WO2000023444A1 - 5,7-disubstituted-4-aminopyrido[2,3-d]pyrimidine compounds - Google Patents

5,7-disubstituted-4-aminopyrido[2,3-d]pyrimidine compounds Download PDF

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WO2000023444A1
WO2000023444A1 PCT/US1999/024901 US9924901W WO0023444A1 WO 2000023444 A1 WO2000023444 A1 WO 2000023444A1 US 9924901 W US9924901 W US 9924901W WO 0023444 A1 WO0023444 A1 WO 0023444A1
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amino
pyrido
bromophenyl
djpyrimidine
pyridyl
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PCT/US1999/024901
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French (fr)
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Shripad S. Bhagwat
Chih-Hung Lee
Marlon D. Cowart
Jeffrey A. Mckie
Anne Laure Grillot
Andrew O. Stewart
Guo Zhu Zheng
Richard J. Perner
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Abbott Laboratories
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • 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
    • A61P9/00—Drugs for disorders of the cardiovascular system

Definitions

  • the present invention relates to a method of inhibiting adenosine kinase by administering 5,7-disubstituted-4-aminopyrido[2,3-d]pyrimidine compounds to a mammal in need of such treatment, 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 adenosine monophosphate (AMP), using adenosine triphosphate (ATP), preferentially, as the phosphate source.
  • AMP adenosine monophosphate
  • ATP adenosine triphosphate
  • Magnesium is also required for the reaction, and the true cosubstrate is probably the MgATP 2" complex (Palella, et al.. J. Biol. Chem. 1980. 255: 5264-5269).
  • Adenosine kinase has been isolated from yeast (Leibach, et al., Hoppe-Seyler's Z. Phvsiol. Chem. 1971, 352: 328-344), a variety of mammalian sources (e.g. Miller, et al., J. Biol.
  • Adenosine kinase is a key enzyme in the control of intracellular adenosine concentration (Arch and Newsholme. Essavs Biochem. 1978. 14: 82-123).
  • Adenosine is a purine nucleoside that is an intermediate in the 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 PI 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).
  • 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, 4: 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 Psvchopharmacology: 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).
  • Adenosine also, inhibits certain neutrophil functions and exhibits anti-inflammatory effects (Cronstein, J. Appl. Phvsiol. 1994. 76: 5-13).
  • An AK inhibitor has been reported to decrease paw swelling in a model of adjuvant arthritis in rats (Firestein, et.al., 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 A, receptor activation on adipocytes plays a role in diabetes by inhibiting lipolysis (Londos. et al.. Proc.
  • 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.
  • Adenosine has a half- life measured in seconds in extracellular fluids (Moser, et al., Am. J. Phvsiol. 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 dysfunctions 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 as epilepsy,
  • 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- Adenosine kinase is also responsible for the activation of many pharmacologically active nucleosides (Miller, et al.. J. Biol.
  • 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.
  • 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- nitrophenyl)pyrido[2,3-d]pyrirnidine 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-amino-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- d]pyrimidine compounds having utility as adenosine kinase inhibitors.
  • the present invention provides a method of inhibiting adenosine kinase by administering a compound of formula I
  • R 3 is selected from the group consisting of alkenyl, alkyl, alkynyl, aryl, arylalkyl, cycloalkyl. cycloalkylalkyl. heterocycle. heterocyclealkyl. heterocyclealkylcarbonyl. (NZ,Z 2 )alkyl, and -R A R B ;
  • R A is selected from the group consisting of aryl and arylalkyl
  • R B is selected from the group consisting of aryl, arylalkoxy, arylalkyl, aryloxy, heterocycle, and heterocyclealkyl
  • R 4 is selected from the group consisting of alkenyl, alkoxyalkynyl, alkyl, alkynyl, cycloalkyl, aryl, arylalkyl, heterocycle, heterocyclealkyl, and -R C R D R E ;
  • R c is selected from the group consisting of aryl, arylalkyl, heterocycle, and heterocyclealkyl;
  • R D is selected from the group consisting of aryl, arylalkoxy, arylalkoxyimino, arylalkyl, aryloxy, heterocycle, heterocyclealkoxy, heterocyclealkyl, heterocyclecarbonyl, heterocycleimino, heterocycleoxy, heterocycleoxyalkyl, heterocycleoxyimino, heterocycleoxyiminoalkyl, and heterocyclesulfonyl;
  • R E is absent or selected from the group consisting of aryl, arylalkoxy, arylalkoxyimino, arylalkyl, aryloxy, heterocycle, heterocylealkoxy, heterocyclealkyl, heterocyclecarbonyl, heterocycleimino, heterocycleoxy, heterocycleoxyalkyl, heterocycleoxyimino, heterocycleoxyiminoalkyl, and heterocyclesulfonyl; and, a dashed line — indicates that a double bond is optionally present provided that proper valencies are maintained; with the pro
  • 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.
  • the present invention provides a method of treating ischemia, neurological disorders, nociperception . inflammation, immunosuppression.
  • 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 administering 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
  • R' and R 2 are each independently selected from the group consisting of hydrogen, alkenyl. alkoxyalkyl, alkoxyalkylcarbonyl, alkoxycarbonyl. alkoxycarbonylalkyl. alkyl, alkylcarbonyl, aminocarbonyl, aryl, arylalkyl, arylalkylcarbonyl, arylcarbonyl, carboxyalkyl. formyl, haloalkylcarbonyi. heterocycle. heterocyclealkyl, heterocyclecarbonyl, hydroxyalkyl. iminoalkyl.
  • R 1 and R 2 may join together with the nitrogen atom to which they are attached to form a 5-7 membered ring optionally containing 1-2 additional heteroatoms selected from the group consisting of O. N, and S;
  • Z, and Z are each independently selected from the group consisting of hydrogen, alkoxycarbonyl, alkyl, alkylcarbonyl, benzyl, benzyloxycarbonyl, and formyl;
  • R 3 is selected from the group consisting of alkenyl, alkyl, alkynyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, heterocycle, heterocyclealkyl. heterocyclealkylcarbonyl, (NZ,Z 2 )alkyl. and -R A R B ;
  • R A is selected from the group consisting aryl and arylalkyl
  • R B is selected from the group consisting of aryl, arylalkoxy, arylalkyl, aryloxy, heterocycle. and heterocyclealkyl;
  • R 4 is selected from the group consisting of alkenyl. alkoxyalkynyl. alkyl, alkynyl, cycloalkyl, aryl, arylalkyl, heterocycle, heterocyclealkyl, and -R C R D R E ;
  • R c is selected from the group consisting of aryl, arylalkyl. heterocycle, and heterocyclealkyl;
  • R D is selected from the group consisting of aryl, arylalkoxy, arylalkoxyimino, arylalkyl, aryloxy, heterocycle, heterocyclealkoxy, heterocyclealkyl, heterocyclecarbonyl, heterocycleimino, heterocycleoxy, heterocycleoxyalkyl. heterocycleoxyimino, heterocycleoxyiminoalkyl, and heterocyclesulfonyl;
  • R E is absent or is selected from the group consisting of aryl, arylalkoxy, arylalkoxyimino, arylalkyl, aryloxy. heterocycle.
  • 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.
  • the present invention provides a process for the preparation of adenosine kinase inhibiting compounds of formula I
  • R 3 is selected from the group consisting of alkenyl, alkyl, alkynyl. aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, heterocycle, heterocyclealkyl, heterocyclealkylcarbonyl, (NZ,Z 2 )alkyl. and -R A R B ;
  • R A is selected from the group consisting aryl and arylalkyl
  • R B is selected from the group consisting of aryl, arylalkoxy, arylalkyl, aryloxy, heterocycle, and heterocyclealkyl
  • R 4 is selected from the group consisting of alkenyl. alkoxyalkynyl, alkyl, alkynyl, cycloalkyl, aryl, arylalkyl, heterocycle, heterocyclealkyl, and -R C R D R E ;
  • R c is selected from the group consisting of aryl, arylalkyl, heterocycle, and heterocyclealkyl;
  • R D is selected from the group consisting of aryl, arylalkoxy, arylalkoxyimino, arylalkyl, aryloxy, heterocycle. heterocyclealkoxy, heterocyclealkyl, heterocyclecarbonyl, heterocycleimino, heterocycleoxy. heterocycleoxyalkyl. heterocycleoxyimino. heterocycleoxyiminoalkyl. and heterocyclesulfonyl; and
  • R E is absent or is selected from the group consisting of aryl, arylalkoxy. arylalkoxyimino, arylalkyl, aryloxy, heterocycle, heterocylealkoxy, heterocyclealkyl, heterocyclecarbonyl, heterocycleimino, heterocycleoxy, heterocycleoxyalkyl, heterocycleoxyimino.
  • heterocycleoxyiminoalkyl, and heterocyclesulfonyl and a dashed line — indicates that a double bond is optionally present provided that proper valencies are maintained; the method comprising (a) reacting a ketone having the formula R 4 -CO-CH 3 , wherein R 4 is as defined above, with an aldehyde having the formula R -CHO, wherein R 3 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
  • the present invention provides a process for the preparation of adenosine kinase inhibiting compounds of formula I
  • R J is selected from the group consisting of alkenyl, alkyl, alkynyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, heterocycle, heterocyclealkyl, heterocyclealkylcarbonyl, (NZ,Z 2 )alkyl, and -R A R B ;
  • R A is selected from the group consisting of aryl and arylalkyl;
  • R B is selected from the group consisting of aryl, arylalkoxy, arylalkyl, aryloxy, heterocycle, and heterocyclealkyl;
  • R 4 is selected from the group consisting of alkenyl, alkoxyalkynyl, alkyl, alkynyl, cycloalkyl, aryl, arylalkyl, heterocycle, heterocyclealkyl, and -R C R D R E ;
  • R c is selected from the group consisting of aryl, arylalkyl, heterocycle, and heterocyclealkyl;
  • R D is selected from the group consisting of aryl, arylalkoxy, arylalkoxyimino, arylalkyl, aryloxy, heterocycle, heterocyclealkoxy, heterocyclealkyl, heterocyclecarbonyl, heterocycleimino, heterocycleoxy, heterocycleoxyalkyl, heterocycleoxyimino, heterocycleoxyiminoalkyl, and heterocyclesulfonyl; and
  • R E is absent or is selected from the group consisting of aryl, arylalkoxy, arylalkoxyimino, arylalkyl, aryloxy, heterocycle, heterocylealkoxy, heterocyclealkyl, heterocyclecarbonyl, heterocycleimino, heterocycleoxy, heterocycleoxyalkyl, heterocycleoxyimino, heterocycleoxyiminoalkyl, and heterocyclesulfonyl; and a dashed line — indicates that a double bond is optionally present provided that proper valencies are maintained; the method comprising
  • step (c) optionally reducing the compound from step (b) to form a partially reduced or fully reduced right side of formula I by catalytic hydrogenation.
  • the present invention relates to 5,7-disubstituted-4-aminopyrido[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, to novel 5,7-disubstituted-4-aminopyrido[2,3-d]pyrimidine compounds and to a process of preparing 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
  • R 1 and R 2 are independently selected from the group consisting of hydrogen, alkenyl. alkoxyalkyl, alkoxyalkylcarbonyl, alkoxycarbonyl, alkyl. alkylcarbonyl, aminocarbonyl. aryl, arylcarbonyl, carboxyalkyl, formyl, haloalkylcarbonyl, heterocyclealkyl, hydroxyalkyl, iminoalkyl, and (NZ,Z 2 )alkyl, or R 1 and R 2 may join together with the nitrogen atom to which they are attached to form a 6 membered ring optionally containing 1 additional heteroatom selected from the group consisting of O. N, and S;
  • R 3 is selected from the group consisting of alkenyl, alkyl. aryl. arylalkyl, cycloalkyl, heterocycle, heterocyclealkyl, (NZ,Z 2 )alkyl, and -R A R B ;
  • R A is selected from the group consisting of aryl and arylalkyl;
  • R B is selected from the group consisting of aryl, arylalkoxy, arylalkyl, aryloxy, and heterocycle;
  • R 4 is selected from the group consisting of alkoxyalkynyl, alkynyl, aryl, heterocycle, and -R C R D R E ;
  • R c is selected from the group consisting of aryl and heterocycle;
  • R D is selected from the group consisting of aryl, arylalkoxy, arylalkyl, aryloxy, heterocycle, heterocyclealkoxy, heterocyclealkyl, heterocyclecarbonyl, heterocycleoxy, and heterocyclesulfonyl;
  • R E is absent or selected from the group consisting of aryl, arylalkoxy, arylalkoxyimino, arylalkyl, aryloxy, heterocycle, heterocylealkoxy, heterocyclealkyl, heterocyclecarbonyl, heterocycleimino, heterocycleoxy, heterocycleoxyalkyl, heterocycleoxyimino, and heterocycleoxyiminoalkyl; and a dashed line — indicates that a double bond is optionally present provided that proper valencies are maintained.
  • the preferred compounds utilized in the above method of inhibiting adenosine kinase are selected from a compound of formula II
  • R 1 and R 2 are each independently selected from the group consisting of hydrogen, alkenyl, alkoxyalkyl, alkoxy alkylcarbonyl. alkoxycarbonyl, alkyl, alkylcarbonyl, aminocarbonyl, aryl, arylcarbonyl. carboxyalkyl, formyl, haloalkylcarbonyl,
  • R 1 and R 2 may join together with the nitrogen atom to which they are attached to form a 6 membered ring optionally containing 1 additional heteroatom selected from the group consisting of O. N, and S;
  • R 3 is selected from the group consisting of alkenyl, alkyl, aryl. arylalkyl, cycloalkyl.
  • R A is selected from the group consisting of aryl and arylalkyl
  • R B is selected from the group consisting of aryl, arylalkoxy, arylalkyl, aryloxy, and heterocycle
  • R 4 is selected from the group consisting of alkoxy alkynyl, alkynyl, aryl, heterocycle, and -R C R D R E ;
  • R c is selected from the group consisting of aryl and heterocycle
  • R D is selected from the group consisting of aryl, arylalkoxy, arylalkyl, aryloxy, heterocycle, heterocyclealkoxy, heterocyclealkyl, heterocyclecarbonyl, heterocycleoxy, and heterocyclesulfonyl
  • R E is absent or is selected from the group consisting of aryl, arylalkoxy, arylalkoxyimino, arylalkyl, aryloxy, heterocycle, heterocylealkoxy, heterocyclealkyl, heterocyclecarbonyl, heterocycleimino, heterocycleoxy, heterocycleoxyalkyl, heterocycleoxyimino, and heterocycleoxyiminoalkyl.
  • an adenosine kinase inhibitor of the present invention is a compound of Formula II above, wherein R 4 is aryl or heterocycle and substituted versions thereof or -R C R D R E .
  • an adenosine kinase inhibitor of the present invention is a compound of Formula II above, wherein R 4 is aryl or heterocycle and substituted versions thereof and R 3 is alkyl, aryl. arylalkyl or heterocycle 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- amino-4-
  • 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-methylenedioxyphenyl; 3-
  • Exemplary and preferred adenosine kinase inhibitor compounds of the invention utilized in the method recited herein include the compounds listed below wherein R 1 , R 2 , R 3 , and R 4 are as described in Formula I in the specific compound: 4-(N-(2J-dihydroxypropyl)amino)-5-(3-bromophenyl)-7-(6-mo ⁇ holinyl-3- pyridinyl)pyrido[2.3-d]pyrimidine,
  • 4-amino-5-(2-phenylethyl)-7-(4-diethylaminophenyl)pyrido[2J-d]pyrimidine 4-amino-5-(2-methylpropyl)-7-(4-diethylaminophenyl)pyrido[2J-d]pyrimidine, 4-amino-5-(butyl)-7-(4-diethylaminophenyl)pyrido[2,3-d]pyrimidine.
  • 3 -pyridy l)pyri do [2 ,3 -djpyrimidine, 4-amino-5-(3,5-diclorophenyl)-7-(6-(l,4-dioxa-8-azaspiro[4J]decan-8-yl)-3- pyridyl)pyrido[2J-d]pyrimidine.
  • 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 3 selected from substituted aryl or heterocycle groups and R 4 selected from substituted aryl or heterocycle groups, the substiuents on the R 3 group are meta and the substituents on the R 4 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.
  • alkenylJ refers to a straight or branched chain hydrocarbon containing from 2 to 6 carbons and containing at least one carbon-carbon double bond formed by the removal of two hydrogens.
  • Representative examples of alkenyl include, but are not limited to, ethenyl, 2-propenyl, 2-methyl-2-propenyl, 3- butenyl, 4-pentenyl, 5-hexenyl, and the like.
  • alkenyloxyJ as used herein refers to an alkenyl group, as defined herein, appended to the parent molecular moiety through an oxy moiety, as defined herein.
  • alkenyloxy include, but are not limited to, 2-propenyloxy, 2- methyl-2-propenyloxy, 3-butenyloxy, 4-pentenyloxy, and the like.
  • alkenyloxyiminoJ refers to an alkenyloxy group, as defined herein, appended to the parent molecular moiety through an imino moiety, as defined herein.
  • alkenyloxyimino include, but are not limited to, 2-propenyloxyimino, 2-methyl-2-propenyloxyimino, 3-butenyloxyimino, 4- pentenyloxyimino, and the like.
  • alkenyloxyiminoalkyl refers to an alkenyloxyimino group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein.
  • alkenyloxyiminoalkyl include, but are not limited to, propen-2-yloxyiminomethyl, 2-[2-methylpropen-2-yloxyimino]ethyl, 2-[buten- 3-yloxyimino]ethyl, 3-[penten-4-yloxyimino]propyl, and the like.
  • alkoxyJ refers to an alkyl group, as defined herein, appended to the parent molecular moiety through an oxy moiety, as defined herein.
  • Representative examples of alkoxy include, but are not limited to. methoxy, ethoxy, propoxy, 2-propoxy, butoxy, tert-butoxy, pentyloxy, hexyloxy and the like.
  • alkoxyalkoxy refers to an alkoxy group, as defined herein, appended to the parent molecular moiety through another alkoxy group, as defined herein.
  • Representative examples of alkoxyalkoxy include, but are not limited to, tert- butoxymethoxy, 2-ethoxyethoxy, 2-methoxyethoxy, methoxymethoxy, and the like.
  • alkoxyalkoxyalkyl refers to an alkoxyalkoxy group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein.
  • alkoxyalkoxyalkyl include, but are not limited to, 2-(tert-butoxymethoxy)ethyl, 4-(2-ethoxyethoxy)butyl, 4-(2-methoxyethoxy)butyl, 2- (methoxymethoxy)ethyl, and the like.
  • alkoxyalkoxyiminoJ refers to an alkoxyalkoxy group, as defined herein, appended to the parent molecular moiety through an imino group, as defined herein.
  • Representative examples of alkoxyalkoxyimino include, but are not limited to, tert-butoxymethoxyimino, 2-(ethoxy)ethoxyimino, (2-methoxy)ethoxyimino, methoxymethoxyimino. and the like.
  • alkoxyalkylJ refers to an alkoxy group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein.
  • Representative examples of alkoxyalkyl include, but are not limited to. tert-butoxymethyl, 2-ethoxy ethyl, 2-methoxyethyl, methoxymethyl, and the like.
  • alkoxyalkynyl refers to an alkoxy group, as defined herein, appended to the parent molecular moiety through an alkynyl group, as defined herein.
  • Representative examples of alkoxyalkynyl include, but are not limited to, 3- (methoxy)propyn-l-yl, 4-(ethoxy)butyn-l-yl, and the like.
  • alkoxyalkylcarbonylJ as used herein refers to an alkoxyalkyl group, as defined herein, appended to the parent molecular moiety through a carbonyl group, as defined herein.
  • alkoxyalkylcarbonyl examples include, but are not limited to, 2-(ethoxy)ethylcarbonyl, 2-(methoxy)ethylcarbonyl, and the like.
  • alkoxycarbonylJ as used herein refers to an alkoxy group, as defined herein, appended to the parent molecular moiety through a carbonyl group, as defined herein.
  • Representative examples of alkoxycarbonyl include, but are not limited to, tert- butoxycarbonyl, ethoxycarbonyl, methoxycarbonyl, and the like.
  • alkoxycarbonylalkenylJ refers to one or two alkoxycarbonyl groups, as defined herein, appended to the parent molecular moiety through an alkenyl group, as defined herein.
  • Representative examples of alkoxycarbonylalkenyl include, but are not limited to, 3-(methoxycarbonyl)propen-l-yl, , 4-(ethoxycarbonyl)buten-2-yl, 4-bis(ethoxycarbonyl)buten-2-yl, and the like.
  • alkoxycarbonylalkoxy refers to an alkoxycarbonyl group, as defined herein, appended to the parent molecular moiety through an alkoxy group.
  • Representative examples of alkoxycarbonylalkoxy include methoxycarbonylmethoxy, ethoxycarbonylmethoxy, 2-(methoxycarbonyl)ethoxy, and the like.
  • alkoxycarbonylalkoxyiminoJ refers to an alkoxycarbonylalkoxy group, as defined herein, appended to the parent molecular moiety through an imino group.
  • Representative examples of alkoxycarbonylalkoxyimino include ethoxycarbonylmethoxyimino, 2-(methoxycarbonyl)ethoxyimino, and the like.
  • alkoxycarbonylalkoxyiminoalkylJ as used herein refers to an alkoxycarbonylalkoxyimino group, as defined herein, appended to the parent molecular moiety through an alkyl group.
  • alkoxycarbonylalkoxyiminoalkyl examples include 2-(ethoxycarbonylmethoxyimino)ethyl, 2-[2- (methoxycarbonyl)ethoxyiminojethyl, and the like.
  • alkoxycarbonylalkylJ refers to an alkoxycarbonyl group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein.
  • Representative examples of alkoxycarbonylalkyl include, but are not limited to, 3-(methoxycarbonyl)propyl, , 4-(ethoxycarbonyl)butyl, and the like.
  • alkoxyiminoJ refers to an alkoxy group, as defined herein, appended to the parent molecular moiety through an imino group, as defined herein.
  • alkoxyimino include, but are not limited to, ethoxyimino, methoxyimino, propoxyimino, isopropoxyimino, and the like.
  • alkoxy iminoalkylJ refers to an alkoxyimino group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein.
  • alkoxyiminoalkyl include, but are not limited to, 2-(ethoxyimino)ethyl, 2-(methoxyimino)ethyl, 2-(propoxyimino)ethyl, 2- (isopropoxyimino)ethyl, and the like.
  • alkylJ refers to a straight or branched chain hydrocarbon containing from 1 to 6 carbon atoms.
  • Representative examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, and the like.
  • alkyleneJ denotes a divalent group derived from a straight or branched chain hydrocarbon of from 1 to 3 carbon atoms.
  • Representative examples of alkylene include, -CH 2 -, -CH 2 CH 2 -, and -CH 2 CH 2 CH 2 -.
  • alkylcarbonylJ refers to an alkyl group, as defined herein, appended to the parent molecular moiety through a carbonyl group, as defined herein.
  • Representative examples of alkylcarbonyl include, but are not limited, methylcarbonyl (acetyl), ethylcarbonyl, and the like.
  • alkylcarbonyloxyJ refers to an alkylcarbonyl group, as defined herein, appended to the parent molecular moiety through an oxy group, as defined herein.
  • Representative examples of alkylcarbonyloxy include, but are not limited, methylcarbonyloxy, ethylcarbonyloxy, and the like.
  • alkylcarbonyloxyalkoxy J refers to an alkylcarbonyloxy group, as defined herein, appended to the parent molecular moiety through an alkoxy group, as defined herein.
  • Representative examples of alkylcarbonyloxyalkoxy include, but are not limited, 2-(methylcarbonyloxy)ethoxy, 3 -(ethylcarbonyloxy )propoxy, and the like.
  • alkylcarbonyloxyalkylJ as used herein refers to an alkylcarbonyloxy group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein.
  • alkylcarbonyloxyalkyl include, but are not limited, 2-(methylcarbonyloxy)ethyl, 3 -(ethylcarbonyloxy )propyl, and the like.
  • alkylcarbonyloxyalkylthioJ as used herein refers to an alkylcarbonyloxyalkyl group, as defined herein, appended to the parent molecular moiety through a thio moiety, as defined herein.
  • Representative examples of alkylcarbonyloxyalkylthio include, but are not limited, 2- (methylcarbonyloxy)ethylsulfanyl, 3-(ethylcarbonyloxy)propylsulfoanyl, and the like.
  • alkylsulfonylJ refers to an alkyl group, as defined herein, appended to the parent molecular moiety through a sulfonyl group, as defined herein.
  • Representative examples of alkylsulfonyl include, but are not limited, methylsulfonyl, ethylsulfonyl, and the like.
  • alkylthio refers to an alkyl group, as defined herein, appended to the parent molecular moiety through a thio moiety, as defined herein.
  • Representative examples of alkylthio include, but are not limited, methylsulfanyl, ethylsulfanyl, tert-butylsulfanyl, hexylsulfanyl, and the like.
  • alkylthioalkylJ refers to an alkylthio group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein.
  • Representative examples of alkylthioalkyl include, but are not limited, methylsulfanylmethyl, 2-(ethylsulfanyl)ethyl, and the like.
  • alkynyl refers to a straight or branched chain hydrocarbon group containing from 2 to 6 carbon atoms and containing at least one carbon-carbon triple bond.
  • Representative examples of alkynyl include, but are not limited, to acetylenyl, 1-propynyl, 2-propynyl, 3-butynyl, 2-pentynyl, 1-butynyl and the like.
  • aminoJ refers to an -NZ,Z 2 group wherein Z, and Z 2 are appended to the parent molecular moiety through a nitrogen atom.
  • Z, and Z 2 are independently selected from hydrogen, alkyl, alkylcarbonyl, benzyl, cycloalkyl, cycloalkylalkyl, formyl, and phenyl.
  • Representative examples of -NZ,Z 2 include, but are not limited to, amino, benzylamino, methylamino. acetylamino, acetylmethylamino, cyclopropylamino, cyclopropylmethylamino, dimethylamino, phenylamino, and the like.
  • aminoalkylJ refers to an amino group, as defined herein, appended to the parent molecular moiety through an alkyl moiety, as defined herein.
  • Representative examples of aminoalkyl include, but are not limited, 3-aminopropyl, 4- dimethylaminobutyl, and the like.
  • aminoalkylcarbonylJ refers to an aminoalkyl group, as defined herein, appended to the parent molecular moiety through a carbonyl moiety, as defined herein.
  • Representative examples of aminoalkylcarbonyl include, but are not limited, 3-(amino)propylcarbonyl, 4-(dimethylamino)butylcarbonyl, and the like.
  • aminoalkynylJ refers to an amino group, as defined herein, appended to the parent molecular moiety through an alkynyl moiety, as defined herein.
  • Representative examples of aminoalkynyl include, but are not limited, 3- (amino)propyn-l-yl, 4-(dimethylamino)butyn-l-yl, and the like.
  • amino-protecting group or “N-protecting groupJ refers to groups intended to protect an amino group against undersirable reactions during synthetic procedures. Commonly used nitrogen-protecting groups are disclosed in Greene, T. W., & Wuts, P. G. M. (1991).
  • nitrogen-protecting groups are formyl, acetyl, benzoyl, pivaloyl, t-butylacetyl, phenylsulfonyl, benzyl, t-butyloxycarbonyl (Boc), and benzyloxycarbonyl (Cbz).
  • aminosulfonylJ refers to an amino group, as defined herein, appended to the parent molecular moiety through a sulfonyl moiety, as defined herein.
  • Representative examples of aminosulfonyl include, but are not limited, aminosulfonyl, dimetylaminosulfonyl, diethylaminosulfonyl, and the like.
  • arylJ refers to a monocyclic-ring system, or a bicyclic- fused ring system wherein one or both of the fused rings are aromatic.
  • Representative examples of aryl include, but are not limited to, azulenyl, indanyl, indenyl, naphthyl, phenyl, tetrahydronaphthyl, and the like.
  • the aryl groups of this invention can be substituted with 1. 2, or 3 substituents independently selected from alkenyl, alkenyloxy, alkenyloxyimino.
  • alkenyloxyiminoalkyl alkoxy, alkoxyalkoxy, alkoxyalkoxyalkyl, alkoxyalkoxyimino, alkoxyalkyl, alkoxyalkynyl, alkoxycarbonyl, alkoxycarbonylalkenyl, alkoxycarbonylalkyl, alkoxycarbonylalkoxyimino, alkoxycarbonylalkoxyiminoalkyl, alkoxyimino, alkoxyiminoalkyl, alkyl, alkylcarbonyl, alkylcarbonyloxy, alkylcarbonyloxyalkoxy, alkylcarbonyloxyalkyl, alkylcarbonyloxyalkylthio, alkylsulfonyl, alkylthio, alkylthioalkyl, aminoalkynyl, aminosulfonyl, azido, carboxy, carboxyalkyl, cyano, cyanoalkyl, cycloal
  • arylalkoxy refers to an aryl group, as defined herein, appended to the parent molecular moiety through an alkoxy group, as defined herein.
  • Representative examples of arylalkoxy include, but are not limited to, 2-phenylethoxy, 3- naphth-2-ylpropoxy, 5-phenylpentyloxy, and the like.
  • arylalkoxycarbonylJ refers to an arylalkoxy group, as defined herein, appended to the parent molecular moiety through a carbonyl group, as defined herein.
  • Representative examples of arylalkoxycarbonyl include, but are not limited to, benzyloxycarbonyl, naphth-2-ylmethoxycarbonyl, and the like.
  • arylalkoxyimino refers to an arylalkoxy group, as defined herein, appended to the parent molecular moiety through an imino group, as defined herein.
  • Representative examples of arylalkoxyimino include, but are not limited to, 2-phenylethoxyimino, 3-naphth-2-ylpropoxyimino, 5-phenylpentyloxyimino, and the like.
  • arylalkyl refers to an aryl group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein.
  • Representative examples of arylalkyl include, but are not limited to, benzyl, 2-phenylethyl, 3-phenylpropyl, 2-naphth-2-ylethyl, and the like.
  • (aryl)alkylJ refers to an aryl group, as defined herein, appended to the parent molecular moiety through another aryl group, as defined herein.
  • Representative examples of (aryl)aryl include, but are not limited to, biphenyl, 4'- methoxybiphenyl, and the like.
  • aryloxyJ refers to an aryl group, as defined herein, appended to the parent molecular moiety through an oxy moiety, as defined herein.
  • Representative examples of aryloxy include, but are not limited to, phenoxy, naphthyloxy, 4- chlorophenoxy, 4-methylphenoxy, 3,5-dimethoxyphenoxy, and the like.
  • zidoJ as used herein refers to a -N 3 group.
  • carbonylJ as used herein refers to a -C(O)- group.
  • carboxyJ as used herein refers to a -CO 2 H group.
  • carboxyalkylJ refers to a carboxy group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein.
  • Representative examples of carboxyalkyl include, but are not limited to, carboxymethyl, 2-carboxyethyl, 3-carboxypropyl, and the like.
  • cyanoJ as used herein refers to a -CN group.
  • cyanoalkyl refers to a cyano group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein.
  • Representative examples of cyanoalkyl include, but are not limited to, cyanomethyl, 2- cyanoethyl, 3-cyanopropyl, and the like.
  • cycloalkyl refers to a saturated cyclic hydrocarbon group containing from 3 to 8 carbons.
  • Representative examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl. cyclohexyl, cycloheptyl, cyclooctyl and the like.
  • cycloalkyl groups of this invention can be substituted with 1 or 2 substituents independently selected from alkenyl, alkenyloxy, alkenyloxyimino, alkenyloxyiminoalkyl, alkoxy, alkoxyalkoxy, alkoxyalkoxyalkyl, alkoxyalkoxyimino, alkoxyalkyl, alkoxyalkynyl, alkoxycarbonyl, alkoxycarbonylalkenyl, alkoxycarbonylalkyl, alkoxycarbonylalkoxyimino, alkoxycarbonylalkoxyiminoalkyl, alkoxyimino, alkoxyiminoalkyl, alkyl, alkylcarbonyl, alkylcarbonyloxy, alkylcarbonyloxyalkoxy, alkylcarbonyloxyalkoxy, alkylcarbonyloxyalkylthio, alkylsulfonyl, alkylthio, alkylthioalky
  • heterocyclealkyl heterocyclealkylcarbonyl, heterocyclesulfonyl, and (NZ 14 Z, 5 )alkyl wherein Z M and Z, 5 are independently selected from the group consisting of hydrogen, alkoxyalkoxyalkyl, alkoxyalkyl, alkoxyalkylcarbonyl, alkyl, alkylcarbonyl, formyl, heterocycle, and hydroxyalkoxyalkyl.
  • cycloalkylalkoxy/ 1 refers to cycloalkyl group, as defined herein, appended to the parent molecular moiety through an alkoxy group, as defined herein.
  • Representative examples of cycloalkylalkoxy include, but are not limited to. cyclopropylmethoxy, 2-cyclobutylethoxy, cyclopentylmethoxy, cyclohexylmethoxy, 4- cycloheptylbutoxy, and the like.
  • cycloalkylalkyl refers to cycloalkyl group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein.
  • cycloalkylalkyl include, but are not limited to, cyclopropylmethyl, 2-cyclobutylethyl, cyclopentylmethyl, cyclohexylmethyl and 4- cycloheptylbutyl, and the like.
  • cycloalkylcarbonyl refers to cycloalkyl group, as defined herein, appended to the parent molecular moiety through a carbonyl group, as defined herein.
  • Representative examples of cycloalkylcarbonyl include, but are not limited to, cyclopropylcarbonyl, 2-cyclobutylcarbonyl, cyclohexylcarbonyl, and the like.
  • cycloalkyloxyJ as used herein refers to cycloalkyl group, as defined herein, appended to the parent molecular moiety through an oxy moiety, as defined herein.
  • Representative examples of cycloalkyloxy include, but are not limited to, cyclopropyloxy, cyclopentyloxy, cyclohexyloxy, and the like.
  • cycloalkyloxyiminoJ refers to cycloalkyloxy group, as defined herein, appended to the parent molecular moiety through an imino group, as defined herein.
  • Representative examples of cycloalkyloxyimino include, but are not limited to, cyclopropyloxyimino, cyclopentyloxyimino, cyclohexyloxyimino, and the like.
  • ethylenedioxy refers to a -OCH(R 20 )CH(R 2I )O- group wherein the oxygen atoms of the ethylenedioxy group are attached to the parent molecular moiety through one carbon atom forming a 5 membered ring or the oxygen atoms of the ethylenedioxy group are attached to the parent molecular moiety through two adjacent carbon atoms forming a six membered ring.
  • R 20 and R 2 are independently selected from hydrogen and alkyl or R 20 and R 21 together with the carbon atoms to which they are attached can join to form a 5 or 6 membered ring optionally containing 1 heteroatom selected from NH, O, or S.
  • ethylenedioxy include, but are not limited to, 3,5-dimethyl-l,2-cyclopentanediol, tetrahydro-3,4-furandiol, 1,2- cyclopentanediol, and the like.
  • formylJ refers to a -C(O)H group.
  • formylalkylJ refers to a formyl group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein.
  • Representative examples of formylalkyl include, but are not limited to, formylmethyl, 2- formylethyl, and the like.
  • halo refers to -Cl, -Br, -I or -F.
  • haloalkoxyJ refers to at least one halogen, as defined herein, appended to the parent molecular moiety through an alkoxy group, as defined herein.
  • Representative examples of haloalkoxy include, but are not limited to, chloromethoxy, 2-fluoroethoxy, trifluoromethoxy, pentafluoroethoxy, and the like.
  • haloalkylJ refers to at least one halogen, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein.
  • Representative examples of haloalkyl include, but are not limited to, chloromethyl, 2- fiuoroethyl, trifluoromethyl, pentafluoroethyl, 2-chloro-3-fluoropentyl, and the like.
  • haloalkylcarbonylJ refers to a haloalkyl group, as defined herein, appended to the parent molecular moiety through a carbonyl group, as defined herein.
  • haloalkylcarbonyl include, but are not limited to, 2-fluoroethylcarbonyl, trifluoromethylcarbonyl, pentafluoroethylcarbonyl, and the like.
  • heterocycle refers to a monocyclic, bicyclic, or tricyclic ring system.
  • Monocyclic ring systems are exemplified by any 3- or 4-membered ring containing a heteroatom independently selected from oxygen, nitrogen and sulfur; or a 5-, 6- or 7-membered ring containing one, two or three heteroatoms wherein the heteroatoms are independently selected from nitrogen, oxygen and sulfur.
  • the 5-membered ring has from 0-2 double bonds and the 6- and 7-membered ring have from 0-3 double bonds.
  • Representative examples of monocyclic ring systems include, but are not limited to, azetidinyl, azepinyl, aziridinyl, diazepinyl, 1,3-dioxolanyl, dioxanyl, dithianyl, furyl, imidazolyl, imidazolinyl, imidazolidinyl, isothiazolyl, isothiazolinyl, isothiazolidinyl, isoxazolyl, isoxazolinyl, isoxazolidinyl, mo ⁇ holinyl, oxadiazolyl, oxadiazolinyl, oxadiazolidinyl, oxazolyl, oxazolinyl, oxazolidinyl, piperazinyl, piperidinyl, pyranyl
  • Bicyclic ring systems are exemplified by any of the above monocyclic ring systems fused to an aryl group as defined herein, a cycloalkyl group as defined herein, or another monocyclic ring system.
  • Bicyclic ring systems are further exemplified by any of the above monocyclic ring systems containing an alkyleneof 1-3 carbon atoms attached to two non-adjacent carbon atoms of the monocyclic ring system.
  • bicyclic ring systems include but are not limited to, for example, benzimidazolyl, benzothiazolyl, benzothiophenyl, benzoxazolyl, benzofuranyl, benzopyranyl, benzothiopyranyl, benzodioxinyl, 1,3-benzodioxolyl, cinnolinyl, hexahydro-lH- uro[3,4-c]pyrrolyl, indazolyl, indolyl, indolinyl, indolizinyl, naphthyridinyl, isobenzofuranyl, isobenzothiophenyl, isoindolyl, isoindolinyl, isoquinolyl, 2-oxa-5-azabicyclo[2.2J]heptanyl, l,4-dioxa-8-azaspiro[4.5]decanyl, l,3-dioxa-8- azas
  • Tricyclic rings systems are exemplified by any of the above bicyclic ring systems fused to an aryl group as defined herein, a cycloalkyl group as defined herein, or a monocyclic ring system.
  • Representative examples of tricyclic ring systems include, but are not limited to, acridinyl, carbazolyl. carbolinyl, dibenzofuranyl, 2,4(lH,3H)-quinazolinedione. dibenzothiophenyl.
  • the heterocycles of this invention can be substituted with 1, 2,or 3 substituents independently selected from alkenyl, alkenyloxy, alkenyloxyimino, alkenyloxyiminoalkyl, alkoxy, alkoxyalkoxy, alkoxyalkoxyalkyl, alkoxyalkoxyimino, alkoxyalkyl, alkoxyalkynyl, alkoxycarbonyl, alkoxycarbonylalkenyl, alkoxycarbonylalkyl, alkoxycarbonylalkoxyimino, alkoxycarbonylalkoxyiminoalkyl, alkoxyimino, alkoxyiminoalkyl, alkyl, alkylcarbonyl, alkylcarbonyloxy, alkylcarbonyloxyalkoxy, alkylcarbonyloxyalkoxy, alkylcarbonyloxyalkyl.
  • alkylcarbonyloxyalkylthio alkylsulfonyl, alkylthio. alkylthioalkyl, aminoalkynyl, aminosulfonyl, azido, carboxy, carboxyalkyl, cyano, cyanoalkyl, cycloalkyl, cycloalkylalkoxy, cycloalkylalkyl, cycloalkyloxy, cycloalkyloxyimino, ethylenedioxy, formyl, formylalkyl, haloalkyl, haloalkylcarbonyl, halogen, hydroxy, hydroxyalkoxy, hydroxyalkoxyalkyl, hydroxyalkyl, hydroxyimino, hydroxyiminoalkyl, methylenedioxy, methylenyl, nitro, oxo, phosphonato, spirocycle, (spirocycle)spirocycle, thioureylene, ureylene,
  • heterocyclealkoxy refers to a heterocycle group, as defined herein, appended to the parent molecular moiety through an alkoxy group, as defined herein.
  • Representative examples of heterocyclealkoxy include, but are not limited to, 2-pyrid-3-ylethoxy, 3-quinolin-3-ylpropoxy, 5-pyrid-4-ylpentyloxy. and the like.
  • heterocyclealkoxy imino J refers to a heterocyclealkoxy group, as defined herein, appended to the parent molecular moiety through an imino group, as defined herein.
  • Representative examples of heterocyclealkoxyimino include, but are not limited to, 2-pyrid-3-ylethoxyimino, 3-quinolin-3-ylpropoxyimino. 5-pyrid-4- ylpentyloxyimino, 3-(4-mo ⁇ holinyl)propoxyimino, and the like.
  • heterocyclealkylJ refers to a heterocycle. as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein.
  • Representative examples of heterocyclealkyl include, but are not limited to, pyrid-3- ylmethyl, 2-pyrimidin-2-ylpropyl, and the like.
