazinyl)- pyrido[2.3-dlpyrimidine hydrochloride
  • the 5-dimethylaminopyrazine-2-carboxaldehyde starting material was prepared as follows:
  • 2-oxobenzoxazolin-6-ethanone_ was reacted with bromobenzaldehyde, malononitrile, and ammonium acetate to prepare the title compound: LRMS m/z 434/436; IR (cm "1 ) 3095, 1760, 1579, 1481, 1350.
  • the 2-oxobenzoxazolin-5-ethanone_starting material was prepared as follows:
  • the l-methyl-2-oxobenzoxazolin-5-ethanone_starting material was prepared as follows:
  • Example 209 4-amino-5-((5-chloro-2-(3-methoxyphenyl)phenyl)methyl)-7-(4- dimethylam ophenyl)pyridor2.3-dlpyrimidine
  • the title compound was prepared from the compound of Example 173 by reaction with 3-methoxyphenylboronic acid, Pd(PPh3)4 and aqueous sodium carbonate under Suzuki reaction conditions.
  • IR (KBr) 3550-3250,3240- 2760,1580,1560,1540,1350; H. Res. MS m/z 496.1902 (M+H)+.
  • Example 210 4-ammo-5-((2-bromophenyl)methyl)-7-(4-m ⁇ ethylammophenyl)pyridor2.3-dlpyrirnidine Following the procedures of Example 157, except substituting l-(4- dimethylaminophenyl)-ethanone for the R 4 reagent and 2-(2-bromophenyl)- acetaldehyde for the R 3 reagent of Example 157, the title compound was prepared as shown in Table 6.
  • Example 212 4-amino-5-(2-((thiophene-3-yl)phenyl)methyl)-7-(4-diethylaminophenyl)pyridor2.3- dlpyrimidine
  • the title compound was prepared from the compound of Example 173 by reaction with 3-thiopheneboronic acid, Pd(PPh3)4 and aqueous sodium carbonate under Suzuki reaction conditions.
  • IR (KBr) 3640-3240, 3240-2800, 1580, 1560, 1540, 1350; H. Res. MS m/z 466.2057 (M+H)+.
  • Example 213 *prepared by deformylation of Example 213 with dilute HCl in methanol. **prepared by acylation of Example 213 with 2-methoxyacetyl chloride/pyridine. ***prepared by formylation of the 7-(3-bromophenyl)-2-cyano-5-(4- aminophenyl)pyridine-2-amine intermediate. ****prepared by acylation of Example 213 with the 2-(dimethylamino)acetyl chloride.
  • Examples 223-225 Following the procedures of Example 157, except substituting the appropriate reagents for the R 4 and R 3 reagents of Example 157 as indicated in Table 8 below, compounds of Examples 223-225 were prepared. Table 8 Examples 223-225
  • Examples 226-228 Following the procedures of Example 1, except substituting the appropriate reagents for R 4 and R 3 as indicated in Table 9 below, compounds of Examples 226-228 were prepared.
  • Examples 231-243 Following the procedures of Example 1, except substituting the appropriate reagents for R 4 and R 3 as indicated in Table 10 below, compounds of Examples 230-243 were prepared. In some cases, the treatment with aqueous HCl was omitted, and the free bases were obtained. Table 10 Examples 231-243
  • the title compound was prepared by condensing l,l-dicyano-(3-(3- bromophenyl)propene (the R 3 reagent) with the compound from Step 246c (the R 4 reagent) and ammonium acetate in ethanol according to the procedure of Example 157d.
  • the title compound was prepared from the compound of Step 246d according to the procedure of Example 157, except substituting formamide for the ammonium sulfate and triethyl orthoformate thereof.
  • step (c) first substituting the appropriate reagent for R 4 as indicated in Table 1 IB below for the R 4 reagent of Example 244 step c, and secondly performing the condensation with ammonium acetate substituting dichloroethane as the solvent in place of the ethanol solvent in Example 244 step c, the compounds of Examples 249-2 1 were prepared. In some cases, the hydrochloride salts were not prepared. Table 1 IB Examples 249-260
  • Step 252a l-(5-bromo-2-pyridyl)ethanone, ethylene ketal
  • dibromopyridine 5.2 g, 21.95 mmol
  • tributyl(l-ethoxyvinyl)tin 9.11 g, 25.24 mmol
  • Pd2(dba)3 0.7 g, 0.8 mmol
  • (2-furyl)3P 0.37 g, 1.6 mmol
  • the reaction mixture was concenttated, and the crude product was purified by elution through a short column of silica gel.
  • Step 252c 4-amino-5-(3-bromophenyl)-7-(5-(N.N-bis(2-methoxyethyl)amino)-2- pyridinyl)pyrido[2,3-dlpyrimidine ttihvdrochloride
  • step (c) first substituting the reagent from Step 252b for the R 4 reagent of Example 244 step c, and secondly performing the condensation with ammonium acetate substituting dichloroethane as the solvent in place of the ethanol solvent in Example 244 step c, the free base of the title compound was prepared.
  • the title compound was prepared from this by treatment with HCL in ether.
  • IR (KBr) 3440, 1635, 1605, 1580, 1360 cm" 1 ; MS mlz 466/468, (M+H)+.
  • Examples 253-260 Following the procedures of Example 244, except in step (c) first substituting the appropriate reagent for R 4 as indicated in Table 1 IB below for the R 4 reagent of Example 244 step c, and secondly performing the condensation with ammonium acetate substituting dichloroethane as the solvent in place of the ethanol solvent in Example 244 step c, the compounds of Examples 253-260 were prepared. In some cases, the hydrochloride salts were not prepared.
  • the compound was prepared by using the method generally described above in
  • Example 262 4-(me ylarruno)-5-(3-bromophenyl)-7-(4-dime ylanjmophenyl)pyridor2.3-d1pyrimidi «e hydrochloride
  • the title compound was prepared by using the method described in Example 200, except substituting methylamine for the 2-(dimeftylammo)ethylamine thereof.
  • Example 263 4-(2-methoxyethylamino)-5-(3-bromophenyl)-7-(4- dimethylaminophenyl)pyrido[2.3-dlpyrimidine hydrochloride
  • the title compound was prepared by using the method described in Example 200, except substituting 2-methoxyethylamine for the 2-(dimethylamino)ethylamine thereof.
  • Step 264a l-(4-(l-Methylimidazol-2-yl)phenyl)ethanone
  • N-methyl imidazole (0.90 g, 11.0 mmol) in 12 mL of THF at -78 °C was treated with n-BuLi (7.5 mL, 1.6 M solution in hexanes, 12.0 mmol) for 0.5 hours at - 78 °C.
  • ZnCl 2 (20 mL, 1.0 M solution in Et 2 O, 20 mmol) was added, and the solution was warmed to 25°C.
  • Step 264b 4-amino-5-(3-bromophenyl)-7-(4-( l-methyl-2-imidazolyl)phenyl)pyrido[2,3- dlpyrimidine ttihvdrochloride
  • step (c) Following the procedures of Example 244, except in step (c) first substituting the R 4 reagent from Step 264a for the R 4 reagent of Example 244 step c, and secondly performing the condensation with ammonium acetate substituting dichloroethane as the solvent in place of the ethanol solvent in Example 244 step c, the title compound was prepared.
  • Example 265-267 Following the procedures of Example 244, except in step (c) first substituting the appropriate reagent for R 4 as indicated in the Table below for the R 4 reagent of Example 244 step c, and secondly performing the condensation with ammonium acetate substituting dichloroethane as the solvent in place of the ethanol solvent in Example 244 step c, the compounds of Examples 264-285 were prepared. In Ex. 266, the hydrochloride salt was not prepared.
  • Example 268 4-amino-5-( ' 3-bromophenylV7-f4-(3-(dimethylarnino propynyl phenyl)pyridor2.3- dlpyrimidine
  • Example 269-271 Following the procedures of Example 268, except substituting the reagent compound shown in the table below for the 3-dimethylaminoprop-l-yne of Example 268, the compounds shown in the table below were prepared.
  • Step 273a 7-acetyl-2H-pyridor3.2-b1-1.4-oxazin-3(4H)-one
  • Step 273b 7-acetyl-4-methyl-2H-pyrido[3.2-bl-1.4-oxazin-3(4H)-one
  • step 273 a The compound from step 273 a was tteated with methyl iodide and Na ⁇ in 1: 1 T ⁇ F/DMF for 6 hours at 0 °C to 25 °C.
  • the reaction was quenched with aqueous sodium bicarbonate solution, the mixture was extracted with dichloromethane, and the resiue was purified by chromatogaphy to give the tide compound.
  • Step 273c 4-amino-5-(3-bromophenyl)-7-(4-methyl-3-oxo-2 ⁇ -4 ⁇ -pyridor3.2-bl-1.4- oxazinyl)pyrido[2.3-dlpyrimidine
  • Example 244 Step c Following the procedure of Example 244 Step c, except first substituting 7-acetyl-4- methyl-2H-pyrido[3,2-b]-l,4-oxazin-3(4H)-one (the R 4 reagent) from Step 273b for the R 4 reagent of Example 244 Step c, and secondly performing the condensation with ammonium acetate substituting dichloroethane as the solvent in place of the ethanol solvent in Example 244 step c, the title compound was prepared. MS (M+ ⁇ ), 463 (1 Br); IR (cm-1) 3400, 3200-2800, 1700, 1640, 1605, 1590, 1395, 1380, 1345.
  • Example 274 4-amino-5-(3-bromophenyl)-7-(4-(2-(dimethylamino)ethyl)-3-oxo-2 ⁇ -4 ⁇ -pyrido[3,2-bl- l,4-oxazin-7-yl)pyridor2.3-dlpyrimidine
  • Step 274a 7-acetyl-4-dimethylaminoethyl -2H-pyridor3.2-bl-1.4-oxazin-3(4H)-one
  • the compound from Example 273 Step a was treated with 2-chloro-(N,N- dimethyl)ethylamine HCl and K2CO3 in aqueous acetone at reflux.
  • the mixture was diluted with water and exttacted with dichloromethane, and the residue was purified by chromatogaphy to give the title compound.
  • Step 274b 4-amino-5-(3-bromophenyl)-7-(4-(2-(dimethylamino)ethyl)-3-oxo-2H-4H- pyrido[3.2-bl-l,4-oxazin-7-yl)pyrido[2,3-dlpyrimidine
  • step c Following the procedures of Example 244 Step c, except in step c first substituting 7-acetyl-4-dimethylaminoethyl -2H-pyrido[3,2-b]-l,4-oxazin-3(4H)-one (the R 4 reagent, from Step 273b) for the R 4 reagent of Example 244 Step c, and secondly performing the condensation with ammonium acetate substituting dichloroethane as the solvent in place of the ethanol solvent in Example 244 step c, the title compound was prepared. MS (M+ ⁇ ), 519 (1 Br); IR (cm-1) 3440, 1685, 1630, 1605, 1580, 1395
  • Step 275a 6-acetyl-2-benzoxazolinone Following the procedures of Example 273 Step a, except substituting 2- benzoxazolinone (Aldrich) for the 2H-pyrido[3,2-b]-l,4-oxazin-3(4H)-one thereof, the title compound was prepared.
  • Step 275b 6-acetyl-3-(dimethylaminoethyl)-2-benzoxazolinone
  • the compound from Example 275 Step a was tteated with 2-chloro-(N,N- dimethyl)ethylarnine ⁇ C1 and K2CO3 in aqueous acetone at reflux. The mixture was diluted with water and exttacted with dichloromethane, and the residue was purified by chromatogaphy to give the title compound.
  • Step 275c 4-amino-5-(3-bromophenyl)-7-(2,3-dihvdro-3-(dimethylaminoethyl)-2- oxobenzoxazol-6-yl)pyridor2.3-dlpyrimidine
  • Example 244 Step c Following the procedures of Example 244 Step c, except in step c first substituting the compound from Step 275a for the R 4 reagent of Example 244 Step c, and secondly performing the condensation with ammonium acetate substituting dichloroethane as the solvent in place of the ethanol solvent in Example 244 step c, the title compound was prepared. MS (M+ ⁇ ), 506 (1 Br); IR (cm-1) 3400, 3050, 1630, 1610, 1360.
  • Example 276 4-amino-5-(3-bromophenyl)-7-(4-methyl-3-oxo-2H-4H-benzo-l,4-oxazin-7-yl)pyridor2.3- dlpyrimidine
  • Example 275 Step a The compound from Example 275 Step a was tteated with methyl iodide and NaH in 1: 1 THF/DMF for 6 hours at 0 °C to 25 °C. The reaction was quenched with aqueous sodium bicarbonate solution, the mixture was exttacted with dichloromethane, and the resiue was purified by chromatogaphy to give the title compound.
  • Step 276b l-(3-hvdroxy-4-methylaminophenyl)-ethanone
  • Step 276c 7-acetyl-4-methyl-2H-4H-benzo-l,4-oxazin-3-one
  • Step 276d 4-amino-5-(3-bromophenyl)-7-(4-methyl-3-oxo-2H-H-benzo- 1 -oxazin-7- yl)pyridor2.3-dlpyrimidine
  • step c first substituting the compound from Step 276c for the R 4 reagent of Example 244 Step c, and secondly performing the condensation with ammonium acetate substituting dichloroethane as the solvent in place of the ethanol solvent in Example 244 step c, the title compound was prepared.
  • Example 277 4-amino-5-(3-bromophenyl)-7-(2.2.4-trimethyl-3-oxo-2H-4H-benzo-1.4-oxazin-7- yl)pyrido[2,3-dlpyrimidine Step 277a. 7-acetyl-2.2.4-trimethyl-2H-4H-benzo-1.4-oxazin-3-one
  • Step 277b 4-amino-5-(3-bromophenyl)-7-(2,2,4-trimethyl-3-oxo-2H-4H-benzo-1.4- oxazin-7-yl)pyridor2.3-dlpyrimidine
  • Example 244 Step c Following the procedures of Example 244 Step c, except in step c first substituting the compound from Step 277a for the R 4 reagent of Example 244 Step c, and secondly performing the condensation with ammonium acetate substituting dichloroethane as die solvent in place of the ethanol solvent in Example 244 step c, the title compound was prepared. MS (M+H), 490 (1 Br); IR (cm-1) 3450, 2900-3100, 1680, 1645, 1610, 1515, 1385, 1365, 1 165.
  • Example 278 4-an ⁇ ino-5-cvclohexyl-7-(4-(2-dimethylamino)ethyl)-2H-4H-benzo-3-oxo-1.4-oxazin-7- yl)pyridor2.3-dlpyrimidine
  • Step 278a l-(3-hvdroxy-4-(2-(dimethylamino)ethyl)phenyl)-ethanone
  • Step 278b 7-acetyl-4-(dimethylamino)ethyl)-2H-4H-benzo- 1.4-oxazin-3-one
  • step c Following the procedures of Example 244 Step c, except in step c first substituting l,l-dicyano-3-cyclohexylethene (prepared according to die method of Moison, et al. (Tetrahedron (1987), 43:537-542) by treating cyclohexane carboxaldehyde with malononitrile in the presence of finely powdered magnesium oxide in dichloromethane) for the R3 reagent of Example 244 Step c, and substituting the compound from Step 278b for the R 4 reagent of Example 244 Step c, and also performing the condensation with ammonium acetate but also substituting dichloroethane as the solvent in place of the ethanol solvent in Example 244 step c, the tide compound was prepared. MS (M+H) 447; IR(cm-l) 3400, 2900, 1690, 1610, 1590, 1395.
  • Step 279a l-(5-methvethyl-2-pyridyl)ethanone
  • Step 279b 4-amino-5-(3-bromophenyl)-7-(5-( l-methylethyl)-2-pyridyl)pyridor2,3- dlpyrimidine
  • Example 244 Step c Following the procedures of Example 244 Step c, except in step c substituting the compound from Step 279a for the R 4 reagent of Example 244 Step c, and performing the condensation with ammonium acetate and also substituting dichloroetfiane as the solvent in place of the ethanol solvent in Example 244 step c, the tide compound was prepared. MS (M+H) 421 (IBr); IR (cm-1) 3489, 2940, 1545, 1482, 1357.
  • Example 244 Step c Following the procedures of Example 244 Step c, except in step c substituting die compound shown below for the R 4 reagent of Example 244 Step c, and performing the condensation with ammonium acetate and also substituting dichloroethane as the solvent in place of the ethanol solvent in Example 244 step c, the compounds shown in the table below were prepared.
  • Step 282a 4-cyanoacetophenone. acetal with 2.2-dimethylpropylene glycol
  • Step 282b 4-(aminomethyl)acetophenone. acetal with 2.2-dimethylpropylene glycol
  • Step 282c l-(4-(BOC-aminomethyl)phenyl)ethanone
  • THF 20 mL
  • IN HCl 20 mL
  • d-tibutyl dicarbonate 2.18 g, 10 mmol
  • the mixture was stirred at room temperature over a weekend.
  • the solution was diluted with water, and the mixture was exttacted with ether and ethyl acetate.
  • the organic extracts were dired (MgSO4), and the solvent was remove under vacuum to give the title compound.
  • step c substituting the compound from Step 282c for the R 4 reagent of Example 244 Step c, and performing the condensation with ammonium acetate but also substituting dichloroethane as die solvent in place of the ethanol solvent in Example 244 step c, the tide compound was prepared.
  • Step 283a 4-(l -amino- l-methylethyl)acetophenone
  • Step 283b 4-(l-(N-BOC- amino)- l-methylethyl)acetophenone
  • Step 283a The compound from Step 283a (2.32 g, 8.77 mmol) was tteated sequentially with HCl and di-t-butyl dicarbonate according to the procedure of Example 282 Step c to give the title compound (1.60 g). MS (M+H) 278.
  • Step 283c 4-amino-5-(3-bromophenylV7-(4-(l-(N-formylamino)-l- methylethyl)phenyl)pyridor2.3-dlpyrimidine
  • Example 244 Step c Following the procedures of Example 244 Step c, except in step c substituting the compound from Step 283b for the R 4 reagent of Example 244 Step c, and performing the condensation with ammonium acetate but also substituting dichloroetiiane as the solvent in place of the ethanol solvent in Example 244 step c, the tide compound was prepared.
  • Step 284a 4-(l-(dimemylamino)-l-methylemyl)acetophenone
  • the compound from Step 283a (1.18 g, 5 mmol) was dissolved in 5 mL formic acid, and 5 mL of formalin (37% ) was added. The mixture was heated at reflux for 4 hours, then cooled and neuttalized widi 2N Na 3 CO 3 . The mixture was exttacted with dichloromethane. The solution was dried (MgSO 4 ), and the solvent was removed to give the title compound (0.94 g).
  • IR (cm-1) 3520, 1640, 1610, 1580, 1375.
  • Examples 285-286 Following die procedures of Example 157, except substituting die appropriate reagents for the R 3 and R 4 reagents of Example 157 as indicated in the Table below, compounds of Examples 285-286 were prepared. For Example 286, treatment with aqueous HCl was omitted, and the free base was obtained.
  • Examples 287-300 Following the procedures of Example 157, except substituting the appropriate R 3 and R 4 reagents as indicated in die Table below and replacing the formamide or formamidine acetate treatment with treatment with triethyl orthoformate at reflux in the presence of a catalytic amount of ammonium sulfate, followed by cooling to 25 °C and addition of excess ammonia in ethanol, compounds of Examples 287-300 were prepared. . After 24 hours, the precipitated amidine compound was filtered and washed with hexanes, then dried under vacuum. The amidine compound was then heated in 1,2-dichloroethane at reflux for 1-8 hours. The reaction mixture was cooled to room temperature and purified by chromatography, and die product was recrystallized if necessary. The treatment with aqueous HCl was omitted in some cases, and the free bases were obtained.
  • the l,l-dicyano-3-cyclohexyled ⁇ ene was prepared according to the method of Moison, et al (Tetrahedron (1987), 43:537-542) by treating cyclohexane carboxaldehyde witii malononitrile in the presence of finely powdered magnesium oxide in dichloromethane.
  • the reagents for the following examples were prepared by this method substituting the compound shown below for the cyclohexane carboxaldehyde used to prepare the reagent of Example 290.
  • Example 298, N-(phenylmethoxylcarbony)piperidine-4-carboxaldehyde (this material was prepared from N-(carbobenzyloxy)-4-(2-hydroxyethyl)piperidine (Brehm et al., Helv.Chim.Acta, 70; (1987), 1981-1987 by treatment with TEMPO (2,2,6,6-tetramethylpiperidinyloxy radical) and potassium bromide in dichloromethane at 0 °C to which was added commercial bleach (Clorox) containing sodium bicarbonate).
  • TEMPO 2,2,6,6-tetramethylpiperidinyloxy radical
  • Example 303 the compounds of Examples 301-305 were prepared.
  • the condensation solvent was DMSO instead of etfianol and dimetiioxyethane.
  • Example 306 4-amino-5-cvclohexyl-7-(6-(4-acetvIpiperazinyl)-3-pyridyl)pyrido[2.3-dlpyrimidine
  • a mixture of 679 mg (2 mmol) of the compound from Example 298 and 1.28 g (10 mmol) of N-acetylpiperazine in 5 mL of DMSO was heated at 110 °C for 5 hours. On cooling a precipitate was deposited, which was collected and washed with 20% metiianol and dried to give 647 mg of the product as orange flakes:
  • IR (cm-1) 3522, 3306, 3110, 2925, 2854, 1670, 1650, 1586, 1506.
  • Example 307-322 Follwing the procedure of Example 306, except substituting the reagent shown in the table below for the N-acetylpiperazine of Example 306, the compounds shown in the table were prepared. The compounds were purified by HPLC chromatography.
  • Example 323 4-an ⁇ mo-5-(l-(2-bromophenyl)ethyl)-7-(l-memyl-5-indolyl)pyridor2.3-dlpyrimidine
  • the procedures of Example 157 were followed, except substituting l',l'-dicyano-3- bromostyrene for the R 3 reagent and l-(l-methyl-5-indolyl)-ethanone for the R 4 reagent .
  • the precipitated amidine compound was filtered and washed with hexanes, then dried under vacuum.
  • the amidine compound was tiien heated in 1,2-dichloroethane at reflux for 1-8 hours.
  • Example 324 4-amino-5-(l-(2-bromophenyl)ethyl)-7-(l-methyl-2.3-dioxo-5-indolyl)pyrido[2.3- dlpyrimidine
  • the tide compound was prepared from the compound of Example 323 by oxidation with CrO3 in sulfuric acid.
  • Examples 325-326 Following the procedures of Example 157, except substituting the appropriate R 3 and R 4 reagents as indicated in the Table below, compounds of Examples 325-326 were prepared. After 24 hours, the precipitated amidine compound was filtered and washed with hexanes, then dried under vacuum. The amidine compound was then heated in 1,2- dichloroediane at reflux for 1-8 hours. The reaction mixture was cooled to room temperature and purified by chromatography, and the product was recrystallized if necessary. The treatment with aqueous HCl was omitted in some cases, and the free bases were obtained.
  • Example 244 Step c Following the procedures of Example 244 Step c, except in step c substituting the compound resulting from the reaction of 2-acetyl-5-chloropyridine in refluxing edianol with the precursor reagent compound (4-piperidinone ethylene ketal) shown below for the R 4 reagent of Example 244 Step c, and substituting dichloroethane as the solvent in place of the ethanol solvent in Example 244 step c, the compound shown in the table below was prepared.
  • Example 328 4-ammo-5-(3-bromophenyl)-7-(6-(4-oxopiperidinyl)-3-pyridyl)pyrido[2.3-dlpyrimidine Treating the compound of Example 327 with dilute HCl, die title compound was prepared.
  • Example 329-331 Following the procedures of Example 244 Step c, except in step c substituting die compound resulting from the reaction of 2-acetyl-5-chloropyridine in refluxing etiianol with the precursor reagent compound shown below for the R 4 reagent of Example 244 Step c, and substituting dichloroethane as the solvent in place of the ethanol solvent in Example 244 step c, the compounds shown in the table below were prepared.
  • Example 332 4-amino-5-(3-bromophenyl)-7-(6-(4,4-dioxothiomo ⁇ hohnyl)-3-pyridyl)pyrido[2,3- dlpyrimidine
  • the compound of Example 331 was treated with 4-chloroperbenzoic acid in metiianol and dichloromethane to give the tide compound.
  • Example 333 4-amino-5-(2-bromophenyl)-7-(6-mo ⁇ holinyl-3-pyridyl)pyrido[2,3-d1pyrimidine
  • Step 333a r,r-dievano-2-bromostyrene
  • the tide compound was prepared by condensation of 2-bromobenzaldehyde with malononitrile and MgO in dichloromethane by the standard procedure of Broekhuis et al. ⁇ Reel J. R. Neth. Chem. Soc, 99: 6-12 (1980)).
  • Step 333b 5-acetyl-2-mo ⁇ holinylpyridine
  • the title compound was prepared by the reaction of 5-acetyl-2-chloropyridine with mo ⁇ holine in refluxing ethanol.
  • the tide compound was prepared by condensation of r,l'-dicyano-2-bromostyrene with 5-acetyl-2-mo ⁇ holinylpyridine and ammonium acetate in dichloroethane at reflux. After the reaction was complete (TLC), the mixture was cooled, and the solvent was removed. The residue was triturated with methanol to give the product
  • Step 333d 4-amino-5-(2-bromophenyl)-7-(6-mo ⁇ holinyl-3-pyridyl)pyrido[2.3- dlpyrimidine
  • Examples 334-336 FoUowing the procedures of Example 333, except in Step a substituting the precursor aldehyde reagent shown below for the 2- bromobenzaldehyde of Example 333 Step a, and carrying the product forward as in procedures 333 Stepbs b-d, the compounds shown in the table below were prepared. Examples 334-336
  • Step b substituting 5-acety 1-2,3- dichloropyridine for the 5-acetyl-2-chloropyridine to give 5-acetyl-3-chloro-2- mo ⁇ holinylpyridine, and substituting 5-acetyl-3-chloro-2-mo ⁇ holinylpyridine for the 5- acetyl-2-mo ⁇ hohnylpyridine in step c, then the carrying the product forward as in Example 333 Step d, the title compound was prepared.
  • Example 338 4-an ⁇ ino-5-(3-bromophenyl)-7-(6-(N-oxidomo ⁇ holinyl)-3-pyridyl)pyrido[2.3-d1pyrimidine
  • the tide compound was prepared by treating die compound of Example 134 witii hydrogen peroxide in acetic acid according to standard procedures.
  • Step 339a .r-dicvano-3-bromostyrene
  • the tide compound was prepared by condensation of 3-bromobenzaldehyde with malononitrile and MgO in dichloromethane by the standard procedure of Broekhuis et al. ⁇ Reel J. R. Neth. Chem. Soc, 99: 6-12 (1980)).
  • the tide compound was prepared by the reaction of 5-acetyl-2-chloropyridine with 2-ed ⁇ oxyeti ⁇ ylamine in refluxing ethanol.
  • Step 339c 4-(3-bromophenyl)-3-cvano-6-(N-(2-ethoxyethyl)amino)pyridine-2-amine
  • the tide compound was prepared by condensation of ,l'-dicyano-2-bromostyrene with 5-acetyl-2-mo ⁇ holinylpyridine and ammonium acetate in dichloroethane at reflux. After the reaction was complete (TLC), the mixture was cooled, and the solvent was removed. The residue was triturated witii methanol to give the product.
  • Step 339d 4-amino-5-(2-bromophenyl)-7-(6-(N-(2-ed ⁇ oxyethyl)amino)-3- pyridyl)pyrido[2.3-dlpyrimidine
  • Example 340 4-amino-5-(3-bromophenyl)-7-(6-(N-(2-hvdroxyethoxyethyl)-N-formyla ⁇ rino)-3- pyridyl)pyridor2,3-dlpyrimidine This compound was isolated by chromatography as a product of the reaction described in Example 239 Step d.
  • Example 341 4-amino-5-(3-bromophenv -7-(6-(N-(2-hvdroxyethoxyethyl)-3-pyridyl-N- oxide)pyridor2.3-dlpyrimidine
  • the tide compound was prepared by treating the compound of Example 341 with hydrogen peroxide in acetic acid according to standard procedures.
  • IR (microscope) 3296, 1628, 1560, 141 1, 1353 cm ' 1 ; MS mlz 497 (M+H)+.
  • Example 342 4-amino-5-(3-bromophenyl)-7-(6-(3-hydroxy)mo ⁇ holinyl)-3-pyridyl)pyrido[2.3- dlpyrimidine
  • the tide compound was prepared from the compound of Example 328 by reduction witii (Lithium Aluminum Hydride, and subsequent workup acccording to standard procedures).
  • Example 343 l-(5-(4-ammo-5-(3-bromophenyl)pyrido[2,3-dlpyrimidin-7-yl)-2-pyridyl)-piperidine-4- phosphate, disodium salt
  • the title compound was prepared from the compound of Example 342 by treatment with POCI3, and subsequent workup acccording to standard procedures.
  • Example 344 4-amino-5-(3-bromophenyl)-7-(6-(2-hvdroxy)mo ⁇ holinyl)-3-pyridyl)pyridor2.3- dlpyrimidine
  • the tide compound was prepared from the compound of Example 339 by oxidation of the free hydroxy group to an aldehyde with TEMPO reagent. During workup of the mixture, the compound self-condensed to give die tide compound.
  • Example 346 4-amino-5-(3-bromophenyl)-7-(4-hvdroxy-4-(hvdroxymethvDpiperidinyl)-3- p yrid yl)p yridor ⁇ .3 -dlpyrimidine
  • the title compound was prepared from the compound of Example 345 by treatment with Os ⁇ 4 in DMSO at room temperature. After quenching, the title compound was extracted, then purified by chromatography.
  • Step 347a l.l-dicvano-3-cvclohexylethene
  • the l,l-dicyano-3-cyclohexylethene was prepared according to the method of Moison, et al. (Tetrahedron (1987), 43:537-542) by tteating cyclohexane carboxaldehyde with malononitrile in the presence of finely powdered magnesium oxide in dichloromethane.
  • Step 347c 4-amino-5-cvclohexyl-7-(6-(4.4-ethylenedioxypiperidinyl)-3- pyridyl)pyridor2.3-d1pyrimidine
  • Example 349 4-ammo-5-cvclohexyl-7-(6-(4-me ylenylpiperidinyl)-3-pyridv pyridor2.3-dlp ii ⁇ idirie
  • the tide compound was prepared from the compound of Example 348 by treatment with methyl triphenylphosphine bromide at -78 °C in DMSO. After quenching and warming the mixture to room temperature, the title compound was exttacted, then purified by chromatography.

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Abstract

A method for inhibiting adenosine kinase by administering a compound having formula (I) wherein R?1 and R2¿ are independently selected from H, loweralkyl, C¿1?-C6alkoxyC1-C6alkyl, arylC1-C6alkyl, -C(O)C1-C6alkyl, -C(O)aryl, -C(O)heterocyclic or may join together with the nitrogen to which they are attached to form a 5-7 membered ring optionally containing 1-2 additional heteroatoms selected from O, N or S; R?3¿ is selected from the group consisting of loweralkyl, loweralkenyl, loweralkynyl, cycloalkyl, aryl, arylalkyl, heteroaryl, heterocyclic group, heteroarylalkyl or heterocycloalkyl wherein the heteroaryl and heterocyclic groups are linked directly or indirectly by a ring carbon; R4 is selected from the group consisting of loweralkyl, loweralkenyl, loweralkynyl, cycloalkyl, aryl, arylalkyl, heteroaryl, heterocyclic group heteroarylalkyl or heterocycloalkyl; and a dashed line --- indicates that a double bond is optionally present provided that proper valencies are maintained, a pharmaceutical composition comprising a therapeutically effective amount of a compound thereof above in combination with a pharmaceutically acceptable carrier, and a method of treating cerebral ischemia, epilepsy, nociperception, inflammation and sepsis in a mammal in need of such treatment, comprising administering to the mammal a therapeutically effective amount of a compound thereof, a process for preparing said compounds, and compounds having the above formula wherein R?1, R2, R3 and R4¿ are separately defined.

Description

5 , 7-DISUBSTITUTED 4-AMIN0PYRID0[2 , 3-D]PYRIMIDINE COMPOUNDS AND THEIR USE AS ADENOSINE KINASE INHIBITORS
Technical Field The present invention relates to a method of inhibiting adenosine kinase by administering 5,7-disubstirated-4-aminopyrido[2,3-d]pyriπύdine compounds, to pharmaceutical compositions containing such compounds, as well as to certain 5,7- disubstituted-4-aminopyrido[2,3-d]pyrimidine compounds.
Background Of The Invention
Adenosine kinase (ATP:adenosine 5'-phosphotransferase, EC 2.7.1.20) is a ubiquitous enzyme which catalyzes the phosphorylation of adenosine to AMP, using ATP, preferentially, as the phosphate source. Adenosine kinase has broad tissue and species distribution, and has been isolated from yeast, a variety of mammalian sources and certain microorganisms. It has been found to be present in virtually every human tissue assayed including kidney, liver, brain, spleen, placenta and pancreas. Adenosine kinase is a key enzyme in the control of the cellular concentrations of adenosine.
Adenosine is a purine nucleoside that is an intermediate in the pathways of purine nucleotide degradation and salvage. Adenosine also has many important physiologic effects, many of which are mediated through the activation of specific ectocellular receptors, termed Pl receptors (Burnstock, in Cell Membrane Receptors for Drugs and Hormones,
1978, (Bolis and Straub, eds.) Raven, New York, pp. 107-118; Fredholm, et al., Pharmacol. Rev. 1994, 46: 143-156).
In the central nervous system, adenosine inhibits the release of certain neurotransmitters (Corradetti, et al., Eur. J. Pharmacol. 1984, 104: 19-26), stabilizes membrane potential (Rudolphi, et al., Cerebrovasc. Brain Metab. Rev. 1992, : 346-360), functions as an endogenous anticonvulsant (Dragunow, Trends Pharmacol. Sci. 1986, 7: 128- 130) and may have a role as an endogenous neuroprotective agent (Rudolphi, et al., Trends Pharmacol. Sci., 1992, 13: 439-445). Adenosine may play a role in several disorders of the central nervous system such as schizophrenia, anxiety, depression and Parkinson's disease. (Williams, M, in Psychopharmacology: The Fourth Generation of Progress; Bloom, Kupfer (eds.), Raven Press, New York, 1995, pp 643-655.
Adenosine has also been implicated in modulating transmission in pain pathways in the spinal cord (Sawynok, et al., Br. J. Pharmacol., 1986, 88: 923-930), and in mediating the analgesic effects of morphine (Sweeney, et al., J. Pharmacol. Exp. Ther. 1987, 243: 657-665). In the immune system, adenosine inhibits certain neutrophil functions and exhibits anti-inflammatory effects (Cronstein, J. Appl. Physiol. 1994, 76: 5-13). An AK inhibitor has been reported to decrease paw swelling in a model of adjuvant arthritis in rats (Firestein, et.ai, Arthritis and Rheumatism, 1993, 36, S48. Adenosine also exerts a variety of effects on the cardiovascular system, including vasodilation, impairment of atrioventricular conduction and endogenous cardioprotection in myocardial ischemia and reperfusion (Mullane and Williams, in Adenosine and Adenosine Receptors, 1990 (Williams, ed.) Humana Press, New Jersey, pp. 289-334). The widespread actions of adenosine also include effects on the renal, respiratory, gastrointestinal and reproductive systems, as well as on blood cells and adipocytes.
Adenosine, via its Al receptor activation on adipocytes, plays a role in diabetes by inhibiting lipolysis [Londos, et al., Proc. Natl. Acad. Sci. USA, 1980, 77, 2551.
Endogenous adenosine release appears to have a role as a natural defense mechanism in various pathophysiologic conditions, including cerebral and myocardial ischemia, seizures, pain, inflammation and sepsis. While adenosine is normally present at low levels in the extracellular space, its release is locally enhanced at the site(s) of excessive cellular activity, trauma or metabolic stress. Once in the extracellular space, adenosine activates specific extracellular receptors to elicit a variety of responses which tend to restore cellular function towards normal (Bruns, Nucleosides Nucleotides, 1991, 10: 931-943; Miller and Hsu, J. Neurotrauma, 1992, 9: S563-S577). Adenosine has a half-life measured in seconds in extracellular fluids (Moser, et al., Am. J. Physiol. 1989, 25: C799-C806), and its endogenous actions are therefore highly localized.
The inhibition of adenosine kinase can result in augmentation of the local adenosine concentrations at foci of tissue injury, further enhancing cytoprotection. This effect is likely to be most pronounced at tissue sites where trauma results in increased adenosine production, thereby minimizing systemic toxicities.
Pharmacologic compounds directed towards adenosine kinase inhibition provide potentially effective new therapies for disorders benefited by the site- and event-specific potentiation of adenosine. Disorders where such compounds may be useful include ischemic conditions such as cerebral ischemia, myocardial ischemia, angina, coronary artery bypass graft surgery (CABG), percutaneous transluminal angioplasty (PTCA), stroke, other ' thrombotic and embolic conditions, and neurological disorders such as epilepsy, anxiety, schizophrenia, nociperception including pain perception, neuropathic pain, visceral pain, as well as inflammation, arthritis, immunosuppression, sepsis, diabetes and gastrointestinal disfunctions such as abnormal gastrointestinal motility.
A number of compounds have been reported to inhibit adenosine kinase. The most potent of these include 5'-amino-5'-deoxyadenosine (Miller, et al., J. Biol. Chem. 1979, 254: 2339-2345), 5-iodotubercidin (Wotring and Townsend, Cancer Res. 1979, 39: 3018- 3023) and 5'-deoxy-5-iodotubercidin (Davies, et al., Biochem. Pharmacol. 1984, 33: 347- 355).
Adenosine kinase is also responsible for the activation of many pharmacologically active nucleosides (Miller, et al., J. Biol. Chem. 1979, 254: 2339-2345), including tubercidin, formycin, ribavirin, pyrazofurin and 6-(methylmercapto)purine riboside. These purine nucleoside analogs represent an important group of antimetabolites which possess cytotoxic, anticancer and antiviral properties. They serve as substrates for adenosine kinase and are phosphorylated by the enzyme to generate the active form. The loss of adenosine kinase activity has been implicated as a mechanism of cellular resistance to the pharmacological effects of these nucleoside analogs {e.g. Bennett, et al., Mol. Pharmacol., 1966, 2: 432-443; Caldwell, et al, Can. J. Biochem., 1967, 45: 735-744; Suttle, et al., Europ. J. Cancer, 1981, 17: 43-51). Decreased cellular levels of adenosine kinase have also been associated with resistance to the toxic effects of 2'-deoxyadenosine (Hershfield and Kredich, Proc. Natl. Acad. Sci. USA, 1980, 77: 4292-4296). The accumulation of deoxyadenosine triphosphate (dATP), derived from the phosphorylation of 2'- deoxyadenosine, has been suggested as a toxic mechanism in the immune defect associated with inheritable adenosine deaminase deficiency (Kredich and Hershfield, in The Metabolic Basis of Inherited Diseases, 1989 (Scriver, et al., eds.), McGraw-Hill, New York, pp. 1045-1075).
B.S. Hurlbert et al. (J. Med. Chem., U: Il l-Ill (1968)) disclose various 2,4- diaminopyrido[2,3-d]pyrimidine compounds having use as antibacterial agents. R. K. Robins et al. (J. Amer. Chem. Soc, 80:3449-3457 (1958)) disclose methods for preparing a number of 2,4-dihydroxy-, 2,4-diamino-, 2-amino-4-hydroxy- and 2-mercapto-4- hydro xypyrido[2,3-d]pyrimidines having antifolic acid activity. R. Sharma et al., {Indian J. Chem., 31B: 719-720 (1992)) disclose 4-amino-5-(4-chlorophenyl)-7-(4- nitrophenyl)pyrido[2,3-d]pyrimidine and 4-amino-5-(4-methoxyphenyl)-7-(4- nitiOphenyl)pyrido[2,3-d]pyrimidine compounds having antibacterial activity. A. Gupta et al., (J. Indian Chem. Soc, lY. 635-636 (1994)) disclose 4-amino-5-(4-fluorophenyl)-7-(4- fluorophenyl)pyrido[2,3-d]pyrimidine and 4-amino-5-(4-chlorophenyl)-7-(4- fluorophenyl)pyrido[2,3-d]pyrimidine compounds having antibacterial activity. L. Prakash et al, Pharmazie, 48: 221-222 (1993)) disclose 4-amino-5-phenyl-7-(4- aminophenyl)pyrido[2,3-d]pyrimidine, 4-amino-5-phenyl-7-(4-bromophenyl)pyrido[2,3- djpyrimidine, 4-ammo-5-(4-methoxyphenyl)-7-(4-aminophenyl)pyrido[2,3-d]pyrimidine, and 4-amino-5-(4-methoxyphenyl)-7-(4-bromophenyl)pyrido[2,3-d]pyrimidine compounds having antifungal activity. P. Victory et al, Tetrahedron, ϋ.: 10253-10258 (1995)) discloses the synthesis of 4-amino-5,7-diphenylpyrido[2,3-d]pyrimidine compounds from acyclic precursors. Bridges et α/.(PCT application WO 95/19774, published July 27, 1995) disclose various bicyclic heteroaromatic compounds as having utility for inhibiting tyrosine kinase of epidermal growth factors.
Summary Of The Invention
The present invention provides for 5,7-disubstituted-4-aminopyrido[2,3- djpyrimidine compounds having utility as adenosine kinase inhibitors.
In one aspect, the present invention provides a method of inhibiting adenosine kinase by administering a compound of formula (I)
Figure imgf000006_0001
wherein
Ri and R^ are independently selected from H, loweralkyl, Ci-CgalkoxyCi- Cόalkyl, arylCι-C6alkyl, -C(O)Cι-C6alkyl, -C(O)aryl, -C(O)heterocyclic or may join together with the nitrogen to which they are attached to form a 5-7 membered ring optionally containing 1-2 additional heteroatoms selected from O, N or S;
R3 is selected from the group consisting of loweralkyl, loweralkenyl, loweralkynyl, cycloalkyl, aryl, arylalkyl, heteroaryl, heterocyclic group, heteroarylalkyl or heterocycloalkyl wherein the heteroaryl and heterocyclic groups are linked directly or indirectly by a ring carbon; R4 is selected from the group consisting of loweralkyl, loweralkenyl, loweralkynyl, cycloalkyl, aryl, arylalkyl, heteroaryl, heterocyclic group heteroarylalkyl or heterocycloalkyl; and a dashed line — indicates that a double bond is optionally present provided that proper valencies are maintained.
In particular, the method of inhibiting adenosine kinase comprises exposing an adenosine kinase to an effective inhibiting amount of a compound of Formula I of the present invention. Where the adenosine kinase is located in vivo, the compound is administered to the organism.
In still another aspect, the present invention provides a method of treating ischemia, neurological disorders, nociperception , inflammation, immunosuppression, gastrointestinal disfunctions, diabetes and sepsis in a mammal in need of such treatment, comprising adiTiinistering to the mammal a therapeutically effective amount of a compound of Formula I of the present invention.
In a preferred aspect, the present invention provides a method of treating cerebral ischemia, myocardial ischemia, angina, coronary artery bypass graft surgery, percutaneous transluminal angioplasty, stroke, thrombotic and embolic conditions, epilepsy, anxiety, schizophrenia, pain perception, neuropathic pain, visceral pain, arthritis, sepsis, diabetes and abnormal gastrointestinal motility in a mammal in need of such treatment, comprising adrninistering to the mammal a therapeutically effective amount of a compound of Formula I of the present invention.
The present invention also contemplates the use of pharmaceutically acceptable salts and amides of compounds having Formula I.
In another aspect, the present invention provides a compound of formula (I)
Figure imgf000007_0001
wherein
Ri and R^ are independently selected from H, loweralkyl, Cι-C6alkoxyCi- Cόalkyl, arylCj-Cόalkyl, -C(O)Cι-C6alkyl, -C(O)aryl, -C(O)heterocyclic or may join together with the nitrogen to which they are attached to form a 5-7 membered ring optionally containing 1-2 additional heteroatoms selected from O, N or S;
R3 is selected from the group consisting of loweralkyl, loweralkenyl, loweralkynyl, cycloalkyl, aryl, arylalkyl, heteroaryl, heterocyclic group, heteroarylalkyl or heterocycloalkyl wherein the heteroaryl and heterocyclic groups are linked directly or indirectly by a ring carbon; R4 is selected from the group consisting of loweralkyl, loweralkenyl, loweralkynyl, cycloalkyl, aryl, arylalkyl, heteroaryl, heterocyclic group heteroarylalkyl or heterocycloalkyl; and a dashed line — indicates that a double bond is optionally present provided that proper valencies are maintained; with the proviso that the compound may not be selected from the group consisting of:
(a) 4-arnino-5-(4-chlorophenyl)-7-(4-nirrophenyl)pyrido[2,3-d]pyrimidine;
(b) 4-amino-5-(4-methoxyphenyl)-7-(4-nitrophenyl)pyrido[2,3-d]pyrimidine;
(c) 4-amino-5-(4-fluorophenyl)-7-(4-fluorophenyl)pyrido[2,3-d]pyrimidine;
(d) 4-amino-5-(4-chlorophenyl)-7-(4-fluorophenyl)pyrido[2,3-d]pyrimidine; (e) 4-amino-5-phenyl-7-(4-arninophenyl)pyrido[2,3-d]pyrimidine;
(f) 4-amino-5-phenyl-7-(4-bromophenyl)pyrido[2,3-d]pyrimidine;
(g) 4-amino-5-(4-methoxyphenyl)-7-(4-aminophenyl)pyrido[2,3-d]pyrimidine;
(h) 4-amino-5-(4-methoxyphenyl)-7-(4-bromophenyl)pyrido[2,3-d]pyrimidine; and (i) 4-amino-5,7-diphenylpyrido[2,3-d]pyrimidine.
In another aspect, the present invention provides a pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula I above in combination with a pharmaceutically acceptable carrier.
In another aspect, the present invention provides a process for the preparation of adenosine kinase inhibiting compounds having the formula
Figure imgf000008_0001
the method comprising
(a) contacting a ketone having the formula R -CO-CH3, wherein R4 is as defined above, with an aldehyde having the formula R3-CHO, wherein R3 is as defined above and malononitrile in the presence of an ammonium salt under anhydrous conditions and isolating a first intermediate compound having the structure
Figure imgf000008_0002
(b) contacting the first intermediate compound with formamide at reflux for from about 1 to about 8 hours, and isolating the compound of formula I with double bonds between the 7 and 8 position and the 5 and 6 position and optionally reducing to form a partially saturated right side or a fully saturated right side to form a compound of formula I.
Detailed Description of the Invention
The present invention relates to 5,7-disubstituted-4-ammopyrido[2,3-d]pyrimidine compounds that are useful in inhibiting adenosine kinase, to pharmaceutical compositions containing such compounds, to a method of using such compounds for inhibiting adenosine kinase, and to novel 5,7-disubstituted-4-aminopyrido[2,3-d]pyrimidine compounds.
In one aspect, the present invention provides 5,7-disubstituted-4-aminopyrido[2,3- d]pyrimidine compounds that are adenosine kinase inhibitors. An adenosine kinase inhibitor of the present invention is a compound of the Formula I, shown above.
As summarized above, the present invention relates to a method of inhibiting adenosine kinase comprising administering a compound of formula I 98/46605
Figure imgf000009_0001
wherein
Ri and R2 are independently selected from H, loweralkyl, arylCι-C6alkyl, - C(O)Cι-C6alkyl, -C(O)aryl, -C(O)heterocyclic or may join together with the nitrogen to which they are attached to from a 5-7 membered ring optionally containing 1-2 additional heteroatoms selected from O, N or S;
R3 and R^ are independently selected from the group consisting of:
Ci-C6alkyl,
C2-C6alkenyl, C2-C6alkynyl,
C3-C8cycloalkyl, heteroarylCo-Cβalkyl or substituted heteroarylCo-Cβalkyl, optionally substituted cycloalkyl, arylCo-Cβalkyl or substituted arylC()-C6alkyl, heteroarylC2-C6alkenyl or substituted heteroarylC2-C6~alkenyl, arylC2-C6alkenyl or substituted arylC2-C6alkenyl, heteroarylC2-C6alkynyl or substituted heteroarylC2-C6alkynyl, arylC2-C6alkynyl or substituted arylC2-C6alkynyl wherein the 1-4 heteroaryl or aryl substituents are independently selected from halogen, oxo, CO2 ^, cyanoCi-Cόalkyl, heteroarylC()-C6alkyl, heterocyclicCo-C alkyl, Ci-Cgalkyloxy, Ci-CόalkyloxyCi-Cgalkyl, arylCo-C6alkyl, arylCi-Cόalkyloxy, R5R6NC(O), cyano, C2-C6alkenyl, C2-C6alkynyl, Cι-C6alkyl, C2-C6alkenyldialkylmalonyl, CF3, HO-, C\- C6alkyloxyCι-C6alkyloxy, Ci-CβalkylSOn wherein n is 1-2, Ci- C6alkylthio, Ci-Ctøalkylacryl, CF3O, CF3, Cι-C4alkylenedioxy, Ci-
C6alkylacryl, R5R6N(CO)NR5, N-formyl(heterocyclic), NO2, NR5R6CØ- Cβalkyl, (R5O)(R6O)-P(O)- C()-C6alkyl, wherein R^ and R^ are independently selected from H, Cι-C6alkyl, HC(O), Cι-C6alkyloxyCι-C6alkyl, Cι-C6alkyloxy, C\- C6alkylC(O), CF3C(O),
Figure imgf000009_0002
phthalimidoCi-
C6C(O), Cι-C6alkylSOn where n is 1-2, CNCι-C6alkyl, R7R8NC(O)NR7-, heteroaryl, NR"7R8Ci-C6al ylC(O), C\- CβalkyloxycarbamidoC 1 -Cόalkyl, wherein R^ and R° are independently selected from those variables identified for R^ and R^ or R^ and R6 or R^ and R^ may join together with the nitrogen atom to which they are attached to form a 5-7 membered unsubstituted or substituted ring optionally containing 1-3 additional heteroatoms selected from O, N or S wherein the substituents are selected from Ci-C6alkyl and a dashed line — indicates a double bond is optionally present. The preferred compounds utilized in the above method of inhibiting adenosine kinase are selected from a compound of formula II
Figure imgf000010_0001
wherein R!-R8 and n are as defined above. The present invention also relates to compounds of formula II with R!-R8 and n as defined above with the proviso that the specific known compounds identified above for a compound of formula I are excluded. In a preferred embodiment, an adenosine kinase inhibitor of the present invention is a compound of Formula (II) above, wherein R4 is aryl or heteroaryl and substituted versions thereof.