  • heterocyclealkylcarbonyl refers to a heterocyclealkyl group, as defined herein, appended to the parent molecular moiety through a carbonyl group, as defined herein.
  • Representative examples of heterocyclealkylcarbonyl include, but are not limited to, pyrid-3-ylmethylcarbonyl, 3-pyrimidin-2-ylpropylcarbonyl, and the like.
  • (heterocycle)arylJ refers to a heterocycle, as defined herein, appended to the parent molecular moiety a aryl group, as defined herein.
  • Representative examples of (heterocycle)aryl include, but are not limited to, 4-(pyridin-3- yl)phenyl, 4-(pyrimidin-2-yl)phenyl, and the like.
  • heterocyclecarbonylJ refers to a heterocycle, as defined herein, appended to the parent molecular moiety through a carbonyl group, as defined herein.
  • Representative examples of heterocyclecarbonyl include, but are not limited to, pyrid-3-ylcarbonyl, quinolin-3-ylcarbonyl, and the like.
  • heterocycleimino/' refers to a heterocycle group, as defined herein, appended to the parent molecular moiety through an imino group, as defined herein.
  • Representative examples of heterocycleimino include, but are not limited to, 4-mo ⁇ holinylimino, and the like.
  • heterocycleoxy refers to a heterocycle group, as defined herein, appended to the parent molecular moiety through an oxy moiety, as defined herein.
  • Representative examples of heterocycleoxy include, but are not limited to, pyrid-3-yloxy, quinolin-3-yloxy, and the like.
  • heterocycleoxyalkyl refers to a heterocycleoxy group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein.
  • Representative examples of heterocycleoxyalkyl include, but are not limited to, pyrid-3-yloxymethyl, 2-quinolin-3-yloxyethyl, and the like.
  • heterocycleoxyimino refers to a heterocycleoxy group, as defined herein, appended to the parent molecular moiety through an imino group, as defined herein.
  • Representative examples of heterocycleoxyimino include, but are not limited to, pyrid-3-yloxyimino, quinolin-3-yloxyimino, and the like.
  • heterocycleoxyiminoalkyl refers to a heterocycleoxyimino group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein.
  • Representative examples of heterocycleoxyiminoalkyl include, but are not limited to, 2-(pyrid-3-yloxyimino)ethyl, 2- (quinolin-3-yloxyimino)ethyl, and the like.
  • heterocyclesulfonyl refers to a heterocycle, as defined herein, appended to the parent molecular moiety through a sulfonyl group, as defined herein.
  • Representative examples of heterocyclesulfonyl include, but are not limited to, pyrid-3-ylsulfonyl, quinolin-3-ylsulfonyl, 4-mo ⁇ holinylsulfonyl, and the like.
  • hydroxy refers to an -OH group.
  • hydroxyalkoxy refers to one or two hydroxy groups, as defined herein, appended to the parent molecular moiety through an alkoxy group, as defined herein.
  • Representative examples of hydroxyalkoxy include, but are not limited to, 2-hydroxyethoxy, 2,3-dihydroxypropoxy, 4-hydroxybutoxy, and the like.
  • hydroxyalkoxyalkyl refers to a hydroxyalkoxy group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein.
  • hydroxyalkoxyalkyl include, but are not limited to, 2-[2-(hydroxy)ethoxyjethyl, 2-[3-(hydroxy)propoxy]ethyl, 4- hydroxybutoxymethyl, and the like.
  • hydroxyalkyl refers to one or two hydroxy groups, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein.
  • Representative examples of hydroxyalkyl include, but are not limited to, 2-hydroxyethyl, 2,3-dihydroxypropyl, and the like.
  • hydroxyiminoalkyl refers to a hydroxyimino group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein. Representative examples of hydroxyiminoalkyl include, but are not limited to, 2-(hydroxyimino)ethyl, 3-(hydroxyimino)propyl, and the like.
  • methylenedioxy refers to a -OCH 2 O- group wherein the oxygen atoms of the methylenedioxy are attached to the parent molecular moiety through two adjacent carbon atoms forming a 5 memebered ring.
  • the carbon atom of methylenedioxy group is optionally substituted with one substituent selected from alkyl and oxo.
  • nitro refers to a -NO 2 group.
  • oxy refers to a -O- moiety.
  • phosphonato refers to a (R 95 O) 2 P(O)O- group wherein R, 5 is alkyl.
  • spirocycle refers to a -X,(CH 2 ) p X 2 - group wherein X, and X 2 are independently selected from CH 2 , NH, O, S, S(O), and S(O) 2 ; and p is an integer from 2-3. X, and X 2 are attached to the parent molecular moiety through one carbon atom forming a 5 or 6 membered ring.
  • Representative examples of spirocycle include, but are not limited to 1,3-dioxolane, 1,3-dioxane, 1,3-oxathiane, 1,3-oxazinane, and the like.
  • the spirocycles of this invention are optionally substituted with 1, 2, or 3 substituents independently selected from alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl, alkylcarbonyl, aminocarbonyl, benzyloxcarbonyl, and formyl.
  • the substituents can be attached to nitrogen or any of the carbon atoms.
  • (spirocycle)spirocycle refers to a spirocycle. as defined herein, attached to the parent molecular moiety through a spirocycle, as defined herein.
  • Representative examples of spirocycle-spirocycle include, but are not limited to, 1 ,7,9- trioxaspiro[4.5]decane, l,4,7,9-tetraoxaspiro[4.5]decane, and the like.
  • thio refers to a -S- moiety.
  • thioureylene refers to -NR 97 C(S)NR 98 R 99 , wherein R, 7 , R, 8 , and R,, are independently selected from hydrogen, alkyl, aryl, and arylalkyl, as defined herein.
  • ureylene refers to -NR 97 C(O)NR 98 R 99 , wherein R, 7 , Rgg, and Rg, are independently selected from hydrogen, alkyl, aryl, and arylalkyl, as defined herein.
  • 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: 0J- 250 nmol/kg/minute, preferably from 1-50 nmol/kg/minute; oral: 0.01-250 ⁇ Mol/kg/day, preferably from about 0J-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.
  • compositions of the present invention 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.
  • Stereoisomers include enantiomers and diastereomers.
  • Individual stereoisomers of compounds of the present invention can be prepared synthetically from commercially available starting materials which contain asymmetric or chiral centers or by preparation of racemic mixtures followed by resolution well-known to those of ordinary skill in the art.
  • 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, benzenesulfonate, bisulfate. butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate. dodecylsulfate. ethanesulfonate, flavianate.
  • 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, myristyi, 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, myristyi, and stearyl chlorides, bromides and iodides
  • arylalkyl halides like benzy
  • 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.
  • 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.
  • 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.
  • 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, corn 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, ethy
  • 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 or a heterocychc group may be prepared by a modification of a method of Kambe et al., Synthesis, 1980, 366-368.
  • R 3 is aryl or a heterocychc group.
  • 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 R 3 substituted 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 4 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 Swern 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 -djpyrimidine 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, heterocycle or heterocychc group
  • R 3 is loweralkyl, loweralkenyl, loweralkynyl, or an arylalkyl group.
  • R 4 may be selected from those additional groups listed in R 3 .
  • 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) Swern 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).
  • a base such as for example, triethyl amine
  • Compound (8) is then treated with an alkali metal base, such as NaOH or the like, to give compound (9).
  • an alkali metal base such as NaOH or the like.
  • 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 HC1, 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.
  • the dicyano compounds (12) may be prepared from the precursor aldehyde (4) by treatment with malononitrile in 1 :1 H 2 O: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' 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 triethylamine or potassium carbonate in a suitable solvent, such as for example, methylene chloride or THF.
  • 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 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.
  • the precursor compound having a halogen atom in place of the amino group at the 4-position may be prepared by substitution of tri ethyl ortho formate for the formamide followed by chlorination of the ring by treatment with phosphorous oxy chloride 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.
  • 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. AK activity of cell supernatants was assayed radiometrically. Assays were carried out at ambient temperature in a final volume of 100 ⁇ L.
  • the reaction mixture contained 64 mM Tris HC1 (pH 7.5), 0.2 mM MgCl 2 , 1 mM ATP, 0.2 ⁇ M U-[ 1 Cj-adenosine or [ 3 H]-adenosine and appropriate volumes of rat brain cytosol as a source of adenosine kinase.
  • the reaction was terminated after 15 min by spotting 40 ⁇ L of the reaction mixture onto disks of Whatman DE-81 anion exchange paper. DE-81 disks were then air-dried, washed for 10 minutes in 2 mM ammonium formate, then rinsed successively with distilled water, methanol and acetone, and dried.
  • DE-81 disks were then soaked for 5 minutes in 0JN HC1/0.4 M KC1 before addition of scintillation cocktail and counting by liquid scintillation counting.
  • 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 alia 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. Phvsiol.. (1982), 7 IB, 367-372), hereby inco ⁇ orated by reference.
  • In vitro adenosine kinase activity can be measured using any of the standard procedures well known in the art.
  • cells containing adenosine kinase such as IMR-32 human neuroblastoma cells, are incubated in the presence and absence of an inhibitor. Inhibition is measured as the ability to inhibit phosphorylation of externally applied 14 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 A,, A 2A , and A 3 receptor binding, adenosine deaminase activity and adenosine transport.
  • the inhibiting compound 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.
  • adenosine kinase inhibitors have been reported to protect rodents (e.g., mice and rats) from experimentally- induced seizure activity (Zhang, G., Murray, T.F., J. Pharmacol. Exp. Ther.. 1993, 264, 1415-1424; Murray, T.F., et al., Drug Dev. Res.. 1993, 28, 410-415; Kowaluk, E. A., et al., Drug Dev. Res., 1996, 37, 190), hereby inco ⁇ orated by reference.
  • a method of inhibiting adenosine kinase in vivo is particularly useful in mammals such as humans.
  • Administering a therapeutic amount of an inhibitor compound is typically accomplished by the parenteral (e.g., intravenous injection) or oral administration of the compound.
  • 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.
  • 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 [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)].
  • Additional compounds of the present invention were tested for adenosine kinase inhibition using the above protocol. These compounds exhibited potent inhibition of adenosine kinase with ED 50 's ranging from 1 to 500 nM.
  • Carrageenan hvperalgesia Test-Hotbox Assay This assay may be indicative of a compound ' s ability to produce analgesia against carrageenan and capsaicin induced hyperalgesia. The assay is further discussed in Hargreaves K, Dubner R, Brown F, Flores C, Joris J (1988), A new and sensitive method for measuring thermal nociception in cutaneous hyperalgesia. Pain 32: 77-88, hereby fully inco ⁇ orated by reference.
  • C/D Sprague Dawley rats (Charles River), body weight range 250-350 g, are acclimated in the test room for 30-60 min. before any treatment (habituation).
  • Carrageenan (CARR) (lambda, from Sigma, St. Louis, MO) is dissolved in heated saline at 10 mg/ml. This solution is sonicated and vortexed and then cooled to room temperature. After rats have been habituated they are injected with 100 ⁇ l of the CARR solution into the plantar surface (s.c) of the right hindpaw. A 26 3/8 g needle is used for injection. The insertion of the needle will start at the midline of the foot between the tori and project toward the heel -0.25 cm .
  • Test compounds are administered at a time predetermined in relation to CARR injection (typically 1 hour pre CARR administration). The left hindpaw receives no injections. After carrageenan injection the rats are returned to their cages until 30 minutes before testing at which time they are placed in the Hargreaves thermal stimulator apparatus (Hotbox) for a 30 minute habituation period. Testing (thermal stimulation) is then performed. Each rat is tested 3 times (both right and left hindpaw) with approx. 5 minute between trials. The standard setting for the thermal stimulator (voltmeter) is 4.5 and the maximum time of exposure is 20.48 seconds.
  • Example 359 1 Example 534 3
  • Additional compounds of the present invention were tested in the carrageenan and capsaicin induced hyperalgesia hotbox assay using the above protocal in C/D Sprague Dawley rats. These compounds exhibited ED 50 's ranging from 1 to >10 micromolar. Compounds exhibiting less potency in the carrageenan hyperalgesia hotbox assay may require a higher dose or potency may be species dependent.
  • Nociperception Nociception (Pain) (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 4 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 R 3 is a substituted aryl or heterocycle moiety wherein the substituent (preferrably halogen) is at the meta or 3 -position relative to the ring attachment and R 4 is a substituted heterocycle or aryl moiety wherein the substituent is at the para or 4-position relative to the ring attachment.
  • R 3 is a substituted aryl or heterocycle moiety wherein the substituent (preferrably halogen) is at the meta or 3 -position relative to the ring attachment and R 4 is a substituted heterocycle or aryl moiety wherein the substituent is at the para or 4-position relative to the ring attachment.
  • R 3 is a substituted aryl or heterocycle moiety wherein the substituent (preferrably halogen) is at the meta or 3 -position relative to the ring attachment
  • R 4 is a substituted heterocycle or aryl moiety wherein the substituent
  • 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 liver 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 HIV-seropositive and HIV- 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).
  • Example 1 4-amino-5- ⁇ -dimethylaminophenyl)-7- ⁇ -bromophenyl)pyrido[2J-d1pyrimidine
  • 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/CH 2 Cl 2 to give the pure title compound.
  • step 157a preparation of 3-bromophenylacetaldehyde (the "R 3 reagent")
  • ethyl 3 -bromopheny lacetate (10.2 g, US patent 2,624,731 (1950)
  • dichloromethane 230 mL
  • IM Dibal-H 10.2 g
  • methanol 10 mL
  • the organic layer was dried over sodium sulfate and the aldehyde used immediately in the next step without purification.
  • step 157b preparation of -(triphenylphosphonium)-4-(dimethylamino phenylethan-l- one chloride
  • - bromo-(4-dimethylaminophenyl)ethan-l-one was treated with triphenylphosphine in triethylamine and acetonitrile.
  • 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-cyano-4-(3-bromophenyl methyl-6-(4- (dimethv0aminophenyl)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 ortho formate 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-dichlorobenzene 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).
  • Example 1 Following the procedures of Example 1 , except substituting the appropriate reagents for the R 4 and R 3 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.
  • Examples 190-198 Following the procedures of Example 189. except substituting the appropriate acylating reagent for the acetic anhydride of ExampleJ 89 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-djpyrimidine in CH 2 C1 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 (SiO 2 , EtOAc/hexanes) to provide the title compound IR (KBr) 3437, 1564, 1355, 1 195; MS m/z 460/462 (M+H) * .
  • the POCl 3 was removed under reduced pressure to provide crude 4-chloro-5-(p-dimethylaminophenyl)-7-(p- bromophenyl)pyrido[2, 3-djpyrimidine.
  • the invention therefore relates to intermediate compounds of formula III 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-dimethylamino)ethylamino')-5-(4-bromophenv ⁇ -7-(4-dimethylaminophenyl) pyrido [2.3-dj pyrimidine trihydrochloride
  • 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 CH 2 C1 2 -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 tetrahydrochloride
  • the product was prepared by treating a solution of 4-amino-5-(p- dimethylaminophenyl)-7-(p-bromophenyl)pyrido[2, 3-djpyrimidine in CH 2 C1 2 -TEA with the 4-(dimethylamino)butylamine and heating the resulting mixture at reflux for 1 hour.
  • Example 202 4- N-allyl-N-formylamino)-5-(4-dimethylaminophenyl)-7- (p-bromophenyl)pyrido[2,3-d1pyrimidine
  • Example 190 above LRMS m/z 504/506.
  • IR (cm " 1 ) 2922, 1726, 1550, 1360, 1197.
  • the 5-aminopyridine-2-carboxaldehyde starting material was prepared as follows:
  • Example 208 4-amino-5-(3-bromophenyl>7- ⁇ -methyl-2-oxobenzoxazolin-6-vP- pyrido ⁇ 2.3-d1pyrimidine
  • 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:
  • Example 157 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 211 4-amino-5-(2-((thiophene-2-yl)phenyl)methyl -7-(4-diethylaminophenyl)pyrido[2J- djpyrimidine
  • the title compound was prepared from the compound of Example 173 by reaction with 2-thiopheneboronic acid. Pd(PPh 3 ) 4 and aqueous sodium carbonate under Suzuki reaction conditions.
  • Example 212 4-amino-5-(2-((thiophene-3-yl)phenyl methv ⁇ -7-(4-diethylaminophenv ⁇ pyridor2J- dlpyrimidine
  • the title compound was prepared from the compound of Example 173 by reaction with 3-thiopheneboronic acid. Pd(PPh 3 ) 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 R 4 and R 3 as indicated in Table 7 below, compounds of Examples 212-222 were prepared.
  • 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.
  • 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. Table 9 Examples 226-228 -
  • 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. Some compounds were isolated as the TFA salt following purification via high pressure liquid chromatography (HPLC).
  • HPLC high pressure liquid chromatography
  • the title compound was prepared by condensing lJ -dicyano-(3-(3- bromophenyl)propene (the R " 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.
  • Examples 249-251 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 249-251 were prepared. In some cases, the hydrochloride salts were not prepared.
  • Step 252a 1 -(5-bromo-2-pyridyl)ethanone. ethylene ketal
  • Step 252c 4-amino-5-(3-bromophenyl)-7-(5-(N.N-bis(2-methoxyethv0amino " )-2- pyridinvDpyrido [2.3 -dlpyrimidine trihydrochloride
  • 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.
  • 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 11 B 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.
  • Example 261 4-amino-5-(3-pyridyl -7-(4-dimethylamino N )phenylpyrido[2J-dlpyrimidine
  • the compound was prepared by using the method generally described above in Scheme 3 and the associated examples using 1 -(4-dimethylaminophenyl)ethanone as the R 4 reagent (7-position) and nicotinaldehyde as the R 3 reagent (5-position).
  • IR (cm-1) 3305.8. 2922, 1606, 1578, 1535, 1360.
  • Step 264a 1 -(4-( 1 -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.
  • ZnC-2 20 mL ' 0 M so tion 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-( 1 -methyl-2-imidazolyl)phenvDpyrido[2,3- djpyrimidine trihydrochloride Following the procedures of Example 244, except in step (c) first substituting the
  • 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-bromophenyl)-7-(4-(3-fdimethylamino propynyl)phenyl)pyrido[2J- dlpyrimidine
  • Example 272 4-amino-5-(3-bromophenyl)-7-(4-carboxypheny0pyrido[2, -djpyrimidine
  • a solution of 4-amino-5-(3-bromophenyl)-7-(4-cyanophenyl)pyrido[2,3- djpyrimidine (the compound of Example 37, (0.47 g, 1J7 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 (0J4 g, 28%).
  • Step 273a 7-acetyl-2H-pyridor3.2-b1-1.4-oxazin-3f4HVone
  • Step 273b 7-acetyl-4-methyl-2H-pyrido[J.2-bl-lJ-oxazin-3(4H -one
  • step 273 a The compound from step 273 a was treated 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 extracted with dichloromethane. and the resiue was purified by chromatogaphy to give the title compound. MS (M+H), 407.
  • Step 273c 4-amino-5-(3-bromophenvn-7J4-methyl-3-oxo-2H-4H-pyrido[3.2-bl-l ,4- oxazinv0pyrido[2J-d]pyrimidine
  • 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+H), 463 (1 Br); IR (cm-1) 3400, 3200-2800, 1700. 1640, 1605, 1590, 1395, 1380, 1345.
  • Example 274 4-amino-5-(3-bromophenv ⁇ -7-(4-( " 2-(dimethylamino)ethyl)-3-oxo-2H-4H-pyrido[3.2-bl- l,4-oxazin-7-yl pyrido[2J-djpyrimidine
  • Step 274a 7-acetyl-4-dimethylaminoethyl -2H-pyrido[3.2-bj-l,4-oxazin-3(4H)-one
  • Example 273 Step a The compound from Example 273 Step a was treated with 2-chloro-(N,N- dimethyl)ethylamine HCl and K 2 CO 3 in aqueous acetone at reflux. The mixture was diluted with water and extracted 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- pyridor3.2-b1-l,4-oxazin-7-yl)pyrido[2J-d1pyrimidine Following the procedures of Example 244 Step c, except in step c first substituting
  • Step 275b 6-acetyl-3-(dimethylaminoethyl)-2-benzoxazolinone
  • Example 275 Step a The compound from Example 275 Step a was treated with 2-chloro-(N,N- dimethyl)ethylamine HCl and K 2 CO 3 in aqueous acetone at reflux. The mixture was diluted with water and extracted with dichloromethane, and the residue was purified by chromatogaphy to give the title compound.
  • Step 275c 4-amino-5-f3-bromophenyl)-7-(2J-dihvdro-3-(dimethylaminoethyl -2- oxobenzoxazol-6-yl)pyrido " 2, -d1pyrimidine
  • 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+H), 506 (1 Br); IR (cm-1) 3400. 3050, 1630, 1610, 1360.
  • Example 275 Step a The compound from Example 275 Step a was treated 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 extracted with dichloromethane, and the resiue was purified by chromatogaphy to give the title compound.
  • Step 276b l-0-hvdroxy-4-methylaminophenyl -ethanone
  • Step 276d 4-amino-5-f3-bromophenyl -7-(4-methyl-3-oxo-2H-H-benzo-l J-oxazin-7- yl)pyrido ⁇ 2J-djpyrimidine
  • Example 244 Step c Following the procedures of Example 244 Step c, except in 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. MS (M+H), 462 (1 Br); IR (cm-1) 3500. 2800-3200, 1690, 1645, 1610, 1590, 1385, 1355.
  • Step 277a 7-acetyl-2.2.4-trimethyl-2H-4H-benzo-l J-oxazin-3-one
  • Step 277b 4-amino-5-(3-bromophenyl -7-(2.2,4-trimethyl-3-oxo-2H-4H-benzo-l ,4- oxazin-7-yl)pyrido[ " 2.3-djpyrimidine
  • 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 the 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,
  • Step 278b 7-acetyl-4-(dimethylamino ethvD-2H-4H-benzo-l ,4-oxazin-3-one
  • Step 278c 4-amino-5-cyclohexyl-7-(4-(dimethylamino ethyl)-2H-4H-benzo-3-oxo-l ,4- oxazin-7-yl)pyrido[2.3-dlpyrimidine
  • step c first substituting lJ-dicyano-3-cyclohexylethene (prepared according to the 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 title compound was prepared.
  • lJ-dicyano-3-cyclohexylethene prepared according to the method of Moison, et al. (Tetrahedron (1987), 43:537-542) by treating cyclohexane carboxaldehyde with malononitrile in
  • Step 279a l-(5-methvethyl-2-pyridyl)ethanone A solution of 2-acetyl-5-bromopyridine (1.45 g, 7.9 mmol), 2-propenyltrimethyltin
  • Step 279b 4-amino-5-(3-bromophenyl)-7-(5-(l-methylethv ⁇ -2-pyridyl)pyrido[2J- djpyrimidine
  • 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 dichloroethane as the solvent in place of the ethanol solvent in Example 244 step c, the title compound was prepared.
  • Examples 280-281 Following the procedures of Example 244 Step c, except in step c substituting the 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-cvanoacetophenone. acetal with 2.2-dimethylpropylene glycol
  • Step 282c l-(4-(BOC-aminomethyl phenyl)ethanone
  • Step 282d 4-amino-5-(3-bromophenyl)-7-(4-(N-formylamino)methyl)phenyl)pyrido[2J- dlpyrimidine
  • Example 244 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 the solvent in place of the ethanol solvent in Example 244 step c. the title compound was prepared. MS (M+H) 434 (1 Br); IR (cm-1) 3440, 2700-3150, 1635, 1580, 1380.
  • Step 283b 4-(l-fN-BOC-amino)-l-methylethv ⁇ acetophenone
  • Step 283c 4-amino-5-(3-bromophenyl)-7-(4-(l-rN-formylamino)-l- methylethyl)phenyl pyrido[2,3-djpyrimidine
  • 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 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) 3440, 1640. 1605. 1580, 1380.
  • Example 285-286 Following the procedures of Example 157, except substituting the 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 the 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 the product was recrystallized if necessary. The treatment with aqueous HCl was omitted in some cases, and the free bases were obtained.
  • the 1 , 1 -dicyano-3-cyclohexylethene was prepared according to the 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.
  • the reagents for the following examples were prepared by this method susbstituting the compound shown below for the cyclohexane carboxaldehyde used to prepare the reagent of Example 290.
  • Example 29 2-ethylbutanaldehyde;
  • Example 295 cyclopentane carboxaldehyde;
  • step (c) substituting the appropriate reagents for methylamine as indicated in the Table below to prepare the correct R 4 reagent, and substituting the R 3 reagent shown below for the R 3 reagent of Example 246 step d, the compounds of Examples 301-305 were prepared.
  • the condensation solvent was DMSO instead of ethanol and dimethoxyethane.
  • Example 306 4-amino-5-cvclohexyl-7-(6-(4-acetylpiperazinyl)-3-pyridyl pyridor2J-d]pyrimidine
  • 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% methanol 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-amino-5-(l-(2-bromophenyl)ethyl)-7-(l-methyl-5-indolyl pyrido[2J-dlpyrimidine
  • the procedures of Example 157 were followed, except substituting l'J'-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 then heated in 1.2-dichloroethane at reflux for 1-8 hours.
  • Example 324 4-amino-5-(l-(2-bromophenyl)ethyl)-7-(l-methyl-2J-dioxo-5-indolv ⁇ pyrido[2J- dlpyrimidine
  • the title 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- 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 in some cases, and the free bases were obtained.
  • 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 ethanol 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-amino-5-f3-bromophenyl)-7-(6-(4-oxopiperidinyl)-3-pyridv ⁇ pyridor2.3-d1pyrimidine Treating the compound of Example 327 with dilute HCl, the title compound was prepared.
  • Example 329-331 Following the procedures of Example 327, except in step c substituting 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 ⁇ holinyl -3-pyridyl ' )pyrido[2J- dlpyrimidine
  • the compound of Example 331 was treated with 4-chloroperbenzoic acid in methanol and dichloromethane to give the title compound.
  • the title 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)).
  • the title compound was prepared by the reaction of 5-acetyl-2-chloro ⁇ yridine with mo ⁇ holine in refluxing ethanol.
  • the title compound was prepared by condensation of l'J'-dicyano-2-bromostyrene with 5-acetyl-2-mo ⁇ holinylpyridine and ammonium acetate in dichloroethane at reflux.
  • Step 333d 4-amino-5-(2-bromophenyl)-7-(6-mo ⁇ holinyl-3-pyridyl pyrido[2,3- djpyrimidine
  • Example 337 4-amino-5-(3-bromophenyl)-7-(5-chloro-6-mo ⁇ holinyl-3-pyridyl)pyrido 2.3- dlpyrimidine
  • Step a substituting 3- bromobenzaldehyde for the 2-bromobenzaldehyd
  • Step b substituting 5-acetyl-2,3- dichloropyridine for the 5-acetyl-2-chloropyridine to give 5-acetyl-3-chloro-2- mo ⁇ holinylpyridine
  • 5-acetyl-3-chloro-2-mo ⁇ holinylpyridine for the 5- acetyl-2-mo ⁇ holinylpyridine in step c, then the carrying the product forward as in Example 333 Step d, the title compound was prepared.
  • the title compound was prepared by treating the compound of Example 134 with hydrogen peroxide in acetic acid according to standard procedures.
  • the title 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 title compound was prepared by the reaction of 5-acetyl-2-chloropyridine with 2-ethoxyethylamine in refluxing ethanol.
  • Step 339c 4-(3 -bromophenyl -3 -cvano-6- ⁇ s" -(2-ethoxyethyl)amino)pyridine-2-amine
  • the title compound was prepared by condensation of 1 'J '-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 339d 4-amino-5-( " 2-bromophenyl)-7-(6-(N-(2-ethoxyethyl)amino)-3- pyridyl pyrido[2J-d]pyrimidine

Abstract

A method of inhibiting adenosine kinase by administering one of more compounds of formula (I), wherein R?1, R2, R3 and R4¿ are defined, 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-DISUBSΗTUTED-4-AMINOPYRIDO[2,3-D]PYRIMIDINE COMPOUNDS
This application is a continuation in part of copending U.S. Patent Application Serial No. 09/176,521 filed October 21, 1998 which in turn is a continuation in part of copending U.S. Patent Application Serial No. 09/062,796 filed April 13. 1998, which in turn is a a conversion of Provisional U.S. Patent Application Serial No. 60/043,251, filed April 16, 1997.
TECHNICAL FIELD The present invention relates to a method of inhibiting adenosine kinase by administering 5,7-disubstituted-4-aminopyrido[2,3-d]pyrimidine compounds to a mammal in need of such treatment, 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 adenosine monophosphate (AMP), using adenosine triphosphate (ATP), preferentially, as the phosphate source. Magnesium is also required for the reaction, and the true cosubstrate is probably the MgATP2" complex (Palella, et al.. J. Biol. Chem. 1980. 255: 5264-5269).
Adenosine kinase has been isolated from yeast (Leibach, et al., Hoppe-Seyler's Z. Phvsiol. Chem. 1971, 352: 328-344), a variety of mammalian sources (e.g. Miller, et al., J. Biol.
Chem. 1979, 254: 2339-2345; Palella, et al., J. Biol. Chem. 1980. 255: 5264-5269;
Yamada. et al.. Comp. Biochem. Phvsiol. 1982, 71B: 367-372; Rottlan and Miras-
Portugal, Eur. J. Biochem.. 1985, 151 : 365-371), and certain microorganisms (e.g.
Lobelle-Rich and Reeves, Am. J. Trop. Med. Hyg. 1983, 32: 976-979: Datta, et al.. J. Biol. Chem. 1987, 262: 5515-5521). It has been found to be present in virtually every human tissue assayed including kidney, liver, brain, spleen, placenta and pancreas (Andres and
Fox. J. Biol. Chem. 1979. 254: 11388-1 1393). Adenosine kinase is a key enzyme in the control of intracellular adenosine concentration (Arch and Newsholme. Essavs Biochem. 1978. 14: 82-123). Adenosine is a purine nucleoside that is an intermediate in the 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 PI 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, 4: 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 Psvchopharmacology: 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). Adenosine also, inhibits certain neutrophil functions and exhibits anti-inflammatory effects (Cronstein, J. Appl. Phvsiol. 1994. 76: 5-13). An AK inhibitor has been reported to decrease paw swelling in a model of adjuvant arthritis in rats (Firestein, et.al., 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 A, 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. Phvsiol. 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 dysfunctions 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- 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., JJ : 711-717 (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- hydroxypyrido[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- nitrophenyl)pyrido[2,3-d]pyrirnidine compounds having antibacterial activity. A. Gupta et al., (J. Indian Chem. Soc, 71.: 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-amino-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. 5J_: 10253-10258 (1995)) discloses the synthesis of 4-amino-5.7-diphenylpyrido[2,3-d]pyrimidine compounds from acyclic precursors. Bridges et al.(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- d]pyrimidine 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 imgf000007_0001
I, or a pharmaceutically acceptable salt or amide thereof in vitro or to a mammal wherein,
R1 and R2 are each independently selected from the group consisting of hydrogen, alkenyl. alkoxyalkyl, alkoxyalkylcarbonyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkyl, alkylcarbonyl, aminocarbonyl, aryl, arylalkyl, arylalkylcarbonyl, arylcarbonyl, carboxyalkyl, formyl, haloalkylcarbonyl, heterocycle, heterocyclealkyl, heterocyclecarbonyl, hydroxyalkyl, iminoalkyl, and (NZ,Z2)alkyl, or R' and R2 may join together with the nitrogen atom to which they are attached to form a 5-7 membered ring optionally containing 1-2 additional heteroatoms selected from the group consisting of O. N, and S; Z, and Z2 are each independently selected from the group consisting of hydrogen, alkoxycarbonyl, alkyl, alkylcarbonyl, benzyl, benzyloxycarbonyl. and formyl;
- R3 is selected from the group consisting of alkenyl, alkyl, alkynyl, aryl, arylalkyl, cycloalkyl. cycloalkylalkyl. heterocycle. heterocyclealkyl. heterocyclealkylcarbonyl. (NZ,Z2)alkyl, and -RARB;
RA is selected from the group consisting of aryl and arylalkyl; RB is selected from the group consisting of aryl, arylalkoxy, arylalkyl, aryloxy, heterocycle, and heterocyclealkyl;
R4 is selected from the group consisting of alkenyl, alkoxyalkynyl, alkyl, alkynyl, cycloalkyl, aryl, arylalkyl, heterocycle, heterocyclealkyl, and -RCRDRE;
Rc is selected from the group consisting of aryl, arylalkyl, heterocycle, and heterocyclealkyl;
RD is selected from the group consisting of aryl, arylalkoxy, arylalkoxyimino, arylalkyl, aryloxy, heterocycle, heterocyclealkoxy, heterocyclealkyl, heterocyclecarbonyl, heterocycleimino, heterocycleoxy, heterocycleoxyalkyl, heterocycleoxyimino, heterocycleoxyiminoalkyl, and heterocyclesulfonyl; RE is absent or selected from the group consisting of aryl, arylalkoxy, arylalkoxyimino, arylalkyl, aryloxy, heterocycle, heterocylealkoxy, heterocyclealkyl, heterocyclecarbonyl, heterocycleimino, heterocycleoxy, heterocycleoxyalkyl, heterocycleoxyimino, heterocycleoxyiminoalkyl, and heterocyclesulfonyl; and, a dashed line — indicates that a double bond is optionally present provided that proper valencies are maintained; with the proviso that the following compounds are excluded,
4-amino-5-(4-chorophenyl)-7-(4-nitrophenyl)pyridol[2,3-d]pyrimidine,
4-amino-5-(4-methoxyphenyl)-7-(4-nitrophenyl)pyridol[2J-d]pyrimidine,
4-amino-5-(4-fluorophenyl)-7-(4-fluorophenyl)pyridol[2J-d]pyrimidine, 4-amino-5-(4-chlorophenyl)-7-(4-fluo henyl)pyridol[2J-d]pyrimidine,
4-amino-5-phenyl-7-(4-aminophenyl)pyrido[2,3-d]pyrimidine.
4-amino-5-phenyl-7-(4-bromphenyl)pyrido[2,3-d]pyrimidine.
4-amino-5-(4-methoxyphenyl)-7-(4-aminophenyl)pyrido[2,3-d]pyrimidine,
4-amino-5-(4-methoxyphenyl)-7-(4-bromphenyl)pyrido[2.3-d]pyrimidine, and 4-amino-5,7-diphenylpyrido[2,3-d]pyrimidine. 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 administering 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 administering 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 imgf000009_0001
I, or a pharmaceutically acceptable salt or amide thereof wherein
R' and R2 are each independently selected from the group consisting of hydrogen, alkenyl. alkoxyalkyl, alkoxyalkylcarbonyl, alkoxycarbonyl. alkoxycarbonylalkyl. alkyl, alkylcarbonyl, aminocarbonyl, aryl, arylalkyl, arylalkylcarbonyl, arylcarbonyl, carboxyalkyl. formyl, haloalkylcarbonyi. heterocycle. heterocyclealkyl, heterocyclecarbonyl, hydroxyalkyl. iminoalkyl. and (NZ,Z2)alkyl, or R1 and R2 may join together with the nitrogen atom to which they are attached to form a 5-7 membered ring optionally containing 1-2 additional heteroatoms selected from the group consisting of O. N, and S;
Z, and Z are each independently selected from the group consisting of hydrogen, alkoxycarbonyl, alkyl, alkylcarbonyl, benzyl, benzyloxycarbonyl, and formyl;
R3 is selected from the group consisting of alkenyl, alkyl, alkynyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, heterocycle, heterocyclealkyl. heterocyclealkylcarbonyl, (NZ,Z2)alkyl. and -RARB;
RA is selected from the group consisting aryl and arylalkyl; RB is selected from the group consisting of aryl, arylalkoxy, arylalkyl, aryloxy, heterocycle. and heterocyclealkyl;
R4 is selected from the group consisting of alkenyl. alkoxyalkynyl. alkyl, alkynyl, cycloalkyl, aryl, arylalkyl, heterocycle, heterocyclealkyl, and -RCRDRE;
Rc is selected from the group consisting of aryl, arylalkyl. heterocycle, and heterocyclealkyl;
RD is selected from the group consisting of aryl, arylalkoxy, arylalkoxyimino, arylalkyl, aryloxy, heterocycle, heterocyclealkoxy, heterocyclealkyl, heterocyclecarbonyl, heterocycleimino, heterocycleoxy, heterocycleoxyalkyl. heterocycleoxyimino, heterocycleoxyiminoalkyl, and heterocyclesulfonyl; RE is absent or is selected from the group consisting of aryl, arylalkoxy, arylalkoxyimino, arylalkyl, aryloxy. heterocycle. heterocylealkoxy, heterocyclealkyl, heterocyclecarbonyl, heterocycleimino, heterocycleoxy, heterocycleoxyalkyl, heterocycleoxyimino, heterocycleoxyiminoalkyl, and heterocyclesulfonyl; 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:
4-amino-5-(4-chlorophenyl)-7-(4-nitrophenyl)pyrido[2,3-d]pyrimidine; 4-amino-5-(4-methoxyphenyl)-7-(4-nitrophenyl)pyrido[2J-d]pyrimidine; 4-amino-5-(4-fluorophenyl)-7-(4-fluorophenyl)pyrido[2,3-d]pyrimidine; 4-amino-5-(4-chlorophenyl)-7-(4-fluorophenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-phenyl-7-(4-aminophenyl)pyrido[2J-d]pyrimidine;
4-amino-5-phenyl-7-(4-bromophenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(4-methoxyphenyl)-7-(4-aminophenyl)pyrido[2,3-d]pyrimidine; 4-amino-5-(4-methoxyphenyl)-7-(4-bromophenyl)pyrido[2J-d]pyrimidine; and
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 of formula I
Figure imgf000011_0001
I, wherein R1 and R2 are hydrogen;
R3 is selected from the group consisting of alkenyl, alkyl, alkynyl. aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, heterocycle, heterocyclealkyl, heterocyclealkylcarbonyl, (NZ,Z2)alkyl. and -RARB;
RA is selected from the group consisting aryl and arylalkyl; RB is selected from the group consisting of aryl, arylalkoxy, arylalkyl, aryloxy, heterocycle, and heterocyclealkyl;
R4 is selected from the group consisting of alkenyl. alkoxyalkynyl, alkyl, alkynyl, cycloalkyl, aryl, arylalkyl, heterocycle, heterocyclealkyl, and -RCRDRE;
Rc is selected from the group consisting of aryl, arylalkyl, heterocycle, and heterocyclealkyl;
RD is selected from the group consisting of aryl, arylalkoxy, arylalkoxyimino, arylalkyl, aryloxy, heterocycle. heterocyclealkoxy, heterocyclealkyl, heterocyclecarbonyl, heterocycleimino, heterocycleoxy. heterocycleoxyalkyl. heterocycleoxyimino. heterocycleoxyiminoalkyl. and heterocyclesulfonyl; and
RE is absent or is selected from the group consisting of aryl, arylalkoxy. arylalkoxyimino, arylalkyl, aryloxy, heterocycle, heterocylealkoxy, heterocyclealkyl, heterocyclecarbonyl, heterocycleimino, heterocycleoxy, heterocycleoxyalkyl, heterocycleoxyimino. heterocycleoxyiminoalkyl, and heterocyclesulfonyl; and a dashed line — indicates that a double bond is optionally present provided that proper valencies are maintained; the method comprising (a) reacting a ketone having the formula R4-CO-CH3, wherein R4 is as defined above, with an aldehyde having the formula R -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 imgf000012_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 the 8 nitrogen, and then, (c) optionally reducing the compound from step (b) to form a partially reduced or fully reduced right side of formula I by catalytic hydrogenation. In another aspect, the present invention provides a process for the preparation of adenosine kinase inhibiting compounds of formula I
Figure imgf000012_0002
I, wherein R1 and R2 are hydrogen;
RJ is selected from the group consisting of alkenyl, alkyl, alkynyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, heterocycle, heterocyclealkyl, heterocyclealkylcarbonyl, (NZ,Z2)alkyl, and -RARB; RA is selected from the group consisting of aryl and arylalkyl;
RB is selected from the group consisting of aryl, arylalkoxy, arylalkyl, aryloxy, heterocycle, and heterocyclealkyl;
R4 is selected from the group consisting of alkenyl, alkoxyalkynyl, alkyl, alkynyl, cycloalkyl, aryl, arylalkyl, heterocycle, heterocyclealkyl, and -RCRDRE; Rc is selected from the group consisting of aryl, arylalkyl, heterocycle, and heterocyclealkyl;
RD is selected from the group consisting of aryl, arylalkoxy, arylalkoxyimino, arylalkyl, aryloxy, heterocycle, heterocyclealkoxy, heterocyclealkyl, heterocyclecarbonyl, heterocycleimino, heterocycleoxy, heterocycleoxyalkyl, heterocycleoxyimino, heterocycleoxyiminoalkyl, and heterocyclesulfonyl; and
RE is absent or is selected from the group consisting of aryl, arylalkoxy, arylalkoxyimino, arylalkyl, aryloxy, heterocycle, heterocylealkoxy, heterocyclealkyl, heterocyclecarbonyl, heterocycleimino, heterocycleoxy, heterocycleoxyalkyl, heterocycleoxyimino, heterocycleoxyiminoalkyl, and heterocyclesulfonyl; and a dashed line — indicates that a double bond is optionally present provided that proper valencies are maintained; the method comprising
(a) reacting a ketone having the formula R4C(O)CH3, wherein R4 is as defined above, with an dicyanoalkene compound having the formula R3CH=C(CN)2, wherein R3 is as defined above by heating at reflux and isolating a first intermediate compound having the structure
Figure imgf000013_0001
(b) reacting the first intermediate compound with formamide at reflux for from about 1 to about 8 hours, and isolating the compound of formulaJ which has a double bond between the 5 and 6 carbons and a double bond between the 7 carbon and the 8 nitrogen 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.