In a more preferred embodiment, an adenosine kinase inhibitor of the present invention is a compound of Formula (II) above, wherein R4 is aryl or heteroaryl and substituted versions thereof and R3 is loweralkyl, aryl, arylalkyl or heteroaryl and substituted versions thereof wherein the substituents are as identified above.
In another preferred embodiment, an adenosine kinase inhibitor of the present invention is a compound of Formula (I) above, wherein R4 is selected from the group consisting of: phenyl; thiophene-2-yl; 3-methyl-2-oxobenzoxazolin-6-yl; 2-(dimethylamino)- 5-pyrimidinyl; 2-(N-formyl-N-methyl amino)-5-pyrimidinyl; 2-(N-methoxyethyl-N-methyl amino)-5-pyrimidinyl; 2-(N-methylamino)-5-pyrimidinyl; 2-(l-mo holinyl)-5-pyrimidinyl; 2-(l-pyrrolidinyl)-5-pyrimidinyl; 2-dimethylamino-5-pyrimidinyl; 2-furanyl; 2- oxobenzoxazolin-6-yl; 2-pyridyl; 3-(dimethylamino)phenyl; 3-amino-4-methoxyphenyl; 3- bromo-4-(dimethylamino)phenyl; 3-methoxyphenyl; 3-methyl-4-(N-acetyl-N- methylamino)phenyl; 3-methyl-4-(N-formyl-N-methylamino)phenyl; 3-methyl-4-(N-methyl- N-(trifluoroacetyl)amino)phenyl; 3-methyl-4-(N-methylamino)phenyl; 3-methyl-4- pyrrolidinylphenyl; 3-pyridyl; 3,4-dichlorophenyl; 3,4-methylenedioxyphenyl; 3,4,5- trimethoxyphenyl; 4-(acetylamino)phenyl; 4-(dimethylamino)-3-fluorophenyl; 4- (dimethylamino)phenyl; 4-(imidazol-l-yl)phenyl; 4-(methylthio)phenyl; 4- (moφholinyl)phenyl; 4-( -(2-(o memylamino)ethyl)amino)phenyl; 4-(N-(2- methoxyethyl)amino)phenyl; 4-(N-acetyl-N-methylamino)phenyl; 4-(N-ethyl-N- formylamino)phenyl; 4-(N-ethylamino)phenyl; 4-(N-formyl-N-(2- methoxyethyl)amino)phenyl; 4-(N-isopropylamino)phenyl; 4-(N-methyl-N-((2- dimethylamino)ethyl)amino)phenyl; 4-(N-methyl-N-(2-(N- phthalimidyl)acetyl)amino)phenyl; 4-(N-me yl-N-(2-cyano)emylamino)phenyl; 4-(N- methyl-N-(2-methoxyethyl)amino)phenyl; 4-(N-methyl-N-(3- methoxy)propionylamino)phenyl; 4-(N-methyl-N-acetylamino)phenyl; 4-(N-methyl-N- formylamino)phenyl; 4-(N-methyl-N-trifluoroacetylamino)phenyl; 4-(N- morpholinyl)phenyl; 4-(thiophene-2-yl)phenyl; 4-(ureido)phenyl; 4-(2- (djmethylamino)acetylamino)phenyl; 4-(2-(2-memoxy)acetylamino)ethyl)amino)phenyl; 4- (2-methoxy)ethoxyphenyl; 4-(2-oxo-3-oxazolidinyl)phenyl; 4-(4-methoxy-2-butyl)phenyl; 4-(4-methylpiperidinyl)phenyl; 4-(5-pyrimidinyl)phenyl; 4-aminophenyl; 4-bromophenyl; 4-butoxyphenyl; 4-carboxamidophenyl; 4-chlorophenyl; 4-cyanophenyl; 4- diethyla inophenyl; 4-diethylmalonylallylphenyl); 4-dimethylaminophenyl; 4- ethoxyphenyl; 4-ethylphenyl; 4-fluorophenyl; 4-hydroxyphenyl; 4-imidazolylphenyl; 4- iodophenyl; 4-isopropylphenyl; 4-methoxyphenyl; 4-methylaminophenyl; 4- methylsulfonylphenyl; 4-morpholinylphenyl; 4-N-(2-(dimethylamino)ethyl)-N- formylamino)phenyl; 4-N-(3-methoxypropionyl)-N-isopropyl-amino)phenyl; 4-N-ethyl-N- (2-methoxyethyl)amino)phenyl; 4-N-formylpiperazinylphenyl; 4-nitrophenyl; 4- piperidinylphenyl; 4-(3-pyridyl)phenyl; 4-pyrrolidinylphenyl; 4-t-butylacrylphenyl; 5- (dimethylamino)thiophene-2-yl; 5-amino-2-pyridyl; 5-dimethylamino-2-pyrazinyl; 3- dimethylaminopyridazin-6-yl; 5-dimethylamino-2-pyridyl; 5-pyrimidinylphenyl; 6-(N- methyl-N-formylamino)-3-pyridinyl; 6-(N-methyl-N-methoxyethylamino)-3-pyridinyl; 6-(2- oxo-3-oxazolidinyl)-3-pyridinyl; 6-dimethylamino-3-pyridinyl; 6-imidazolyl-3-pyridinyl; 6- morpholinyl-3-pyridinyl; 6-pyrrolidinyl-3-pyridinyl; 6-(2-propyl)-3-pyridinyl; and (4- f ormy lamino)phenyl .
In another preferred embodiment, an adenosine kinase inhibitor of the present invention is a compound of Formula (I) above, wherein R3 is selected from the group consisting of: (thiophene-2-yl)methyl; (thiophene-3-yl)methyl; butyl; cycloheptyl; pentyl; thiophene-2-yl; l-(3-bromophenyl)ethyl; 2-(N-phenylmethoxycarbonyl)aminophenyl; 2-(3- bromophenyl)ethyl; 2-(3-cyanophenyl)methyl; 2-(4-bromophenyl)ethyl; 2-(5-chloro-2- (thiophen-3-yl)phenyl; 2-bromophenyl; 2-furanyl; 2-methylpropyl; 2-phenylethyl; phenylmethyl; 2,3-dimethoxyphenyl; 2,3-methylenedioxyphenyl; 3-(furan-2-yl)phenyl; 3- (thiophen-2-yl)phenyl; 3-(2-pyridyl)phenyl; 3-(3-methoxybenzyl)phenyl; 2-(3- aminopropynyl)phenylmethyI; 3-benzyloxyphenyl; 3-bromo-4-fluorophenyl; 3-bromo-5- iodophenyl; 3-bromo-5-methoxyphenyl; 3-bromophenyl; 3-bromophenylmethyl; 3- carboxamidophenyl; 3-chlorophenyl; 3-cyanophenyl; 3-diethylmalonylallylphenyl; 3- dimethylaminophenyl; 3-ethoxyphenyl; 3-fluoro-5-trifluoromethylphenyl; 3-fluorophenyl; 3- hydroxyphenyl; 3-iodophenyl; 3-methoxyethyoxyphenyl; 3-methoxyphenyl; 3- methylphenyl; 3-methylsulfonylphenyl; 3-methylthiophenyl; 3-t-butylacrylphenyl; 3- trifloromethyoxyphenyl; 3-trifluoromethylphenyl; 3-vinylpyridinylphenyl; 3,4- dichlorophenyl; 3,4-dimethoxyphenyl; 3,4-methylenedioxyphenyl; 3,4,5-trimethoxyphenyl; 3,5-di(trifluoromethyl)phenyl; 3,5-dibromophenyl; 3,5-dichlorophenyl; 3,5- dimethoxyphenyl; 3,5-dimethylphenyl; 4-(2-propyl)phenyl; 4-(2-propyl)oxyphenyl; 4- benzyloxyphenyl; 4-bromophenyl; 4-bromothiophene-2-yl; 4-butoxyphenyl; 4- dimethylaminophenyl; 4-fluoro-3-trifluoromethylphenyl; 4-methoxyphenyl; 4- neopentylphenyl; 4-phenoxyphenyl; 5-bromothiophene-2-yl; 5-cyclohexyl; 5-cyclopropyl; 5-hexyl; 5-methyl; 5-phenyl; (2-bromo-5-chlorophenyl)methyl; (2-bromophenyl)methyl; and (5-chloro-2-(3-methoxyphenyl)phenyl)methyl. Exemplary and preferred adenosine kinase inhibitor compounds of the invention utilized in the method recited herein include the compounds listed below wherein Rl and R^ in a compound of formula II are selected from H, the groups identified at the 5-position are included within R3 and the groups identified at the 7-position are included within R^, R5- R8 are as described in the specific compound: 4-arnino-5-(4-dime ylaminophenyl)-7-(4-bromophenyl)pyrido[2,3-d]pyrirnidine;
4-ammo-5-(4-dimethylaιninophenyl)-7-(4-dimethylaminophenyl)pyrido[2,3- djpyrimidine;
4-amirιo-5-(4-methoxyphenyl)-7-(4-dime ylaminophenyl)pyrido[2,3-d]pyrirnidine;
4-ammo-5-(4-dimethylaminophenyl)-7-(4-methoxyphenyl)pyrido[2,3-d]pyrimidine; 4-amino-5-(4-(2-propyl)phenyl)-7-(4-methoxyphenyl)pyrido[2,3-d]pyrimidine;
4-arm^o-5-(4-neopentylphenyl)-7-(4-methox3φhenyl)pyrido[2,3-d]pyrimidine;
4-anιino-5-(4-butyloxyphenyl)-7-(4-methoxyphenyl)pyrido[2,3-d]pyrimidine;
4-anrύno-5-(4-met oxyphenyl)-7-(4-bromophenyl)pyrido[2,3-d]pyrimidine;
4-aιτύno-5-(4-(2-propyl)oxyphenyl)-7-(4-memoxyphenyl)pyrido[2,3-d]pyrimidine; 4-amino-5-(4-butoxyphenyl)-7-(4-N-formylpiperazinylphenyl)pyrido[2,3- d]pyrimidine;
4-amino-5-(4-benzyloxyphenyl)-7-(4-methoxyphenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(4-phenoxyphenyl)-7-(4-methoxyphenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(4-(2-propyl)phenyl)-7-(4-diethylmalonylallylphenyl)pyrido[2,3- d]pyrimidine;
4-amino-5-(4-(2-propyl)phenyl)-7-(4-t-butylacrylphenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(4-dimethylaminophenyl)pyrido[2,3-d]pyrimidine; 4-ammo-5-(3,4-dimethoxyphenyl)-7-(4-dimethylaminophenyl)pyrido[2,3- d]pyrimidine;
4-am o-5-(3-t-butylacrylphenyl)-7-(4-dimethylaminophenyl)pyrido[2,3- d]pyrimidine; 4-ammo-5-(3-methoxyphenyl-7-(4-dimethylam ophenyl)pyrido[2,3-d]pyrimidine;
4-ammo-5-(3,5-djroethoxyphenyl-7-(4-dimethylaminophenyl)pyrido[2,3- d]pyrimidine;
4-anτino-5-(3-diethylmalonylallylphenyl)-7-(4-dime ylarninophenyl)pyrido[2,3- djpyrimidine; 4-amino-5-(3-vmylpyridinylphenyl)-7-(4-dimethylaminophenyl)pyrido[2,3- d]pyrimidine;
4-arnino-5-(3-lrifluoromethylphenyl)-7-(4-dimethylaminophenyl)pyridot2,3- djpyrimidine;
4-amino-5-(3-carboxamidophenyl)-7-(4-dimethylaminophenyl)pyrido[2,3- djpyrimidine;
4-ammo-5-(3-cyanophenyl)-7-(4-dimethylan inophenyl)pyrido[2,3-d]pyrimidine;
4-am o-5-(3-benzyloxyphenyl)-7-(4-dimemylaminophenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-methoxyphenyl)-7-(4-me oxyphenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(4-butoxyphenyl)pyrido[2,3-d]pyrimidine; 4-amino-5-(3-(2-pyridyl)phenyl)-7-(4-dimethylaminophenyl)pyrido[2,3- djpyrimidine;
4-ammo-5-(3-memylphenyl)-7-(4-dimethylaminophenyl)pyrido[2,3-d]pyrirnidine;
4-ammo-5-(3-cMorophenyl)-7-(4-dimethylaminophenyl)pyrido[2,3-d]pyrimidine;
4-arnmo-5-(3-fluorophenyl)-7-(4-dimethylaminophenyl)pyrido[2,3-d]pyrimidine; 4-amino-5-(3-bromophenyl)-7-(4-methoxyphenyl)pyrido[2,3-d]pyrirnidine;
4-amino-5-(3-memoxyphenyl)-7-(4-bromophenyl)pyrido[2,3-d]pyrirnidine;
4-amino-5-(3-bromophenyl)-7-phenylpyrido [2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(4-ethylphenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(4-bromophenyl)pyrido[2,3-d]pyrimidine; 4-arrino-5-(3-bromophenyl)-7-(4-cyanophenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(4-hydroxyphenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-iodophenyl)-7-(4-dimethylaminophenyl)pyrido[2,3-d]pyrimidine;
4-am o-5-(3-emoxyphenyl)-7-(4-dimemylaminophenyl)pyrido[2,3-d]pyrirm^ine;
4-amino-5-(3-trifloromethyoxyphenyl)-7-(4-dimethylaminophenyl)pyrido[2,3- djpyrimidine;
4-amino-5-(3,5-dicWorophenyl)-7-(4-dimethylaminophenyl)pyrido[2,3-d]pyrimidine; 4-amino-5-(3-bromo-4-fluorophenyl)-7-(4-chmethylaminophenyl)pyrido[2,3- d]pyrimidine; amino-5-(3-hydroxyphenyl)-7-(4-dimethylaminophenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(4-moroholinylphenyl)pyrido[2,3-d]pyrimidine; 4-amino-5-(3-bromophenyl)-7-(4-piperio nylphenyl)pyrido[2,3-d]pyrimidine; armno-5-(3-bromophenyl)-7-(4-(imidazol-l-yl)phenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(4-chlorophenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(4-isopropylphenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(4-trifluorophenyl)pyrido[2,3-d]pyrimidine; 4-amino-5-(3-bromophenyl)-7-(4-diethylamiιιophenyl)pyrido[2,3-d]pyrimidine; amirιo-5-(3-bromophenyl)-7-(3,4,5-trimethoxyphenyl)pyrido[2,3-d]pyrimidine;
4-arnino-5-(3-(3-memoxybenzyl)phenyl)-7-(4-dimemylaminophenyl)pyrido[2,3- d]pyrimidine;
4-an^no-5-(3-me oxyeAyoxyphenyl)-7-(4-dime ylaminophenyl)pyrido[2,3- d]pyrimidine;
4-amino-5-(3,4-methylenedioxyphenyl)-7-(4-dimethylaminophenyl)pyrido[2,3- djpyrimidine;
4-amino-5-(3-bromophenyl)-7-(4-ethoxyphenyl)pyrido[2,3-d]pyrimidine;
4-ammo-5-(3-bromophenyl)-7-(2'-thiophene)pyrido[2,3-d]pyrimidine; 4-amino-5-(3-bromophenyl)-7-(4-fluorophenyl)pyrido[2,3-d]pyrimidine;
4-ammo-5-(3-dimemylaminophenyl)-7-(4-m^ethylaminophenyl)pyrido[2,3- d]pyrimidine;
4-ammo-5-phenyl-7-(4-dimethylaminophenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3,4,5-trimethoxyphenyl)-7-(4-dimethylaminophenyl)pyrido[2,3- d]pyrimidine;
4-ar no-5-(3-bromophenyl)-7-(4-nitrophenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(4-iodophenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(3,4-methylenedioxyphenyl)pyrido[2,3-d]pyrirnidine;
4-amino-5-(thiophen-2-yl)-7-(4-morpholinylphenyl)pyrido [2,3-d]pyrimidine; 4-amino-5-(3,5-dimethoxyphenyl)-7-(thiophen-2-yle)pyrido [2,3-d]pyrimidine;
4-an ino-5-(3-bromophenyl)-7-(4-carboxamidophenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(4-(2-methoxy)ethoxyphenyl)pyrido[2,3- djpyrimidine;
4-amino-5-(3,5-dimethoxyphenyl)-7-(4-morpholinylphenyl)pyrido[2,3-d]pyrimidine; 4-amino-5-(3-trifluoromethylphenyl)-7-(thiophene-2-yl)pyrido [2 ,3 -djpyrimidine;
4-anτino-5-(3-bromophenyl)-7-(4-aminophenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromo-4-fluorophenyl)-7-(thiophene-2-yl)pyrido [2,3-d]pyrimidine; 4-amino-5-(3-bromo-4-fluorophenyl)-7-(2-furanyl)pyrido [2,3-d]pyrimidine; 4-ammo-5-(3,5-dimemoxyphenyl)-7-(4-iodophenyl)pyrido[2,3-d]pyrimidine; amino-5-(3,5-diJΩethoxyphenyl)-7-(4-imidazolylphenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3,5-dimethoxyphenyl)-7-(4-(thiophene-2-yl)phenyl)pyrido[2,3- d]pyrimidine;
4-amino-5-(3,5-dirnemoxyphenyl)-7-(4-(3-pyridyl)phenyl)pyrido[2,3-d]pyrimidine; 4-amino-5-(3-bromophenyl)-7-(4-(4-methylpiperidinyl)phenyl)pyrido[2,3- d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(4-pyrrolidinylphenyl)pyrido[2,3-d]pyrimidine; 4-ammo-5-(4-bromomiophene-)-7-(4-dimemylan inophenyl)pyrido[2,3-d]pyrirnidine;
4-amino-5-(4-bromothiophene-2-yl)-7-(4-morpholinylphenyl)pyrido[2,3- d]pyrimidine;
4-mo holinyl-5-(3-bromophenyl)-7-(4-dimemylaminophenyl)pyrido[2,3- djpyrimidine; 4-amino-5-(5-bromothiophene-2-yl)-7-(4-morpholinylphenyl)pyrido[2,3- d]pyrimidine; ammo-5-(4-bromophenyl)-7-(4-dimemylamirιophenyl)pyrido[2,3-d]pyrirnidine; 4-ammo-5-(3-bromophenyl)-7-(4-(acetylamino)phenyl)pyrido[2,3-d]pyrimidine; 4-ammo-5-(3-bromophenyl)-7-(4-dimethylammophenyl)pyrido[2,3-d]pyrimidine; 4-amino-5-(3,5-dirnethoxyphenyl)-7-(5-pyrirnidinylphenyl)pyrido[2,3-d]pyrimidine;
4-(4-fluorophenyl)amino)-5-(3-bromophenyl)-7-(4- dimemylaminophenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(4-bromothiophene-2-yl)-7-(4-pyrrolidinylphenyl)pyrido[2,3- d]pyrimidine; 4-amino-5-(4-bromomiophene-2-yl)-7-(thiophene-2-yl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(5-(dime ylamino)thiophene-2-yl)pyrido[2,3- d pyrimidine;
4-amino-5-(3-bromo-5-iodophenyl)-7-(4-(dimethylamino)phenyl)pyrido[2,3- d pyrimidine; 4-amino-5-(3,5-di(trifluoromethyl)phenyl)-7-(4-(dimethylamino)phenyl)pyrido[2,3- djpyrimidine;
4-amino-5-(3,5-di(trifluoromethyl)phenyl)-7-(4-morpholinylphenyl)pyrido[2,3- djpyrirnidine;
4-amino-5-(3,5-dibromophenyl)-7-(4-(dimethylamino)phenyl)pyrido[2,3- d]pyrimidine;
4-amino-5-(3,5-dibromophenyl)-7-(4-morpholinylphenyl)pyrido[2,3-d]pyrimidine; 4-amino-5-(4-bromothiophene-2-yl)-7-(4-(4-methylpiperidinyl)phenyl)pyrido[2,3- djpyrimidine;
4-amino-5-(3,5-dibromophenyl)-7-( (dimethylamino)phenyl)pyrido[2,3- d]pyrimidine; 4-amino-5-(3-bromophenyl)-7-(3-(dime ylarnino)phenyl)pyrido[2,3-d]pyrimidine;
4-arnino-5-(3-bromophenyl)-7-(4-methylsulfonylphenyl)pyrido[2,3-d]pyrimidine;
4-anτino-5-(3-bromophenyl)-7-(3-methoxyphenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(4-(methyl io)phenyl)pyrido[2,3-d]pyrimidine;
4-am o-5-(3-bromophenyl)-7-(3,4-dichlorophenyl)pyrido[2,3-d]pyrimidine; 4-amino-5-(3-bromophenyl)-7-(4-(N-methyl-N-formylamino)phenyl)pyrido[2,3- djpyrimidine;
4-amino-5-(3-bromophenyl)-7-(4-methylammophenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromo-4-fluorophenyl)-7-(4-methylsulfonylphenyl)pyrido[2,3- d]pyrimidine; 4-arnino-5-(3-bromophenyl)-7-(3-anτino-4-methoxyphenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(3-bromo-4-(dirnethylamino)phenyl)pyrido[2,3- djpyrimidine;
4-amino-5-(3-bromophenyl)-7-(3-memyl-4-(dimethylamino)phenyl)pyrido[2,3- d]pyrimidine; 4-amino-5-(3-bromophenyl)-7-(4-(N-methyl-N- trMuoroacetylamino)phenyl)pyιido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(4-(dimethylamino)-3-fluorophenyl)pyrido[2,3- djpyrimidine;
4-amino-5-(3-bromophenyl)-7-(4-(N-ethyl-N-formylamino)phenyl)pyrido[2,3- d]pyrimidine;
4,4-bis(acetylamino)-5-(3-bromophenyl)-7-(4-(N-methyl-N- acetylamino)phenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(4-(N-acetyl-N-methylamino)phenyl)pyrido[2,3- d]pyrimidine; 4-amino-5-(3-bromophenyl)-7-(4-(N-ethylammo)phenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(4-(N-methyl-N-(2- me oxyethyl)amino)phenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(4-(N-isopropylamino)phenyl)pyrido[2,3- d]pyrimidine; 4-amino-5-(3-bromophenyl)-7-(4-N-ethyl-N-(2- memoxyethyl)amino)phenyl)pyrido[2,3-d]pyrimidine; 4-amino-5-(3-bromophenyl)-7-(4-N-(3-methoxypropionyl)-N-isopropyl- amino)phenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(4-N-(2-(dimethylamino)ethyl)-N- formylamino)phenyl)pyrido[2,3-d]pyrimidine; 4-amino-5-(3-bromophenyl)-7-(4-(N-(2-
(dimethylamino)e yl)amino)phenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(4-(N-methyl-N-(2- cyano)ethylamino)phenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(4-(N-methyl-N-(3- me oxy)propionylamino)phenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(3-methyl-4-(N-formyl-N- memylamino)phenyl)pyrido[2,3-d]pyrimidine;
4-arnino-5-(3-bromophenyl)-7-(3-methyl-4-(N-methylamino)phenyl)pyrido[2,3- d]pyrimidine; 4-amino-5-(3-bromophenyl)-7-(4-(4-methoxy-2-butyl)phenyl)pyrido[2,3- d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(4-(N-methyl-N-(2-(N- phthaUr dyl)acetyl)amino)phenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(3-methyl-4-(N-methyl-N- (trifluoroacetyl)ar no)phenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(3-methyl-4-(N-acetyl-N- memylamino)phenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(6-dimethylamino-3-pyridinyl)pyrido[2,3- d]pyrimidine; 4-armno-5-(3-cyanophenyl)-7-(4-methylsulfonylphenyl)pyrido[2,3-d]pyrimidine;
4-andno-5-(3-cyanophenyl)-7-(4-(N-methyl-N-formylamino)-phenyl)pyrido[2,3- d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(6-(N-methyl-N-formylamino)-3- pyridinyl)pyrido[2,3-d]pyrimidine; 4-aιτdno-5-(3-bromophenyl)-7-(6-mo holinyl-3-pyridinyl)pyrido[2,3-d]pyrimidine;
4-am o-5-(3-bromophenyl)-7-(6-(N-methyl-N-methoxyethylamino)-3- pyridinyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(6-pyrroUdinyl-3-pyridmyl)pyrido[2,3-d]pyrimidine;
4-aπύno-5-(3-bromophenyl)-7-(2-(dirne ylam o)-5-pyrirnidinyl)pyrido[2,3- d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(2-(N-methoxyethyl-N-methyl amino)-5- pyrimidinyl)pyrido[2,3-d]pyrimidine; 4-amino-5-(3-bromophenyl)-7-(2-(N-formyl-N-methyl amino)-5- pyrimidinyl)pyrido[2,3-d]pyrimidine; anr no-5-(3-bromophenyl)-7-(2-(N-memylanrύno)5-pyrimidinyl)pyrido[2,3- d]pyrimidine; 4-arnino-5-(3-bromophenyl)-7-(2-(l-pyrrolidinyl)-5-pyrimidinyl)pyrido[2,3- d pyrimidine;
4-amino-5-(3-bromophenyl)-7-(2-(l-morphohnyl)-5-pyrimidinyl)pyrido[2,3- d pyrimidine;
4-amino-5-(3-bromophenyl)-7-(6-(2-oxo-3-oxazolidinyl)-3-pyridinyl)pyrido[2,3- d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(2-pyridyl)pyrido[2,3-d]pyrimidine;
4-armno-5-(3-bromophenyl)-7-(3-pyridyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-(thiophen-2-yl)phenyl)-7-(4-dimethylaminophenyl)pyrido[2,3- d]pyrimidine; 4-anτino-5-(3-(furan-2-yl)phenyl)-7-(4-dimemylaminophenyl)pyrido[2,3- d pyrimidine;
4-amino-5-(3-(3-methoxyphenyl)phenyl)-7-(4-dimemylaminophenyl)pyrido[2,3- d]pyrimidine;
4-arru^o-5-phenyl-7-(4-dimethylaminophenyl)pyrido[2,3-d]pyrimidine; 4-amino-5-(3-cWorophenyl)-7-(4-(mo holirιyl)phenyl)pyrido[2,3-d]pyrijτιidine;
4-amino-5-(3-bromo-4-fluorophenyl)-7-(4-(moφholinyl)phenyl)pyrido[2,3- d]pyrimidine;
4-amino-5-(3-chlorophenyl)-7-(4-iodophenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-chlorophenyl)-7-(4-(miophen-2-yl)phenyl)pyrido[2,3-d]pyrimidine; 4-amino-5-(3-chlorophenyl)-7-(4-(5-pyrimidinyl)phenyl)pyrido[2,3-d]pyrimidine;
4-arnino-5-(3-bromo-4-fluorophenyl)-7-(4-iodophenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(4-bromothiophene-2-yl)-7-(4-methoxyphenyl)pyrido[2,3-d]pyrirnidine;
4-amino-5-(3-bromophenyl)methyl-7-(4-(dimethylamino)phenyl)pyrido[2,3- d]pyrimidine; 4-am o-5-(2-phenylethyl)-7-(4-diemylamirιophenyl)pyrido[2,3-d]pyrimidine;
4-ammo-5-(2-methylpropyl)-7-(4-diethylarn ophenyl)pyrido[2,3-d]pyrimidine;
4-ammo-5-(butyl)-7-(4-diethylaminophenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(2-(4-bromophenyl)ethyl)-7-(4-diethylaminophenyl)pyrido[2,3- djpyrimidine; 4-ammo-5-(butyl)-7-(4-dimethylaminophenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(2-(3-cyanophenyl)memyl)-7-(4-dimethylaminophenyl)pyrido[2,3- djpyrimidine; 4-am o-5-(2-(N-phenylmethoxycarbonyl)aminoethyl)-7-(4- dimemylaminophenyl)pyrido[2,3-d]pyrimidine; ammo-5-(cycloheptyl)-7-(4-dimethylan mophenyl)pyrido[2,3-d]pyrirnidine;
4-amino-5-(2-(5-chloro-2-(thiophen-3-yl)phenylmethyl)-7-(4- dimethylaminophenyl)pyrido[2,3-d]pyrimidine;
4-amirιo-5-(pentyl)-7-(4-diethylanιinophenyl)pyrido[2,3-d]pyrimidine; 4-amino-5-hexyl-7-(4-diethylaminophenyl)pyrido[2,3-d]pyrimidine; 4-amino-5-(2-(3-bromophenyl)ethyl)-7-(4-diethylaminophenyl)pyrido[2,3- d]pyτimidine; 4-aιrιino-5-((2-bromophenyl)methyl)-7-(4-diethylaminophenyl)pyrido[2,3- djpyrimidine;
4-amino-5-cyclopropyl-7-(4-dimethylam ophenyl)pyrido[2,3-d]pyrimidine; 4-amirιo-5-cyclohexyl-7-(4-djme ylarninophenyl)pyrido[2,3-d]pyrinτidme; 4-amino-5-((2-bromo-5-chlorophenyl)memyl)-7-(4-diethylaminophenyl)pyrido[2,3- djpyrimidine;
4-amirιo-5-me yl-7-(4-diethylammophenyl)pyrido[2,3-d]pyrimidine; 4-amino-5-(2,3-methylenedioxyphenyl)-7-(4-dimethylaminophenyl)pyrido[2,3- d]pyrimidine;
4- amino-5 - (3-fluor o-5-trifluoromethylphenyl)-7 - (4- dimethylaminophenyl)pyrido [2,3-d]pyrimidine;
4-ammo-5-(2-bromophenyl)-7-(4-dime ylam ophenyl)pyrido[2,3-d]pyrimidine; 4-amino-5-(3,5-dimethylphenyl)-7-(4-dimethylaminophenyl)pyrido[2,3- d]pyrimidine;
4-ar no-5-(34-dichlorophenyl)-7-(4-dimethylaminophenyl)pyrido[2,3-d]pyrimidine; 4-amino-5-(4-fluoro-3-trifluoromethylphenyl)-7-(4- dimemylaminophenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromo-5-methoxyphenyl)-7-(4-moφholinylphenyl)pyrido[2,3- d]pyrimidine;
4-amino-5-(3-bromo-5-methoxyphenyl)-7-(4-pyrrolidinylphenyl)pyrido[2,3- d]pyrimidine;
4-amino-5-(3-bromo-5-methoxyphenyl)-7-(4-piperidinylphenyl)pyrido[2,3- d]pyrimidine;
4-amino-5-(3-bromo-5-methoxyphenyl)-7-(4-dimethylaminophenyl)pyrido[2,3- d]pyrimidine; 4-amino-5-(3-methylthiophenyl)-7-(4-dimethylaminophenyl)pyrido[2,3- d]pyrimidine;
4-amιno-5-(3-bromo-5-methoxyphenyl)-7-(thiophene-2-yl)pyrido[2,3-d]pyrimidine; 4-an ino-5-(2,3-dimethoxyphenyl)-7-(4-dimethylaminophenyl)pyrido[2,3- d]pyrimidine;
4-amino-5-(3-memylsulfonylphenyl)-7-(4-dime ylaminophenyl)pyrido[2,3- d]pyrimidine: 4-acetylarnino-5-(3-bromophenyl)-7-(4-dimethylaminophenyl)pyrido[2,3- d]pyrimidine;
4-foιτnylamino-5-(3-bromophenyl)-7-(4-dimethylaminophenyl)pyrido[2,3- d]pyrimidine;
4-(methoxyacetyl)amino-5-(3-bromophenyl)-7-(4-diethylaminophenyl)pyrido[2,3- d]pyrimidine;
4-trifluoroacetylarnmo-5-(3-bromophenyl)-7-(4-dimethylaminophenyl)pyrido[2,3- d]pyrimidine;
4-pentanoylamino-5-(3-bromophenyl)-7-(4-dimethylarninophenyl)pyrido[2,3- d pyrimidine; 4-b€nzoylamino-5-(3-bromophenyl)-7-(4-dimethylaminophenyl)pyrido[2,3- d]pyrimidine;
4-(N-BOC-glycyl)amino-5-(3-bromophenyl)-7-(4-dimethylaminophenyl)pyrido[2,3- djpyrimidine;
4-(N-phthalimidylglycyl)amino-5-(3-bromophenyl)-7-(4- dimethylaminophenyl)pyrido[2,3-d]pyrimidine;
4-(ethoxycarbonyl)amino-5-(3-bromophenyl)-7-(4-dimethylaminophenyl)pyrido[2,3- d]pyrimidine;
4-(ethylaminocarbonyl)amino-5-(3-bromophenyl)-7-(4- dimethylaminophenyl)pyrido[2,3-d]pyrimidine; 4-allylamino-5-(3-bromophenyl)-7-(4-dimethylaminophenyl) pyrido[2,3- djpyrimidine;
4-(2-(Ν,Ν-dirnethylamino)ethylamino)-5-(4-bromophenyl)-7-(4- dime ylammophenyl) pyrido[2,3-d]pyrimidine;
4-(4-(N,N-dimethylamino)butylamino)-5-(3-bromophenyl)-7-(4- dimethylaminophenyl) pyrido[2,3-d]pyrimidine;
4-(N-allyl-N-formylamino)-5-(4-dimethylaminophenyl)-7-(4- bromophenyl)pyrido[2,3-d]pyrimidine;
4-diacerylam o-5-(p-djmethylarninophenyl)-7-(4- bromophenyl)pyrido[2,3-d]pyrimidine; 4-amino-5-(3-bromophenyl)-7-(5-amino-2-pyridyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(5-dime ylamino-2-pyridyl)pyrido[2,3-d]pyrimidine; 4-amino-5-(3-bromophenyl)-7-(5-dimethylamino-2- pyrazinyl)pyrido[2,3-d]pyrimidine;
4-arnino-5-(3-bromophenyl)-7-(2-oxobenzoxazolin-6-yl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(l-methyl-2-oxobenzoxazolin-6- yl)pyrido[2,3-d]pyrimidine;
4-amino-5-((5-chloro-2-(3-methoxyphenyl)phenyl)methyl)-7-(4- dmethylaminophenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-((thiophene-2-yl)methyl)-7-(4-diethylaminophenyl)pyrido[2,3- djpyrimidine; 4-armno-5-((thiophene-3-yl)methyl)-7-(4-diethylaminophenyl)pyrido[2,3- djpyrirnidine;
4-amino-5-((2-bromophenyl)methyl)-7-(4-dimethylaminophenyl)pyrido[2,3- d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(4-(N-formyl-N-(2- memoxyethyl)amino)phenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(4-(N-(2-methoxyethyl)amino)phenyl)pyrido[2,3- djpyrimidine;
4-amino-5-(3-bromophenyl)-7-(4-(N-methyl-N-((2- dijmethylan ino)emyl)amino)phenyl)pyrido[2,3-d]pyrimidine; 4-amino-5-(3-bromophenyl)-7-(4-(2- methoxy)acetylamino)emyl)ammo)phenyl)pyrido[2,3-d]pyrimidine;
4-an^no-5-(3-bromophenyl)-7-((4-formylaπ ino)phenyl)pyrido[2,3-d]pyrimidine; 4-arrώιo-5-(3-bromophenyl)-7-(4-(2-(dimeΛylam o)acetylamino)phenyl)pyrido[2,3- d]pyrimidine; 4-amino-5-(3-bromophenyl)-7-(4-(2-oxo-3-oxazolidinyl)phenyl)pyrido[2,3- d]pyrimidine;
4-anτino-5-(3-bromophenyl)-7-(6-(2-propyl)-3-pyridinyl)pyrido[2,3-d]pyrimidine; 4-amino-5-(3-bromophenyl)-7-(3-methyl-4-pyrrolidinylphenyl)pyrido[2,3- d]pyrimidine; 4-amino-5-(3-bromophenyl)-7-(6-imidazolyl-3-pyridinyl)pyrido[2,3-d]pyrimidine;
4-amino-5-phenylmethyl-7-(4-diethylaminophenyl)pyrido[2,3-d]pyrirnidine; 4-amino-5-(2-(3-aminopropynyl)phenylmethyl)-7-(4-diethylaminophenyl)pyrido[2,3- d]pyrimidine;
4-amino-5-(l-(3-bromophenyl)ethyl)-7-(4-diethylaminophenyl)pyrido[2,3- d]pyrimidine;
4-anτino-5-(4-dimethylaminophenyl)-7-(4-bromophenyl)pyrido[2,3-d]pyrirnidine; 4-amino-5-(2-furanyl)-7-(4-(N-moφholinyl)phenyl)pyrido[2,3-d]pyrimidine; 4-amino-5-(3-bromophenyl)-7-(2-dimethylan mo-5-pyrirrιidinyl)pyrido[2,3- d]pyrimidine;
4-anτino-5-(3-bromophenyl)-7-(4-(ureido)phenyl)pyrido[2,3-d]pyrimidine; 4-amino-5-(l-phenylmemyl-3-piperidinyl)-7-(4-diethylaminophenyl)pyrido[2,3- d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(6-(3-methyl-5-isoxazolyl))-3- pyridinyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(6-chloro-3-pyridinyl)pyrido[2,3-d]pyrimidine; 4-arr no-5-(3-bromophenyl)-7-(6-methoxy-3-pyridinyl)pyrido[2,3-d]pyrimidine; 4-amino-5-(3-bromophenyl)-7-(6-(l,2,4-triazol-4-yl)-3-pyridinyl)pyrido[2,3- d pyrimidine;
4-amino-5-(3-bromophenyl)-7-(2-moφholinyl-5-pyrimidinyl)pyrido[2,3- d]pyrimidine;
4-amino-5-(2-thiazolyl)-7-(4-pyrrolidinylphenyl)-pyrido[2,3-d]pyrimidine; 4-amino-5-(3-bromophenyl)-7-(6-pyrazolyl-3-pyridinyl))-pyrido[2,3- djpyrimidine;
4-amino-5-(3-bromophenyl)-7-(4-(l-methyl-ureido)phenyl)-pyrido[2,3- d]pyrimidine;
4-amijιo-5-(3-bromophenyl)-7-(4-(N-methyl-N-(2-pyrimidmyl)amino)phenyl)- pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(3-fluoro-4-(N-formyl-N-methylamino)phenyl)- pyrido[2,3-d]pyrimidine;
4-formylamino-5-(3-bromophenyl)-7-(3-fluoro-4-(N-formyl-N- memylanτmo)phenyl)-pyrido[2,3-d]pyrimidine; 4-ammo-5-(3-bromophenyl)-7-(4-(N-me yl-N-methylsulfonylamino)- phenyl)pyrido[2,3-d]pyrimidine;
4-arnino-5-(3-bromophenyl)-7-(6-(N-methyl-N-methylsulfonylamino)-3- pyridinyl)pyrido[2,3-d]pyrimidine;
4-ammo-5-(3-bromophenyl)-7-(l-methyl-5-indolinyl)pyrido[2,3-d]pyrimidine; 4-amirιo-5-(3-bromophenyl)-7-(l-methyl-5-r^nzimidazolyl)pyrido[2,3- d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(6-dimemylamino-3-pyridazinyl)pyrido[2,3- d]pyrimidine;
4-amino-5-(3bromophenyl)-7-(6-moφholinyl-3-pyridazinyl)pyrido[2,3- d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(6-pyrrolidinyl-3-pyridazinyl)pyrido[2,3- djpyrimidine; 4-arnino-5-(3-bromophenyl)-7-(5-moφholinyl-2-pyrazinyl)pyrido[2,3- d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(5-(N-(2-methoxyethyl)-N-methylamino)-2- pyrazinyl)pyrido[2,3-d]pyrimidine; 4-amino-5-(3-bromophenyl)-7-(4-(moφholinylmethyl)-phenyl)pyrido[2,3- d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(5-(N,N-bis(2-methoxyethyl)amino)-2- pyridinyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(4-(imidazolylmethyl)-phenyl)pyrido[2,3- d]pyrirnidine;
4-amino-5-(3-bromophenyl)-7-(5-(l-moφholinyl)-2-pyridinyl)pyrido[2,3- d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(4-((dimethylamino)methyl)-phenyl)pyrido[2,3- djpyrimidine; 4-amino-5-(3-bromophenyl)-7-(5-(4-hydroxy-l-piperidinyl)-2- pyridinyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(5-(N-formyl-N-methylamino)-2- pyridinyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(5-(2-propenyl)-2-pyridinyl)pyrido[2,3- dlpyrimidine;
4-amino-5-(3-bromophenyl)-7-(3-(2-methoxyethyl)-2-oxo-6- benzoxazoly l)pyrido [2 ,3-d] pyrimidine;
4-amino-5-(3-bromophenyl)-7-(4-(l-(N-formylamino)-ethyl)phenyl)pyrido[2,3- d]pyrimidine; 4-(me ylamino)-5-(3-bromophenyl)-7-(4-dimethylaminophenyl)pyrido[2,3- djpyrimidine hydrochloride;
4-(2-methoxyethylamino)-5-(3-bromophenyl)-7-(4- dimemylammophenyl)pyrido[2,3-d]pyrimidine hydrochloride;
4-amino-5-(3-bromophenyl)-7-(4-(l-methyl-2-imidazolyl)phenyl)pyrido[2,3- dlpyrimidine trihydrochloride;
4-aιmfιo-5-(3-bromophenyl)-7-(4-(aminomethyl)phenyl)pyrido[2,3-d]pyrirnidine; 4-amino-5-(3-bromophenyl)-7-(2-bromo-4-(dimethylamino)phenyl)pyrido[2,3- d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(4-(dimemylaminoethyl)phenyl)pyrido[2,3- dlpyrimidine;
4-anιino-5-(3-bromophenyl)-7-(4-(3-(dimethylamino)propynyl)phenyl)pyrido[2,3- dlpyrimidine; 4-amino-5-(3-bromophenyl)-7-(4-(3-amino-3-methylbutynyl)phenyl)pyrido[2,3- dlpyrimidine;
4-amino-5-(3-bromophenyl)-7-(4-dimethylphosphonatophenyl)pyrido[2,3- d]pyrimidine; 4-amino-5-(3-bromophenyl)-7-(4-(3-(methoxypropynyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(4-carboxyphenyl)pyrido[2,3-d]pyrimidine; 4-amino-5-(3-bromophenyl)-7-(4-methyl-3-oxo-2H-4H-pyrido[3,2-b]-l,4-oxazin- 7-yl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(4-(2-(dimethylamino)ethyl)-3-oxo-2H-4H- pyrido[3,2-b]- 1 ,4-oxazin-7-yl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(2,3-dihydro-3-(dimethylaminoethyl)-2- oxobenzoxazol-6-yl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(4-methyl-3-oxo-2H-4H-benzo-l,4-oxazin-7- yl)pyrido[2,3-d]pyrimidine; 4-amino-5-(3-bromophenyl)-7-(2,2,4-trimethyl-3-oxo-2H-4H-benzo-l,4-oxazin-7- yl)pyrido [2 ,3-d]pyrimidine;
4-ammo-5-cyclohexyl-7-(4-(2-dimethylamino)ethyl)-2H-4H-benzo-3-oxo-l,4- oxazin-7-yl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(5-(l-methylethyl)-2-pyridyl)pyrido[2,3- d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(5-piperidin-l-ylpyrid-2-yl)pyrido[2,3-d]pyrimidine; 4-amino-5-(l-(4-bromophenyl)ethyl)-7-(6-moφholinylpyrid-3-yl)pyrido[2,3- d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(4-((N-formylamino)methyl)phenyl)pyrido[2,3- dlpyrimidine;
4-anήno-5-(3-bromophenyl)-7-(4-(l-methyl-l-(N-methylamino)ethyl)phenyl)- pyrido[2,3-d]pyrimidine:
4-amino-5-(3-bromophenyl)-7-(4-(l-(dimethylamino)-l- methylethyl)phenyl)pyrido[2,3-d]pyrimidine; 4-ammo-5-(3-bromophenyl)-7-(N-acetyl-5-indoUnyl)pyrido[2,3-d]pyrimidine;
4-amino-5-cyclohexyl-7-(6-cWoro-3-pyridyl)pyrido[2,3-d]pyrimidine; 4-anτino-5-(l-(2-bromophenyl)ethyl)-7-(6-diemylamino-3-pyridyl)pyrido[2,3- d]pjτimidine;
4-amino-5-(l-(2-bromophenyl)ethyl)-7-(6-moφholinyl-3-pyridyl)pyrido[2,3- dlpyrimidine;
4-amijιo-5-(l-(2-bromophenyl)emyl)-7-(4-(N-methyl-N-formyl)arnino)- phenyl)pyrido[2,3-d]pyrimidine; 4-am o-5-cyclohexyl-7-(6-moφhoUnyl-3-pyridyl)pyrido[2,3-d]pyrimidine; 4-armno-5-((2-bromophenyl)methyl)-7-(6-moφholinyl-3-pyridyl)pyrido[2,3- djpyrimidine;
4-amino-5-(4-tetrahydropyranyl)-7-(6-moφholinyl-3-pyridyl)pyrido[2,3- dlpyrimidine;
4-amirιo-5-cyclohexyl-7-(6-dimethylaιτιirιo-3-pyridyl)pyrido[2,3-d]pyrimidine; 4-ammo-5-(l-ethylpropyl)-7-(6-dimemylamιno-3-pyridyl)pyrido[2,3-d]pyrimidine; 4-anήno-5-cyclopentyl-7-(6-moφholinyl-3-pyridyl)pyrido[2,3-d]pyrimidine; 4-amino-5-cyclohexyl-7-(2-chloro-3-pyridyl)pyrido[2,3-d]pyrimidine; 4-amirio-5-(3,5-dimemylcyclohexyl)-7-(6-dimethylamino-3-pyridyl)pyrido[2,3- d]pyrimidine;
4-amino-5-((N-(benzyloxycarbonyl)-4-piperidinyl)methyl)-7-(6-moφholinyl-3- pyridyl)pyrido[2,3-d]pyrimidine;
4-amino-5-cyclohexyl-7-(6-bromo-3-pyridyl)pyrido[2,3-d]pyrimidine; 4-amino-5-cyclohexyl-7-(3-cyanophenyl)pyrido[2,3-d]pyrimidine;
4-amirιo-5-(l-(2-bromophenyl)ethyl)-7-(6-dimethylamino-3-pyridazinyl)pyrido[2,3- d]pyrimidine;
4-am o-5-(3-bromophenyl)-7-(6-irnidazolyl-3-pyridazmyl)pyrido[2,3-d]pyrimidine; 4-amino-5-(3-bromophenyl)-7-(6-(azacycloheptanyl)-3-pyridazinyl)pyrido[2,3- dlpyrimidine;
4-ammo-5-(3-bromophenyl)-7-(6-(N-methyl-N-(l-methylethyl))amino)-3- pyridazinyl)pyrido[2,3-dlpyrimidine;
4-amino-5-(l-(2-bromophenyl)ethyl)-7-(6-moφholinyl-3-pyridazinyl)pyrido[2,3- dlpyrimidine; 4-amino-5-cyclohexyl-7-(6-(4-acetylpiperazinyl)-3-pyridyl)pyrido[2,3-d]pyrimidine;
4-amino-5-cyclohexyl-7-(6-(4-acetyl-l,4-diazacycloheptanyl)-3-pyridyl)pyrido[2,3- dlpyrimidine;
4-amino-5-cyclohexyl-7-(6-(4-methyl- 1 ,4-diazacycloheptanyl)-3- pyridyl)pyrido[2,3-dlpyrimidine; 4-amino-5-cyclohexyl-7-(6-(N-methyl-N-(2-(2-pyridyl)ethyl)amino)-3- pyridyl)pyrido[2,3-d]pyrimidine;
4-amino-5-cyclohexyl-7-(6-2-(N-(N',N'-dimethylaminoethyl)-N-methylamino)-3- pyridyl)pyrido[2,3-dlpyrimidine;
4-arnino-5-cyclohexyl-7-(6-azetidmyl-3-pyridyl)pyrido[2,3-d]pyrimidine; 4-amino-5-cyclohexyl-7-(6-(3-(N-methylacetamido)pyrrolidinyl)pyridyl)pyrido[2,3- dlpyrimidine; 4-amino-5-cyclohexyl-7-(6-(3-(formamido)pyrrolidinyl)pyridyl)pyιido[2,3- dlpyrimidine;
4-amino-5-cyclohexyl-7-(4-oxo-l-phenyl-l,3,8-rriazaspiro[4.5[decan-8- yl)pyrido[2,3-d]pyrimidine; 4-amino-5-cyclohexyl-7-(6-(2-methoxymethyl)pyrrolidin-l-yl)pyridyl)pyrido[2,3- dlpyrimidine;
4-amino-5-cyclohexyl-7-(6-(N-methoxyethyl-N-propylamino)pyridyl)pyrido[2,3- dlpyrimidine;
4-aιτύno-5-cyclohexyl-7-(N-methyl-N-(2,2-dimemoxyethyl)amino)pyrido[2,3- dlpyrimidine;
4-am o-5-cyclohexyl-7-(6-(4-(dimethylan ino)piperidinyl)pyridyl)pyrido[2,3- dlpyrimidine;
4-amino-5-cyclohexyl-7-(6-(4-(aminocarbonyl))piperidinyl)pyridyl)pyrido[2,3- dlpyrimidine; 4-amino-5-cyclohexyl-7-(N-memyl-N-(3-(dieΛylamino)propyl)aminopyrid-3- yl)pyrido[2,3-dlpyrimidine;
4-amino-5-cyclohexyl-7-(6-(N-methyl-N-(4-pyridyl)ethylamino)pyrid-3- yl)pyrido[2,3-dlpyrimidine;
4-arnino-5-cyclohexyl-7-(6-(N-methyl-N-(3-pyridylmethylamino)pyrid-3- yl)pyrido[2,3-dlpyrimidine;
4-amino-5-(l-(2-bromophenyl)ethyl)-7-(l-methyl-5-indolyl)pyrido[2,3- dlpyrimidine;
4-amino-5-(l-(2-bromophenyl)ethyl)-7-(l-methyl-2,3-dioxo-5-indolyl)pyrido[2,3- dlpyrimidine; 4-amino-5-(3-bromophenyl)-7-(3-fluoro-4-(l-moφholinyl)phenyl)pyrido[2,3- dlpyrimidine;
4-amino-5-(3-bromophenyl)-7-(4-hydroxy-3-nittophenyl)pyrido[2,3-dlpyrimidine;
4-amino-5-(3-bromophenyl)-7-(6-(4,4-ethylenedioxypiperidinyl)-3- pyridyl)pyrido[2,3-dlpyrimidine; 4-amino-5-(3-bromophenyl)-7-(6-(4-oxopiperidinyl)-3-pyridyl)pyrido[2,3- dlpyrimidine;
4-amino-5-(3-bromophenyl)-7-(6-(4-formylpiperazinyl)-3-pyridyl)pyrido[2,3- dlpyrimidine;
4-amino-5-(3-bromophenyl)-7-(6-(4-methylpiperazinyl)-3-pyridyl)pyrido[2,3- dlpyrimidine;
4-amino-5-(3-bromophenyl)-7-(6-thiomoφhoUnyl-3-pyridyl)pyrido[2,3- dlpyrimidin; 4-amino-5-(3-bromophenyl)-7-(6-(4,4-dioxothiomoφholinyl)-3-pyridyl)pyrido[2,3- dlpyrimidine;
4-amino-5-(2-bromophenyl)-7-(6-moφholinyl-3-pyridyl)pyrido[2,3-dlpyrimidine; 4-amino-5-(3-bromo-4-methoxyphenyl)-7-(6-moφholinyl-3-pyridyl)pyrido[2,3- dlpyrimidine;
4-amino-5-(4-bromophenyl)-7-(6-moφholinyl-3-pyridyl)pyrido[2,3-d]pyrimidine; 4-arnino-5-(3-chlorophenyl)-7-(6-moφhoUnyl-3-pyridyl)pyrido[2,3-dlpyrimidine; 4-amino-5-(3-bromophenyl)-7-(5-chloro-6-moφholinyl-3-pyridyl)pyrido[2,3- dlpyrimidine; 4-amino-5-(3-bromophenyl)-7-(6-(N-oxidomoφholinyl)-3-pyridyl)pyrido[2,3- dlpyrimidine;
4-amino-5-(3-bromophenyl)-7-(6-(N-(2-hydroxyethoxyethyl)amino)-3- pyridyl)pyrido[2,3-dlpyrimidine;
4-arr no-5-(3-bromophenyl)-7-(6-(N-(2-hydroxyethoxyethyl)-N-formylamino)-3- pyridyl)pyrido[2,3-dlpyrimidine;
4-arnino-5-(3-bromophenyl)-7-(6-(N-(2-hydroxyethoxyethyl)-3-pyridyl-N- oxide)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(6-(3-hydroxy)moφholinyl)-3-pyridyl)pyrido[2,3- dlpyrimidine; l-(5-(4-ammo-5-(3-bromophenyl)pyrido[2,3-d]pyrimidin-7-yl)-2-pyridyl)- piperidine-4-phosphate, disodium salt;
4-amino-5-(3-bromophenyl)-7-(4-methylenylpiperidinyl)-3-pyridyl)pyrido[2,3- dlpyrimidine;
4-amino-5-(3-bromophenyl)-7-(4-hydroxy-4-(hydroxymethyl)piperidinyl)-3- pyridyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(6-(4,4-ethylenedioxypiperidinyl)-3- pyridyl)pyrido[2,3-d]pyrirnidine;
4-arnmo-5-cyclohexyl-7-(6-(4-oxo-piperid yl)-3-pyridyl)pyrido[2,3-dlpyrimidine; 4-amino-5-cyclohexyl-7-(6-(4-methylenylpiperidinyl)-3-pyτidyl)pyrido[2,3- dlpyrimidine;
4-N-(iminomethyl)amino-5-cyclohexyl-7-(6-dimethylamino-3-pyridyl)pyrido[2.3- dlpyrimidine; and pharmaceutically acceptable salts and amides thereof. In addition, the and pharmaceutically acceptable salts and amides thereof. The partially saturated and fully saturated versions of the above compounds are also included within the scope of the method of inhibiting adenosine kinase in a patient in need of treatment thereof. The above compounds may be treated with hydrogen and a catalyst to form a compound of formula I wherein the double bonds on the right side are absent or there is a double bond between the 5,6 carbons; the 6,7 carbons or the 7 carbon, 8 nitrogen.