DETAILED DESCRIPTION OF THE INVENTION The present invention relates to 5,7-disubstituted-4-aminopyrido[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, to novel 5,7-disubstituted-4-aminopyrido[2,3-d]pyrimidine compounds and to a process of preparing 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
Figure imgf000014_0001
I wherein
R1 and R2 are independently selected from the group consisting of hydrogen, alkenyl. alkoxyalkyl, alkoxyalkylcarbonyl, alkoxycarbonyl, alkyl. alkylcarbonyl, aminocarbonyl. aryl, arylcarbonyl, carboxyalkyl, formyl, haloalkylcarbonyl, heterocyclealkyl, hydroxyalkyl, iminoalkyl, and (NZ,Z2)alkyl, or R1 and R2 may join together with the nitrogen atom to which they are attached to form a 6 membered ring optionally containing 1 additional heteroatom selected from the group consisting of O. N, and S;
R3 is selected from the group consisting of alkenyl, alkyl. aryl. arylalkyl, cycloalkyl, heterocycle, heterocyclealkyl, (NZ,Z2)alkyl, and -RARB; RA is selected from the group consisting of aryl and arylalkyl;
RB is selected from the group consisting of aryl, arylalkoxy, arylalkyl, aryloxy, and heterocycle;
R4 is selected from the group consisting of alkoxyalkynyl, alkynyl, aryl, heterocycle, and -RCRDRE; Rc is selected from the group consisting of aryl and heterocycle;
RD is selected from the group consisting of aryl, arylalkoxy, arylalkyl, aryloxy, heterocycle, heterocyclealkoxy, heterocyclealkyl, heterocyclecarbonyl, heterocycleoxy, and heterocyclesulfonyl;
RE is absent or selected from the group consisting of aryl, arylalkoxy, arylalkoxyimino, arylalkyl, aryloxy, heterocycle, heterocylealkoxy, heterocyclealkyl, heterocyclecarbonyl, heterocycleimino, heterocycleoxy, heterocycleoxyalkyl, heterocycleoxyimino, and heterocycleoxyiminoalkyl; and a dashed line — indicates that a double bond is optionally present provided that proper valencies are maintained. The preferred compounds utilized in the above method of inhibiting adenosine kinase are selected from a compound of formula II
Figure imgf000015_0001
II, wherein R1 and R2 are each independently selected from the group consisting of hydrogen, alkenyl, alkoxyalkyl, alkoxy alkylcarbonyl. alkoxycarbonyl, alkyl, alkylcarbonyl, aminocarbonyl, aryl, arylcarbonyl. carboxyalkyl, formyl, haloalkylcarbonyl,
- I .)- heterocyclealkyl, hydroxyalkyl. iminoalkyl. and (NZ:Z2)alkyl. or R1 and R2 may join together with the nitrogen atom to which they are attached to form a 6 membered ring optionally containing 1 additional heteroatom selected from the group consisting of O. N, and S; R3 is selected from the group consisting of alkenyl, alkyl, aryl. arylalkyl, cycloalkyl. heterocycle, heterocyclealkyl, (NZ,Z2)alkyl, and -RARB; RA is selected from the group consisting of aryl and arylalkyl; RB is selected from the group consisting of aryl, arylalkoxy, arylalkyl, aryloxy, and heterocycle; R4 is selected from the group consisting of alkoxy alkynyl, alkynyl, aryl, heterocycle, and -RCRDRE;
Rc is selected from the group consisting of aryl and heterocycle; RD is selected from the group consisting of aryl, arylalkoxy, arylalkyl, aryloxy, heterocycle, heterocyclealkoxy, heterocyclealkyl, heterocyclecarbonyl, heterocycleoxy, and heterocyclesulfonyl; and
RE is absent or is selected from the group consisting of aryl, arylalkoxy, arylalkoxyimino, arylalkyl, aryloxy, heterocycle, heterocylealkoxy, heterocyclealkyl, heterocyclecarbonyl, heterocycleimino, heterocycleoxy, heterocycleoxyalkyl, heterocycleoxyimino, and heterocycleoxyiminoalkyl. In a preferred embodiment, an adenosine kinase inhibitor of the present invention is a compound of Formula II above, wherein R4 is aryl or heterocycle and substituted versions thereof or -RCRDRE.
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 heterocycle and substituted versions thereof and R3 is alkyl, aryl. arylalkyl or heterocycle 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- moφholinyl)-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- methy lamino)pheny 1 ; 3 -methy l-4-(N-methyl-N-(trifluoroacety l)amino)pheny 1 ; 3 -methy 1- 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- (methy lthio)phenyl; 4-(moφholinyl)phenyl; 4-(N-(2-(dimethylamino)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-methyl-N-(2-cyano)ethylamino)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- moφholinyl)phenyl; 4-(thiophene-2-yl)phenyl; 4-(ureido)phenyl; 4-(2- (dimethylamino)acetylamino)phenyl; 4-(2-(2-methoxy)acetylamino)ethyl)amino)phenyl; 4-(2-methoxy )ethoxypheny 1 ; 4-(2-oxo-3 -oxazolidiny l)pheny 1 ; 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-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-moφholinyl-3-pyridinyl: 6-pyrrolidinyl-3-pyridinyl; 6-(2-propyl)-3-pyridinyl; (4-formylamino)phenyl; 6-(4-oxopiperidinyl)-3-pyridazinyl; 6-(4- moφholinyliminopiperidinyl)-3-pyridazinyl; 6-((l S,4S)-2-oxa-5-azabicyclo[2.2J]heptan- 5-yl)-3-pyridazinyl; 6-(4-methoxyiminopiperidinyl)-3-pyridazinyl; 6-phenylmethoxy-3- pyridaziny 1 ; 6-( 1 J -dioxidoythiazolidin-3 -y l)-3 -pyridy 1 ; 6-( 1 ,3 -dioxa-8- azaspiro[4.5]decan-8-yl)-3-pyridyl; 6-(l-oxa-4-thia-8-azaspiro[4.5]decan-8-yl)-3-pyridyl; 6-( 1 J -dioxidoythiomoφholinyl)-3 -pyridazinyl; 6-( 1 -oxa-4,4-dioxido-4-thia-8- azaspiro[4.5]decan-8-yl)-3-pyridyl; 6-( 1 -oxa-4-oxo-4-thia-8-azaspiro[4.5]decan-8-yl)-3- pyridyl; 6-(3-hydroxy-8-azabicyclo[3.2J]octan-8-yl)-3-pyridyl; 6-(4-oxo- 1-phenyl- 1,3, 8- triazaspiro[4.5]decan-8-yl)-3-pyridyl; 6-(4-oxo- 1-phenyl- 1,3, 8-triazaspiro[4.5]dec-2-en-8- yl)-3-pyridyl; 6-(N-l,4-dioxa-8-azaspiro[4.5]decan-8-yl)-3-pyridylsulfonamide; 2-(lJ- dioxidothiomoφholinyl)-5-thiazoyl; 5-(l,4-dioxa-8-azaspiro[4.5]decan-8-yl)-2-pyrazinyl; 2-(l,4-dioxa-8-azaspiro[4.5]decan-8-yl)-5-thiazoyl; 6-(hexahydro-lH-furo[3,4-c]pyrrol-5- yl)-3-pyridazinyl; 6-(hexahydro-lH-furo[3,4-c]pyrrol-5-yl)-3-pyridyl; 6-(4- methoxypiperidinyl)-3-pyridyl; 6-(4,7-epoxy-7-methyl-2,3,3A,4,5,6,7,7a-octahydro-lH- isoindolyl)-3-pyridazinyl; 6-(4-(4-tetrahydropyranyloxy)iminopiperidinyl)-3-pyridazinyl; 6-isopropoxy-3 -pyridazinyl; 6-(2,4-dioxo-(lH,3H)-quinazolin-3-yl)-3-pyridyl; 6-(4-(N- methylpiperazinyl)iminopiperidinyl)-3-pyridazinyl; 6-(4-tetrahydropyranyloxy)-3- pyridazinyl: 6-moφholinylethoxy-3 -pyridazinyl; 6-(4-ethoxypiperidinyl)-3 -pyridazinyl; 6- (l,4-dioxa-8-azaspiro[4.5]decan-8-yl)-3-pyridyl; 6-(4-(2-ethoxyethoxy)piperidinyl)-3- pyridazinyl; 6-((3aR,6aS)-2-oxo-tetrahydro-3aH-[lJ]dioxolo[4,5-c]pyrrol-5-yl)-3-pyridyl; 6-(4-(4-tetrapyranyloxyethyl)piperidinyl)-3-pyridazinyl; 6-(3-(R)- tetrahydrofuranyloxy)piperidinyl)-3-pyridazinyl; 6-(3-(S)- tetrahydrofuranyloxy)piperidinyl)-3-pyridazinyl; 6-(trans-3-ethoxy-4- hydroxy)pyrrolidinyl)-3-pyridazinyl; 6-(cis-3-ethoxy-4-hydroxy)pyrrolidinyl)-3- pyridazinyl; 6-(trans-3-ethoxy-4-hydroxy)pyrrolidinyl)-3-pyridyl; 6-(trans-3.4-bis- ethoxy)pyrrolidinyl)-3-pyridazinyl; 6-(trans-3.4-bis-ethoxy)pyrrolidinyl)-3-pyridyl; 6-(cis- 3,4-bis-ethoxy)pyrrolidinyl)-3-pyridyl: 6-(cis-3.4-bis-ethoxy)pyrrolidinyl)-3-pyridazinyl; 6-(cis-3-ethoxy-4-hydroxy)pyrrolidinyl)-3-pyridyl; 6-(cis-3-amino-4- hydroxy)pyrrolidinyl)-3-pyridazinyl; 6-(cis-3-amino-4-hydroxy)pyrrolidinyl)-3-pyridyl; 6- ( 1 ,5-dioxa-9-azaspiro [5.5 ] undecan-9-y l)-3 -pyridazinyl ; 6-(4-tertbuty l)piperidinyl-3 - pyridazinyl; 6-(4-N-formyl)piperidinyl-3-pyridazinyl; 6-moφholinyl-3-pyridazinyl; 4-N- l,4-dioxa-8-azaspiro[4.5]decan-8-ylbenzenesulfonamide; 4-(4-dioxa-8- azaspiro[4.5]decan-8-ylcarboxamide)phenyl; 6-(3-methoxy- 1 ,5-dioxa-9- azaspiro[5.5]undecan-9-yl)-3-pyridazinyl; 6-(l,5-dioxa-3-hydroxymethyl-9- azaspiro[5.5]undecan-9-yl)-3-pyridazinyl; 6-(S-O-ethyl-2-hydroxymethylpyrrolidinyl)-3- pyridazinyl; 6-(4-acetyl-l-oxa-4,8-diazaspiro[4.5]decan-8-yl)-3-pyridazinyl; 6-((2R,3R)- 2,3-bis(methoxymethyl)-l,4-dioxa-8-azaspiro[4.5]decan-8-yl)-3-yridazinyl; 6-((2S,3S)- 2,3-dimethyl-l,4-dioxa-8-azaspiro[4.5]decan-8-yl)-3-pyridazinyl; 6-(4,4-(cis-l,2- dioxycyclopentane)piperidinyl)-3-pyridazinyl; 6-(4,4-(l S,2S- dimethoxymethylethanedioxy)piperidinyl)-3-pyridazinyl; 6-(4,4-(cis-3,4-dioxy- oxacyclopentane)piperidinyl)-3-pyridazinyl; 6-(4,4-(l,3-dioxy-2- methoxypropylene)piperidinyl)-3-pyridazinyl; 6-(4,4-( 1 ,3-dioxy-2- hydroxymethylpropylene)piperidinyl)-3-pyridazinyl; 6-(4,4-(2-(2,2-spiro- oxacyclopropane-l,3-dioxypropylene)piperidinyl)-3-pyridazinyl; 6-moφholinyl-3- pyridazinyl; 6-(4-moφholinyliminopiperidinyl)-3-pyridyl; 6-(4-(N- methylpiperazinyl)iminopiperidinyl)-3-pyridyl; 6-(4-(l,2,4-triazol-l-yl)iminopiperidinyl)- 3 -pyridyl ; 6-(4-ethylpiperidinylcarboxy late)-3 -pyridy 1 ; 2-phenylmethy 1-3 (2H)- pyridazinone-6-yl; 6-(4-(moφholinylcarboxamide)piperidinyl)-3-pyridyl; 6-(4-(N- moφholinylaminocarboxamide)piperidinyl)-3-pyridyl; 6-(4-(N,N- dimethylaminocarboxamide)piperidinyl)-3-pyridyl; 6-(4-(N-methyl-N- methoxyethy lcarboxamide)piperidiny l)-3 -pyridy 1 ; 6-(4-(N- methoxyethylcarboxamide)piperidinyl)-3-pyridyl; 6-(4-hydroxymethylpiperidinyl)-3- pyridyl; 6-(4-hydroxypiperidinyl)-3-pyridyl; 6-(4-N-acetylpiperazinyl)-3-pyridyl; 6-(4- cyanopiperidinyl)-3 -pyridyl; 6-(4-N-(4-fluorophenyl)piperazinyl)-3-pyridyl; 4- moφholinylbenzenesulfonamide; 4-N-4.4-ethylenedioxypiperidinylbenzenesulfonamide; 4-N-cyclopropylbenzenesulfonamide; 4-piperidinebenzenesulfonamide: 4-(4- cyanopiperidine)benzenesulfonamide; 4-N-cyclopropylmethylbenzenesulfonamide; 4- N,N-dimethylaminobenzenesulfonamide; 4-N-(S)-2- hydroxymethylpyrrolidinebenzenesulfonamide; 4-(4- hydroxypiperidine)benzenesulfonamide; 4-(cis-3,5- dimethylmoφholinyl)benzenesulfonamide; 3-fluoro-4-thiomoφholinylphenyl; 6- (thiomoφholinyl)-3-pyridyl; 6-(4.4-dioxothiomoφholinyl)-3-pyridyl; 4-(4,4- ethylenedioxypiperidinylcarboxamide)phenyl; 4-(N-cyclopropylcarboxamide)phenyl; 4- (moφholinylcarboxamide)pheny 1 ; 6-N-cyclopropy lamino-3 -pyridy 1 ; 4-(4- hydroxypiperidinylcarboxamide)phenyl; 6-(S)-hydroxymethylpyrrolidinyl-3-pyridazinyl; 6-(4-(2-ethoxyethoxy)piperidinyl)-3-pyridyl; 6-hexahydropyrimidine)-3 -pyridyl; 6-(S)-2- ethoxyethoxypyrrolidinyl)-3-pyridyl; 6-(R)-2-ethoxyethoxypyrrolidinyl)-3-pyridyl; 6-(cis- 3,4-dihydroxypyrolidinyl)-3-pyridyl; 6-[(3aR,6aS)-tetrahydro-3aH-[l,3]dioxolo[4,5- c]pyrrol-2-one-5-yl]-3-pyridyl; 6-(cis-2,3-dihydroxypyrrolidinyl)-3-pyridazinyl; 6-(S,R-2- hydroxymethyl-4-hydroxypyrrolidinyl)-3-pyridyl; 6-(R-2-hydroxymethyl-4-pyrrolidinyl)- 3 -pyridazinyl; 6-(lS,4S)-2-aza-5-oxa-bicyclo[2.2J]heptane)-3-pyridyl; 6-(2- imidizolidone-l-yl)-3-pyridyl; 4-(2.4-(lH,3H)-quinazolinedion-3-yl)phenyl; 6- moφholinylcarboxamide-3 -pyridazinyl; 6-methoxy-3 -pyridazinyl ; 6-N,N- diethoxyethylamino-3-pyridazinyl; 6-(4-ethoxymethylpiperidinyl)-3-pyridazinyl; 6-(4-(4- tetrahydropyranylmethyl)piperidinyl)-3-pyridazinyl; 6-(4- ethoxyethoxymethylpiperidinyl)-3 -pyridazinyl; 6-N-methyl-N-1.3- dioxalanemethylamino)-3 -pyridazinyl ; 6-(4,4-dioxyethylenecyclohexyloxy)-3 -pyridazinyl ; 6-dihydroxymethylmethoxy-3-pyridazinyl; 6-(3-pyridyloxy)-3-pyridazinyl; 4,7-epoxy-7- methyl-2,3,3A,4,5,6,7,7a-octahydro-lH-isoindolyl; 6-(4-N-methyl-N-methoxyethyl)-3- pyridazinyl; 6-(3,4-dimethoxymethoxypyrrolidinyl)-3 -pyridazinyl; 6-(trans-3-hydroxy-4- methylpyrrolidinyl)-3-pyridazinyh 6-(trans-3-hydroxy-4-methylpyrrolidinyl)-3-pyridyl; 6- (cis-3-hydroxy-4-methylpyrrolidinyl)-3-pyridazinyl; 6-(cis-3-hydroxy-4- methylpyrrolidinyl)-3-pyridyl; 6-(trans-3-cyano-4-hydroxylpyrrolidinyl)-3-pyridyl; 6-(3- hydroxy-4-tert-butylcarboxamidepyrrolidinyl)-3-pyridyl; 6-(S-2-(4- tetrahydropyranyloxy)methylpyrrolidinyl)-3-pyridazinyl; 6-(2-(4- tetrahydropyranyloxy)iminopyrrolidinyl)-3-pyridazinyl; 2-moφholinyl-5-thiazoyl; 5- bromo-2-thienyl; 2,5-dimethyl-3-thienyl; 5-chloro-2-thienyl; 2J-dimethyl-5-thiazoyl; 5- methyl-2-thienyl; 2-furanyl; 2-(4,4-dioxyethylenepiperidinyl)-5-thiazoyl; 3-thienyl; 3- methyl-2-thienyl; 2-moφholinyl-4-thiazoyl; 2-moφholinyl-4-trifluoromethy-5-thiazoyl; 5-moφholinyl-2-thienyl; 4-methyl-2-moφholinyl-5-thiazoyl; 2,5-dichloro-3-thienyl; 2,5- dimethyl-3-furanyl; N-methyl-2-pyrrolyl; 2-N,N-dimethylamino-5-thiazoyl; 2- moφholinyl-5-thiazoyl; 2-(4,4-dioxythiomoφholinyl)-5-thiazoyl; 1 -N-methyl-2- moφholinyl-5-imidazoyl; 2-moφholinyl-5-oxazolyl; 2-N-methyl-N-methoxyethylamino- 5-thiazoyl; 2-N-methyl-N-ethylamino-5-thiazoyl; 2-N-pyrrolidinyl-5-thiazoyl; 2-N- methyl-N-propylamino-5-thiazoyl; 2-N,N-diethylamino-5-thiazoyl; 2-(N- methypiperazinyl)-5-thiazoyl; 2-(N-(2-pyridyl)piperazinyl)-5-thiazoyl; 2-N-methy-N-(2- pyridylethyl)-5-thiazoyl; 2-(4-oxopiperazinyl)-5-thiazoyl; 2-(4-(N- moφholinyl)iminopiperazinyl)-5-thiazoyl; 6-N-moφholine-3-pyridinesulfonamide; 2-(4- oxopiperidinyl)-5-pyrimidyl; 2-(4,4-dioxethylenepiperidinyl)-5-pyrimidyl; 5-(4,4- dioxethylenepiperidinyl)-2-pyriazinyl; 5-(4-oxopiperidinyl)-2-pyrazinyl; 6-N-cyclopropyl- 3-pyridinesulfonamide; 6-N-(4,4-dioxethylenepiperidinyl)-3-pyridinesulfonamide; 2-(4- (4-tetrahydropyranyloxy)iminopiperidinyl)-5-pyrazinyl; 6-(4-
(phenylmethoxy)iminopiperidinyl)-3-pyridyl; 6-(4-(tert-butyloxy)iminopiperidinyl)-3- pyridyl: 6-(4-(cyclohexyloxy)iminopiperidinyl)-3-pyridyl; 6-(4-hydroxyiminopiperidinyl)- 3 -pyridyl; 6-(4-(4-tetrahydropyranyloxy)iminopiperidinyl)-3 -pyridyl; 6-(4- methoxyethoxyiminopiperidinyl)-3-pyridyl; 6-(4-(2-thenylmethoxy)iminopiperidinyl)-3- pyridy 1 ; 6-(4-(4 ' -(5 'H-2-oxyfurany l)-4-hydroxy )piperidiny l)-3 -pyridy 1 ; 6-(4-( 1 -(4- tetrahydropyranyloxy)iminoethyl))-4-hydroxypiperidinyl)-3-pyridazinyl; 6-(4-(4'-acetyl- 4'-hydroxypiperidinyl)-3-pyridazinyl; 6-(4-(l-(isopropylcaboxymethoxy)iminoethyl))-4- hydroxypiperidinyl)-3-pyridyl; 6-(4-( 1 -(ethylcaboxymethoxy)iminoethyl))-4- hydroxypiperidinyl)-3 -pyridyl; 6-(4-( 1 -(methylcaboxymethoxy)iminoethyl))-4- hydroxypiperidinyl)-3-pyridyl; 6-(4-(l-(2-tetrahydropyranyloxy)iminoethyl))-4- hydroxypiperidinyl)-3 -pyridyl; 6-(4-(l-(allyloxy)iminoethyl))-4-hydroxypiperidinyl)-3- pyridyl: 6-(4-(l-(ethoxy)iminoethyl))-4-hydroxypiperidinyl)-3-pyridyl; 6-(4-(l- (methoxy)iminoethyl))-4-hydroxypiperidinyl)-3-pyridyl; 6-(4-( 1 -(hydroxy)iminoethyl))-4- hydroxypiperidinyl)-3-pyridyl; 6-(4-(2-tetrahydropyranyloxy)iminopiperidinyl)-3-pyridyl; 6-(4-(isopropylcarboxymethoxy)iminopiperidinyl)-3-pyridyl; 6-(4-hydroxy-4-( 1 -(4- tetrahydropyranyloxy)iminoethyl))-4-hydroxypiperidinyl)-3-yridyl; 6-(4-(3- butyrolactone)-4-hydroxypiperidinyl)-3-pyridyl; 6-(4-(2-butyrolactone)-4- hydroxypiperidinyl)-3 -pyridazinyl; 6-(4-acetyl-4-hydroxypiperidinyl)-3-pyridyl; 6-(3- hydroxyazetidinyl)-3 -pyridyl; 6-(cis-3-hydroxytropanyl)-3-pyridyl; 6-(cis-2,3- dihydroxypiperidinyl)-3-pyridyl; 6-(N-methyl-N-(3-pyridylmethyl)amino)-3 -pyridazinyl; 6-(l,2J,6-tetrahydropyridyl)-3-pyridyl; 6-(4-(N-4'methoxyphenylcarbamoyl)piperidinyl)- 3 -pyridazinyl ; 6-(4-(2-butyrolactone)-4-hydroxypiperidinyl)-3 -pyridyl ; 6-(trans-3 ,4-bis(N- 4'-methoxyphenylcarbamoyl)pyrrolidinyl)-3-pyridyl; 6-(trans-3-hydroxytropanyl)-3- pyridyl; 6-(S,S-trans-3,4-dihydroxypyrrolidinyl)-3-pyridyl; 6-(R,R-trans-3,4- dihydroxypyrrolidiny l)-3 -pyridazinyl ; 6-(R,R-trans-3 ,4-dihydroxypyrrolidinyl)-3 -pyridy 1 ; 6-(8-(l-phenyl-l,3,8-triaza-2-spiro[4,5]deceN-4-one)-3-pyridyl; 6J8-(l-phenyl-l,3,8- triaza-2-spiro[4,5]deceN-4-one)-3-pyridyl; 6-(4-(2-keto-l-benzimidazolinyl)piperidinyl)- 3-pyridazinyl; 6-(4-oxothiomoφholinyl)-3-pyridyl; 6-(4-(2-keto-l- benzimidazolinyl)piperidinyl)-3 -pyridyl; 6-(N-methyl-N-(2-pyridylethyl)amino)-3- pyridyl; 6-(N-methyl-N-(4-pyridylethyl)amino)-3-pyridyl; 6-N-(3-pyridylmethyl)amino-3- pyridyl; 6-(2-hydroxymethylpiperidinyl)-3 -pyridyl; 6-(4-hydroxy-4-(4- bromophenyl)piperidinyl)-3 -pyridyl; 6-(4-N-(2-pyridnyl)piperazinyl)-3-pyridyl; 6-(4-N- (2-hydroxyethyloxyethyl)piperazinyl)-3 -pyridyl; 6-(4,4-diacetoxyethylthio)piperidinyl)-3- pyridy 1 ; 6-(N-methy-N-(3-pyridy lmethy l)amino)-3 -pyridy 1 ; 6-(4-pyrrolidiny lpiperidiny 1)- 3 -pyridyl ; 6-(4-N-cyanomethylpiperazinyl)-3 -pyridy 1; 6-(3 -hydroxypyrroldinyl)-3 -pyridyl ; 6-(4-methylpiperidinyl)-3-pyridyl; 6-(cis-3,5-dimethylmoφholinyl)-3-pyridyl; 6-(4,4- difluoropipridinyl)-3 -pyridyl; 6-(4.4-dioxythiomoφholinyl)-3 -pyridazinyl ; 6- thiazolidinyl-3-pyridyl; 6-(lJ-dioxythiazolidinyl)-3-pyridyl; 6-thiomoφholinyl-3- pyridazinyl; 6-(2.5-dihydropyrrolyl)-3-pyridyl; 6-hydroxy-3 -pyridazinyl; 6-piperidinyl-3- pyridyl; and 6-(4-tetrahydropyranyloxy)iminopyrrolidinyl-3-pyridyl; 6-moφholinyl-3- pyridyl.
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)phenylmethyl; 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; (5-chloro-2-(3-methoxyphenyl)phenyl)methyl; 3-bromophenyl; 2-pyridyl; 2- ethoxyphenyl; 5-ethoxyphenyl; 2,5-dichlorophenyl; 2,5-dimethylphenyl; 3-fluorophenyl; 3-trifluoromethylphenyl; 5-trifluoromethylphenyl; 3,5-diclorophenyl; 4-bromo-2-thienyl; 3-bromo-2-thienyl; 3-cyanophenyl: 4-tetrahydropyranyl; 3-indolyl; 5-indolyl; 4-quinolyl; 2-bromophenyl; 4-fluorophenyl; 4,4-difluorocyclohexyl; lJ-dimethyl-3-butenyl; 2,3- dichlorophenyl; isopropyl; and 2-trifluorophenylphenyl.
Exemplary and preferred adenosine kinase inhibitor compounds of the invention utilized in the method recited herein include the compounds listed below wherein R1, R2, R3, and R4 are as described in Formula I in the specific compound: 4-(N-(2J-dihydroxypropyl)amino)-5-(3-bromophenyl)-7-(6-moφholinyl-3- pyridinyl)pyrido[2.3-d]pyrimidine,
4-(N-(3-moφholinylpropyl)amino)-5-(3-bromophenyl)-7-(6-moφholinyl-3- pyridinyl)pyrido[2,3-d]pyrimidine, 4-(N-(2-(4-imidazolyl)ethyl)amino)-5-(3-bromophenyl)-7-(6-moφholinyl-3- pyridinyl)pyrido[2,3-d]pyrimidine,
4-(N-(3-carboxypropyl)amino)-5-(3-bromophenyl)-7-(6-moφholinyl-3- pyridinyl)pyrido[2,3-d]pyrimidine,
(S)-4-amino-5-(3-bromophenyl)-7-(6-(O-methyl-2-hydroxymethylpyrrolidinyl)-3- pyridinyl)pyrido[2,3-d]pyrimidine,
(S)-4-amino-5-(3-bromophenyl)-7-(6-(2-hydroxymethylpyrrolidinyl)-3- pyridinyl)pyrido[2J-d]pyrimidine,
4-amino-5-(2-bromophenyl)-7-(6-(4-hydroxypiperidinyl)-3-pyridinyl)pyrido[2,3- djpyrimidine, 4-amino-5-(4-fluorophenyl)-7-(6-(4,4-ethylenedioxypiperidinyl)-3- pyridinyl)pyrido[2,3-d]pyrimidine,
4-amino-5-(2-bromophenyl)-7-(6-(4-hydroxypiperidinyl)-3-pyridazyl)pyrido[2,3- djpyrimidine,
4-amino-5-(3-bromophenyl)-7-(6-(4,4-ethylenedioxypiperidinyl)-3- pyridazyl)pyrido[2,3-d]pyrimidine,
4-amino-5-(3-bromophenyl)-7-(2-moφholinyl-4-thiazolyl)pyrido[2J- djpyrimidine,
4-amino-5-(N-methyl-3 -indoly l)-7-(6-moφholiny 1-3 -pyridiny l)pyrido [2,3 - d]pyrimidine, 4-amino-5-(3-bromophenyl)-7-(6-(4-ethoxyiminopiperidinyl)-3- pyridinyl)pyrido[2,3-d]pyrimidine,
4-amino-5-(3-bromophenyl)-7-(6-(4-ethoxycarbonylmethoxyiminopiperidinyl)-3- pyridinyl)pyrido[2,3-d]pyrimidine,
4-amino-5-(4-dimethylaminophenyl)-7-(4-bromophenyl)pyrido[2.3-d]pyrimidine, 4-amino-5-(4-dimethylaminophenyl)-7-(4-dimethylaminophenyl)pyrido[2J- djpyrimidine,
4-amino-5-(4-methoxyphenyl)-7-(4-dimethylaminophenyl)pyrido[2,3- djpyrimidine, 4-amino-5-(4-dimethylaminophenyl)-7-(4-methoxyphenyl)pyrido[2J- djpyrimidine,
4-amino-5-(4-(2-propyl)phenyl)-7-(4-methoxyphenyl)pyrido[2,3-d]pyrimidine, 4-amino-5-(4-neopentylphenyl)-7-(4-methoxyphenyl)pyrido[2,3-d]pyrimidine, 4-amino-5-(4-butyloxyphenyl)-7-(4-methoxyphenyl)pyrido[2,3-d]pyrimidine, 4-amino-5-(4-methoxyphenyl)-7-(4-bromophenyl)pyrido[2,3-d]pyrimidine,
4-amino-5-(4-(2-propyl)oxyphenyl)-7-(4-methoxyphenyl)pyrido[2J-d]pyrimidine, 4-amino-5-(4-butoxyphenyl)-7-(4-N-formylpiperazinylphenyl)pyrido[2J- djpyrimidine,
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- djpyrimidine,
4-amino-5-(4-(2-propyl)phenyl)-7-(4-t-butylacylphenyl)pyrido[2,3-d]pyrimidine, 4-amino-5-(3-bromophenyl)-7-(4-dimethylaminophenyl)pyrido[2,3-d]pyrimidine, 4-amino-5-(3,4-dimethoxyphenyl)-7-(4-dimethylaminophenyl)pyrido[2J- djpyrimidine.
4-amino-5-(3-t-butylacrylphenyl)-7-(4-dimethylaminophenyl)pyrido[2.3- djpyrimidine,
4-amino-5-(3-methoxyphenyl-7-(4-dimethylaminophenyl)pyrido[2J-d]pyrimidine, 4-amino-5-(3,5-dimethoxyphenyl-7-(4-dimethylaminophenyl)pyrido[2.3- djpyrimidine.
4-amino-5-(3-diethylmalonylallylphenyl)-7-(4-dimethylaminophenyl)pyrido[2J- djpyrimidine.
4-amino-5-(3-vinylpyridinylphenyl)-7-(4-dimethylaminophenyl)pyrido[2,3- djpyrimidine.
-93- 4-amino-5-(3-trifluoromethylphenyl)-7-(4-dimethylaminophenyl)pyrido[2J- djpyrimidine.
4-amino-5-(3-carboxamidophenyl)-7-(4-dimethylaminophenyl)pyrido[2,3- djpyrimidine. 4-amino-5-(3-cyanophenyl)-7-(4-dimethylaminophenyl)pyrido[2.3-d]pyrimidine,
4-amino-5-(3-benzyloxyphenyl)-7-(4-dimethylaminophenyl)pyrido[2,3- djpyrimidine,
4-amino-5-(3-methoxyphenyl)-7-(4-methoxyphenyl)pyrido[2J-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-amino-5-(3-methylphenyl)-7-(4-dimethylaminophenyl)pyrido[2.3-d]pyrimidine, 4-amino-5-(3-chlorophenyl)-7-(4-dimethylaminophenyl)pyrido[2,3-d]pyrimidine, 4-amino-5-(3-fluorophenyl)-7-(4-dimethylaminophenyl)pyrido[2,3-d]pyrimidine, 4-amino-5-(3-bromophenyl)-7-(4-methoxyphenyl)pyrido[2,3-d]pyrimidine,
4-amino-5-(3-methoxyphenyl)-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-d]pyrimidine,
4-amino-5-(3-bromophenyl)-7-(4-hydroxyphenyl)pyrido[2,3-d]pyrimidine, 4-amino-5-(3-iodophenyl)-7-(4-dimethylaminophenyl)pyrido[2J-d]pyrimidine, 4-amino-5-(3-ethoxyphenyl)-7-(4-dimethylaminophenyl)pyrido[2J-d]pyrimidine, 4-amino-5-(3-trifloromethyoxyphenyl)-7-(4-dimethylaminophenyl)pyrido[2,3- djpyrimidine,
4-amino-5-(3,5-dichlorophenyl)-7-(4-dimethylaminophenyl)pyrido[2J- d]pyrimidine,
4-amino-5-(3-bromo-4-fluorophenyl)-7-(4-dimethylaminophenyl)pyrido[2J- djpyrimidine, 4-amino-5-(3-hydroxyphenyl)-7-(4-dimethylaminophenyl)pyrido[2J-d]pyrimidine, 4-amino-5-(3-bromophenyl)-7-(4-moφholinylphenyl)pyrido[2J-d]pyrimidine, 4-amino-5-(3-bromophenyl)-7-(4-piperidinylphenyl)pyrido[2J-d]pyrimidine, 4-amino-5-(3-bromophenyl)-7-(4-(imidazol-l-yl)phenyl)pyrido[2.3-d]pyrimidine, 4-amino-5-(3-bromophenyl)-7-(4-chlorophenyl)pyrido[2J-d]pyrimidine, 4-amino-5-(3-bromophenyl)-7-(4-isopropylphenyl)pyrido[2J-d]pyrimidine,
4-amino-5-(3-bromophenyl)-7-(4-trifluorophenyl)pyrido[2J-d]pyrimidine, 4-amino-5-(3-bromophenyl)-7-(4-diethylaminophenyl)pyrido[2J-d]pyrimidine, 4-amino-5-(3-bromophenyl)-7-(3,4,5-trimethoxyphenyl)pyrido[2J-d]pyrimidine, 4-amino-5-(3-(3-methoxybenzyl)phenyl)-7-(4-dimethylaminophenyl)pyrido[2,3- djpyrimidine,
4-amino-5-(3-methoxyethyoxyphenyl)-7-(4-dimethylaminophenyl)pyrido[2,3- djpyrimidine,
4-amino-5-(3,4-methylenedioxyphenyl)-7-(4-dimethylaminophenyl)pyrido[2,3- d]pyrimidine, 4-amino-5-(3-bromophenyl)-7-(4-ethoxyphenyl)pyrido[2J-d]pyrimidine,
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-dimethylaminophenyl)-7-(4-dimethylaminophenyl)pyrido[2,3- djpyrimidine, 4-amino-5-phenyl-7-(4-dimethylaminophenyl)pyrido[2,3-d]pyrimidine,
4-amino-5-(3,4.5-trimethoxyphenyl)-7-(4-dimethylaminophenyl)pyrido[2J- djpyrimidine,
4-amino-5-(3-bromophenyl)-7-(4-nitrophenyl)pyrido[2J-d]pyrimidine, 4-amino-5-(3-bromophenyl)-7-(4-iodophenyl)pyrido[2,3-d]pyrimidine, 4-amino-5-(3-bromophenyl)-7-(3J-methylenedioxyphenyl)pyrido[2J- djpyrimidine.
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 [2J-d]pyrimidine, 4-amino-5-(3-bromophenyl)-7-(4-carboxamidophenyl)pyrido[2J-d]pyrimidine. 4-amino-5 3-bromophenyl)-7-(4-(2-methoxy)ethoxyphenyl)pyrido[2,3- djpyrimidine,
4-amino-5 3,5-dimethoxyphenyl)-7-(4-moφholinylphenyl)pyrido[2,3- djpyrimidine,
4-amino-5-< 3-trifluoromethylphenyl)-7-(thiophene-2-yl)pyrido [2,3 -djpyrimidine,
4-amino-5-ι 3-bromophenyl)-7-(4-aminophenyl)pyrido[2J-djpyrimidine,
4-amino-5-< 3-bromo-4-fluorophenyl)-7-(thiophene-2-yl)pyrido [23 -djpyrimidine.
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-djpyrimidine,
4-amino-5 3,5-dimethoxyphenyl)-7-(4-imidazolylphenyl)pyrido[2J-d]pyrimidine,
4-amino-5 3,5-dimethoxyphenyl)-7-(4-(thiophene-2-yl)phenyl)pyrido[2J- djpyrimidine,
4-amino-5- 3,5-dimethoxyphenyl)-7-(4-(3-pyridyl)phenyl)pyrido[2,3-d]pyrimidine, 4-amino-5- 3-bromophenyl)-7-(4-(4-methylpiperidinyl)phenyl)pyrido[2,3- djpyrimidine,
4-amino-5- 3-bromophenyl)-7-(4-pyrrolidinylphenyl)pyrido[2,3-djpyrimidine, 4-amino-5- 4-bromothiophene-)-7-(4-dimethylaminophenyl)pyrido[2J- djpyrimidine,
4-amino-5-(4-bromothiophene-2-yl)-7-(4-moφholinylphenyl)pyrido[2,3- djpyrimidine,
4-moφholinyl-5-(3-bromophenyl)-7-(4-dimethylaminophenyl)pyrido[2,3- djpyrimidine,
4-amino-5-(5-bromothiophene-2-yl)-7-(4-moφholinylphenyl)pyrido[2,3- djpyrimidine,
4-amino-5-(4-bromophenyl)-7-(4-dimethylaminophenyl)pyrido[2,3-d]pyrimidine,
4-amino-5-(3-bromophenyl)-7-(4-(acetylamino)phenyl)pyrido[2.3-djpyrimidine.