Exemplary and preferred compounds of the invention, again with the variables Rl- R^ as specifically shown below, include:
4-arm^o-5-(4-dimethylaminophenyl)-7-(4-bromophenyl)pyrido[2,3-dlpyrimidine; 4-ammo-5-(4-dimethylanιinophenyl)-7-(4-dimethylaminophenyl)pyrido[2,3- dlpyrimidine;
4-arm^o-5-(4-methoxyphenyl)-7-(4-dimemylanιinophenyl)pyrido[2,3-dlpyrirnidine; 4-ammo-5-(4-o methylanτinophenyl)-7-(4-methoxyphenyl)pyrido[2,3-dlpyrimidine;
4-amino-5-(4-(2-propyl)phenyl)-7-(4-methoxyphenyl)pyrido[2,3-dlpyrimidine; 4-arm^o-5-(4-neopentylphenyl)-7-(4-methoxyphenyl)pyrido[2,3-d]pyrimidine; 4-amino-5-(4-butyloxyphenyl)-7-(4-methoxyphenyl)pyrido[2,3-dlpyrirnidine; 4-amino-5-(4-memoxyphenyl)-7-(4-bromophenyl)pyrido[2,3-dlpyrimidine; 4-amino-5-(4-(2-propyl)oxyphenyl)-7-(4-me oxyphenyl)pyrido[2,3-d]pyrimidine;
4- amino-5 - (4- butoxypheny 1) -7 - (4-N-f ormylpiperazinylphenyl)pyrido [2,3- dlpyrimidine;
4-amino-5-(4-benzyloxyphenyl)-7-(4-me oxyphenyl)pyrido[2,3-d]pyrimidine; 4-amino-5-(4-phenoxyphenyl)-7-(4-methoxyphenyl)pyrido[2,3-dlpyrimidine; 4-amino-5-(4-(2-propyl)phenyl)-7-(4-diethylmalonylallylphenyl)pyrido[2,3- dlpyrimidine;
4-aιr no-5-(4-(2-propyl)phenyl)-7-(4-t-butylacrylphenyl)pyrido[2,3-dlpyrimidine; 4-ammo-5-(3-bromophenyl)-7-(4-dimethylarn ophenyl)pyrido[2,3-dlpyrimidine; 4-arnino-5-(3,4-dimethoxyphenyl)-7-(4-dimethylaminophenyl)pyrido[2,3- dlpyrimidine;
4-am o-5-(3-t-butylacrylphenyl)-7-(4-dimethylaminophenyl)pyrido[2,3- dlpyrimidine;
4-amino-5- (3-methoxyphenyl-7- (4-mmethylarninophenyl)pyrido[2,3-d]pyrimidine; 4-amino-5-(3,5-dirnethoxyphenyl-7-(4-dimethylaminophenyl)pyrido[2,3- dlpyrimidine;
4-am o-5-(3-diethylmalonylallylphenyl)-7-(4-dimemylarninophenyl)pyrido[2,3- dlpyrimidine;
4-amino-5-(3-vinylpyridinylphenyl)-7-(4-dimemylaπιinophenyl)pyrido[2,3- dlpyrimidine; 4-am o-5-(3-trifluoromethylphenyl)-7-(4-dimethylaminophenyl)pyrido[2,3- dlpyrimidine; 4-amino-5-(3-carboxamidophenyl)-7-(4-dimethylaminophenyl)pyrido[2,3- dlpyrimidine;
4-ammo-5-(3-cyanophenyl)-7-(4-dimethylan mophenyl)pyrido[2,3-dlpyrimidine;
4-ammo-5-(3-benzyloxyphenyl)-7-(4-dimemylaminophenyl)pyrido[2,3-d]pyrimidine; 4-amino-5-(3-methoxyphenyl)-7-(4-methoxyphenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(4-butoxyphenyl)pyrido[2,3-dlpyrimidine;
4-amino-5-(3-(2-pyridyl)phenyl)-7-(4-dimethylaminophenyl)pyrido[2,3- d]pyrimidine;
4-ammo-5-(3-methylphenyl)-7-(4-dimethylaminophenyl)pyrido[2,3-dlpyrimidine; 4-ammo-5-(3-cUorophenyl)-7-(4-c methylarrιmophenyl)pyrido[2,3-dlpyrimidine;
4-am o-5-(3-fluorophenyl)-7-(4-dimethylaminophenyl)pyrido[2,3-d]pyrimidine;
4-arnino-5-(3-bromophenyl)-7-(4-methoxyphenyl)pyrido[2,3-dlpyrimidine;
4-anιino-5-(3-memoxyphenyl)-7-(4-bromophenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-phenylpyrido [2,3-d]pyrimidine; 4-amino-5-(3-bromophenyl)-7-(4-ethylphenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(4-bromophenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(4-cyanophenyl)pyrido[2,3-dlpyrimidine;
4-amino-5-(3-bromophenyl)-7-(4-hydroxyphenyl)pyrido[2,3-d]pyrimidine;
4-am o-5-(3-iodophenyl)-7-(4-diιnethylaminophenyl)pyrido[2,3-d]pyrimidine; 4-ammo-5-(3-emoxyphenyl)-7-(4-dimemylaminophenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-trifloromethyoxyphenyl)-7-(4-dimethylaminophenyl)pyrido[2,3- dlpyrimidine;
4-amino-5-(3,5-dichlorophenyl)-7-(4-dimethylaminophenyl)pyrido[2,3-dlpyrimidine;
4-amino-5-(3-bromo-4-fluorophenyl)-7-(4-dimethylaminophenyl)pyrido[2,3- dlpyrimidine;
4-amino-5-(3-hydroxyphenyl)-7-(4-dimethylaminophenyl)pyrido[2,3-dlpyrimidine;
4-amino-5-(3-bromophenyl)-7-(4-moφholmylphenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(4-piperidinylphenyl)pyrido[2,3-d]pyrimidine;
4-ar no-5-(3-bromophenyl)-7-(4-(imidazol-l-yl)phenyl)pyrido[2,3-dlpyrimidine; 4-amino-5-(3-bromophenyl)-7-(4-chlorophenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(4-isopropylphenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(4-trifluorophenyl)pyrido[2,3-dlpyrimidine;
4-amino-5-(3-bromophenyl)-7-(4-diemylam ophenyl)pyrido[2,3-dlpyrimidine;
4-ammo-5-(3-bromophenyl)-7-(3,4,5-trimethoxyphenyl)pyrido[2,3-dlpyrimidine; 4-aιτ no-5-(3-(3-memoxybenzyl)phenyl)-7-(4-dimethylaminophenyl)pyrido[2,3- d]pyrimidine; 4-amino-5- 3-memoxyethyoxyphenyl)-7-(4-dimemylaminophenyl)pyrido[2,3- dlpyrimidine;
4-amino-5- 3,4-methylenedioxyphenyl)-7-(4-dimethylaminophenyl)pyrido[2,3- dlpyrimidine; 4-amino-5- 3-bromophenyl)-7-(4-ethoxyphenyl)pyrido[2,3-dlpyrimidine;
4-amino-5- 3-bromophenyl)-7-(2'-thiophene)pyrido[2,3-d]pyrimidine;
4-amino-5- 3-bromophenyl)-7-(4-fluorophenyl)pyrido[2,3-d]pyrimidine;
4-amino-5- 3-dimemylar nophenyl)-7-(4-dimethylaminophenyl)pyrido[2,3- dlpyrimidine; 4-amino-5- phenyl-7-(4-dimethylaminophenyl)pyrido[2,3-d]pyrimidine;
4-amino-5- 3,4,5-trimethoxyphenyl)-7-(4-dimethylaminophenyl)pyrido[2,3- dlpyrimidine;
4-amino-5- 3-bromophenyl)-7-(4-nitrophenyl)pyrido[2,3-d]pyrimidine; 4-amino-5- 3-bromophenyl)-7-(4-iodophenyl)pyrido[2,3-dlpyrimidine; 4-amino-5- 3-bromophenyl)-7-(3,4-methylenedioxyphenyl)pyrido[2,3-dlpyrimidine;
4-amino-5- thiophen-2-yl)-7-(4-moφholinylphenyl)pyrido [2,3-d]pyrimidine; 4-amino-5- 3,5-dimethoxyphenyl)-7-(thiophen-2-yle)pyrido [2,3-dlpyrimidine; 4-amino-5- 3-bromophenyl)-7-(4-carboxamidophenyl)pyrido[2,3-dlpyrimidine; 4-amino-5- 3-bromophenyl)-7-(4-(2-methoxy)ethoxyphenyl)pyrido[2,3- dlpyrimidine;
4-amino-5- ;3,5-dimethoxyphenyl)-7-(4-moφholinylphenyl)pyrido[2,3-dlpyrimidine; 4-amino-5- 3-trifluoromethylphenyl)-7-(thiophene-2-yl)pyrido [2,3-dlpyrimidine; 4-amino-5- 3-bromophenyl)-7-(4-aminophenyl)pyrido[2,3-d]pyrimidine; 4-amino-5- 3-bromo-4-fluorophenyl)-7-(thiophene-2-yl)pyrido [2,3-d]pyrimidine; 4-amino-5- 3-bromo-4-fluorophenyl)-7-(2-furanyl)pyrido [2,3-d]pyrimidine;
4-amino-5- 3,5-dimemoxyphenyl)-7-(4-iodophenyl)pyrido[2,3-dlpyrimidine; 4-amino-5- 3,5-dimethoxyphenyl)-7-(4-imidazolylphenyl)pyrido[2,3-dlpyrimidine; 4-amino-5- 3,5-dimethoxyphenyl)-7-(4-(thiophene-2-yl)phenyl)pyrido[2,3- dlpyrimidine; 4-amino-5- 3,5-dimemoxyphenyl)-7-(4-(3-pyridyl)phenyl)pyrido[2,3-d]pyrimidine;
4-amino-5- 3-bromophenyl)-7-(4-(4-methylpiperidinyl)phenyl)pyrido[2,3- d]pyrimidine;
4-amino-5- 3-bromophenyl)-7-(4-pyrrolidinylphenyl)pyrido[2,3-dlpyrimidine;
4-amino-5- 4-bromomiophene-)-7-(4-dimethylarrdnophenyl)pyrido[2,3-dlpyrimidine; 4-amino-5- 4-bromothiophene-2-yl)-7-(4-moφholinylphenyl)pyrido[2,3- dlpyrimidine; moφhol yl-5-(3-bromophenyl)-7-(4-dimethylarninophenyl)pyrido[2,3- dlpyrimidine;
4-amino-5-(5-bromothiophene-2-yl)-7-(4-moφholinylphenyl)pyrido[2,3- dlpyrimidine; 4-amirιo-5-(4-bromophenyl)-7-(4-dimethylaminophenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(4-(acetylamino)phenyl)pyrido[2,3-dlpyrimidine; 4-amirιo-5-(3-bromophenyl)-7-(4-dimet ylaminophenyl)pyrido[2,3-d]pyrimidine; 4-amino-5-(3,5-dimemoxyphenyl)-7-(5-pyrinτidinylphenyl)pyrido[2,3-dlpyrimidine; 4-(4-fluorophenyl)amino)-5-(3-bromophenyl)-7-(4- dimemylaminophenyl)pyrido[2,3-dlpyrimidine;
4-amino-5-(4-bromothiophene-2-yl)-7-(4-pyrrolidinylphenyl)pyrido[2,3- d]pyrimidine;
4-amino-5-(4-bromothiophene-2-yl)-7-(thiophene-2-yl)pyrido[2,3-dlpyrimidine; 4-amino-5-(3-bromophenyl)-7-(5-(dimemylaιnino)thiophene-2-yl)pyrido[2,3- dlpyrimidine;
4-amino-5-(3-bromo-5-iodophenyl)-7-(4-(dimethylamino)phenyl)pyrido[2,3- dlpyrimidine;
4-amino-5-(3,5-di(trifluoromethyl)phenyl)-7-(4-(dimethylamino)phenyl)pyrido[2,3- dlpyrimidine; 4-amino-5-(3,5-di(trifluoromethyl)phenyl)-7-(4-moφholinylphenyl)pyrido[2,3- dlpyrimidine;
4-anήno-5-(3,5-dibromophenyl)-7-(4-(dimethylamino)phenyl)pyrido[2,3- dlpyrimidine;
4-arnino-5-(3,5-dibromophenyl)-7-(4-moφholinylphenyl)pyrido[2,3-dlpyrimidine; 4-arnino-5-(4-bromothiophene-2-yl)-7-(4-(4-methylpiperidinyl)phenyl)pyrido[2,3- dlpyrimidine;
4-aιnino-5-(3,5-dibromophenyl)-7-(4-(dimethylamino)phenyl)pyrido[2,3- dlpyrimidine;
4-amino-5-(3-bromophenyl)-7-(3-(dime ylanτino)phenyl)pyrido[2,3-dlpyrimidine; 4-amino-5-(3-bromophenyl)-7-(4-methylsulfonylphenyl)pyrido[2,3-dlpyrimidine;
4-amino-5-(3-bromophenyl)-7-(3-methoxyphenyl)pyrido[2,3-d]pyrimidine; 4-amino-5-(3-bromophenyl)-7-(4-(methylthio)phenyl)pyrido[2,3-dlpyrimidine; 4-aιnino-5-(3-bromophenyl)-7-(3,4-dichlorophenyl)pyrido[2,3-dlpyrimidine; 4-amino-5-(3-bromophenyl)-7-(4-(N-methyl-N-formylamino)phenyl)pyrido[2,3- dlpyrimidine;
4-amino-5-(3-bromophenyl)-7-(4-methylaminophenyl)pyrido[2,3-dlpyrimidine; 4-amino-5-(3-bromo-4-fluorophenyl)-7-(4-methylsulfonylphenyl)pyrido[2,3- d]pyrimidine;
4"amino-5-(3-bromophenyl)-7-(3-amino-4-methoxyphenyl)pyrido[2,3-d]pyrimidine; 4-amino-5-(3-bromophenyl)-7-(3-bromo-4-(dimethylamino)phenyl)pyrido[2,3- dlpyrimidine;
4-amino-5-(3-bromophenyl)-7-(3-methyl-4-(dimethylamino)phenyl)pyrido[2,3- d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(4-(N-methyl-N- tiifluoroacetylamino)phenyl)pyrido[2,3-dlpyrimidine; 4-amino-5-(3-bromophenyl)-7-(4-(dimethylamino)-3-fluorophenyl)pyrido[2,3- dlpyrimidine;
4-amino-5-(3-bromophenyl)-7-(4-(N-ethyl-N-formylamino)phenyl)pyrido[2,3- dlpyrimidine;
4,4-bis(acetylamino)-5-(3-bromophenyl)-7-(4-(N-methyl-N- acetylamino)phenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(4-(N-acetyl-N-memylamino)phenyl)pyrido[2,3- dlpyrimidine;
4-amino-5-(3-bromophenyl)-7-(4-(N-emylan ino)phenyl)pyrido[2,3-d]pyrimidine; 4-amino-5-(3-bromophenyl)-7-(4-(N-methyl-N-(2- methoxyethyl)amino)phenyl)pyrido[2,3-dlpyrimidine;
4-amino-5-(3-bromophenyl)-7-(4-(N-isopropylamino)phenyl)pyrido[2,3- dlpyrimidine;
4-amino-5-(3-bromophenyl)-7-(4-N-ethyl-N-(2- methoxyethyl)amino)phenyl)pyrido[2,3-d]pyrimidine; 4-anιino-5--(3-bromophenyl)-7-(4-N-(3-methoxypropionyl)-N-isopropyl- amino)phenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(4-N-(2-(dimethylamino)ethyl)-N- formylamino)phenyl)pyrido[2,3-d]pyrimidine; 4-amino-5-(3-bτomophenyl)-7-(4-(N-(2- (dime ylamino)emyl)arrύno)phenyl)pyrido[2,3-dlpyrimidine; 4-amino-5-(3-bromophenyl)-7-(4-(N-methyl-N-(2- cyano)ethylamino)phenyl)pyrido[2,3-dlpyrimidine;
4-amino-5-(3-bromophenyl)-7-(4-(N-methyl-N-(3- memoxy)propionylamino)phenyl)pyrido[2,3-dlpyrirnidine; 4-amino-5-(3-bromophenyl)-7-(3-methyl-4-(N-formyl-N- meAylarnino)phenyl)pyrido[2,3-d]pyrimidine; 4-amino-5-(3-bromophenyl)-7-(3-methyl-4-(N-methylamino)phenyl)pyrido[2,3- dlpyrimidine;
4-amino-5-(3-bromophenyl)-7-(4-(4-methoxy-2-butyl)phenyl)pyrido[2,3- dlpyrimidine; 4-amino-5-(3-bromophenyl)-7-(4-(N-methyl-N-(2-(N- phthaUmidyl)acetyl)aιτ no)phenyl)pyrido[2,3-d]pyrirnidine;
4-amino-5-(3-bromophenyl)-7-(3-methyl-4-(N-methyl-N- (trifluoroacetyl)amino)phenyl)pyrido[2,3-dlpyrimidine;
4-amino-5-(3-bromophenyl)-7-(3-methyl-4-(N-acetyl-N- me ylamino)phenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(6-dimethylamino-3-pyridinyl)pyrido[2,3- dlpyrimidine;
4-amino-5-(3-cyanophenyl)-7-(4-methylsulfonylphenyl)pyrido[2,3-dlpyrirnidine;
4-amino-5-(3-cyanophenyl)-7-(4-(N-memyl-N-formylamino)-phenyl)pyrido[2,3- dlpyrimidine;
4-amino-5-(3-bromophenyl)-7-(6-(N-methyl-N-formylamino)-3- pyridinyl)pyrido[2,3-dlpyrimidine;
4-amino-5-(3-bromophenyl)-7-(6-moφholinyl-3-pyridinyl)pyrido[2,3-dlpyrimidine;
4-amino-5-(3-bromophenyl)-7-(6-(N-methyl-N-methoxyethylamino)-3- pyridinyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(6-pyrroUdinyl-3-pyridmyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(2-(dime ylammo)-5-pyrimidinyl)pyrido[2,3- dlpyrimidine;
4-amino-5-(3-bromophenyl)-7-(2-(N-methoxyethyl-N-methyl amino)-5- pyriιmdinyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(2-(N-formyl-N-methyl amino)-5- pyrimidinyl)pyrido[2,3-dlpyrimidine;
4-anr no-5-(3-bromophenyl)-7-(2-(N-me ylamino)5-pyriπύdinyl)pyrido[2,3- dlpyrimidine; 4-amino-5-(3-bromophenyl)-7-(2-(l-pyrrolidinyl)-5-pyrimidinyl)pyrido[2,3- dlpyrimidine;
4-amino-5-(3-bromophenyl)-7-(2-(l-moφholinyl)-5-pyrimidinyl)pyrido[2,3- dlpyrimidine;
4-amino-5-(3-bromophenyl)-7-(6-(2-oxo-3-oxazolidinyl)-3-pyridinyl)pyrido[2,3- dlpyrimidine;
4-amino-5-(3-bromophenyl)-7-(2-pyridyl)pyrido[2 -dlpyrimidine;
4-amino-5-(3-bromophenyl)-7-(3-pyridyl)pyrido[2,3-dlpyrimidine; 4-aι no-5-(3-(tMophen-2-yl)phenyl)-7-(4-dimethylaminophenyl)pyrido[2,3- dlpyrimidine;
4-ammo-5-(3-(furan-2-yl)phenyl)-7-(4-dimethylaminophenyl)pyrido[2,3- dlpyrimidine; 4-amino-5-(3-(3-methox>φhenyl)phenyl)-7-(4-dimethylaminophenyl)pyrido[2,3- dlpyrimidine;
4-am o-5-phenyl-7-(4-dimemylaminophenyl)pyrido[2,3-dlpyrimidine; 4-amino-5-(3-chlorophenyl)-7-(4-(moφholinyl)phenyl)pyrido[2,3-d]pyrimidine; 4-amino-5-(3-bromo-4-fluorophenyl)-7-(4-(moφholinyl)phenyl)pyrido[2,3- dlpyrimidine;
4-amino-5-(3-chlorophenyl)-7-(4-iodophenyl)pyrido[2,3-d]pyrimidine; 4-amino-5-(3-chlorophenyl)-7-(4-( iophen-2-yl)phenyl)pyrido[2,3-d]pyrimidine; 4-anrύno-5-(3-cWorophenyl)-7-(4-(5-pyrimidinyl)phenyl)pyrido[2,3-d]pyrimidine; 4-amino-5-(3-bromo-4-fluorophenyl)-7-(4-iodophenyl)pyrido[2,3-dlpyrimidine; 4-amino-5-(4-bromomiophene-2-yl)-7-(4-methoxyphenyl)pyrido[2,3-dlpyrimidine;
4-amino-5-(3-bromophenyl)methyl-7-(4-(dimethylamino)phenyl)pyrido[2,3- dlpyrimidine;
4-ammo-5-(2-phenylethyl)-7-(4-diemylaminophenyl)pyrido[2,3-dlpyrimidine; 4-ammo-5-(2-methylpropyl)-7-(4-diethylaminophenyl)pyrido[2,3-d]pyrimidine; 4-ammo-5-(butyl)-7-(4-diemylaminophenyl)pyrido[2,3-dlpyrimidine;
4-amino-5-(2-(4-bromophenyl)ethyl)-7-(4-diethylaminophenyl)pyrido[2,3- dlpyrimidine;
4-amino-5-(butyl)-7-(4-dimemylaminophenyl)pyrido[2,3-d]pyrimidine; 4-amirιo-5-(2-(3-cyanophenyl)memyl)-7-(4-o methylaminophenyl)pyrido[2,3- dlpyrimidine;
4-arrιino-5-(2-(N-phenylmethoxycarbonyl)arninoethyl)-7-(4- dimemylaminophenyl)pyrido[2,3-d]pyrimidine;
4-ammo-5-(cycloheptyl)-7-(4-dimethylammophenyl)pyrido[2,3-d]pyrimidine; 4-amino-5-(2-(5-chloro-2-(thiophen-3-yl)phenylmethyl)-7-(4- dimemylaminophenyl)pyrido[2,3-dlpyrirnidine;
4-am o-5-(pentyl)-7-(4-diemylanτ ophenyl)pyrido[2,3-dlpyrimidine; 4-a ino-5-hexyl-7-(4-diethylaminophenyl)pyrido[2,3-d]pyrimidine; 4-amino-5-(2-(3-bromophenyl)ethyl)-7-(4-diethylaminophenyl)pyrido[2,3- dlpyri idine; 4-amino-5-((2-bromophenyl)methyl)-7-(4-diethylaminophenyl)pyrido[2,3- dlpyrimidine;
4-amirιo-5-cyclopropyl-7-(4-dimethylaminophenyl)pyrido[2,3-dlpyrimidine; 4-am o-5-cyclohexyl-7-(4-dimemylammophenyl)pyrido[2,3-dlpyrimidine; 4-amino-5-((2-bromo-5-chlorophenyl)memyl)-7-(4-diethylaminophenyl)pyrido[2,3- dlpyrirnidine;
4-amino-5-methyl-7-(4-diethylarninophenyl)pyrido[23-dlpyrimidine: 4-amino-5-(2,3-methylenedioxyphenyl)-7-(4-dimethylaminophenyl)pyrido[2,3- dlpyrimidine;
4-amino-5-(3-fluoro-5-trifluoromethylphenyl)-7-(4- dimemylaminophenyl)pyrido[2,3-dlpyrimidine;
4-amino-5- 2-bromophenyl)-7-(4-dimemylaminophenyl)pyrido[2,3-dlpyrimidine; 4-amino-5- 3,5-dimethylphenyl)-7-(4-dimethylaminophenyl)pyrido[2,3- dlpyrimidine;
4-amino-5- 3,4-dichlorophenyl)-7-(4-dimethylaminophenyl)pyrido[2,3-dlpyrimidine; 4-amino-5- 4-fluoro-3-trifluoromethylphenyl)-7-(4- dime ylarninophenyl)pyrido[2,3-d]pyrimidine;
4-amino-5- 3-bromo-5-methoxyphenyl)-7-(4-moφholinylphenyl)pyrido[2,3- dlpyrimidine;
4-amino-5-( 3-bromo-5-methoxyphenyl)-7-(4-pyrrolidinylphenyl)pyrido[2,3- dlpyrimidine;
4-amino-5- 3-bromo-5-methoxyphenyl)-7-(4-piperidinylphenyl)pyrido[2,3- dlpyrimidine;
4-amino-5- 3-bromo-5-methoxyphenyl)-7-(4-dimethylaminophenyl)pyrido[2,3- dlpjπimidine;
4-amino-5- 3-methylthiophenyl)-7-(4-dimethylaminophenyl)pyrido[2,3- dlpyrimidine; 4-amino-5- 3-bromo-5-memoxyphenyl)-7-(thiophene-2-yl)pyrido[2,3-d]pyrirnidine;
4-amino-5- 2,3-dimethoxyphenyl)-7-(4-dimethylaminophenyl)pyrido[2,3- dlpyrimidine;
4-amino-5-(3-me ylsulfonylphenyl)-7-(4-dimethylaminophenyl)pyrido[2,3- dlpyrimidine; 4-acetylamino-5-(3-bromophenyl)-7-(4-dimethylaminophenyl)pyrido[2,3- dlpyrimidine;
4-formylaιmno-5-(3-bromophenyl)-7-(4-dimethylaminophenyl)pyrido[2,3- dlpyrimidine;
4-(methoxyacetyl)amino-5-(3-bromophenyl)-7-(4-diethylaminophenyl)pyrido[2,3- dlpyrimidine;
4-trifluoroacetylarnino-5-(3-bromophenyl)-7-(4-dimethylaminophenyl)pyrido[2,3- dlpyrimidine; 4-pentanoylamino-5-(3-bromophenyl)-7-(4-dimethylaminophenyl)pyrido[2,3- dlpyrimidine;
4-benzoylamino-5-(3-bromophenyl)-7-(4-dimemylaminophenyl)pyrido[2,3- dlpyrimidine; 4-(/V-BOC-glycyl)amino-5-(3-bromophenyl)-7-(4-dimethylaminophenyl)pyrido[2,3- d]pyrimidine;
4-(N-phthalimidylglycyl)amino-5-(3-bromophenyl)-7-(4- dimethylaminophenyl)pyrido[2,3-dlpyrimidine;
4-(e oxycarbonyl)amino-5-(3-bromophenyl)-7-(4-dimethylaminophenyl)pyrido[2,3- dlpyrimidine;
4-(ethylaminocarbonyl)amino-5-(3-bromophenyl)-7-(4- dimethylaminophenyl)pyrido[2,3-d]pyrimidine;
4-allylamino-5-(3-bromophenyl)-7-(4-dimethylaminophenyl) pyrido[2,3- dlpyrimidine; 4-(2-(Ν,Ν-dimethylamino)ethylamino)-5-(4-bromophenyl)-7-(4- dimethylaminophenyl) pyrido[2,3-dlpyrimidine;
4-(4-(N,N-dimethylamino)butylamino)-5-(3-bromophenyl)-7-(4- dimemylaminophenyl) pyrido[2,3-d]pyrimidine;
4-(N-allyl-N-formylamino)-5-(4-dimethylaminophenyl)-7-(4- bromophenyl)pyrido[2,3-dlpyrimidine;
4-diacetylamino-5-(p-dimethylaminophenyl)-7-(4- bromophenyl)pyrido[2,3-d]pyrimidine;
4-an ino-5-(3-bromophenyl)-7-(5-amino-2-pyridyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(5-dirnethylamino-2-pyridyl)pyrido[2,3-dlpyrimidine; 4-ammo-5-(3-bromophenyl)-7-(5-dimethylamino-2- pyrazinyl)pyrido [2 ,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(2-oxobenzoxazolin-6-yl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(l-methyl-2-oxobenzoxazolin-6- yl)pyrido[2,3-d]pyrimidine; 4-amino-5-((5-chloro-2-(3-methoxyphenyl)phenyl)methyl)-7-(4- dimethylaminophenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-((thiophene-2-yl)methyl)-7-(4-diethylaminophenyl)pyrido[2,3- dlpyrimidine;
4-amino-5-((thiophene-3-yl)methyl)-7-(4-diethylaminophenyl)pyrido[2,3- dlpyrimidine;
4-amino-5-((2-bromophenyl)methyl)-7-(4-dimethylaminophenyl)pyrido[2,3- dlpyrimidine; 4-amino-5-(3-bromophenyl)-7-(4-(N-formyl-N-(2- methoxyethyl)amino)phenyl)pyrido[2,3-dlpyrimidine;
4-amino-5-(3-bromophenyl)-7-(4-(N-(2-methoxyethyl)amino)phenyl)pyrido[2,3- dlpyrimidine; 4-amino-5-(3-bromophenyl)-7-(4-(N-methyl-N-((2- dimethylanr no)ethyl)amino)phenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(4-(2- methoxy)acetylanτino)ethyl)amino)phenyl)pyrido[2,3-dlpyrirnidine;
4-amino-5-(3-bromophenyl)-7-((4-formylamino)phenyl)pyrido[2,3-dlpyrimidine; 4-amino-5-(3-bromophenyl)-7-(4-(2-(dimemylamino)acetylamino)phenyl)pyrido[2,3- dlpyrimidine;
4-amino-5-(3-bromophenyl)-7-(4-(2-oxo-3-oxazolidinyl)phenyl)pyrido[2,3- dlpyrirnidine;
4-amino-5-(3-bromophenyl)-7-(6-(2-propyl)-3-pyridinyl)pyrido[2,3-dlpyrimidine; 4-amino-5-(3-bromophenyl)-7-(3-methyl-4-pyrrolidinylphenyl)pyrido[2,3- dlpyrimidine;
4-amino-5-(3-bromophenyl)-7-(6-inrύdazolyl-3-pyrio nyl)pyrido[2,3-d]pyrimidine;
4-amino-5-phenylmethyl-7-(4-diethylaminophenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(2-(3-arninopropynyl)phenylmethyl)-7-(4-diethylaminophenyl)pyrido[2,3- dlpyrimidine;
4-amino-5-(l-(3-bromophenyl)ethyl)-7-(4-diethylaminophenyl)pyrido[2,3- dlpyrimidine;
4-aπιmo-5-(4-dimemylaminophenyl)-7-(4-bromophenyl)pyrido[2,3-d]pyrimidine;
4-aιτ no-5-(2-furanyl)-7-(4-(N-moφholinyl)phenyl)pyrido[2,3-d]pyrimidine; 4-anήno-5-(3-bromophenyl)-7-(2-dimethylammo-5-pyrirnidinyl)pyrido[2,3- dlpyrimidine;
4-amino-5-(3-bromophenyl)-7-(4-(ureido)phenyl)pyrido[2,3-d]pyrimidine;
4-ammo-5-(l-phenylme yl-3-piperidinyl)-7-(4-diethylaminophenyl)pyrido[2,3- dlpyrimidine; 4-amino-5-(3-bromophenyl)-7-(6-(3-methyl-5-isoxazolyl))-3- pyridinyl)pyrido[2,3-dlpyrimidine;
4-amino-5-(3-bromophenyl)-7-(6-chloro-3-pyridinyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(6-methoxy-3-pyridinyl)pyrido[2,3-d]pyrirnidine;
4-amino-5-(3-bromophenyl)-7-(6-(l,2,4-triazol-4-yl)-3-pyridinyl)pyrido[2,3- dlpyrimidine;
4-amino-5-(3-bromophenyl)-7-(2-moφholinyl-5-pyrimidinyl)pyrido[2,3- d]pyrimidine; 4-ammo-5-(2-thiazolyl)-7-(4-pyπ-otidinylphenyl)-pyrido[2,3-dlpyrimidine;
4-amino-5-(3-bromophenyl)-7-(6-pyrazolyl-3-pyridinyl))-pyrido[2,3- dlpyrimidine;
4-amino-5-(3-bromophenyl)-7-(4-(l-methyl-ureido)phenyl)-pyrido[2,3- dlpyrimidine;
4-amino-5-(3-bromophenyl)-7-(4-(N-memyl-N-(2-pyrirnidinyl)amino)phenyl)- pyrido[2,3-d]pyrimidine;
4-arnino-5-(3-bromophenyl)-7-(3-fluoro-4-(N-formyl-N-methylamino)phenyl)- pyrido[2,3-d]pyrimidine; 4-formylamino-5-(3-bromophenyl)-7-(3-fluoro-4-(N-formyl-N- methylamino)phenyl)-pyrido[2,3-dlpyrimidine;
4-ammo-5-(3-bromophenyl)-7-(4-(N-me yl-N-memylsulfonylamino)- phenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(6-(N-methyl-N-methylsulfonylamino)-3- pyridinyl)pyrido[2,3-dlpyrimidine;
4-amino-5-(3-bromophenyl)-7-(l-methyl-5-indolinyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(l-methyl-5-benzimidazolyl)pyrido[2,3- dlpyrimidine;
4-ammo-5-(3-bromophenyl)-7-(6-dimemylamino-3-pyridazinyl)pyrido[2,3- dlpyrimidine;
4-amino-5-(3bromophenyl)-7-(6-moφholinyl-3-pyridazinyl)pyrido[2,3- dlpyrimidine;
4-amino-5-(3-bromophenyl)-7-(6-pyrrolidinyl-3-pyridazinyl)pyrido[2,3- dlpyrimidine; 4-amino-5-(3-bromophenyl)-7-(5-moφholinyl-2-pyrazinyl)pyrido[2,3- dlpyrimidine;
4-amino-5-(3-bromophenyl)-7-(5-(N-(2-methoxyethyl)-N-methylamino)-2- pyrazinyl)pyrido[2,3-dlpyrimidine;
4-amino-5-(3-bromophenyl)-7-(4-(moφholinylmethyl)-phenyl)pyrido[2,3- dlpyrimidine;
4-amino-5-(3-bromophenyl)-7-(5-(N,N-bis(2-methoxyethyl)amino)-2- pyridinyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(4-(imidazolylmethyl)-phenyl)pyrido[2,3- dlpyrimidine; 4-amino-5-(3-bromophenyl)-7-(5-(l-moφholinyl)-2-pyridinyl)pyrido[2,3- dlpyrimidine; 4-am o-5-(3-bromophenyl)-7-(4-((o^methylamino)methyl)-phenyl)pyrido[2,3- dlpyrimidine;
4-amino-5-(3-bromophenyl)-7-(5-(4-hydroxy-l-piperidinyl)-2- pyridinyl)pyrido[2,3-dlpyrimidine; 4-arm^o-5-(3-bromophenyl)-7-(5-(N-formyl-N-methylamino)-2- pyridinyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(5-(2-propenyl)-2-pyridinyl)pyrido[2,3- dlpyrimidine;
4-amino-5-(3-bromophenyl)-7-(3-(2-methoxyethyl)-2-oxo-6- benzoxazolyl)pyrido[2,3-d]pyrimidine;
4-anτino-5-(3-bromophenyl)-7-(4-(l-(N-formylamino)-ethyl)phenyl)pyrido[2,3- dlpyrimidine;
4-(me ylamino)-5-(3-bromophenyl)-7-(4-dimethylaminophenyl)pyrido[2,3- dlpyrirnidine hydrochloride; 4-(2-methoxyethylamino)-5-(3-bromophenyl)-7-(4- dimethylaminophenyl)pyrido[2,3-dlpyrimidine hydrochloride;
4-amino-5-(3-bromophenyl)-7-(4-(l-methyl-2-imidazolyl)phenyl)pyrido[2,3- dlpyrimidine trihydrochloride;
4-amino-5-(3-bromophenyl)-7-(4-(aminomemyl)phenyl)pyrido[2,3-dlpyrimidine; 4-amino-5-(3-bromophenyl)-7-(2-bromo-4-(dimethylamino)phenyl)pyrido[2,3- dlpyrimidine;
4-amino-5-(3-bromophenyl)-7-(4-(dimemylaminoethyl)phenyl)pyrido[2,3- dlpyrimidine;
4-amino-5-(3-bromophenyl)-7-(4-(3-(dimethylamino)propynyl)phenyl)pyrido[2,3- dlpyrimidine;
4-amino-5-(3-bromophenyl)-7-(4-(3-amino-3-methylbutynyl)phenyl)pyrido[2,3- dlpyrimidine;
4-amino-5-(3-bromophenyl)-7-(4-dimethylphosphonatophenyl)pyrido[2,3- dlpyrimidine; 4-amino-5-(3-bromophenyl)-7-(4-(3-(methoxypropynyl)pyrido[2,3-d]pyrirnidine;
4-amino-5-(3-bromophenyl)-7-(4-carboxyphenyl)pyrido[2,3-d]pyrimidine; 4-amino-5-(3-bromophenyl)-7-(4-methyl-3-oxo-2H-4H-pyrido[3,2-bl-l,4-oxazin- 7-yl)pyrido[2.3-dlpyrimidine;
4-amino-5-(3-bromophenyl)-7-(4-(2-(dimethylamino)ethyl)-3-oxo-2H-4H- pyrido[3.2-b]- 1 ,4-oxazin-7-yl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(2,3-dihydro-3-(dimethylaminoethyl)-2- oxobenzoxazol-6-yl)pyrido[2,3-dlpyrimidine; 4-amino-5-(3-bromophenyl)-7-(4-methyl-3-oxo-2H-4H-benzo-l,4-oxazin-7- yl)pyrido[2,3-dlpyrimidine;
4-amino-5-(3-bromophenyl)-7-(2,2,4-trimethyl-3-oxo-2H-4H-benzo-l,4-oxazin-7- yl)pyrido[2,3-dlpyrimidine; 4-amino-5-cyclohexyl-7-(4-(2-dimethylamino)ethyl)-2H-4H-benzo-3-oxo- 1.4- oxazin-7-yl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(5-(l-methylethyl)-2-pyridyl)pyrido[2,3- dlpyrimidine;
4-amino-5-(3-bromophenyl)-7-(5-piperidin-l-ylpyrid-2-yl)pyrido[2,3-dlpyrimidine; 4-amino-5-(l-(4-bromophenyl)ethyl)-7-(6-moφholinylpyrid-3-yl)pyrido[2,3- dlpyrimidine;
4-amino-5-(3-bromophenyl)-7-(4-((N-formylamino)methyl)phenyl)pyrido[2,3- dlpyrimidine;
4-amino-5-(3-bromophenyl)-7-(4-(l-methyl-l-(N-methylamino)ethyl)phenyl)- pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(4-(l-(dimethylamino)-l- memylethyl)phenyl)pyrido[2,3-d]pyrimidine;
4-anτino-5-(3-bromophenyl)-7-(N-acetyl-5-indolinyl)pyrido[2,3-d]pyrirnidine;
4-amino-5-cyclohexyl-7-(6-chIoro-3-pyridyl)pyrido[2,3-d]pyrimidine; 4-ammo-5-(l-(2-bromophenyl)emyl)-7-(6-diethylanτino-3-pyridyl)pyrido[2,3- dlpyrimidine;
4-amino-5-(l-(2-bromophenyl)ethyl)-7-(6-moφholinyl-3-pyridyl)pyrido[2,3- dlpyrimidine;
4-ammo-5-(l-(2-bromophenyl)ethyl)-7-(4-(N-methyl-N-formyl)amino)- phenyl)pyrido[2,3-d]pyrimidine;
4-aπιmo-5-cyclohexyl-7-(6-moφhohnyl-3-pyridyl)pyrido[2,3-dlpyrimidine;
4-amino-5-((2-bromophenyl)methyl)-7-(6-moφholinyl-3-pyridyl)pyrido[2,3- dlpyrimidine;
4-amino-5-(4-tetrahydropyranyl)-7-(6-moφholinyl-3-pyridyl)pyrido[2,3- dlpyrimidine;
4-ammo-5-cyclohexyl-7-(6-dimethylanιino-3-pyridyl)pyrido[2,3-dlpyrimidine;
4-ammo-5-(l-ethylpropyl)-7-(6-dimemylan^no-3-pyridyl)pyrido[2,3-d]pyrimidine;
4-am o-5-cyclopentyl-7-(6-moφholinyl-3-pyridyl)pyrido[2,3-d]pyrimidine;
4-amino-5-cyclohexyl-7-(2-chloro-3-pyridyl)pyrido[2,3-d]pyrimidine; 4-am o-5-(3,5-d ιethylcyclohexyl)-7-(6-dimethylamino-3-pyridyl)pyrido[2,3- dlpyrimidine; 4-amino-5-((N-(benzyloxycarbonyl)-4-piperidinyl)methyl)-7-(6-moφholinyl-3- pyridyl)pyrido[2,3-dlpyrimidine;
4-arrύno-5-cyclohexyl-7-(6-bromo-3-pyridyl)pyrido[2,3-d]pyrimidine; 4-amino-5-cyclohexyl-7-(3-cyanophenyl)pyrido[2,3-dlpyrimidine; 4-amino-5-(l-(2-bromophenyl)ethyl)-7-(6-dimethylamino-3-pyridazinyl)pyrido[2,3- dlpyrimidine;
4-ammo-5-(3-bromophenyl)-7-(6-imidazolyl-3-pyridazmyl)pyrido[2,3-d]pyrirnidine; 4-amino-5-(3-bromophenyl)-7-(6-(azacycloheptanyl)-3-pyridazinyl)pyrido[2,3- dlpyrimidine; 4-amino-5-(3-bromophenyl)-7-(6-(N-methyl-N-(l-methylethyl))amino)-3- pyridazinyl)pyrido[2,3-dlpyrimidine;
4-amino-5-(l-(2-bromophenyl)ethyl)-7-(6-moφholinyl-3-pyridazinyl)pyrido[2,3- dlpyrimidine;
4-amino-5-cyclohexyl-7-(6-(4-acetylpiperazinyl)-3-pyridyl)pyrido[2,3-dlpyrimidine; 4-amino-5-cyclohexyl-7-(6-(4-acetyl-l,4-diazacycloheptanyl)-3-pyridyl)pyrido[2,3- dlpyrimidine;
4-amino-5-cyclohexyl-7-(6-(4- methyl- 1 ,4-diazacycloheptanyl)-3- pyridyl)pyrido[2,3-dlpyrimidine;
4-amino-5-cyclohexyl-7-(6-(N-methyl-N-(2-(2-pyridyl)ethyl)amino)-3- pyridyl)pyrido[2,3-dlpyrimidine;
4-ammo-5-cyclohexyl-7-(6-2-(N-(N',N'-dimethylaminoethyl)-N-methylamino)-3- pyridyl)pyrido[2,3-d]pyrimidine;
4-ammo-5-cyclohexyl-7-(6-azetidmyl-3-pyridyl)pyrido[2,3-dlpyrimidine; 4-ammo-5-cyclohexyl-7-(6-(3-(N-methylacetamido)pyrrolidinyl)pyridyl)pyrido[2,3- dlpyrimidine;
4-ammo-5-cyclohexyl-7-(6-(3-(formamido)pyrrolidinyl)pyridyl)pyrido[2,3- dlpyrimidine;
4-amino-5-cyclohexyl-7-(4-oxo-l-phenyl-l,3,8-triazaspiro[4.5[decan-8- yl)pyrido[2,3-d]pyrimidine; 4-am o-5-cyclohexyl-7-(6-(2-methoxymethyl)pyrrolidin-l-yl)pyridyl)pyrido[2,3- dlpyrimidine;
4-amino-5-cyclohexyl-7-(6-(N-methoxyethyl-N-propylamino)pyridyl)pyrido[2,3- dlpyrimidine;
4-amino-5-cyclohexyl-7-(N-methyl-N-(2,2-dimemoxyethyl)amino)pyrido[2,3- dlpyrimidine;
4-arr no-5-cyclohexyl-7-(6-(4-(dimethylamino)piperidinyl)pyridyl)pyrido[2,3- dlpyrimidine; 4-amino-5-cyclohexyl-7-(6-(4-(aminocarbonyl))piperidinyl)pyridyl)pyrido[2,3- dlpyrimidine;
4-arnino-5-cyclohexyl-7-(N-memyl-N-(3-(die ylamino)propyl)aminopyrid-3- yl)pyrido[2,3-dlpyrimidine; 4-amino-5-cyclohexyl-7-(6-(N-methyl-N-(4-pyridyl)ethylamino)pyrid-3- yl)pyrido[2,3-dlpyrimidine;
4-amino-5-cyclohexyl-7-(6-(N-methyl-N-(3-pyridylmethylamino)pyrid-3- yl)pyrido[2,3-dlpyrimidine;
4-amino-5-(l-(2-bromophenyl)ethyl)-7-(l-methyl-5-indolyl)pyrido[2,3- dlpyrimidine;
4-amino-5-(l-(2-bromophenyl)ethyl)-7-(l-methyl-2,3-dioxo-5-indolyl)pyrido[2,3- dlpyrimidine;
4-amino-5-(3-bromophenyl)-7-(3-fluoro-4-(l-moφholinyl)phenyl)pyrido[2,3- dlpyrimidine; 4-anf no-5-(3-bromophenyl)-7-(4-hydroxy-3-nittophenyl)pyrido[2,3-dlpyrimidine;
4-amino-5-(3-bromophenyl)-7-(6-(4,4-ethylenedioxypiperidinyl)-3- pyridyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(6-(4-oxopiperidinyl)-3-pyridyl)pyrido[2,3- dlpyrimidine; 4-amino-5-(3-bromophenyl)-7-(6-(4-formylpiperazinyl)-3-pyridyl)pyrido[2,3- dlpyrimidine;
4-amino-5-(3-bromophenyl)-7-(6-(4-methylpiperazinyl)-3-pyridyl)pyrido[2,3- dlpyrimidine;
4-amino-5-(3-bromophenyl)-7-(6-thiomoφholinyl-3-pyridyl)pyrido[2,3- dlpyrimidin;
4-amino-5-(3-bromophenyl)-7-(6-(4,4-dioxothiomoφholinyl)-3-pyridyl)pyrido[2,3- dlpyrimidine;
4-amino-5-(2-bromophenyl)-7-(6-moφholinyl-3-pyridyl)pyrido[2,3-d]pyrimidine; 4-amino-5-(3-bromo-4-methoxyphenyl)-7-(6-moφholinyl-3-pyridyl)pyrido[2,3- dlpyrimidine;
4-amino-5-(4-bromophenyl)-7-(6-moφholinyl-3-pyridyl)pyrido[2,3-dlpyrimidine; 4-amino-5-(3-chlorophenyl)-7-(6-moφholinyl-3-pyridyl)pyrido[2,3-dlpyrimidine; 4-amino-5-(3-bromophenyl)-7-(5-chloro-6-moφholinyl-3-pyridyl)pyrido[2,3- dlpyrimidine; 4-amino-5-(3-bromophenyl)-7-(6-(N-oxidomoφholinyl)-3-pyridyl)pyrido[2,3- d]pyrimidine; 4-amino-5-(3-bromophenyl)-7-(6-(N-(2-hydroxyethoxyethyl)amino)-3- pyridyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(6-(N-(2-hydroxyethoxyethyl)-N-formylamino)-3= pyridyl)pyrido[2,3-dlpyrimidine; 4-amino-5-(3-bromophenyl)-7-(6-(N-(2-hydroxyethoxyethyl)-3-pyridyl-N- oxide)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(6-(3-hydroxy)moφholinyl)-3-pyridyl)pyrido[2,3- dlpyrimidine; l-(5-(4-anιino-5-(3-bromophenyl)pyrido[2,3-dlpyrimidin-7-yl)-2-pyridyl)- piperidine-4-phosphate, disodium salt;
4-amino-5-(3-bromophenyl)-7-(4-methylenylpiperidinyl)-3-pyridyl)pyrido[2,3- dlpyrimidine;
4-amino-5-(3-bromophenyl)-7-(4-hydroxy-4-(hydroxymethyl)piperidinyl)-3- pyridyl)pyrido[2,3-d]pyrirnidine; 4-amino-5-(3-bromophenyl)-7-(6-(4,4-ethylenedioxypiperidinyl)-3- pyridyl)pyrido[2,3-d]pyrimidine;
4-amino-5-cyclohexyl-7-(6-(4-oxo-piperidmyl)-3-pyridyl)pyrido[2,3-d]pyrimidine; 4-amino-5-cyclohexyl-7-(6-(4-methylenylpiperidinyl)-3-pyridyl)pyrido[2,3- dlpyrimidine; 4-N-(iminomethyl)amino-5-cyclohexyl-7-(6-dimethylamino-3-pyridyl)pyrido[2,3- dlpyrimidine; and pharmaceutically acceptable salts and amides thereof. In addition, the partially hydrogenated or fully hydrogenated versions wherein the 5,6 and/or the 7,8 double bonds are hydrogenated of the compounds identified above are also included within the scope of the invention. The preferred substitution pattern on the R3 group when it is selected from, for example, a substituted aryl group, is having at least one substituent at the meta position. The preferred substitution pattern on the R^ position when it is selected from, for example, a substituted heteroaryl group, is having at least one substituent at the para position. The present invention is therefore directed to compounds of formula I or II with the variables recited as above wherein, in the case of R selected from substituted aryl or heteroaryl groups and R^ selected from substituted aryl or heteroaryl groups, the substiuents on the R group are meta and the substituents on the R^ group are para. In addition, the present invention encompasses pro-drugs of the above compounds which may be active in their own right or are metabolized or converted to the non pro-drug form as exemplified above. The invention is not limited to synthetic versions of the claimed compounds and includes the compounds-per-se or pro-drugs or metabolites thereof regardless of how or where they are manufactured or made. The term "acyl", as used herein, refers to a moiety attached by a carbonyl linkage, as for example, loweralkyl-carbonyl or aryl-carbonyl, wherein loweralkyl and aryl are as defined herein. Examples of acyl include, for example, acetyl, propionyl, hexanoyl, trifluoroacetyl, benzoyl, 4-methylbenzoyl, methoxyacetyl, pentanoyl, N- Bocglycylimidazoyl, N-phthalimidylglycyl and the like or others as specified herein.