4-amino-5-(3-bromophenyl)-7-(4-dimethylaminophenyl)pyrido[2.3-d]pyrimidine,
4-amino-5-(3,5-dimethoxyphenyl)-7-(5-pyrimidinylphenyl)pyrido[2J- djpyrimidine, 4-(4-fluorophenyl)amino)-5-(3-bromophenyl)-7-(4- dimethylaminophenyl)pyrido[2J-d]pyrimidine,
4-amino-5-(4-bromothiophene-2-yl)-7-(4-pyrrolidinylphenyl)pyrido[2,3- djpyrimidine, 4-amino-5 4-bromothiophene-2-yl)-7-(thiophene-2-yl)pyrido[2,3-d]pyrimidine,
4-amino-5 3-bromophenyl)-7-(5-(dimethylamino)thiophene-2-yl)pyrido[2,3- djpyrimidine,
4-amino-5 3-bromo-5-iodophenyl)-7-(4-(dimethylamino)phenyl)pyrido[2,3- djpyrimidine, 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-moφholinylphenyl)pyrido[2,3- djpyrimidine,
4-amino-5- 3 ,5 -dibromopheny l)-7-(4-(dimethylamino)pheny l)pyrido [2,3 - djpyrimidine,
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- djpyrimidine,
4-amino-5- 3,5-dibromophenyl)-7-(4-(dimethylamino)phenyl)pyrido[2,3- djpyrimidine,
4-amino-5- 3-bromophenyl)-7-(3-(dimethylamino)phenyl)pyrido[2J-d]pyrimidine, 4-amino-5- 3-bromophenyl)-7-(4-methylsulfonylphenyl)pyrido[2J-d]pyrimidine, 4-amino-5- 3-bromophenyl)-7-(3-methoxyphenyl)pyrido[2J-d]pyrimidine, 4-amino-5- 3-bromophenyl)-7-(4-(methylthio)phenyl)pyrido[2,3-d]pyrimidine, 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[2J- djpyrimidine,
4-amino-5- 3-bromophenyl)-7-(4-methylaminophenyl)pyrido[2J-d]pyrimidine, 4-amino-5- 3-bromo-4-fluorophenyl)-7-(4-methylsulfonylphenyl)pyrido[2,3- djpyrimidine, 4-amino-5-(3-bromophenyl)-7-(3-amino-4-methoxyphenyl)pyrido[2,3- djpyrimidine,
4-amino-5-(3-bromophenyl)-7-(3-bromo-4-(dimethylamino)phenyl)pyrido[2,3- djpyrimidine. 4-amino-5-(3-bromophenyl)-7-(3-methyl-4-(dimethylamino)phenyl)pyrido[2,3- djpyrimidine,
4-amino-5-(3-bromophenyl)-7-(4-(N-methyl-N- trifluoroacetylamino)phenyl)pyrido [2,3 -djpyrimidine,
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- djpyrimidine,
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- djpyrimidine,
4-amino-5 -(3 -bromopheny l)-7-(4-(N-ethy lamino)pheny l)pyri do [2,3 -djpyrimidine,
4-amino-5-(3-bromophenyl)-7-(4-(N-methyl-N-(2- methoxyethyl)amino)phenyl)pyrido[2,3-djpyrimidine, 4-amino-5-(3-bromophenyl)-7-(4-(N-isopropylamino)phenyl)pyrido[2,3- djpyrimidine,
4-amino-5-(3-bromophenyl)-7-(4-N-ethyl-N-(2- methoxyethyl)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-djpyrimidine,
4-amino-5-(3-bromophenyl)-7-(4-(N-(2- (dimethylamino)ethyl)amino)phenyl)pyrido[2,3-d]pyrimidine, 4-amino-5-(3-bromophenyl)-7-(4-(N-methyl-N-(2- cyano)ethylamino)phenyl)pyrido[2J-d]pyrimidine,
4-amino-5-(3-bromophenyl)-7-(4-(N-methyl-N-(3- methoxy)propionylamino)phenyl)pyrido[2J-d]pyrimidine, 4-amino-5-(3-bromophenyl)-7-(3-methyl-4-(N-formyl-N- methylamino)phenyl)pyrido[2J-djpyrimidine,
4-amino-5-(3-bromophenyl)-7-(3-methyl-4-(N-methylamino)phenyl)pyrido[2J- djpyrimidine,
4-amino-5-(3-bromophenyl)-7-(4-(4-methoxy-2-butyl)phenyl)pyrido[2,3- djpyrimidine,
4-amino-5-(3-bromophenyl)-7-(4-(N-methyl-N-(2-(N- phthalimidyl)acetyl)amino)phenyl)pyrido[2,3-d]pyrimidine,
4-amino-5-(3-bromophenyl)-7-(3-methyl-4-(N-methyl-N- (trifluoroacetyl)amino)phenyl)pyrido[2,3-d]pyrimidine, 4-amino-5-(3-bromophenyl)-7-(3-methyl-4-(N-acetyl-N- methylamino)phenyl)pyrido[2,3-djpyrimidine,
4-amino-5-(3-bromophenyl)-7-(6-dimethylamino-3-pyridinyl)pyrido[2,3- djpyrimidine,
4-amino-5-(3-cyanophenyl)-7-(4-methylsulfonylphenyl)pyrido[2J-d]pyrimidine, 4-amino-5-(3-cyanophenyl)-7-(4-(N-methyl-N-formylamino)-phenyl)pyrido[2,3- djpyrimidine,
4-amino-5-(3-bromophenyl)-7-(6-(N-methyl-N-formylamino)-3- pyridinyl)pyrido[2,3-d]pyrimidine,
4-amino-5-(3-bromophenyl)-7-(6-moφholinyl-3-pyridinyl)pyrido[2,3- djpyrimidine,
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-pyrrolidinyl-3-pyridinyl)pyrido[2J-d]pyrimidine,
4-amino-5-(3-bromophenyl)-7-(2-(dimethylamino)-5-pyrimidinyl)pyrido[2J- djpyrimidine, 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[2J-d]pyrimidine, 4-amino-5-(3-bromophenyl)-7-(2-(N-methylamino)5-pyrimidinyl)pyrido[2J- djpyrimidine,
4-amino-5-(3-bromophenyl)-7-(2-(l-pyrrolidinyl)-5-pyrimidinyl)pyrido[2J- djpyrimidine,
4-amino-5-(3-bromophenyl)-7-(2-(l-moφholinyl)-5-pyrimidinyl)pyrido[2J- djpyrimidine,
4-amino-5-(3-bromophenyl)-7-(6-(2-oxo-3-oxazolidinyl)-3-pyridinyl)pyrido[2,3- djpyrimidine,
4-amino-5-(3-bromophenyl)-7-(2-pyridyl)pyrido[2,3-djpyrimidine, 4-amino-5 -(3 -bromopheny l)-7-(3 -pyridyl)pyri do [2,3-djpyrimidine, 4-amino-5-(3-(thiophen-2-yl)phenyl)-7-(4-dimethylaminophenyl)pyrido[2,3- djpyrimidine,
4-amino-5-(3-(furan-2-yl)phenyl)-7-(4-dimethylaminophenyl)pyrido[2,3- djpyrimidine,
4-amino-5-(3-(3-methoxyphenyl)phenyl)-7-(4-dimethylaminophenyl)pyrido[2,3- djpyrimidine,
4-amino-5-phenyl-7-(4-dimethylaminophenyl)pyrido[2,3-d]pyrimidine,
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[2J- djpyrimidine, 4-amino-5-(3-chlorophenyl)-7-(4-iodophenyl)pyrido[2,3-d]pyrimidine,
4-amino-5-(3-chlorophenyl)-7-(4-(thiophen-2-yl)phenyl)pyrido[2J-d]pyrimidine, 4-amino-5-(3-chlorophenyl)-7-(4-(5-pyrimidinyl)phenyl)pyrido[2J-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[2J-d]pyrimidine. 4-amino-5-(3-bromophenyl)methyl-7-(4-(dimethylamino)phenyl)pyrido[2,3- djpyrimidine,
4-amino-5-(2-phenylethyl)-7-(4-diethylaminophenyl)pyrido[2J-d]pyrimidine. 4-amino-5-(2-methylpropyl)-7-(4-diethylaminophenyl)pyrido[2J-d]pyrimidine, 4-amino-5-(butyl)-7-(4-diethylaminophenyl)pyrido[2,3-d]pyrimidine.
4-amino-5-(2-(4-bromophenyl)ethyl)-7-(4-diethylaminophenyl)pyrido[2J- djpyrimidine,
4-amino-5-(butyl)-7-(4-dimethylaminophenyl)pyrido[2,3-d]pyrimidine, 4-amino-5-(2-(3-cyanophenyl)methyl)-7-(4-dimethylaminophenyl)pyrido[2,3- djpyrimidine,
4-amino-5-(2-(N-phenylmethoxycarbonyl)aminoethyl)-7-(4- dimethylaminophenyl)pyrido[2J-d]pyrimidine,
4-amino-5-(cycloheptyl)-7-(4-dimethylaminophenyl)pyrido[2,3-djpyrimidine, 4-amino-5-(2-(5-chloro-2-(thiophen-3-yl)phenylmethyl)-7-(4- dimethylaminophenyl)pyrido[2,3-d]pyrimidine,
4-amino-5-(pentyl)-7-(4-diethylaminophenyl)pyrido[2,3-d]pyrimidine, 4-amino-5-hexyl-7-(4-diethylaminophenyl)pyrido[2,3-djpyrimidine, 4-amino-5-(2-(3-bromophenyl)ethyl)-7-(4-diethylaminophenyl)pyrido[2,3- djpyrimidine, 4-amino-5-((2-bromophenyl)methyl)-7-(4-diethylaminophenyl)pyrido[2,3- djpyrimidine,
4-amino-5-cyclopropyl-7-(4-dimethylaminophenyl)pyrido[2,3-d]pyrimidine, 4-amino-5-cyclohexyl-7-(4-dimethylaminophenyl)pyrido[2J-djpyrimidine, 4-amino-5-((2-bromo-5-chlorophenyl)methyl)-7-(4-diethylaminophenyl)pyrido[2,3- djpyrimidine,
4-amino-5-methyl-7-(4-diethylaminophenyl)pyrido[2,3-d]pyrimidine, 4-amino-5-(2,3-methylenedioxyphenyl)-7-(4-dimethylaminophenyl)pyrido[2J- djpyrimidine,
4-amino-5-(3-fluoro-5-trifluoromethylphenyl)-7-(4- dimethylaminophenyl)pyrido[2,3-d]pyrimidine. 4-amino-5-(2-bromophenyl)-7-(4-dimethylaminophenyl)pyrido[2J-d]pyrimidine,
4-amino-5-(3.5-dimethylphenyl)-7-(4-dimethylaminophenyl)pyrido[2J- djpyrimidine,
4-amino-5-(3,4-dichlorophenyl)-7-(4-dimethylaminophenyl)pyrido[2,3- djpyrimidine,
4-amino-5 -(4-fluoro-3 -trifluoromethy lpheny l)-7-(4- dimethylaminophenyl)pyrido[2,3-d]pyrimidine,
4-amino-5-(3-bromo-5-methoxyphenyl)-7-(4-moφholinylphenyl)pyrido[2J- djpyrimidine, 4-amino-5-(3-bromo-5-methoxyphenyl)-7-(4-pyrrolidinylphenyl)pyrido[2,3- djpyrimidine,
4-amino-5-(3-bromo-5-methoxyphenyl)-7-(4-piperidinylphenyl)pyrido[2J- djpyrimidine,
4-amino-5-(3-bromo-5-methoxyphenyl)-7-(4-dimethylaminophenyl)pyrido[2,3- djpyrimidine,
4-amino-5-(3-methylthiophenyl)-7-(4-dimethylaminophenyl)pyrido[2,3- djpyrimidine,
4-amino-5-(3-bromo-5-methoxyphenyl)-7-(thiophene-2-yl)pyrido[2,3-d]pyrimidine,
4-amino-5-(2,3-dimethoxyphenyl)-7-(4-dimethylaminophenyl)pyrido[2,3- djpyrimidine,
4-amino-5-(3-methylsulfonylphenyl)-7-(4-dimethylaminophenyl)pyrido[2J- djpyrimidine,
4-acetylamino-5-(3-bromophenyl)-7-(4-dimethylaminophenyl)pyrido[2J- djpyrimidine, 4-formylamino-5-(3-bromophenyl)-7-(4-dimethylaminophenyl)pyrido[2,3- djpyrimidine,
4-(methoxyacetyl)amino-5-(3-bromophenyl)-7-(4-diethylaminophenyl)pyrido[2,3- djpyrimidine,
4-trifluoroacetylamino-5-(3-bromophenyl)-7-(4-dimethylaminophenyl)pyrido[2J- djpyrimidine, 4-pentanoylamino-5-(3-bromophenyl)-7-(4-dimethylaminophenyl)pyrido[2,3- djpyrimidine,
4-benzoylamino-5-(3-bromophenyl)-7-(4-dimethylaminophenyl)pyrido[2,3- djpyrimidine, 4-(N-BOC-glycyl)amino-5J3-bromophenyl)-7-(4- dimethylaminophenyl)pyrido[2.3-d]pyrimidine,
4-(N-phthalimidylglycyl)amino-5-(3-bromophenyl)-7-(4- dimethy laminopheny l)pyrido [2 ,3 -djpyrimidine,
4-(ethoxycarbonyl)amino-5-(3-bromophenyl)-7-(4- dimethylaminophenyl)pyrido[2J-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-(N,N-dimethylamino)ethylamino)-5-(4-bromophenyl)-7-(4- dimethylaminophenyl) pyrido[2,3-djpyrimidine,
4-(4-(N,N-dimethylamino)butylamino)-5-(3-bromophenyl)-7-(4- dimethylaminophenyl) pyrido[2,3-djpyrimidine,
4-(N-allyl-N-formylamino)-5-(4-dimethylaminophenyl)-7-(4- bromophenyl)pyrido[2,3-d]pyrimidine,
4-diacetylamino-5-(p-dimethylaminophenyl)-7-(4- bromophenyl)pyrido[2,3-d]pyrimidine,
4-amino-5-(3-bromophenyl)-7-(5-amino-2-pyridyl)pyrido[2J-d]pyrimidine,
4-amino-5-(3-bromophenyl)-7-(5-dimethylamino-2- pyridyl)pyrido[2,3-d]pyrimidine,
4-amino-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-djpyrimidine,
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- dimethy laminophenyl)pyrido [2.3 -djpyrimidine,
4-amino-5-((thiophene-2-yl)methyl)-7-(4-diethylaminophenyl)pyrido[2,3- djpyrimidine, 4-amino-5-((thiophene-3-yl)methyl)-7-(4-diethylaminophenyl)pyrido[2J- djpyrimidine,
4-amino-5-((2-bromophenyl)methyl)-7-(4-dimethylaminophenyl)pyrido[2J- djpyrimidine,
4-amino-5-(3-bromophenyl)-7-(4-(N-formyl-N-(2- methoxyethyl)amino)phenyl)pyrido[2,3-d]pyrimidine,
4-amino-5 -(3 -bromopheny l)-7-(4-(N-(2-methoxyethyl)amino)pheny ljpyrido [2,3 - djpyrimidine,
4-amino-5-(3-bromophenyl)-7-(4-(N-methyl-N-((2- dimethylamino)ethyl)amino)phenyl)pyrido[2,3-djpyrimidine, 4-amino-5-(3-bromophenyl)-7-(4-(2- methoxy)acetylamino)ethyl)amino)phenyl)pyrido[2,3-d]pyrimidine,
4-amino-5-(3-bromophenyl)-7-((4-formylamino)phenyl)pyrido[2,3-d]pyrimidine,
4-amino-5-(3-bromophenyl)-7-(4-(2- (dimethy lamino)acety lamino)pheny l)pyrido [2,3 -djpyrimidine, 4-amino-5-(3-bromophenyl)-7-(4-(2-oxo-3-oxazolidinyl)phenyl)pyrido[2J- djpyrimidine,
4-amino-5-(3-bromophenyl)-7-(6-(2-propyl)-3-pyridinyl)pyrido[2J-djpyrimidine,
4-amino-5-(3-bromophenyl)-7-(3-methyl-4-pyrrolidinylphenyl)pyrido[2,3- djpyrimidine, 4-amino-5-(3-bromophenyl)-7-(6-imidazolyl-3-pyridinyl)pyrido[2J-d]pyrimidine,
4-amino-5-phenylmethyl-7-(4-diethylaminophenyl)pyrido[2,3-d]pyrimidine.
4-amino-5-(2-(3-aminopropynyl)phenylmethyl)-7-(4- diethylaminophenyl)pyrido[2J-d]pyrimidine,
4-amino-5-(l-(3-bromophenyl)ethyl)-7-(4-diethylaminophenyl)pyrido[2J- djpyrimidine,
54- 4-amino-5-(4-dimethylaminophenyl)-7-(4-bromophenyl)pyrido[2J-d]pyrimidine,
4-amino-5-(2-furanyl)-7-(4-(N-moφholinyl)phenyl)pyrido[2J-d]pyrimidine,
4-amino-5-(3-bromophenyl)-7-(2-dimethylamino-5-pyrimidinyl)pyrido[2J- djpyrimidine, 4-amino-5-(3-bromophenyl)-7-(4-(ureido)phenyl)pyrido[2.3-d]pyrimidine,
4-amino-5 -( 1 -pheny lmethy 1-3 -piperidiny l)-7-(4- diethylaminophenyl)pyrido[2,3-d]pyrimidine,
4-amino-5-(3-bromophenyl)-7-(6-(3-methyl-5-isoxazolyl))-3- pyridinyl)pyrido[2J-d]pyrimidine, 4-amino-5-(3-bromophenyl)-7-(6-chloro-3-pyridinyl)pyrido[2J-d]pyrimidine,
4-amino-5-(3-bromophenyl)-7-(6-methoxy-3-pyridinyl)pyrido[2J- djpyrimidine,
4-amino-5-(3-bromophenyl)-7-(6-(l,2,4-triazol-4-yl)-3-pyridinyl)pyrido[2,3- djpyrimidine, 4-amino-5-(3-bromophenyl)-7-(2-moφholinyl-5-pyrimidinyl)pyrido[2,3- djpyrimidine,
4-amino-5-(2-thiazolyl)-7-(4-pyrrolidinylphenyl)-pyrido[2J-d]pyrimidine,
4-amino-5 -(3 -bromopheny l)-7-(6-pyrazolyl-3 -pyridiny l))-pyri do [2,3 - djpyrimidine, 4-amino-5-(3-bromophenyl)-7-(4-(l-methyl-ureido)phenyl)-pyrido[2.3- djpyrimidine,
4-amino-5-(3-bromophenyl)-7-(4-(N-methyl-N-(2-pyrimidinyl)amino)phenyl)- pyrido [23 -djpyrimidine,
4-amino-5-(3-bromophenyl)-7-(3-fluoro-4-(N-formyl-N-methylamino)phenyl)- pyrido[2J-d]pyrimidine,
4-formylamino-5-(3-bromophenyl)-7-(3-fluoro-4-(N-formyl-N- methylamino)phenyl)-pyrido[2,3-d]pyrimidine,
4-amino-5-(3-bromophenyl)-7-(4-(N-methyl-N-methylsulfonylamino)- phenyl)pyrido[2J-djpyrimidine, 4-amino-5-(3-bromophenyl)-7-(6-(N-methyl-N-methylsulfonylamino)-3- pyridiny l)pyrido [2.3 -djpyrimidine,
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- djpyrimidine,
4-amino-5-(3-bromophenyl)-7-(6-dimethylamino-3-pyridazinyl)pyrido[2J- djpyrimidine,
4-amino-5-(3bromophenyl)-7-(6-moφholinyl-3-pyridazinyl)pyrido[2,3- djpyrimidine, 4-amino-5-(3-bromophenyl)-7-(6-pyrrolidinyl-3-pyridazinyl)pyrido[2,3- djpyrimidine,
4-amino-5-(3-bromophenyl)-7-(5-moφholinyl-2-pyrazinyl)pyrido[2J- djpyrimidine,
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- djpyrimidine,
4-amino-5-(3-bromophenyl)-7-(5-(N,N-bis(2-methoxyethyl)amino)-2- pyridinyl)pyrido[2J-d]pyrimidine, 4-amino-5-(3-bromophenyl)-7-(4-(imidazolylmethyl)-phenyl)pyrido[2J- djpyrimidine,
4-amino-5-(3-bromophenyl)-7-(5-(l-moφholinyl)-2-pyridinyl)pyrido[2,3- djpyrimidine,
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[2J-d]pyrimidine.
4-amino-5-(3-bromophenyl)-7-(5-(N-formyl-N-methylamino)-2- pyridinyl)pyrido[2J-d]pyrimidine. 4-amino-5-(3-bromophenyl)-7-(5-(2-propenyl)-2-pyridinyl)pyrido[2,3- djpyrimidine,
4-amino-5-(3-bromophenyl)-7-(3-(2-methoxyethyl)-2-oxo-6- benzoxazolyl)pyrido[2J-d]pyrimidine. 4-amino-5-(3-bromophenyl)-7-(4-( 1 -(N-formylamino)-ethyl)phenyl)pyrido[2,3- djpyrimidine,
4-(methylamino)-5-(3-bromophenyl)-7-(4-dimethylaminophenyl)pyrido[2J- djpyrimidine hydrochloride;
4-(2-methoxyethy lamino)-5 -(3 -bromopheny l)-7-(4- dimethylaminophenyl)pyrido[2,3-djpyrimidine hydrochloride;
4-amino-5-(3-bromophenyl)-7-(4-(l-methyl-2-imidazolyl)phenyl)pyrido[2J- djpyrimidine 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- djpyrimidine,
4-amino-5-(3-bromophenyl)-7-(4-(dimethylaminoethyl)phenyl)pyrido[2,3- djpyrimidine,
4-amino-5-(3-bromophenyl)-7-(4-(3-(dimethylamino)propynyl)phenyl)pyrido[2,3- djpyrimidine, 4-amino-5-(3-bromophenyl)-7-(4-(3-amino-3-methylbutynyl)phenyl)pyrido[2,3- djpyrimidine,
4-amino-5-(3-bromophenyl)-7-(4-dimethylphosphonatophenyl)pyrido[2J- djpyrimidine,
4-amino-5-(3-bromophenyl)-7-(4-(3-(methoxypropynyl)pyrido[2,3-d]pyrimidine, 4-amino-5-(3-bromophenyl)-7-(4-carboxyphenyl)pyrido[2J-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 -djpyrimidine,
4-amino-5-(3-bromophenyl)-7-(4-(2-(dimethylamino)ethyl)-3-oxo-2H-4H- pyrido[3.2-b]-l,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[2J-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[2J-d]pyrimidine,
4-amino-5-cyclohexyl-7-(4-(2-dimethylamino)ethyl)-2H-4H-benzo-3-oxo-l,4- oxazin-7-yl)pyrido[2J-d]pyrimidine,
4-amino-5-(3-bromophenyl)-7-(5-(l-methylethyl)-2-pyridyl)pyrido[2,3- djpyrimidine,
4-amino-5-(3-bromophenyl)-7-(5-piperidin-l-ylpyrid-2-yl)pyrido[2,3- djpyrimidine,
4-amino-5-(l-(4-bromophenyl)ethyl)-7-(6-moφholinylpyrid-3-yl)pyrido[2,3- djpyrimidine, 4-amino-5-(3-bromophenyl)-7-(4-((N-formylamino)methyl)phenyl)pyrido[2,3- djpyrimidine,
4-amino-5-(3-bromophenyl)-7-(4-( 1 -methyl- 1 -(N-methylamino)ethyl)phenyl)- pyrido[2J-d]pyrimidine,
4-amino-5-(3-bromophenyl)-7-(4-( 1 -(dimethylamino)- 1 - methy lethy l)phenyl)pyrido [23 -djpyrimidine,
4-amino-5-(3-bromophenyl)-7-(N-acetyl-5-indolinyl)pyrido[2J-d]pyrimidine,
4-amino-5-cyclohexyl-7-(6-chloro-3-pyridyl)pyrido[2J-d]pyrimidine,
4-amino-5-( 1 -(2-bromopheny l)ethy l)-7-(6-diethy lamino-3 -pyridy l)pyri do [2,3 - djpyrimidine, 4-amino-5-(l-(2-bromophenyl)ethyl)-7-(6-moφholinyl-3-pyridyl)pyrido[2,3- djpyrimidine,
4-amino-5-(l-(2-bromophenyl)ethyl)-7-(4-(N-methyl-N-formyl)amino)- phenyl)pyrido[2,3-d]pyrimidine.
4-amino-5-cyclohexyl-7-(6-moφholinyl-3-pyridyl)pyrido[2J-d]pyrimidine, 4-amino-5-((2-bromophenyl)methyl)-7-(6-moφholinyl-3-pyridyl)pyrido[2J- djpyrimidine.
4-amino-5-(4-tetrahydropyranyl)-7-(6-moφholinyl-3-pyridyl)pyrido[2,3- djpyrimidine. 4-amino-5-cyclohexyl-7-(6-dimethylamino-3-pyridyl)pyrido[2,3-d]pyrimidine,
4-amino-5-(l-ethylpropyl)-7-(6-dimethylamino-3-pyridyl)pyrido[2.3-d]pyrimidine,
4-amino-5-cyclopentyl-7-(6-moφholinyl-3-pyridyl)pyrido[2,3-d]pyrimidine,
4-amino-5-cyclohexyl-7-(2-chloro-3-pyridyl)pyrido[2,3-djpyrimidine,
4-amino-5-(3,5-dimethylcyclohexyl)-7-(6-dimethylamino-3-pyridyl)pyrido[2,3- djpyrimidine,
4-amino-5-((N-(benzyloxycarbonyl)-4-piperidinyl)methyl)-7-(6-moφholinyl-3- pyridyl)pyrido [2,3 -djpyrimidine,
4-amino-5-cyclohexyl-7-(6-bromo-3-pyridyl)pyrido[2,3-d]pyrimidine,
4-amino-5 -cyclohexy l-7-(3 -cyanopheny l)pyrido [2,3 -djpyrimidine, 4-amino-5-( 1 -(2-bromopheny l)ethyl)-7-(6-dimethylamino-3- pyridazinyl)pyrido[2,3 -djpyrimidine,
4-amino-5-(3-bromophenyl)-7-(6-imidazolyl-3-pyridazinyl)pyrido[2,3- djpyrimidine,
4-amino-5-(3-bromophenyl)-7-(6-(azacycloheptanyl)-3-pyridazinyl)pyrido[2J- djpyrimidine,
4-amino-5-(3-bromophenyl)-7-(6-(N-methyl-N-(l-methylethyl))amino)-3- pyridazinyl)pyrido[2,3-d]pyrimidine,
4-amino-5-(l-(2-bromophenyl)ethyl)-7-(6-moφholinyl-3-pyridazinyl)pyrido[2,3- djpyrimidine, 4-amino-5-cyclohexyl-7-(6-(4-acetylpiperazinyl)-3-pyridyl)pyrido[2J- djpyrimidine,
4-amino-5-cyclohexyl-7-(6-(4-acetyl-l,4-diazacycloheptanyl)-3- pyridyl)pyrido[2J-d]pyrimidine,
4-amino-5-cyclohexyl-7-(6-(4-methyl- 1 ,4-diazacycloheptanyl)-3- pyridyl)pyrido[2J-d]pyrimidine, 4-amino-5-cyclohexyl-7-(6-(N-methyl-N-(2-(2-pyridyl)ethyl)amino)-3- pyridyl)pyrido[2J-djpyrimidine,
4-amino-5-cyclohexyl-7-(6-2-(N-(N'.N'-dimethylaminoethyl)-N-methylamino)-3- pyridyl)pyrido[2J-d]pyrimidine, 4-amino-5-cyclohexyl-7-(6-azetidinyl-3-pyridyl)pyrido[2J-d]pyrimidine,
4-amino-5-cyclohexyl-7-(6-(3-(N- methylacetamido)pyrrolidinyl)pyridyl)pyrido[2,3-d]pyrimidine,
4-amino-5-cyclohexyl-7-(6-(3-(formamido)pyrrolidinyl)pyridyl)pyrido[2,3- djpyrimidine, 4-amino-5-cyclohexyl-7-(4-oxo-l-phenyl-lJ,8-triazaspiro[4.5[decan-8- yl)pyrido[2,3-d]pyrimidine,
4-amino-5-cyclohexyl-7-(6-(2-methoxymethyl)pyrrolidin-l-yl)pyridyl)pyrido[2J- djpyrimidine,
4-amino-5-cyclohexyl-7-(6-(N-methoxyethyl-N-propylamino)pyridyl)pyrido[2,3- djpyrimidine,
4-amino-5-cyclohexyl-7-(N-methyl-N-(2,2-dimethoxyethyl)amino)pyrido[2,3- djpyrimidine,
4-amino-5-cyclohexyl-7-(6-(4-(dimethylamino)piperidinyl)pyridyl)pyrido[2,3- djpyrimidine, 4-amino-5-cyclohexyl-7-(6-(4-(aminocarbonyl))piperidinyl)pyridyl)pyrido[2,3- djpyrimidine,
4-amino-5-cyclohexyl-7-(N-methyl-N-(3-(diethylamino)propyl)aminopyrid-3- yl)pyrido[2,3-d]pyrimidine,
4-amino-5-cyclohexyl-7-(6-(N-methyl-N-(4-pyridyl)ethylamino)pyrid-3- yl)pyrido [2,3 -djpyrimidine,
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- djpyrimidine. 4-amino-5-(l-(2-bromophenyl)ethyl)-7-(l-methyl-2.3-dioxo-5-indolyl)pyrido[2J- djpyrimidine,
4-amino-5-(3-bromophenyl)-7-(3-fluoro-4-(l-moφholinyl)phenyl)pyrido[2J- djpyrimidine. 4-amino-5-(3-bromophenyl)-7-(4-hydroxy-3-nitrophenyl)pyrido[2.3-d]pyrimidine,
4-amino-5-(3-bromophenyl)-7-(6-(4,4-ethylenedioxypiperidinyl)-3- pyridy l)pyrido [2,3 -djpyrimidine,
4-amino-5-(3-bromophenyl)-7-(6-(4-oxopiperidinyl)-3-pyridyl)pyrido[2,3- djpyrimidine, 4-amino-5-(3-bromophenyl)-7-(6-(4-formylpiperazinyl)-3-pyridyl)pyrido[2,3- djpyrimidine,
4-amino-5-(3-bromophenyl)-7-(6-(4-methylpiperazinyl)-3-pyridyl)pyrido[2,3- djpyrimidine,
4-amino-5-(3 -bromopheny l)-7-(6-thiomoφholiny 1-3 -pyridyl)pyri do [2,3 - djpyrimidin;
4-amino-5-(3-bromophenyl)-7-(6-(4,4-dioxothiomoφholinyl)-3- pyridyl)pyrido [2,3 -djpyrimidine,
4-amino-5-(2-bromophenyl)-7-(6-moφholinyl-3-pyridyl)pyrido[2J-d]pyrimidine,
4-amino-5 -(3 -bromo-4-methoxypheny l)-7-(6-moφholiny 1-3 -pyridy l)pyri do [2,3 - djpyrimidine,
4-amino-5-(4-bromophenyl)-7-(6-moφholinyl-3-pyridyl)pyrido[2,3-d]pyrimidine,
4-amino-5-(3-chlorophenyl)-7-(6-moφholinyl-3-pyridyl)pyrido[2J-d]pyrimidine,
4-amino-5-(3-bromophenyl)-7-(5-chloro-6-moφholinyl-3-pyridyl)pyrido[2,3- djpyrimidine, 4-amino-5-(3-bromophenyl)-7-(6-(N-oxidomoφholinyl)-3-pyridyl)pyrido[2,3- djpyrimidine,
4-amino-5-(3-bromophenyl)-7-(6-(N-(2-hydroxyethoxyethyl)amino)-3- pyridyl)pyrido[2J-djpyrimidine,
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-djpyrimidine.
4-amino-5-(3-bromophenyl)-7-(6-(3-hydroxy)moφholinyl)-3-pyridyl)pyrido[2J- djpyrimidine, l-(5-(4-amino-5-(3-bromophenyl)pyrido[2J-d]pyrimidin-7-yl)-2-pyridyl)- piperidine-4-phosphate, disodium salt;
4-amino-5-(3-bromophenyl)-7-(4-methylenylpiperidinyl)-3-pyridyl)pyrido[2J- djpyrimidine,
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-djpyrimidine.
4-amino-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[2J- djpyrimidine,
4-N-(iminomethy l)amino-5 -cyclohexy l-7-(6-dimethy lamino-3 -pyridy l)pyri do [2,3 - djpyrimidine,
4-allylamino-5-(4-bromophenyl)-7-(4-dimethylaminophenyl) pyrido[2J- djpyrimidine, 4-amino-5-(3-bromophenyl)-7-(6-(4-hydroxypiperdinyl)-3-pyridyl)pyrido[2,3- djpyrimidine,
4-amino-5-(cyclohexyl)-7-(6-(4,4-ethylenedioxypiperidinyl)-3-pyridyl)pyrido[2J- djpyrimidine,
4-amino-5-(3-bromophenyl)-7-(2-moφholinyl-5-thiazolyl)pyrido[2,3- djpyrimidine,
4-(N-(2.3-dihydroxypropyl)amino)-5-(3-bromophenyl)-7-(6-moφholinyl-3- pyridinyl)pyrido[2J-d]pyrimidine,
4-(N-(3-moφholinylpropyl)amino)-5-(3-bromophenyl)-7-(6-moφholinyl-3- pyridinyl)pyrido[2,3-d]pyrimidine. 4-(N-(2-(4-imidazolyl)ethyl)amino)-5-(3-bromophenyl)-7-(6-moφholinyl-3- pyridinyl)pyrido[2,3-d]pyrimidine,
4-(N-(3-carboxypropyl)amino)-5-(3-bromophenyl)-7-(6-moφholinyl-3- pyridinyl)pyrido[2.3-d]pyrimidine. (S)-4-amino-5-(3-bromophenyl)-7-(6-(O-methyl-2-hydroxymethylpyrrolidinyl)-3- pyridinyl)pyrido[2J-d]pyrimidine,
(S)-4-amino-5-(3-bromophenyl)-7-(6-(2-hydroxymethylpyrrolidinyl)-3- pyridinyl)pyrido[2J-d]pyrimidine,
4-amino-5-(2-bromophenyl)-7-(6-(4-hydroxypiperidinyl)-3-pyridinyl)pyrido[2,3- djpyrimidine,
4-amino-5-(4-fluorophenyl)-7-(6-(4,4-ethylenedioxypiperidinyl)-3- pyridinyl)pyrido [2,3 -djpyrimidine,
4-amino-5-(2-bromophenyl)-7-(6-(4-hydroxypiperidinyl)-3-pyridazyl)pyrido[2,3- djpyrimidine, 4-amino-5-(3-bromophenyl)-7-(6-(4,4-ethylenedioxypiperidinyl)-3- pyridazyl)pyrido[2,3-d]pyrimidine,
4-amino-5-(3-bromophenyl)-7-(2-moφholinyl-4-thiazolyl)pyrido[2J- djpyrimidine,
4-amino-5-(N-methyl-3-indolyl)-7-(6-moφholinyl-3-pyridinyl)pyrido[2,3- djpyrimidine,
4-amino-5-(3-bromophenyl)-7-(6-(4-ethoxyiminopiperidinyl)-3- pyridinyl)pyrido[2,3-d]pyrimidine,
4-amino-5-(3-bromophenyl)-7-(6-(4-ethoxycarbonylmethoxyiminopiperidinyl)-3- pyridinyl)pyrido[2,3-d]pyrimidine, 4-amino-5-(3-bromophenyl)-7-(-6-(4-oxopiperidinyl)-3-pyridazinyll)pyrido[2J- djpyrimidine,
4-amino-5-(3-bromophenyl)-7-(6-(4-moφholinyliminopiperidinyl )-3- pyridazinyll)pyrido[2J-d]pyrimidine,
4-amino-5J3-bromophenyl)-7-(6-(( 1 S,4S)-2-oxa-5-azabicyclo[2.2.1 ]heptan-5-yl)-3- pyridazyl)pyrido[2J-d]pyrimidine.
-42 4-amino-5-(3-bromophenyl)-7-(6-(4-methoxyiminopiperidinyl )-3- pyridazinyll)pyrido[2.3-d]pyrimidine.
4-amino-5-(3-bromophenyl)-7-(6-phenylmethoxy-3-pyridazinyll)pyrido[2J-d]pyrimidine,
4-amino-5-(3-bromophenyl)-7-(6-(4-methoxypiperidinyl)-3-pyridyl)pyrido[2J- djpyrimidine.
4-amino-5-(3-bromophenyl)-7-(6-(4-(4-tetrahydropyranyloxy)iminopiperidinyl )-3- pyridazinyll)pyrido[2J-djpyrimidine,
4-amino-5-(3-bromophenyl)-7-(6-isobutoxy-3-pyridazinyl)pyrido[2J-d]pyrimidine,
4-amino-5-(3-bromophenyl)-7-(6-(4-(N-methylpiperazinyl)iminopiperidinyl )-3- pyridazinyll)pyrido[2J-d]pyrimidine,
4-amino-5-(3-bromophenyl)-7-(6-(4-tetrahydropyranyloxy)-3-pyridazinyll)pyrido[2,3- djpyrimidine.
4-amino-5-(3 -bromophenyl)-7-(6-moφholinylethoxy-3 -pyridaziny ll)pyrido [2,3 - djpyrimidine, 4-amino-5-(3-bromophenyl)-7-(6-(4-ethoxypiperidinyl)-3-pyridazinyll)pyrido[2,3- djpyrimidine,
4-amino-5-(3-bromophenyl)-7-(6-(4-(2-ethoxyethoxy)piperidinyl)-3- pyridaziny ll)pyrido [2,3 -djpyrimidine,
4-amino-5-(3-bromophenyl)-7-(6-(4-(4-tetrapyranyloxyethyl)piperidinyl)-3- pyridaziny ll)pyri do [2,3 -djpyrimidine.
4-amino-5-(3-bromophenyl)-7-(6-(3-(R)-tetrahydrofuranyloxy)piperidinyl)-3- pyridazinyll)pyrido[2J-d]pyrimidine,
4-amino-5-(3-bromophenyl)-7-(6-(3-(S)-tetrahydrofuranyloxy)piperidinyl)-3- pyridazinyll)pyrido[2,3-d]pyrimidine, 4-amino-5-(3-bromophenyl)-7-(6-(trans-3-ethoxy-4-hydroxy)pyrrolidinyl)-3- pyridazinyll)pyrido[2J-d]pyrimidine,
4-amino-5-(3-bromophenyl)-7-(6-(cis-3-ethoxy-4-hydroxy)pyrrolidinyl)-3- pyridazinyll)pyrido[2.3-d]pyrimidine.
4-amino-5-(3-bromophenyl)-7-(6-(trans-3-ethoxy-4-hydroxy)pyrrolidinyl)-3- pyridyl)pyrido[2J-djpyrimidine, 4-amino-5-(3-bromophenyl)-7-(6-(trans-3.4-bis-ethoxy)pyrrolidinyl)-3- pyridazinyll)pyrido[2.3-d]pyrimidine.
4-amino-5-(3-bromophenyl)-7-(6-(trans-3.4-bis-ethoxy)pyrrolidinyl)-3-pyridyl)pyrido[2,3- djpyrimidine, 4-amino-5-(3-bromophenyl)-7-(6-(cis-3,4-bis-ethoxy)pyrrolidinyl)-3-pyridyl)pyrido[2J- djpyrimidine,
4-amino-5-(3-bromophenyl)-7-(6-(cis-3,4-bis-ethoxy)pyrrolidinyl)-3- pyridazinyll)pyrido[2,3-d]pyrimidine.
4-amino-5-(3-bromophenyl)-7-(6-(cis-3-ethoxy-4-hydroxy)pyrrolidinyl)-3- pyridyl)pyrido[2,3-d]pyrimidine,
4-amino-5-(3-bromophenyl)-7-(6-(cis-3-amino-4-hydroxy)pyrrolidinyl)-3- pyridazinyll)pyrido[2J-d]pyrimidine.
4-amino-5-(3-bromophenyl)-7-(6-(cis-3-amino-4-hydroxy)pyrrolidinyl)-3- pyridyl)pyrido[2,3 -djpyrimidine, 4-amino-5-(2-pyridyl)-7-(6-(l,4-dioxa-8-azaspiro[4.5]decan-8-yl)-3-pyridyl)pyrido[2,3- djpyrimidine,
4-amino-5-(2,3-dichlorophenyl)-7-(6-moφholinyl-3-pyridyl)pyrido[2,3 -djpyrimidine,
4-amino-5-(2-pyridyl)-7-(6-mθφholinyl-3-pyridyl)pyrido[2,3-d]pyrimidine,
4-amino-5-(2-ethoxyphenyl)-7-(6-(l,4-dioxa-8-azaspiro[4.5]decan-8-yl)-3- pyridyl)pyrido[2,3-djpyrimidine,
4-amino-5-(2-bromo-5-ethoxyphenyl)-7-(6-moφholinyl-3-pyridyl)pyrido[2J- djpyrimidine,
4-amino-5-(2,5-dichlorophenyl)-7-(6-moφholinyl-3-pyridyl)pyrido[2J-d]pyrimidine,
4-amino-5-(2,5-dimethylphenyl)-7-(6-moφholinyl-3-pyridyl)pyrido[2J-d]pyrimidine 4-amino-5-(3-fluorophenyl)-7-(6-moφholinyl-3-pyridyl)pyrido[2,3-d]pyrimidine,
4-amino-5-(3-trifluoromethylphenyl)-7-(6-moφholinyl-3-pyridyl)pyrido[2J- djpyrimidine.
4-amino-5-(3-fluoro-5-trifluoromethylphenyl)-7-(6-(l J-dioxa-8-azaspiro[4.5]decan-8-yl)-
3 -pyridy l)pyri do [2 ,3 -djpyrimidine, 4-amino-5-(3,5-diclorophenyl)-7-(6-(l,4-dioxa-8-azaspiro[4J]decan-8-yl)-3- pyridyl)pyrido[2J-d]pyrimidine.