The term "aryl" or "substituted aryl" as used herein, refers to a carbocyclic aromatic radical, including, for example, phenyl and 1- or 2-naphthyl, which may be unsubstituted or substituted respectively by independent replacement of one, two or three of the hydrogen atoms thereon with Cl, Br, F, I, cyano, carboxamido, hydroxy, loweralkoxy, loweralkyl, loweralkenyl, loweralkynyl, amino, loweralkylamino, di(loweralkylamino), N-loweralkyl- N-loweralkoxyamino, trifluoromethyl or methoxymethyl groups. In addition, the term "aryl" refers to a phenyl group substituted with one ureido, methylsulfonyl, pyrimidinyl, pyridinyl, pyridazinyl, moφholinyl, phenyl-loweralkoxy, phenyl-loweralkenyl or cycloalkyl-loweralkyl group. Examples of aryl radicals include, but are not limited to, 3- bromophenyl, 3-chlorophenyl, 4-chlorophenyl, 3-methoxyphenyl, 3-(2-propyl)phenyl, 3,4- dimethoxyphenyl, 3-trifluromethylphenyl, 3-trifluoro-4-fluorophenyl, 4-(N-methyl-N- methoxyl)ethylaminophenyl, 4-dimethylaminophenyl, 3-fluoro-4-methylphenyl, 4- methylphenyl, 4-cyanophenyl, 4-propylmethyl, 3,5-dichlorophenyl, 3,4- methylenedioxyphenyl, 3-cyanopropylphenyl, 4-ureidophenyl, 3-methylsulfonylphenyl, 3- carboxamidopropylphenyl.
The term "arylalkyl" refers to a loweralkyl radical having appended thereto an aryl group, as defined above, as for example benzyl and phenylethyl.
The term "aryloxy" refers to a aryl radical which is appended to the molecule via an ether linkage {i.e., through an oxygen atom), as for example phenoxy, naphthyloxy, 4- chlorophenoxy, 4-methylphenoxy, 3,5-dimethoxypehenoxy, and the like.
The term "cycloalkyl" refers to a cyclic saturated hydrocarbon radical having from 3 to 7 ring atoms. Examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl. Cycloalkyl is also described as C3-C8cycloalkyl.
The term "cycloalkyl-loweralkyl" refers to a loweralkyl radical as defined below substituted with a cycloalkyl group as defined above by replacement of one hydrogen atom. Examples of cycloalkyl-loweralkyl include cyclopropylmethyl, cyclobutylethyl, cyclopentylmethyl, cyclohexylmethyl and cycloheptylbutyl, and the like.
The term "heteroaryl" or "substituted heteroaryl" refers to a monocyclic aromatic radical having from five to seven ring atoms of which one ring atom is nitrogen, oxygen or sulfur; zero, one or two ring atoms are additional heteroatoms independently selected from S, O and N; and the remaining ring atoms are carbon, the radical being joined to the rest of the molecule via any of the ring atoms. A heteroaryl group may be unsubstituted or substituted by independent replacement of one, two or three of the hydrogen atoms thereon with Cl, Br, F, I, cyano, carboxamido, hydroxy, loweralkoxy, loweralkyl, loweralkenyl, loweralkynyl, amino, loweralkylamino, di(loweralkylarnino), N-loweralkyl-N- loweralkoxyamino, trifluoromethyl or methoxymethyl groups. In addition, the term "heteroaryl " refers to a heteroaryl group substituted with one ureido, methylsulfonyl, pyrimidinyl, pyridinyl, pyridazinyl, moφholinyl, phenyl-loweralkoxy. phenyl-loweralkenyl or cycloalkyl-loweralkyl group. In addition a heteroaryl group may be substituted by replacement of any two adjacent hydrogen atoms with a grouping of atoms to form a fused benzene ring, e.g., benz derivatives such as indole, benzoxazole and the like. Examples of heteroaryl include pyridinyl, pyrazinyl, pyrimidinyl, pyrrolyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, isoxazolyl, thiadiazolyl, oxadiazolyl, furanyl, thiophenyl, 5- methylthiophene-2-yl, 5-nitrothiophene-2-yl, 5-methylfuranyl, benzofuranyl, benzothiophenyl, and the like and those additionally described herein.
The term "heterocyclic" refers to a saturated or unsaturated monocyclic ring system radical having from four to seven ring atoms of which one is nitrogen or oxygen; zero, one or two ring atoms are additional heteroatoms independently selected from S, O and N; and the remainder are carbon, the radical being joined to the rest of the molecule via any of the ring carbon atoms and being optionally substituted, either on a nitrogen or a carbon atom, by an additional radical selected from among aryl(loweralkyl), alkoxycarbonyl, loweralkyl, halo(loweralkyl), amino (loweralkyl), hydroxy-substituted loweralkyl, hydroxy, loweralkoxy, halogen, amino, loweralkylamino, and amino, (loweralkyl)amino or alkanoylamino of from one to eight carbon atoms in which the amino group may be further substituted with alkanoyl of from one to eight carbons, an alpha-amino acid or a polypeptide. Examples of heterocyclic include pyrrolidine, tetrahydrofuran, dihydropyrrole, isoxazolidine, oxazolidine, tetrahydropyridine, piperidine, piperazine, moφholine, thiomoφholine, aziridine and azetidine or those additionally described herein.
The term "heterocyclic-loweralkyl" refers to a loweralkyl radical as defined below substituted with a heterocyclic-group as defined above by replacement of one hydrogen atom. Examples of cycloalkyl-loweralkyl include pyrrolidinylmethyl, piperidinylethyl, and the like.
The term "loweralkyl", as used herein, refers to saturated, straight- or branched- chain hydrocarbon radicals containing from one to six carbon atoms including, which may be unsubstituted or substituted by independent replacement of one, two or three of the hydrogen atoms thereon with Cl, Br, F, I. cyano, carboxamido, hydroxy, loweralkoxy, amino, loweralkylamino, iminoloweralkylamino,di(loweralkylamino) or N-loweralkyl-N- loweralkoxyamino groups. Examples of loweralkyl include, but are not limited to, methyl, ethyl, propyl, isopropyl, π-butyl, tert-butyl. neopentyl, n-hexyl, hydroxyethyl, methoxymethyl, trifluoromethyl, 3-cyanopropyl, 3-carboxamidopropyi, and the like. In certain cases, the group "Cι-C6alkyl" is described and has a similar meaning as above for loweralkyl but is more specifically recited. Likewise, the term "Co-C6alkyl" indicates the carbon atoms which may be present in the alkyl chain including zero. These terms are also provided adjacent to aryl or heteroaryl or other generic group and represent or have the same meaning as, for example, "arylalkyl" or "heteroarylalkyl".
The term "loweralkenyl", as used herein, refers to mono-unsaturated straight- or branched-chain hydrocarbon radicals containing from two to six carbon atoms including, but not limited to, vinyl, propenyl, n-butenyl, -butenyl, n-pentenyl, and n-hexenyl. These variables are also recited as, for example, C2-C6alkenyl.
The term "loweralkoxy" refers to a loweralkyl radical which is appended to the molecule via an ether linkage {i.e., through an oxygen atom), as for example methoxy, ethoxy, propoxy, 2-propoxy, 2-methyl-2-propoxy, tert-butoxy, pentyloxy, hexyloxy, isomeric forms thereof and the like. This term is also described as Ci-C6alkyloxy. The term "loweralkynyl", as used herein, refers to straight- or branched-chain hydrocarbon radicals possessing a single triple bond and containing from two to six carbon atoms including, but not limited to, ethynyl, propynyl, n-butynyl, n-pentynyl, and n- hexynyl. This term is also described as C2-C6alkynyl.
The term "mammal" has its ordinary meaning and includes human beings. In a further aspect of the present invention pharmaceutical compositions are disclosed which comprise a compound of the present invention in combination with a pharmaceutically acceptable carrier.
The present invention includes one or more compounds, as set forth above, formulated into compositions together with one or more non-toxic physiologically tolerable or acceptable diluents, carriers, adjuvants or vehicles that are collectively referred to herein as diluents, for parenteral injection, for oral administration in solid or liquid form, for rectal or topical administration, or the like. As is well known in the art, a compound of the present invention can exist in a variety of forms including pharmaceutically-acceptable salts, amides and the like. Compositions may be prepared that will deliver the correct amount of a compound or compounds of the invention. The following dosages are thought to provide the optimal therapy: iv infusions: 0.1- 250 nmol/kg/minute, preferably from 1-50 nmol/kg/minute; oral: 0.01-250 μMol/kg/day, preferably from about 0.1-50 μMol/kg/day; these oral molar dosage ranges correspond to 0.005-125 mg/kg/day, preferably 0.05-25 mg/kg/day. For treatment of acute disorders the preferred route of administration is intravenous; the preferred method of treating chronic disorders is orally by means of a tablet or sustained release formulation. "Pharmaceutically-acceptable amide" refers to the pharmaceutically-acceptable, nontoxic amides of the compounds of the present invention which include amides formed with suitable organic acids or with amino acids, including short peptides consisting of from l-to-6 amino acids joined by amide linkages which may be branched or linear, wherein the amino acids are selected independently from naturally-occurring amino acids, such as for example, glycine, alanine, leucine, valine, phenylalanine, proline, methionine, tryptophan, asparagine, aspartic acid, glutamic acid, glutamine, serine, threonine, lysine, arginine, tyrosine, histidine, ornithine, and the like.
"Pharmaceutically-acceptable salts" refers to the pharmaceutically-acceptable, nontoxic, inorganic or organic acid addition salts of the compounds of the present invention, as described in greater detail below.
The compounds of the present invention can be used in the form of pharmaceutically-acceptable salts derived from inorganic or organic acids. These salts include, but are not limited to, the following: acetate, adipate, alginate, aspartate, benzoate, benzenesulf onate, bisulfate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, flavianate, fumarate, glucoheptonate, glycerophosphate, hemisulfate, heptonate, hexonoate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxy-ethanesulfonate, lactate, maleate, methanesulfonate, nicotinate, 2-naphthalenesulfonate, oxalate, palmoate, pectinate, persulfate, 3- phenylpropionate, phosphate, picrate, pivalate, propionate, succinate, tartrate, thiocyanate, tosylate, and undecanoate.
Appropriate cationic salts are also readily prepared by conventional procedures such as treating an acid of Formula I with an appropriate amount of base, such as an alkali or alkaline earth metal hydroxide, e.g., sodium, potassium, lithium, calcium, or magnesium, or an organic base such as an amine, e.g., dibenzylethylenediamine, cyclohexylamine, dicyclohexylamine, triethylamine, piperidine, pyrrolidine, benzylamine, and the like, or a quaternary ammonium hydroxide such as tetramethylammonium hydroxide and the like. Also, the basic nitrogen-containing groups can be quaternized with such agents as loweralkyl halides, such as methyl, ethyl, propyl, and butyl chlorides, bromides, and iodides; dialkyl sulfates; long chain halides such as decyl, lauryl, myristyl, and stearyl chlorides, bromides and iodides; arylalkyl halides like benzyl and phenethyl bromides, and others. Water or oil-soluble or dispersible products are thereby obtained.
The salts of the present invention can be synthesized from the compounds of Formula I which contain a basic or acidic moiety by conventional methods, such as by reacting the free base or acid with stoichiometric amounts or with an excess of the desired salt forming inorganic acid or base in a suitable solvent or various combinations of solvents. Further included within the scope of the present invention are pharmaceutical compositions comprising one or more of the compounds of formula (I) prepared and formulated in combination with one or more non-toxic pharmaceutically acceptable carriers compositions, in the manner described below. Compositions suitable for parenteral injection may comprise pharmaceutically acceptable sterile aqueous or nonaqueous solutions, dispersions, suspensions or emulsions and sterile powders for reconstitution into sterile injectable solutions or dispersions. Examples of suitable aqueous and nonaqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols (propylene glycol, polyethylene glycol, glycerol, and the like), suitable mixtures thereof, vegetable oils (such as olive oil) and injectable organic esters such as ethyl oleate. Proper fluidity may be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants.
These compositions may also contain adjuvants such as preserving, wetting, emulsifying, and dispersing agents. Prevention of the action of microorganisms may be ensured by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, and the like. It may also be desirable to include isotonic agents, for example, sugars, sodium chloride and the like. Prolonged absoφtion of the injectable pharmaceutical form may be brought about by the use of agents delaying absoφtion, for example, aluminum monostearate and gelatin.
If desired, and for more effective distribution, the compounds may be incoφorated into slow-release or targeted-delivery systems, such as polymer matrices, liposomes, and microspheres. They may be sterilized, for example, by filtration through a bacteria-retaining filter, or by incoφorating sterilizing agents in the form of sterile solid compositions, which may be dissolved in sterile water, or some other sterile injectable medium immediately before use.
Solid dosage forms for oral administration may include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound is admixed with at least one inert customary excipient (or carrier), such as sodium citrate or dicalcium phosphate, and additionally (a) fillers or extenders, as for example, starches, lactose, sucrose, glucose, mannitol and silicic acid; (b) binders, as for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and acacia; (c) humectants, as for example, glycerol; (d) disintegrating agents, as for example, agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates and sodium carbonate; (e) solution retarders, as for example paraffin; (f) absoφtion accelerators, as for example, quaternary ammonium compounds; (g) wetting agents, as for example, cetyl alcohol and glycerol monostearate; (h) adsorbents, as for example, kaolin and bentonite; and (i) lubricants, as for example, talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate or mixtures thereof. In the case of capsules, tablets and pills, the dosage forms may also comprise buffering agents.
Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules, using such excipients as lactose or milk sugar, as well as high molecular weight polyethylene glycols, and the like.
Solid dosage forms such as tablets, dragees, capsules, pills and granules may be prepared with coatings and shells, such as enteric coatings and others well known in this art. They may contain pacifying agents, and may also be of such composition that they release the active compound or compounds in a certain part of the intestinal tract in a delayed manner. Examples of embedding compositions which may be used are polymeric substances and waxes.
The active compounds may also be in micro-encapsulated form, if appropriate, with one or more of the above-mentioned excipients. Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups and elixirs. In addition to the active compounds, the liquid dosage forms may contain inert diluents commonly used in the art, such as water or other solvents, solubilizing agents and emulsifiers, as for example, ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils, in particular, cottonseed oil, groundnut oil, com germ oil, olive oil, castor oil and sesame oil, glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan or mixtures of these substances, and the like.
Besides such inert diluents, these liquid dosage forms may also include adjuvants, such as wetting agents, emulsifying and suspending agents, sweetening, flavoring and perfuming agents.
Suspensions, in addition to the active compounds, may contain suspending agents, as for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, or mixtures of these substances, and the like.
Compositions for rectal or vaginal administrations are preferably suppositories which can be prepared by mixing the compounds of this invention with suitable non- irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax, which are solid at ordinary temperatures but liquid at body temperature and therefore, melt in the rectum or vaginal cavity and release the active component.
Dosage forms for topical or transdermal administration of a compound of this invention further include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants or transdermal patches. Transdermal administration via a transdermal patch is a particularly effective and preferred dosage form of the present invention. The active component is admixed under sterile conditions with a pharmaceutically acceptable carrier and any needed preservative, buffers or propellants as may be required. It is known that some agents may require special handling in the preparation of transdermal patch formulations. For example, compounds that are volatile in nature may require admixture with special formulating agents or with special packaging materials to assure proper dosage delivery. In addition, compounds which are very rapidly absorbed through the skin may require formulation with absoφtion-retarding agents or barriers. Ophthalmic formulations, eye ointments, powders and solutions are also contemplated as being within the scope of this invention.
The present compounds may also be administered in the form of liposomes. As is known in the art, liposomes are generally derived from phospholipids or other lipid substances. Liposomes are formed by mono- or multi-lamellar hydrated liquid crystals that are dispersed in an aqueous medium. Any non-toxic, physiologically acceptable and metabolizable lipid capable of forming liposomes may be used. The present compositions in liposome form may contain, in addition to the compounds of the present invention, stabilizers, preservatives, excipients, and the like. The preferred lipids are the phospholipids and the phosphatidyl cholines (lecithins), both natural and synthetic. Methods to form liposomes are known in the art. See, for example, Prescott, Ed., Methods in Cell Biology, Volume XIV, Academic Press, New York, N. Y., (1976), p 33 et seq.
Synthetic Methods
The compounds and processes of the present invention will be better understood in connection with the following synthetic schemes which illustrate the methods by which the compounds of the invention may be prepared. The R groups are as defined above unless otherwise noted below.
Figure imgf000051_0001
Figure imgf000051_0002
The compounds of the present invention may be synthesized by methods illustrated in Schemes 1 and 2. In accordance with Scheme 1, the 5,7-disubstituted compounds wherein R4 and R3 are aryl, heteroaryl, or a heterocyclic group may be prepared by a modification of a method of Kambe et al, Synthesis, 1980, 366-368. An appropriately substituted acetophenone (1, the "R4 Reagent"), wherein R4 is aryl, heteroaryl, or a heterocyclic group, an appropriately substituted aldehyde (2, the "R3 Reagent"), R3 is aryl, heteroaryl, or a heterocyclic group, and malononitrile are heated in the presence of ammonium acetate, or another suitable ammonium salt, such as for example, ammonium propionate, ammonium iodide, or the like, in an aprotic solvent to produce compound (3). The water of the reaction may removed by use of a Dean Stark apparatus or by another suitable means, such as 4 A molecular sieves. Suitable aprotic solvents include benzene, toluene, methylene chloride, DMF, THF, dioxane, and the like. The reaction may be performed at from about 40 °C to about 200 °C, and preferably at the reflux temperature of the solvent, for from about 1 hour to about 24 hours, preferably about 4 hours to 8 hours. The product (3) is preferably purified by chromatography after isolation from the reaction mixture. The above reaction may also proceed by contacting the aldehyde (2) with malononitrile and isolating the resulting dicyano R3substituted alkene which is then reacted with the ketone (1) to form, upon addition of ammonium and cyclization, compound (3). Aliphatic aldehydes do not work effectively by this route. The ketone (1) may, however, include R^ as alkyl groups. The acetophenone starting materials (1) may be obtained commercially, or prepared easily by Friedel-Craft acylation of a suitable aromatic substrate, for example. The appropriate aldehyde starting materials (2) also may be obtained commercially, or may be prepared easily, for example by reductions of esters or acids with DIBAL or another suitable hydride reducing agent, or oxidation of alcohols under Swem conditions, for example. Compound (3) is then treated with excess formamide by heating at reflux. The formation of product is monitored by TLC, and when the reaction is complete (after about 1 to about 8 hours) the reaction mixture is cooled to room temperature. The 5,7-disubstituted pyrido[2,3-d]pyrimidine product (I) is then removed by filtration and purified by column chromatography. This compound may then be partially or fully reduced by catalytic hydrogenation to the partially saturated or fully saturated version(s) (on the right side of the molecule) of the compounds shown in Scheme 1 or of Formula I. Stereoisomers produced during these reduction steps are included within the scope of the invention. The present invention also contemplates reductions which produce single bonds between the 5,6 and 7,8 positions and a double bond between the 6,7 carbons. The stereoisomers may be isolated and purified by conventional means.
In accordance with Scheme 2 are prepared compounds of Formula (I) wherein R4 is preferrably an aryl, heteroaryl or heterocyclic group, and R3 is loweralkyl, loweralkenyl, loweralkynyl, or an arylalkyl group. In addition, R^ may be selected from those additional groups listed in R3.
Compound (4, the "R3 Reagent") may be obtained commercially or prepared from the precursor ester (5) or alcohol (5) by suitable reactions. Compound (5) may be reduced with a suitable reducing agent, such as for example, diisobutylaluminum hydride or another similar alkylaluminum hydride, under conditions well known to the art. Compound (6) may be oxidized to the aldehyde (4) Swem oxidation conditions, or other reactions known to those skilled in the art. The desired compound (4) is freshly prepared before its use in the reaction described below.
Compound (9), the "R4 Reagent")) may be prepared from the precursor alpha-bromo ketone (7) by a two-step procedure. Compound (7) is treated with triphenylphosphine in the presence of a base, such as for example, triethyl amine, to give compound (8). Compound (8) is then treated with an alkali metal base, such as NaOH or the like, to give compound (9). The procedure is normally accomplished by vigorous mixing of a solution of (8) in an organic solvent with an aqueous solution of base.
Compounds (4) and (9) are mixed and the mixture is held at ambient temperature until the reaction is complete (monitoring by TLC), and the product (10) is purified by chromatography. A mixture of the cis and trans isomers is obtained and taken to the next step without further separation. Compound (10) is condensed with malononitrile by heating in the presence of ammonium acetate as defined for Scheme 1 above to produce compound (11).
Scheme 2
Figure imgf000053_0001
4
Figure imgf000053_0002
Figure imgf000053_0003
10
Figure imgf000053_0004
(I)
Compound (11) is then treated with excess formamide by heating at reflux. The formation of product is monitored by TLC, and when the reaction is complete (routinely, after about 1 to about 8 hours) the reaction mixture is cooled to room temperature. The 5,7- disubstituted pyrido[2,3-d]pyrimidine product (I) is then removed by filtration and purified by column chromatography. In an alternate procedure, compound (11) is treated by heating with formamidine acetate in ethoxyethanol, followed by purification by flash chromatography. In another alternate procedure, compound (11) and ammonium sulfate are heated at reflux in triethyl orthoformate for about 1 to about 8 hours, but preferably about 2 hours. The reaction mixture is cooled and added to a mixture of ammonia in ethanol. The mixture is stirred for about 12 to 24 hours at 25 °C, then at reflux for from one to 4 hours, and the solvent is removed in vacuo. The residue is purified by trituration with chloroform/ethyl acetate, and the product may be converted to a hydrochloride salt by suspension in 3M HCl, followed by lyophilization.
Scheme 3
Figure imgf000054_0001
Scheme 3 illustrates an alternate method for preparing the compounds (I) of the invention. Compounds (1), prepared as described above, are reacted with a dicyanoalkene compound (12) by heating with a suitable ammonium salt, such as for example, ammonium acetate, ammonium propionate, ammonium iodide, or the like, at reflux in an alcoholic or aprotic solvent to give the compound (I). Suitable solvents for the reaction may be easily determined by those skilled in the art, without undue trial and error, and may include, for example, ethanol, propanol, isopropanol, t-butanol, n-butanol, 1,2-dichloroethane, benzene, chloroform, carbon tetrachloride, toluene, dioxane, dimethoxyethane, and the like. A preferred solvent is 1,2-dichloroethane. The dicyano compounds (12) may be prepared from the precursor aldehyde (4) by treatment with malononitrile in 1 : 1 H2θ:EtOH in the presence of a catalytic amount of glycine according to the method of Bastus {Tetrahedron Lett. , 1963: 955), or alternately MgO in dichloromethane or a similar aprotic solvent (cf. Broekhuis, et al., Reel. J. R. Neth. Chem. Soc, 99: 6-12 (1980); Moison, et al. Tetrahedron (1987), 43:537-542). To prepare compounds of formula (I) wherein R1 and R2 are not both hydrogen atoms, it is possible to prepared the desired derivative from the compound of Formula (I) wherein R1 and R2 are both hydrogen atoms. When R1 or R2 is loweralkyl this may be accomplished by reaction of the free amino group with the appropriate alkylating reagent, such as an alkyl halide, an alkyl mesylate or an alkyl tosylate, for example, in the presence of a base such as triethylamine or potassium carbonate in a suitable solvent, such as for example, methylene chloride or THF. When R1 or R2 is arylalkyl this may be accomplished by reaction of the free amino group with the appropriate arylalkyl halide, an alkyl mesylate or an alkyl tosylate, for example, in the presence of a base such as triemylamine or potassium carbonate in a suitable solvent, such as for example, methylene chloride or THF. When R1 or R2 is acyl this may be accomplished by reaction of the free amino group with the appropriate acid anhydride, acyl chloride or activated acyl group, in the presence of a base such as triethylamine or potassium carbonate in a suitable solvent, such as for example, methylene chloride or THF. When R1 and R2 are taken together with the nitrogen atom to which they are attached to form a 5-to-7 membered ring optionally containing an additional oxygen or nitrogen atom, the compound may be prepared by reacting a precursor compound having a halogen atom in place of the amino group at the 4-position with a 5-7 membered ring compound optionally containing an additional oxygen or nitrogen atom. Examples of such compounds include, but are not limited to, moφholine, piperidine, pyrrolidine, piperazine, thiomoφholine, and the like. Also, this alternate procedure may be used to prepare alkyl substituted amino compounds, for example by reacting the chloro compound with a mono- or disubstituted amine, such as for example, diethylamine, allyl amine, dibutylamine. This reaction takes place readily in a solvent such as methylene chloride, for example, in the presence of a tertiary amine. The precursor compound having a halogen atom in place of the amino group at the 4-position may be prepared by substitution of triethyl orthoformate for the formamide followed by chlorination of the ring by treatment with phosphorous oxychloride or thionyl chloride in the presence of DMF in Scheme 1 wherein compound (3) is converted to compound (I).
Method of Inhibiting Kinase
In yet another aspect of the present invention a process of inhibiting adenosine kinase is disclosed. In accordance with that process, an adenosine kinase enzyme is exposed to an effective inhibiting amount of an adenosine kinase inhibitor compound of the present invention. Preferred such compounds for use in the process are the same as set forth above. Means for determining an effective inhibiting amount are well known in the art.
The adenosine kinase to be inhibited can be located in vitro, in situ or in vivo. Where the adenosine kinase is located in vitro, adenosine kinase is contacted with the inhibitor compound, typically by adding the compound to an aqueous solution containing the enzyme, radiolabeled substrate adenosine, magnesium chloride and ATP. The enzyme can exist in intact cells or in isolated subcellular fractions containing the enzyme. The enzyme is then maintained in the presence of the inhibitor for a period of time and under suitable physiological conditions. Means for determining maintenance times are well known in the art and depend inter aha on the concentrations of enzyme and the physiological conditions. Suitable physiological conditions are those necessary to maintain adenosine kinase viability and include temperature, acidity, tonicity and the like. Inhibition of adenosine kinase can be performed, by example, according to standard procedures well known in the art (Yamada, et al, Comp. Biochem. Physiol. 1982, 71B: 367-372).
Where the adenosine kinase is located in situ or in vivo, is typically administered to a fluid perfusing the tissue containing the enzyme. That fluid can be a naturally occuring fluid such as blood or plasma or an artificial fluid such as saline, Ringer's solution and the like. A method of inhibiting adenosine kinase in vivo is particularly useful in mammals such as humans. Administering an inhibitor compound is typically accomplished by the parenteral {e.g., intravenous injection or oral) administration of the compound. The amount administered is an effective inhibiting or therapeutic amount.
By a "therapeutically-effective amount" of the compound of the invention is meant a sufficient amount of the compound to treat adenosine kinase related disorders or those conditions or diseases which are ameliorated or modified by local inhibition of the enzyme which results in an increase in the concentration of adenosine. It will be understood, however, that the total daily usage of the compounds and compositions of the present invention is to be decided by the attending physician within the scope of sound medical judgment. The specific therapeutically-effective dose level for any particular patient will depend upon a variety of factors including the disorder being treated and the severity of the disorder; activity of the specific compound employed; the specific composition employed; the age, body weight, general health, gender and diet of the patient; the time of administration, route of administration, and rate of excretion of the specific compound employed; the duration of the treatment; drugs used in combination or coincidental with specific compound employed; and the like factors well known in the medical arts and well within the capabilities of attending physicians. Compounds of the present invention inhibit adenosine kinase activity in vitro and in vivo. In vitro adenosine kinase activity can be measured using any of the standard procedures well known in the art. By way of example, cells containing adenosine kinase, such as IMR-32 human neuroblastoma cells, are cultured in the presence and absence of an inhibitor. Inhibition is measured as the ability to inhibit phosphorylation of endogenous or externally applied ^C-adenosine by these cells. The cells can be intact or broken. The specificity of adenosine kinase inhibitory activity is determined by studying the effects of inhibitors on adenosine Al and A2α receptor binding, adenosine deaminase activity and adenosine transport.
Compounds of the present invention are effective in inhibiting adenosine kinase activity in vivo. Numerous animal models for studying adenosine kinase activity and the affects of inhibiting such activity are well known in the art. By way of example, adenosine kinase inhibitors have been reported to protect rodents {e.g., mice and rats) from seizures induced by the subcutaneous administration of pentylenetetrazol (PTZ). Typically the rodents are injected with various doses of a given inhibitor followed at various times by the subcutaneous administration of from about 10 to about 500 milligrams per kilogram of PTZ, The injected animals are then observed for the onset of seizures. The compounds of the invention were tested in vivo in the hot plate test of analgesia in mammals such as mice. For example, the compounds of examples 6, 79, 104, 130, 133, 134, 137, 205, 246 and 256 in the procedure described directly below were tested thirty minutes after pretreatment with the drugs (30 μmol/kg i.p.) for latency to 10th jump (in seconds). The longer the number of seconds, the more effective the drug at masking the pain felt from the hot plate. Compound 6 resulted in 152 seconds relative to the vehicle alone of 72.8±10.5 seconds (average±standard deviation); compound 79 resulted in 143 seconds; compound 104 resulted in 180 seconds; compound 130 resulted in 158 seconds; compound 133 resulted in 131 seconds; compound 134 resulted in 137 seconds; compound 137 resulted in 159 seconds; compound 205 resulted in 158 seconds, compound 246 resulted in 160 seconds and compound 256 resulted in 143 seconds. Compounds of the invention are therefore potent pain relievers as demonstrated in this animal model.
Mouse Hot Plate Assay
Male CF1 mice (Charles River) of approximately 25-30 g body weight are pretreated with 10 ml/kg of the test compounds, i.p. or p.o, in groups of 8 animals per dose. At the end of the pretreatment period, the mice are placed in an Omnitech Electronics Automated 16 Animal Hot Plate Analgesia Monitor (Columbus, OH; Model AHP16AN) in individual, 9.8 x 7.2 x 15.3 cm (1 x w x h) plastic enclosures on top of a copper plate warmed to 55°C. Infared sensors located near the top of each enclosure record beam crossings that occur as the mice jump off of the heated surface. Latency times for each jump are automatically recorded, and latency to both the first and tenth jumps are used for data analysis. Mice that do not reach the criteria of 10 jumps by 180 seconds are immediately removed from the hotplate to avoid tissue damage, and they are assigned the maximum value of 180 seconds as their latency to tenth jump. Numerous other animal models of adenosine kinase activity have been described
[See, e.g., Davies,, et al, Biochem. Pharmacol, 33:347-355 (1984); Keil, et al, Eur. J. Pharmacol, 271:37 '-46 (1994); Murray, et al, Drug Development Res., 28:410-415 (1993)].
Compounds of the present invention were also tested in vitro . The results of some representative studies are shown below in Tables 1 below. The Examples provided before the claims are all adenosine kinase inhibitors. The data indicate that the compounds inhibit adenosine kinase and are useful as adenosine kinase inhibitors. The compounds of the invention including compounds of formula I and II with the variables recited herein are also useful as screening tools or as comparative indicators of adenosine kinase inhibition activity relative to unknown inhibitors or potential inhibitors.
Table 1 Inhibition of Adenosine Kinase by Representative Compounds of the Invention
Figure imgf000058_0001
Figure imgf000059_0001
Method of Treating Cerebral Ischemia, Epilepsy,
Nociperception (Nociception) (Pain), Inflammation including conditions such as Septic Shock due to Sepsis Infection In yet another aspect of the present invention a method of treating cerebral ischemia, epilepsy, nociperception or nociception, inflammation including conditions such as septic shock due to sepsis infection in a human or lower mammal is disclosed, comprising administering to the mammal a therapeutically effective amount of a compound of formula I with R -R° as defined herein. The preferred compounds are those of formula II with the R variables as defined previously. In particular, the present invention relates to a method of treating the above disorders comprising administering a compound of formula II wherein R3 is a substituted aryl or heteroaryl moiety wherein the substituent (preferrably halogen) is at the meta position relative to the ring attachment and R^ is a substituted heteroaryl or aryl moiety wherein the substituent is at the para position relative to the ring attachment. The most preferred use is in the treatment of pain.
Alterations in cellular adenosine kinase activity have been observed in certain disorders. Adenosine kinase activity was found to be decreased, relative to normal liver, in a variety of rat hepatomas: activity of the enzyme giving a negative correlation with tumor growth rate (Jackson, et al, Br. J. Cancer, 1978, 37: 701-713). Adenosine kinase activity was also diminished in regenerating Uver after partial hepatectomy in experimental animals (Jackson, et al, Br. J. Cancer, 1978, 37: 701-713). Erythrocyte Adenosine kinase activity was found to be diminished in patients with gout (Nishizawa, et al, Clin. Chim. Acta 1976, 67: 15-20). Lymphocyte adenosine kinase activity was decreased in patients infected with the human immunodeficiency virus (HIV) exhibiting symptoms of AIDS, and increased in asymptomatic HIY-seropositive and HTV-seronegative high-risk subjects, compared to normal healthy controls (Renouf, et al, Clin. Chem. 1989, 35: 1478-1481). It has been suggested that measurement of adenosine kinase activity may prove useful in monitoring the clinical progress of patients with HIV infection (Renouf, et al, Clin. Chem. 1989, 35: 1478-1481). Sepsis infection may lead to a systemic inflammatory syndrome (SIRS), characterized by an increase in cytokine production, neutrophil accumulation, hemodynamic effects, and tissue damage or death. The ability of adenosine kinase inhibitor to elevate adenosine levels in tissues has been demonstrated to ameliorate syndrome symptoms, due to the known anti-inflammatory effects of adenosine. (Firestein, et al., J. of Immunology, 1994: 5853-5859). The ability of adenosine kinase inhibitors to elevate adenosine levels is expected to alleviate pain states, since it has been demonstrated that administration of adenosine or its analogs results in antinociception or antinociperception. (Swaynok, et al, Neuroscience, 1989, 32:557-569).
The following Examples illustrate preferred embodiments of the present invention and are not limiting of the specification and claims in any way.
Example 1
4-amino-5-(p-dimemylammophenyl)-7-(p-bromophenyl)pyrido[2.3-dlpyrimidine
A sample of 4-(4-bromophenyl)-3-cyano-6-(4-(dimethylamino)phenyl)pyridine-2- amine (1 g), was suspended in formamide (20 mL), and the reaction was heated to reflux. After about 3 hours, the reaction was complete as monitored by TLC, and the reaction mixture was cooled to room temperature. The product was allowed to precipitate, then recovered by filtration and washed with water. Additional product was recovered from the filtrate. The product was purified by column chromatography eluting with 10% MeOH/CH2Cl2 to give the pure title compound. IR (KBr) 3503, 3398, 1731, 1658, 1510, 1467, 1278cm- 1; MS mil All (M+H)+.
The 4-(4-bromophenyl)-3-cyano-6-(4-(dimemylamino)phenyl)pyridine-2-amine compound was prepared as follows:
The reagents, 4-bromoacetophenone (10 mmol, the "R4 reagent"), 4- dimethylaminobenzaldehyde (10 mmol, the "R3 reagent"), malononitrile (10 mmol) and ammonium acetate (1.4 g) were added to 25 mL of benzene. The reaction mixture was heated to reflux in a vessel fitted with a Dean-Stork apparatus. After 3.5 hours, the mixture was cooled, and the solvent was removed. The residue was purified by flash chromatography, eluting with methylene chloride, with optional addition of 5% ethyl acetate to the eluant. MS mlz 394 (M+H)+.
Examples 2-156 Following the procedures of Example 1, except substituting the appropriate reagents for R4 and R3 as indicated in Table 2 below, compounds of Examples 2-156 were prepared. Table 2 Examples 2-156
Figure imgf000061_0001
Figure imgf000062_0001
Figure imgf000063_0001
Figure imgf000064_0001
Figure imgf000065_0001
Figure imgf000066_0001
Figure imgf000067_0001
Figure imgf000068_0001
Figure imgf000069_0001
Figure imgf000070_0001
Figure imgf000071_0001
Figure imgf000072_0001
Figure imgf000073_0001
Figure imgf000074_0001
Figure imgf000075_0001
Figure imgf000076_0001
Example 157 4-amino-5-(3-bromophenyl)methyl-7-(4-(dimemylamino)phenyl)pyrido[2,3-dlpyrimidine hydrochloride
A mixture of 3-cyano-4-(3-bromophenyl)methyl-6-(4- (dimethyl)ammophenyl)pyridme-2-amine (1.58 g) and ammonium sulfate (40 mg) in triethyl orthoformate was heated at reflux for 2 hours. The reaction mixture was cooled and added to a mixture of 8 g of ammonia in 150 mL of ethanol. After 16 hours at 25 °C, the reaction was heated at reflux for two hours, and the solvent was removed in vacuo. The residue was purified by chromatography, then converted to the hydrochloride salt by treatment with ether/HCl, followed by drying to give the title compound.
The 3-cyano-4-(3-bromophenyl)methyl-6-(4-(dimethyl)aminophenyl)pyridine-2- amine was prepared by a four-step procedure as follows:
step 157a: preparation of 3-bromophenylacetaldehyde (the "R3 reagent")
To a solution of ethyl 3-bromophenylacetate (10.2 g, US patent 2,624,731 (1950)) in 230 mL of dichloromethane was added 42 mL of 1M Dibal-H in toluene at -78 °C with stirring. After 40 minutes at -78 °C, 10 mL of methanol was added, and the reaction allowed to warm to room temperature and partitioned between 50 mL of dichloromethane and 1200 mL of saturated aqueous potassium sodium tartrate. The organic layer was dried over sodium sulfate and the aldehyde used immediately in the next step without purification.
step 157b: preparation of α-(triphenylphosphonium)-4-(dimethylamino)phenylethan-l-one chloride
Following the procedure of Fukui et al. {J. Org. Chem. 33: 3594-3507 (1968)), α- bromo-(4-dimethylaminophenyl)ethan-l-one (the "R4 reagent", CAS #37904-72-6; Chem.
Abst. (1956), 864) was treated with triphenylphosphine in triethylamine and acetonitrile.
The α-bromo-(4-dimethylaminophenyl)ethan-l-one was prepared by bromination with bromine in hydrobromic acid according to the method of Suzuki et al (J. Pharm. Soc. Japan, (1955), 75:54. Removal of solvent and recrystallization from methanol/ethyl acetate/toluene gave the title product as a white powder.
step 157c: preparation of l-(4-(dimethylamino')phenyl)-4-(3-bromophenyl)-but-2-en-l-one 20 g of α-(triphenylphosphonium)-4-(dimethylamino)phenylethan-l-one chloride
(from step b) was partitioned between dichloromethane and 50 mL of 2N NaOH. The organic phase was dried over sodium sulfate and concentrated in vacuo. The residue was mixed with 3-bromophenylacetaldehyde (from step a) for 24 hours at 25 °C. The mixture was purified by chromatography to give 8.35 g (61%) of a cis/trans mixture of the title compound. The cis/trans mixture was taken to the next step without separation of the isomers.
step 157d: preparation of 3-cvano-4-(3-bromophenyl)methyl-6- (4- fdimethyl)am ophenyl)pyridine-2-amine A mixture of l-(4-(dimethylamino)phenyl)-4-(3-bromophenyl)-but-2-en-l-one chloride (3.85 g, from step c), ammonium acetate (2.6 g) and malononitrile (739 mg) in 3 mL of dimethoxyethane and 22 mL of ethanol was heated at 115 °C for 5 hours, then cooled and worked up by partitioning between dichloromethane and water. The residue obtained on concentration of the organic phase was purified by flash chromatography to give the title compound.
Examples 158-174 Following the procedures of Example 157, except substituting the appropriate reagents for the R4 and R3 reagents of Example 157 as indicated in Table 3 below, compounds of Examples 158-174 were prepared. The treatment with aqueous HCl was omitted, and the free bases were obtained except as indicated.
In Examples 167-174, the formamide or formamidine acetate (added periodically until the reaction was complete) treatment was replaced by treatment with triethyl orthoformate at reflux in the presence of a catalytic amount of ammonium sulfate, followed by cooling to 25 °C and addition of excess ammonia in ethanol. After 24 hours, the precipitated amidine compound was filtered and washed with hexanes, then dried under vacuum. The amidine compound was then heated in 1,2-dichloro benzene at 120-180 °C for 1-8 hours. The reaction mixture was cooled to room temperatureand purified by chromatography, and the product was recrystallized if necessary (chloroform in methanol). Table 3 Examples 158-187
Figure imgf000078_0001
Figure imgf000079_0001
* prepared from the compound of Example 157 by reaction with Pd(PPh3)4 and zinc cyanide in DMF under Suzuki reaction conditions. ** prepared from the compound of Example 173 by reaction with 2-thiopheneboronic acid, Pd(PPh3)4 and aqueous sodium carbonate under Suzuki reaction conditions.
Examples 175-188
Following the procedures of Example 1, except substituting the appropriate reagents for the R4 and R3 reagents of Example 1 as indicated in Table 4 below, compounds of Examples 175-188 were prepared. The treatment with aqueous HCl was omitted, and the free bases were obtained except as indicated.
Table 4 Examples 175-188
Figure imgf000080_0001
Figure imgf000081_0001
Figure imgf000082_0001
Example 189 4-acetylamino-5-(3-bromophenyl)-7-(4-dimemylaminophenyl)pyridor2.3-dlpyrimidine
A suspension of 4-amino-5-(3-bromophenyl)-7-(4- dime ylaπύnophenyl)pyrido[2,3-dlpyrimidine (from Example 15, 0.28 g, 0.67 mole) in pyridine (3 mL) was treated with acetic anhydride (0.10 g, 1.0 mmol) and the reaction mixture was stirred for 4 hours at 25 °C. The volatiles were removed under reduced pressure, and the residue was purified by flash chromatography (Siθ2, EtOAc/hexanes) to provide the title compound (0.23 g, 73% theoretical): IR (KBr) 3368, 3048, 1695, 1567; MS mlz 462/464 (M+H)+.
Examples 190-198 Following the procedures of Example 189, except substituting the appropriate acylating reagent for the acetic anhydride of Example 189 as indicated in Table 5 below, compounds of Examples 190-198 were prepared.
Table 5 Examples 190-198
Figure imgf000082_0002
Figure imgf000083_0001
The product was prepared by treating a solution of 4-chloro-5-(p- dimethylaminophenyl)-7-(p-bromophenyl)pyrido[2,3-d]pyrimidine in CH2 2-TEA with allylamine and heating the resulting mixture at reflux for 1 hour. The volatiles were removed under reduced pressure, and the residue was purified by flash chromatography (Siθ2, EtOAc/hexanes) to provide the title compound IR (KBr) 3437, 1564, 1355, 1195; MS mlz 460/462 (M+H)+.
The 4-chloro-5-(p-dimethylaminophenyl)-7-(p-bromophenyl)pyrido [2,3- dlpyrimidine was prepared as follows. A sample of 4-(4-bromophenyl)-3-cyano-6-(4-(dimethylamino)phenyl)pyridine-2- amine (from Example 1, 5.0 g, 12.7 mmol) in 20 mL of H2SO4 was heated at 80 °C for 30 minutes. Ice was added, and the reaction mixture was neutralized with aqueous NaOH. The resulting crude 3-carboxamide was collected by filtration, triturated with EtOAc- hexanes, then dried under reduced pressure (4.95 g, 95% theoretical). A solution of the carboxamide (4.25 g, 10.3 mmol) in triethylorthoformate (20 mL) was treated with p- toluenesulfonic acid (catalytic) and the reaction mixture was warmed at 80 °C for 4 hours. The volatiles were removed and the crude bicyclic 4-hydroxyl-5-(p-dimethylaminophenyl)- 7-(p-bromophenyl)pyrido[2,3-d]pyrimidineproduct was suspended in POCI3 (15 mL) then warmed at 100 "C for 2 hours. The POCl3 was removed under reduced pressure to provide crude 4-chloro-5-(p-dimethylaπ nophenyl)-7-(p-bromophenyl)pyrido[2,3-d]pyrimidine. The invention therefore relates to intermediate compounds of formula HI wherein X is selected from hydroxyl or halogen and the remaining variables are the same as in formula I or II.
Example 200 4-(2-(N.N-dimemylamino)ethylamino)-5-(4-bromophenyl)-7-(4-dimethylaminophenyl) pyrido r2,3-dl pyrimidine trihvdrochloride The product was prepared by treating a solution of 4-chloro-5-(p- dimethylaminophenyl)-7-(p-bromophenyl)pyrido[2,3-d]pyrimidine (prepared as in Example 199) in CH2CI2-TEA with the 2-(dimethylamino)ethylamine and heating the resulting mixture at reflux for 1 hour. The volatiles were removed under reduced pressure, and the residue was purified by flash chromatography (Siθ2, EtOAc/hexanes) to provide the title compound. The product was treated with excess 2M HCl (aq) followed by lyophilization to give the product as the tiihydrochloride salt; IR (KBr) 3385, 1561, 1356, 1197; MS mlz 491/493 (M+H)+.
Example 201 4-(4-(N.N-dimethylamino)butylamino)-5-(3-bromophenyl)-7-(4- dimethylaminophenyl) pyrido [2.3-dl pyrimidine tetrahvdrochlori.de
The product was prepared by treating a solution of 4-amino-5-(p- dimethylaminophenyl)-7-(p-bromophenyl)pyrido[2,3-dlpyrimidine in CH2CI2-TEA with the 4-(dimethylamino)butylamine and heating the resulting mixture at reflux for 1 hour. The volatiles were removed under reduced pressure, and the residue was purified by flash chromatography (Siθ2, EtOAc/hexanes). The product was treated with excess 2M HCl (aq) followed by lyophilization to give the product as the tetrahydrochloride salt; IR (KBr) 3439, 1567, 1356, 1196; MS mlz 519/521 (M+H)+.
Example 202 4-(N-allyl-N-formylamino)-5-(4-dimethylaminophenyl)-7-
(p-bromophenyl)pyridor2.3-dlpyrimidine
A sample of the compound from Example 190 above, 4-formylamino-5-(2- phenylethyl)-7-(4-diethylaminophenyl)-pyrido[2,3-d]pyrimidine (0.27 g, 0.6 mmol) in 3 mL of a 4: 1 mixture of THF and DMF at 0°C was treated with NaH (60% dispersion, 36 mg, 0.9 mmol) and the solution was stirred for 0.5 hour. Allyl bromide (0.29 g, 2.4 mmol) was added, and the reaction mixture was stirred for an additional 0.5 hour. Aqueous workup followed by flash chromatography provided the title compound: LRMS mlz 488/490. IR (cm'1) 3428, 2910, 1696, 1551, 1362,
1 193.
Example 203
4-diacetylamino-5-f4-dimethylaminophenyl)-7-(p-bromophenyl)- pyridor2.3-dlpyrimidine
This compound was isolated as a minor product from the reaction mixture of Example 190 above: LRMS mlz 504/506. IR (cm 1) 2922, 1726, 1550, 1360, 1197.
Example 204 4-amino-5-(3-bromophenyl)-7-(5-amino-2-pyridyl)pyrido[2,3-dlpyrimidine
A solution of 5-aminopyridine-2-ethanone (1.15 g, 8.45 mmol), 3- bromobenzaldehyde (1.70 g, 9.2 mmol), malononitrile (0.61 g, 9.2 mmol), and ammonium acetate (1.15 g, 15 mmol) in 25 mL of benzene was heated at reflux with azeotropic removal of water. After 6 hours the reaction mixture was concentrated, and the desired intermediate (1.82 g, 49%) was isolated following flash chromatography (Siθ2, EtOAc-CH2Cl2). LRMS mlz 366/368. The intermediate was suspended in 15 mL of formamide, and the reaction mixture was heated at 180 °C for 4 hours. The solution was cooled to 25 °C, 10 mL of 4M HCl (aq) was added, and the mixture was stirred for 1 hour. The aqueous solution was neutralized with NaOH (aq), and the precipitate was collected by filtration. The title compound (1.3 g, 68%) was isolated following flash chromatography of the precipitate: LRMS mlz 393/395; IR (cm- 1) 3481, 3161, 1620, 1573, 1483, 1359.
The 5-aminopyridine-2-carboxaldehyde starting material was prepared as follows: 204a. 5-amino-2-bromopyridine
A solution of 2-bromo-5-nitropyridine (5.1 g, 25 mmol) in 50 mL of a 10: 1 mixture of acetic acid and water was treated with iron powder (7.8 g, 140 mmol) in several portions over 20 minutes. After an additional 30 minutes the volatiles were removed under reduced pressure, and the residue was quenched with 5% aqueous sodium carbonate. The aqueous solution was extracted with methylene chloride, and the combined organic layer was dried (sodium suifate) then concentrated in vacuo to provide the desired product as a white solid (4.25 g, 98%).
204b. 5-aminopyridine-2-ethanone
A sample of 5-amino-2-bromopyridine (4.25 g, 24 mmol), PdCl2(PPh3)2 (0.34 g, 2 mole%), Cul (0.09 g, 2 mole%), and trimethyl silylacetylene (3.0 g, 31 mmol) were dissolved in 100 mL of a 4: 1 mixture of triethylamine and acetonitrile, and the reaction mixture was stirred 24 hours at 25 °C. The reaction mixture was concentrated, and the residue was dissolved in 100 mL of a 10:1 mixture of acetone and water. Hg(O2CCF3)2 (11.1 g, 26 mmol) and H2SO4 (72 mmol) were added to the reaction mixture, and the solution was heated at reflux for 2 hours. The reaction mixture was cooled to 25 °C and neutralized with saturated aqueous sodium carbonate. The aqueous layer was extracted with methylene chloride, then the combined organic layer was dried (Na2SO4) and concentrated in vacuo. Flash chromatography (SiO2, EtOAc -Hexanes) provided the title compound: LRMS mlz 137 (M = H+); IR (cm"1) 3428, 1668, 1646, 1582, 1358, 1274.
Example 205 4-am o-5-(3-bromophenyl)-7-(5-dimemylamino-2-pyridyl)pyridor2,3-dlpyrirrudine trihvdrochloride salt
Following the procedure of Example 204, 5-dimethylaminopyridine-2- ethanone was reacted with bromobenzaldehyde, malononitrile, and ammonium acetate to give the title compound. The residue was triturated with excess HCl/ether, the volatiles were removed under reduced pressure, and the title compound was dried under high vacuum: LRMS m/z 421/423. IR (cm-1) 3245, 1664, 1545, 1395.
The 5-dimethylammopyridine-2-carboxaldehyde starting material was prepared as follows:
205a..3-/V,A^-dimethylaminopyridine
A solution of 3-aminopyridine (9.4 g, 0.10 mol) in a 1: 1 mixture of formic acid (96%) and formaldehyde (37% aqueous solution) was heated at reflux for 18 hours. The volatiles were removed under reduced pressure and the residue was neutralized with saturated aqueous NaHCO3. The aqueous layer was extracted with CH2CI2, then the combined organic layer was dried (Na2SO4) and concentrated under reduced pressure. Flash chromatography (SiO2, EtOAc-Hexanes) provided the title compound: (1 1.1 g, 91%), LRMS mlz 123 (M + H+).
205b. 2-bromo-5-/V . /V-dimethylaminopyridine
A solution of 3-NiV-dimethylaminopyridine (5.88 g, 48.1 mmol) in 150 mL of CH2C12 at 0 °C was treated with 2,4,4,6-tetrabromo-2,5-cyclohexadienone (20.7 g, 50 mmol) in several portions over 30 minutes. After 2 hours at 0 °C the reaction mixture was concentrated, and the desired 2-bromo-5-NN-dimethylaminopyridine was isolated following flash chromatography (16.5 g, 82%): LRMS mlz 201/203.
204c. 5-N . Ν-dimemylaminopyridine-2-ethanone
Following the procedure of Example 203b, 2-bromo-5-NN- dimethylaminopyridine, except converting the compound to the trihydrochloride salt by treatment with HCl ether, was converted to the title compound: LRMS mlz 165; IR (cm-1) 3480, 1666, 1581, 1368, 1272.
Example 206 4-am o-5-(3-bromophenyl)-7-(5-dimethylamino-2-pyrazinyl)- pyrido[2.3-dlpyrimidine hydrochloride
Following the procedure of Example 204, 5-dimethylaminopyrazine-2- ethanone was reacted with bromobenzaldehyde, malononitrile, and ammonium acetate to give the title compound. The residue was triturated with excess HCl/ether, the volatiles were removed under reduced pressure, and the title compound was dried under high vacuum: LRMS m/z 422/424. IR (cm"1) 3310, 1630, 1525, 1444, 1375.
The 5-dimethylaminopyrazine-2-carboxaldehyde starting material was prepared as follows:
206a. 5-dimethylaminopyrazine-2-ethanone
A solution of 5-hydroxypyrazine-2-carboxylic acid (4.0 g, 28.5 mmol) in 50 mL of thionyl chloride and 0.1 mL of DMF was heated at reflux for 8 hours. The volatiles were removed under reduced pressure, and the residue was dissolved in 20 mL of toluene. This solution was added to a solution of dimethyl malonate (4.75 g, 36 mmol), MgCl2 (2.09 g, 22 mmol) and triethyl amine (7.08 g, 70 mmol) in 100 mL of toluene. The reaction mixture was stirred for 1 hour at 25 °C, quenched by addition of water, and the product was extracted with methylene chloride. The solvent was removed, the crude intermediate was dissolved in 25 mL of a 25: 1 mixture of DMSO and water, and the resulting solution was warmed at 150 °C for 2 hours. The reaction was quenched by addition of water, and the product was extracted with methylene chloride to provide 2-acetyl-5-chloropyrazine (LRMS mlz 156). This intermediate was treated with aqueous dimethylamine at room temperature for 30 minutes to afford 5- dimethylaminopyrazine-2-ethanone.(LRMS mlz 166): LRMS m/z 422/424; IR (cm"1) 3310, 1630, 1525, 1444, 1375.
Example 207 4-amino-5-(3-bromophenyl)-7-(2-oxobenzoxazohn-6-yl)pyrido[2.3-dlpyrimidine
Following the procedure of Example 204, 2-oxobenzoxazolin-6-ethanone_was reacted with bromobenzaldehyde, malononitrile, and ammonium acetate to prepare the title compound: LRMS m/z 434/436; IR (cm"1) 3095, 1760, 1579, 1481, 1350. The 2-oxobenzoxazolin-5-ethanone_starting material was prepared as follows:
207a. 2-oxobenzoxazolin-6-ethanone
DMF (9 mL) was added dropwise to A1C13 (58.7 g, 440 mmol) over 20 minutes and the resulting suspension was stirred 15 minutes at 25 °C. Acetic anhydride (7.14 g, 70 mmol) and 2-benzoxazolinone (6.0 g, 44 mmol) were added and the reaction mixture was warmed at 80 °C and stirred for 4 hours. The mixture was cooled to 25 °C and poured into ice/H2O. The resulting precipitate was collected by filtration and dried under vacuum to provide the title compound (6.4 g, 81%, LRMS mlz 11).
Example 208 4-amino-5-(3-bromophenyl)-7-(l-methyl-2-oxobenzoxazohn-6-yl)- pyrido[2,3-dlpyrimidine
Following the procedure of Example 204, l-methyl-2-oxobenzoxazolin-5- ethanone was reacted with bromobenzaldehyde, malononitrile, and ammonium acetate to prepare the title compound: LRMS m/z 448/450; IR (cm"1) 3440, 1782, 1605, 1458, 1350.
The l-methyl-2-oxobenzoxazolin-5-ethanone_starting material was prepared as follows:
208a. 1 -methyl-2-oxobenzoxazolin-5-ethanone A solution of 2-oxobenzoxazolin-5-ethanone_(from Example 206a, 2.50 g, 14.1 mmol) in 20 mL of a 4: 1 mixture of THF and DMF at 0 °C was treated with NaH (60 % dispersion, 0.8 g, 20 mmol) and the mixture was stirred 20 minutes at 0 °C. Methyl iodide (3.97 g, 28 mmol) was added and the reaction mixture was warmed to 25 °C and stirred for 15 minutes. Saturated aqueous NaHCO3was added and the aqueous layer was extracted with CH:C12. The desired product (2.55 g, 94%, LRMS mlz 191), was isolated following flash chromatography (SiO2, EtOAc-CH2Cl2).
Example 209 4-amino-5-((5-chloro-2-(3-methoxyphenyl)phenyl)methyl)-7-(4- dimethylam ophenyl)pyridor2.3-dlpyrimidine The title compound was prepared from the compound of Example 173 by reaction with 3-methoxyphenylboronic acid, Pd(PPh3)4 and aqueous sodium carbonate under Suzuki reaction conditions. IR (KBr) 3550-3250,3240- 2760,1580,1560,1540,1350; H. Res. MS m/z 496.1902 (M+H)+.
Example 210 4-ammo-5-((2-bromophenyl)methyl)-7-(4-m^ethylammophenyl)pyridor2.3-dlpyrirnidine Following the procedures of Example 157, except substituting l-(4- dimethylaminophenyl)-ethanone for the R4 reagent and 2-(2-bromophenyl)- acetaldehyde for the R3 reagent of Example 157, the title compound was prepared as shown in Table 6.
Table 6
Figure imgf000089_0001
Example 211
4-amino-5-(2-((thiophene-2-yl phenyl)methyl)-7-(4-diethylaminophenyl)pyrido[2.3- dlpyrimidine The title compound was prepared from the compound of Example 173 by reaction with 2-thiopheneboronic acid, Pd(PPh3)4 and aqueous sodium carbonate under Suzuki reaction conditions. IR (KBr) 3640-3240, 3240-2800, 1580, 1560, 1540, 1350; H. Res. MS m/z 466.2070 (M+H)+. Example 212 4-amino-5-(2-((thiophene-3-yl)phenyl)methyl)-7-(4-diethylaminophenyl)pyridor2.3- dlpyrimidine The title compound was prepared from the compound of Example 173 by reaction with 3-thiopheneboronic acid, Pd(PPh3)4 and aqueous sodium carbonate under Suzuki reaction conditions. IR (KBr) 3640-3240, 3240-2800, 1580, 1560, 1540, 1350; H. Res. MS m/z 466.2057 (M+H)+.
Examples 213-222
Following the procedures of Example 1, except substituting the appropriate reagents for R4 and R3 as indicated in Table 7 below, compounds of Examples 212-222 were prepared.
Table 7 Examples 213-222
Figure imgf000090_0001
Figure imgf000091_0001
*prepared by deformylation of Example 213 with dilute HCl in methanol. **prepared by acylation of Example 213 with 2-methoxyacetyl chloride/pyridine. ***prepared by formylation of the 7-(3-bromophenyl)-2-cyano-5-(4- aminophenyl)pyridine-2-amine intermediate. ****prepared by acylation of Example 213 with the 2-(dimethylamino)acetyl chloride.
Examples 223-225 Following the procedures of Example 157, except substituting the appropriate reagents for the R4 and R3 reagents of Example 157 as indicated in Table 8 below, compounds of Examples 223-225 were prepared. Table 8 Examples 223-225
Figure imgf000092_0001
*prepared from the compound of Example 170 by reaction with propargylamine, Cul and Pd(PPh3)4 under Suzuki reaction conditions.
Examples 226-228 Following the procedures of Example 1, except substituting the appropriate reagents for R4 and R3 as indicated in Table 9 below, compounds of Examples 226-228 were prepared.
Table 9 Examples 226-228
Figure imgf000092_0002
Figure imgf000093_0001
Example 229 4-amino-5-(3-bromophenyl -7-(4-(ureido)phenyl)pyrido[2,3-d1pyrimidine
A solution of 4-amino-5-(3-bromophenyl)-7-(4-aminophenyl)pyrido[2,3- dlpyrimidine (Example 71, 310 mg, 0.79 mmol) in 2 mL of acetic acid was treated with sodium cyanate (56 mg, 0.87 mmol). and the reaction mixture was stirred for 30 minutes at 25 °C. The solution was concentrated and the residue was suspended in aqueous NaHCO . The crude product was collected by filtration, then purified by flash chromatography. The product was dissolved in methanol and treated with excess 2M aqueous HCl to provide the hydrochloride salt: LRMS m/z 435/437. IR (cm"1) 3442, 2212, 3186, 3059, 1681, 1582, 1525, 1358.
Example 230
4-arnino-5-(l-phenylmethyl-3-piperidinyl)-7-(4-diethylaminophenyl)pyridor2.3- dlpyrimidine Following the procedures of Example 157, except substituting l-(4-diethylamino- phenyl)-ethanone for the R4 reagent and l-phenylmethylpiperidine-3-carboxaldehyde (prepared as described by Gilligan et al, J. Med. Chem., 35:4344-4361 (1992)) for the R3 reagent thereof, the title compound was prepared. The treatment with aqueous HCl was omitted, and the free base was obtained. IR (KBr) 3440, 3100-2800-1640, 1605, 1595, 1535 cm" 1; MS mlz Aβl (M+H)+; mp 218-220 °C.
Examples 231-243 Following the procedures of Example 1, except substituting the appropriate reagents for R4 and R3 as indicated in Table 10 below, compounds of Examples 230-243 were prepared. In some cases, the treatment with aqueous HCl was omitted, and the free bases were obtained. Table 10 Examples 231-243
Figure imgf000094_0001
Figure imgf000095_0001
* separated by chromatography om the same reaction mixture; formylation occurs during the cyclization step
Example 244 4-aniino-5-(3-bromophenyl)-7-(l-methyl-5-indohnyl)pyrido[2.3-dlpyrimidine dihydrochloride
A sample of 4-(3-bromophenyl)-3-cyano-6-(l-methyl-5-indohnyl)pyridine-2- amine was heated at reflux in formamide. The reaction was monitored by TLC, and when the reaction was complete the mixture was cooled to room temperature. The product was allowed to precipitate, then recovered by filtration and washed with water. Additional product was extracted from the filtrate. The product was purified by column chromatography eluting with 10% MeOH/CH2θ2 and converted to the hydrochloride salt by treatment with ether/HCl. The salt was isolated and dried under vacuum to give the title compound. LRMS m/z 432/434; IR (cm"1) 3500, 3400, 3300, 3200-2800, 1610, 1580, 1560, 1540.
The 4-(3-bromophenyl)-3-cyano-6-( 1 -methyl-5-indolyl)pyridine-2-amine starting material was prepared as follows:
244a. 5- bromo- 1 -meth ylindoline Acetic acid (60 mL) was added to a mixture of 5-bromo-l-methylindole (10 g, 47.6 mmol) and sodium cyanoborohydride (8 g). After one hour at 15 °C, the reaction was basified with aqueous NaOH and extracted with toluene. The organic phase was dried over MgSO4 and concentrated to a powder under vacuum. This material was purified by flash chromatography to give the title compound, 8.62 g (82 %): MS 212, 214 [M+H]+.
244b. 5-acetyl-l-methylindoline
A mixture of 5-bromo-l-methylindoline (8.6 g, 40.7 mmol), trimethylsilylacetylene (12 mL), palladium bis-triphenylphosphine dichloride (600 mg), Cul (620 mg) and triethylamine (16 mL) in acetonitrile (20 mL) was heated at 75 °C for 3 days, then cooled and concentrated in vacuo. The residue was dissolved in 120 mL of 1: 1 ethyl acetate/hexane, and the solids were removed by filtration. The solvent was removed and a sample of the residue (5 g) was dissolved in 90% aqueous acetone (44 mL). To this solution was added sulfuric acid (2.2 g), and
Hg(OCOCF3)2 (9 g). The reaction was heated at reflux for 20 minutes, cooled, made basic with aqueous sodium hydroxide and extracted with ethyl acetate. The organic layer was dried over MgSO4 and concentrated to an oil, which was purified by flash chromatography to give 850 mg of the title compound: MS 176 [M4-H]+.
244c. 4-(3-bromophenyl)-3-cvano-6-(l-methyl-5-indolinyl)pyridine-2-amine
Prepared by condensation of ,l'-dicyano-3-bromostyrene (prepared by condensation of 3-bromobenzaldehyde with malononitrile in ethanol in the presence of a catalytic amount of glycine) and the 5-acetyl-l-methylindoline (the R4 reagent) with ammonium acetate in ethanol. The reaction mixture was heated to reflux in a vessel fitted with a Dean-Stark apparatus. After 3.5 hours, the mixture was cooled, and the solvent was removed. The residue was purified by flash chromatography, eluting with methylene chloride, to give the title compound (588 mg, 30% yield; MS m/z 394 (M+H)+.
Example 245
4-am o-5-(3-bromophenyl)-7-( l-memyl-5-benzimidazolyl)pyrido[2,3-dlpyrimidine tetrahvdrochloride The title compound was prepared according to the procedure of Example 1, except substituting l-methyl-5-acetyl-benzimidazole (prepared according to the procedure of D. J. Evans et. al, J. Chem. Soc. Perkin Trans. II, 1978, 865) for the 4- dimethylaminobenzaldehyde (the R3 reagent) therein. IR (KBr) 3650-3230, 3230-2000, 1635, 1605, 1590, 1555, 1365 cm"1; MS mlz 431/433, 431.0605 (M+H)+
Example 246
4-amino-5-(3-bromophenyl)-7-(6-dimethylamino-3-pyridazinyl)pyrido[2,3-dlpyrirnidine tettahvdrochloride
246a. 6-( 1 -butoxyethenyl)-3-chloropyridazine To a solution of 20 g (200 mmol) of butyl vinyl ether in 80 mL of THF at -78 °C was added 130 mL of a 1.7 M solution of t-butyl lithium in pentane over about 20 minutes. The yellow suspension was stirred while allowing to warm to 0 °C. THF (150 mL) was added, and the mixture cooled to -78 °C and a solution of 23 mL (200 mmol) of trimethyl borate in 50 mL of THF was added. The reaction was warmed to 20 °C, 20 mL of methanol was added, and the solution concenttated in vacuo. The residue was diluted with 400 mL of dioxane, and 20.9 g (140 mmol) of 3,6-dichloropyridazine, 2.31 g of Pd(PPh3)4, and 200 mL of 2 M- aqueous sodium carbonate was added. The reaction was heated to reflux over one hour, then cooled and filtered to remove solids. The filtrate was concentrated in vacuo and partitioned between ethyl acetate and 1 M sodium hydroxide. The organic phase was dried over Na2SO4, concenttated in vacuo, and purified by flash chromatography to give 6.3 g (21%) of the title compound. MS {M + 1+ 213, 215.
246b. 1 -(6-chloropyridazin-3-yl)ethanone
A mixture 6.3 g of the compound from Step 246a in 40 mL of dimethoxyethane, 10 mL of water, and 4 mL of 12 M HCl was stirred for 20 minutes, then 125 mL of water was added, and the reaction was neutralized with 12 g of NaHCO3. The reaction was extracted with ethyl acetate, dried over Na2SO4, and concenttated in vacuo to give a yellow solid, 4.7
246c. l-(3-(6-(dimethylamino)pyridazin-3-yl))ethanone (the R4 reagent)
A solution of 1.57 g (10 mmol) of l-(6-chloropyridazin-3-yl)ethanone (from Step 246b) in 15 mL of dimethoxyethane was treated with 50 mmol of 40% aqueous dimethylamine. After one hour, the reaction was partitioned between CH2CI2 and water. The organic phase was dried over CH2CI2 , and concenttated in vacuo to give the title compound. 246d. 3-acetyl-6-(dimethylamino)pyridazine
The title compound was prepared by condensing l,l-dicyano-(3-(3- bromophenyl)propene (the R3 reagent) with the compound from Step 246c (the R4 reagent) and ammonium acetate in ethanol according to the procedure of Example 157d.
246e. 4-amino-5-(3-bromophenyl)-7-(6-dimethylamino-3-pyridazinyl)pyrido[2.3- dlpyrimidine tetrahvdrochloride
The title compound was prepared from the compound of Step 246d according to the procedure of Example 157, except substituting formamide for the ammonium sulfate and triethyl orthoformate thereof.
Examples 247-248 Following the procedures of Example 246, except in step (c) substituting the appropriate reagents for methylamine as indicated in the Table 11 A below, compounds of Examples 247-248 were prepared.
Figure imgf000098_0001
Examples 249-251
Following the procedures of Example 244, except in step (c) first substituting the appropriate reagent for R4 as indicated in Table 1 IB below for the R4 reagent of Example 244 step c, and secondly performing the condensation with ammonium acetate substituting dichloroethane as the solvent in place of the ethanol solvent in Example 244 step c, the compounds of Examples 249-2 1 were prepared. In some cases, the hydrochloride salts were not prepared. Table 1 IB Examples 249-260
Figure imgf000099_0001
Example 252
4-arruno-5-(3-bromophenyl)-7-(5-(N.N-bis(2-methoxyethyl)amino)-2-pyridinyl)pyrido[2,3- dlpyrimidine trihydrochloride
Step 252a. l-(5-bromo-2-pyridyl)ethanone, ethylene ketal A solution of dibromopyridine (5.2 g, 21.95 mmol), tributyl(l-ethoxyvinyl)tin (9.11 g, 25.24 mmol), Pd2(dba)3 (0.7 g, 0.8 mmol), and (2-furyl)3P (0.37 g, 1.6 mmol) in 50 mL of toluene THF (5: 1) was warmed at reflux for 10 hours. The reaction mixture was concenttated, and the crude product was purified by elution through a short column of silica gel. The resulting enol-ether compound, ethylene glycol (2.79 g, 45 mmol), and p-toluene sulfonic acid (0.1 g) were dissolved in 50 mL of toluene and the solution was warmed at reflux for 10 hours. The reaction mixture was quenched by the addition of saturated aqueous NaHCO3, and the aqueous layer was extracted with CH2CI2. The combined organic layer was dried (Na2SO4), concenttated under reduced pressure, and the resulting crude product was purified by flash chromatography to provide the title compound (3.68 g, 79%). Step 252b. l-(5-(bis(2-methoxyethyl)amino)-2-pyridyl)ethanone
Following literature procedure (J. Org. Chem. 1996, 61, 720), a suspension of the compound from step 252a, bis(2-methoxyethyl)amine, t-BuONa, Pd2(dba)3, and BINAP toluene was warmed at 80 °C for 8 hours. The reaction mixture was quenched by the addition of saturated aqueous NaHCO3 and the aqueous layer was extracted with CH2CI2.
The combined organic layer was concenttated and the resulting residue was dissolved in 20 mL THF/3 M HCl (4: 1) and stirred for 4 h. The reaction mixture was neutralized by the addition of 2 M NaOH (aq) and the aqueous layer was exttacted with Q-^Cb- The combined organic layer was dried, concenttated under reduced pressure, and the crude product was purified by flash chromatography to provide the title compound
Step 252c. 4-amino-5-(3-bromophenyl)-7-(5-(N.N-bis(2-methoxyethyl)amino)-2- pyridinyl)pyrido[2,3-dlpyrimidine ttihvdrochloride
Following the procedures of Example 244, except in step (c) first substituting the reagent from Step 252b for the R4 reagent of Example 244 step c, and secondly performing the condensation with ammonium acetate substituting dichloroethane as the solvent in place of the ethanol solvent in Example 244 step c, the free base of the title compound was prepared. The title compound was prepared from this by treatment with HCL in ether. IR (KBr) 3440, 1635, 1605, 1580, 1360 cm"1; MS mlz 466/468, (M+H)+.
Examples 253-260 Following the procedures of Example 244, except in step (c) first substituting the appropriate reagent for R4 as indicated in Table 1 IB below for the R4 reagent of Example 244 step c, and secondly performing the condensation with ammonium acetate substituting dichloroethane as the solvent in place of the ethanol solvent in Example 244 step c, the compounds of Examples 253-260 were prepared. In some cases, the hydrochloride salts were not prepared.
Figure imgf000100_0001
Figure imgf000101_0001
* Prepared as in Ex. 252b, except substituting moφholine for the bis(2- methoxyethyl)amine thereof.
** Prepared as in Ex. 252b, except substituting 4-hydroxypiperidine for the bis(2-methoxyethyl)amine thereof.
Example 261
4-amino-5-(3-pyridyl)-7-(4-dimethylaminos)phenylpyrido[2.3-dlpyrimidine
The compound was prepared by using the method generally described above in
Scheme 3 and the associated examples using l-(4-dimethylaminophenyl)ethanone as the R reagent (7-position) and nicotinaldehyde as the R^ reagent (5-position). IR (cm-1) 3305.8,
2922, 1606, 1578, 1535, 1360. MS (M+H) 342. Example 262 4-(me ylarruno)-5-(3-bromophenyl)-7-(4-dime ylanjmophenyl)pyridor2.3-d1pyrimidi«e hydrochloride The title compound was prepared by using the method described in Example 200, except substituting methylamine for the 2-(dimeftylammo)ethylamine thereof. MS (M+H), 478 (IBr); IR (cm-1) 3455, 3047, 2959, 1580, 1351, 1234.
Example 263 4-(2-methoxyethylamino)-5-(3-bromophenyl)-7-(4- dimethylaminophenyl)pyrido[2.3-dlpyrimidine hydrochloride The title compound was prepared by using the method described in Example 200, except substituting 2-methoxyethylamine for the 2-(dimethylamino)ethylamine thereof. MS (M+H), 522 (IBr); IR (cm-1) 3415, 2920, 1569, 1321, 1234.
Example 264 4-amino-5-(3-bromophenyl)-7-(4-(l-memyl-2-imidazolyl)phenyl)pyrido[2.3-dlpyrimidine trihvdrochloride
Step 264a. l-(4-(l-Methylimidazol-2-yl)phenyl)ethanone
A solution of N-methyl imidazole (0.90 g, 11.0 mmol) in 12 mL of THF at -78 °C was treated with n-BuLi (7.5 mL, 1.6 M solution in hexanes, 12.0 mmol) for 0.5 hours at - 78 °C. Next, ZnCl2 (20 mL, 1.0 M solution in Et2O, 20 mmol) was added, and the solution was warmed to 25°C. To this solution was added Pd(PPh3)4 (70 mg, 0.06 mmol) followed by 4-iodoacetophenone ethylene acetal (prepared from iodoacetophenone and ethylene glycol in the presence of an acid catalyst by standard procedures), and the reaction mixture was heated at reflux for 4 hours. The solution was then cooled to 25 °C and quenched by the addition of saturated aqueous NaHCO3 (10 mL). The aqueous layer was extracted with CT^Cf?, and the combined organic layer was concentrated under reduced pressure. The residue was dissolved in 30 mL of THF, 15 mL of 3 M aqueous HCl was added, and the mixture was stirred for 2 hours at 25 °C. The solution was neuttalized by the addition of saturated aqueous NaHCO3, and the aqueous layer was exttacted with QH^C^-
The combined organic layer was dried (MgSO4) then concentrated under reduced pressure.
The crude product was purified by flash chromatography to provide the title compound (0.89 g, 64%). Step 264b. 4-amino-5-(3-bromophenyl)-7-(4-( l-methyl-2-imidazolyl)phenyl)pyrido[2,3- dlpyrimidine ttihvdrochloride
Following the procedures of Example 244, except in step (c) first substituting the R4 reagent from Step 264a for the R4 reagent of Example 244 step c, and secondly performing the condensation with ammonium acetate substituting dichloroethane as the solvent in place of the ethanol solvent in Example 244 step c, the title compound was prepared. MS (M+H) 458 (IBr); IR (cm- 1) 3051, 2948, 1577, 1474, 1354.
Examples 265-267 Following the procedures of Example 244, except in step (c) first substituting the appropriate reagent for R4 as indicated in the Table below for the R4 reagent of Example 244 step c, and secondly performing the condensation with ammonium acetate substituting dichloroethane as the solvent in place of the ethanol solvent in Example 244 step c, the compounds of Examples 264-285 were prepared. In Ex. 266, the hydrochloride salt was not prepared.
Figure imgf000103_0001
Example 268 4-amino-5-('3-bromophenylV7-f4-(3-(dimethylarnino propynyl phenyl)pyridor2.3- dlpyrimidine
A suspension of the compound of Example 63 (0.80 g, 1.59 mmol), PdCl2(PPh3)2, Cul, and 3-dimethylaminoprop-l-yne in 20 mL of DMF/TEA (4: 1) was heated at 50 °C for 3 hours. The volatiles were removed under reduced pressure, and the residue was purified by flash chromatography to provide the title compound (0.50 g, 68 %). MS (M+H), 459 (IBr); IR (cm-1) 3027, 2964, 1513, 1470, 1360.
Examples 269-271 Following the procedures of Example 268, except substituting the reagent compound shown in the table below for the 3-dimethylaminoprop-l-yne of Example 268, the compounds shown in the table below were prepared.
Figure imgf000104_0001
Example 272
4-amino-5-(3-bromophenyl)-7-(4-carboxyphenyl)pyrido[2.3-d1pyrimidine A solution of 4-amino-5-(3-bromophenyl)-7-(4-cyanophenyl)pyrido[2,3- dlpyrimidine (the compound of Example 37, (0.47 g, 1.17 mmol) in 15 mL of 6 M HCl (aqueous) was heated at 60 °C for 8 hours. The mixture was lyophilized and the crude product was purified by flash chromatography to provide the title compound (0.14 g, 28%). MS (M+H), 422 (IBr); IR (cm-1) 3064, 2628, 1692, 1403, 1273.
Example 273
4-amino-5-(3-bromophenvn-7-(4-methyl-3-oxo-2H-4H-pyridor3.2-b1-1.4- oxazinyl)pyrido[2.3-dlpyrimidine
Step 273a. 7-acetyl-2H-pyridor3.2-b1-1.4-oxazin-3(4H)-one
A solution of 2H-pyrido[3,2-b]-l,4-oxazin-3(4H)-one (9.8 g, 65.27 mmol, Aldrich) in 120 mL of TΗF/MeOΗ (5:1) was tteated with 0.4 mL of concenttated ΗC1
(aqueous) followed by N-bromosuccinimide (17.8 g, 100 mmol) in several portions over 10 minutes. After 12 hours at 25 °C the reaction mixture was quenched by the addition of saturated aqueous NaHSO - The aqueous layer was exttacted with CH2CI2 and the combined organic layer was dried (T^SO^, concenttated under reduced pressure, and purified by flash chromatography to provide 7-bromo-2H-pyrido[3,2-b]-l,4-oxazin-3(4H)- one (8.4 g, 56%). A mixture of 7-bromo-2H-pyrido[3,2-b]-l,4-oxazin-3(4H)-one (3.2 g, 14 mmol), tributyl(l-ethoxyvinyl)tin (6.1 g, 17 mmol), Pd2(dba)3 (0.5 g, 0.56 mmol), and
(2-furyl)3P (0.3 g, 1.2 mmol) in 30 mL of toluene/TΗF (5:1) was warmed at reflux for 10 hours. The reaction mixture was concenttated under reduced pressure, and the residue was dissolved in 50 mL of TΗF. 15 mL of 4 M ΗC1 (aqueous) was added, and the mixture was stirred for 4 hours at 25 °C. The solution was neuttalized by the addition of NaΗC03 (aqueous), and the aqueous layer was exttacted with
Figure imgf000105_0001
The combined organic layer was dried (Na2SO ), concentrated, and the crude product was purified by flash chromatography to provide 7-acetyl-2H-pyrido[3,2-b]-l,4-oxazin-3(4H)-one (2.37 g, 88%). MS (M+Η), 463 (1 Br); IR (cm-1) 3400, 3200-2800, 1700, 1640, 1605, 1590, 1395, 1380, 1345.
Step 273b. 7-acetyl-4-methyl-2H-pyrido[3.2-bl-1.4-oxazin-3(4H)-one
The compound from step 273 a was tteated with methyl iodide and NaΗ in 1: 1 TΗF/DMF for 6 hours at 0 °C to 25 °C. The reaction was quenched with aqueous sodium bicarbonate solution, the mixture was extracted with dichloromethane, and the resiue was purified by chromatogaphy to give the tide compound. MS (M+Η), 407.
Step 273c. 4-amino-5-(3-bromophenyl)-7-(4-methyl-3-oxo-2Η-4Η-pyridor3.2-bl-1.4- oxazinyl)pyrido[2.3-dlpyrimidine
Following the procedure of Example 244 Step c, except first substituting 7-acetyl-4- methyl-2H-pyrido[3,2-b]-l,4-oxazin-3(4H)-one (the R4 reagent) from Step 273b for the R4 reagent of Example 244 Step c, and secondly performing the condensation with ammonium acetate substituting dichloroethane as the solvent in place of the ethanol solvent in Example 244 step c, the title compound was prepared. MS (M+Η), 463 (1 Br); IR (cm-1) 3400, 3200-2800, 1700, 1640, 1605, 1590, 1395, 1380, 1345.
Example 274 4-amino-5-(3-bromophenyl)-7-(4-(2-(dimethylamino)ethyl)-3-oxo-2Η-4Η-pyrido[3,2-bl- l,4-oxazin-7-yl)pyridor2.3-dlpyrimidine
Step 274a. 7-acetyl-4-dimethylaminoethyl -2H-pyridor3.2-bl-1.4-oxazin-3(4H)-one The compound from Example 273 Step a was treated with 2-chloro-(N,N- dimethyl)ethylamine HCl and K2CO3 in aqueous acetone at reflux. The mixture was diluted with water and exttacted with dichloromethane, and the residue was purified by chromatogaphy to give the title compound.
Step 274b. 4-amino-5-(3-bromophenyl)-7-(4-(2-(dimethylamino)ethyl)-3-oxo-2H-4H- pyrido[3.2-bl-l,4-oxazin-7-yl)pyrido[2,3-dlpyrimidine
Following the procedures of Example 244 Step c, except in step c first substituting 7-acetyl-4-dimethylaminoethyl -2H-pyrido[3,2-b]-l,4-oxazin-3(4H)-one (the R4 reagent, from Step 273b) for the R4 reagent of Example 244 Step c, and secondly performing the condensation with ammonium acetate substituting dichloroethane as the solvent in place of the ethanol solvent in Example 244 step c, the title compound was prepared. MS (M+Η), 519 (1 Br); IR (cm-1) 3440, 1685, 1630, 1605, 1580, 1395
Example 275
4-ammo-5-(3-bromophenyl)-7-(2,3-dihvdro-3-(dimethylaminoethyl)-2-oxobenzoxazol-6- yl)pyrido[2.3-dlpyrimidine
Step 275a. 6-acetyl-2-benzoxazolinone Following the procedures of Example 273 Step a, except substituting 2- benzoxazolinone (Aldrich) for the 2H-pyrido[3,2-b]-l,4-oxazin-3(4H)-one thereof, the title compound was prepared.
Step 275b. 6-acetyl-3-(dimethylaminoethyl)-2-benzoxazolinone The compound from Example 275 Step a was tteated with 2-chloro-(N,N- dimethyl)ethylarnine ΗC1 and K2CO3 in aqueous acetone at reflux. The mixture was diluted with water and exttacted with dichloromethane, and the residue was purified by chromatogaphy to give the title compound.
Step 275c. 4-amino-5-(3-bromophenyl)-7-(2,3-dihvdro-3-(dimethylaminoethyl)-2- oxobenzoxazol-6-yl)pyridor2.3-dlpyrimidine
Following the procedures of Example 244 Step c, except in step c first substituting the compound from Step 275a for the R4 reagent of Example 244 Step c, and secondly performing the condensation with ammonium acetate substituting dichloroethane as the solvent in place of the ethanol solvent in Example 244 step c, the title compound was prepared. MS (M+Η), 506 (1 Br); IR (cm-1) 3400, 3050, 1630, 1610, 1360. Example 276 4-amino-5-(3-bromophenyl)-7-(4-methyl-3-oxo-2H-4H-benzo-l,4-oxazin-7-yl)pyridor2.3- dlpyrimidine
Step 276a. 6-acetyl-3-methyl-2-benzoxazolinone
The compound from Example 275 Step a was tteated with methyl iodide and NaH in 1: 1 THF/DMF for 6 hours at 0 °C to 25 °C. The reaction was quenched with aqueous sodium bicarbonate solution, the mixture was exttacted with dichloromethane, and the resiue was purified by chromatogaphy to give the title compound.
Step 276b. l-(3-hvdroxy-4-methylaminophenyl)-ethanone
The compound from Step 276a (1.60 g, 8.37 mmol) was dissolved in acetone (70 mL) and tteated with IM aqueous K2CO3 solution (25 mL) with heating at reflux overnight. The mixture was neuttalized with acid, then exttacted with diethyl ether. The solvent was dried (MgSO4) and removed under vacuum to give the title compound (2.01 g)
Step 276c. 7-acetyl-4-methyl-2H-4H-benzo-l,4-oxazin-3-one
The compound from Step 276b (2.01 g, 8.37 mmol) was dissolved in DMSO and treated with sodium ethoxide (8.4 mmol) and bromoacetic acid (1.40 g, 8.4 mmol) at room temperature overnight. The mixture was diluted with water and ether, and the title compound was isolated by filtration (0.48 g). MS (M+H), 206.
Step 276d. 4-amino-5-(3-bromophenyl)-7-(4-methyl-3-oxo-2H-H-benzo- 1 -oxazin-7- yl)pyridor2.3-dlpyrimidine Following the procedures of Example 244 Step c, except in step c first substituting the compound from Step 276c for the R4 reagent of Example 244 Step c, and secondly performing the condensation with ammonium acetate substituting dichloroethane as the solvent in place of the ethanol solvent in Example 244 step c, the title compound was prepared. MS (M+H), 462 (1 Br); IR (cm-1) 3500, 2800-3200, 1690, 1645, 1610, 1590, 1385, 1355.
Example 277 4-amino-5-(3-bromophenyl)-7-(2.2.4-trimethyl-3-oxo-2H-4H-benzo-1.4-oxazin-7- yl)pyrido[2,3-dlpyrimidine Step 277a. 7-acetyl-2.2.4-trimethyl-2H-4H-benzo-1.4-oxazin-3-one
The compound from Step 276b (2.25 g, 9 mmol) was dissolved in DMSO and tteated with sodium ethoxide (9 mmol) and 2-bromo-2-methylpropanoic acid (1.76 g, 9 mmol) at room temperature overnight. The mixture was diluted with water, and the mixture was exttacted with ether.ethyl acetate. The exttact was dried (MgSO4), the solvent was removed under vacuum, and the residue was purified by chromatography (silica gel) to give the title compound (1.33 g) MS (M+H), 234.
Step 277b. 4-amino-5-(3-bromophenyl)-7-(2,2,4-trimethyl-3-oxo-2H-4H-benzo-1.4- oxazin-7-yl)pyridor2.3-dlpyrimidine
Following the procedures of Example 244 Step c, except in step c first substituting the compound from Step 277a for the R4 reagent of Example 244 Step c, and secondly performing the condensation with ammonium acetate substituting dichloroethane as die solvent in place of the ethanol solvent in Example 244 step c, the title compound was prepared. MS (M+H), 490 (1 Br); IR (cm-1) 3450, 2900-3100, 1680, 1645, 1610, 1515, 1385, 1365, 1 165.
Example 278 4-anτino-5-cvclohexyl-7-(4-(2-dimethylamino)ethyl)-2H-4H-benzo-3-oxo-1.4-oxazin-7- yl)pyridor2.3-dlpyrimidine
Step 278a. l-(3-hvdroxy-4-(2-(dimethylamino)ethyl)phenyl)-ethanone
A sample of 6-acetyl-3-(dimethylaminoethyl)-2-benzoxazoUnone (from Example 275 Step b) was dissolved in acetone and treated with IM aqueous K2CO3 solution with heating at reflux overnight. The mixture was neuttalized with acid, then exttacted with diethyl ether. The solvent was dried (MgSO4) and removed under vacuum to give the title compound.
Step 278b. 7-acetyl-4-(dimethylamino)ethyl)-2H-4H-benzo- 1.4-oxazin-3-one
A sample of the compound from Step 278a (8.94 g, 32 mmol) was dissolved in DMSO and tteated with sodium ethoxide (32 mmol) and bromoacetic acid (5.34 g, 32 mmol) at room temperature for 2 days. The mixture was diluted with water then exttacted with ether. The extract was dried (MgSO4), the solvent was removed under vacuum, and the residue was purified by chromatography (silica gel) to give the title compound (1.94 g). MS (M+H), 263. Step 278c. 4-amino-5-cvclohexyl-7-(4-(dimethylamino)ethyl)-2H-4H-benzo-3-oxo-1.4- oxazin-7-yl)pyridor2.3-d1pyrimidine
Following the procedures of Example 244 Step c, except in step c first substituting l,l-dicyano-3-cyclohexylethene (prepared according to die method of Moison, et al. (Tetrahedron (1987), 43:537-542) by treating cyclohexane carboxaldehyde with malononitrile in the presence of finely powdered magnesium oxide in dichloromethane) for the R3 reagent of Example 244 Step c, and substituting the compound from Step 278b for the R4 reagent of Example 244 Step c, and also performing the condensation with ammonium acetate but also substituting dichloroethane as the solvent in place of the ethanol solvent in Example 244 step c, the tide compound was prepared. MS (M+H) 447; IR(cm-l) 3400, 2900, 1690, 1610, 1590, 1395.
Example 279
4-amino-5-(3-bromophenyl)-7-(5-(l-memylethyl)-2-pyridyl)pyrido[2.3-dlpyrimidine
Step 279a. l-(5-methvethyl-2-pyridyl)ethanone
A solution of 2-acetyl-5-bromopyridine (1.45 g, 7.9 mmol), 2-propenylttimethyltin (1.77 g, 8.7 mmol), Pd2(dba)3 (0.33 g, 0.36 mmol), and tti-2-furylphosphine (0.17 g,
0.72 mmol) in 25 mL of benzene was warmed at 60 °C for 4 hours. The reaction mixture was concenttated and the coupled product was purified by flash chromatography (1.22 g, 96
%). The product was dissolved in 25 mL of EtOH and the solution was purged with a stream of H2. 10% Palladium on charcoal (50 mg) in 0.5 mL of EtOH was added and the reaction mixture was stirred for 12 h under an armoshpere of H2. The reaction mixture was filtered and the resulting solution was concenttated under reduced pressure. The title compound, 2, ( 1.04 g, 84%) was isolated following flash chromatography.
Step 279b. 4-amino-5-(3-bromophenyl)-7-(5-( l-methylethyl)-2-pyridyl)pyridor2,3- dlpyrimidine
Following the procedures of Example 244 Step c, except in step c substituting the compound from Step 279a for the R4 reagent of Example 244 Step c, and performing the condensation with ammonium acetate and also substituting dichloroetfiane as the solvent in place of the ethanol solvent in Example 244 step c, the tide compound was prepared. MS (M+H) 421 (IBr); IR (cm-1) 3489, 2940, 1545, 1482, 1357.
Examples 280-281
Following the procedures of Example 244 Step c, except in step c substituting die compound shown below for the R4 reagent of Example 244 Step c, and performing the condensation with ammonium acetate and also substituting dichloroethane as the solvent in place of the ethanol solvent in Example 244 step c, the compounds shown in the table below were prepared.
Figure imgf000110_0001
Prepared as in Ex. 252b, except substituting moφholine for the bis(2- methoxyethyl)amine thereof.
** prepared by treatment of 5-acetyl-2-chloro-pyridine with moφholine in refluxing ethanol.
Example 282
4-amino-5-(3-bromophenyl)-7-(4-((N-formylanτino)methyl)phenyl)pyrido[2.3-dlpyrimidine
Step 282a. 4-cyanoacetophenone. acetal with 2.2-dimethylpropylene glycol
A sample of 4-cyanoacetophenone (4.35 g, 30 mmol) was dissolved in 150 mL of hexanes, and to this solution were added 2,2-dimethylpropylene glycol (3.44 g, 33 mmol) and a catalytic amount (10 mg) of p-toluene sulfonic acid. The reaction was heated overnight at reflux with a Dean-Stark trap, and an additional portion of glycol (33 mmol) was added. The reaction was continued for 3 hours, then cooled and the solvent was removed. The residue was dissolved in ethyl acetate, and this solution was washed with aqueous NaHCO3, water and brine, and dried over MgSO4. The solvent was removed under vacuum to give the title compound (7.46 g).
Step 282b. 4-(aminomethyl)acetophenone. acetal with 2.2-dimethylpropylene glycol
The compound from Step 282a (2.31 g, 10 mmol) was dissolved in ether (50 mL) and stirred with lithium aluminum hydride (0.76 g, 20 mmol) at ambient temperature overnight. The reaction was quenched with MgSO4»10 H2O, and the mixture was diluted with ether. The mixture was filtered, and the filtrate removed to give the tide compound.
Step 282c. l-(4-(BOC-aminomethyl)phenyl)ethanone The compound from Step 282b (1.18 g, 5 mmol) was dissolved in THF (20 mL), IN HCl (20 mL) was added, and the mixture was stirred for 2 days. The volatiles were removed under vacuum, the residue was dissolved in THF (20 mL), and d-tibutyl dicarbonate (2.18 g, 10 mmol) was added. The mixture was stirred at room temperature over a weekend. The solution was diluted with water, and the mixture was exttacted with ether and ethyl acetate. The organic extracts were dired (MgSO4), and the solvent was remove under vacuum to give the title compound.
Ste 282d. 4-amino-5-(3-bromophenyl)-7-(4-rN-formylamino)methyl)phenyl)pyrido[2.3- dlpyrimidine
Following the procedures of Example 244, except in step c substituting the compound from Step 282c for the R4 reagent of Example 244 Step c, and performing the condensation with ammonium acetate but also substituting dichloroethane as die solvent in place of the ethanol solvent in Example 244 step c, the tide compound was prepared. MS (M+H) 434 (1 Br); IR (cm-1) 3440, 2700-3150, 1635, 1580, 1380.