4-amino-5-(3-bromophenyl)-7-(6-(l ,5-dioxa-9-azaspiro[5.5jundecan-9-yl)-3- pyridazinyll)pyrido[2J-d]pyrimidine, 4-amino-5-(4-bromo-2-thienyl)-7-(6-(l,4-dioxa-8-azaspiro[4.5jdecan-8-yl)-3- pyridyl)pyrido[2J-d]pyrimidine,
4-amino-5-(3-bromophenyl)-7-(6-(4-tertbutyl)piperidinyl-3-pyridazinyll)pyrido[2J- djpyrimidine,
4-amino-5-(3-bromophenyl)-7-(6-(4-N-formyl)piperidinyl-3-pyridazinyll)pyrido[2,3- djpyrimidine,
4-amino-5-(3-bromo-2-thienyl)-7-(6-(4,4-ethylenedioxypiperidinyl)-3-pyridyl)pyrido[2J- djpyrimidine,
4-amino-5 -(3 -cyanopheny l)-7-(6-moφholiny 1-3 -pyridaziny ll)pyrido [2,3 -djpyrimidine,
4-amino-5-(3-Bromophenyl)-7-(6-(S-O-ethyl-2-hydroxymethylpyrrolidinyl)-3- pyridazinyll)pyrido[2,3, djpyrimidine,
4-amino-5-(3-bromophenyl)-7-(6-((2S,3S)-2,3-dimethyl-l,4-dioxa-8-azaspiro[4.5jdecan-
8-y l)-3 -pyridazinyl)pyrido [2,3 -djpyrimidine,
4-amino-5-(3-bromophenyl)-7-(6-(4,4-(cis-l,2-dioxycyclopentyl)piperidinyl)-3- pyridazinyl)pyrido[2J-d]pyrimidine,
4-amino-5-(3-bromophenyl)-7-(6-(4-acetyl-l-oxa-4,8-diazaspiro[4.5]decan-8-yl)-3- pyridazinyl)pyrido[2,3-d]pyrimidine,
4-amino-5-(3-bromophenyl)-7-(6-((2R,3R)-2J-bis(methoxymethyl)-l,4-dioxa-8- azaspiro [4.5] decan-8-y l)-3 -pyridaziny l)pyri do [2.3 -djpyrimidine, 4-amino-5-(3-bromophenyl)-7-(6-(4,4-(cis-3.4-dioxy-oxacyclopentyl)piperidinyl)-3- pyridazinyl)pyrido[2J-d]pyrimidine,
4-amino-5-(3-bromophenyl)-7-(6-(3-methoxy-1.5-dioxa-9-azaspiro[5.5]undecan-9-yl)-3- pyridazinyl)pyrido[2J-djpyrimidine,
4-amino-5-(3-bromophenyl)-7-(6-(l,5-dioxa-3-hydroxymethyl-9-azaspiro[5.5]undecan-9- yl)-3-pyridazinyl)pyrido[2,3-djpyrimidine, 4-amino-5-(3-bromophenyl)-7-(6-(UJ4-trioxa-l l-azadispiro[4.2.5.2jpentadecan-l l-yl)-
3-pyridazinyl)pyrido[2,3-d]pyrimidine,
4-amino-5-(4-tetrahydropyranyl)-7-(6-moφholinyl-3-pyridazinyll)pyrido[2,3- djpyrimidine, 4-amino-5-(3-bromophenyl)-7-(6-(4-moφholinyliminopiperidinyl )-3-pyridyl)pyrido[2,3- djpyrimidine,
4-amino-5-(3-bromophenyl)-7-(6-(4-(N-methylpiperazinyl)iminopiperidinyl )-3- pyridyl)pyrido [2,3 -djpyrimidine,
4-amino-5-(3-bromophenyl)-7-(6-(4-(l ,2,4-triazol-l -yl)iminopiperidinyl )-3- pyridyl)pyrido[2,3-d]pyrimidine,
4-amino-5 -(3 -indoly l)-7-(6-moφholiny 1-3 -pyridyl)pyrido [2,3 -djpyrimidine.
4-amino-5-(5-indolyl)-7-(6-moφholinyl-3-pyridyl)pyrido[2J-d]pyrimidine.
4-amino-5-(3-bromophenyl)-7-(6-(4-ethylpiperidinylcarboxylate)-3-pyridyl)pyrido[2,3- djpyrimidine, 4-amino-5-(3-bromophenyl)-7-(2-phenylmethyl-3(2H)-pyridazinone-6-yl)pyrido[2,3- djpyrimidine,
4-amino-5-(3-bromophenyl)-7-(6-(4-(moφholinylcarboxamide)piperidinyl)-3- pyridyl)pyrido[2,3-d]pyrimidine,
4-amino-5-(3-bromophenyl)-7-(6-(4-(N-moφholinylaminocarboxamide)piperidinyl)-3- pyridy l)pyrido [2,3 -djpyrimidine,
4-amino-5-(3-bromophenyl)-7-(6-(4-(N,N-dimethylaminocarboxamide)piperidinyl)-3- pyridyl)pyrido[2,3-d]pyrimidine,
4-amino-5-(3-bromophenyl)-7-(6-(4-(N-methyl-N-methoxyethylcarboxamide)piperidinyl)-
3-pyridyl)pyrido[2,3-d]pyrimidine, 4-amino-5-(4-quinolyl)-7-(6-moφholinyl-3-pyridyl)pyrido[2,3-d]pyrimidine,
4-amino-5-(3-bromophenyl)-7-(6-(4-(N-methoxyethylcarboxamide)piperidinyl)-3- pyridyl)pyrido[2J-d]pyrimidine,
4-amino-5-(3-bromophenyl)-7-(6-(4-hydroxymethylpiperidinyl)-3-pyridyl)pyrido[2,3- djpyrimidine, 4-amino-5-(2-bromophenyl)-7-(6-(1.4-dioxa-8-azaspiro[4.5]decan-8-yl)-3- pyridyl)pyrido[2J-d]pyrimidine.
4-amino-5-(2-bromophenyl)-7-(6-(4-hydroxypiperidinyl)-3-pyridyl)pyrido[2J- djpyrimidine. 4-amino-5-(3-bromophenyl)-7-(6-(4-N-acetylpiperazinyl)-3-pyridyl)pyrido[2,3- djpyrimidine,
4-amino-5-(3-bromophenyl)-7-(6-(4-cyanopiperidinyl)-3-pyridyl)pyrido[2J-d]pyrimidine,
4-amino-5-(3-bromophenyl)-7-(6-(4-N-(4-fluorophenyl)piperazinyl)-3-pyridyl)pyrido[2J- djpyrimidine, 4-amino-5-(4-fluorophenyl)-7-(6-moφholinyl-3-pyridyl)pyrido[2,3-djpyrimidine,
4-amino-5-(3-bromophenyl)-7-(4-moφholinylbenzenesulfonamide)pyrido[2,3- djpyrimidine,
4-amino-5-(3-bromophenyl)-7-(4-N-l,4-dioxa-8-azaspiro[4.5]decan-8- ylbenzenesulfonamide)pyrido[2,3-d]pyrimidine, 4-amino-5-(3-bromophenyl)-7-(4-N-cyclopropylbenzenesulfonamide)pyrido[2,3- djpyrimidine,
4-amino-5-(3-bromophenyl)-7-(4-piperidinebenzenesulfonamide)pyrido[2,3-d]pyrimidine,
4-amino-5-(3-bromophenyl)-7-(4-(4-cyanopiperidine)benzenesulfonamide)pyrido[2,3- djpyrimidine, 4-amino-5-(3-bromophenyl)-7-(4-N-cyclopropylmethylbenzenesulfonamide)pyrido[2,3- djpyrimidine,
4-amino-5-(3-bromophenyl)-7-(4-N,N-dimethylaminobenzenesulfonamide)pyrido[2J- djpyrimidine,
4-amino-5-(3-bromophenyl)-7-(4-N-(S)-2- hydroxymethylpyrrolidinebenzenesulfonamide)pyrido[2,3-d]pyrimidine.
4-amino-5-(3-bromophenyl)-7-(4-(4-hydroxypiperidine)benzenesulfonamide)pyrido[2J- djpyrimidine,
4-amino-5-(3-bromophenyl)-7-(4-(cis-3,5- dimethylmoφholinyl)benzenesulfonamide)pyrido[2J-d]pyrimidine. 4-amino-5-(3-bromophenyl)-7-(3-fluoro-4-thiomoφholinylphenyl)pyrido[2,3- djpyrimidine,
4-amino-5-(4-fluorophenyl)-7-(6-(thiomoφholinyl)-3-pyridyl)pyrido[2J-d]pyrimidine,
4-amino-5-(4-fluorophenyl)-7-(6-(4,4-dioxothiomoφholinyl)-3-pyridyl)pyrido[2,3- djpyrimidine,
4-methoxy-5-(3-bromophenyl)-7-(6-moφholinyl-3-pyridyl)pyrido[2J-d]pyrimidine,
4-amino-5-(3-bromophenyl)-7-(4-(4-dioxa-8-azaspiro[4.5]decan-8- ylcarboxamide)phenyl)pyrido[2J-d]pyrimidine,
4-amino-5-(3-bromophenyl)-7-(4-(N-cyclopropylcarboxamide)phenyl)pyrido[2J- djpyrimidine,
4-amino-5-(3-bromophenyl)-7-(4-(moφholinylcarboxamide)phenyl)pyrido[2,3- djpyrimidine,
4-amino-5-(3-bromophenyl)-7-(6-N-cyclopropylamino-3-pyridyl)pyrido[2,3-d]pyrimidine,
4-amino-5-(3-bromophenyl)-7-(4-(4-hydroxypiperidinylcarboxamide)phenyl)pyrido[2,3- djpyrimidine,
4-amino-5-(3-bromophenyl)-7-(6-(S)-hydroxymethylpyrrolidinyl-3- pyridazinyll)pyrido[2,3-d]pyrimidine,
4-amino-5-(3-bromophenyl)-7-(6-(4-(2-ethoxyethoxy)piperidinyl)-3-pyridyl)pyrido[2,3- djpyrimidine, 4-amino-5-(3 -bromopheny l)-7-(6-hexahydropyrimidine )-3 -pyridy l)pyrido [2,3 - djpyrimidine,
4-amino-5-(4,4-difluorocyclohxeyl)-7-(6-(l,4-dioxa-8-azaspiro[4.5jdecan-8-yl)-3- pyridyl)pyrido[2,3-djpyrimidine,
4-amino-5-(3-bromophenyl)-7-(6-(S)-2-ethoxyethoxypyrrolidinyl)-3-pyridyl)pyrido[2,3- djpyrimidine,
4-amino-5-(3-bromophenyl)-7-(6-(R)-2-ethoxyethoxypyrrolidinyl)-3- pyridyl)pyrido[2,3-d]pyrimidine,
4-amino-5-(3-bromophenyl)-7-(6-(cis-3.4-dihydroxypyrolidinyl)-3-pyridyl)pyrido[2J- djpyrimidine. 4-amino-5-(3-bromophenyl)-7-(6-((3aR,6aS)-2-oxo-tetrahydro-3aH-[lJ dioxolo[4,5- c]pyrrol-5-yl)-3-pyridyl)pyrido[2J-d]pyrimidine,
4-amino-5-(3-bromophenyl)-7-(6-(cis-2J-dihydroxypyrrolidinyl)-3- pyridazinyll)pyrido[2J-d]pyrimidine, 4-amino-5-(3-bromophenyl)-7-(6-(S,R-2-hydroxymethyl-4-hydroxypyrrolidinyl)-3- pyridyl)pyrido[2,3-d]pyrimidine,
4-amino-5-(3-bromophenyl)-7-(6-(R-2-hydroxymethyl-4-pyrrolidinyl)-3- pyridazinyll)pyrido[2,3-d]pyrimidine,
4-amino-5-(3-bromophenyl)-7-(6-((lS.4S)-2-oxa-5-azabicyclo[2.2Jjheptan-5-yl)-3- pyridyl)pyrido[2,3-djpyrimidine,
4-amino-5-(3-bromophenyl)-7-(6-(2-imidizolidone-l-yl)-3-pyridyl)pyrido[2J- djpyrimidine,
4-amino-5 -( 1 , 1 -dimethy 1-3 -buteny l)-7-(6-moφholinyl-3 -pyridy l)pyri do [2,3 -djpyrimidine,
4-amino-5-(3-bromophenyl)-7-(6-(2,4-dioxo-(lH,3H)-quinazolin-3-yl)-3- pyridyl)pyrido[2,3-d]pyrimidine,
4-amino-5-(3-bromophenyl)-7-(6-carboxamide-3-pyridazinyll)pyrido[2,3-djpyrimidine,
4-amino-5-(3-bromophenyl)-7-(6-moφholinylcarboxamide-3-pyridazinyll)pyrido[2,3- djpyrimidine,
4-amino-5-(3-bromophenyl)-7-(6-methoxy-3-pyridazinyll)pyrido[2,3-d]pyrimidine, 4-amino-5 -(3 -bromopheny l)-7-(6-N,N-diethoxyethylamino-3 -pyridazinyll)pyrido [2,3 - djpyrimidine,
4-amino-5 -(3 -bromopheny l)-7-(6-(4-ethoxymethylpiperidinyl)-3-pyridazinyll)pyrido [2,3 - djpyrimidine,
4-amino-5-(3-bromophenyl)-7-(6-(4-(4-tetrahydropyranyloxymethyl)piperidinyl)-3- pyridazinyll)pyrido[2J-d]pyrimidine,
4-amino-5-(3-bromophenyl)-7-(6-(4-ethoxyethoxymethylpiperidinyl)-3- pyridazinyll)pyrido[2J-d]pyrimidine,
4-amino-5-(3-bromophenyl)-7-(6-N-methyl-N-lJ-dioxalanemethylamino )-3- pyridazinyll)pyrido[2,3-djpyrimidine. 4-amino-5-(3-bromophenyl)-7-(6-(l,4-dioxaspiro[4.5]decanyl-8-oxy)-3- pyridazinyl)pyrido[2.3-djpyrimidine,
4-amino-5-(3-bromophenyl)-7-(6-dihydroxymethylmethoxy-3-pyridazinyll)pyrido[2J- djpyrimidine, 4-amino-5-(3-bromophenyl)-7-(6-(3-pyridyloxy)-3-pyridazinyll)pyrido[2J-djpyrimidine,
4-amino-5-(3-bromophenyl)-7-(6-(4,7-epoxy-7-methyl-2J,3A,4,5,6,7,7a-octahydro-lH- isoindolyl)-3-pyridazinyl)pyrido[2,3-djpyrimidine,
4-amino-5-(3-bromophenyl)-7-(6-(4-N-ethyl-N-methoxyethyl)-3-pyridazinyll)pyrido[2J- djpyrimidine, 4-amino-5-(3-bromophenyl)-7-(6-(4-N-methyl-N-methoxyethyl)-3- pyridazinyll)pyrido[2,3-d]pyrimidine,
4-amino-5-(3-bromophenyl)-7-(6-(3,4-dimethoxymethoxypyrrolidinyl)-3- pyridazinyll)pyrido[2,3-d]pyrimidine,
4-amino-5-(3-bromophenyl)-7-(6-(hexahydro-lH-furo[3,4-c]pyrrol-5-yl)-3- pyridazinyl)pyrido[2,3-d]pyrimidine,
4-amino-5-(3-bromophenyl)-7-(6-(hexahydro-lH-furo[3,4-cjpyrrol-5-yl)-3- pyridyl)pyrido[2,3 -djpyrimidine,
4-amino-5-(3-bromophenyl)-7-(6-(trans-3-hydroxy-4-methylpyrrolidinyl)-3- pyridazinyll)pyrido[2,3-d]pyrimidine, 4-amino-5-(3-bromophenyl)-7-(6-(trans-3-hydroxy-4-methylpyrrolidinyl)-3- pyridyl)pyrido[2J-d]pyrimidine,
4-amino-5-(3-bromophenyl)-7-(6-(cis-3-hydroxy-4-methylpyrrolidinyl)-3- pyridazinyll)pyrido[2,3-d]pyrimidine,
4-amino-5 -(3 -bromopheny l)-7-(6-(cis-3 -hydroxy-4-methy lpyrrolidiny l)-3 - pyridy pyrido [2,3 -djpyrimidine,
4-amino-5 -(3 -bromopheny l)-7-(6-(trans-3 -cyano-4-hydroxy lpyrrolidiny l)-3 - pyridyl)pyrido[2,3-d]pyrimidine,
4-amino-5-(3-bromophenyl)-7-(6-(3-hydroxy-4-tert-butylcarboxamidepyrrolidinyl)-3- pyridyl)pyrido[2.3-d]pyrimidine, 4-amino-5-(3-bromophenyl)-7-(6-(S-2-(4-tetrahydropyranyloxy)methylpyrrolidinyl)-3- pyridazinyll)pyrido[2J-djpyrimidine,
4-amino-5-(3-bromophenyl)-7-(6-(3-(4-tetrahydropyranyloxy)iminopyrrolidinyl)-3- pyridazinyll)pyrido[2J-d]pyrimidine, 4-amino-5-(3-bromophenyl)-7-(2-moφholinyl-5-thiazoyl)pyrido[2,3-djpyrimidine, 4-amino-5-(3-bromophenyl)-7-(5-bromo-2-thienyl)pyrido[2J-d]pyrimidine, 4-amino-5-(3-bromophenyl)-7-(2,5-dimethyl-3-thienyl)pyrido[2,3-d]pyrimidine, 4-amino-5-(3-bromophenyl)-7-(5-chloro-2-thienyl)pyrido[2J-d]pyrimidine, 4-amino-5-(3-bromophenyl)-7-(2,4-dimethyl-5-thiazoyl)pyrido[2,3-d]pyrimidine, 4-amino-5-(3-bromophenyl)-7-(5-methyl-2-thienyl)pyrido[2,3-d]pyrimidine, 4-amino-5-(3-bromophenyl)-7-(2-furanyl)pyrido[2,3-d]pyrimidine, 4-amino-5-(3-bromophenyl)-7-(2-(l,4-dioxa-8-azaspiro[4.5jdecan-8-yl)-5- thiazoyl)pyrido[2,3-d]pyrimidine, 4-amino-5-(3-bromophenyl)-7-(3-thienyl)pyrido[2,3-d]pyrimidine, 4-amino-5-(3-bromophenyl)-7-(3-methyl-2-thienyl)pyrido[2,3-djpyrimidine,
4-amino-5-(3-bromophenyl)-7-(2-moφholinyl-4-thiazoyl)pyrido[2,3-d]pyrimidine, 4-amino-5-(3-bromophenyl)-7-(2-moφholinyl-4-trifluoromethy-5-thiazoyl)pyrido[2,3- djpyrimidine, 4-amino-5-(3-bromophenyl)-7-(5-moφholinyl-2-thienyl)pyrido[2,3-d]pyrimidine, 4-amino-5-(3-bromophenyl)-7-(4-methyl-2-moφholinyl-5-thiazoyl)pyrido[2,3- djpyrimidine,
4-amino-5-(3-bromophenyl)-7-(2,5-dichloro-3-thienyl)pyrido[2,3-d]pyrimidine, 4-amino-5-(3-bromophenyl)-7-(2,5-dimethyl-3-furanyl)pyrido[2,3-d]pyrimidine, 4-amino-5-(3-bromophenyl)-7-(N-methyl-2-pyrrolyl)pyrido[2J-djpyrimidine, 4-amino-5-(3-bromophenyl)-7-(2-N,N-dimethylamino-5-thiazoyl)pyrido[2,3- djpyrimidine,
4-amino-5-(3-bromophenyl)-7-(2-moφholinyl-5-thiazoyl)pyrido[2,3-d]pyrimidine, 4-amino-5-(3-bromophenyl)-7-(2-(4,4-dioxythiomoφholinyl)-5-thiazoyl)pyrido[2,3- djpyrimidine, 4-amino-5-(3-bromophenyl)-7-(2-( 1.1 -dioxidothiomoφholinyl)-5-thiazoyl)pyrido[2,3- djpyrimidine,
4-amino-5-(3-bromophenyl)-7-(2-moφholinyl-5-oxazolyl)pyrido[2,3-d]pyrimidine,
4-amino-5-(3-bromophenyl)-7-(2-N-methyl-N-methoxyethylamino-5-thiazoyl)pyrido[2,3- djpyrimidine,
4-amino-5-(3 -bromopheny l)-7-(2-N-methyl-N-ethy lamino-5 -thiazoy l)pyrido [2,3 - djpyrimidine,
4-amino-5-(3-bromophenyl)-7-(2-N-pyrrolidinyl-5-thiazoyl)pyrido[2,3-d]pyrimidine,
4-amino-5-(3-bromophenyl)-7-(2-N-methyl-N-propylamino-5-thiazoyl)pyrido[2,3- djpyrimidine,
4-amino-5-(3-bromophenyl)-7-(2-N.N-diethylamino-5-thiazoyl)pyrido[2J-d]pyrimidine,
4-amino-5-(3-bromophenyl)-7-(2-(N-methypiperazinyl)-5-thiazoyl)pyrido[2J- djpyrimidine,
4-amino-5-(3-bromophenyl)-7-(2-(N-(2-pyridyl)piperazinyl)-5-thiazoyl)pyrido[2,3- djpyrimidine,
4-amino-5-(3-bromophenyl)-7-(2-N-methy-N-(2-pyridylethyl)-5-thiazoyl)pyrido[2,3- djpyrimidine,
4-amino-5-(3-bromophenyl)-7-(2-(4-oxopiperazinyl)-5-thiazoyl)pyrido[2,3-d]pyrimidine,
4-amino-5-(3-bromophenyl)-7-(2-(4-(N-moφholinyl)iminopiperazinyl)-5- thiazoyl)pyrido [2,3 -djpyrimidine,
4-amino-5-(3-bromophenyl)-7-(6-N-moφholine-3-pyridinesulfonamide)pyrido[2J- djpyrimidine,
4-amino-5-(3-bromophenyl)-7-(2-(4-oxopiperidinyl)-5-pyrimidyl)pyrido[2,3- djpyrimidine, 4-amino-5-(3-bromophenyl)-7-(2-(4,4-dioxethylenepiperidinyl)-5-pyrimidyl)pyrido[2,3- djpyrimidine,
4-amino-5-(3-bromophenyl)-7-(5-(1.4-dioxa-8-azaspiro[4.5]decan-8-yl)-2- pyrazinyl)pyrido[2,3-d]pyrimidine,
4-amino-5-(3-bromophenyl)-7-(5-(4-oxopiperidinyl)-2-pyrazinyl)pyrido[2J-d]pyrimidine, 4-amino-5-(3-bromophenyl)-7-(6-N-cyclopropyl-3-pyridinesulfonamide)pyrido[2,3- djpyrimidine,
4-amino-5-(3-bromophenyl)-7-(6-(N-l,4-dioxa-8-azaspiro[4.5jdecan-8-yl)-3- pyridylsulfonamide)pyrido[2J-djpyrimidine, 4-amino-5 -(3 -bromopheny l)-7-(2-(4-(4-tetrahydropyranyloxy)iminopiperidinyl )-5 - pyrazinyl)pyrido[2,3-d]pyrimidine,
4-amino-5-(3-bromophenyl)-7-(6-(4-(phenylmethoxy)iminopiperidinyl)-3- pyridyl)pyrido [2,3 -djpyrimidine,
4-amino-5 -(3 -bromopheny l)-7-(6-(4-(tert-buty loxy )iminopiperidinyl)-3 - pyridyl)pyrido[2,3-d]pyrimidine,
4-amino-5-(3-bromophenyl)-7-(6-(4-(cyclohexyloxy)iminopiperidinyl)-3- pyridyl)pyrido[2,3-djpyrimidine,
4-amino-5-(3 -bromopheny l)-7-(6-(4-hydroxy iminopiperidiny l)-3 -pyridyl)pyrido [2,3 - djpyrimidine, 4-amino-5-(3-bromophenyl)-7-(6-(4-(4-tetrahydropyranyloxy)iminopiperidinyl)-3- pyridyl)pyrido[2,3-d]pyrimidine,
4-amino-5-(3-bromophenyl)-7-(6-(4-methoxyethoxyiminopiperidinyl)-3- pyridyl)pyrido[2,3-d]pyrimidine,
4-amino-5-(3-bromophenyl)-7-(6-(4-(2-thenylmethoxy)iminopiperidinyl)-3- pyridyl)pyrido[2,3-d]pyrimidine,
4-amino-5-(3-bromophenyl)-7-(6-(4-(4'-(5'H-2-oxyfuranyl)-4-hydroxy)piperidinyl)-3- pyridyl)pyrido[2,3-d]pyrimidine,
4-amino-5 -(3 -bromopheny l)-7-(6-(4-( 1 -(4-tetrahydropyrany loxy)iminoethyl))-4- hydroxypiperidinyl)-3 -pyridaziny ll)pyrido [2,3 -djpyrimidine, 4-amino-5-(3-bromophenyl)-7-(6-(4-(4'-acetyl-4'-hydroxypiperidinyl)-3- pyridazinyll)pyrido[2,3-d]pyrimidine,
4-amino-5-(3-bromophenyl)-7-(6-(4-(l-(isopropylcaboxymethoxy)iminoethyl))-4- hydroxypiperidinyl)-3-pyridyl)pyrido[2J-d]pyrimidine,
4-amino-5-(3 -bromopheny l)-7-(6-(4-( 1 -(ethylcaboxymethoxy)iminoethyl))-4- hydroxypiperidinyl)-3-pyridyl)pyrido[2.3-d]pyrimidine, 4-amino-5-(3-bromophenyl)-7-(6-(4-(l-(methylcaboxymethoxy)iminoethyl))-4- hydroxypiperidinyl)-3-pyridyl)pyrido[2J-d]pyrimidine,
4-amino-5-(3-bromophenyl)-7-(6-(4-(l-(2-tetrahydropyranyloxy)iminoethyl))-4- hydroxypiperidiny l)-3 -pyridy l)pyrido [2,3 -djpyrimidine, 4-amino-5-(3-bromophenyl)-7-(6-(4-(l-(allyloxy)iminoethyl))-4-hydroxypiperidinyl)-3- pyridyl)pyrido [2,3 -djpyrimidine,
4-amino-5-(3-bromophenyl)-7-(6-(4-(l-(ethoxy)iminoethyl))-4-hydroxypiperidinyl)-3- pyridyl)pyrido[2,3 -djpyrimidine,
4-amino-5-(3-bromophenyl)-7-(6-(4-(l-(methoxy)iminoethyl))-4-hydroxypiperidinyl)-3- pyridyl)pyrido[2,3-djpyrimidine,
4-amino-5-(3-bromophenyl)-7-(6-(4-(l-(hydroxy)iminoethyl))-4-hydroxypiperidinyl)-3- pyridyl)pyrido[2,3-d]pyrimidine,
4-amino-5-(3-bromophenyl)-7-(6-(4-(2-tetrahydropyranyloxy)iminopiperidinyl)-3- pyridyl)pyrido [2,3 -djpyrimidine, 4-amino-5-(3-bromophenyl)-7-(6-(4-(isopropylcarboxymethoxy)iminopiperidinyl)-3- pyridyl)pyrido [2,3 -djpyrimidine,
4-amino-5-(3-bromophenyl)-7-(6-(4-hydroxy-4-(l-(4-tetrahydropyranyloxy)iminoethyl))-
4-hydroxypiperidinyl)-3-pyridyl)pyrido[2,3-djpyrimidine,
4-amino-5-(3-bromophenyl)-7-(6-(4-(3-butyrolactone)-4-hydroxypiperidinyl)-3- pyridy l)pyrido [2,3 -djpyrimidine,
4-amino-5-(3-bromophenyl)-7-(6-(4-(2-butyrolactone)-4-hydroxypiperidinyl)-3- pyridaziny ll)pyrido [2,3 -djpyrimidine,
4-amino-5-(3-bromophenyl)-7-(6-(4-acetyl-4-hydroxypiperidinyl)-3-pyridyl)pyrido[2,3- djpyrimidine, 4-amino-5-(3-bromophenyl)-7-(6-(3-hydroxyazetidinyl)-3-pyridyl)pyrido[2,3- djpyrimidine,
4-amino-5-(3-bromophenyl)-7-(6-((lR.5S)-3-hydroxy-8-azabicyclo[3.2J]octan-8-yl)-3- pyridy l)pyrido [2,3 -djpyrimidine,
4-amino-5-(3-bromophenyl)-7-(6-(cis-2J-dihydroxypiperidinyl)-3-pyridyl)pyrido[2,3- djpyrimidine, 4-amino-5-(3-bromophenyl)-7-(6-(N-methyl-N-(3-pyridylmethyl)amino)-3- pyridazinyll)pyrido[2J-d]pyrimidine,
4-amino-5 -(3 -bromopheny l)-7-(6-( 1,2,3 ,6-tetrahydropyridyl)-3-pyridyl)pyrido[2,3- djpyrimidine, 4-amino-5-(3-bromophenyl)-7-(6-(4-(N-4'methoxyphenylcarbamoyl)piperidinyl)-3- pyridazinyll)pyrido[2,3 -djpyrimidine,
4-amino-5-(3-bromophenyl)-7-(6-(4-(2-butyrolactone)-4-hydroxypiperidinyl)-3- pyridyl)pyrido [2,3 -djpyrimidine,
4-amino-5-(3-bromophenyl)-7-(6-(trans-3,4- bis(N-4'- methoxyphenylcarbamoyl)pyrrolidinyl)-3-pyridyl)pyrido[2,3-d]pyrimidine,
4-amino-5-(3-bromophenyl)-7-(6-((lS,5R)-3-hydroxy-8-azabicyclo[3.2J]octan-8-yl)-3- pyridyl)pyrido [2,3 -djpyrimidine,
4-amino-5-(3-bromophenyl)-7-( 6-(S,S-trans-3,4-dihydroxypyrrolidinyl)-3- pyridyl)pyrido[2,3-d]pyrimidine, 4-amino-5-(3-bromophenyl)-7-( 6-(R,R-trans-3,4-dihydroxypyrrolidinyl)-3- pyridazinyll)pyrido[2,3-d]pyrimidine,
4-amino-5-(3-bromophenyl)-7-( 6-(R,R-trans-3,4-dihydroxypyrrolidinyl)-3- pyridyl)pyrido[2,3-d]pyrimidine,
4-amino-5-(3-bromophenyl)-7-(6-(4-oxo-l-phenyl-l,3,8-triazaspiro[4.5jdecan-8-yl)-3- pyridy l)pyrido [2,3 -djpyrimidine,
4-amino-5-(3-bromophenyl)-7-(6-(l-oxa-4-oxo-4-thia-8-azaspiro[4.5]decan-8-yl)-3- pyridyl)pyrido[2,3-d]pyrimidine,
4-amino-5-(3-bromophenyl)-7-(6-(l-oxa-4,4-dioxido-4-thia-8-azaspiro[4.5]decan-8-yl)-3- pyridyl)pyrido[2,3-d]pyrimidine, 4-amino-5-(3-bromophenyl)-7-(6-(4-oxo-l-phenyl-lJ,8-triazaspiro[4.5jdec-2-en-8-yl)-3- pyridyl)pyrido [2,3 -djpyrimidine,
4-amino-5-(3-bromophenyl)-7-(6-(4-(2-keto-l-benzimidazolinyl)piperidinyl)-3- pyridazinyll)pyrido[2,3-d]pyrimidine,
4-amino-5-(3-bromophenyl)-7-(6-(4-oxothiomoφholinyl)-3-pyridyl)pyrido[2,3- djpyrimidine, 4-amino-5-(3-bromophenyl)-7-(6-(4-(2-keto-l-benzimidazolinyl)piperidinyl)-3- pyridyl)pyrido[2J-d]pyrimidine,
4-amino-5-(3-bromophenyl)-7-(6-(N-methyl-N-(2-pyridylethyl)amino)-3- pyridyl)pyrido[2J-d]pyrimidine, 4-amino-5 -(3 -bromopheny l)-7-(6-(N-methy l-N-(4-pyridy lethy l)amino)-3 - pyridy l)pyri do [2,3 -djpyrimidine,
4-amino-5-(3-bromophenyl)-7-(6-N-(3-pyridylmethyl)amino-3-pyridyl)pyrido[2,3- djpyrimidine,
4-amino-5-(3-bromophenyl)-7-(6-(2-hydroxymethylpiperidinyl)-3-pyridyl)pyrido[2,3- djpyrimidine,
4-amino-5-(3-bromophenyl)-7-(6-(l-oxa-4-thia-8-azaspiro[4.5]decan-8-yl)-3- pyridyl)pyrido[2J-d]pyrimidine,
4-amino-5-(3-bromophenyl)-7-(6-(4-hydroxy-4-(4-bromophenyl)piperidinyl)-3- pyridyl)pyrido[2,3-d]pyrimidine, 4-amino-5-(3-bromophenyl)-7-(6-(4-N-(2-pyridnyl)piperazinyl)-3-pyridyl)pyrido[2,3- djpyrimidine,
4-amino-5-(3-bromophenyl)-7-(6-(4-N-(2-hydroxyethyloxyethyl)piperazinyl)-3- pyridyl)pyrido[2,3-d]pyrimidine,
4-amino-5-(3-bromophenyl)-7-(6-(4,4-diacetoxyethylthio)piperidinyl)-3- pyridyl)pyrido[2,3-djpyrimidine,
4-amino-5-(3-bromophenyl)-7-(6-(N-methy-N-(3-pyridylmethyl)amino)-3- pyridyl)pyrido[2,3-d]pyrimidine,
4-amino-5-(3-bromophenyl)-7-(6-(4-pyrrolidinylpiperidinyl)-3-pyridyl)pyrido[2,3- djpyrimidine, 4-amino-5-(3-bromophenyl)-7-(6-(2-( 1 H-imidazol-4-yl)ethylamino)-3- pyridazinyl)pyrido[2,3-djpyrimidine,
4-amino-5-(3-bromophenyl)-7-(6-(4-N-cyanomethylpiperazinyl)-3-pyridyl)pyrido[2,3- djpyrimidine,
4-amino-5-(3-bromophenyl)-7-(6-(3-hydroxypyrroldinyl)-3-pyridyl)pyrido[2,3- djpyrimidine, 4-amino-5-(3-bromophenyl)-7-(6-(4-methylpiperidinyl)-3-pyridyl)pyrido[2,3- djpyrimidine,
4-amino-5-(3-bromophenyl)-7-(6-(cis-3.5-dimethylmoφholinyl)-3-pyridyl)pyrido[2J- djpyrimidine, 4-amino-5-(3-bromophenyl)-7-(6-(4,4-difluoropipridinyl)-3-pyridyl)pyrido[2J- djpyrimidine,
4-amino-5-(3-bromophenyl)-7-(6-(lJ-dioxidoythiomoφholinyl)-3- pyridazinyl)pyrido [2,3 -djpyrimidine,
4-amino-5 -(3 -bromopheny l)-7-(6-thiazolidinyl-3 -pyridyl)pyri do [2,3 -djpyrimidine, 4-amino-5 -(3 -bromophenyl)-7-(6-( 1 , 1 -dioxidoythiazolidin-3 -yl)-3-pyridyl)pyrido [2,3 - djpyrimidine,
4-amino-5-(3-bromophenyl)-7-(6-thiomoφholinyl-3-pyridazinyll)pyrido[2,3- djpyrimidine,
4-amino-5-(3-bromophenyl)-7-(6-(2,5-dihydropyrrolyl)-3-pyridyl)pyrido[2,3- djpyrimidine,
4-amino-5-(3-bromophenyl)-7-(6-(l,3-dioxa-8-azaspiro[4.5]decan-8-yl)-3- pyridyl)pyrido[2,3-d]pyrimidine,
4-amino-5-(3-bromophenyl)-7-(6-hydroxy-3-pyridazinyll)pyrido[2,3-djpyrimidine, amino-5-(2,3-dichlorophenyl)-7-(6-(l,4-dioxa-8-azaspiro[4.5jdecan-8-yl)-3- pyridy l)pyrido [2,3 -djpyrimidine,
4-amino-5-isopropyl-7-(6-(l,4-dioxa-8-azaspiro[4.5]decan-8-yl)-3-pyridyl)pyrido[2,3- djpyrimidine,
4-amino-5-(3-bromophenyl)-7-(6-piperidinyl-3-pyridyl)pyrido[2,3-d]pyrimidine,
4-amino-5-(3-bromophenyl)-7-(6-(3-(4-tetrahydropyranyloxyimino)pyrrolidinyl)-3- pyridyl)pyrido [2,3 -djpyrimidine, and
4-amino-5-(2-trifluorophenylphenyl)-7-(6-moφholinyl-3-pyridyl)pyrido[2,3- djpyrimidine 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 R4 position when it is selected from, for example, a substituted heterocycle or aryl 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 R3 selected from substituted aryl or heterocycle groups and R4 selected from substituted aryl or heterocycle groups, the substiuents on the R3 group are meta and the substituents on the R4 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.
Definitions of Terms The term "alkenylJ as used herein, refers to a straight or branched chain hydrocarbon containing from 2 to 6 carbons and containing at least one carbon-carbon double bond formed by the removal of two hydrogens. Representative examples of alkenyl include, but are not limited to, ethenyl, 2-propenyl, 2-methyl-2-propenyl, 3- butenyl, 4-pentenyl, 5-hexenyl, and the like. The term "alkenyloxyJ as used herein, refers to an alkenyl group, as defined herein, appended to the parent molecular moiety through an oxy moiety, as defined herein. Representative examples of alkenyloxy include, but are not limited to, 2-propenyloxy, 2- methyl-2-propenyloxy, 3-butenyloxy, 4-pentenyloxy, and the like.
The term "alkenyloxyiminoJ as used herein, refers to an alkenyloxy group, as defined herein, appended to the parent molecular moiety through an imino moiety, as defined herein. Representative examples of alkenyloxyimino include, but are not limited to, 2-propenyloxyimino, 2-methyl-2-propenyloxyimino, 3-butenyloxyimino, 4- pentenyloxyimino, and the like.
The term "alkenyloxyiminoalkyl." as used herein, refers to an alkenyloxyimino group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein. Representative examples of alkenyloxyiminoalkyl include, but are not limited to, propen-2-yloxyiminomethyl, 2-[2-methylpropen-2-yloxyimino]ethyl, 2-[buten- 3-yloxyimino]ethyl, 3-[penten-4-yloxyimino]propyl, and the like.
The term "alkoxyJ as used herein, refers to an alkyl group, as defined herein, appended to the parent molecular moiety through an oxy moiety, as defined herein. Representative examples of alkoxy include, but are not limited to. methoxy, ethoxy, propoxy, 2-propoxy, butoxy, tert-butoxy, pentyloxy, hexyloxy and the like.
The term "alkoxyalkoxy," as used herein, refers to an alkoxy group, as defined herein, appended to the parent molecular moiety through another alkoxy group, as defined herein. Representative examples of alkoxyalkoxy include, but are not limited to, tert- butoxymethoxy, 2-ethoxyethoxy, 2-methoxyethoxy, methoxymethoxy, and the like.
The term "alkoxyalkoxyalkyl," as used herein, refers to an alkoxyalkoxy group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein. Representative examples of alkoxyalkoxyalkyl include, but are not limited to, 2-(tert-butoxymethoxy)ethyl, 4-(2-ethoxyethoxy)butyl, 4-(2-methoxyethoxy)butyl, 2- (methoxymethoxy)ethyl, and the like.
The term "alkoxyalkoxyiminoJ as used herein, refers to an alkoxyalkoxy group, as defined herein, appended to the parent molecular moiety through an imino group, as defined herein. Representative examples of alkoxyalkoxyimino include, but are not limited to, tert-butoxymethoxyimino, 2-(ethoxy)ethoxyimino, (2-methoxy)ethoxyimino, methoxymethoxyimino. and the like.
The term "alkoxyalkylJ as used herein, refers to an alkoxy group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein. Representative examples of alkoxyalkyl include, but are not limited to. tert-butoxymethyl, 2-ethoxy ethyl, 2-methoxyethyl, methoxymethyl, and the like.
The term "alkoxyalkynyl," as used herein, refers to an alkoxy group, as defined herein, appended to the parent molecular moiety through an alkynyl group, as defined herein. Representative examples of alkoxyalkynyl include, but are not limited to, 3- (methoxy)propyn-l-yl, 4-(ethoxy)butyn-l-yl, and the like. The term "alkoxyalkylcarbonylJ as used herein, refers to an alkoxyalkyl group, as defined herein, appended to the parent molecular moiety through a carbonyl group, as defined herein. Representative examples of alkoxyalkylcarbonyl include, but are not limited to, 2-(ethoxy)ethylcarbonyl, 2-(methoxy)ethylcarbonyl, and the like. The term "alkoxycarbonylJ as used herein, refers to an alkoxy group, as defined herein, appended to the parent molecular moiety through a carbonyl group, as defined herein. Representative examples of alkoxycarbonyl include, but are not limited to, tert- butoxycarbonyl, ethoxycarbonyl, methoxycarbonyl, and the like.
The term "alkoxycarbonylalkenylJ as used herein, refers to one or two alkoxycarbonyl groups, as defined herein, appended to the parent molecular moiety through an alkenyl group, as defined herein. Representative examples of alkoxycarbonylalkenyl include, but are not limited to, 3-(methoxycarbonyl)propen-l-yl, , 4-(ethoxycarbonyl)buten-2-yl, 4-bis(ethoxycarbonyl)buten-2-yl, and the like.
The term "alkoxycarbonylalkoxy" as used herein refers to an alkoxycarbonyl group, as defined herein, appended to the parent molecular moiety through an alkoxy group. Representative examples of alkoxycarbonylalkoxy include methoxycarbonylmethoxy, ethoxycarbonylmethoxy, 2-(methoxycarbonyl)ethoxy, and the like.
The term "alkoxycarbonylalkoxyiminoJ as used herein refers to an alkoxycarbonylalkoxy group, as defined herein, appended to the parent molecular moiety through an imino group. Representative examples of alkoxycarbonylalkoxyimino include ethoxycarbonylmethoxyimino, 2-(methoxycarbonyl)ethoxyimino, and the like. The term "alkoxycarbonylalkoxyiminoalkylJ as used herein refers to an alkoxycarbonylalkoxyimino group, as defined herein, appended to the parent molecular moiety through an alkyl group. Representative examples of alkoxycarbonylalkoxyiminoalkyl include 2-(ethoxycarbonylmethoxyimino)ethyl, 2-[2- (methoxycarbonyl)ethoxyiminojethyl, and the like.