Example 283 4-amino-5-(3-bromophenyl)-7-(4-(l-(N-methylamino)-l-methylethyl)phenyl)pyridor2.3- dlpyrimidine
Step 283a. 4-(l -amino- l-methylethyl)acetophenone
CeCl3 (10 g, 34.9 mmol) was suspended in THF (60 mL), and the mixture was cooled to -78 °C. Methyl lithium (1.4 M, 2 mL) was added, and the mixture was stiπed for 20 minutes. Then the compound from Example 282 Step a, (4-cyanoacetophenone acetal with 2,2-dimethylpropylene glycol, 2.31 g, 10 mmol) in 2 mL of THF was added. After stirring for 4 hours, the mixture was allowed to warm to room temperature while stirring for 16 hours. The reaction was quenched with water and ammonium hydroxide, filtered, and the filtrate was exttacted with dichloromethane. The solution was dried (MgSO4), and the solvent was removed to give the tide compound.
Step 283b. 4-(l-(N-BOC- amino)- l-methylethyl)acetophenone
The compound from Step 283a (2.32 g, 8.77 mmol) was tteated sequentially with HCl and di-t-butyl dicarbonate according to the procedure of Example 282 Step c to give the title compound (1.60 g). MS (M+H) 278. Step 283c. 4-amino-5-(3-bromophenylV7-(4-(l-(N-formylamino)-l- methylethyl)phenyl)pyridor2.3-dlpyrimidine
Following the procedures of Example 244 Step c, except in step c substituting the compound from Step 283b for the R4 reagent of Example 244 Step c, and performing the condensation with ammonium acetate but also substituting dichloroetiiane as the solvent in place of the ethanol solvent in Example 244 step c, the tide compound was prepared. MS (M+H) 462 (1 Br); IR (cm-1) 3440, 1640, 1605, 1580, 1380.
Example 284
4-amino-5-(3-bromophenyl)-7-(4-( 1 -(N.N-dimethylamino)- 1 - methylethyl)phenyl)pyridor2.3-dlpyrimidine
Step 284a. 4-(l-(dimemylamino)-l-methylemyl)acetophenone The compound from Step 283a (1.18 g, 5 mmol) was dissolved in 5 mL formic acid, and 5 mL of formalin (37% ) was added. The mixture was heated at reflux for 4 hours, then cooled and neuttalized widi 2N Na3CO3. The mixture was exttacted with dichloromethane. The solution was dried (MgSO4), and the solvent was removed to give the title compound (0.94 g). MS (M+H) 462 (1 Br); IR (cm-1) 3520, 1640, 1610, 1580, 1375.
Examples 285-286 Following die procedures of Example 157, except substituting die appropriate reagents for the R3 and R4 reagents of Example 157 as indicated in the Table below, compounds of Examples 285-286 were prepared. For Example 286, treatment with aqueous HCl was omitted, and the free base was obtained.
Examples 285-286
Figure imgf000112_0001
286 4-amino-5-cyclohexyl- l,l-dicyano-3- l-(6-chloro-3- mp 240-242 °C. IR (cm- 7-(6-chloro-3- cyclohexylethene pyridyl)- 1) 3528, 3300, 3086, pyridyl)pyrido[2,3- ethanone 2936, 2853, 1645, 1590, 1575, 1565,1350. LRMS dlpyrimidine [M+H]+ m/z 340.
Examples 287-300 Following the procedures of Example 157, except substituting the appropriate R3 and R4 reagents as indicated in die Table below and replacing the formamide or formamidine acetate treatment with treatment with triethyl orthoformate at reflux in the presence of a catalytic amount of ammonium sulfate, followed by cooling to 25 °C and addition of excess ammonia in ethanol, compounds of Examples 287-300 were prepared. . After 24 hours, the precipitated amidine compound was filtered and washed with hexanes, then dried under vacuum. The amidine compound was then heated in 1,2-dichloroethane at reflux for 1-8 hours. The reaction mixture was cooled to room temperature and purified by chromatography, and die product was recrystallized if necessary. The treatment with aqueous HCl was omitted in some cases, and the free bases were obtained.
Examples 287-300
Figure imgf000113_0001
-I l l-
Figure imgf000114_0001
* The l,l-dicyano-3-cyclohexyledιene was prepared according to the method of Moison, et al (Tetrahedron (1987), 43:537-542) by treating cyclohexane carboxaldehyde witii malononitrile in the presence of finely powdered magnesium oxide in dichloromethane. The reagents for the following examples were prepared by this method substituting the compound shown below for the cyclohexane carboxaldehyde used to prepare the reagent of Example 290.
Example 292, tettahydropyran-4-carboxaldehyde;
Example 294, 2-ethylbutanaldehyde;
Example 295, cyclopentane carboxaldehyde;
Example 297, 3,5-dimethylcyclohexane carboxaldehyde;
Example 298, N-(phenylmethoxylcarbony)piperidine-4-carboxaldehyde (this material was prepared from N-(carbobenzyloxy)-4-(2-hydroxyethyl)piperidine (Brehm et al., Helv.Chim.Acta, 70; (1987), 1981-1987 by treatment with TEMPO (2,2,6,6-tetramethylpiperidinyloxy radical) and potassium bromide in dichloromethane at 0 °C to which was added commercial bleach (Clorox) containing sodium bicarbonate).
Examples 301-305
Following the procedures of Example 246, except in step (c) substituting the appropriate reagents for methylamine as indicated in die Table below to prepare the correct R4 reagent, and substituting die R3 reagent shown below for the R3 reagent of Example 246 step d, the compounds of Examples 301-305 were prepared. For Example 302 only, the condensation solvent was DMSO instead of etfianol and dimetiioxyethane.
Examples 301-305
Figure imgf000115_0001
Figure imgf000116_0001
Example 306 4-amino-5-cvclohexyl-7-(6-(4-acetvIpiperazinyl)-3-pyridyl)pyrido[2.3-dlpyrimidine A mixture of 679 mg (2 mmol) of the compound from Example 298 and 1.28 g (10 mmol) of N-acetylpiperazine in 5 mL of DMSO was heated at 110 °C for 5 hours. On cooling a precipitate was deposited, which was collected and washed with 20% metiianol and dried to give 647 mg of the product as orange flakes: IR (cm-1) 3522, 3306, 3110, 2925, 2854, 1670, 1650, 1586, 1506. LRMS [M+H]+ m/z 432.
Examples 307-322 Follwing the procedure of Example 306, except substituting the reagent shown in the table below for the N-acetylpiperazine of Example 306, the compounds shown in the table were prepared. The compounds were purified by HPLC chromatography.
Figure imgf000116_0002
Figure imgf000117_0001
Figure imgf000118_0001
Example 323 4-anτmo-5-(l-(2-bromophenyl)ethyl)-7-(l-memyl-5-indolyl)pyridor2.3-dlpyrimidine The procedures of Example 157 were followed, except substituting l',l'-dicyano-3- bromostyrene for the R3 reagent and l-(l-methyl-5-indolyl)-ethanone for the R4 reagent . After 24 hours, the precipitated amidine compound was filtered and washed with hexanes, then dried under vacuum. The amidine compound was tiien heated in 1,2-dichloroethane at reflux for 1-8 hours. The reaction mixture was cooled to room temperature and purified by chromatography, and the product was recrystallized if necessary. The treatment with aqueous HCl was omitted, and the free bases was obtained. IR (KBr) cπr 1 3500, 1578, 1500; MS m/z 431 (M+H)+.
Example 324 4-amino-5-(l-(2-bromophenyl)ethyl)-7-(l-methyl-2.3-dioxo-5-indolyl)pyrido[2.3- dlpyrimidine
The tide compound was prepared from the compound of Example 323 by oxidation with CrO3 in sulfuric acid. IR (microscope) 3471, 1765, 1500 cm"1; MS mlz 461(M+H)+. Examples 325-326 Following the procedures of Example 157, except substituting the appropriate R3 and R4 reagents as indicated in the Table below, compounds of Examples 325-326 were prepared. After 24 hours, the precipitated amidine compound was filtered and washed with hexanes, then dried under vacuum. The amidine compound was then heated in 1,2- dichloroediane at reflux for 1-8 hours. The reaction mixture was cooled to room temperature and purified by chromatography, and the product was recrystallized if necessary. The treatment with aqueous HCl was omitted in some cases, and the free bases were obtained.
Examples 325-326
Figure imgf000119_0001
Example 327
Following the procedures of Example 244 Step c, except in step c substituting the compound resulting from the reaction of 2-acetyl-5-chloropyridine in refluxing edianol with the precursor reagent compound (4-piperidinone ethylene ketal) shown below for the R4 reagent of Example 244 Step c, and substituting dichloroethane as the solvent in place of the ethanol solvent in Example 244 step c, the compound shown in the table below was prepared.
Figure imgf000119_0002
Example 328 4-ammo-5-(3-bromophenyl)-7-(6-(4-oxopiperidinyl)-3-pyridyl)pyrido[2.3-dlpyrimidine Treating the compound of Example 327 with dilute HCl, die title compound was prepared. IR (microscope) 3438, 3051, 1645, 1605, 1558, 1450, 1371, 1240 cm"l; MS mlz 475 (M+H)+.
Examples 329-331 Following the procedures of Example 244 Step c, except in step c substituting die compound resulting from the reaction of 2-acetyl-5-chloropyridine in refluxing etiianol with the precursor reagent compound shown below for the R4 reagent of Example 244 Step c, and substituting dichloroethane as the solvent in place of the ethanol solvent in Example 244 step c, the compounds shown in the table below were prepared.
Examples 329-331
Figure imgf000120_0001
Example 332 4-amino-5-(3-bromophenyl)-7-(6-(4,4-dioxothiomoφhohnyl)-3-pyridyl)pyrido[2,3- dlpyrimidine The compound of Example 331 was treated with 4-chloroperbenzoic acid in metiianol and dichloromethane to give the tide compound. IR (microscope) 3471, 1601, 1581, 1562, 1510, 1353, 1316, 1285, 1122 cm"1; MS mlz 511(M+H)+. Example 333 4-amino-5-(2-bromophenyl)-7-(6-moφholinyl-3-pyridyl)pyrido[2,3-d1pyrimidine
Step 333a. r,r-dievano-2-bromostyrene The tide compound was prepared by condensation of 2-bromobenzaldehyde with malononitrile and MgO in dichloromethane by the standard procedure of Broekhuis et al. {Reel J. R. Neth. Chem. Soc, 99: 6-12 (1980)).
Step 333b. 5-acetyl-2-moφholinylpyridine The title compound was prepared by the reaction of 5-acetyl-2-chloropyridine with moφholine in refluxing ethanol.
Step 333c. 4-(2-bromophenyl)-3-cvano-6-moφholinylpyridine-2-amine
The tide compound was prepared by condensation of r,l'-dicyano-2-bromostyrene with 5-acetyl-2-moφholinylpyridine and ammonium acetate in dichloroethane at reflux. After the reaction was complete (TLC), the mixture was cooled, and the solvent was removed. The residue was triturated with methanol to give the product
Step 333d. 4-amino-5-(2-bromophenyl)-7-(6-moφholinyl-3-pyridyl)pyrido[2.3- dlpyrimidine
A sample of 4-(2-bromophenyl)-3-cyano-6-moφholinylpyridine-2-amine was heated at 180-190 °C in formamide. The reaction was monitored by TLC, and when the reaction was complete the mixture was cooled to room temperature. The product was allowed to precipitate, then recovered by filtration and washed with water. Additional product was exttacted from the filtrate. The product was purified by column chromatography eluting with 10% MeOH/CH Cl2. IR (microscope) 3493, 1547, 1109cm" 1; MS mlz 464 (M+H)+.
Examples 334-336 FoUowing the procedures of Example 333, except in Step a substituting the precursor aldehyde reagent shown below for the 2- bromobenzaldehyde of Example 333 Step a, and carrying the product forward as in procedures 333 Stepbs b-d, the compounds shown in the table below were prepared. Examples 334-336
Figure imgf000122_0001
Example 337 4-arnino-5-(3-bromophenyl)-7-(5-chloro-6-moφhoUnyl-3-pyridyl)pyrido[2.3-dlpyrimidine
Following the procedures of Example 333, except in Step a substituting 3- bromobenzaldehyde for the 2-bromobenzaldehyd, in Step b substituting 5-acety 1-2,3- dichloropyridine for the 5-acetyl-2-chloropyridine to give 5-acetyl-3-chloro-2- moφholinylpyridine, and substituting 5-acetyl-3-chloro-2-moφholinylpyridine for the 5- acetyl-2-moφhohnylpyridine in step c, then the carrying the product forward as in Example 333 Step d, the title compound was prepared. IR (microscope) 3493, 1635, 1585, 1555, 1492, 1340, 1241, 1113 cm"1; MS mlz 497 (M+H)+.
Example 338 4-anτino-5-(3-bromophenyl)-7-(6-(N-oxidomoφholinyl)-3-pyridyl)pyrido[2.3-d1pyrimidine The tide compound was prepared by treating die compound of Example 134 witii hydrogen peroxide in acetic acid according to standard procedures. IR (microscope) 3486, 1579, 1552, 1353, 1121. 1020 cm"1; MS mlz 479 (M+H)+.
Example 339 4-amino-5-(3-bromophenvI)-7-(6-(N-(2-hvdroxyethoxyedιyl)amino)-3-pyridyl)pyridor2.3- dlpyrimidine
Step 339a. .r-dicvano-3-bromostyrene
The tide compound was prepared by condensation of 3-bromobenzaldehyde with malononitrile and MgO in dichloromethane by the standard procedure of Broekhuis et al. {Reel J. R. Neth. Chem. Soc, 99: 6-12 (1980)).
Step 339b. 5-acetyl-2-(N-(2-ethoxyethyl)amino)pyridine
The tide compound was prepared by the reaction of 5-acetyl-2-chloropyridine with 2-edιoxyetiιylamine in refluxing ethanol.
Step 339c. 4-(3-bromophenyl)-3-cvano-6-(N-(2-ethoxyethyl)amino)pyridine-2-amine The tide compound was prepared by condensation of ,l'-dicyano-2-bromostyrene with 5-acetyl-2-moφholinylpyridine and ammonium acetate in dichloroethane at reflux. After the reaction was complete (TLC), the mixture was cooled, and the solvent was removed. The residue was triturated witii methanol to give the product.
Step 339d. 4-amino-5-(2-bromophenyl)-7-(6-(N-(2-edιoxyethyl)amino)-3- pyridyl)pyrido[2.3-dlpyrimidine
A sample of the compound from Step 239d was tteated according to the procedure of Example 233d to give the title compound. IR (microscope) 3301, 1610, 1579, 1543, 1346, 1304, 1120 cm"1; MS m/z 481 (M+H)+.
Example 340 4-amino-5-(3-bromophenyl)-7-(6-(N-(2-hvdroxyethoxyethyl)-N-formylaιτrino)-3- pyridyl)pyridor2,3-dlpyrimidine This compound was isolated by chromatography as a product of the reaction described in Example 239 Step d. IR (microscope) 3306, 1679, 1596, 1577, 1548, 1493, 1352, 1125 cm-1; MS m/z 509 (M+H)+. Example 341 4-amino-5-(3-bromophenv -7-(6-(N-(2-hvdroxyethoxyethyl)-3-pyridyl-N- oxide)pyridor2.3-dlpyrimidine The tide compound was prepared by treating the compound of Example 341 with hydrogen peroxide in acetic acid according to standard procedures. IR (microscope) 3296, 1628, 1560, 141 1, 1353 cm' 1; MS mlz 497 (M+H)+.
Example 342 4-amino-5-(3-bromophenyl)-7-(6-(3-hydroxy)moφholinyl)-3-pyridyl)pyrido[2.3- dlpyrimidine
The tide compound was prepared from the compound of Example 328 by reduction witii (Lithium Aluminum Hydride, and subsequent workup acccording to standard procedures). IR (microscope) 3349, 1510, 1116 cm" 1; MS mlz 478 (M+H)+.
Example 343 l-(5-(4-ammo-5-(3-bromophenyl)pyrido[2,3-dlpyrimidin-7-yl)-2-pyridyl)-piperidine-4- phosphate, disodium salt The title compound was prepared from the compound of Example 342 by treatment with POCI3, and subsequent workup acccording to standard procedures. IR (microscope) 3498, 1500, 1444 cm"1; MS mlz 556 (M+H)+.
Example 344 4-amino-5-(3-bromophenyl)-7-(6-(2-hvdroxy)moφholinyl)-3-pyridyl)pyridor2.3- dlpyrimidine The tide compound was prepared from the compound of Example 339 by oxidation of the free hydroxy group to an aldehyde with TEMPO reagent. During workup of the mixture, the compound self-condensed to give die tide compound. IR (microscope) cm- 1; MS mlz 492 (M+CH3θH-H2θ)+.
Example 345
4-arrdno-5-(3-bromophenyl)-7-(4-methylenylpiperim^yl)-3-pyridyl)pyrido[2.3-dlpyrirnidine The title compound was prepared from the compound of Example 328 by treatment with methyl triphenylphosphine bromide at -78 °C in DMSO. After quenching and warming the mixture to room temperature, the title compound was exttacted, then purified by chromatography. IR (microscope) 3055, 1602, 1559, 1508, 1440, 1344, 1174 cm"1; MS mlz 473 (M+H)+. Example 346 4-amino-5-(3-bromophenyl)-7-(4-hvdroxy-4-(hvdroxymethvDpiperidinyl)-3- p yrid yl)p yridor∑.3 -dlpyrimidine The title compound was prepared from the compound of Example 345 by treatment with Osθ4 in DMSO at room temperature. After quenching, the title compound was extracted, then purified by chromatography. IR (microscope) 3304, 1603, 1580, 1557, 1509, 1352, 1241 cm" 1; MS mlz 507 (M+H)+.
Example 347 4-amino-5-(3-bromophenyl)-7-(6-(4,4-ethylenedioxypiperidinyl)-3-pyridyl)pyridor2.3- dlpyrimidine
Step 347a. l.l-dicvano-3-cvclohexylethene
The l,l-dicyano-3-cyclohexylethene was prepared according to the method of Moison, et al. (Tetrahedron (1987), 43:537-542) by tteating cyclohexane carboxaldehyde with malononitrile in the presence of finely powdered magnesium oxide in dichloromethane.
Step 347b. 2-acetyl-5-(4,4-ethylenedioxypiperidinyl)pyridine
A sample of 2-acetyl-5-chloropyridine was treated in refluxing ethanol with 4- piperidinone ethylene ketal to give the tide compound.
Step 347c. 4-amino-5-cvclohexyl-7-(6-(4.4-ethylenedioxypiperidinyl)-3- pyridyl)pyridor2.3-d1pyrimidine
Following the procedures of example 339 Step c, except substituting the compounds from Step 347a and 347b for the compounds of Steps 339a and 339b, and carrying the product forward according to the procedure of example 339 Step d, the tide compound was prepared. IR (microscope) 2929, 1604, 1585, 1557, 1514, 1426, 1344, 1238, 1106 cm" 1; MS mlz AA1 (M+H)+.
Example 348
4-arnmo-5-cvclohexyl-7-(6-(4-oxo-piperidinyl)-3-pyridyl)pyrido[2.3-dlpyrimidine The title compound was prepared from the compound of Example 347 by treatment with dilute HCl in etiianol. The title compound was purified by chromatography. IR (microscope) 2928, 1715, 1603, 1585, 1559, 1507, 1344, 1226 cm"1; MS mlz 403 (M+H)+. Example 349 4-ammo-5-cvclohexyl-7-(6-(4-me ylenylpiperidinyl)-3-pyridv pyridor2.3-dlp iiιτιidirie The tide compound was prepared from the compound of Example 348 by treatment with methyl triphenylphosphine bromide at -78 °C in DMSO. After quenching and warming the mixture to room temperature, the title compound was exttacted, then purified by chromatography. IR (microscope) 2929, 1604, 1584, 1557, 1506, 1342, 1239 cm" 1; MS mlz 401 (M+H)+.
Example 350
4-N-(iminomethyl)amino-5-cvclohexyl-7-(6-dimethylamino-3-pyridyl)pyrido[2.3- dlpyrimidine This compound was isolated from die reaction mixture of Example 293 as a side product: IR (cm-1) 3289, 3089, 2930, 2841, 1674, 1606, 1559, 1531. LRMS [M+H]+ m/z 376.

Claims

WHAT IS CLAIMED IS:
1 . A method for inhibiting adenosine kinase by administering a compound, or a pharmaceutically acceptable salt or amide thereof, having the formula
Figure imgf000127_0001
wherein
R1 and R are independently selected from H, loweralkyl, Ci-CβalkoxyCi- Cβalkyl, arylCι-C6alkyl, -C(O)Cι-C6alkyl, -C(O)aryl, -C(O)heterocyclic or may join together with the nittogen to which they are attached to form a 5-7 membered ring optionally containing 1-2 additional heteroatoms selected from O, N or S;
R3 is selected from the group consisting of loweralkyl, loweralkenyl, loweralkynyl, cycloalkyl, aryl, arylalkyl, heteroaryl, heterocyclic group, heteroarylalkyl or heterocycloalkyl wherein the heteroaryl and heterocyclic groups are linked directly or indirectly by a ring carbon; R4 is selected from the group consisting of loweralkyl, loweralkenyl, loweralkynyl, cycloalkyl, aryl, arylalkyl, heteroaryl, heterocyclic group heteroarylalkyl or heterocycloalkyl; and a dashed line — indicates that a double bond is optionally present provided that proper valencies are maintained, in vitro or to a mammal.
2. A method of inhibiting adenosine kinase according to Claim 1 comprising administering a compound of formula I
Figure imgf000127_0002
wherein
R1 and R are independently selected from H, loweralkyl, arylCi-C6alkyl, - C(O)Cι-C6alkyl, -C(O)aryl, -C(O)heterocyclic or may join together with the nittogen to which they are attached to from a 5-7 membered ring optionally containing 1-2 additional heteroatoms selected from O, N or S;
R and R^ are independently selected from the group consisting of: Cι-C6alkyl,
C2-C6alkenyl, C2-C6alkynyl, C3-C8cycloalkyl, heteroarylCo-Cόalkyl or substituted heteroarylC()-C6alkyl, optionally substituted cycloalkyl, arylCo-Cόalkyl or substituted arylCo-Cόalkyl, heteroarylC2-C6alkenyl or substituted heteroarylC2-C6alkenyl, arylC2-C6alkenyl or substituted arylC2-C6alkenyl, heteroarylC2-C6alkynyl or substituted heteroarylC2-C6alkynyl, arylC2-C6alkynyl or substituted arylC2-C6alkynyl wherein the 1-4 heteroaryl or aryl substituents are independently selected from halogen, oxo, CO2R-\ cyanoCi-Cβalkyl, heteroarylCo-Cβalkyl, heterocyclicCo-C6alkyl, Cι-C6alkyloxy, Cι-C6alkyloxyCι-C6alkyl, arylCθ-C6alkyl, arylCi-Cόalkyloxy, R5R6NC(O), cyano, C2-C6alkenyl, C2-C6alkynyl, Ci-CtøalkyL C2-C6alkenyldialkylmalonyl, CF3, HO-, Ci-
C6alkyloxyCι-C6alkyloxy, Cι-C6alkylSOn wherein n is 1-2, Ci- Cόalkylthio, Cι-C6alkylacryl, CF3O, CF3, Cι-C4alkylenedioxy, C\- Cβalkylacryl, R5R6N(CO)NR5, N-formyl(heterocyclic), NO2, NR5R6 )- C6alkyl, (R5θ)(R6θ)-P(O)-Co-C6alkyl, wherein R5 and R^ are independently selected from H, Ci-Cβalkyl,
HC(O), Cι-C6alkyloxyCι-C6alkyl, Cι-C6alkyloxy, Ci- C6alkylC(O), CF3C(O), NR7R8Cι-C6alkyl, phthalimidoCi- C6C(O), Cι-C6alkylSOn where n is 1-2, CNCi-Cβalkyl, R7R8NC(O)NR7-, heteroaryl, NR7R8Cι-C6alkylC(O), C\- C6alkyloxycarbamidoCι-C6alkyl, wherein R7 and R8 are independently selected from tiiose variables identified for R^ and R^ or R^ and R6 or R7 and R8 may join together with the nittogen atom to which they are attached to form a 5-7 membered unsubstituted or substituted ring optionally containing 1-3 additional heteroatoms selected from O, N or S wherein the substituents are selected from Ci-C alkyl and a dashed line — indicates a double bond is optionally present.
3. A method according to Claim 2 wherein the method of inhibiting adenosine kinase comprises administering a pharmaceutically effective amount of a compound of formula π
Figure imgf000129_0001
wherein R -R8 and n are as defined above to a patient in need of treatment tiiereof.
4. A memod according to Claim 3 wherein R4 is selected from the group consisting of: phenyl; thiophene-2-yl; 3-methyl-2-oxobenzoxazolin-6-yl; 2-(dimethylamino)- 5-pyrimidinyl; 2-(N-formyl-N-methyl amino)-5-pyrimidinyl; 2-(N-methoxyethyl-N-methyl amino)-5-pyrimidinyl; 2-(N-methylamino)5-pyrimidinyl; 2-( 1 -moφholmyl)-5-pyrimidinyl; 2-(l-pyπoUdinyl)-5-pyrimidinyl; 2-dimemylamino-5-pyrimidinyl; 2-furanyl; 2- oxobenzoxazolin-6-yl; 2-pyridyl; 3-(dimedιylamino)phenyl; 3-amino-4-methoxyphenyl; 3- bromo-4-(dimethylamino)phenyl; 3-methoxyphenyl; 3-methyl-4-(N-acetyl-N- methylamino)phenyl; 3-methyl-4-(N-formyl-N-methylamino)phenyl; 3-methyl-4-(N-methyl- N-(trifluoroacetyl)amino)phenyl; 3-methyl-4-(N-methylamino)phenyl; 3-medιyl-4- pyπolidinylphenyl; 3-pyridyl; 3,4-dichlorophenyl; 3,4-methylenedioxyphenyl; 3,4,5- trimedioxyphenyl; 4-(acetylamino)phenyl; 4-(dimedιylamino)-3-fluorophenyl; 4- (dimethylamino)phenyl; 4-(imidazol-l-yl)phenyl; 4-(methylthio)phenyl; 4- (moφhoUnyl)phenyl; 4-(N-(2-(dimemylamino)ethyl)amino)phenyl; 4-(N-(2- methoxyethyl)ammo)phenyl; 4-(N-acetyl-N-methylamino)phenyl; 4-(N-ethyl-N- formylamino)phenyl; 4-(N-ethylamino)phenyl; 4-(N-formyl-N-(2- methoxyethyl)amino)phenyl; 4-(N-isopropylamino)phenyl; 4-(N-methyl-N-((2- dimethylamino)ethyl)amino)phenyl; 4-(N-methyl-N-(2-(N- phthahmidyl)acetyl)amino)phenyl; 4-(N-methyl-N-(2-cyano)ethylamino)phenyl; 4-(N- methyl-N-(2-methoxyedιyl)amino)phenyl; 4-(N-methyl-N-(3- medιoxy)propionylamino)phenyl; 4-(N-methyl-N-acetylamino)phenyl; 4-(N-methyl-N- formylamino)phenyl; 4-(N-methyl-N-ttifluoroacetylamino)phenyl; 4-(N- moφholinyl)phenyl; 4-(thiophene-2-yl)phenyl; 4-(ureido)phenyl; 4-(2- (dimethylamino)acetylamino)phenyl; 4-(2-methoxy)acetylamino)ethyl)amino)phenyl; 4-(2- methoxy)ethoxyphenyl; 4-(2-oxo-3-oxazoUdinyl)phenyl; 4-(4-methoxy-2-butyl)phenyl; 4- (4-methylpiperidinyl)phenyl; 4-(5-pyrimidinyl)phenyl; 4-aminophenyl; 4-bromophenyl; 4- butoxyphenyl: 4-carboxamidophenyl; 4-chlorophenyl; 4-cyanophenyl; 4- diethylaminophenyl; 4-diethylmalonylallylphenyl; 4-dimethylaminophenyl; 4- ethoxyphenyl; 4-ethylphenyl; 4-fluorophenyl; 4-hydroxyphenyl; 4-imidazolylphenyl; 4- iodophenyl; 4-isopropylphenyl; 4-methoxyphenyl; 4-methylaminophenyl; 4- methylsulfonylphenyl; 4-moφholinylphenyl; 4-N-(2-(dimethylamino)ethyl)-N- formylamino)phenyl; 4-N-(3-methoxypropionyl)-N-isopropyl-amino)phenyl; 4-N-ethyl-N- (2-methoxyethyl)amino)phenyl; 4-N-formylpiperazinylphenyl) 4-nittophenyl; 4- piperidinylphenyl; 4-(3-pyridyl)phenyl; 4-pyrroUdinylphenyl; 4-t-butylacrylphenyl; 5- (dimethylamino)thiophene-2-yl; 5-amino-2-pyridyl; 5-dimethylamino-2-pyrazinyl; 3- dimethylaminopyridazin-6-yl; 5-dimethylamino-2-pyridyl; 5-pyrimidinylphenyl; 6-(N- methyl-N-formylamino)-3-pyridinyl; 6-(N-methyl-N-methoxyethylamino)-3-pyridinyl; 6-(2- oxo-3-oxazolidinyl)-3-pyridinyl; 6-dimethylamino-3-pyridinyl;
Figure imgf000130_0001
6- moφhoUnyl-3-pyridinyl; 6-pyrrolidinyl-3-pyridinyl; 6-(2-propyl)-3-pyridinyl; and (4- formylamino)phenyl.
5. A method according to Claim 3 wherein R3 is selected from the group consisting of (thiophene-2-yl)methyl; (thiophene-3-yl)meuiyl; butyl; cycloheptyl; pentyl; thiophene-2-yl; l-(3-bromophenyl)ethyl; 2-(N-phenylmethoxycarbonyl)aminophenyl; 2-(3- bromophenyl)ethyl; 2-(3-cyanophenyl)methyl; 2-(4-bromophenyl)ethyl; 2-(5-chloro-2- (thiophen-3-yl)phenyl; 2-bromophenyl; 2-furanyl; 2-methylpropyl; 2-phenylethyl; phenylmethyl; 2,3-dimethoxyphenyl; 2,3-methylenedioxyphenyl; 3-(furan-2-yl)phenyl; 3- (thiophen-2-yl)phenyl; 3-(2-pyridyl)phenyl; 3-(3-methoxybenzyl)phenyl; 2-(3- aminopropynyl)phenylmethyl; 3-benzyloxyphenyl; 3-bromo-4-fluorophenyl; 3-bromo-5- iodophenyl; 3-bromo-5-methoxyphenyl; 3-bromophenyl; 3-bromophenyl)methyl; 3- carboxamidophenyl; 3-chlorophenyl; 3-cyanophenyl; 3-diethylmalonylallylphenyl; 3- dimethylaminophenyl; 3-ethoxyphenyl; 3-fluoro-5-trifluoromethylphenyl; 3-fluorophenyl; 3- hydroxyphenyl; 3-iodophenyl; 3-methoxyethyoxyphenyl; 3-methoxyphenyl; 3- methylphenyl; 3-methylsulfonylphenyl; 3-methylthiophenyl; 3-t-butylacrylphenyl; 3- trifloromediyoxyphenyl; 3-trifluoromethylphenyl; 3-vinylpyridinylphenyl; 3,4- dichlorophenyl; 3,4-dimethoxyphenyl; 3,4-methylenedioxyphenyl; 3,4,5-trimethoxyphenyl; 3,5-di(trifluoromethyl)phenyl; 3,5-dibromophenyl; 3,5-dichlorophenyl; 3,5- dimethoxyphenyl; 3,5-dimethylphenyl; 4-(2-propyl)phenyl; 4-(2-propyl)oxyphenyl; 4- benzyloxyphenyl; 4-bromophenyl; 4-bromothiophene-2-yl; 4-butoxyphenyl; 4- dimethylaminophenyl; 4-fluoro-3-trifluoromethylphenyl; 4-methoxyphenyl; 4- neopentylphenyl; 4-phenoxyphenyl; 5-bromothiophene-2-yl; 5-cyclohexyl; 5-cyclopropyl; 5-hexyl; 5-methyl; 5-phenyl; (2-bromo-5-chlorophenyl)methyl; (2-bromophenyl)methyl; and (5-chloro-2-(3-medιoxyphenyl)phenyl)methyl.
6. A method according to Claim 1 wherein the compound is selected from:
4-amino-5- 4-dimethylanιinophenyl)-7-(4-bromophenyl)pyrido[2,3-dlpyrimidine; 4-amino-5- 4-dimemylaminophenyl)-7-(4-dimethylaminophenyl)pyrido[2,3- dlpyrimidine; 4-amino-5- 4-methoxyphenyl)-7-(4-dimethylaminophenyl)pyrido[2,3-d]pyrimidine;
4-amino-5- 4-dimethylaminophenyl)-7-(4-medιoxyphenyl)pyrido[2,3-d]pyrimidine; 4-amino-5- 4-(2-propyl)phenyl)-7-(4-methoxyphenyl)pyrido[2,3-d]pyrimidine; 4-amino-5- 4-neopentylphenyl)-7-(4-memoxyphenyl)pyrido[2,3-d]pyrimidine; 4-amino-5- 4-butyloxyphenyl)-7-(4-methoxyphenyl)pyrido[2,3-d]pyrimidine; 4-amino-5- 4-memox3φhenyl)-7-(4-bromophenyl)pyrido[2,3-dlpyrimidine;
4-amino-5- 4-(2-propyl)oxyphenyl)-7-(4-memoxyphenyl)pyrido[2,3-d]pyrimidine; 4-amino-5- 4-butoxyphenyl)-7-(4-N-formylpiperazinylphenyl)pyrido[2,3- dlpyrimidine;
4-amino-5- 4-benzyloxyphenyl)-7-(4-medιoxyphenyl)pyrido[2,3-dlpyrimidine; 4-amino-5- 4-phenoxyphenyl)-7-(4-methoxyphenyl)pyrido[2,3-d]pyrimidine;
4-amino-5- 4-(2-propyl)phenyl)-7-(4-diethylmalonylallylphenyl)pyrido[2,3- dlpyrimidine;
4-amino-5- 4-(2-propyl)phenyl)-7-(4-t-butylacrylphenyl)pyrido[2,3-dlpyrimidine;
4-amino-5- 3-bromophenyl)-7-(4-dimethylarrdnophenyl)pyrido[2,3-d]pyrimidine; 4- amino- 5- 3,4-dimethoxyphenyl)-7-(4-dimethylaminophenyl)pyrido[2,3- dlpyrimidine;
4-amino-5- 3-t-butylacrylphenyl)-7-(4-dimethylaminophenyl)pyrido[2,3- dlpyrimidine;
4-amino-5- 3-memoxyphenyl-7-(4-dimethylarrdnophenyl)pyrido[2,3-d]pyrimidine; 4-amino-5- 3 ,5 -dimethoxyphenyl-7- (4-dimethylaminophenyl)pyrido [2,3 - dlpyrimidine;
4-amino-5- 3-diethylmalonylallylphenyl)-7-(4-dimemylaminophenyl)pyrido[2,3- dlpyrimidine;
4-amino-5- 3-vinylpyridinylphenyl)-7-(4-dimethylaminophenyl)pyrido[2,3- dlpyrimidine;
4-amino-5- 3-trifluoromethylphenyl)-7-(4-dimethylaminophenyl)pyrido[2,3- dlpyrimidine;
4-amino-5- 3-carboxamidophenyl)-7-(4-dimethylaminophenyl)pyrido[2,3- dlpyrimidine; 4-amino-5- 3-cyanophenyl)-7-(4-dimethylaπιkophenyl)pyrido[2,3-dlpyrimidine;
4-amino-5- 3-benzyloxyphenyl)-7-(4-dimethylarninophenyl)pyrido[2,3-dlpyrimidine; 4-amino-5- 3-methoxyphenyl)-7-(4-methoxyphenyl)pyrido[2,3-dlpyrimidine; 4- amino- 5- 3-bromophenyl)-7-(4-butoxyphenyl)pyrido[2,3-dlpyrimidine;
4-amino-5- 3-(2-pyridyl)phenyl)-7-(4-dimethylaminophenyl)pyrido[2,3- dlpyrimidine;
4-amino-5- 3-methylphenyl)-7-(4- ^ethylarninophenyl)pyrido[2,3-dlpyrimidine; 4-amino-5- 3-chlorophenyl)-7-(4-dimethylaminophenyl)pyrido[2,3-dlpyrimidine; 4-amino-5- 3-fluorophenyl)-7-(4-dimethylanιinophenyl)pyrido[2,3-d]pyrimidine; 4-amino-5- 3-bromophenyl)-7-(4-methoxyphenyl)pyrido[2,3-dlpyrirnidine; 4-amino-5- 3-memoxyphenyl)-7-(4-bromophenyl)pyrido[2,3-dlpyrimidine;
4-amino-5- 3-bromophenyl)-7-phenylpyrido [2,3-dlpyrimidine; 4-amino-5- 3-bromophenyl)-7-(4-ethylphenyl)pyrido[2,3-dlpyrimidine; 4-amino-5- 3-bromophenyl)-7-(4-bromophenyl)pyrido[2,3-d]pyrimidine; 4-amino-5- 3-bromophenyl)-7-(4-cyanophenyl)pyrido[2,3-d]pyrimidine; 4-amino-5- 3-bromophenyl)-7-(4-hydroxyphenyl)pyrido[2,3-dlpyrimidine;
4-amino-5- 3-iodophenyl)-7-(4-dimethylarmnophenyl)pyrido[2,3-d]pyrimidine;
4-amino-5- 3-ethoxyphenyl)-7-(4-dimethylarnJnophenyl)pyrido[2,3-dlpyrimidine;
4-amino-5- 3-trifloromethyoxyphenyl)-7-(4-dimethylaminophenyl)pyrido[2,3- dlpyrimidine; 4-amino-5- 3,5-dichlorophenyl)-7-(4-dimethylaminophenyl)pyrido[2,3-d]pyrimidine;
4-amino-5- 3-bromo-4-fluorophenyl)-7-(4-dimethylaminophenyl)pyrido[2,3- dlpyrimidine;
4-amino-5-1 3-hydroxyphenyl)-7-(4-dimethylaminophenyl)pyrido[2,3-dlpyrimidine; 4-amino-5- 3-bromophenyl)-7-(4-moφholinylphenyl)pyrido[2,3-d]pyrimidine; 4-amino-5-1 3-bromophenyl)-7-(4-piperidinylphenyl)pyrido[2,3-d]pyrimidine;
4-amino-5- 3-bromophenyl)-7-(4-(imidazol-l-yl)phenyl)pyrido[2,3-dlpyrimidine; 4-amino-5- 3-bromophenyl)-7-(4-chlorophenyl)pyrido[2,3-d]pyrimidine; 4-amino-5- 3-bromophenyl)-7-(4-isopropylphenyl)pyrido[2,3-dlpyrimidine; 4-amino-5- 3-bromophenyl)-7-(4-trifluorophenyl)pyrido[2,3-dlpyrimidine; 4-amino-5- 3-bromophenyl)-7-(4-diedιylaminophenyl)pyrido[2,3-d]pyrimidine;
4-amino-5- 3-bromophenyl)-7-(3,4,5-trimethoxyphenyl)pyrido[2,3-d]pyrimidine; 4-amino-5- 3-(3-memoxybenzyl)phenyl)-7-(4-dimethylaminophenyl)pyrido[2,3- dlpyrimidine;
4-amino-5-' 3-memoxyethyoxyphenyl)-7-(4-dimethylaminophenyl)pyrido[2,3- dlpyrimidine;
4-amino-5- 3,4-methylenedioxyphenyl)-7-(4-dimethylaminophenyl)pyrido[2,3- dlpyrimidine;
4-amino-5- 3-bromophenyl)-7-(4-ethoxyphenyl)pyrido[2,3-dlpyrimidine; 4-amino-5- 3-bromophenyl)-7-(2'-thiophene)pyrido[2,3-d]pyrimidine; 75 4-amino-5- 3-bromophenyl)-7-(4-fluorophenyl)pyrido[2,3-dlpyrimidine;
4-amino-5- 3-dime ylaminophenyl)-7-(4-dimethylaminophenyl)pyrido[2,3- dlpyrimidine;
4-amino-5-phenyI-7-(4-dimemylaminophenyl)pyrido[2,3-dlpyrimidine;
4-amino-5- 3,4,5-tτimethoxyphenyl)-7-(4-dimethylaminophenyl)pyrido[2,3- 80 dlpyrimidine;
4-amino-5- 3-bromophenyl)-7-(4-nittophenyl)pyrido[2,3-d]pyrimidine; 4-amino-5- 3-bromophenyl)-7-(4-iodophenyl)pyrido[2,3-d]pyrimidine; 4-amino-5- 3-bromophenyl)-7- (3 ,4-methylenedioxyphenyl)pyrido [2,3-d]pyrimidine; 4-amino-5- thiophen-2-yl)-7-(4-moφholinylphenyl)pyrido [2,3-dlpyrimidine;
85 4-amino-5- 3,5-dimethoxyphenyl)-7-(thiophen-2-yle)pyrido [2,3-d]pyrimidine; 4-amino-5- 3-bromophenyl)-7-(4-carboxamidophenyl)pyrido[2,3-dlpyrimidine; 4-amino-5- 3-bromophenyl)-7-(4-(2-methoxy)ethoxyphenyl)pyrido[2,3- dlpyrimidine;
4-amino-5- 3,5-dimethoxyphenyl)-7-(4-moφholinylphenyl)pyrido[2,3-dlpyrimidine;
90 4-amino-5- 3-trifiuoromethylphenyl)-7-(thiophene-2-yl)pyrido [2,3-dlpyrimidine; 4-amino-5- 3-bromophenyl)-7-(4-aminophenyl)pyrido[2,3-dlpyrimidine; 4-amino-5- 3-bromo-4-fluorophenyl)-7-(thiophene-2-yl)pyrido [2,3-d]pyrimidine; 4-amino-5- 3-bromo-4-fluorophenyl)-7-(2-furanyl)pyrido [2,3-djpyrimidine; 4-amino-5- 3,5-dimethoxyphenyl)-7-(4-iodophenyl)pyrido[2,3-dlpyrimidine;
95 4-amino-5- 3,5-dirnethoxyphenyl)-7-(4-imidazolylphenyl)pyrido[2,3-d]pyrimidine; 4-amino-5- 3,5-dimethoxyphenyl)-7-(4-(thiophene-2-yl)phenyl)pyrido[2,3- dlpyrimidine;
4-amino-5- 3,5-dimethoxyphenyl)-7-(4-(3-pyridyl)phenyl)pyrido[2,3-dlpyrimidine; 4-amino-5- 3-bromophenyl)-7-(4-(4-methylpiperidinyl)phenyl)pyrido[2,3-
100 dlpyrimidine;
4-amino-5- 3-bromophenyl)-7-(4-pyπolidinylphenyl)pyrido[2,3-dlpyrimidine; 4-amino-5- 4-bromomiophene-)-7-(4-dimeΛylaminophenyl)pyrido[2,3-d]pyrimidine; 4-amino-5- 4-bromothiophene-2-yl)-7-(4-moφholinylphenyl)pyrido[2,3- dlpyrimidine; 105 4-moφholinyl-5-(3-bromophenyl)-7-(4-dimemylaminophenyl)pyrido[2,3- dlpyrimidine;
4-amino-5-(5-bromothiophene-2-yl)-7-(4-moφhohnylphenyl)pyrido[2,3- dlpyrimidine;
4-ammo-5-(4-bromophenyl)-7-(4-dimethylaιτdnophenyl)pyrido[2,3-dlpyrimidine; 110 4-amino-5-(3-bromophenyl)-7-(4-(acetylamino)phenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(4-dimethylaιτιinophenyl)pyrido[2,3-dlpyrimidine; 4-ammo-5-(3,5-dimemoxyphenyl)-7-(5-pyrimidinylphenyl)pyrido[2,3-dlpyrimidiFAξ 4-(4-fluorophenyl)amino)-5-(3-bromophenyl)-7-(4- dimethylarmrιophenyl)pyrido[2,3-d]pyrimidine;
115 4-amino-5- 4-bromodιiophene-2-yl)-7-(4-pyrrolidinylphenyl)pyrido[2,3- dlpyrimidine;
4-amino-5- 4-bromothiophene-2-yl)-7-(thiophene-2-yl)pyrido[2,3-dlpyrimidine; 4-amino-5- 3-bromophenyl)-7-(5-(dimethylamino)thiophene'-2-yl)pyrido[2,3- dlpyrimidine; 120 4-amino-5- 3-bromo-5-iodophenyl)-7-(4-(dimethylamino)phenyl)pyrido[2,3- dlpyrimidine;
4-amino-5- 3,5-di(ttifluoromedιyl)phenyl)-7-(4-(dimethylamino)phenyl)pyrido[2,3- dlpyrimidine;
4-amino-5- 3,5-di(ttifluoromethyl)phenyl)-7-(4-moφhohnylphenyl)pyrido[2,3- 125 dlpyrimidine;
4-amino-5- 3,5-dibromophenyl)-7-(4-(dimethylamino)phenyl)pyrido[2,3- dlpyrimidine;
4-amino-5- 3,5-dibromophenyl)-7-(4-moφholinylphenyl)pyrido[2,3-d]pyrimidine; 4-amino-5- 4-bromothiophene-2-yl)-7-(4-(4-methylpiperidinyl)phenyl)pyrido[2,3- 130 dlpyrimidine;
4-amino-5- 3,5-dibromophenyl)-7-(4-(dimethylamino)phenyl)pyrido[2,3- dlpyrimidine;
4-amino-5- 3-bromophenyl)-7-(3-(dimethylaιrdno)phenyl)pyrido[2,3-d]pyrimidine; 4-amino-5- 3-bromophenyl)-7-(4-medιylsulfonylphenyl)pyrido[2,3-d]pyrimidine; 135 4-amino-5- 3-bromophenyl)-7-(3-methoxyphenyl)pyrido[2,3-dlpyrimidine;
4-amino-5- 3-bromophenyl)-7-(4-(methylthio)phenyl)pyrido[2,3-dlpyrimidine; 4-amino-5- 3-bromophenyl)-7-(3,4-dichlorophenyl)pyrido[2,3-d]pyrimidine; 4-amino-5- 3-bromophenyl)-7-(4-(N-methyl-N-formylamino)phenyl)pyrido[2,3- dlpyrimidine; 140 4-amino-5 3-bromophenyl)-7-(4-methylammophenyl)pyrido[2,3-d]pyrimidine;
4-amino-5- 3-bromo-4-fluorophenyl)-7-(4-meuiylsuifonylphenyl)pyrido[2,3- dlpyrimidine;
4-amino-5-' 3-bromophenyl)-7-(3-amino-4-methoxyphenyl)pyrido[2,3-dlpyrimidine; 4- amino- 5- 3-bromophenyl)-7-(3-bromo-4-(dimethylamino)phenyl)pyrido[2,3-
145 dlpyrimidine:
4-amino-5-(3-bromophenyl)-7-(3-medιyl-4-(dimethylamino)phenyl)pyrido[2,3- dlpyrimidine; 4-amino-5-(3-bromophenyl)-7-(4-(N-methyl-N- ttifluoroacetylaιnino)phenyl)pyrido[2,3-d]pyrimidine; 150 4-amino-5-(3-bromophenyl)-7-(4-(dimethylamino)-3-fluorophenyl)pyrido[2,3- dlpyrimidine;
4-amino-5-(3-bromophenyl)-7-(4-(N-ethyl-N-formylamino)phenyl)pyrido[2,3- dlpyrimidine;
4,4-bis(acetylamino)-5-(3-bromophenyl)-7-(4-(N-methyl-N- 155 acetylamino)phenyl)pyrido[2,3-dlpyrimidine;
4-amino-5-(3-bromophenyl)-7-(4-(N-acetyl-N-methylamino)phenyl)pyrido[2,3- dlpyrimidine;
4-amino-5-(3-bromophenyl)-7-(4-(N-eu ylammo)phenyl)pyrido[2,3-dlpyrimidine;
4-amino-5-(3-bromophenyl)-7-(4-(N-methyl-N-(2- 160 methoxyethyl)amino)phenyl)pyrido[2,3-dlpyrimidine;
4-amino-5-(3-bromophenyl)-7-(4-(N-isopropylamino)phenyl)pyτido[2,3- dlpyrimidine;
4-amino-5-(3-bromophenyl)-7-(4-N-ethyl-N-(2- memoxyethyl)amino)phenyl)pyrido[2,3-d]pyrimidine; 165 4-amino-5-(3-bromophenyl)-7-(4-N-(3-methoxypropionyl)-N-isopropyl- amino)phenyl)pyrido[2,3-dlpyrimidine;
4-amino-5-(3-bromophenyl)-7-(4-N-(2-(dimethylamino)ethyl)-N- formylammo)phenyl)pyrido[2,3-dlpyrimidine;
4-amino-5-(3-bromophenyl)-7-(4-(N-(2- 170 (dimemylanιino)ethyl)amino)phenyl)pyrido[2,3-dlpyrirnidine;
4-amino-5-(3-bromophenyl)-7-(4-(N-methyl-N-(2- cyano)ethylamino)phenyl)pyrido[2,3-dlpyrimidine;
4-amino-5-(3-bromophenyl)-7-(4-(N-methyl-N-(3- memoxy)propionylammo)phenyl)pyrido[2,3-dlpyrimidine; 175 4-amino-5-(3-bromophenyl)-7-(3-methyl-4-(N-formyl-N- methylamino)phenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(3-methyl-4-(N-methylamino)phenyl)pyrido[2,3- dlpyrimidine;
4-amino-5-(3-bromophenyl)-7-(4-(4-methoxy-2-butyl)phenyl)pyrido[2,3- 180 dlpyrimidine;
4-amino-5-(3-bromophenyl)-7-(4-(N-methyl-N-(2-(N- phthahmidyl)acetyl)aιτuno)phenyl)pyrido[2,3-dlpyrimidine;
4-amino-5-(3-bromophenyl)-7-(3-methyl-4-(N-methyl-N- (trifluoroacetyl)amino)phenyl)pyrido[2,3-dlpyrimidine; 185 4-amino-5-(3-bromophenyl)-7-(3-methyl-4-(N-acetyl-N- methylarnmo)phenyl)pyrido[2,3-dlpyrimidine;
4-amino-5-(3-bromophenyl)-7-(6-dimethylamino-3-pyridinyl)pyrido[2,3- dlpyrimidine;
4-amino-5-(3-cyanophenyl)-7-(4-methylsulfonylphenyl)pyrido[2,3-d]pyrimidine; 190 4-amino-5-(3-cyanophenyl)-7-(4-(N-methyl-N-formylamino)-phenyl)pyrido[2,3- dlpyrimidine;
4-amino-5-(3-bromophenyl)-7-(6-(N-methyl-N-formylamino)-3- pyridinyl)pyrido[2,3-d]pyrimidine;
4-armno-5-(3-bromophenyl)-7-(6-moφholinyl-3-pyridinyl)pyrido[2,3-dlpyrimidine; 195 4-amino-5-(3-bromophenyl)-7-(6-(N-methyl-N-methoxyetiιylamino)-3- pyridinyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(6-pyπoUm^yl-3-pyridinyl)pyrido[2,3-dlpyrimidine; 4-amino-5-(3-bromophenyl)-7-(2-(dime ylarnmo)-5-pyrimidinyl)pyrido[2,3- dlpyrimidine; 200 4-amino-5-(3-bromophenyl)-7-(2-(N-methoxyethyl-N-methyl amino)-5- pyrinιidinyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(2-(N-formyl-N-methyl amino)-5- pyrimidinyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(2-( -methylamino)5-pyrimidinyl)pyrido[2,3- 205 dlpyrimidine;
4-arnino-5-(3-bromophenyl)-7-(2-(l-pyπolidinyl)-5-pyrimidinyl)pyrido[2,3- dlpyrimidine;
4-amino-5-(3-bromophenyl)-7-(2-(l-moφhoUnyl)-5-pyrimidinyl)pyrido[2,3- dlpyrimidine; 210 4-amino-5-(3-bromophenyl)-7-(6-(2-oxo-3-oxazolidinyl)-3-pyridinyl)pyrido[2,3- dlpyrimidine;
4-amino-5-(3-bromophenyl)-7-(2-pyridyl)pyrido[2,3-d]pyrimidine; 4-amino-5-(3-bromophenyl)-7-(3-pyridyl)pyrido[2,3-dlpyrimidine; 4-amino-5-(3-(thiophen-2-yl)phenyl)-7-(4-dimethylaminophenyl)pyrido[2,3- 215 dlpyrimidine;
4-amino-5-(3-(furan-2-yl)phenyl)-7-(4-dimemylaminophenyl)pyrido[2,3- d]pyrimidine;
4-amino-5-(3-(3-methoxyphenyl)phenyl)-7-(4-dimethylaminophenyl)pyrido[2,3- dlpyrimidine; 220 4-amino-5-phenyl-7-(4-dimedιylanτinophenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-chlorophenyl)-7-(4-(moφholinyl)phenyl)pyrido[2,3-dlpyrimidine; 4-amino-5-(3-bromo-4-fluorophenyl)-7-(4-(moφholinyl)phenyl)pyrido[2,3- dlpyrimidine;
4-amino-5-(3-chlorophenyl)-7-(4-iodophenyl)pyrido[2,3-dlpyrimidine;
225 4-ar no-5-(3-chlorophenyl)-7-(4-(thiophen-2-yl)phenyl)pyrido[2,3-d]pyrimidine:
4-amino-5-(3-cMorophenyl)-7-(4-(5-pyrimidinyl)phenyl)pyrido[2,3-d]pyrimidine: 4-amino-5-(3-bromo-4-fluorophenyl)-7-(4-iodophenyl)pyrido[2,3-d]pyrimidine; 4-amino-5-(4-bromothiophene-2-yl)-7-(4-methoxyphenyl)pyrido[2,3-d]pyrimidine; 4-amino-5-(3-bromophenyl)methyl-7-(4-(dimethylamino)phenyl)pyrido[2,3- 230 dlpyrimidine;
4-am o-5-(2-phenylethyl)-7-(4-diemylam ophenyl)pyrido[2,3-dlpyrimidine; 4-amino-5-(2-methylpropyl)-7-(4-diethylarnmophenyl)pyrido[2,3-d]pyrimidine; 4-ammo-5-(butyl)-7-(4-diethylarrdnophenyl)pyrido[2,3-d]pyrimidine; 4-amino-5-(2-(4-bromophenyl)ethyl)-7-(4-diethylaminophenyl)pyrido[2,3- 235 dlpyrimidine;
4-anrιmo-5-(butyl)-7-(4-dimethylanτinophenyl)pyrido[2,3-d]pyrimidine; 4-amino-5-(2-(3-cyanophenyl)methyl)-7-(4-dimethylaminophenyl)pyrido[2,3- dlpyrimidine;
4-am o-5-(2-(N-phenylmemoxycarbonyl)aminoethyl)-7-(4- 240 dimethylarninophenyl)pyrido[2,3-dlpyrimidine;
4-ammo-5-(cycloheptyl)-7-(4-dimethylarmiιophenyl)pyrido[2,3-d]pyrirnidine; 4-amino-5-(2-(5-chloro-2-(thiophen-3-yl)phenylmethyl)-7-(4- dime ylaminophenyl)pyrido[2,3-d]pyrimidine;
4-ammo-5-(pentyl)-7-(4-diethylammophenyl)pyrido[2,3-d]pyrimidine; 245 4-ammo-5-hexyl-7-(4-diethylammophenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(2-(3-bromophenyl)ethyl)-7-(4-diethylaminophenyl)pyrido[2,3- dlpyrimidine;
4-amino-5-((2-bromophenyl)methyl)-7-(4-diemylaminophenyl)pyrido[2,3- d]pyrimidine; 250 4-ammo-5-cyclopropyl-7-(4-dimethylarrrinophenyl)pyrido[2,3-dlpyrimidine;
4-arn o-5-cyclohexyl-7-(4-dimemylammophenyl)pyrido[2,3-d]pyιimidine; 4-amino-5-((2-bromo-5-chlorophenyl)methyl)-7-(4-diethylaminophenyl)pyrido[2,3- dlpyrimidine;
4-amino-5-memyl-7-(4-diethylam ophenyl)pyrido[2,3-d]pyrimidine; 255 4-amino-5-(2,3-methylenedioxyphenyl)-7-(4-dimethylaminophenyl)pyrido[2,3- dlpyrirnidine;
4-amino-5-(3-fluoro-5-trifluoromethylphenyl)-7-(4- dimemylaminophenyl)pyrido[2,3-dlpyrimidine; 4-amino-5 2-bromophenyl)-7-(4-dimethylamιnophenyl)pyrido[2,3-dlpyrimidine; 260 4-amino-5 3,5-dimethylphenyl)-7-(4-dimethylaminophenyl)pyrido[2,3- dlpyrimidine;
4-amino-5 3,4-dichlorophenyl)-7-(4-dimethylaminophenyl)pyrido[2,3-d]pyrimidine; 4-amino-5 4-fluoro-3-trifluoromethylphenyl)-7-(4- d τιethylaminophenyl)pyrido[2,3-d]pyrimidine; 265 4-amino-5- 3-bromo-5-methoxyphenyl)-7-(4-moφhoUnylphenyl)pyrido[2,3- dlpyrimidine;
4-amino-5- 3-bromo-5-methoxyphenyl)-7-(4-pyrroUdinylphenyl)pyrido[2,3- dlpyrimidine;
4-amino-5-(3-bromo-5-methoxyphenyl)-7-(4-piperidinylphenyl)pyrido[2,3- 270 dlpyrimidine;
4-amino-5- 3-bromo-5-methoxyphenyl)-7-(4-dimethylaminophenyl)pyrido[2,3- dlp>τimidine;
4-amino-5- 3-methylthiophenyl)-7-(4-dimethylaminophenyl)pyrido[2,3- dlpyrimidine; 275 4-amino-5-' 3-bromo-5-medιoxyphenyl)-7-(thiophene-2-yl)pyrido[2,3-d]pyrimidine;
4-amino-5- 2,3-dimethoxyphenyl)-7-(4-dimethylaminophenyl)pyrido[2,3- dlpyrimidine;
4-amino-5-(3-memylsulfonylphenyl)-7-(4-dimethylaminophenyl)pyrido[2,3- dlpyrimidine; 280 4-acetylammo-5-(3-bromophenyl)-7-(4-dimethylaminophenyl)pyrido[2,3- dlpyri idine;
4-formylamino-5-(3-bromophenyl)-7-(4-dimeuιylaminophenyl)pyrido[2,3- dlpyrimidine;
4-(methoxyacetyl)amino-5-(3-bromophenyl)-7-(4-diethylaminophenyl)pyrido[2,3- 285 dlpyrimidine;
4-trifluoroacetylammo-5-(3-bromophenyl)-7-(4-dimethylaminophenyl)pyrido[2,3- dlpyrimidine;
4-pentanoylamino-5-(3-bromophenyl)-7-(4-dimethylaminophenyl)pyrido[2,3- dlpyrimidine; 290 4-benzoylamino-5-(3-bromophenyl)-7-(4-dimemylaminophenyl)pyrido[2,3- dlpyrimidine;
4-(N-BOC-glycyl)amino-5-(3-bromophenyl)-7-(4-dimethylaminophenyl)pyrido[2,3- dlpyrimidine;
4-(N-phdιaUmidylglycyl)amino-5-(3-bromophenyl)-7-(4- 295 dimethylaminophenyl)pyrido[2,3-dlpyrimidine; 4-(ethoxycarbonyl)amino-5-(3-bromophenyl)-7-(4-dimethylarnrnophenyl)pyrido[2,3- dlpyrimidine;
4-(ethylarnmocarbonyl)amino-5-(3-bromophenyl)-7-(4- dimethylaminophenyl)pyrido[2,3-d]pyrimidine; 300 4-allylarmiιo-5-(3-bromophenyl)-7-(4-dimethylaminophenyl) pyrido[2,3- dlpyrimidine;
4-(2-(N,N-dimethylamino)ethylamino)-5-(4-bromophenyl)-7-(4- dimemylam ophenyl) pyrido[2,3-d]pyrimidine;
4-(4-(N,N-dimethylamino)butylamino)-5-(3-bromophenyl)-7-(4- 305 dimethylaminophenyl) pyrido[2,3-dlpyrimidine; (N-allyl-N-formylamino)-5-(4-dimethylaminophenyl)-7-(4- bromophenyl)pyrido[2,3-dlpyrimidine; diacetylamino-5-(p-dimedιylaminophenyl)-7-(4- bromophenyl)pyrido[2,3-d]pyrimidine; 310 4-amino-5-(3-bromophenyl)-7-(5-arrύno-2-pyridyl)ρyrido[2,3-dlpyrimidine;
4-amino-5-(3-bromophenyl)-7-(5-dimedιylarmno-2-pyridyl)pyrido[2,3-d]pyrimidine;
4-ammo-5-(3-bromophenyl)-7-(5-dimethylamino-2- pyrazinyl)pyrido[2,3-dlpyrimidine; amino-5-(3-bromophenyl)-7-(2-oxobenzoxazolin-6-yl)pyrido[2,3-dlpyrimidine; 315 4-amino-5-(3-bromophenyl)-7-(l-methyl-2-oxobenzoxazoUn-6- yl)pyrido [2,3-dlpyrimidine;
4-amino-5-((5-chloro-2-(3-methoxyphenyl)phenyl)methyl)-7-(4- dimethylaminophenyl)pyrido[2,3-d]pyrimidine; am o-5-((thiophene-2-yl)methyl)-7-(4-diethylaminophenyl)pyrido[2,3- 320 dlpyrimidine;
4-am o-5-((thiophene-3-yl)methyl)-7-(4-diethylaminophenyl)pyrido[2,3- dlpyrimidine;
4-amino-5-((2-bromophenyl)methyl)-7-(4-dimethylaminophenyl)pyrido[2,3- dlpyrimidine; 325 4-amino-5-(3-bromophenyl)-7-(4-(N-formyl-N-(2- meιhoxyethyl)amino)phenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(4-(N-(2-methoxyethyl)amino)phenyl)pyrido[2,3- dlpyrimidine;
4-amino-5-(3-bromophenyl)-7-(4-(N-methyl-N-((2- 330 dimethylarmno)emyl)amino)phenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(4-(2- methoxy)acetylarmno)ethyl)am o)phenyl)pyrido[2,3-dlpyrimidine; 4-ar no-5-(3-bromophenyl)-7-((4-formylarmno)phenyl)pyrido[2,3-dlpyriιτιidine; 4-arn o-5-(3-bromophenyl)-7-(4-(2-(dimemylarmno)acetylamino)phenyl)pyrido[2,3- 335 dlpyrimidine;
4-amino-5-(3-bromophenyl)-7-(4-(2-oxo-3-oxazolidinyl)phenyl)pyrido[2,3- dlpyrimidine;
4-amino-5-(3-bromophenyl)-7-(6-(2-propyl)-3-pyridinyl)pyrido[2,3-d]pyrimidine; 4-amino-5-(3-bromophenyl)-7-(3-methyl-4-pyrrolidinylphenyl)pyrido[2,3- 340 dlpyrimidine;
4-amino-5-(3-bromophenyl)-7-(6-in idazolyl-3-pyridinyl)pyrido[2,3-dlpyrimidine; 4-am o-5-phenylmethyl-7-(4-diedιylarr nophenyl)pyrido[2,3-d]pyrimidine; 4-amino-5-(2-(3-aminopropynyl)phenylmethyl)-7-(4-diethylaminophenyl)pyrido[2,3- dlpyrimidine; 345 4-amino-5-(l-(3-bromophenyl)ethyl)-7-(4-diethylaminophenyl)pyrido[2,3- dlpyrimidine;
4-am o-5-(4-dimemylaminophenyl)-7-(4-bromophenyl)pyrido[2,3-d]pyrimidine; 4-amino-5-(2-furanyl)-7-(4-(N-moφholinyl)phenyl)pyrido[2,3-dlpyrimidine; 4-armno-5-(3-bromophenyl)-7-(2-dimethylanιmo-5-pyrimidinyl)pyrido[2,3- 350 dlpyrimidine;
4-armno-5-(3-bromophenyl)-7-(4-(ureido)phenyl)pyrido[2,3-dlpyrimidine; 4-ammo-5-(l-phenylmeAyl-3-piperidinyl)-7-(4-diethylaminophenyl)pyrido[2,3- dlpyrimidine;
4-amino-5-(3-bromophenyl)-7-(6-(3-methyl-5-isoxazolyl))-3- 355 pyridinyl)pyrido[2,3-dlpyrimidine;
4-amino-5-(3-bromophenyl)-7-(6-chloro-3-pyridinyl)pyιido[2,3-dlpyrimidine; 4-amino-5-(3-bromophenyl)-7-(6-methoxy-3-pyridinyl)pyrido[2,3-dlpyrimidine; 4-amino-5-(3-bromophenyl)-7-(6-(l,2,4-ttiazol-4-yl)-3-pyridinyl)pyrido[2,3- dlpyrimidine; 360 4-amino-5-(3-bromophenyl)-7-(2-moφholinyl-5-pyrirnidinyl)pyrido[2,3- dlpyrimidine;
4-ammo-5-(2-thiazolyl)-7-(4-pyπolidinylphenyl)-pyrido[2,3-d]pyrimidine: 4-amino-5-(3-bromophenyl)-7-(6-pyrazolyl-3-pyridinyl))-pyrido[2,3- dlpyrimidine; 365 4-amino-5-(3-bromophenyl)-7-(4-(l-methyl-ureido)phenyl)-pyrido[2,3- dlpyrimidine;
4-amko-5-(3-bromophenyl)-7-(4-(N-methyl-N-(2-pyrimidinyl)amino)phenyl)- pyrido[2.3-d]pyrimidine: 4-armno-5-(3-bromophenyl)-7-(3-fluoro-4-(N-formyl-N-methylamino)phenyl)- 370 pyrido[2,3-d]pyrimidine;
4-formylamino-5-(3-bromophenyl)-7-(3-fluoro-4-(N-formyl-N- methylam o)phenyl)-pyrido[2,3-d]pyrirnidine;
4-amko-5-(3-bromophenyl)-7-(4-(N-methyl-N-methylsulfonylamino)- phenyl)pyrido[2,3-dlpyrimidine; 375 4-amino-5-(3-bromophenyl)-7-(6-(N-methyl-N-methylsulfonylamino)-3- pyridinyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(l-methyl-5-indoUnyl)pyrido[2,3-d]pyrimidine; 4-arnino-5-(3-bromophenyl)-7-(l-methyl-5-benzimidazolyl)pyrido[2,3- dlpyrimidine; 380 4-amino-5-(3-bromophenyl)-7-(6-dimethylamino-3-pyridazinyl)pyrido[2,3- dlpyrimidine;
4-amino-5-(3bromophenyl)-7-(6-moφholinyl-3-pyridazinyl)pyrido[2,3- dlpyrimidine;
4-amino-5-(3-bromophenyl)-7-(6-pyrroUdinyl-3-pyridazinyl)pyrido[2,3- 385 dlpyrimidine;
4-amino-5-(3-bromophenyl)-7-(5-moφholinyl-2-pyrazinyl)pyrido[2,3- dlpyrimidine;
4-amino-5-(3-bromophenyl)-7-(5-(N-(2-methoxyethyl)-N-methylamino)-2- pyrazinyl)pyrido[2,3-d]pyrimidine; 390 4-amino-5-(3-bromophenyl)-7-(4-(moφholinylmethyl)-phenyl)pyrido[2,3- dlpyrimidine;
4-amino-5-(3-bromophenyl)-7-(5-(N,N-bis(2-methoxyethyl)amino)-2- pyridinyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(4-(imidazolylmethyl)-phenyl)pyrido[2,3- 395 dlpyrimidine;
4-amino-5-(3-bromophenyl)-7-(5-(l-moφholinyl)-2-pyridinyl)pyrido[2,3- dlpyrimidine;
4-amino-5-(3-bromophenyl)-7-(4-((dimethylamino)methyl)-phenyl)pyrido[2,3- dlpyrimidine; 400 4-amino-5-(3-bromophenyl)-7-(5-(4-hydroxy-l-piperidinyl)-2- pyridinyl)pyrido[2,3-dlpyrimidine:
4-amino-5-(3-bromophenyl)-7-(5-(N-formyl-N-medιylamino)-2- pyridinyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(5-(2-propenyl)-2-pyridinyl)pyrido[2,3- 405 dlpyrimidine; 4-amino-5-(3-bromophenyl)-7-(3-(2-methoxyethyl)-2-oxo-6- benzoxazolyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(4-(l-(N-formylamino)-ethyl)phenyl)pyrido[23" dlpyrimidine; 410 4-(methylamino)-5-(3-bromophenyl)-7-(4-dimethylaminophenyl)pyrido[2,3- d]pyrimidine hydrochloride;
4-(2-methoxyethylamino)-5-(3-bromophenyl)-7-(4- dimethylaminophenyl)pyrido[2,3-dlpyrimidine hydrochloride;
4-amino-5-(3-bromophenyl)-7-(4-(l-methyl-2-irnidazolyl)phenyl)pyrido[2,3- 415 dlpyrimidine trihydrochloride;
4-amino-5-(3-bromophenyl)-7-(4-(aminomethyl)phenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(2-bromo-4-(dimethylamino)phenyl)pyrido[2,3- dlpyrimidine;
4-am o-5-(3-bromophenyl)-7-(4-(dime ylaminoethyl)phenyl)pyrido[2,3- 420 dlpyrimidine;
4-amino-5-(3-bromophenyl)-7-(4-(3-(dimethylamino)propynyl)phenyl)pyrido[2,3- dlpyrimidine;
4-arnino-5-(3-bromophenyl)-7-(4-(3-amino-3-methylbutynyl)phenyl)pyrido[2,3- dlpyrimidine; 425 4-amino-5-(3-bromophenyl)-7-(4-dimethylphosphonatophenyl)pyrido[2,3- dlpyrimidine;
4-amino-5-(3-bromophenyl)-7-(4-(3-(methoxypropynyl)pyrido[2,3-dlpyrimidine;
4-amino-5-(3-bromophenyl)-7-(4-carboxyphenyl)pyrido[2,3-dlpyrimidine;
4-amino-5-(3-bromophenyl)-7-(4-methyl-3-oxo-2H-4H-pyrido[3,2-b]-l,4-oxazin- 430 7-yl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(4-(2-(dime ylamino)ethyl)-3-oxo-2H-4H- pyrido[3,2-b]- 1 ,4-oxazin-7-yl)pyrido[2,3-dlpyrimidine;
4-amino-5-(3-bromophenyl)-7-(2,3-dihydro-3-(dimethylaminoethyl)-2- oxobenzoxazol-6-yl)pyrido[2,3-dlpyrimidine; 435 4-amino-5-(3-bromophenyl)-7-(4-methyl-3-oxo-2H-4H-benzo- 1 ,4-oxazin-7- yl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(2,2,4-trimethyl-3-oxo-2H-4H-benzo-l,4-oxazin-7- yl)pyrido [2,3-d]pyrimidine;
4-amino-5-cyclohexyl-7-(4-(2- ^ethylarrιino)ethyl)-2H-4H-benzo-3-oxo-l,4- 440 oxazin-7-yl)pyrido[2,3-dJpyrimidine;
4-amino-5-(3-bromophenyl)-7-(5-(l-methylethyl)-2-pyridyl)pyrido[2,3- dlpyrimidine; 4-arnino-5-(3-bromophenyl)-7-(5-piperidin-l-ylpyrid-2-yl)pyrido[2,3-dlpyrimidine; 4-amino-5-(l-(4-bromophenyl)ethyl)-7-(6-moφhoUnylpyrid-3-yl)pyrido[2,3- 445 dlpyrimidine;
4-amino-5-(3-bromophenyl)-7-(4-((N-formylamino)methyl)phenyl)pyrido[2,3- dlpyrimidine;
4-amino-5-(3-bromophenyl)-7-(4-(l-methyl-l-(N-methylamino)ethyl)phenyl)- pyrido[2,3-d]pyrimidine: 450 4-am o-5-(3-bromophenyl)-7-(4-(l-(dimethylamino)-l- methylethyl)phenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(N-acetyl-5-indohnyl)pyrido[2,3-dlpyrimidine; 4-arnino-5-cyclohexyl-7-(6-cMoro-3-pyridyl)pyrido[2,3-dlpyrimidine; 4-ammo-5-(l-(2-bromophenyl)emyl)-7-(6-die ylamino-3-pyridyl)pyrido[2,3- 455 dlpyrimidine;
4-amino-5-(l-(2-bromophenyl)ethyl)-7-(6-moφhoUnyl-3-pyridyl)pyrido[2,3- dlpyrimidine;
4-am o-5-(l-(2-bromophenyl)e yl)-7-(4-(Η-memyl-N-formyl)amino)- phenyl)pyrido[2,3-dlpyrimidine; 460 4-arnino-5-cyclohexyl-7-(6-moφhoUnyl-3-pyridyl)pyrido[2,3-dlpyrimidine;
4-amino-5-((2-bromophenyl)methyl)-7-(6-moφholinyl-3-pyridyl)pyrido[2,3- dlpyrimidine;
4-amino-5-(4-tetrahydropyranyl)-7-(6-moφhoUnyl-3-pyridyl)pyrido[2,3- dlpyrimidine; 465 4-ammo-5-cyclohexyl-7-(6-dimemylarnmo-3-pyridyl)pyrido[2,3-d]pyrimidine;
4-ammo-5-(l-ethylpropyl)-7-(6-dimemylamino-3-pyridyl)pyrido[2,3-d]pyrimidine; 4-am o-5-cyclopentyl-7-(6-moφholmyl-3-pyridyl)pyrido[2,3-dlpyrimidine; 4-amino-5-cyclohexyl-7-(2-cWoro-3-pyridyl)pyrido[2,3-dlpyrimidine; 4-ammo-5-(3,5-dimethylcyclohexyl)-7-(6-dimethylamino-3-pyridyl)pyrido[2,3- 470 dlpyrimidine;
4-amino-5-((N-(benzyloxycarbonyl)-4-piperidinyl)methyl)-7-(6-moφholinyl-3- pyridyl)pyrido[2,3-d]pyrimidine;
4-amino-5-cyclohexyl-7-(6-bromo-3-pyridyl)pyrido[2,3-dlpyrimidine; 4-amino-5-cyclohexyl-7-(3-cyanophenyl)pyτido[2,3-dlpyrimidine; 475 4-ammo-5-(l-(2-bromophenyl)ethyl)-7-(6-dimethylamino-3-pyridazinyl)pyrido[2,3- dlpyrimidine;
4-ammo-5-(3-bromophenyl)-7-(6-imidazolyl-3-pyridazinyl)pyrido[2,3-dlpyrimidine; 4-amino-5-(3-bromophenyl)-7-(6-(azacycloheptanyl)-3-pyridazinyl)pyrido[2,3- dlpyrimidine; 480 4-amino-5-(3-bromophenyl)-7-(6-(N-methyl-N-(l-methylethyl))amino)-3- pyridazinyl)pyrido[2,3-dlpyrimidine;
4-amino-5-(l-(2-bromophenyl)ethyl)-7-(6-moφhoUnyl-3-pyridazinyl)pyrido[2,3- dlpyrimidine;
4-amino-5-cyclohexyl-7-(6-(4-acetylpiperazinyl)-3-pyridyl)pyrido[2,3-d]pyrimidine; 485 4-amino-5-cyclohexyl-7-(6-(4-acetyl-l,4-diazacycloheptanyl)-3-pyridyl)pyrido[2,3- dlpyrimidine;
4-amino-5-cyclohexyl-7-(6-(4-metiιyl- 1 ,4-diazacycloheptanyl)-3- pyridyl)pyrido[2,3-d]pyrimidine;
4-amino-5-cyclohexyl-7-(6-(N-methyl-N-(2-(2-pyridyl)ethyl)amino)-3- 490 pyridyl)pyrido[2,3-dlpyrimidine;
4-amino-5-cyclohexyl-7-(6-2-(N-(N',N'-dimethylaminoethyl)-N-methylamino)-3- pyridyl)pyrido[2,3-dlpyrimidine;
4-armno-5-cyclohexyl-7-(6-azetidmyl-3-pyridyl)pyrido[2,3-dlpyrimidine; 4-am o-5-cyclohexyl-7-(6-(3-(N-methylacetaιτιido)pyrrolidinyl)pyridyl)pyrido[2,3- 495 dlpyrimidine;
4-arrdno-5-cyclohexyl-7-(6-(3-(formarnido)pyπohdinyl)pyridyl)pyrido[2,3- dlpyrimidine;
4-amino-5-cyclohexyl-7-(4-oxo-l-phenyl-l,3,8-ttiazaspiro[4.5[decan-8- yl)pyrido[2,3-dlpyrimidine; 500 4-amino-5-cyclohexyl-7-(6-(2-methoxymethyl)pyπolidin-l-yl)pyridyl)pyrido[2,3- dlpyrimidine;
4-amino-5-cyclohexyl-7-(6-(N-methoxyethyl-N-propylamino)pyridyl)pyrido[2,3- dlp}τimidine;
4-amino-5-cyclohexyl-7-(N-methyl-N-(2,2-dimethoxyethyl)amino)pyrido[2,3- 505 dlpyrimidine;
4-ammo-5-cyclohexyl-7-(6-(4-(dimethylarnino)piperidinyl)pyridyl)pyrido[2,3- dlpyrimidine;
4-amino-5-cyclohexyl-7-(6-(4-(aminocarbonyl))piperidinyl)pyridyl)pyrido[2,3- dlpyrimidine; 510 4-anτino-5-cyclohexyl-7-(N-memyl-N-(3-(diedιylamino)propyl)arninopyrid-3- yl)pyrido[2,3-dlpyrimidine;
4-ammo-5-cyclohexyl-7-(6-(N-memyl-N-(4-pyridyl)ethylamino)pyrid-3- yl)pyrido[2,3-d]pyrimidine;
4-aιτ no-5-cyclohexyl-7-(6-(N-methyl-N-(3-pyridylmethylamino)pyrid-3- 515 yl)pyrido[2,3-dlpyrimidine; 4-amino-5-( 1 -(2-bromophenyl)ethyl)-7-( 1 -methyl-5-indolyl)pyrido[2,3- dlpyrimidine;
4-amino-5-(l-(2-bromophenyl)ethyl)-7-(l-methyl-2,3-dioxo-5-indolyl)pyrido[2,3- dlpyrimidine; 520 4-amino-5-(3-bromophenyl)-7-(3-fluoro-4-(l-moφhohnyl)phenyl)pyrido[2,3- dlpyrimidine;
4-amino-5-(3-bromophenyl)-7-(4-hydroxy-3-nitrophenyl)pyrido[2,3-dlpyrimidine; 4-amino-5-(3-bromophenyl)-7-(6-(4,4-ethylenedioxypiperidinyl)-3- pyridyl)pyrido[2,3-d]pyrimidine; 525 4-amino-5-(3-bromophenyl)-7-(6-(4-oxopiperidinyl)-3-pyridyl)pyrido[2,3- dlpyrimidine;
4-amino-5-(3-bromophenyl)-7-(6-(4-formylpiperazinyl)-3-pyridyl)pyrido[2,3- dlpyrimidine;
4-amino-5-(3-bromophenyl)-7-(6-(4-methylpiperazinyl)-3-pyridyl)pyrido[2,3- 530 dlpyrimidine;
4-amino-5-(3-bromophenyl)-7-(6-thiomoφhohnyl-3-pyridyl)pyrido[2,3- dlpyrimidin;
4-amino-5-(3-bromophenyl)-7-(6-(4,4-dioxothiomoφhoUnyl)-3-pyridyl)pyrido[2,3- dlpyrimidine; 535 4-amino-5-(2-bromophenyl)-7-(6-moφhoUnyl-3-pyridyl)pyrido[2,3-dlpyrimidine;
4-amino-5-(3-bromo-4-methoxyphenyl)-7-(6-moφholinyl-3-pyridyl)pyrido[2,3- dlpyrimidine;
4-amino-5-(4-bromophenyl)-7-(6-moφhohnyl-3-pyridyl)pyrido[2,3-dlpyrimidine; 4-amino-5-(3-chlorophenyl)-7-(6-moφhoUnyl-3-pyridyl)pyrido[2,3-d]pyrimidine; 540 4-amino-5-(3-bromophenyl)-7-(5-chloro-6-moφhoUnyl-3-pyridyl)pyrido[2,3- dlpyrimidine;
4-amino-5-(3-bromophenyl)-7-(6-(N-oxidomoφholinyl)-3-pyridyl)pyrido[2,3- dlpyrimidine;
4-arnino-5-(3-bromophenyl)-7-(6-(N-(2-hydroxyethoxyethyl)amino)-3- 545 pyridyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(6-(N-(2-hydroxyethoxyethyl)-N-formylamino)-3- pyridyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(6-(N-(2-hydroxyethoxyethyl)-3-pyridyl-N- oxide)pyrido[2,3-dlpyrimidine; 550 4-amino-5-(3-bromophenyl)-7-(6-(3-hydroxy)moφholinyl)-3-pyridyl)pyrido[2,3- dlpyrimidine; l-(5-(4-arnino-5-(3-bromophenyl)pyrido[2,3-dlpyrimidin-7-yl)-2-pyridyl)- piperidine-4-phosphate, disodium salt;
4-amino-5-(3-bromophenyl)-7-(4-methylenylpiperidinyl)-3-pyridyl)pyrido[2,3-
555 dlpyrimidine;
4-amino-5-(3-bromophenyl)-7-(4-hydroxy-4-(hydroxymethyl)piperidinyl)-3- pyridyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(6-(4,4-ethylenedioxypiperidinyl)-3- pyridyl)pyrido[2,3-d]pyrimidine; 560 4-ammo-5-cyclohexyl-7-(6-(4-oxo-piperidinyl)-3-pyridyl)pyrido[2,3-d]pyrimidine;
4-amino-5-cyclohexyl-7-(6-(4-meuiylenylpiperidinyl)-3-pyridyl)pyrido[2,3- dlpyrimidine;
4-N-(iminomethyl)amino-5-cyclohexyl-7-(6-dimethylamino-3-pyridyl)pyrido[2,3- d]pyrimidine.
565
7. A pharmaceutical composition comprising a therapeutically effective amount of a compound according to Claim 1 in combination with a pharmaceutically acceptable carrier.
8. A method of tteating ischemia, neurological disorders, nociperception , inflammation, immunosuppression, gastrointestinal disfunctions, diabetes and sepsis in a mammal in need of such treatment, comprising administering to the mammal a therapeutically effective amount of a compound according to Claim 1 or 3.
9. A method according to Claim 8 wherein the method consists of treating cerebral ischemia, myocardial ischemia, angina, coronary artery bypass graft surgery, percutaneous ttansluminal angioplasty, stroke, drrombotic and embolic conditions, epilepsy, anxiety, schizophrenia, pain perception, neuropathic pain, visceral pain, arthritis, sepsis, diabetes and abnormal gasttointestinal motility.
10. A compound, or a pharmaceutically acceptable salt or amide thereof, of formula (I)
Figure imgf000146_0001
wherein R and R^ are independendy selected from H, loweralkyl, Ci-C6alkoxyCi-
C6alkyl, arylCi-Cόalkyl, -C(O)Cl-C6alkyl, -C(O)aryl, -C(O)heterocyclic or may join together with the nittogen to which they are attached to form a 5-7 membered ring optionally containing 1-2 additional heteroatoms selected from O. N or S;
R is selected from the group consisting of loweralkyl, loweralkenyl, loweralkynyl, cycloalkyl, aryl, arylalkyl, heteroaryl, heterocyclic group, heteroarylalkyl or heterocycloalkyl wherein the heteroaryl and heterocyclic groups are linked directly or indirectly by a ring carbon;
R4 is selected from the group consisting of loweralkyl, loweralkenyl, loweralkynyl, cycloalkyl, aryl, arylalkyl, heteroaryl, heterocyclic group heteroarylalkyl or heterocycloalkyl; and a dashed line — indicates that a double bond is optionally present provided that proper valencies are maintained; with die proviso tiiat the compound may not be selected from the group consisting of:
(a) 4-anιmo-5-(4-chlorophenyl)-7-(4-nittophenyl)pyrido[2,3-d]pyrimidine; (b) 4-amino-5-(4-methoxyphenyl)-7-(4-nittophenyl)pyrido[2,3-dlpyrimidine;
(c) 4-arr no-5-(4-fluorophenyl)-7-(4-fluorophenyl)pyrido[2,3-dlpyrimidine;
(d) 4-amino-5-(4-chlorophenyl)-7-(4-fluorophenyl)pyrido[2,3-d]pyrimidine;
(e) 4-am o-5-phenyl-7-(4-aminophenyl)pyrido[2,3-dlpyrimidine;
(f) 4-amino-5-phenyl-7-(4-bromophenyl)pyrido[2,3-dlpyrimidine; (g) 4-arrώιo-5-(4-memoxyphenyl)-7-(4-arninophenyl)pyrido[2,3-dlpyrimidine;
(h) 4-am o-5-(4-methoxyphenyl)-7-(4-bromophenyl)pyrido[2,3-dlpyrimidine; and (i) 4-amino-5,7-diphenylpyrido[2,3-d]pyrimidine.
11. A compound according to Claim 10 of formula II
Figure imgf000147_0001
wherein
R1 and R^ are independently selected from H, loweralkyl, arylCi-C6alkyl, - C(O)Cι-C6alkyl, -C(O)aryl, -C(O)heterocyclic or may join together with the nittogen to which they are attached to from a 5-7 membered ring optionally containing 1-2 additional heteroatoms selected from O, N or S;
R3 and R4 are independently selected from the group consisting of:
Ci-C6alkyl, C2-C6alkenyl,
C2-C6alkynyl,
C3-C8cycloalkyl, heteroarylCo-C6alkyl or substituted heteroarylCo-C6alkyl, optionally substituted cycloalkyl, arylCo-C6alkyl or substituted arylCo-C6alkyl, heteroarylC2-C6alkenyl or substituted heteroarylC2- ;alkenyl, arylC2-C6alkenyl or substituted arylC2-C6alkenyl, heteroarylC2-C6alkynyl or substituted heteroarylC2-C6alkynyl, arylC2-C6alkynyl or substituted arylC2-C6alkynyl wherein the 1-4 heteroaryl or aryl substituents are independently selected from halogen, oxo, CO2R^, cyanoCι-C6alkyl, heteroarylQ)-C6alkyl, heterocyclicCo-C alkyl, Cι-C6alkyloxy, Cι-C6alkyloxyCι-C6alkyl, arylCo-C6alkyl, arylCι-C6alkyloxy, R5R6NC(O), cyano, C2-C6alkenyl, C2-C6alkynyl, Ci-Ctøalkyl, C2-C6alkenyldialkylmalonyl, CF3, HO-, Ci- C6alkyloxyCι-C6alkyloxy, Cι-C6alkylSOn wherein n is 1-2, Ci-
Cόalkylthio, Cι-C6alkylacryl, CF3O, CF3, Cι-C4alkylenedioxy, Ci- C6alkylacryl, R5R6N(CO)NR5, N-formyl(heterocyclic), NO2, NR5R6C0- C6alkyl, (R5θ)(R6θ)-P(O)- Q)-C6alkyl, wherein R^ and R6 are independently selected from H, Ci-Cβalkyl, HC(O), Cι-C6alkyloxyCι-C6alkyl, Cι-C6alkyloxy, C\-
C6alkylC(O), CF3C(O), NR7R8Cι-C6alkyl, phthalimidoCi- C6C(O), Cι-C6alkylSOn where n is 1-2, CNCi-Cβalkyl, R7R8NC(O)NR7-, heteroaryl, NR7R8Cι-C6alkylC(O), Ci- CόalkyloxycarbamidoC 1 -Cόalkyl, wherein R7 and R8 are independently selected from those variables identified for R^ and R^ or R^ and R6 or R7 and R8 may join together with the nittogen atom to which they are attached to form a 5-7 membered unsubstituted or substituted ring optionally containing 1-3 additional heteroatoms selected from O, N or S wherein the substituents are selected from
Cι-C6alkyl and with the proviso that the compound may not be selected from the group consisting of:
(a) 4-arn o-5-(4-cWorophenyl)-7-(4-nittophenyl)pyrido[2,3-dlpyrimidine;
(b) 4-amino-5-(4-methoxyphenyl)-7-(4-nitrophenyl)pyrido[2,3-d]pyrimidine; (c) 4-arnino-5-(4-fluorophenyl)-7-(4-fluorophenyl)pyrido[2,3-d]pyrimidine;
(d) 4-amino-5-(4-chlorophenyl)-7-(4-fluorophenyl)pyrido[2,3-dlpyrimidine; (e) 4-amino-5-phenyl-7-(4-aminophenyl)pyrido[2,3-dlpyrimidine;
(f) 4-amino-5-phenyl-7-(4-bromophenyl)pyrido[2,3-dlpyrimidine;
(g) 4-amino-5-(4-me oxyphenyl)-7-(4-aminophenyl)pyrido[2,3-dlpyrimidine; (h) 4-ammo-5-(4-methoxyphenyl)-7-(4-bromophenyl)pyrido[2,3-dlpyrimidine; and
(i) 4-amino-5,7-diphenylpyrido[2,3-d]pyrimidine.
12. A compound according to Claim 10, wherein R4 is selected from the group consisting of: phenyl; thiophene-2-yl; 3-methyl-2-oxobenzoxazolin-6-yl; 2-(dimethylamino)- 5-pyrimidinyl; 2-(N-formyl-N-methyl amino)-5-pyrimidinyl; 2-(N-methoxyethyl-N-methyl amino)-5-pyrimidinyl; 2-(N-methylamino)5-pyrimidinyl; 2-( 1 -moφholinyl)-5-pyrimidinyl; 2-(l-pyrrohdinyl)-5-pyrimidinyl; 2-dimemylamino-5-pyrimidinyl; 2-furanyl; 2- oxobenzoxazohn-6-yl; 2-pyridyl; 3-(dimethylamino)phenyl; 3-amino-4-medιoxyphenyl; 3- bromo-4-(dimethylamino)phenyl; 3-methoxyphenyl; 3-methyl-4-(N-acetyl-N- methylamino)phenyl; 3-methyl-4-(N-formyl-N-methylamino)phenyl; 3-methyl-4-(N-methyl- N-(trifluoroacetyl)amino)phenyl; 3-methyl-4-(N-methylamino)phenyl; 3-methyl-4- pyπolidinylphenyl; 3-pyridyl; 3,4-dichlorophenyl; 3,4-methylenedioxyphenyl; 3,4,5- trimethoxyphenyl; 4-(acetylamino)phenyl; 4-(dimethylamino)-3-fluorophenyl; 4- (dimedιylamino)phenyl; 4-(imidazol-l-yl)phenyl; 4-(medιylthio)phenyl; 4- (moφhohnyl)phenyl; 4-(N-(2-(dime ylamino)e yl)amino)phenyl; 4-(N-(2- methoxyethyl)amino)phenyl; 4-(N-acetyl-N-methylamino)phenyl; 4-(N-etiιyl-N- formylamino)phenyl; 4-(N-ethylamino)phenyl; 4-(N-formyl-N-(2- methoxyethyl)amino)phenyl; 4-(N-isopropylamino)phenyl; 4-(N-methyl-N-((2- dimethylamino)ethyl)amino)phenyl; 4- (N-methyl-N- (2- (N- phthaUmidyl)acetyl)amino)phenyl; 4-(N-methyl-N-(2-cyano)ethylamino)phenyl; 4-(N- medιyl-N-(2-methoxyethyl)amino)phenyl; 4-(N-methyl-N-(3- methoxy)propionylamino)phenyl; 4-(N-methyl-N-acetylamino)phenyl; 4-(N-methyl-N- formylamino)phenyl; 4-(N-methyl-N-trifluoroacetylamino)phenyl; 4-(N- moφhohnyl)phenyl; 4-(thiophene-2-yl)phenyl; 4-(ureido)phenyl; 4-(2- (dimethylamino)acetylamino)phenyl; 4-(2-methoxy)acetylamino)ethyl)amino)phenyl; 4-(2- methoxy)ethoxyphenyl; 4-(2-oxo-3-oxazohdinyl)phenyl; 4-(4-methoxy-2-butyl)phenyl; 4- (4-methylpiperidinyl)phenyl; 4-(5-pyrimidinyl)phenyl; 4-aminophenyl; 4-bromophenyl) 4- butoxyphenyl; 4-carboxamidophenyl; 4-chlorophenyl; 4-cyanophenyl; 4- diediylaminophenyl; 4-diedιylmalonylallylphenyl) 4-dimethylaminophenyl) 4- ethoxyphenyl; 4-ethylphenyl; 4-fluorophenyl; 4-hydroxyphenyl; 4-imidazolylphenyl; 4- iodophenyl; 4-isopropylphenyl; 4-methoxyphenyl) 4-methylaminophenyl; 4- mediylsulfonylphenyl; 4-moφholinylphenyl; 4-N-(2-(dimethylamino)ethyi)-N- formylamino)phenyl; 4-N-(3-methoxypropionyl)-N-isopropyl-amino)phenyl; 4-N-ethyl-N- (2-methoxyetfιyl)amino)phenyl; 4-N-formylpiperazinylphenyl) 4-nitrophenyl; 4- piperidinylphenyl; 4-(3-pyridyl)phenyl; 4-pyπolidinylphenyl; 4-t-butylacrylphenyl; 5- (dimedιylamino)dιiophene-2-yl; 5-amino-2-pyridyl; 5-dimethylamino-2-pyrazinyl; 5- dimethylamino-2-pyridyl; 5-pyrimidinylphenyl; 6-(N-methyl-N-foιτnylamino)-3-pyridinyl; 6-(N-methyl-N-methoxyethylamino)-3-pyridinyl; 6-(2-oxo-3-oxazolidinyl)-3-pyridinyl; 6- dimethylamino-3-pyridinyl; 6-imidazolyl-3-pyridinyl; 6-moφholinyl-3-pyridinyl; 6- pyrrolidinyl-3-pyridinyl; 6-(2-propyl)-3-pyτidinyl; and (4-formylamino)phenyl.
13. A compound according to Claim 10, wherein R3 is selected from the group consisting of: (thiophene-2-yl)methyl; (thiophene-3-yl)methyl; butyl; cycloheptyl; pentyl; thiophene-2-yl; l-(3-bromophenyl)ethyl; 2-(N-phenylmethoxycarbonyl)aminophenyl; 2-(3- bromophenyl)ethyl; 2-(3-cyanophenyl)methyl; 2-(4-bromophenyl)ethyl; 2-(5-chloro-2- (thiophen-3-yl)phenyl; 2-bromophenyl; 2-furanyl; 2-methylpropyl; 2-phenylethyl; phenylmethyl; 2,3-dimethoxyphenyl; 2,3-methylenedioxyphenyl; 3-(furan-2-yl)phenyl; 3- (thiophen-2-yl)phenyl; 3-(2-pyridyl)phenyl; 3-(3-methoxybenzyl)phenyl; 2-(3- aminopropynyl)phenylmethyl; 3-benzyloxyphenyl; 3-bromo-4-fluorophenyl; 3-bromo-5- iodophenyl; 3-bromo-5-methoxyphenyl; 3-bromophenyl; 3-bromophenyl)methyl; 3- carboxamidophenyl; 3-chlorophenyl; 3-cyanophenyl; 3-diethylmalonylallylphenyl; 3- dimethylaminophenyl; 3-ethoxyphenyl; 3-fluoro-5-trifluoromethylphenyl; 3-fluorophenyl; 3- hydroxyphenyl; 3-iodophenyl; 3-methoxyedιyoxyphenyl; 3-methoxyphenyl; 3- methylphenyl; 3-methylsulfonylphenyl; 3-methylthiophenyl; 3-t-butylacrylphenyl; 3- trifloromethyoxyphenyl; 3-trifluoromethylphenyl; 3-vinylpyridinylphenyl; 3,4- dichlorophenyl; 3,4-dimethoxyphenyl; 3,4-methylenedioxyphenyl; 3,4,5-trimethoxyphenyl; 3,5-di(trifluoromethyl)phenyl; 3,5-dibromophenyl; 3,5-dichlorophenyl; 3,5- dimethoxyphenyl; 3,5-dimethylphenyl; 4-(2-propyl)phenyl; 4-(2-propyl)oxyphenyl; 4- benzyloxyphenyl; 4-bromophenyl; 4-bromothiophene-2-yl; 4-butoxyphenyl; 4- dimethylaminophenyl; 4-fluoro-3-trifluoromedιylphenyl; 4-methoxyphenyl; 4- neopentylphenyl; 4-phenoxyphenyl; 5-bromothiophene-2-yl; 5-cyclohexyl; 5-cyclopropyl; 5-hexyl; 5-methyl; 5-phenyl; (2-bromo-5-chlorophenyl)methyl; (2-bromophenyl)methyl; and (5-chloro-2-(3-methoxyphenyl)phenyl)methyl.