The term "alkoxycarbonylalkylJ as used herein, refers to an alkoxycarbonyl group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein. Representative examples of alkoxycarbonylalkyl include, but are not limited to, 3-(methoxycarbonyl)propyl, , 4-(ethoxycarbonyl)butyl, and the like.
The term "alkoxyiminoJ as used herein, refers to an alkoxy group, as defined herein, appended to the parent molecular moiety through an imino group, as defined herein. Representative examples of alkoxyimino include, but are not limited to, ethoxyimino, methoxyimino, propoxyimino, isopropoxyimino, and the like.
The term " alkoxy iminoalkylJ as used herein, refers to an alkoxyimino group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein. Representative examples of alkoxyiminoalkyl include, but are not limited to, 2-(ethoxyimino)ethyl, 2-(methoxyimino)ethyl, 2-(propoxyimino)ethyl, 2- (isopropoxyimino)ethyl, and the like.
The term "alkylJ as used herein, refers to a straight or branched chain hydrocarbon containing from 1 to 6 carbon atoms. Representative examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, and the like.
The term "alkyleneJ denotes a divalent group derived from a straight or branched chain hydrocarbon of from 1 to 3 carbon atoms. Representative examples of alkylene include, -CH2-, -CH2CH2-, and -CH2CH2CH2-.
The term "alkylcarbonylJ as used herein, refers to an alkyl group, as defined herein, appended to the parent molecular moiety through a carbonyl group, as defined herein. Representative examples of alkylcarbonyl include, but are not limited, methylcarbonyl (acetyl), ethylcarbonyl, and the like.
The term "alkylcarbonyloxyJ as used herein, refers to an alkylcarbonyl group, as defined herein, appended to the parent molecular moiety through an oxy group, as defined herein. Representative examples of alkylcarbonyloxy include, but are not limited, methylcarbonyloxy, ethylcarbonyloxy, and the like.
The term " alkylcarbonyloxyalkoxy J as used herein, refers to an alkylcarbonyloxy group, as defined herein, appended to the parent molecular moiety through an alkoxy group, as defined herein. Representative examples of alkylcarbonyloxyalkoxy include, but are not limited, 2-(methylcarbonyloxy)ethoxy, 3 -(ethylcarbonyloxy )propoxy, and the like. The term "alkylcarbonyloxyalkylJ as used herein, refers to an alkylcarbonyloxy group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein. Representative examples of alkylcarbonyloxyalkyl include, but are not limited, 2-(methylcarbonyloxy)ethyl, 3 -(ethylcarbonyloxy )propyl, and the like. The term "alkylcarbonyloxyalkylthioJ as used herein, refers to an alkylcarbonyloxyalkyl group, as defined herein, appended to the parent molecular moiety through a thio moiety, as defined herein. Representative examples of alkylcarbonyloxyalkylthio include, but are not limited, 2- (methylcarbonyloxy)ethylsulfanyl, 3-(ethylcarbonyloxy)propylsulfoanyl, and the like. The term "alkylsulfonylJ as used herein, refers to an alkyl group, as defined herein, appended to the parent molecular moiety through a sulfonyl group, as defined herein. Representative examples of alkylsulfonyl include, but are not limited, methylsulfonyl, ethylsulfonyl, and the like.
The term "alkylthio," as used herein, refers to an alkyl group, as defined herein, appended to the parent molecular moiety through a thio moiety, as defined herein. Representative examples of alkylthio include, but are not limited, methylsulfanyl, ethylsulfanyl, tert-butylsulfanyl, hexylsulfanyl, and the like.
The term "alkylthioalkylJ as used herein, refers to an alkylthio group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein. Representative examples of alkylthioalkyl include, but are not limited, methylsulfanylmethyl, 2-(ethylsulfanyl)ethyl, and the like.
The term "alkynyl," as used herein, refers to a straight or branched chain hydrocarbon group containing from 2 to 6 carbon atoms and containing at least one carbon-carbon triple bond. Representative examples of alkynyl include, but are not limited, to acetylenyl, 1-propynyl, 2-propynyl, 3-butynyl, 2-pentynyl, 1-butynyl and the like.
The term "aminoJ refers to an -NZ,Z2 group wherein Z, and Z2 are appended to the parent molecular moiety through a nitrogen atom. Z, and Z2 are independently selected from hydrogen, alkyl, alkylcarbonyl, benzyl, cycloalkyl, cycloalkylalkyl, formyl, and phenyl. Representative examples of -NZ,Z2 include, but are not limited to, amino, benzylamino, methylamino. acetylamino, acetylmethylamino, cyclopropylamino, cyclopropylmethylamino, dimethylamino, phenylamino, and the like.
The term "aminoalkylJ as used herein, refers to an amino group, as defined herein, appended to the parent molecular moiety through an alkyl moiety, as defined herein. Representative examples of aminoalkyl include, but are not limited, 3-aminopropyl, 4- dimethylaminobutyl, and the like.
The term "aminoalkylcarbonylJ as used herein, refers to an aminoalkyl group, as defined herein, appended to the parent molecular moiety through a carbonyl moiety, as defined herein. Representative examples of aminoalkylcarbonyl include, but are not limited, 3-(amino)propylcarbonyl, 4-(dimethylamino)butylcarbonyl, and the like.
The term "aminoalkynylJ as used herein, refers to an amino group, as defined herein, appended to the parent molecular moiety through an alkynyl moiety, as defined herein. Representative examples of aminoalkynyl include, but are not limited, 3- (amino)propyn-l-yl, 4-(dimethylamino)butyn-l-yl, and the like. The term "amino-protecting group" or "N-protecting groupJrefers to groups intended to protect an amino group against undersirable reactions during synthetic procedures. Commonly used nitrogen-protecting groups are disclosed in Greene, T. W., & Wuts, P. G. M. (1991). Protectective Groups In Organic Synthesis (2nd ed.). New York: John Wiley & Sons. Preferred nitrogen-protecting groups are formyl, acetyl, benzoyl, pivaloyl, t-butylacetyl, phenylsulfonyl, benzyl, t-butyloxycarbonyl (Boc), and benzyloxycarbonyl (Cbz).
The term "aminosulfonylJ as used herein, refers to an amino group, as defined herein, appended to the parent molecular moiety through a sulfonyl moiety, as defined herein. Representative examples of aminosulfonyl include, but are not limited, aminosulfonyl, dimetylaminosulfonyl, diethylaminosulfonyl, and the like.
The term "arylJ as used herein, refers to a monocyclic-ring system, or a bicyclic- fused ring system wherein one or both of the fused rings are aromatic. Representative examples of aryl include, but are not limited to, azulenyl, indanyl, indenyl, naphthyl, phenyl, tetrahydronaphthyl, and the like. The aryl groups of this invention can be substituted with 1. 2, or 3 substituents independently selected from alkenyl, alkenyloxy, alkenyloxyimino. alkenyloxyiminoalkyl, alkoxy, alkoxyalkoxy, alkoxyalkoxyalkyl, alkoxyalkoxyimino, alkoxyalkyl, alkoxyalkynyl, alkoxycarbonyl, alkoxycarbonylalkenyl, alkoxycarbonylalkyl, alkoxycarbonylalkoxyimino, alkoxycarbonylalkoxyiminoalkyl, alkoxyimino, alkoxyiminoalkyl, alkyl, alkylcarbonyl, alkylcarbonyloxy, alkylcarbonyloxyalkoxy, alkylcarbonyloxyalkyl, alkylcarbonyloxyalkylthio, alkylsulfonyl, alkylthio, alkylthioalkyl, aminoalkynyl, aminosulfonyl, azido, carboxy, carboxyalkyl, cyano, cyanoalkyl, cycloalkyl, cycloalkylalkoxy, cycloalkylalkyl, cycloalkyloxy, cycloalkyloxyimino, ethylenedioxy, formyl, formylalkyl, haloalkyl, haloalkylcarbonyl, halogen, hydroxy, hydroxyalkoxy, hydroxyalkoxy alkyl, hydroxyalkyl, hydroxyimino, hydroxyiminoalkyl, methylenedioxy, methylenyl, nitro, oxo, l-phenyl-l,3,8-triazaspiro[4.5]decan-4-one, 1- phenyl-1 ,3,8-triazaspiro[4.5]dec-2-en-4-one, phosphonato, spirocycle, (spirocycle)spirocycle, thioureylene, ureylene, -NZ!2Z13, (NZ12Z13)alkyl, (NZ12Z13)carbonyl, and (NZι2Z13)carbonyloxy wherein Z12 and Z13 are independently selected from hydrogen, alkoxyalkyl, alkyl, alkylcarbonyl, alkylsulfonyl, aminoalkylcarbonyl, aminosulfonyl, aryl, arylalkyl, arylalkylcarbonyl, cyanoalkyl, cycloalkyl, cycloalkylalkyl, formyl, haloalkylcarbonyl, heterocycle, heterocyclealkyl, heterocyclealkylcarbonyl, heterocyclesulfonyl, and (NZ14Z15)alkyl wherein ZM and Z15 are independently selected from the group consisting of hydrogen, alkoxyalkoxyalkyl, alkoxyalkyl, alkoxyalkylcarbonyl, alkyl, alkylcarbonyl, formyl, heterocycle, and hydroxy alkoxy alky 1.
The term "arylalkoxy," as used herein, refers to an aryl group, as defined herein, appended to the parent molecular moiety through an alkoxy group, as defined herein. Representative examples of arylalkoxy include, but are not limited to, 2-phenylethoxy, 3- naphth-2-ylpropoxy, 5-phenylpentyloxy, and the like.
The term "arylalkoxycarbonylJ as used herein, refers to an arylalkoxy group, as defined herein, appended to the parent molecular moiety through a carbonyl group, as defined herein. Representative examples of arylalkoxycarbonyl include, but are not limited to, benzyloxycarbonyl, naphth-2-ylmethoxycarbonyl, and the like. The term "arylalkoxyimino," as used herein, refers to an arylalkoxy group, as defined herein, appended to the parent molecular moiety through an imino group, as defined herein. Representative examples of arylalkoxyimino include, but are not limited to, 2-phenylethoxyimino, 3-naphth-2-ylpropoxyimino, 5-phenylpentyloxyimino, and the like.
The term "arylalkyl," as used herein, refers to an aryl group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein. Representative examples of arylalkyl include, but are not limited to, benzyl, 2-phenylethyl, 3-phenylpropyl, 2-naphth-2-ylethyl, and the like. The term "(aryl)alkylJ as used herein, refers to an aryl group, as defined herein, appended to the parent molecular moiety through another aryl group, as defined herein. Representative examples of (aryl)aryl include, but are not limited to, biphenyl, 4'- methoxybiphenyl, and the like.
The term "aryloxyJ refers to an aryl group, as defined herein, appended to the parent molecular moiety through an oxy moiety, as defined herein. Representative examples of aryloxy include, but are not limited to, phenoxy, naphthyloxy, 4- chlorophenoxy, 4-methylphenoxy, 3,5-dimethoxyphenoxy, and the like. The term "azidoJ as used herein, refers to a -N3 group. The term "carbonylJ as used herein, refers to a -C(O)- group. The term "carboxyJ as used herein, refers to a -CO2H group.
The term "carboxyalkylJ as used herein, refers to a carboxy group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein. Representative examples of carboxyalkyl include, but are not limited to, carboxymethyl, 2-carboxyethyl, 3-carboxypropyl, and the like. The term "cyanoJ as used herein, refers to a -CN group.
The term "cyanoalkyl," as used herein, refers to a cyano group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein. Representative examples of cyanoalkyl include, but are not limited to, cyanomethyl, 2- cyanoethyl, 3-cyanopropyl, and the like. The term "cycloalkyl," as used herein, refers to a saturated cyclic hydrocarbon group containing from 3 to 8 carbons. Representative examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl. cyclohexyl, cycloheptyl, cyclooctyl and the like.
The cycloalkyl groups of this invention can be substituted with 1 or 2 substituents independently selected from alkenyl, alkenyloxy, alkenyloxyimino, alkenyloxyiminoalkyl, alkoxy, alkoxyalkoxy, alkoxyalkoxyalkyl, alkoxyalkoxyimino, alkoxyalkyl, alkoxyalkynyl, alkoxycarbonyl, alkoxycarbonylalkenyl, alkoxycarbonylalkyl, alkoxycarbonylalkoxyimino, alkoxycarbonylalkoxyiminoalkyl, alkoxyimino, alkoxyiminoalkyl, alkyl, alkylcarbonyl, alkylcarbonyloxy, alkylcarbonyloxyalkoxy, alkylcarbonyloxyalkyl, alkylcarbonyloxyalkylthio, alkylsulfonyl, alkylthio, alkylthioalkyl, aminoalkynyl, aminosulfonyl, azido, carboxy, carboxyalkyl, cyano, cyanoalkyl, cycloalkyl, cycloalkylalkoxy, cycloalkylalkyl, cycloalkyloxy, cycloalkyloxyimino, ethylenedioxy, formyl, formylalkyl, haloalkyl, haloalkylcarbonyl, halogen, hydroxy, hydroxyalkoxy, hydroxyalkoxyalkyl, hydroxyalkyl, hydroxyimino, hydroxyiminoalkyl, methylenedioxy, methylenyl, nitro, oxo, l-phenyl-l,3,8-triazaspiro[4.5jdecan-4-one, 1- phenyl-1 ,3,8-triazaspiro[4.5]dec-2-en-4-one, phosphonato, spirocycle, (spirocycle)spirocycle, thioureylene, ureylene, -NZ12Z13, (NZ12Z,3)alkyl, (NZ12Z13)carbonyl, and (NZ12Zl3)carbonyloxy wherein Z12 and Z13 are independently selected from hydrogen, alkoxyalkyl, alkyl, alkylcarbonyl, alkylsulfonyl, aminoalkylcarbonyl, aminosulfonyl, aryl, arylalkyl, arylalkylcarbonyl, cyanoalkyl, cycloalkyl, cycloalkylalkyl, formyl, haloalkylcarbonyl, heterocycle. heterocyclealkyl, heterocyclealkylcarbonyl, heterocyclesulfonyl, and (NZ14Z,5)alkyl wherein ZM and Z,5 are independently selected from the group consisting of hydrogen, alkoxyalkoxyalkyl, alkoxyalkyl, alkoxyalkylcarbonyl, alkyl, alkylcarbonyl, formyl, heterocycle, and hydroxyalkoxyalkyl.
The term "cycloalkylalkoxy/1 as used herein, refers to cycloalkyl group, as defined herein, appended to the parent molecular moiety through an alkoxy group, as defined herein. Representative examples of cycloalkylalkoxy include, but are not limited to. cyclopropylmethoxy, 2-cyclobutylethoxy, cyclopentylmethoxy, cyclohexylmethoxy, 4- cycloheptylbutoxy, and the like. The term "cycloalkylalkyl," as used herein, refers to cycloalkyl group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein. Representative examples of cycloalkylalkyl include, but are not limited to, cyclopropylmethyl, 2-cyclobutylethyl, cyclopentylmethyl, cyclohexylmethyl and 4- cycloheptylbutyl, and the like.
The term "cycloalkylcarbonyl," as used herein, refers to cycloalkyl group, as defined herein, appended to the parent molecular moiety through a carbonyl group, as defined herein. Representative examples of cycloalkylcarbonyl include, but are not limited to, cyclopropylcarbonyl, 2-cyclobutylcarbonyl, cyclohexylcarbonyl, and the like. The term "cycloalkyloxyJ as used herein, refers to cycloalkyl group, as defined herein, appended to the parent molecular moiety through an oxy moiety, as defined herein. Representative examples of cycloalkyloxy include, but are not limited to, cyclopropyloxy, cyclopentyloxy, cyclohexyloxy, and the like.
The term "cycloalkyloxyiminoJ as used herein, refers to cycloalkyloxy group, as defined herein, appended to the parent molecular moiety through an imino group, as defined herein. Representative examples of cycloalkyloxyimino include, but are not limited to, cyclopropyloxyimino, cyclopentyloxyimino, cyclohexyloxyimino, and the like.
The term "ethylenedioxy," as used herein, refers to a -OCH(R20)CH(R2I)O- group wherein the oxygen atoms of the ethylenedioxy group are attached to the parent molecular moiety through one carbon atom forming a 5 membered ring or the oxygen atoms of the ethylenedioxy group are attached to the parent molecular moiety through two adjacent carbon atoms forming a six membered ring. R20 and R2, are independently selected from hydrogen and alkyl or R20 and R21 together with the carbon atoms to which they are attached can join to form a 5 or 6 membered ring optionally containing 1 heteroatom selected from NH, O, or S. Representative examples of ethylenedioxy include, but are not limited to, 3,5-dimethyl-l,2-cyclopentanediol, tetrahydro-3,4-furandiol, 1,2- cyclopentanediol, and the like.
The term "formylJ as used herein, refers to a -C(O)H group. The term "formylalkylJ as used herein, refers to a formyl group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein. Representative examples of formylalkyl include, but are not limited to, formylmethyl, 2- formylethyl, and the like.
The term "halo" or "halogen," as used herein, refers to -Cl, -Br, -I or -F. The term "haloalkoxyJ as used herein, refers to at least one halogen, as defined herein, appended to the parent molecular moiety through an alkoxy group, as defined herein. Representative examples of haloalkoxy include, but are not limited to, chloromethoxy, 2-fluoroethoxy, trifluoromethoxy, pentafluoroethoxy, and the like.
The term "haloalkylJ as used herein, refers to at least one halogen, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein. Representative examples of haloalkyl include, but are not limited to, chloromethyl, 2- fiuoroethyl, trifluoromethyl, pentafluoroethyl, 2-chloro-3-fluoropentyl, and the like. The term "haloalkylcarbonylJ as used herein, refers to a haloalkyl group, as defined herein, appended to the parent molecular moiety through a carbonyl group, as defined herein. Representative examples of haloalkylcarbonyl include, but are not limited to, 2-fluoroethylcarbonyl, trifluoromethylcarbonyl, pentafluoroethylcarbonyl, and the like. The term "heterocycle" as used herein, refers to a monocyclic, bicyclic, or tricyclic ring system. Monocyclic ring systems are exemplified by any 3- or 4-membered ring containing a heteroatom independently selected from oxygen, nitrogen and sulfur; or a 5-, 6- or 7-membered ring containing one, two or three heteroatoms wherein the heteroatoms are independently selected from nitrogen, oxygen and sulfur. The 5-membered ring has from 0-2 double bonds and the 6- and 7-membered ring have from 0-3 double bonds. Representative examples of monocyclic ring systems include, but are not limited to, azetidinyl, azepinyl, aziridinyl, diazepinyl, 1,3-dioxolanyl, dioxanyl, dithianyl, furyl, imidazolyl, imidazolinyl, imidazolidinyl, isothiazolyl, isothiazolinyl, isothiazolidinyl, isoxazolyl, isoxazolinyl, isoxazolidinyl, moφholinyl, oxadiazolyl, oxadiazolinyl, oxadiazolidinyl, oxazolyl, oxazolinyl, oxazolidinyl, piperazinyl, piperidinyl, pyranyl, pyrazinyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, pyridyl, pyrimidinyl, pyridazinyl, pyrrolyl, pyrrolinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, tetrazinyl, tetrazolyl, thiadiazolyl, thiadiazolinyl, thiadiazolidinyl, thiazolyl, thiazolinyl, thiazolidinyl, thiophenyl, thiomoφholinyl, lJ-dioxidothiomoφholinyl, thiopyranyl, triazinyl, triazolyl, trithianyl. and the like. Bicyclic ring systems are exemplified by any of the above monocyclic ring systems fused to an aryl group as defined herein, a cycloalkyl group as defined herein, or another monocyclic ring system. Bicyclic ring systems are further exemplified by any of the above monocyclic ring systems containing an alkyleneof 1-3 carbon atoms attached to two non-adjacent carbon atoms of the monocyclic ring system. Representative examples of bicyclic ring systems include but are not limited to, for example, benzimidazolyl, benzothiazolyl, benzothiophenyl, benzoxazolyl, benzofuranyl, benzopyranyl, benzothiopyranyl, benzodioxinyl, 1,3-benzodioxolyl, cinnolinyl, hexahydro-lH- uro[3,4-c]pyrrolyl, indazolyl, indolyl, indolinyl, indolizinyl, naphthyridinyl, isobenzofuranyl, isobenzothiophenyl, isoindolyl, isoindolinyl, isoquinolyl, 2-oxa-5-azabicyclo[2.2J]heptanyl, l,4-dioxa-8-azaspiro[4.5]decanyl, l,3-dioxa-8- azaspiro[4.5]decanyl, l,5-dioxa-9-azaspiro[5.5jundecanyl, l-oxa-4-thia-8- azaspiro[4.5 jdecanyl, 1 -oxa-4,4-dioxo-4-thia-8-azaspiro[4.5]decanyl, 1 -oxa-4-oxo-4-thia- 8-azaspiro[4.5]decanyl, phthalazinyl, pyranopyridyl, 2,4-(lH,3H)-quinazolinedion-3-yl, quinolyl, quinolizinyl, quinoxalinyl, quinazolinyl, (3aR,6aS)-tetrahydro-3aH- [l,3]dioxolo[4,5-cjpyrrol-2-one, tetrahydroisoquinolyl, tetrahydroquinolyl, thiopyranopyridyl, and the like. Tricyclic rings systems are exemplified by any of the above bicyclic ring systems fused to an aryl group as defined herein, a cycloalkyl group as defined herein, or a monocyclic ring system. Representative examples of tricyclic ring systems include, but are not limited to, acridinyl, carbazolyl. carbolinyl, dibenzofuranyl, 2,4(lH,3H)-quinazolinedione. dibenzothiophenyl. 4,7-epoxy-7-methyl-2,3,3A,4,5,6,7,7a- octahydro-lH-isoindolyl, naphthofuranyl, naphthothiophenyl, oxanthrenyl, phenazinyl, phenoxathiinyl, phenoxazinyl, phenothiazinyl, thianthrenyl, thioxanthenyl, xanthenyl, and the like. The heterocycles of this invention can be substituted with 1, 2,or 3 substituents independently selected from alkenyl, alkenyloxy, alkenyloxyimino, alkenyloxyiminoalkyl, alkoxy, alkoxyalkoxy, alkoxyalkoxyalkyl, alkoxyalkoxyimino, alkoxyalkyl, alkoxyalkynyl, alkoxycarbonyl, alkoxycarbonylalkenyl, alkoxycarbonylalkyl, alkoxycarbonylalkoxyimino, alkoxycarbonylalkoxyiminoalkyl, alkoxyimino, alkoxyiminoalkyl, alkyl, alkylcarbonyl, alkylcarbonyloxy, alkylcarbonyloxyalkoxy, alkylcarbonyloxyalkyl. alkylcarbonyloxyalkylthio. alkylsulfonyl, alkylthio. alkylthioalkyl, aminoalkynyl, aminosulfonyl, azido, carboxy, carboxyalkyl, cyano, cyanoalkyl, cycloalkyl, cycloalkylalkoxy, cycloalkylalkyl, cycloalkyloxy, cycloalkyloxyimino, ethylenedioxy, formyl, formylalkyl, haloalkyl, haloalkylcarbonyl, halogen, hydroxy, hydroxyalkoxy, hydroxyalkoxyalkyl, hydroxyalkyl, hydroxyimino, hydroxyiminoalkyl, methylenedioxy, methylenyl, nitro, oxo, phosphonato, spirocycle, (spirocycle)spirocycle, thioureylene, ureylene, -NZ12Z13, (NZ12Z13)alkyl, (NZ12Z13)carbonyl, and (NZ12Z13)carbonyloxy wherein Z12 and Z13 are independently selected from hydrogen, alkoxyalkyl, alkyl, alkylcarbonyl, alkylsulfonyl, aminoalkylcarbonyl, aminosulfonyl, aryl, arylalkyl, arylalkylcarbonyl, cyanoalkyl, cycloalkyl, cycloalkylalkyl, formyl, haloalkylcarbonyl, heterocycle, heterocyclealkyl, heterocyclealkylcarbonyl, heterocyclesulfonyl, and (NZ14Z15)alkyl wherein Z14 and Z15 are independently selected from the group consisting of hydrogen, alkoxyalkoxyalkyl, alkoxyalkyl, alkoxyalkylcarbonyl, alkyl, alkylcarbonyl, formyl, heterocycle, and hydroxyalkoxyalkyl. Representative examples include, but are not limited to 4,4-(cis-l,2- dioxycyclopentyl)piperidinyl,
The term "heterocyclealkoxy ' as used herein, refers to a heterocycle group, as defined herein, appended to the parent molecular moiety through an alkoxy group, as defined herein. Representative examples of heterocyclealkoxy include, but are not limited to, 2-pyrid-3-ylethoxy, 3-quinolin-3-ylpropoxy, 5-pyrid-4-ylpentyloxy. and the like.
The term "heterocyclealkoxy imino J as used herein, refers to a heterocyclealkoxy group, as defined herein, appended to the parent molecular moiety through an imino group, as defined herein. Representative examples of heterocyclealkoxyimino include, but are not limited to, 2-pyrid-3-ylethoxyimino, 3-quinolin-3-ylpropoxyimino. 5-pyrid-4- ylpentyloxyimino, 3-(4-moφholinyl)propoxyimino, and the like.
The term "heterocyclealkylJ as used herein, refers to a heterocycle. as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein. Representative examples of heterocyclealkyl include, but are not limited to, pyrid-3- ylmethyl, 2-pyrimidin-2-ylpropyl, and the like. The term "heterocyclealkylcarbonyl," as used herein, refers to a heterocyclealkyl group, as defined herein, appended to the parent molecular moiety through a carbonyl group, as defined herein. Representative examples of heterocyclealkylcarbonyl include, but are not limited to, pyrid-3-ylmethylcarbonyl, 3-pyrimidin-2-ylpropylcarbonyl, and the like.
The term "(heterocycle)arylJ as used herein, refers to a heterocycle, as defined herein, appended to the parent molecular moiety a aryl group, as defined herein. Representative examples of (heterocycle)aryl include, but are not limited to, 4-(pyridin-3- yl)phenyl, 4-(pyrimidin-2-yl)phenyl, and the like. The term "heterocyclecarbonylJ as used herein, refers to a heterocycle, as defined herein, appended to the parent molecular moiety through a carbonyl group, as defined herein. Representative examples of heterocyclecarbonyl include, but are not limited to, pyrid-3-ylcarbonyl, quinolin-3-ylcarbonyl, and the like.
The term "heterocycleimino/' as used herein, refers to a heterocycle group, as defined herein, appended to the parent molecular moiety through an imino group, as defined herein. Representative examples of heterocycleimino include, but are not limited to, 4-moφholinylimino, and the like.
The term "heterocycleoxy," as used herein, refers to a heterocycle group, as defined herein, appended to the parent molecular moiety through an oxy moiety, as defined herein. Representative examples of heterocycleoxy include, but are not limited to, pyrid-3-yloxy, quinolin-3-yloxy, and the like.
The term "heterocycleoxyalkyl," as used herein, refers to a heterocycleoxy group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein. Representative examples of heterocycleoxyalkyl include, but are not limited to, pyrid-3-yloxymethyl, 2-quinolin-3-yloxyethyl, and the like.
The term "heterocycleoxyimino," as used herein, refers to a heterocycleoxy group, as defined herein, appended to the parent molecular moiety through an imino group, as defined herein. Representative examples of heterocycleoxyimino include, but are not limited to, pyrid-3-yloxyimino, quinolin-3-yloxyimino, and the like. The term "heterocycleoxyiminoalkyl," as used herein, refers to a heterocycleoxyimino group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein. Representative examples of heterocycleoxyiminoalkyl include, but are not limited to, 2-(pyrid-3-yloxyimino)ethyl, 2- (quinolin-3-yloxyimino)ethyl, and the like.
The term "heterocyclesulfonyl," as used herein, refers to a heterocycle, as defined herein, appended to the parent molecular moiety through a sulfonyl group, as defined herein. Representative examples of heterocyclesulfonyl include, but are not limited to, pyrid-3-ylsulfonyl, quinolin-3-ylsulfonyl, 4-moφholinylsulfonyl, and the like. The term "hydroxy," as used herein, refers to an -OH group.
The term "hydroxyalkoxy," as used herein, refers to one or two hydroxy groups, as defined herein, appended to the parent molecular moiety through an alkoxy group, as defined herein. Representative examples of hydroxyalkoxy include, but are not limited to, 2-hydroxyethoxy, 2,3-dihydroxypropoxy, 4-hydroxybutoxy, and the like. The term "hydroxyalkoxyalkyl," as used herein, refers to a hydroxyalkoxy group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein. Representative examples of hydroxyalkoxyalkyl include, but are not limited to, 2-[2-(hydroxy)ethoxyjethyl, 2-[3-(hydroxy)propoxy]ethyl, 4- hydroxybutoxymethyl, and the like. The term "hydroxyalkyl," as used herein, refers to one or two hydroxy groups, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein. Representative examples of hydroxyalkyl include, but are not limited to, 2-hydroxyethyl, 2,3-dihydroxypropyl, and the like.
The term "hydroxyimino," as used herein, refers to a HON= group. The term "hydroxyiminoalkyl," as used herein, refers to a hydroxyimino group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein. Representative examples of hydroxyiminoalkyl include, but are not limited to, 2-(hydroxyimino)ethyl, 3-(hydroxyimino)propyl, and the like. The term "imino," as used herein, refers to a HN= group. The term "mammal," has its ordinary meaning and includes human beings. The term "methylenedioxy," as used herein, refers to a -OCH2O- group wherein the oxygen atoms of the methylenedioxy are attached to the parent molecular moiety through two adjacent carbon atoms forming a 5 memebered ring. The carbon atom of methylenedioxy group is optionally substituted with one substituent selected from alkyl and oxo.
The term "methylenyl," as used herein refers to a H2C= group.
The term "nitro," as used herein, refers to a -NO2 group.
The term "oxo," as used herein, refers to a O= moiety.
The term "oxy," as used herein, refers to a -O- moiety. The term "phosphonato," refers to a (R95O)2P(O)O- group wherein R,5 is alkyl.
The term "spirocycle," as used herein, refers to a -X,(CH2)pX2- group wherein X, and X2 are independently selected from CH2, NH, O, S, S(O), and S(O)2; and p is an integer from 2-3. X, and X2 are attached to the parent molecular moiety through one carbon atom forming a 5 or 6 membered ring. Representative examples of spirocycle include, but are not limited to 1,3-dioxolane, 1,3-dioxane, 1,3-oxathiane, 1,3-oxazinane, and the like.
The spirocycles of this invention are optionally substituted with 1, 2, or 3 substituents independently selected from alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl, alkylcarbonyl, aminocarbonyl, benzyloxcarbonyl, and formyl. The substituents can be attached to nitrogen or any of the carbon atoms.
The term "(spirocycle)spirocycle," as used herein, refers to a spirocycle. as defined herein, attached to the parent molecular moiety through a spirocycle, as defined herein. Representative examples of spirocycle-spirocycle include, but are not limited to, 1 ,7,9- trioxaspiro[4.5]decane, l,4,7,9-tetraoxaspiro[4.5]decane, and the like. The term "thio," as used herein, refers to a -S- moiety.
The term "thioureylene," as used herein, refers to -NR97C(S)NR98R99, wherein R,7, R,8, and R,, are independently selected from hydrogen, alkyl, aryl, and arylalkyl, as defined herein. The term "ureylene," as used herein, refers to -NR97C(O)NR98R99, wherein R,7, Rgg, and Rg, are independently selected from hydrogen, alkyl, aryl, and arylalkyl, as defined herein.
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: 0J- 250 nmol/kg/minute, preferably from 1-50 nmol/kg/minute; oral: 0.01-250 μMol/kg/day, preferably from about 0J-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.
Compounds of the present invention can exist as stereoisomers wherein asymmetric or chiral centers are present. These compounds are designated by the symbols "R" or "S," depending on the configuration of subsitiuents around the chiral carbon atom. The present invention contemplates various stereoisomers and mixtures thereof. Stereoisomers include enantiomers and diastereomers. Individual stereoisomers of compounds of the present invention can be prepared synthetically from commercially available starting materials which contain asymmetric or chiral centers or by preparation of racemic mixtures followed by resolution well-known to those of ordinary skill in the art. These methods of resolution are exemplified by (1) attachment of a mixture of enantiomers to a chiral auxiliary, separation of the resulting mixture of diastereomers by recrystallization or chromatography and liberation of the optically pure product from the auxiliary or (2) direct separation of the mixture of optical enantiomers on chiral chromatographic columns.
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, benzenesulfonate, 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, myristyi, 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, corn 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.
Scheme
Figure imgf000083_0001
Figure imgf000083_0002
(I)
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 or a heterocychc 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 or a heterocychc group, an appropriately substituted aldehyde (2, the "R3 Reagent"). R3 is aryl or a heterocychc 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 R3 substituted 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 R4 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 Swern 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 -djpyrimidine 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, heterocycle or heterocychc group, and R3 is loweralkyl, loweralkenyl, loweralkynyl, or an arylalkyl group. In addition, R4 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) Swern 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 imgf000086_0001
Figure imgf000086_0002
Figure imgf000086_0003
10
Figure imgf000086_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 HC1, followed by lyophilization.
Scheme 3
Figure imgf000087_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 H2O: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 prepare 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 R' 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 triethylamine 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 R' 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 tri ethyl ortho formate for the formamide followed by chlorination of the ring by treatment with phosphorous oxy chloride 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. 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. AK activity of cell supernatants was assayed radiometrically. Assays were carried out at ambient temperature in a final volume of 100 μL. The reaction mixture contained 64 mM Tris HC1 (pH 7.5), 0.2 mM MgCl2, 1 mM ATP, 0.2 μM U-[1 Cj-adenosine or [3H]-adenosine and appropriate volumes of rat brain cytosol as a source of adenosine kinase. The reaction was terminated after 15 min by spotting 40 μL of the reaction mixture onto disks of Whatman DE-81 anion exchange paper. DE-81 disks were then air-dried, washed for 10 minutes in 2 mM ammonium formate, then rinsed successively with distilled water, methanol and acetone, and dried. DE-81 disks were then soaked for 5 minutes in 0JN HC1/0.4 M KC1 before addition of scintillation cocktail and counting by liquid scintillation counting. 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 alia 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. Phvsiol.. (1982), 7 IB, 367-372), hereby incoφorated by reference. 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 incubated in the presence and absence of an inhibitor. Inhibition is measured as the ability to inhibit phosphorylation of externally applied 14C-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 A,, A2A, and A3 receptor binding, adenosine deaminase activity and adenosine transport.
Where the adenosine kinase is located in situ or in vivo, the inhibiting compound 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.
Numerous animal models for studying adenosine kinase activity and the effects 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 experimentally- induced seizure activity (Zhang, G., Murray, T.F., J. Pharmacol. Exp. Ther.. 1993, 264, 1415-1424; Murray, T.F., et al., Drug Dev. Res.. 1993, 28, 410-415; Kowaluk, E. A., et al., Drug Dev. Res., 1996, 37, 190), hereby incoφorated by reference. Other animal models of adenosine kinase activity have been described (See, e.g., Davies, et al., Biochem. Pharmacol.. 1984, 33, 347-355; Keil, et al., Eur. J. Pharmacol., 1994, 271, 37- 46; Murray, et al., Drug Development Res.. 1993, 28, 410-415), hereby incoφorated by reference.
A method of inhibiting adenosine kinase in vivo is particularly useful in mammals such as humans. Administering a therapeutic amount of an inhibitor compound is typically accomplished by the parenteral (e.g., intravenous injection) or oral administration of the compound.
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. 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 imgf000092_0001
Figure imgf000093_0001
Figure imgf000094_0001
Additional compounds of the present invention were tested for adenosine kinase inhibition using the above protocol. These compounds exhibited potent inhibition of adenosine kinase with ED50's ranging from 1 to 500 nM.
Carrageenan hvperalgesia Test-Hotbox Assay This assay may be indicative of a compound's ability to produce analgesia against carrageenan and capsaicin induced hyperalgesia. The assay is further discussed in Hargreaves K, Dubner R, Brown F, Flores C, Joris J (1988), A new and sensitive method for measuring thermal nociception in cutaneous hyperalgesia. Pain 32: 77-88, hereby fully incoφorated by reference.
C/D Sprague Dawley rats (Charles River), body weight range 250-350 g, are acclimated in the test room for 30-60 min. before any treatment (habituation). Carrageenan (CARR)(lambda, from Sigma, St. Louis, MO) is dissolved in heated saline at 10 mg/ml. This solution is sonicated and vortexed and then cooled to room temperature. After rats have been habituated they are injected with 100 μl of the CARR solution into the plantar surface (s.c) of the right hindpaw. A 26 3/8 g needle is used for injection. The insertion of the needle will start at the midline of the foot between the tori and project toward the heel -0.25 cm . Needle is then slowly removed from the skin to prevent seepage. Test compounds are administered at a time predetermined in relation to CARR injection (typically 1 hour pre CARR administration). The left hindpaw receives no injections. After carrageenan injection the rats are returned to their cages until 30 minutes before testing at which time they are placed in the Hargreaves thermal stimulator apparatus (Hotbox) for a 30 minute habituation period. Testing (thermal stimulation) is then performed. Each rat is tested 3 times (both right and left hindpaw) with approx. 5 minute between trials. The standard setting for the thermal stimulator (voltmeter) is 4.5 and the maximum time of exposure is 20.48 seconds. Scoring is based on latency to withdrawal from the thermal stimuli (0-20.48 seconds) The 2 lowest times of the three taken are averaged and the means are then determined for both the right and left paws (n=6 in most cases). Data is analyzed using GB Stat, with ANOVA protected T-tests to determine significant carrageenan effect (right versus left in same animal) and analgesic effect (right drug treated vs. right control). Results are indicated below as ED50 values in micromolar concentration. For those values in nanomolar concentration, the values are designated by "nm".
Compound ED^ value (micromole/kg) Example 134 0.6
Example 351 3
Example 352 3
Example 353 3 Example 354 1
Example 355 1
Example 356 1
Example 357 3
Example 359 1 Example 534 3
Additional compounds of the present invention were tested in the carrageenan and capsaicin induced hyperalgesia hotbox assay using the above protocal in C/D Sprague Dawley rats. These compounds exhibited ED50's ranging from 1 to >10 micromolar. Compounds exhibiting less potency in the carrageenan hyperalgesia hotbox assay may require a higher dose or potency may be species dependent.
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'-R4 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 heterocycle moiety wherein the substituent (preferrably halogen) is at the meta or 3 -position relative to the ring attachment and R4 is a substituted heterocycle or aryl moiety wherein the substituent is at the para or 4-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 liver 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 HIV-seropositive and HIV- 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-ψ-dimethylaminophenyl)-7-ψ-bromophenyl)pyrido[2J-d1pyrimidine 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 m/z 421 (M+H . The 6-(4-bromophenyl)-3 -cyano-4-(4-(dimethylamino)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 m/z 394 (M+H)J
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 imgf000099_0001
Figure imgf000100_0001
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Figure imgf000113_0001
-Ill-
Figure imgf000114_0001
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Figure imgf000128_0001
Figure imgf000129_0001
Figure imgf000130_0001
Figure imgf000131_0001
Figure imgf000132_0001
Example 157 4-amino-5-(3-bromophenyl)methyl-7-(4-(dimethylamino)phenyl)pyrido[2J-djpyrimidine hydrochloride
A mixture of 3-cyano-4-(3-bromophenyl)methyl-6-(4- (dimethy l)aminophenyl)pyridine-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 -bromopheny l)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 -bromopheny lacetate (10.2 g, US patent 2,624,731 (1950)) in 230 mL of dichloromethane was added 42 mL of IM 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 -(triphenylphosphonium)-4-(dimethylamino phenylethan-l- one chloride Following the procedure of Fukui et al. (J. Org. Chem. 33: 3594-3507 (1968)), - 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-cyano-4-(3-bromophenyl methyl-6-(4- (dimethv0aminophenyl)pyridine-2-amine A mixture of 1 -(4-(dimethy lamino)pheny l)-4-(3 -bromophenyl)-but-2-en- 1 -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 ortho formate 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-dichlorobenzene 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 imgf000135_0001
Figure imgf000136_0001
Figure imgf000137_0001
Figure imgf000138_0001
Figure imgf000139_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 imgf000139_0002
Figure imgf000140_0001
Figure imgf000141_0001
Figure imgf000142_0001
Figure imgf000143_0001
Figure imgf000144_0001
Example 189 4-acetylamino-5-(3-bromophenyl)-7-(4-dimethylaminophenyl)pyridor2.3-dlpyrimidine
A suspension of 4-amino-5-(3-bromophenyl)-7-(4- dimethylaminophenyl)pyrido [2,3 -djpyrimidine (from Example 15, 0.28 g, 0.67 mole) in pyridine (3 mL) was treated with acetic anhydride (0J0 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 (SiO,, EtOAc/hexanes) to provide the title compound (0.23 g, 73% theoretical): IR (KBr) 3368. 3048, 1695. 1567; MS m/z 462/464 (M+H)*.
Examples 190-198 Following the procedures of Example 189. except substituting the appropriate acylating reagent for the acetic anhydride of ExampleJ 89 as indicated in Table 5 below, compounds of Examples 190-198 were prepared.
Table 5 Examples 190-198
Figure imgf000145_0001
Figure imgf000146_0001
Example 199 4-allylamino-5-(4-bromophenviy7-f4-dimethylaminophenyl) pyrido [2.3-d] pyrimidine
The product was prepared by treating a solution of 4-chloro-5-(p- dimethylaminophenyl)-7-(p-bromophenyl)pyrido[2, 3-djpyrimidine in CH2C12-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 (SiO2, EtOAc/hexanes) to provide the title compound IR (KBr) 3437, 1564, 1355, 1 195; MS m/z 460/462 (M+H)*.
The 4-chloro-5-(p-dimethylaminophenyl)-7-(p-bromophenyl)pyrido [2,3- djpyrimidine 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 POCl3 (15 mL) then warmed at 100 °C for 2 hours. The POCl3 was removed under reduced pressure to provide crude 4-chloro-5-(p-dimethylaminophenyl)-7-(p- bromophenyl)pyrido[2, 3-djpyrimidine. The invention therefore relates to intermediate compounds of formula III 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-dimethylamino)ethylamino')-5-(4-bromophenvπ-7-(4-dimethylaminophenyl) pyrido [2.3-dj pyrimidine trihydrochloride 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 CH2C12-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 (SiO2, 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 trihydrochloride salt; IR (KBr) 3385, 1561, 1356, 1 197; MS m z 491/493 (M+H)*.
Example 201 4-(4-(N.N-dimethylamino butylamino -5-(3-bromophenyl)-7-(4- dimethylaminophenyl) pyrido [2.3-dl pyrimidine tetrahydrochloride The product was prepared by treating a solution of 4-amino-5-(p- dimethylaminophenyl)-7-(p-bromophenyl)pyrido[2, 3-djpyrimidine in CH2C12-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 (SiO2, 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, 1 196; MS m/z 519/521 (M+H)*.
Example 202 4- N-allyl-N-formylamino)-5-(4-dimethylaminophenyl)-7- (p-bromophenyl)pyrido[2,3-d1pyrimidine
A sample of the compound from Example 190 above, 4-formylamino-5-(2- phenylethyl)-7-(4-diethylaminophenyl)-pyrido [2,3 -djpyrimidine (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 m z 488/490. IR (cm_1) 3428, 2910, 1696, 1551, 1362, 1193.
Example 203
4-diacetylamino-5-(4-dimethylaminophenvQ-7-(p-bromophenvJ)- pyrido |"2,3 -dlpyrimidine This compound was isolated as a minor product from the reaction mixture of
Example 190 above: LRMS m/z 504/506. IR (cm" 1) 2922, 1726, 1550, 1360, 1197.
Example 204 4-amino-5-(3-bromophenyl)-7-(5-amino-2-pyridvπpyridof2.3-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 J5 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 (SiO2. EtOAc-CH2Cl2). LRMS m/z 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 m/z 393/395; IR (cm-l) 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 (5J 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 sulfate) 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 trimethylsilylacetylene (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 (Na,SO.) and concentrated in vacuo. Flash chromatography (SiO2. EtOAc-Hexanes) provided the title compound: LRMS m/z 137 (M = H+); IR (cm 1) 3428. 1668. 1646, 1582. 1358, 1274.
Example 205
4-amino-5-(3-bromophenyl)-7-(,5-dimethylamino-2-pyridyl pyrido[2J-djpyrimidine trihydrochloride salt
Following the procedure of Example 204, 5 -dimethy laminopyridine-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-dimethylaminopyridine-2-carboxaldehyde starting material was prepared as follows:
205a..3-N.N-dimethylaminopyridine
A solution of 3-aminopyridine (9.4 g, 0J0 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 CH2C12, 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 m/z 123 (M + H+).
205b. 2-bromo-5-N.N-dimethylaminopyridine
A solution of 3-N.N-dimethylaminopyridine (5.88 g, 48J 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-N,N-dimethylaminopyridine was isolated following flash chromatography (16.5 g, .82%): LRMS m/z 201/203.
204c . 5 -N.N-dimethylaminopyridine-2-ethanone Following the procedure of Example 203b. 2-bromo-5-N,N- dimethylaminopyridine, except converting the compound to the trihydrochloride salt by treatment with HCl/ether, was converted to the title compound: LRMS m/z 165; IR (cm-l) 3480, 1666, 1581, 1368, 1272.
Example 206
4-amino-5-(3-bromophenyl)-7-f5-dimethylamino-2-pyrazinyl)- pyrido[2. -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 ^m"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 0J 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 m z 156). This intermediate was treated with aqueous dimethylamine at room temperature for 30 minutes to afford 5-dimethylaminopyrazine-2-ethanone_(LRMS m z 166): LRMS m/z 422/424: IR (cm" 1) 3310, 1630, 1525. 1444, 1375.
Example 207 4-amino-5-(3-bromophenyl)-7-(2-oxobenzoxazolin-6-yl pyrido[2J-djpyrimidine
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 (7J4 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 m z 177).
Example 208 4-amino-5-(3-bromophenyl>7-π-methyl-2-oxobenzoxazolin-6-vP- pyrido~2.3-d1pyrimidine 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, 14J 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 NaHCO3 was added and the aqueous layer was extracted with CH2C12. The desired product (2.55 g, 94%, LRMS m z 191), was isolated following flash chromatography (SiO2, EtOAc- CH2C12).
Example 209 4-amino-5-((5-chloro-2-(3-methoxyphenyl)pheny0methyl -7-(4- dimethylaminophenyl)pyridor2J-dlpyrimidine
The title compound was prepared from the compound of Example 173 by reaction with 3 -methoxypheny lboronic acid, Pd(PPh3)4 and aqueous sodium carbonate under Suzuki reaction conditions. IR (KBr) 3550-3250.3240- 2760J580J560J540J350; H. Res. MS m z 496J902 (M+H)*.
Example 210 4-amino-5-((2-bromophenvπmethvπ-7-(4-dimethylaminophenvπpyrido[2J-dlpyrimidine
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 imgf000154_0001
Example 211 4-amino-5-(2-((thiophene-2-yl)phenyl)methyl -7-(4-diethylaminophenyl)pyrido[2J- djpyrimidine 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 methvπ-7-(4-diethylaminophenvπpyridor2J- 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 imgf000155_0001
Figure imgf000156_0001
Figure imgf000157_0001
**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 imgf000157_0002
Figure imgf000158_0001
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 imgf000159_0001
Example 229
4-amino-5-(3-bromophenyl)-7-(4-(ureido phenyl)pyrido[2J-d1pyrimidine
A solution of 4-amino-5-(3-bromophenyl)-7-(4-aminophenyl)pyrido[2,3- djpyrimidine (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 NaHCO3. 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-amino-5-(l-phenylmethyl-3-piperidinyl)-7-(4-diethylaminophenvπpyrido[2J- dlpyrimidine Following the procedures of Example 157, except substituting 1 -(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 m/z 467 (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. Some compounds were isolated as the TFA salt following purification via high pressure liquid chromatography (HPLC).
Table 10 Examples 231-243
Figure imgf000161_0001
Figure imgf000162_0001
Figure imgf000163_0001
the cyclization step Example 244 4-amino-5-(3-bromophenyl)-7-(l-methyl-5-indolinyl)pyrido[2.3-d1pyrimidine dihydrochloride
A sample of 4-(3-bromophenyl)-3-cyano-6-(l-methyl-5-indolinyl)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/CH2Cl2 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" ) 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-l-methylindoline
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+Hj+.
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 J 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 [M+H]*.
244c. 4-("3-bromophenyl -3-cyano-6-( 1 -methyl-5-indolinyl)pyridine-2-amine Prepared by condensation of l'J'-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. 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-amino-5-(3-bromophenyl)-7-(l -methyl-5-benzimidazolyl)pyrido[2J-d]pyrimidine tetrahydrochloride
The title compound was prepared according to the procedure of Example 1 , except substituting 1 -methy 1-5 -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 m/z 431/433, 431.0605 (M+H)*.
Example 246
4-amino-5-(3-bromophenvπ-7-(6-dimethylamino-3-pyridazinvπpyrido[2J-djpyrimidine tetrahydrochloride 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 concentrated 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(PPh,) , 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, concentrated in vacuo. and purified by flash chromatography to give 6.3 g (21%) of the title compound. MS {M + ]+ 213, 215.
246b. 1 -(6-chloropyridazin-3-vPethanone
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 concentrated in vacuo to give a yellow solid. 4.7 g.
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 CH2C12 and water. The organic phase was dried over CH2C12 , and concentrated in vacuo to give the title compound. 246d. 3-acetyl-6-(dimethylamino)pyridazine
The title compound was prepared by condensing lJ -dicyano-(3-(3- bromophenyl)propene (the R" 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[2J- djpyrimidine tetrahydrochloride
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 11A below, compounds of Examples 247-248 were prepared.
Table 11A Examples 247-248
Figure imgf000167_0001
Figure imgf000168_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 249-251 were prepared. In some cases, the hydrochloride salts were not prepared.
Table 11B Examples 249-260
Figure imgf000168_0002
Figure imgf000169_0001
Example 252
4-amino-5-(3-bromophenyl -7-(5-(T .N-bisf2-methoxyethyl)amino)-2- pyridinyl)pyrido[2.3-d]pyrimidine trihydrochloride
Step 252a. 1 -(5-bromo-2-pyridyl)ethanone. ethylene ketal
A solution of dibromopyridine (5.2 g, 21.95 mmol), tributyl( 1 -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 concentrated, and the crude product was purified by elution through a short column of silica gel. The resulting enol-ether compound, ethvlene glycol (2.79 g, 45 mmol), and p- toluene sulfonic acid (0J 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 NaHCO,, and the aqueous layer was extracted with CH2C12. The combined organic layer was dried (Na2SO4), concentrated 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-methoxyethvDamino)-2-pyridvDethanone
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 CH2C12. The combined organic layer was concentrated 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 extracted with CH2CI2. The combined organic layer was dried, concentrated 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-methoxyethv0amino")-2- pyridinvDpyrido [2.3 -dlpyrimidine trihydrochloride 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 m/z 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 11 B 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 imgf000171_0001
Figure imgf000172_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-dimethylaminoN)phenylpyrido[2J-dlpyrimidine The compound was prepared by using the method generally described above in Scheme 3 and the associated examples using 1 -(4-dimethylaminophenyl)ethanone as the R4 reagent (7-position) and nicotinaldehyde as the R3 reagent (5-position). IR (cm-1) 3305.8. 2922, 1606, 1578, 1535, 1360. MS (M+H) 342.
Example 262 4-Cmethylamino -5-(3-bromophenvπ-7-(4-dimethylaminophenyl)pyrido[2.3-dlpyrimidine hydrochloride
The title compound was prepared by using the method described in Example 200, except substituting methylamine for the 2-(dimethylamino)ethylamine thereof. MS (M+H), 478 (IBr); IR (cm-1) 3455, 3047, 2959, 1580, 1351, 1234.
Example 263
4-(2-methoxyethylamino)-5J3-bromophenyl)-7-(4- dimethylaminophenvDpyrido^J-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-methyl-2-imidazolyl)phenyl pyrido[2.3-djpyrimidine trihydrochloride
Step 264a. 1 -(4-( 1 -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. ZnC-2 (20 mL' 0 M so tion in Et2O, 20 mmol) was added, and the solution was warmed to 25°C. To this solution was added Pd(PPl-3) (70 mg, 0.06 mmol) followed by 4-iodoacetophenone ethvlene 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 CH2CI2, 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 neutralized by the addition of saturated aqueous NaHCO3, and the aqueous layer was extracted with CH2G2. The combined organic layer was dried (MgSO j.) 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-( 1 -methyl-2-imidazolyl)phenvDpyrido[2,3- djpyrimidine trihydrochloride 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 imgf000175_0001
Example 268 4-amino-5-(3-bromophenyl)-7-(4-(3-fdimethylamino propynyl)phenyl)pyrido[2J- 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-l) 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 imgf000176_0001
Example 272 4-amino-5-(3-bromophenyl)-7-(4-carboxypheny0pyrido[2, -djpyrimidine A solution of 4-amino-5-(3-bromophenyl)-7-(4-cyanophenyl)pyrido[2,3- djpyrimidine (the compound of Example 37, (0.47 g, 1J7 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 (0J4 g, 28%). MS (M+H), 422 (IBr); IR (cm-1) 3064. 2628, 1692, 1403, 1273. Example 273 4-amino-5-(3-bromophenyl)-7-(4-methyl-3-oxo-2H-4H-pyrido[3.2-bl-lJ- oxazinyl)pyrido[2J-d1pyrimidine
Step 273a. 7-acetyl-2H-pyridor3.2-b1-1.4-oxazin-3f4HVone
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 THF/MeOH (5: 1) was treated with 0.4 mL of concentrated HCl (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 NaHSO3- The aqueous layer was extracted with CH2CI2 and the combined organic layer was dried
Figure imgf000177_0001
concentrated 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 (6J g, 17 mmol), Pd2(dba)3 (0.5 g, 0.56 mmol), and (2-fiιryl)3P
(0.3 g, 1.2 mmol) in 30 mL of toluene/THF (5:1) was warmed at reflux for 10 hours. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in 50 mL of THF. 15 mL of 4 M HCl (aqueous) was added, and the mixture was stirred for 4 hours at 25 °C. The solution was neutralized by the addition of NaHCO3 (aqueous), and the aqueous layer was extracted with CH2CI2. The combined organic layer was dried
(Na2SO4), 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+H), 463 (1 Br); IR (cm-1) 3400, 3200-2800, 1700, 1640, 1605, 1590, 1395, 1380, 1345.
Step 273b. 7-acetyl-4-methyl-2H-pyrido[J.2-bl-lJ-oxazin-3(4H -one
The compound from step 273 a was treated 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 extracted with dichloromethane. and the resiue was purified by chromatogaphy to give the title compound. MS (M+H), 407.
Step 273c. 4-amino-5-(3-bromophenvn-7J4-methyl-3-oxo-2H-4H-pyrido[3.2-bl-l ,4- oxazinv0pyrido[2J-d]pyrimidine
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+H), 463 (1 Br); IR (cm-1) 3400, 3200-2800, 1700. 1640, 1605, 1590, 1395, 1380, 1345.
Example 274 4-amino-5-(3-bromophenvπ-7-(4-("2-(dimethylamino)ethyl)-3-oxo-2H-4H-pyrido[3.2-bl- l,4-oxazin-7-yl pyrido[2J-djpyrimidine
Step 274a. 7-acetyl-4-dimethylaminoethyl -2H-pyrido[3.2-bj-l,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 extracted 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- pyridor3.2-b1-l,4-oxazin-7-yl)pyrido[2J-d1pyrimidine 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+H), 519 (1 Br); IR (cm-1) 3440. 1685, 1630, 1605, 1580, 1395 Example 275 4-amino-5-(3-bromophenyl)-7-(2J-dihvdro-3-(dimethylaminoethyl)-2-oxobenzoxazol-6- yl)pyrido[2. -djpyrimidine
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-bj-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 treated with 2-chloro-(N,N- dimethyl)ethylamine HCl and K2CO3 in aqueous acetone at reflux. The mixture was diluted with water and extracted with dichloromethane, and the residue was purified by chromatogaphy to give the title compound.
Step 275c. 4-amino-5-f3-bromophenyl)-7-(2J-dihvdro-3-(dimethylaminoethyl -2- oxobenzoxazol-6-yl)pyrido"2, -d1pyrimidine
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+H), 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 J-oxazin-7-vπpyrido[2J- dlpyrimidine
Step 276a. 6-acetyl-3-methyl-2-benzoxazolinone
The compound from Example 275 Step a was treated 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 extracted with dichloromethane, and the resiue was purified by chromatogaphy to give the title compound.
Step 276b. l-0-hvdroxy-4-methylaminophenyl -ethanone
The compound from Step 276a (1.60 g, 8.37 mmol) was dissolved in acetone (70 mL) and treated with IM aqueous K2CO3 solution (25 mL) with heating at reflux overnight. The mixture was neutralized with acid, then extracted 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-1.4-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-f3-bromophenyl -7-(4-methyl-3-oxo-2H-H-benzo-l J-oxazin-7- yl)pyrido~2J-djpyrimidine
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-(2,2J-trimethyl-3-oxo-2H-4H-benzo-l J-oxazin-7- yl)pyrido[2.3-d1pyrimidine
Step 277a. 7-acetyl-2.2.4-trimethyl-2H-4H-benzo-l J-oxazin-3-one
The compound from Step 276b (2.25 g, 9 mmol) was dissolved in DMSO and treated 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 extracted with ether.ethyl acetate. 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 (1.33 g) MS (M+H), 234.
Step 277b. 4-amino-5-(3-bromophenyl -7-(2.2,4-trimethyl-3-oxo-2H-4H-benzo-l ,4- oxazin-7-yl)pyrido["2.3-djpyrimidine
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 the 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, 1165.
Example 278
4-amino-5-cvclohexyl-7-(4-(2-dimethylamino)ethyl)-2H-4H-benzo-3-oxo-l,4-oxazin-7- yl)pyridor2,3-d1pyrimidine Step 278a. 1 -(3-hvdroxy-4-(2-(dimethylamino)ethyl)phenyl)-ethanone
A sample of 6-acetyl-3-(dimethylaminoethyl)r2-benzoxazolinone (from Example 275 Step b) was dissolved in acetone and treated with 1 M aqueous K2CO3 solution with heating at reflux overnight. The mixture was neutralized with acid, then extracted with diethyl ether. The solvent was dried (MgSO ) and removed under vacuum to give the title compound.
Step 278b. 7-acetyl-4-(dimethylamino ethvD-2H-4H-benzo-l ,4-oxazin-3-one
A sample of the compound from Step 278a (8.94 g, 32 mmol) was dissolved in DMSO and treated 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 extracted 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-cyclohexyl-7-(4-(dimethylamino ethyl)-2H-4H-benzo-3-oxo-l ,4- oxazin-7-yl)pyrido[2.3-dlpyrimidine
Following the procedures of Example 244 Step c, except in step c first substituting lJ-dicyano-3-cyclohexylethene (prepared according to the 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 title compound was prepared. MS (M+H) 447; IR(cm-l) 3400. 2900. 1690, 1610, 1590, 1395. Example 279 4-amino-5-(3-bromophenvπ-7-(5-(l-methylethvπ-2-pyridvπpyridor2J-dlpyrimidine
Step 279a. l-(5-methvethyl-2-pyridyl)ethanone A solution of 2-acetyl-5-bromopyridine (1.45 g, 7.9 mmol), 2-propenyltrimethyltin
(1.77 g, 8.7 mmol), Pd2(dba)3 (0.33 g, 0.36 mmol), and tri-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 concentrated 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 atmoshpere of H2. The reaction mixture was filtered and the resulting solution was concentrated 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-methylethvπ-2-pyridyl)pyrido[2J- djpyrimidine
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 dichloroethane as the solvent in place of the ethanol solvent in Example 244 step c, the title 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 the 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 imgf000184_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-formylamino)methyl)phenyl)pyridor2J- dlpyrimidine
Step 282a. 4-cvanoacetophenone. 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 title compound.
Step 282c. l-(4-(BOC-aminomethyl phenyl)ethanone
The compound from Step 282b (1J8 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 (2J8 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 extracted with ether and ethyl acetate. The organic extracts were dired (MgSO4), and the solvent was remove under vacuum to give the title compound.
Step 282d. 4-amino-5-(3-bromophenyl)-7-(4-(N-formylamino)methyl)phenyl)pyrido[2J- 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 the solvent in place of the ethanol solvent in Example 244 step c. the title 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-rN-methylamino -l-methylethyl)phenyl)pyrido[2J- dlpyrimidine Step 283a. 4-(l -amino- l-methylethyl)acetophenone
CeCl, (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 stirred 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 extracted with dichloromethane. The solution was dried (MgSO4), and the solvent was removed to give the title compound.
Step 283b. 4-(l-fN-BOC-amino)-l-methylethvπacetophenone
The compound from Step 283a (2.32 g, 8.77 mmol) was treated 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-bromophenyl)-7-(4-(l-rN-formylamino)-l- methylethyl)phenyl pyrido[2,3-djpyrimidine
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 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) 3440, 1640. 1605. 1580, 1380.
Example 284
4-amino-5-(3-bromophenyl)-7-(4-(l-(N.N-dimethylamino)-l- methylethyl)phenvDpyrido[2.3-djpyrimidine Step 284a. 4-( 1 -(dimethylamino - 1 -methylethyl)acetophenone
The compound from Step 283a (1 J8 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 neutralized with 2N Na3CO3. The mixture was extracted 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 the procedures of Example 157, except substituting the 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 imgf000187_0001
Figure imgf000188_0001
Examples 287-300 Following the procedures of Example 157, except substituting the appropriate R3 and R4 reagents as indicated in the 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 the 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 imgf000188_0002
Figure imgf000189_0001
Figure imgf000190_0001
Figure imgf000191_0001
Figure imgf000192_0001
* The 1 , 1 -dicyano-3-cyclohexylethene was prepared according to the 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.
The reagents for the following examples were prepared by this method susbstituting the compound shown below for the cyclohexane carboxaldehyde used to prepare the reagent of Example 290.
Example 292, tetrahydropyran-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 the Table below to prepare the correct R4 reagent, and substituting the 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 ethanol and dimethoxyethane.
Examples 301-305
Figure imgf000193_0001
Figure imgf000194_0001
Figure imgf000195_0001
Example 306 4-amino-5-cvclohexyl-7-(6-(4-acetylpiperazinyl)-3-pyridyl pyridor2J-d]pyrimidine 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% methanol 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 imgf000195_0002
Figure imgf000196_0001
Figure imgf000197_0001
Figure imgf000198_0001
Figure imgf000199_0001
Example 323 4-amino-5-(l-(2-bromophenyl)ethyl)-7-(l-methyl-5-indolyl pyrido[2J-dlpyrimidine The procedures of Example 157 were followed, except substituting l'J'-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 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 the product was recrystallized if necessary. The treatment with aqueous HCl was omitted, and the free bases was obtained. IR (KBr) cm'1 3500, 1578, 1500; MS m z 431 (M+H)*.
Example 324 4-amino-5-(l-(2-bromophenyl)ethyl)-7-(l-methyl-2J-dioxo-5-indolvπpyrido[2J- dlpyrimidine The title compound was prepared from the compound of Example 323 by oxidation with CrO3 in sulfuric acid. IR (microscope) 3471, 1765, 1500 cm"1; MS m/z 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- 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 in some cases, and the free bases were obtained.
Examples 325-326
Figure imgf000200_0001
Figure imgf000201_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 ethanol 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 imgf000201_0002
Example 328 4-amino-5-f3-bromophenyl)-7-(6-(4-oxopiperidinyl)-3-pyridvπpyridor2.3-d1pyrimidine Treating the compound of Example 327 with dilute HCl, the title compound was prepared. IR (microscope) 3438. 3051, 1645. 1605. 1558. 1450. 1371. 1240 cm"1; MS m/z 475 (M+H)*. Examples 329-331 Following the procedures of Example 327, except in step c substituting 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 imgf000202_0001
Example 332 4-amino-5-(3-bromophenyl -7-(6-(4.4-dioxothiomoφholinyl -3-pyridyl')pyrido[2J- dlpyrimidine The compound of Example 331 was treated with 4-chloroperbenzoic acid in methanol and dichloromethane to give the title compound. IR (microscope) 3471, 1601, 1581, 1562, 1510, 1353, 1316, 1285, 1 122 cm"1; MS m/z 511(M+H)*.
Example 333 4-amino-5-(2-bromophenyl)-7-(6-moφholinyl-3-pyridyl)pyrido[2.3-d]pyrimidine
Step 333a. JJ'-dicvano-2-bromostyrene
The title 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-chloroρyridine with moφholine in refluxing ethanol.
Step 333c. 4-(2-bromophenyl)-3-cvano-6-moφholinylpyridine-2-amine
The title compound was prepared by condensation of l'J'-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- djpyrimidine
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 extracted from the filtrate. The product was purified by column chromatography eluting with 10% MeOH/CH2Cl2. IR (microscope) 3493, 1547, 1 109cm" 'j MS m/z 464 (M+H)*.
Examples 334-336 Following 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 imgf000204_0001
Figure imgf000205_0001
Example 337 4-amino-5-(3-bromophenyl)-7-(5-chloro-6-moφholinyl-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-acetyl-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-moφholinylpyridine 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 m/z 497 (M+H)*.
Example 338 4-amino-5-f3-bromophenyl)-7-(6-CN-oxidomoφholinyl)-3-pyridv0pyrido[2J- d] pyrimidine
The title compound was prepared by treating the compound of Example 134 with hydrogen peroxide in acetic acid according to standard procedures. IR (microscope) 3486, 1579, 1552, 1353, 1121, 1020 cm"1; MS m/z 479 (M+H)+.
Example 339 4-amino-5-(3-bromophenyl)-7-f6-(N-(2-hvdroxyethoxyethyl amino -3-pyridvπpyrido[2J- dlpyrimidine
Step 339a. rJ'-dicyano-3-bromostyrene
The title 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 title compound was prepared by the reaction of 5-acetyl-2-chloropyridine with 2-ethoxyethylamine in refluxing ethanol.
Step 339c 4-(3 -bromophenyl -3 -cvano-6-πs"-(2-ethoxyethyl)amino)pyridine-2-amine The title compound was prepared by condensation of 1 'J '-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 339d. 4-amino-5-("2-bromophenyl)-7-(6-(N-(2-ethoxyethyl)amino)-3- pyridyl pyrido[2J-d]pyrimidine
A sample of the compound from Step 239d was treated according to the procedure of Example 233d to give the title compound. IR (microscope) 3301, 1610, 1579, 1543,
1346, 1304, 1 120 cm"1; MS m/z 481 (M+H)J
Example 340 4-amino-5-(3-bromophenyl)-7-('6-fN-(2-hvdroxyethoxyethyl)-N-formylamino)-3- pyridyl pyrido[2.3-d]pyrimidine 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-bromophenyl)-7-(6- N-(2-hvdroxyethoxyethyl)-3-pyridyl-N- oxide)pyrido[2.3-djpyrimidine
The title 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, 1411, 1353 cm"1; MS m/z 497 (M+H)*.
Example 342
4-amino-5-f3-bromophenylV7-(6-(4-hvdroxypiperdinviy3-pyridvDpyridor2J- dlpyrimidine The title compound was prepared from the compound of Example 328 by reduction with (Lithium Aluminum Hydride, and subsequent workup acccording to standard procedures). IR (microscope) 3349, 1510, 1 116 cm"1 ; MS m/z 478 (M+H)*.
Example 343 l-(5-f4-amino-5-(3-bromophenyl)pyrido[2J-d1pyrimidin-7-vO-2-pyridylVpiperidine-4- phosphate. disodium salt The title compound was prepared from the compound of Example 342 by treatment with POCl3, and subsequent workup acccording to standard procedures. IR (microscope) 3498, 1500, 1444 cm"1; MS m/z 556 (M+H)*. Example 344 4-amino-5-(3-bromophenyl)-7-(6-(2-hvdroxy)moφholinvI -3-pyridyl)pyrido[2J- dlpyrimidine The title 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 the title compound. MS m/z 492 (M+CH3OH-H2O)*.
Example 345 4-amino-5-β-bromophenv0-7-(4-methylenylpiperidinvD-3-pyridyl)pyrido[2,3- dlpyrimidine 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 extracted, then purified by chromatography. IR (microscope) 3055, 1602, 1559, 1508, 1440, 1344, 1174 cm"1; MS m z 473 (M+H)+.
Example 346 4-amino-5-('3-bromophenyl)-7-(4-hvdroxy-4-(hvdroxymethyl piperidinyl')-3- pyridyl)pyridor2J-d]pyrimidine
The title compound was prepared from the compound of Example 345 by treatment with OsO4 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 m/z 507 (M+H)+.
Example 347 4-amino-5-(cvclohexyl)-7-(6-(4,4-ethylenedioxypiperidinyl)-3-pyridyl')pyrido[2.3- dlpyrimidine
Step 347a. l J-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 treating 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 title compound.
Step 347c. 4-amino-5-cvclohexyl-7-(6-(4,4-ethylenedioxypiperidinvI>3- pyridvDpyrido [2,3 -dlpyrimidine
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 title compound was prepared. IR (microscope) 2929, 1604, 1585, 1557, 1514, 1426, 1344,
1238, 1106 cm 1; MS m/z 447 (M+H)*.
Example 348 4-amino-5-cvclohexyl-7-(6-(4-oxo-piperidinyl)-3-pyridyl pyrido[2J-d]pyrimidine The title compound was prepared from the compound of Example 347 by treatment with dilute HCl in ethanol. The title compound was purified by chromatography. IR (microscope) 2928, 1715, 1603, 1585, 1559, 1507, 1344, 1226 cm"1; MS m/z 403 (M+H)+.
Example 349
4-amino-5-cvclohexyl-7-('6-(4-methylenylpiperidinyl)-3-pyridvπpyridor2.3-d1pyrimidine
The title 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 extracted, then purified by chromatography. IR (microscope) 2929, 1604. 1584. 1557. 1506, 1342. 1239 cm"1; MS m/z 401 (M+H)*.
Example 350 4-N-(iminomethvπamino-5-cvclohexyl-7-(6-dimethylamino-3-pyridyl)pyrido[2.3- dlpyrimidine This compound was isolated from the reaction mixture of Example 293 as a side product: IR (cm-1) 3289, 3089, 2930. 2841, 1674, 1606, 1559. 1531. LRMS [M+HJ+ m/z 376.
Example 351 (S)-4-amino-S-(3-bromophenyl)-7-(6-(O-methyl-2-hvdroxymethylpyrrolidinyl)-3- pyridiny0pyrido[2J-dlpyrimidine Prepared as described for Examples 2-156; using (S)-l-(6-(O-methyl-2- pyrrolidinemethanol)-3-pyridinyl)ethanone as R4 reagent (for position 7) and 3- bromobenzaldehyde for R3 reagent (for 5-position). MS (ESI(+)) 489/491 (M+H*; 79Br/81Br); IR (KBr pellet) vma„ 3484, 3203, 1603, 1581, 1556 cm"1.
Example 352
(S)-4-amino-5-(3-bromophenvD-7-(6-(2-hydroxy ethylpyrrolidinyl)-3- pyridinvDpyrido"2. -d]pyrimidine Prepared as described for Examples 2-156; using (S)-l-(6-(2-pyrrolidinemethanol)- 3-pyridinyl)ethanone as R4 reagent (for position 7) and 3 -bromobenzaldehyde for R3 reagent(for 5-position).
MS (ESI(+)) 477/479 (M+H*; 7 Br/81Br);
IR (KBr pellet) vmax. 3487, 3303. 3208, 2949, 1605, 1577. 1558, 1510, 1415, 1351 , 1244,
1 158. 828, 704 cm"1.
Example 353 4-amino-5-(2-bromophenvπ-7-(6-(4-hvdroxypiperidinyl)-3-pyridinyl)pyrido[2J- dlpyrimidine Prepared as described for Examples 2-156. using l-(6-(4-hydroxypiperidine)-3- pyridinyl)ethanone as R4 reagent (for position 7) and 2-bromobenzaldehyde for R3 reagent(for 5-position).
MS (ESI(+)) 477/479 (M+H*; 79Br/81Br);
IR (KBr pellet) vma 3485, 3298, 3198. 2938, 2848, 1600, 1574, 1557, 1351, 1225,1024,
766 cm"1.
Example 354
4-amino-5-f4-fluorophenviy7-(6-(4J-ethylenedioxypiperidinyl)-3-pyridinv0pyrido[2J- dlpyrimidine Prepared as described for Example 327: using 4-fluorobenzaldehyde instead of 3- bromobenzaldehyde as precursor reagent as described in example 244 Step C. MS (ESI(+)) 459 (M+H)*;
IR (KBr pellet) vmax 3487, 3299, 3066, 1959, 1604, 1577, 1559, 1510, 1355, 1235, 1107, 943, 897, 792 cm"1.
Example 355 4-amino-5-(2-bromophenyl)-7-f6-(4-hvdroxypiperidinyl)-3-pyridazyl pyrido[2J- dlpyrimidine Prepared as described for Examples 301-305, using 4-hydroxypiperidine as reagent for Step C (to prepare correct R4 reagent). MS (ESI(+)) 478/480 (M+H*; 79Br/81Br); IR (KBr pellet) vmax 3487, 3312, 1576. 1549, 1486, 1353, 1081 cm"1.
Example 356 4-amino-S-f3-bromophenyl)-7-(6-(4.4-ethylenedioxypiperidinyl)-3-pyridazyl)pyrido[2.3- dlpyrimidine Prepared as described for Examples 301-305; using 4-piperidinone ethylene ketal as reagent for Step C (to prepare correct R reagent).
MS (ESI(+)) 520/522 (M+H*; 79Br81Br);
IR (KBr pellet) vma 3476. 3297. 1574, 1561, 1461, 1354, 1 145. 1 103 cm"1.
Example 357
4-amino-5-(3-bromophenyl -7-(2-morpholinyl-5-thiazovπpyrido[2J-d]pyrimidine A solution of the product from 357d (2.49 g, 5.30 mmol) in o-dichlorobenzene (15 mL) was heated to reflux overnight. The reaction mixture was cooled to room temperature, the solid collected by filtration and purified by silica gel chromatography (elution with 3% methanohdichloromethane) to provide 1.06 g (43%) of the desired title product as a yellow solid, mp: >280 °C; MS (DCI/NH3) m z 469/471 (M+H)*; IR (microscope) 3481, 2046. 1506, 1491, 1116 cm 1.
357a: 2-moφholinylthiazole 2-bromothiazole (12.63 g, 77.00 mmol) in moφholine (30.0 mL) was sealed into a tube and heated to 100 °C for 3 days. The mixture was cooled, partitioned between water and dichloromethane, the layers separated and the organic phase dried (Na2SO4) and concentrated to afford 12.5 g (95%) of the desired compound as a brown oil. Material used directly in the next reaction. MS (DCI/NH3) m z 171 (M+H)*.
357b: 5-acetyl-2-moφholinylthiazole
A solution of the product from Example 357a (7.20 g, 42.3 mmol) in tetrahydrofuran (80 mL) at -78 °C was treated with N-BuLi (2 M in hexanes. 23.5 mL). After 30 minutes, the reaction mixture was transferred via cannula to a solution of acetic anhydride (10 mL) in tetrahydrofuran (50 mL) at -60 °C and stirred for 1 hour. The slurry was then warmed to room temperature for an additional 30 minutes, quenched with saturated sodium bicarbonate and extracted with diethyl ether. The organic phase was dried (Na2SO4), concentrated and purified by silica gel chromatography (elution with 50% dichloromethane/ethyl acetate) to provide 3.70 g (41%) of the desired compound. MS (DCI/NHJ m/z 213 (M+H)*. 357c: 4-(3-Bromophenviy3-cvano-6-(2-momholinethiazolo)pyridine-2-amine
A slurry of the product from 357b (4.91 g, 23J mmol) and ammonium acetate (9.75 g. 127 mmol) in 1,2-dichloroethane (50 mL) was treated with 2-(3- bromobenzylidene)malononitrile (10.78 g, 46.3 mmol; J. Am. Chem. Soc. 1949, 71, 2949) and the mixture heated to reflux overnight. The solution was cooled to room temperature, hexanes (50 mL) added and stirring continued for 3 hours. The solid was collected by filtration, washed with methanol and dried to provide 4.57 g (45%) of the desired material as an orange solid. MS (DCI/NH3) m/z 442/444 (M+H)*.
357d: 4-(3-Bromophenyl)-3-cvano-6-(2-morpholinethiazolo)pyridine-2-amidine
A solution of the product from 357c (1.50 g, 3.39 mmol) and triethylorthoformate (34 mL) with a catalytic amount of ammonium sulfate was heated to reflux for 6 hours. The dark mixture was cooled, ammonia in ethanol (2 M, 70 mL) added and the mixture stirred overnight. The solid product was collected by filtration and dried to provide 1 J 7 g (73%) of the desired product as a yellow solid. MS (DCI/NH3) m/z 469/471 (M+H)*.
Example 358 4-amino-5-(N-methyl-3-indolyl)-7-(6-moφholinyl-3-pyridinyl)pyrido[2J-d]pyrimidine Prepared as described for Examples 2-156; using l-(6-moφholinyl-3- pyridinyl)ethanone as R4 reagent (for position 7) and N-methylindole-3 -carboxaldehyde for R3 reagent (for 5-position). MS (DCI/NH3) 438 (M+H)*; IR (mic) 3453, 1641, 1556, 1244, 1120 cm"1.
Example 359 4-amino-5-(3-bromophenyl)-7-(6-(4-ethoxyiminopiperidinvπ-3-pyridinvπpyrido[2J- dlpyrimidine A suspension of Example 328 (282 mg. 0.593 mmol) in absolute ethanol (3 mL) was treated sequentially with ethoxyamine hydrochloride (64 mg, 0.65 mmol), and 2 drops cone. aq. HCl. heated to reflux 1.5 hours, cooled and partitioned, between CH2C12 (25 mL) and saturated NaHCO3 (15 mL). The separated aqueoμs phase was extracted with CH2C12 (1 x 10 mL), and the combined organic layers were washed with brine, dried (Na2SO ), and concentrated in vacuo. The crude product was purified by flash chromatography eluting with 5% MeOH/CH2Cl2 to yield 240 mg (78%) of the designated, compound.
'H NMR (300 MHz, DMSO-d6) δ 1.19 (t, 3H), 2.41 (m, 2H). 2.58 (m, 2H), 3.77-3.86 (m, 4H), 4.02 (q, 2H), 6.99 (d, IH), 7.50-7.60 (m, 2H), 7.79 (dt, IH), 7.85 (m. 2H), 8.47 (dd, IH), 8.5 3 (s, lH), 9.08 (d, IH); MS (DCI/NHj) m/e 518/520 (M+H)*; Anal, calcd for C25H24BrN7O: C, 57.92; H, 4.67; N, 18.91. Found: C, 57.69; H, 4.66; N, 18.65.
Example 360 4-amino-5-(3-bromophenyl)-7-(6-('4-ethylcarbomethoxyiminopiperidinyl)-3- pyridinyl)pyrido[2.3-d1pyrimidine
Prepared as described for Example 359, substituting carbomethoxylamine for ethoxyamine.
Η NMR (300 MHz, DMSO-d6) δ 1.20 (t, 3H), 2.42 (m, 2H), 2.65 (m, 2H), 3.77-3.90 (m, 4H), 4.13 (q, 2H), 4.61 (s, 2H), 7.01 (d, IH), 7.55 (m, 2H), 7.79 (dt, IH), 7.86 (m, 2H), 8.48 (dd, IH), 8.53 (s, IH). 9.09 (d, IH); MS (DCI/NH3) m/e 576/578 (M+H)*;
Anal, calcd for C21H26BrN70-0.5 H20: C. 55.39; H, 4.65; N, 16.75. Found: C, 55.66; H, 4.61; N, 16.37.
Example 361 4-(N-(2J-dihvdroxypropy0amino)-5-(3-bromophenyQ-7-(6-moφholinyl-3- pyridinyl pyrido[2, -d1pyrimidine Example 134 formamide complex (200 mg, 0339 mmol) and 3-amino-l,2- propanediol (155 mL, 2.0 mmol) were placed in a 50 mL round-bottomed flask furnished with a magnetic stirbar. DMSO (dimethyl sulfoxide) (6 mL),was added. The mixture was then heated to 120 °C for about 10 min until a homogeneous solution was formed. Catalytic amount of acetic acid was then added, and the reaction mixture was allowed to stir at 120 °C for about 1.5 days. DMSO was removed under vacuum. The residue was dissolved in CH2C12, and washed with water. NaHCO, (saturated), water, and then dried over Na2SO4. The crude mixture was first purified by column chromatography (SiO2), 10% MeOH/CH2Cl2). The desired product was collected and was subjected to another column chromatographic purification (SiO2, ethyl acetate and then 25% NCCH3, 7.5% MeOH and 67.5% CH2CI2) to give a pure yellow solid (60 mg. 29% yield; M.P. 189-191 °C). MS (ESI(+)) = 537/539 (M+H)*; 79Br/81 Br; IR (MIC) vmax = 3433, 3354, 2914, 2853, 1568, 1506, 1236, 1 1 14, 945 cm"1.
Examnle 362
4-(N-(3-morpholinylpropyl)amino)-5-f3-bromophenyl)-7-(6-moφholinyl-3- pyridinyl)pyrido[2.3-dlpyrimidine Prepared as described for Example 360, but replacing 3-amino-l,2-propanediol with 4-(3-aminopropyl)moφholine.
MS (ESI(+)) = 590/592 (M+H*; 79Br/81Br;
IR (MIC): vmax = 3433, 2959, 2854, 1567, 1506, 1235, 1117, 945 cm"1.