14. A compound according to Claim 10, or a pharmaceutically acceptable salt or amide thereof, which is
4-am o-5-(4-dimethylanιinophenyl)-7-(4-bromophenyl)pyrido[2,3-d]pyrimidine; 4-am o-5-(4-dimemylarrύnophenyl)-7-(4-dimethylaminophenyl)pyrido[2,3- dlpyrimidine;
4-am o-5-(4-methoxyphenyl)-7-(4-dimethylaminophenyl)pyrido[2,3-dlpyrimidine; 4-amino-5-(4-αimethylarrι ophenyl)-7-(4-memoxyphenyl)pyrido[2,3-dlpyrimid e; ammo-5-(4-(2-propyl)phenyl)-7-(4-methoxyphenyl)pyrido[2,3-d]pyrirnidine;
4-arnino-5-(4-neopentylphenyl)-7-(4-memoxyphenyl)pyrido[2,3-d]pyrimidine; 4-amino-5-(4-butyloxyphenyl)-7-(4-methoxyphenyl)pyrido[2.3-d]pyrimidine;
4-amino-5-(4-me oxyphenyl)-7-(4-bromophenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(4-(2-propyl)oxyphenyl)-7-(4-memoxyphenyl)pyrido[2,3-dlpyrimidine;
4-amino-5-(4-butoxyphenyl)-7-(4-N-formylpiperazinylphenyl)pyrido[2,3- dlpyrimidine; 4-an^no-5-(4-benzyloxyphenyl)-7-(4-memoxyphenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(4-phenoxyphenyl)-7-(4-methoxyphenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(4-(2-propyl)phenyl)-7-(4-diethylmalonylallylphenyl)pyrido[2,3- dlpyrimidine;
4-arnino-5-(4-(2-propyl)phenyl)-7-(4-t-butylacrylphenyl)pyrido[2,3-dlpyrimidine; 4-ammo-5-(3-bromophenyl)-7-(4-dimemylaminophenyl)pyrido[2,3-dlpyrimidine;
4-amino-5-(3,4-dimethoxyphenyl)-7-(4-dimethylaminophenyl)pyrido[2,3- dlpyrimidine;
4-ammo-5-(3-t-butylacrylphenyl)-7-(4-dimethylaminophenyl)pyrido[2,3- dlpyiimidine; 4-ammo-5-(3-memoxyphenyl-7-(4-dimethylaminophenyl)pyrido[2,3-d]pyrimidine;
4-an no-5-(3,5-dimethox5φhenyl-7-(4-dimethylaminophenyl)pyrido[2,3- dlpyrimidine;
4-arn o-5-(3-dieAylmalonylallylphenyl)-7-(4-dimethylaminophenyl)pyrido[2,3- dlpyrimidine; 4-anιino-5-(3-vinylpyrim^ylphenyl)-7-(4-dimemylaminophenyl)pyrido[2,3- d]pyrimidine;
4-amino-5-(3-ttifluoromethylphenyl)-7-(4-dimethylarninophenyl)pyrido[2,3- dlpyrimidine;
4-amino-5-(3-carboxamidophenyl)-7-(4-dimethylaminophenyl)pyrido[2,3- dlpyrimidine;
4-arnmo-5-(3-cyanophenyl)-7-(4-c methylammophenyl)pyrido[2,3-dlpyrimidine;
4-ammo-5-(3-benzyloxyphenyl)-7-(4-dimeΛylarninophenyl)pyrido[2,3-dlpyrimidine;
4-amino-5-(3-methoxyphenyl)-7-(4-memoxyphenyl)pyrido[2.3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(4-butoxyphenyl)pyrido[2,3-dlpyrimidine; 4-amino-5-(3-(2-pyridyl)phenyl)-7-(4-dimethylaminophenyl)pyrido[2,3- dlpyrimidine;
4-arnmo-5-(3-methylphenyl)-7-(4- ^ethylarninophenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-chlorophenyl)-7-(4-dimethylaminophenyl)pyrido[2,3-dlpyrimidine; 4- amino - 3-fluorophenyl)-7-(4-m^ethylar nophenyl)pyrido[2,3-dlpyrimidine; 4-amino ■5- 3-bromophenyl)-7-(4-methoxyphenyl)pyrido[2,3-d]pyrimidine;
4- amino ■5- 3-me oxyphenyl)-7-(4-bromophenyl)pyrido[2,3-dlpyrimidine; 4-amino •5- 3-bromophenyl)-7-phenylpyrido [2,3-d]pyrimidine; 4-amino •5- 3-bromophenyl)-7-(4-ethylphenyl)pyrido[2,3-d]pyrimidine; 4- amino ■5- 3-bromophenyl)-7-(4-bromophenyl)pyrido[2,3-dlpyrimidine; 4- amino ■5- 3-bromophenyl)-7-(4-cyanophenyl)pyrido[2,3-dlpyrimidine;
4- amino -5- 3-bromophenyl)-7-(4-hydroxyphenyl)pyrido[2,3-d]pyrimidine; 4- amino ■5- 3-iodophenyl)-7-(4-dimethylaminophenyl)pyrido[2,3-dlpyrimidine; 4- amino ■5- 3-emoxyphenyl)-7-(4-dimemylaminophenyl)pyrido[2,3-d]pyrimidine; 4- amino ■5- 3-trifloromethyoxyphenyl)-7-(4-dimethylaminophenyl)pyrido[2,3- dlpyrimidine; 4- amino- ■5- 3,5-dichlorophenyl)-7-(4-dimethylaminophenyl)pyrido[2,3-d]pyrimidine; 4- amino •5- 3-bromo-4-fluorophenyl)-7-(4-dimethylaminophenyl)pyrido[2,3- dlpyrimidine; 4- amino- •5- 3-hydroxyphenyl)-7-(4-dimethylan inophenyl)pyrido[2,3-dlpyrimidine; 4- amino ■5- 3-bromophenyl)-7-(4-moφholmylphenyl)pyrido[2,3-dlpyrimidine;
4-amino- ■5- 3- bromophenyl)-7 -(4-piperidinylphenyl)pyrido [2,3 -dlpyrimidine; 4- mino- ■5- 3-bromophenyl)-7-(4-(imidazol-l-yl)phenyl)pyrido[2,3-dlpyrimidine; 4- amino- ■5- 3-bromophenyl)-7-(4-chlorophenyl)pyrido[2,3-d]pyrimidine; 4- amino ■5- 3-bromophenyl)-7-(4-isopropylphenyl)pyrido[2,3-dlpyrimidine; 4- amino- ■5- 3-bromophenyl)-7-(4-trifluorophenyl)pyrido[2,3-dlpyrimidine;
4- amino- ■5- 3-bromophenyl)-7-(4-m^dιylarninophenyl)pyrido[2,3-d]pyrimidine;
4-amino- •5- 3-bromophenyl)-7-(3,4,5-trimethoxyphenyl)pyrido[2,3-d]pyrimidine;
4- amino- •5- 3-(3-me oxybenzyl)phenyl)-7-(4-dimeuhylaminophenyl)pyrido[2,3- dlpyrimidine; 4- amino -5- 3-memoxyemyoxyphenyl)-7-(4-dime ylaιτιinophenyl)pyrido[2,3- dlpyrimidine;
4- amino 3,4-methylenedioxyphenyl)-7-(4-dimethylaminophenyl)pyrido[2,3- dlpyrimidine; 4- amino 3-bromophenyl)-7-(4-ethoxyphenyl)pyrido[2,3-dlpyrimidine; 4- amino 3-bromophenyl)-7-(2'-thiophene)pyrido[2,3-dlpyrimidine;
4- amino 3-bromophenyl)-7-(4-fluorophenyl)pyrido[2,3-d]pyrimidine;
4-amino 3-dimeuiylaminophenyl)-7-(4-dimethylaminophenyl)pyrido[2,3- dlpyrimidine;
4- amino -5-phenyl-7-(4-dimethylaminophenyl)pyrido[2,3-d]pyrimidine; 80 4-amino-5-(3,4,5-ttimethoxyphenyl)-7-(4-dimethylarninophenyl)pyrido[2,3- djpyrimidine;
4-amino-5- 3-bromophenyl)-7-(4-nitrophenyl)pyrido[2,3-dlpyrimidine; 4-amino-5- 3-bromophenyl)-7-(4-iodophenyl)pyrido[2,3-d]pyrimidine; 4-amino-5- 3-bromophenyl)-7-(3,4-methylenedioxyphenyl)pyrido[2,3-d]pyrimidine;
85 4-amino-5- thiophen-2-yl)-7-(4-moφholinylphenyl)pyrido [2,3-dlpyrimidine; 4-amino-5- 3,5-dimethoxyphenyl)-7-(thiophen-2-yle)pyrido [2,3-dlpyrimidine; 4-amino-5- 3-bromophenyl)-7-(4-carboxamidophenyl)pyrido[2,3-d]pyrimidine; 4-amino-5- 3-bromophenyl)-7-(4-(2-methoxy)ethoxyphenyl)pyrido[2,3- dlpyrimidine;
90 4-amino-5- 3,5-dimethoxjφhenyl)-7-(4-moφholinylphenyl)pyrido[2,3-dlpyrimidine; 4-amino-5- 3-tιifluoromethylphenyl)-7-(thiophene-2-yl)pyrido [2,3-dlpyrimidine; 4-amino-5- ;3-bromophenyl)-7-(4-aminophenyl)pyrido[2,3-dlpyrimidine; 4-amino-5- 3-bromo-4-fluorophenyl)-7-(thiophene-2-yl)pyrido [2,3-dlpyrimidine; 4-amino-5- 3-bromo-4-fluorophenyl)-7-(2-furanyl)pyrido [2,3-d]pyrimidine;
95 4-amino-5- 3,5-dimethoxyphenyl)-7-(4-iodophenyl)pyrido[2,3-dlpyrimidine; 4-amino-5- 3,5-dimethoxyphenyl)-7-(4-imidazolylphenyl)pyrido[2,3-dlpyrimidine; 4-amino-5- 3,5-dimethoxyphenyl)-7-(4-(thiophene-2-yl)phenyl)pyrido[2,3- dlpyrimidine;
4-amino-5- 3,5-dimeΛoxyphenyl)-7-(4-(3-pyridyl)phenyl)pyrido[2,3-dlpyrimidine;
100 4- amino- 5- -bromophenyl)-7-(4-(4-methylpiperidinyl)phenyl)pyrido[2,3- dlpyrimidine;
4-amino-5- 3-bromophenyl)-7-(4-pyrrolidinylphenyl)pyrido[2,3-d]pyrimidine; 4-amino-5- 4-bromoΛiophene-)-7-(4-dimemylarmnophenyl)pyrido[2,3-d]pyrimidine; 4-amino-5- 4-bromothiophene-2-yl)-7-(4-moφhohnylphenyl)pyrido[2,3-
105 dlpyrimidine;
4-moφholinyl-5-(3-bromophenyl)-7-(4-dimethylaminophenyl)pyrido[2,3- dlpyrimidine;
4-amino-5-(5-bromothiophene-2-yl)-7-(4-moφhohnylphenyl)pyrido[2,3- dlpyrimidine;
110 4-ammo-5-(4-bromophenyl)-7-(4-dimemylam ophenyl)pyrido[2,3-dlpyrimidine; 4-arnino-5-(3-bromophenyl)-7-(4-(acetylamino)phenyl)pyrido[2,3-d]pyrimidine; 4-amino-5-(3-bromophenyl)-7-(4-dimethylaπιinophenyl)pyrido[2,3-dlpyrimidine; 4-amino-5-(3,5-dimethoxyphenyl)-7-(5-pyrimidinylphenyl)pyrido[2,3-dlpyrimidine; 4-(4-fluorophenyl)amino)-5-(3-bromophenyl)-7-(4-
115 dimethylaminophenyl)pyrido[2,3-d]pyrimidine; 4-amino-5-(4-bromothiophene-2-yl)-7-(4-pyrcolidinylphenyl)pyrido[2,3- dlpyrimidine;
4-amino-5-(4-bromo iophene-2-yl)-7-(t ophene-2-yl)pyrido[2,3-dlpyrirr dine;
4-amino-5-(3-bromophenyl)-7-(5-(dimethylamino)thiophene-2-yl)pyrido[2,3- 120 dlpyrimidine;
4-amino-5-(3-bromo-5-iodophenyl)-7-(4-(dimethylamino)phenyl)pyrido[2,3- dlpyrimidine;
4-amino-5-(3,5-di(trifluoromethyl)phenyl)-7-(4-(dimethylamino)phenyl)pyrido[2,3- dlpyrimidine; 125 4-amino-5-(3,5-di(trifluoromethyl)phenyl)-7-(4-moφhoUnylphenyl)pyrido[2,3- dlpyrimidine;
4-amino-5-(3,5-dibromophenyl)-7-(4-(dimethylamino)phenyl)pyrido[2,3- dlpyrimidine;
4-amino-5-(3,5-m^romophenyl)-7-(4-moφholinylphenyl)pyrido[2,3-d]pyτimidine; 130 4-amino-5-(4-bromothiophene-2-yl)-7-(4-(4-medιylpiperidinyl)phenyl)pyrido[2,3- dlpyrimidine;
4-amino-5-(3,5-dibromophenyl)-7-(4-(dimethylamino)phenyl)pyrido[2,3- dlpyrimidine;
4-arm^o-5-(3-bromophenyl)-7-(3-(dimethylamino)phenyl)pyrido[2,3-dlpyriιτddine; 135 4-amino-5-(3-bromophenyl)-7-(4-me ylsulfonylphenyl)pyrido[2,3-dlpyrimidine;
4-amino-5-(3-bromophenyl)-7-(3-methoxyphenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(4-(methylmio)phenyl)pyrido[2,3-d]pyrimidine;
4-anrύno-5-(3-bromophenyl)-7-(3,4-dichlorophenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(4-(N-methyl-N-formylamino)phenyl)pyrido[2,3- 140 dlpyrimidine;
4-amino-5-(3-bromophenyl)-7-(4-methylam ophenyl)pyrido[2,3-dlpyrimidine;
4-amino-5-(3-bromo-4-fluorophenyl)-7-(4-methylsuifonylphenyl)pyrido[2,3- dlpyrimidine;
4-arnino-5-(3-bromophenyl)-7-(3-anτino-4-methoxyphenyl)pyrido[2,3-dlpyτimidine; 145 4-arnino-5-(3-bromophenyl)-7-(3-bromo-4-(dimedιylamino)phenyl)pyrido[2,3- dlpyrimidine;
4-amino-5-(3-bromophenyl)-7-(3-medιyl-4-(dimethylamino)phenyl)pyrido[2,3- dlpyrimidine;
4-amino-5-(3-bromophenyl)-7-(4-(N-methyl-N- 150 trifluoroacetylamino)phenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(4-(dimethylamino)-3-fluorophenyl)pyrido[2,3- dlpyrimidine; 4-amino-5-(3-bromophenyl)-7-(4-(N-ethyl-N-formylamino)phenyl)pyrido[2,3- dlpyrimidine; 155 4,4-bis(acetylamino)-5-(3-bromophenyl)-7-(4-(N-methyl-N- acetylamino)phenyl)pyrido[2,3-dlpyrimidine;
4-amino-5-(3-bromophenyl)-7-(4-(N-acetyl-N-methylamino)phenyl)pyrido[2,3- dlpyrimidine;
4-amino-5-(3-bromophenyl)-7-(4-(N-e ylamino)phenyl)pyrido[2,3-dlpyrimidine; 160 4-amino-5-(3-bromophenyl)-7-(4-(N-methyl-N-(2- methoxyethyl)amino)phenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(4-(N-isopropylamino)phenyl)pyrido[2,3- dlpyrimidine;
4-amino-5-(3-bromophenyl)-7-(4-N-ethyl-N-(2- 165 memoxyethyl)amino)phenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(4-N-(3-methoxypropionyl)-N-isopropyl- amino)phenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(4-N-(2-(dimethylamino)ethyl)-N- formylamino)phenyl)pyrido[2,3-d]pyrimidine; 170 4-amino-5-(3-bromophenyl)-7-(4-(N-(2-
(dimethylanιino)e yl)arrdno)phenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(4-(N-methyl-N-(2- cyano)ethylamino)phenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(4-(N-methyl-N-(3- 175 methoxy )propionylarruno)phenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(3-methyl-4-(N-formyl-N- methylamino)phenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(3-methyl-4-(N-methylamino)phenyl)pyrido[2,3- dlpyrimidine; 180 4-amino-5-(3-bromophenyl)-7-(4-(4-methoxy-2-butyl)phenyl)pyrido[2,3- dlpyrimidine;
4-amino-5-(3-bromophenyl)-7-(4-(N-methyl-N-(2-(N- phthaUrnidyl)acetyl)arm^o)phenyl)pyrido[2,3-dlpyrimidine;
4-amino-5-(3-bromophenyl)-7-(3-methyl-4-(N-methyl-N- 185 (ttifluoroacetyl)amino)phenyl)pyrido[2,3-dlpyrimidine;
4-amino-5-(3-bromophenyl)-7-(3-methyl-4-(N-acetyl-N- me ylamino)phenyl)pyrido[2,3-dlpyrimidine;
4-amino-5-(3-bromophenyl)-7-(6-dimethylamino-3-pyridinyl)pyrido[2,3- dlpyrimidine; 190 4-armno-5-(3-cyanophenyl)-7-(4-methylsulfonylphenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-cyanophenyl)-7-(4-(N-methyl-N-formylamino)-phenyl)pyrido[2,3- dlpyrimidine;
4-amino-5-(3-bromophenyl)-7-(6-(N-methyl-N-formylamino)-3- pyridinyl)pyrido[2,3-d]pyrimidine; 195 4-aπιino-5-(3-bromophenyl)-7-(6-moφholinyl-3-pyridinyl)pyrido[2,3-dlpyrimidine;
4-ammo-5-(3-bromophenyl)-7-(6-(N-methyl-N-methoxyethylamino)-3- pyridinyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(6-pynoUm^yl-3-pyrid yl)pyrido[2,3-d]pyrimidine; 4-amino-5-(3-bromophenyl)-7-(2-(dimethylammo)-5-pyrimidinyl)pyrido[2,3- 200 dlpyrimidine;
4-amino-5-(3-bromophenyl)-7-(2-(N-methoxyethyl-N-methyl amino)-5- pyrimidmyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(2-(N-formyl-N-methyl amino)-5- pyriπύdinyl)pyrido[2,3-djpyrimidine; 205 4-arnino-5-(3-bromophenyl)-7-(2-(N-memylamino)5-pyrimidinyl)pyrido[2,3- dlpyrimidine;
4-ar no-5-(3-bromophenyl)-7-(2-(l-pynolidinyl)-5-pyrimidinyl)pyrido[2,3- dlpyrimidine;
4-amino-5-(3-bromophenyl)-7-(2-(l-moφhoUnyl)-5-pyrimidinyl)pyrido[2,3- 210 dlpyrimidine;
4-amino-5-(3-bromophenyl)-7-(6-(2-oxo-3-oxazolidinyl)-3-pyridinyl)pyrido[2,3- dlpyrimidine;
4-amino-5-(3-bromophenyl)-7-(2-pyridyl)pyrido[2,3-dlpyrimidine; 4-amino-5-(3-bromophenyl)-7-(3-pyridyl)pyrido[2,3-dlpyrimidine; 215 4-amino-5-(3-(thiophen-2-yl)phenyl)-7-(4-dimethylaminophenyl)pyrido[2,3- dlpyrimidine; amino-5-(3-(furan-2-yl)phenyl)-7-(4-dimemylarninophenyl)pyrido[2,3- dlpyrimidine;
4-amino-5-(3-(3-methoxyphenyl)phenyl)-7-(4-dimedιylaminophenyl)pyrido[2,3- 220 dlpyrimidine;
4-ammo-5-phenyl-7-(4-αimethylaminophenyl)pyrido[2,3-d]pyrirnidine; 4-armno-5-(3-cUorophenyl)-7-(4-(moφholinyl)phenyl)pyrido[2,3-dlpyrimidine; 4-amino-5-(3-bromo-4-fluorophenyl)-7-(4-(moφhoUnyl)phenyl)pyrido[2,3- dlpyrimidine; 225 4-amino-5-(3-chlorophenyl)-7-(4-iodophenyl)pyrido[2,3-dlpyrimidine;
4-armno-5-(3-chlorophenyl)-7-(4-(miophen-2-yl)phenyl)pyrido[2,3-dlpyrimidine; 4-amino-5-(3-cWorophenyl)-7-(4-(5-pyrirrύdinyl)phenyl)pyrido[2,3-d]pyrimidine; amino-5-(3-bromo-4-fluorophenyl)-7-(4-iodophenyl)pyrido[2,3-dlpyrimidine; 4-amino-5-(4-bromoΛiophene-2-yl)-7-( methoxyphenyl)pyrido[2,3-d]pyriτnidine; 230 4-amino-5-(3-bromophenyl)methyl-7-(4-(dimethylamino)phenyl)pyrido[2,3- dlpyrimidine;
4-ammo-5-(2-phenylethyl)-7-(4-diethylaιτdnophenyl)pyrido[2,3-d]pyrimidine; 4-ammo-5-(2-methylpropyl)-7-(4-diethylaminophenyl)pyrido[2,3-d]pyrimidine; 4-ammo-5-(butyl)-7-(4-diethylaminophenyl)pyrido[2,3-d]pyrimidine; 235 4-amino-5-(2-(4-bromophenyl)ethyl)-7-(4-diethylaminophenyl)pyrido[2,3- dlpyrimidine;
4-arruiιo-5-(butyl)-7-(4-dimemylaminophenyl)pyrido[2,3-dlpyrimidine; ammo-5-(2-(3-cyanophenyl)memyl)-7-(4-dimethylaminophenyl)pyrido[2,3- dlpyrimidine; 240 arrniιo-5-(2-(N-phenylmemoxycarbonyl)aminoethyl)-7-(4- dimethylammophenyl)pyrido[2,3-d]pyrimidine;
4-ammo-5-(cycloheptyl)-7-(4-dimethylammophenyl)pyrido[2,3-d]pyrimidine; 4-amino-5-(2-(5-chloro-2-(thiophen-3-yl)phenylmethyl)-7-(4- dimethylaminophenyl)pyrido[2,3-d]pyrimidine; 245 4-am o-5-(pentyl)-7-(4-diedιylammophenyl)pyrido[2,3-d]pyrimidine;
4-ammo-5-hexyl-7-(4-diethylam ophenyl)pyrido[2,3-dlpyrimidine; 4-amino-5-(2-(3-bromophenyl)ethyl)-7-(4-diethylaminophenyl)pyrido[2,3- dlpyrimidine;
4-amino-5-((2-bromophenyl)methyl)-7-(4-m^thylaminophenyl)pyrido[2,3- 250 dlpyrimidine;
4-ammo-5-cyclopropyl-7-(4-dimethylaιrunophenyl)pyrido[2,3-dlpyrimidine; 4-arrdno-5-cyclohexyl-7-(4-dimemylanιmophenyl)pyrido[2,3-d]pyrimidine; 4-ar no-5-((2-bromo-5-chlorophenyl)memyl)-7-(4-diethylaminophenyl)pyrido[2,3- dlpyrimidine; 255 4-ammo-5-memyl-7-(4-m^thylarrώιophenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(2,3-methylenedioxyphenyl)-7-(4-dimethylaminophenyl)pyrido[2,3- dlpyrimidine;
4-amino-5-(3-fluoro-5-trifluoromethylphenyl)-7-(4- dimethylaminophenyl)pyrido[2,3-d]pyrimidine; 260 4-ammo-5-(2-bromophenyl)-7-(4-dime ylammophenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3,5-dimethylphenyl)-7-(4-dimethylaminophenyl)pyrido[2,3- dlpyrimidine;
4-amino-5-(3,4-dichlorophenyl)-7-(4-dimethylaminophenyl)pyrido[2,3-dlpyrimidine; 4-amino-5-(4-fluoro-3-ttifluoromethylphenyl)-7-(4-
265 dimemylaminophenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromo-5-methoxyphenyl)-7-(4-moφhoUnylphenyl)pyrido[2,3- dlpyrimidine;
4-amino-5-(3-bromo-5-methoxyphenyl)-7-(4-pyrrohdinylphenyl)pyrido[2,3- dlpyrimidine;
270 4-amino-5-(3-bromo-5-medιoxyphenyl)-7-(4-piperidinylphenyl)pyrido[2,3- dlpyrimidine;
4-arrdno-5-(3-bromo-5-methoxyphenyl)-7-(4-m^ethylaminophenyl)pyrido[2,3- dlpyrimidine;
4"amino-5-(3-methylthiophenyl)-7-(4-dimethylaminophenyl)pyrido[2,3-
275 dlpyrimidine;
4-arnino-5-(3-bromo-5-memoxyphenyl)-7-(thiophene-2-yl)pyrido[2,3-dlpyτimidine;
4-amino-5-(2,3-dimethoxyphenyl)-7-(4-dimethylaminophenyl)pyrido[2,3- dlpyrimidine;
4-amino-5-(3-medιylsulfonylphenyl)-7-(4-dιrnedιylaminophenyl)pyrido[2,3-
280 dlpyrimidine; acetylammo-5-(3-bromophenyl)-7-(4-dimethylaminophenyl)pyrido[2,3- dlpyrimidine;
4-formylamino-5-(3-bromophenyl)-7-(4-dimemylarninophenyl)pyrido[2,3- dlpyrimidine;
285 4-(methoxyaceιyl)amino-5-(3-bromophenyl)-7-(4-diedιylaminophenyl)pyrido[2,3- dlpyrimidine;
4-trifluoroacetylammo-5-(3-bromophenyl)-7-(4-dimethylarninophenyl)pyrido[2,3- dlpyrimidine;
4-pentanoylamino-5-(3-bromophenyl)-7-(4-dimetiιylaminophenyl)pyrido[2,3-
290 dlpyrimidine;
4-benzoylan ino-5-(3-bromophenyl)-7-(4-dimethylaminophenyl)pyrido[2,3- dlpyrimidine;
4-(N-BOC-glycyl)amino-5-(3-bromophenyl)-7-(4-dimethylaminophenyl)pyrido[2,3- dlpyrimidine;
295 4-(N-phthahmidylglycyl)amino-5-(3-bromophenyl)-7-(4- dimemylaminophenyl)pyrido[2,3-dlpyrimidine;
4-(emoxycarbonyl)amino-5-(3-bromophenyl)-7-(4-dimethylaminophenyl)pyrido[2,3- d]pyrimidine;
4-(ethylaminocarbonyl)amino-5-(3-bromophenyl)-7-(4-
300 dimethylaminophenyl)pyrido[2,3-dlpyrimidine; 4-allylamino-5-(3-bromophenyl)-7-(4-dimethylaminophenyl) pyrido[2,3- dlpyrimidine;
4-(2-(N,N-dimedιylamino)ethylamino)-5-(4-bromophenyl)-7-(4- dimethylaminophenyl) pyrido[2,3-d]pyrimidine; 305 4-(4-(N,N-dimethylamino)butylamino)-5-(3-bromophenyl)-7-(4- dimeώylaminophenyl) pyrido[2,3-dlpyrimidine;
4-(N-allyl-N-formylamino)-5-(4-dimethylaminophenyl)-7-(4- bromophenyl)pyrido[2, 3-d]pyrimidine;
4-diacetylam o-5-(p-dime ylaminophenyl)-7-(4- 310 bromophenyl)pyrido[2,3-dlpyrimidine;
4-arrύno-5-(3-bromophenyl)-7-(5-an^no-2-pyridyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(5-dimemylamino-2-pyridyl)pyrido[2,3-dlpyrimidine;
4-arnmo-5-(3-bromophenyl)-7-(5-dimethylamino-2- pyrazinyl)pyrido [2,3-d]pyrimidine; 315 4-amino-5-(3-bromophenyl)-7-(2-oxobenzoxazolin-6-yl)pyrido[2,3-dlpyrimidine;
4-amino-5-(3-bromophenyl)-7-(l-methyl-2-oxobenzoxazohn-6- yl)pyrido[2,3-dlpyrimidine;
4-amino-5-((5-chloro-2-(3-methoxyphenyl)phenyl)methyl)-7-(4- dimethylarn ophenyl)pyrido[2,3-dlpyrimidine; 320 4-ammo-5-((thiophene-2-yl)methyl)-7-(4-diethylaminophenyl)pyrido[2,3- dlpyrimidine;
4-ammo-5-((thiophene-3-yl)methyl)-7-(4-diethylaminophenyl)pyrido[2,3- dlpyrimidine;
4-amino-5-((2-bromophenyl)methyl)-7-(4-dimethylaminophenyl)pyrido[2,3- 325 dlpyrimidine;
4-amino-5-(3-bromophenyl)-7-(4-(N-formyl-N-(2- memoxyethyl)amino)phenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(4-(N-(2-methoxyethyl)amino)phenyl)pyrido[2,3- dlpyrimidine; 330 4-amino-5-(3-bromophenyl)-7-(4-(N-methyl-N-((2- dimethylarnino)ethyl)amino)phenyl)pyrido[2,3-dlpyrimidine;
4-amino-5-(3-bromophenyl)-7-(4-(2- methoxy)acetylaιτdno)ethyl)am o)phenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-((4-formylamino)phenyl)pyrido[2,3-d]pyrimidine; 335 4-anrιino-5-(3-bromophenyl)-7-(4-(2-(dimethylaπιino)acetylarnino)phenyl)pyrido[2,3- dlpyrimidine; 4-amino-5-(3-bromophenyl)-7-(4-(2-oxo-3-oxazolidinyl)phenyl)pyrido[2,3- dlpyrimidine;
4-armno-5-(3-bromophenyl)-7-(6-(2-propyl)-3-pyridinyl)pyrido[2,3-dlpyrimidine; 340 4-amino-5-(3-bromophenyl)-7-(3-methyl-4-pyrrolidinylphenyl)pyrido[2,3- d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(6-imidazolyl-3-pyridinyl)pyrido[2,3-dlpyrimidine; 4-amino-5-phenylmethyl-7-(4-die ylaminophenyl)pyrido[2,3-d]pyrimidine; 4-arnino-5-(2-(3-aminopropynyl)phenylmethyl)-7-(4-diethylaminophenyl)pyrido[2,3- 345 dlpyrimidine;
4-amino-5-(l-(3-bromophenyl)ethyl)-7-(4-diethylaminophenyl)pyrido[2,3- dlpyrimidine;
4-ammo-5-(4-dimemylarr nophenyl)-7-(4-bromophenyl)pyrido[2,3-dlpyrimidine; 4-amino-5-(2-furanyl)-7-(4-(N-moφholinyl)phenyl)pyrido[2,3-dlpyrimidine; 350 4-armno-5-(3-bromophenyl)-7-(2-dimethylammo-5-pyrimidinyl)pyrido[2,3- dlpyrimidine;
4-arrdno-5-(3-bromophenyl)-7-(4-(ureido)phenyl)pyrido[2,3-dlpyrimidine; 4-ammo-5-(l-phenylmemyl-3-piperidinyl)-7-(4-diethylarninophenyl)pyrido[2,3- d]pyrimidine; 355 4-amino-5-(3-bromophenyl)-7-(6-(3-methyl-5-isoxazolyl))-3- pyridinyl)pyrido[2,3-d]pyrimidine;
4-amino-5- (3-bromophenyl)-7- (6-chloro-3-pyridinyl)pyrido [2,3-d]pyrimidine; 4-anτino-5-(3-bromophenyl)-7-(6-methoxy-3-pyridinyl)pyrido[2,3-dlpyrimidine; 4-amino-5-(3-bromophenyl)-7-(6-(l,2,4-ttiazol-4-yl)-3-pyridinyl)pyrido[2,3- 360 dlpyrimidine;
4-amino-5-(3-bromophenyl)-7-(2-moφholinyl-5-pyrimidinyl)pyrido[2,3- dlpyrimidine;
4-am o-5-(2-t azolyl)-7-(4-pyrrolidmylphenyl)-pyrido[2,3-d]pyrimidine; 4-amino-5-(3-bromophenyl)-7-(6-pyrazolyl-3-pyridinyl))-pyrido[2,3- 365 dlpyrimidine;
4-amino-5-(3-bromophenyl)-7-(4-(l-methyl-ureido)phenyl)-pyrido[2,3- dlpyrimidine;
4-am o-5-(3-bromophenyl)-7-(4-(N-meuιyl-N-(2-pyrimidmyl)amino)phenyl)- pyrido[2,3-d]pyrimidine; 370 4-amino-5-(3-bromophenyl)-7-(3-fluoro-4-(N-formyl-N-medιylamino)phenyl)- pyrido[2.3-d]pyrimidine:
4-formylamino-5-(3-bromophenyl)-7-(3-fluoro-4-(N-formyl-N- me ylaπτino)phenyl)-pyrido[2,3-dlpyrimidine; 4-ammo-5-(3-bromophenyl)-7-(4-(N-memyl-N-methylsulfonylamino)- 375 phenyl)pyrido[2,3-dlpyrimidine;
4-amino-5-(3-bromophenyl)-7-(6-(N-methyl-N-methylsulfonylamino)-3- pyridinyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(l-methyl-5-indohnyl)pyrido[2,3-dlpyrimidine; 4-amino-5-(3-bromophenyl)-7-(l-methyl-5-benzimidazolyl)pyrido[2,3- 380 dlpyrimidine;
4-arrr o-5-(3-bromophenyl)-7-(6-dimedιylamino-3-pyridazinyl)pyrido[2,3- dlpyrimidine;
4-amino-5-(3bromophenyl)-7-(6-moφholinyl-3-pyridazinyl)pyrido[2,3- dlpyrimidine; 385 4-amino-5-(3-bromophenyl)-7-(6-pyrroUdinyl-3-pyridazinyl)pyrido[2,3- dlpyrimidine;
4-amino-5-(3-bromophenyl)-7-(5-moφholinyl-2-pyrazinyl)pyrido[2,3- dlpyrimidine;
4-amino-5-(3-bromophenyl)-7-(5-(N-(2-methoxyethyl)-N-methylamino)-2- 390 pyraz yl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(4-(moφholinylmethyl)-phenyl)pyrido[2,3- dlpyrimidine;
4-amino-5-(3-bromophenyl)-7-(5-(N,N-bis(2-methoxyethyl)amino)-2- pyridinyl)pyτido[2,3-d]pyrimidine; 395 4-amino-5-(3-bromophenyl)-7-(4-(imidazolylmethyl)-phenyl)pyrido[2,3- dlpyrimidine;
4-amino-5-(3-bromophenyl)-7-(5-(l-moφholinyl)-2-pyridinyl)pyrido[2,3- dlpyrimidine;
4-am o-5-(3-bromophenyl)-7-(4-((dimethylamino)methyl)-phenyl)pyrido[2,3- 400 dlpyrimidine;
4-amino-5-(3-bromophenyl)-7-(5-(4-hydroxy-l-piperidinyl)-2- pyridinyl)pyrido[2,3-dlpyrimidine;
4-amino-5-(3-bromophenyl)-7-(5-(N-formyl- -medιylamino)-2- pyridinyl)pyrido[2,3-d]pyrimidine; 405 4-amino-5-(3-bromophenyl)-7-(5-(2-propenyl)-2-pyridinyl)pyrido[2,3- dlpyrimidine;
4-amino-5-(3-bromophenyl)-7-(3-(2-methoxyethyl)-2-oxo-6- benzoxazolyl)pyrido[2,3-d]pyrimidine:
4-aιτ no-5-(3-bromophenyl)-7-(4-(l-(N-foιmylamino)-ethyl)phenyl)pyrido[2,3- 410 dlpyrimidine; 4-(memylamino)-5-(3-bromophenyl)-7-(4-dimethylaminophenyl)pyrido[2,3- dlpyrimidine hydrochloride;
4-(2-methoxyethylamino)-5-(3-bromophenyl)-7-(4- dimethylammophenyl)pyrido[2,3-dlpyrimidine hydrochloride; 415 4-amino-5-(3-bromophenyl)-7-(4-(l-methyl-2-imidazolyl)phenyl)pyrido[2,3- dlpyrimidine trihydrochloride;
4-am o-5-(3-bromophenyl)-7-(4-(aminome yl)phenyl)pyrido[2,3-d]pyrimidine; 4-ar ^o-5-(3-bromophenyl)-7-(2-bromo-4-(dimethylamino)phenyl)pyrido[2,3- dlpyrimidine; 420 4-ammo-5-(3-bromophenyl)-7-(4-(dimemylaπιinoethyl)phenyl)pyrido[2,3- dlpyrimidine;
4-amino-5-(3-bromophenyl)-7-(4-(3-(dimethylarnino)propynyl)phenyl)pyrido[2,3- dlpyrimidine;
4-amino-5-(3-bromophenyl)-7-(4-(3-amino-3-methylbutynyl)phenyl)pyrido[2,3- 425 dlpyrimidine;
4-amino-5-(3-bromophenyl)-7-(4-dimethylphosphonatophenyl)pyrido[2,3- dlpyrimidine;
4-amino-5-(3-bromophenyl)-7-(4-(3-(methoxypropynyl)pyrido[2,3-d]pyrimidine; 4-amino-5-(3-bromophenyl)-7-(4-carboxyphenyl)pyrido[2,3-d]pyrimidine; 430 4-amino-5-(3-bromophenyl)-7-(4-methyl-3-oxo-2H-4H-pyrido[3,2-bl-l,4-oxazin-
7-yl)pyrido[2,3-dlpyrimidine;
4-am o-5-(3-bromophenyl)-7-(4-(2-(m^ethylamino)ethyl)-3-oxo-2H-4H- pyrido[3,2-b]- 1 ,4-oxazin-7-yl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(2,3-dihydro-3-(dimethylaminoethyl)-2- 435 oxobenzoxazol-6-yl)pyrido[2,3-dlpyrimidine;
4-amino-5-(3-bromophenyl)-7-(4-methyl-3-oxo-2H-4H-benzo-l,4-oxazin-7- yl)pyrido[2,3-dlpyrimidine;
4-amino-5-(3-bromophenyl)-7-(2,2,4-trimethyl-3-oxo-2H-4H-benzo-l,4-oxazin-7- yl)pyrido[2,3-dlpyrimidine; 440 4-am o-5-cyclohexyl-7-(4-(2-dime ylamino)ethyl)-2H-4H-benzo-3-oxo- 1 ,4- oxazin-7-yl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(5-(l-methylethyl)-2-pyridyl)pyrido[2,3- dlpyri idine;
4-amino-5-(3-bromophenyl)-7-(5-piperidin-l-ylpyrid-2-yl)pyrido[2,3-d]pyrimidine; 445 4-amino-5-(l-(4-bromophenyl)ethyl)-7-(6-moφholinylpyrid-3-yl)pyrido[2,3- dlpyrimidine; 4-amino-5-(3-bromophenyl)-7-(4-((N-formylamino)methyl)phenyl)pyrido[2,3- dlpyrimidine;
4-amino-5-(3-bromophenyl)-7-(4-( 1 -methyl- 1 -(N-methylamino)ethyl)phenyl)- 450 pyrido[2.3-d]pyrimidine;
4-arnino-5-(3-bromophenyl)-7-(4-(l-(dimethylamino)-l- methylethyl)phenyl)pyrido[2,3-dlpyrimidine;
4-amino-5-(3-bromophenyl)-7-(N-acetyl-5-indoUnyl)pyrido[2,3-dlpyrimidine; 4-amino-5-cyclohexyl-7-(6-chloro-3-pyridyl)pyrido[2,3-dlpyrimidine; 455 4-ammo-5-(l-(2-bromophenyl)emyl)-7-(6-diethylamino-3-pyridyl)pyrido[2,3- dlpyrimidine;
4-amino-5-(l-(2-bromophenyl)ethyl)-7-(6-moφhoUnyl-3-pyridyl)pyrido[2,3- dlpyrimidine;
4-ammo-5-(l-(2-bromophenyl)emyl)-7-(4-(N-memyl-N-formyl)amino)- 460 phenyl)pyrido[2,3-d]pyrimidine;
4-ammo-5-cyclohexyl-7-(6-moφhoUnyl-3-pyridyl)pyrido[2,3-dlpyrimidine; 4-amino-5-((2-bromophenyl)methyl)-7-(6-moφholinyl-3-pyridyl)pyrido[2,3- dlpyrimidine;
4-amino-5-(4-tettahydropyranyl)-7-(6-moφhoUnyl-3-pyridyl)pyrido[2,3- 465 dlpyrimidine;
4-arrdno-5-cyclohexyl-7-(6-dimemylarruno-3-pyridyl)pyrido[2,3-dlpyrimidine; 4-am o-5-(l-ethylpropyl)-7-(6-dimethylamino-3-pyridyl)pyrido[2,3-dlpyrimidine; 4-arrr o-5-cyclopentyl-7-(6-moφhol yl-3-pyridyl)pyrido[2,3-d]pyrimidine; 4-amino-5-cyclohexyl-7-(2-cWoro-3-pyridyl)pyrido[2,3-dlpyrimidine; 470 4-amino-5-(3,5-dime ylcyclohexyl)-7-(6-dimethylamino-3-pyridyl)pyrido[2,3- dlpyrimidine;
4-amino-5-((N-(benzyloxycarbonyl)-4-piperidinyl)methyl)-7-(6-moφholinyl-3- pyridyl)pyrido[2,3-dlpyrimidine;
4-aιnino-5-cyclohexyl-7-(6-bromo-3-pyridyl)pyrido[2,3-d]pyrimidine; 475 4-arnino-5-cyclohexyl-7-(3-cyanophenyl)pyrido[2,3-d]pyrimidine;
4-am o-5-(l-(2-bromophenyl)ethyl)-7-(6-dimethylamino-3-pyridazinyl)pyrido[2,3- dlpyrimidine:
4-amino-5-(3-bromophenyl)-7-(6-imidazolyl-3-pyridazmyl)pyrido[2,3-d]pyrimidine; 4-amino-5-(3-bromophenyl)-7-(6-(azacycloheptanyl)-3-pyridazinyl)pyrido[2,3- 480 dlpyrimidine:
4-amino-5-(3-bromophenyl)-7-(6-(N-methyl-N-(l-methylethyl))amino)-3- pyridazinyl)pyrido[2,3-d]pyιimidine; 4-amino-5-(l-(2-bromophenyl)ethyl)-7-(6-moφhoUnyl-3-pyridazinyl)pyτido[2,3- dlpyrimidine; 485 4-amino-5-cyclohexyl-7-(6-(4-ace1ylpiperazinyl)-3-pyridyl)pyrido[2,3-dlpyrimidine;
4-amino-5-cyclohexyl-7-(6-(4-acetyl-l,4-diazacycloheptanyl)-3-pyridyl)pyrido[2,3- dlpyrimidine:
4-amino-5-cyclohexyl-7-(6-(4-methyl-l,4-diazacycloheptanyl)-3- pyridyl)pyrido[2,3-d]pyrimidine; 490 4-arnino-5-cyclohexyl-7-(6-(N-methyl-N-(2-(2-pyridyl)ethyl)amino)-3- pyridyl)pyrido[2,3-d]pyrimidine;
4-ammo-5-cyclohexyl-7-(6-2-(N-(N N'-dimethylanιinoethyl)-N-methylamino)-3- pyridyl)pyrido[2,3-d]pyrimidine;
4-ammo-5-cyclohexyl-7-(6-azetidmyl-3-pyridyl)pyrido[2,3-d]pyrimidine; 495 4-ammo-5-cyclohexyl-7-(6-(3-(N-methylacetamido)pyrrolidinyl)pyridyl)pyrido[2,3- dlpyrimidine;
4-arrι o-5-cyclohexyl-7-(6-(3-(formamido)pyrrohdinyl)pyridyl)pyrido[2,3- dlpyrimidine;
4-amino-5-cyclohexyl-7-(4-oxo-l-phenyl-l,3,8-triazaspiro[4.5[decan-8- 500 yl)pyrido[2,3-d]pyrimidine;
4-amino-5-cyclohexyl-7-(6-(2-methoxymethyl)pyrrolidin-l-yl)pyridyl)pyrido[2,3- dlpyrimidine;
4-amino-5-cyclohexyl-7-(6-(N-methoxyethyl-N-propylamino)pyridyl)pyrido[2,3- dlpyrimidine; 505 4-amino-5-cyclohexyl-7-(N-methyl-N-(2,2-dimethoxyethyl)amino)pyrido[2,3- dlpyrimidine;
4-arnmo-5-cyclohexyl-7-(6-(4-(dimethylarrrino)piperidinyl)pyridyl)pyrido[2,3- dlpyrimidine;
4-amino-5-cyclohexyl-7-(6-(4-(aminocarbonyl))piperidinyl)pyridyl)pyrido[2,3- 510 dlpyrimidine;
4-ar no-5-cyclohexyl-7-(N-memyl-N-(3-(diedιylamino)propyl)aminopyrid-3- yl)pyrido[2,3-dlpyrimidine;
4-animo-5-cyclohexyl-7-(6-(N-memyl-N-(4-pyridyl)ethylamino)pyrid-3- yl)pyrido[2,3-dlpyrimidine; 515 4-amino-5-cyclohexyl-7-(6-(N-methyl-N-(3-pyridylmethylamino)pyrid-3- yl)pyrido[2,3-d]pyrimidine;
4-amino-5-(l-(2-bromophenyl)ethyl)-7-(l-methyl-5-indolyl)pyrido[2,3- dlpyrimidine: 4-amino-5-(l-(2-bromophenyl)ethyl)-7-(l-methyl-2,3-dioxo-5-indolyl)pyrido[2,3- 520 dlpyrimidine;
4-amino-5-(3-bromophenyl)-7-(3-fluoro-4-(l-moφhoUnyl)phenyl)pyrido[2,3- dlpyrimidine;
4-amino-5-(3-bromophenyl)-7-(4-hydroxy-3-nitrophenyl)pyrido[2,3-dlpyrimidine; 4-amino-5-(3-bromophenyl)-7-(6-(4,4-ethylenedioxypiperidinyl)-3- 525 pyridyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(6-(4-oxopiperidinyl)-3-pyridyl)pyrido[2,3- dlpyrimidine;
4-amino-5-(3-bromophenyl)-7-(6-(4-formylpiperazinyl)-3-pyridyl)pyrido[2,3- dlpyrimidine; 530 4-amino-5-(3-bromophenyl)-7-(6-(4-methylpiperazinyl)-3-pyridyl)pyrido[2,3- dlpyrimidine;
4-amino-5-(3-bromophenyl)-7-(6-thiomoφhoUnyl-3-pyridyl)pyrido[2,3- dlpyrimidin;
4-amino-5-(3-bromophenyl)-7-(6-(4,4-dioxothiomoφhohnyl)-3-pyridyl)pyrido[2,3- 535 dlpyrimidine;
4-armno-5-(2-bromophenyl)-7-(6-moφholinyl-3-pyridyl)pyrido[2,3-dlpyrimidine; 4-amino-5-(3-bromo-4-methoxyphenyl)-7-(6-moφholinyl-3-pyridyl)pyrido[2,3- dlpyrimidine;
4-ammo-5-(4-bromophenyl)-7-(6-moφhoUnyl-3-pyridyl)pyrido[2,3-d]pyrimidine; 540 4-ammo-5-(3-chlorophenyl)-7-(6-moφhoUnyl-3-pyridyl)pyrido[2,3-dlpyrimidine;
4-amino-5-(3-bromophenyl)-7-(5-chloro-6-moφhoUnyl-3-pyridyl)pyrido[2,3- dlpyrimidine;
4-amino-5-(3-bromophenyl)-7-(6-(N-oxidomoφholinyl)-3-ρyridyl)pyrido[2,3- dlpyrimidine; 545 4-amino-5-(3-bromophenyl)-7-(6-(N-(2-hydroxyethoxyethyl)amino)-3- pyridyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(6-(N-(2-hydroxyethoxyethyl)-N-formylamino)-3- pyridyl)pyrido[2,3-dlpyrimidine;
4-amino-5-(3-bromophenyl)-7-(6-(N-(2-hydroxyethoxyethyl)-3-pyridyl-N- 550 oxide)pyrido[2,3-dlpyrimidine;
4-amino-5-(3-bromophenyl)-7-(6-(3-hydroxy)moφholinyl)-3-pyridyl)pyrido[2,3- dlpyrimidine; l-(5-(4-amino-5-(3-bromophenyl)pyrido[2,3-d]pyrimidin-7-yl)-2-pyridyl)- piperidine-4-phosphate, disodium salt; 555 4-amino-5-(3-bromophenyl)-7-(4-methylenylpiperidinyl)-3-pyridyl)pyrido[2,3- dlpyrimidine;
4-amino-5-(3-bromophenyl)-7-(4-hydroxy-4-(hydroxymethyl)piperidinyl)-3- pyridyl)pyrido[2,3-dlpyrimidine;
4-amino-5-(3-bromophenyl)-7-(6-(4,4-ethylenedioxypiperidinyl)-3- 560 pyridyl)pyrido[2,3-d]pyrimidine;
4-arnino-5-cyclohexyl-7-(6-(4-oxo-piperidinyl)-3-pyridyl)pyrido[2,3-d]pyrimidine; 4-amino-5-cyclohexyl-7-(6-(4-methylenylpiperidinyl)-3-pyridyl)pyrido[2,3- dlpyrimidine;
4-N-(iminomethyl)amino-5-cyclohexyl-7-(6-dimedιylamino-3-pyridyl)pyrido[2,3- 565 dlpyrimidine.
15. A pharmaceutical composition comprising a compound according to Claim 10 and a pharmaceutically acceptable carrier.
16. A compound of formula HI
Figure imgf000166_0001
wherein X is selected from -OH or halogen and R and R4 are as defined above and a dashed line — indicates a double bond is optionally present. 5
17. A compound according to Claim 16 wherein said compound is an intermediate in a process to produce a compound according to Claim 10 or 11.
18. A process for the preparation of an adenosine kinase inhibiting compound having die formula
N R3 H
2 NXN 4 , (I) wherein R1 and R2 are hydrogen, the method comprising
5 (a) reacting a ketone having the formula R4-CO-CH3, wherein R4 is as defined above, with an aldehyde having the formula R3-CHO, wherein R3 is as defined above and malononitrile in the presence of an ammonium salt under anhydrous conditions and isolating a first intermediate compound having the structure
Figure imgf000167_0001
(b) reacting the first intermediate compound with formamide at reflux for from about 1 to about 8 hours, and isolating the compound of formula (I) which has a double bond between the 5,6 carbons and a double bond between the 7 carbon and die 8 nittogen and
(c) optionally reducing the compound from step (b) to form a partially reduced or fully reduced right side of formula I by catalytic hydrogenation.
19. A process for the preparation of an adenosine kinase inhibiting compound having the formula
Figure imgf000167_0002
, (I) wherein R1 and R2 are hydrogen, the metiiod comprising (a) reacting a ketone having the formula R -CO-CH3, wherein R4 is as defined above, with an dicyanoalkene compound having the formula R3-CH=C(CN)2, wherein R3 is as defined above by heating at reflux and isolating a first intermediate compound having the structure
Figure imgf000167_0003
(b) reacting die first intermediate compound with formamide at reflux for from about 1 to about 8 hours, and isolating the compound of formula (I) which has a double bond between the 5,6 carbons and a double bond between the 7 carbon and the 8 nittogen and
(c) optionally reducing the compound from step (b) to form a partially reduced or fully reduced right side of formula I by catalytic hydrogenation.
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IL131618A0 (en) 2001-01-28
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AR012436A1 (en) 2000-10-18
PL336304A1 (en) 2000-06-19
CA2286909A1 (en) 1998-10-22
BG103842A (en) 2000-06-30
SK141799A3 (en) 2000-08-14
HUP0001434A2 (en) 2000-10-28
NO995036L (en) 1999-10-15
CN1252070A (en) 2000-05-03
BR9809055A (en) 2000-08-08
AU7108398A (en) 1998-11-11
ZA983177B (en) 1999-01-22
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