Example 363 4-(N-(2-(4-imidazolyl')ethvπamino)-5-(3-bromophenyl)-7-(6-moφholinyl-3- pyridinyppyrido [2.3 -djpyrimidine Prepared as described for Example 360, but replacing 3-amino-l,2-propanediol with histamine.
MS (ESI(+)) = 557/559 (M+H*; 79Br/81Br); IR (MIC) vma = 3433, 3091, 2954, 2893, 2854, 1571, 1564, 1505. 1235, 1123, 944 cm"1.
Example 364
4-(N-f3-carboxypropyl)amino)-5-(3-bromophenvπ-7-(6-moφholinyl-3- pyridinyl)pyrido[2J-d]pyrimidine Prepared as described for Example 360. but replacing 3-amino-1.2-propanediol with 3-aminopropionic acid (β-alanine). MS (ESI(+)) = 53 5/537 (M+H*; 79Br/81Br);
IR (MIC) vma = 3429, 3051, 2959. 2855. 2528. 1927. 1718, 1585, 1559, 1352, 1332, 1236, 1 118, 944 cm"1.
Example 365 4-amino-5-(3-bromophenyl>7-f-6-(4-oxopiperidinyl)-3-pyridazinvDpyrido[2.3- dlpyrimidine Prepared as described for Example 328; substituting Example 356 for Example327.
MS (APCI+) m/z 475 (M+H)*;
Η NMR (300 MHz, DMSO-dJ δ 8.60(s, IH), 8.45(d, IH), 8.28(s, IH), 7.85 (m, 2H), 7.50 (m, 3H), 4J0 (m, 4H).
Example 366
4-amino-5-(3-bromophenyl)-7-(6-(4-moφholinyliminopiperidinyl )-3- pyridazinyl)pyrido[2J-d]pyrimidine Prepared as described for Example 359; substituting Example365 for Example328 and 4-aminomoφholine for ethoxylamine hydrochloride. MS (APCI+) m/z 560 (M+H)*;
Η NMR (300 MHz, DMSO-d6) δ 8.59(s, IH), 8.40(d, IH), 8.26(s. IH), 7.84 (m, 2H), 7.55 (m, 3H), 3.93 (m, 4H), 3.68 (m 4H). 2.75 (m, 2H), 2.63 (m, 4H), 2.47 (m, 2H)
Example 367 4-amino-5-(3-bromophenyl)-7-(6-(( 1 S.4S -2-oxa-5-azabicvclo[2.2.1 ]heptan-5-yl)-3- pyridazinyl'pyrido[2.3-d]pyrimidine stepa 4-amino-5-(3-bromo phenvπ-7-("6-chloro-3-pyridazinvD pyrido[2J-d]pyrimidine
Prepared by a modification of the method of Example 333 step C. a mixture of 22 mmol of 3-acetyl-6-chloropyridazine (Example 246). 26 mmol of 1 -(3-bromophenyl) 1,1- dicyanoethylene, and 110 mmol of ammonium acetate in 150 mL of dichloroethane was heated at reflux for an hour to give the intermediate amino cyanopyridine. which was purified by flash column chromatography. By a modification of the method of Example 287, the intermediate 2-amino-3-cyano-4-(3-bromo phenyl)-6-((6-chloro) pyridazin-3- yl)pyridine was heated in 40 mL of triethylortho formate with 1 mmol of ammonium sulfate for one hour. A 2M solution of ammonia in ethanol was added (30 mL) stirring, and after 14 hours, the solid amidine intermediate was collected by filtration and dried in vacuo. The amidine intermediate was then heated in 25 mL of 1.2-dichlorobenzene at 120 °C for two hours. On cooling, a precipitate was deposited. Ether was added, and the precipitate was collected by filtration, washed with ether and dried. M/z [M+Hj* C , 7H 10N6BrCl at 413 ,414,415.
Η NMR (CD3CO2D) δ 8.72 (d, J = 8.7 Hz. 1 H), 8.64 (s, 1 H). 8.48 (s, 1 H), 7.73 (d, J = 8.7 Hz, 1 H), 7.70 (t, J = 1.0 Hz, 1 H), 7.64 (dt, J = 8.1 , 1.0 Hz), 7.45 (dt, J = 8.1, 1.0 Hz, 1 H), 7.42 (m, IH).
4-amino-5-(3-bromophenyl)-7-(6-(l S,4S)-2-aza-5-oxa-bicvclo[2.2J]heptane)-3-
Pyridazinyl)pyrido[2,3-d]pyrimidine A solution of 0.73 mmol of 4-amino-5-(3'-bromo phenyl)-7-(6-(chloro) pyridaziN- 3-yl) [2,3-d] pyridopyrimidine (prepared in step a), 3J mmol of (l S,4S)-2-aza-5-oxa- bicyclo[2.2J]heptane (Aldrich Chemical Co.), and 2.4 mmol of potassium carbonate was heated at 120 °C in DMSO for 14 hours, then cooled and poured into 10 mL of water. The mixture was partitioned between dichloromethane and water, and the organic phase was dried (Na2SO4), and concentrated in vacuo to give the title compound. This material was recrystallized from chloroform/methanol and converted to the hydrochloride salt by lyophilization from 12 mL of 2.5 M HCl. mp 222-226 °C;
CHN calculated for C22H,8N7OBr(3.0 HCl): C 45.1 1. H 3.61, N 16.74; found: C 45.00, H
3.90, N 16.82. MS [M+H]+ at 478;
IR 3434.3056, 1640, 1610.1558.1376 cm"1.
Example 368 4-amino-5-(3-bromophenvD-7-(6-(4-methoxyiminopiperidinyl )-3-pyridazinyl)pyrido[2.3- dlpyrimidine . Prepared as described for Example 359 substituting Example 365 for Example328 and methoxylamine hydrochloride for ethoxylamine hydrochloride. MS (ESI+) m/z 504 (M+H)*;
Η NMR (300 MHz, DMSO-d6) δ 8.59(s, IH), 8.40 (d, IH), 8.26(s, IH), 7.82 (m, 2H), 7.54 (m. 3H), 3.90 (m, 4H). 3.77 (s, IH), 2.62 (m, 2H), 2.47 (m, 2H)
Example 369 4-amino-5-("3-bromophenyl)-7-(6-phenylmethoxy-3-pyridazinyl)pyrido[2J-d1pyrimidine Sodium and benzyl alcohol were heated at 60 °C in toluene for 3 hours. It was cooled to room temperature and added to a suspension of 4-amino-5-(3-bromo phenyl)-7- (6-chloro-3 -pyridazinyl) pyrido[2,3-d]pyrimidine (prepared in Example 367) in anhydrous DMSO to give the title compound. Treatment with IM HCl ether in chloroform and methanol at room temperature provided the HCl salt. MS (ESI+) m/z 485 (M+H)+;
Η NMR (300 MHz, DMSO-d6) δ 10.07 (bs, IH), 8.95 (s, IH), 8.59 (d, IH), 8.50 (s, IH), 7.95-7.30 (m, 10H), 5.63 (s, 2H)
Example 370 4-amino-5-('3-bromophenyl)-7-(6-(4-methoxypiperidinyl)-3-pyridyl)pyridor2J- dlpyrimidine Step a 2-amino-3-cvano-4-(3-bromophenyl)-6-(6-chloro-3-piridyl)pyridine
Prepared as described in Example 244 substituting 5-acetyl-2-chloropyridine for 5- acetyl-1-methylindoline in step c.
Step b 4-amino-5-(3-bromophenyl)-7-(6-chloro-3-pyridvDpyrido[2.3-d1pyrimidine
2-Amino-3-cyano-4-(3-bromophenyl)-6-(6-chloro-3-piridyl)pyridine prepared in step a was reacted with 10 eq. of N.N*,N"-methylidynetrisformamide in formamide at 125° for 3 days. The slurry was cooled, poured into 3 volumes of water, and the resulting solid was collected by filtration and washed with water. The chloropyridyl product was dried under vacuum and used without further purification. -
step c 4-methoxypiperidine 4-Hydroxypiperidine is treated with 1 eq. of Boc2O in CH2C12 and stirred at room temperature for 5 min. The solution is then washed with water and brine, dried over Na2SO4, and concentrated in vacuo. The protected species is then dissolved in DMF and treated with 7 eq. of NaH. The mixture is stirred for 5 min. then methyl iodide (2 eq) is added, and the reaction is stirred at room temperature overnight. After this time, it is quenched with water and extracted with 2:1 ether-hexanes. The organic solution is dried (Na2SO4) and concentrated in vacuo. The oil thus obtained is finally stirred in 4M HC1- dioxane for 30 minutes. The solvent was removed in vacuo, then the residue was basified with 50% aq. NaOH solution and extracted with ether. Drying (Na2SO4) of the extracts, followed by removal of the solvent in vacuo, afforded 4-methoxypiperidine.
Step d.
3.0 equivalents of 4-methoxypiperidine (step c) and 1 equivalent of 4-amino-5-(3- bromophenyl)-7-(6-chloro-3-pyridyl)pyrido[2,3-d]pyrimidine (step b) were stirred in DMSO at 100° for 16 hours. The mixture was cooled, quenched with 3 volumes of water, and the precipitated solid was collected by filtration and washed with water. Purification by recrystallization afforded the title compound. Η NMR (300 MHz, d6-DMSO) δ 9.05 (d, IH), 8.52 (s, IH), 8.42 (dd, 1 H), 7.84 (d, IH), 7.83 (s, IH), 7.78 (dt, IH), 7.54 (2 overlapping m, 2H), 6.99 (br d, IH), 4.07 (m, 2H), 3.45 (m, 2H), 3.36 (m, IH), 3.29 (s, 3H), 1.92 (m, 2H), 1.46 (m, 2H); MS (ESI) m/z 491/493 (M*+H, 79Br/81Br).
Example 371 4-amino-5-(3-bromophenyl)-7-(6-(4-(4-tetrahvdropyranyloxy iminopiperidinyl )-3- pyridazinyl)pyrido[2.3-d]pyrimidine Prepared as described for Example 359; substituting Example365 for Example328 and O-tetrahydro-2H-pyran-4-yl-hydroxylamine hydrochloride (JP 94-177353 19940729) for ethoxylamine hydrochloride. MS (ESI+) m/z 574 (M+H)*; Η NMR (300 MHz, CDClrdl) δ 8.78 (s. IH), 8.69 (d, IH). 8.59 (s, IH). 7.71 (m, 2H), 7.46 (m, 2H), 7.10 (d, IH), 4.26 (m, IH), 3.98 (m, 6H), 3.53 (m, 2H), 2.79 (m, 2H), 2.59 (m, 2H), 2.00 (m, 2H), 1.69 (m, 2H)
Example 372 4-amino-5-f3-bromophenyl)-7-(6-isobutoxy-3-pyridazinyl)pyrido[2J-d]pyrimidine
Sodium isobutoxide was made by heating sodium and isobutanol at 60°C for 45 minutes. 4-amino-5-(3-bromo phenyl)-7-(6-chloro-3-pyridazinyl) pyrido[2, 3-djpyrimidine (prepared as in Example 367) was added to this mixture and heated at 60°C for 2 hours to give the title compound. MS (APCI+) m/z 451 (M+H)*;
Η NMR (300 MHz, DMSO-d6) δ 10.07 (bs, IH), 8.96 (s, IH), 8.53 (s, IH), 8.52 (d, IH), 7.95 (m, IH), 7.85 (m, IH), 7.60 (m, 3H), 4.34 (d, 2H), 2.15 (m, IH), 1.05 (d, 6H)
Example 373 4-amino-5-(3-bromophenyl -7-(6-(4-rN-methylpiperazinyl iminopiperidinyl )-3- pyridazinyl)pyrido[2.3-dlpyrimidine Prepared as described for Example 359; substituting Example 365 for Example 328 and 4-amino-4-N-methylpiperazine for ethoxylamine hydrochloride. MS (APCI+) m/z 575 (M+H)*; "H NMR (300 MHz, DMSO-d6) δ 8.59 (s, IH), 8.42 (d, IH), 8.27 (s, IH). 7.84 (m. 2H), 7.55 (m, 3H), 3.92 (m, 4H), 2.71 (m, 4H), 2.63 (m, 4H), 2.43 (m, 4H), 2.19 (s, 3H)
Example 374 4-amino-5-(3-bromophenyl -7-(6-(4-tetrahvdropyranyloxy -3-pyridazinyl)pyrido[2J- d]pyrimidine Prepared as described for Example 369; substituting tetrahydro-4H-pyran-4-ol for benzyl alcohol.
MS (FAB+) m z 479 (M+H)*;
Η NMR (300 MHz, DMSO-dJ δ 9.80 (bs. IH). 8.85 (s, IH), 8.56 (d, IH), 8.52 (s, IH), 7.93 (m, IH), 7.84 (m, IH), 7.70-7.50 (m, 3H). 5.51 (m, IH), 3.91 (m, 2H), 3.55 (m, 2H), 2J3 (m, 2H), 1.77 (m, 2H)
Example 375 4-amino-5 -(3 -bromophenyl)-7-(6-morpholinylethoxy-3 -pyridazinvDpyrido \23- dlpyrimidine
Prepared as described for Example 369; substituting N-(2' -hydroxy lethyl)- moφholine for benzyl alcohol. MS (FAB+) m/z 508 (M+H)*;
Η NMR (300 MHz, DMSO-d6) δ 12.10 (bs, IH), 10.05 (bs, IH), 8.92 (s, IH), 8.57 (d, IH), 8.48 (s, IH), 7.95-7.52 (m, 5H), 7.45 (bs, 2H), 5.05 (m, 2H), 3.97 (m, 4H), 3.69 (m, 2H), 3.60-3J8 (m, 4H)
Example 376 4-amino-5-(3-bromophenvπ-7-('6-(4-ethoxypiperidinyl)-3-pyridazinyl)pyrido[2J- dlpyrimidine
Treatment of N-Boc-4-hydroxylpiperidine with sodium hydride and ethyl iodide gave N-Boc-4-ethoxypiperidine, which was treated with 4M HCl in dioxane to give 4- ethoxypiperidine.
The title compound was prepared as described for Example 367 substituting 4- ethoxypiperidine for (lS,4S)-2-aza-5-oxa-bicyclo[2.2J]heptane, followed by treatment with IM HCl ether. MS (FAB+) m/z 506 (M+H)*;
Η NMR (300 MHz, DMSO-d6) δ 10.10 (bs, IH). 8.90 (s, IH), 8.38 (s, IH), 8.26 (d, IH), 7.92-7.42 (m. 5H), 3.78-3.38 (m, 7H), 1.96 (m. 2H), 1.55 (m, 2H). 1.10 (t, 3H) Example 377 4-amino-5-(3-bromophenylV7-(6-(4-(2-ethqxyethoxy)piperidinyl)-3- pyridazinyl pyrido~2J-d]pyrimidine Treatment of N-Boc-4-hydroxylpiperidine with sodium hydride and chloroethyl ethyl ether gave N-Boc-4-(2'-ethoxyl-ethoxyl)-piperidine, which was treated with 4M HCl in dioxane to give 4-(2'-ethoxyl-ethoxyl)-piperidine.
The title compound was prepared as described for Example 367 substituting 4-(2'- ethoxyl-ethoxy)-piperidine for (lS,4S)-2-aza-5-oxa-bicyclo[2.2J]heptane. followed by treatment with IM HCl ether. MS (APCI+) m/z 550 (M+H)*;
'H NMR (300 MHz, DMSO-d6) δ 10.10 (bs. IH), 8.94 (s, IH), 8.41 (s, IH). 8.23 (d. IH), 7.95-7.45 (m, 5H), 7.39 (bs, IH), 4.15 (m, 3H), 3.70-3.30 (m, 6H), 1.94 (m, 3H), 1.50 (m, 3H), 1.08 (t, 3H)
Example 378
4-amino-5-(3-bromophenyl)-7-(6-(4-(4-tetrapyranyloxyethyl)piperidinvD-3- pyridazinyl pyrido[2J-djpyrimidine 4-(2' -Hydroxy lethyl)-piperidine was treated with triethylamine and Boc-anhydride in THF at room temperature. This crude product was treated with mesyl chloride and triethylamine in dichloromethane to give the mesylate. This mesylate was then treated with sodium tetrahydro-4H-pyran-4-oxide (Example 372), followed by deprotection with 4M HCl in dioxane to give 4-(2'-(4"-azacyclohexyl)-ethoxyl)-tetrahydro-4H-pyran.
The title compound was prepared as described for Example 367 substituting 4-(2'- (4"-azacyclohexyl)-ethoxyl)-tetrahydro-4H-pyran for (1 S,4S)-2-aza-5-oxa- bicyclo[2.2J jheptane, followed by treatment with IM HCl ether. MS (APCI+) m/z 590 (M+H)*;
Η NMR (300 MHz, DMSO-d6) δ 10.10 (bs, IH), 8.79 (s, IH), 8.22 (s, IH). 8.18 (d, IH), 7.70-7.40 (m, 5H), 4.42 (m, 2H). 3.63 (m, 2H), 3.34 (m, 3H). 3J9 (m, 2H). 3.01 (m, 2H), 1.70 (m. 5H), 1.33 (m, 2H), 1.23 (m, 2H), 1.08 (m, 2H) Example 379 4-amino-5-(3-bromophenyl)-7-(6-(3-(R)-tetrahvdrofuranyloxy)piperidinyl)-3- pyridazinyl)pyrido[2J-d1pyrimidine Prepared as described for Example 369; substituting (R)-3-hydroxytetrahydrofuran for benzyl alcohol.
MS (APCI+) m/z 465 (M+H)*;
'H NMR (300 MHz, DMSO-d6) δ 10.08 (bs, IH), 8.93 (s, IH), 8.52 (d, IH), 8.51 (s, IH),
7.98-7.40 (m, 6H), 5.80 (m, IH), 4.05-3.78 (m, 4H), 2.36 (m, IH), 2.15 (m, IH)
Example 380
4-amino-5-(3-bromophenyl)-7-(6-(3-(S -tetrahvdrofuranyloxy piperidinyl)-3- pyridazinvPpyridor2.3-d]pyrimidine Prepared as described for Example 369; substituting (S)-3 -hydro xytetrahydrofuran for benzyl alcohol. MS (APCI+) m/z 465 (M+H)+;
Η NMR (300 MHz, DMSO-d6) δ 10.08 (bs, IH), 8.93 (s, IH), 8.52 (d, IH), 8.51 (s, IH), 7.98-7.40 (m, 6H), 5.80 (m, IH), 4.05-3.78 (m, 4H), 2.36 (m, IH), 2.15 (m, IH)
Example 381 4-amino-5-('3-bromophenyl)-7-(6-(trans-3-ethoxy-4-hvdroxy)pyrrolidinyl')-3- pyridaziny 1 )p yri do |"23 -d] pyrimidine The title compound was prepared as described for Example 367 substituting anti-3- ethoxy-4-hydroxypyrrolidine (Chemical and Pharmaceutical Bulletin, 41, 1993, 132, Okada, T.) for (lS,4S)-2-aza-5-oxa-bicyclo[2.2J]heptane, followed by treatment with IM HCl ether.
MS (APCI+) m/z 508 (M+H)*;
Η NMR (300 MHz, DMSO-d6) δ 10.12 (bs, IH), 8.89 (s, IH), 8.38 (d, IH), 8.28 (s, IH),
7.90-7.40 (m, 5H), 4.40-3.40 (m. 9H). 1J0 (t, 3H)
Example 382 4-amino-5-(3-bromophenyl)-7-(6-(cis-3-ethoxy-4-hvdroxy pyrrolidinyl)-3- pyridazinvπpyrido [2.3 -dlpyrimidine Treatment of anti-N-Boc-3-ethoxy-4-hydroxypyrrolidine (Chemical and Pharmaceutical Bulletin. 41, 1993, 132, Okada, T.) with triphenylphosphine, 4- nitrobenzoic acid and diethyl azodicarboxylate in THF at 0°C to room temperature gave a syn-N-Boc-3-ethoxy-4-(4'-nitrophenylcarbonyloxy)pyrrolidine. This was then hydrolyzed with sodium hydroxide in methanol to give syn-N-Boc-3-ethoxy-4-hydroxypyrrolidine, which was subsequently deprotected with 4M HCl in dioxane to give syn-3-ethoxy-4- hydroxypyrrolidine. The titl compound was prepared as described for Example 367 substituting syn-3- ethoxy-4-hydroxypyrrolidine for (lS,4S)-2-aza-5-oxa-bicyclo[2.2.1]heptane, followed by treatment with IM HCl ether. MS (ESI+) m/z 508 (M+H)*;
Η NMR (300 MHz, DMSO-d6) δ 10.17 (bs, IH), 8.91 (s, IH), 8.38 (d, IH), 8.28 (s, IH), 7.91-7.79 (m, 2H), 7.67-7.49 (m, 4H), 4.80-3.50 (m, 9H), 1.39 (t, 3H)
Example 383 4-amino-5-(3-bromophenyl -7-(6-(trans-3-ethoxy-4-hvdroxy pyrrolidinyl)-3- pyridyl pyrido[2.3-d]pyrimidine The title compound was prepared as described for Example 370 substituting anti-3- ethoxy-4-hydroxypyrrolidine (Chemical and Pharmaceutical Bulletin, 41, 1993, 132, Okada, T.) for 4-methoxypiperidine, followed by treatment with IM HCl ether. MS (ESI+) m/z 507 (M+H)*;
•H NMR (300 MHz, DMSO-d6) δ 10.00 (bs, IH), 9.03 (s, IH), 8.87 (s, IH), 8.74 (d, IH), 8.23 (s, IH), 7.97 (s, IH), 7.80 (m, IH), 7.59 (m, 2H), 7.36 (m, IH), 7.11 (m, IH), 4.40- 3.00 (m, 9H), 1.10 (t, 3H)
Example 384 4-amino-5-('3-bromophenyl)-7-(6-(trans-3J-bis-ethoxy)pyrrolidinyl -3- pyridazinyl)pyridor2.3-d1pyrimidine Treatment of anti-N-Boc-3-ethoxy-4-hydroxypyrrolidine (Chemical and Pharmaceutical Bulletin, 41, 1993. 132, Okada. T.) with sodium hydride and ethyl iodide in anhydrous DMF gave anti-N-Boc-3,4-diethoxypyrrolidine. which was subsequently deprotected with 4M HCl in dioxane to give anti-3,4-diethoxypyrrolidine. The title compound was prepared as described for Example 367 substituting anti-
3,4-diethoxypyrrolidine for (lS,4S)-2-aza-5-oxa-bicyclo[2.2J]heptane. followed by treatment with 1 M HCl ether. MS (FAB+) m/z 536 (M+H)*;
'H NMR (300 MHz, DMSO-d6) δ 10.18 (bs, IH), 8.82 (s, IH), 8.39 (d, IH), 8.34 (s, IH), 7.90 (m, 2H), 7.70-7.46 (m, 4H), 4.25 (m, 2H), 3.84 (m, 4H), 3.67 (m, 4H), 1.2 (t, 6H)
Example 385
4-amino-5-(3-bromophenyl)-7-(6-(trans-3.4-bis-ethoxy pyrrolidinyl)-3-pyridyl)pyridor2J- djpyrimidine The title compound was prepared as described for Example 370 substituting anti-
3,4-diethoxypyrrolidine (Example 382) for 4-methoxypiperidine, followed by treatment with IM HCl ether.
MS (ESI+) m/z 535 (M+H)*;
Η NMR (300 MHz, DMSO-d6) δ 10.00 (bs, IH), 9.03 (m, IH), 8.87 (s, IH), 8.71 (m, IH). 8.22 (s, IH), 7.95 (m, IH), 7.80 (m, IH), 7.58 (m, 2H). 7.35 (bs, IH), 7.09 (m, IH), 4.25-
3.20 (m, 10H), 1.12 (t, 6H)
Example 386 4-amino-5-(3-bromophenyl)-7-(6-(cis-3.4-bis-ethoxy)pyrrolidinvπ-3-pyridyl)pyrido[2J- dlpyrimidine
Treatment of N-benzyl-3-pyrroline with osmium tetroxide and N-methyl- moφholine-N-oxide in THF gave syn-N-Boc-3,4-dihydroxypyrrolidine, which was then treated with sodium hydride (5eq.) and ethyl iodide (5 eq) in DMF to give syn-N-Boc-3,4- diethoxypyrrolidine. This was debenzylated under pressure in H2 atmosphere to afford syn-3,4-diethoxypyrrolidine. The title compound was prepared as described for Example 370 substituting syn- 3.4-diethoxypyrrolidine for 4-methoxypiperidine. followed by treatment with IM HCl ether.
MS (ESI+) m z 535 (M+H)*; Η NMR (300 MHz, DMSO-d6) δ 10.03 (bs. IH), 9.03 (m, IH), 8.89 (s. IH). 8.74 (m, IH), 8.25 (s. IH), 7.95 (m, IH), 7.62 (m, IH), 7.60 (m. 2H), 7.39 (bs, IH), 7.11 (m, IH), 4.30- 3.40 (m. 10H), 1.16 (t, 6H)
Example 387 4-amino-5-(3-bromophenvD-7-(6-(cis-3.4-bis-ethoxy pyrrolidinyl)-3-
PyridazinvDpyridor2.3-d]pyrimidine The title compound was prepared as described for Example 367 substituting syn- 3,4-diethoxypyrrolidine ( prepared in Example 384) for (lS,4S)-2-aza-5-oxa- bicyclo[2.2J]heptane, followed by treatment with IM HCl ether. MS (ESI+) m z 536.1 (M+H)+;
'H NMR (300 MHz, DMSO-d6) δ 10.13 (bs, IH), 8.87 (s, IH), 8.35 (d, IH), 8.28 (s, IH), 7.82 (m. 2H), 7.63-7.40 (m, 4H), 4.40-3.40 (m, 10H), 1.16 (t, 6H)
Example 388 4-amino-5-(3-bromophenyl)-7-(6-(cis-3-ethoxy-4-hydroxy)pyrrolidinyl)-3-
PVridyl)pyrido[2J-d]pyrimidine The title compound was prepared as described for Example 370 substituting syn-3- ethoxy-4-hydroxypyrrolidine (prepared as in Example 382) for 4-methoxypiperidine, followed by treatment with IM HCl ether. MS (ESI+) m/z 507 (M+H)*;
Η NMR (300 MHz, DMSO-d6) δ 10.00 (bs, IH), 9.02 (m, IH), 8.88 (s. IH), 8.72 (m, IH), 8.22 (s. IH), 7.97 (m, IH), 7.81 (m, IH), 7.60 (m, 2H), 7.39 (bs, IH), 7J7 (m, IH), 4.40- 3.40 (m. 9H), 1.17 (t, 3H)
Example 389 4-amino-5-(3-bromophenyl>7-(6-(cis-3-amino-4-hvdroxy)pyrrolidinyl)-3- pyridazinyl)pyridor2J-dlpyrimidine Syn-N-benzyl-3-hydroxy-4-(t-butylcarbonylamy)pyrrolidine was made by Shaφless method (JACS 120 1998 1215, Shaφless, K.B.; Tetrahedron asymmetry 5(7) 1994 1333, Saigo K.). This was debenzylated under H2 to give syn-3-hydroxy-4-(t- butylcarbonylamy)pyrrolidine.
The title compound was prepared as described for Example 367 substituting syn-3- hydroxy-4-(t-butylcarbonylamy)pyrrolidine for (lS,4S)-2-aza-5-oxa- bicyclo[2.2J]heptane, followed by treatment with 4M HCl dioxane. MS (ESI+) m/z 479.2 (M+H)*;
Η NMR (300 MHz, DMSO-d6) δ 10.07 (bs, IH), 8.94 (s, IH), 8.59 (bs, 2H), 8.35 (m, 2H), 7.85 (m, 2H), 7.70-7.30 (m, 4H), 4.70-3.20 (m, 9H)
Example 390 4-amino-5-(3-bromophenyl)-7-(6-(cis-3-amino-4-hvdroxy pyrrolidinyl -3- pyridyl)pyrido[2J-d]pyrimidine
The title compound was prepared as described for Example 370 substituting syn-3- hydroxy-4-(t-butylcarbonylamy)pyiTOlidine (prepared in Example 389) for 4- methoxypiperidine, followed by treatment with 4M HCl dioxane. MS (APCI+) m/z 478 (M+H)*; Η NMR (300 MHz, DMSO-d6) δ 10.07 (bs, IH), 9.08 (m, IH), 8.88 (s, IH). 8.64 (m, 3H), 8.21 (s, IH). 7.97 (s, IH), 7.82 (m, IH), 7.60 (m, 2H), 7.36 (m, IH), 7.03 (m. IH), 4.65- 3.65 (m, 9H)
Example 391 4-amino-5-(2-pyridvπ-7-(6-(1.4-dioxa-8-azaspiro[4.51decan-8-yl)-3-pyridyl pyrido[2J- dlpyrimidine Prepared according to the procedure of Example 392, except substituting 5-acetyl- 2-(-l,4-dioxa-8-azaspiro[4.5]decan-8-yl)pyridine for 5-acetyl-2-moφholinylpyridine, and 3-pyridinecarboxaldehyde for 2.3-dichlorobenzaldehyde. The treatment with FICl/ethanol to form the hvdrochloride salt was omitted, and the free base was obtained instead. IR (MIC) 3500, 3310. 3100. 2982. 1605. 1580, 1555, 1512, 1351. 1238, 1 100cm"1: MS m/z 442 (M+H)*
Example 392 4-amino-5-(2.3-dichlorophenyl)-7-(6-moφholinyl-3-pyridvπpyridor2J-djpyrimidine
4-(2,3-Dichlorophenyl)-3-cyano-6-(6-moφholinyl-3-pyridyl)pyridine-2-amine (0.47 g) and ammonium sulfate (20 mg) was dissolved in triethylorthoformate (25 ml) and heated to reflux for about 6.5 hours. The reaction mixture was cooled to room temperature, and a 2 M solution of ammonia in ethanol (50 ml) was added. The reaction was stirred at room temperature for about 18 hours, then heated to reflux for about 6 hours, and then cooled again to room temperature. The solvents were removed under vacuum. The residue was purified by flash chromatography eluting with 5% of 19: 1 ethanol: ammonium hydroxide in ethyl acetate, and then converted to the hydrochloride salt by treatment with HCl/EtOH, followed by removal of solvent and tituration with ether to give the title compound.
IR (MIC) 3355, 2980, 1644, 1602, 1437, 1369, 1250cm"1; MS m/z 453 (M+H)*
Step a 4-(2J-dichlorophenyl)-3-cvano-6-(6-morpholinyl-3-pyridyl)pyridine-2-amine Malononitrile (0.33 g) and 2.3-dichlorobenzaldehyde (0.88 g) were dissolved in
1 ,2-dichloroethane, and 1-2 drops of triethylamine were added. The reaction was stirred at room temperature for about 2.5 hours, then 5-acetyl-2-moφholinylpyridine (0.62 g) and ammonium acetate (2.31 g) were added. The reaction was heated to reflux for about 5 hours, then cooled to room temperature. The reaction mixture was purified by flash chromatography eluting with 30% EtOAc/Hexanes.
Example 393 4-amino-5-(2-pyridyl)-7-(6-moφholinyl-3-pyridyl pyrido[2J-d]pyrimidine Prepared according to the procedure of Example 392 except substituting 3- pyridinecarboxaldehyde for 2,3-dichlorobenzaldehyde. IR (MIC) 3050. 1650. 1603, 1540, 1440. 1375, 1252cm 1; MS m/z 386 (M+H)*
Example 394 4-amino-5-(2-ethoxyphenyl)-7-(6-(l J-dioxa-8-azaspiro[4.51decan-8-vπ-3- pyridvDpyrido f 23 -djpyrimidine Prepared according to the procedure of Example 392. except substituting 5-acetyl- 2-(-l,4-dioxa-8-azaspiro[4.5]decan-8-yl)pyridine for 5-acetyl-2-moφholinylpyridine, and 2-ethoxybenzaldehyde for 2,3-dichlorobenzaldehyde. The treatment with HCl/ethanol to form the hydrochloride salt was omitted, and the free base was obtained instead.
IR (MIC) 3480, 3060, 1738, 1640, 1600, 1560, 1537, 1500, 1345, 1230, 1220, 1100cm"1; MS m/z 485 (M+H)*
Example 395 4-amino-5-("2-bromo-5-ethoxyphenyl)-7-(6-moφholinyl-3-pyridyl)pyrido[2J- djpyrimidine Prepared according to the procedure of Example 392, except substituting 2- methoxy-5-bromobenzaldehyde for 2,3-dichlorobenzaldehyde. IR (MIC) 3440, 2975, 1642, 1600, 1490, 1440, 1370, 1250cm"1; MS m/z 493 (M+H)*
Example 396 4-amino-5-(2.5-dichlorophenyl -7-(6-moφholinyl-3-pyridyl)pyridor2J-d]pyrimidine 4-(2,5-dichlorophenyl)-3-cyano-6-(6-moφholinyl-3-pyridyl)pyridine-2-amine (0.28 g) and ammonium sulfate (10 mg) were dissolved in triethylorthoformate (10 ml) and heated to reflux for about 4 hours. The reaction mixture was cooled to room temperature, and a 2 M solution of ammonia in ethanol (20 ml) was added. The reaction was stirred at room temperature for about 18 hours, then a solution of 1 M sodium methoxide in methanol (5 ml) was added. The reaction was heated to reflux for about 2.5 hours, and then cooled again to room temperature. The reaction mixture was neutralized with a solution of 1 N aqueous HCl (5 ml) and the solvents were removed under vacuum. The residue was purified by flash chromatography eluting with 2.5% of 19J ethanol :ammonium hydroxide in ethyl acetate, and then converted to the hydrochloride salt by treatment with HCl/EtOH, followed by removal of solvent and tituration with ether to give the title compound.
IR (MIC) 3480, 3060, 1640, 1600. 1580, 1440, 1371, 1260, 1239cm 1; MS m/z 453.2 (M+H)*
The 4-(2,5 -dichloropheny l)-3 -cyano-6-(6-moφholinyl-3 -pyridy l)pyridine-2-amine was prepared following the conditions given under Example 392 except substituting 2,5- dichlorobenzaldehyde for 2,3-dichlorobenzaldehyde.
Example 397 4-amino-5-(2,5-dimethylphenyl)-7-f6-moφholinyl-3-pyridyl)pyrido[2J-djpyrimidine Prepared according to the procedure of Example 396, except substituting 2,5- dimethylbenzaldehyde for 2,5-dichlorobenzaldehyde. IR (MIC) 3420, 2910, 1640, 1600, 1580, 1240cm"1; MS m/z 413.2 (M+H)+
Example 399 4-amino-5-(3-fluorophenyl)-7-(6-morpholinyl-3-pyridyl)pyrido[2J-d1pyrimidine
Prepared according to the procedure of Example 396, except substituting 3- fluorobenzaldehyde for 2,5-dichlorobenzaldehyde. IR (KBr) 3480, 1672, 1639, 1617, 1480, 1421, 1315, 1305cm"1; MS m/z 403 (M+H)*
Example 400 4-amino-5-(3-trifluoromethylphenyl)-7-(6-moφholinyl-3-pyridyl)pyrido[2J-d]pyrimidine
Prepared according to the procedure of Example 396, except substituting 3- trifluoromethylbenzaldehyde for 2,5-dichlorobenzaldehyde. IR (MIC) 3000, 1641, 1600, 1440, 1369. 1324, 1239, 1 120cm"1; MS m/z 453 (M+H)*
Example 401 4-amino-5-("3-fluoro-5-trifluoromethylphenyl -7-(6-(lJ-dioxa-8-azaspiro[4.5]decan-8-yl)- 3-pyridyl)pyrido[2.3-d1pyrimidine
Prepared according to the procedure of Example 327, substituting 3-fluoro-5- trifluoromethylbenzaldehyde for 3-bromobenzaldehyde. mp: unmelted at 300°C;
MS (FAB)* m/z calc'd for C26H23N6O2p4: 527.1813, found 527.1810. IR (cm"'): 3314, 3081, 1580, 1558, 1515, 1428, 1357, 1329, 1238, 1139, 1106.
Example 402 4-amino-5-(3.5-diclorophenvπ-7-(6-(1.4-dioxa-8-azaspiro[4.5]decan-8-yl)-3- pyridyl pyrido[2,3-dlpyrimidine Prepared according to the procedure of Example 327, except substituting 3,5- dichlorobenzaldehyde for 3-bromobenzaldehyde. mp: unmelted at 300°C;
MS (FAB)* m/z calc'd for C25H23N6O2Cl2: 509.1254, found: 509.1246 IR (cm"1): 3487, 3299, 3065, 1578, 1556, 1515, 1431, 1354, 1238, 1104.
Example 403 4-amino-5-(3-bromophenvπ-7-(6-(1.5-dioxa-9-azaspiro[5.5]undecan-9-yl)-3- pyridazinyl)pyridor2J-d1pyrimidine Prepared according to the procedure of Example 367, except substituting l,5-dioxa-9- azaspiro[5.5]undecane for (lS,4S)-2-aza-5-oxa-bicyclo[2.2J]heptane. mp: δ 190°C;
MS (FAB)* m/z calc'd for C25H25N7O2 81Br: 536.1233. found: 536.1233. IR (cm"1): 3471, 3297, 3059, 2961, 1579, 1562, 1461, 1407, 1354, 1236, 1104.
Example 404 4-amino-5-(4-bromo-2-thienyl)-7-(6-(l J-dioxa-8-azaspiro[4.5]decan-8-yl)-3- pyridvDpyrido [2.3 -dlpyrimidine Prepared according to the procedure of Example 327. substituting 4-bromothiophene-2- carboxaldehyde for 3-bromobenzaldehyde. mp: δ 245°C;
MS (FAB)* m/z calc'd for C23H22N6O2S79Br: 525.0703, found: 525.0699. IR (cm 1): 3477, 3296, 3094, 1603, 1579, 1556, 1511, 1428, 1352, 1239, 1104.
Example 405 4-amino-5-(3-bromophenyl)-7-(6-(4-tertbutyl)piperidinyl-3-pyridazinyl)pyrido[2J- djpyrimidine Prepared by the method of Example 367, substituting 4-tertbutylpiperidine for (lS,4S)-2- aza-5-oxa-bicyclo[2.2.1 ]heptane. mp: δ > 270°C; MS (FAB)* m/z calc'd for C26H29N7 79Br: 520.1647, found: 520.1652.
IR (cm 1): 3474, 3298, 3085, 2952, 1578, 1553, 1461, 1405, 1351, 1254, 1191, 1159.
Example 406 4-amino-5-(3-bromophenyl)-7-(6-(4-N-formyl)piperidinyl-3-pyridazinyl)pyridor2.3- djpyrimidine
2-Amino-4-(3-bromophenyl)-3-cyano-6-(6-chloro-3-pyridazinyl)pyridine (31 Omg), prepared in Example 367, and 1,3-propylenedioxypiperidine (354mg) were dissolved into DMSO (2.5ml) and stirred 48 hours. The reaction mixture was partitioned between 0.4M pH7 aqueous potassium phosphate buffer and worked up as usual. The intermediate was suspended in formamide (15ml) and o-dichlorobenzene (7ml) and heated at 200°C for 2.5h. The reaction mixture was partitioned between salt water and dichlomethane, and the organic phase was separated, filtered through celite, and worked up as usual. Chromatographed (MeOH/EtOAc/CH2Cl2). mp: δ l90°C; MS (FAB)* m/z calc'd for C23H22N8O7 9Br: 505.1094. found: 505.1095. IR (cm 1): 3472, 3299, 1654. 1578. 1555. 1478, 1418, 1354. 1225.
Example 407 4-amino-5-(3-bromo-2-thienyl)-7-(6-(4J-ethylenedioxypiperidinyl)-3-pyridyl)pyrido[2J- dlpyrimidine
Prepared by the method of Example 327, substituting 3-bromothiophene-2- carboxaldehyde for 3-bromobenzaldehyde. mp: δ 230°C;
MS (FAB)* m z calc'd for C23H22N6O2S79Br: 527.0688, found: 527.0692. IR (cm'1): 3472, 3297, 3091, 1611, 1581, 1557, 1519, 1428, 1351, 1334, 1229, 1112.
Example 408 4-amino-5-(3-cvanophenyl)-7-(6-moφholinyl-3-pyridazinyl)pyrido[2J-d]pyrimidine
A formamide complex of Example 134 (762mg), Zn(CN)2 (94mg), and Pd(PPh3)4 (173mg) were heated in DMF (5ml) at 105°C for 3h 40m. The reaction mixture was partitioned between CH2C12 and water and worked up as usual. Recrystallization of the crude solid from CHC13 gave the title compound. mp: δ 3 290°C;
MS (FAB)* m/z calc'd for C23H20N7O: 410.1724, found: 410.1722. IR (cm 1): 3482, 3313, 2232, 1588, 1542, 1507, 1357, 1240.
Example 409 4-amino-5-(3-Bromophenyl)-7-(6-(S-O-ethyl-2-hvdroxymethylpyrrolidinyl)-3- pyridazinvDpyrido [2.3 dlpyrimidine
Prepared by the method of Example 367, substituting (S)-O-ethyl-2- hydroxymethylpyrrolidine for ( 1 S,4S)-2-aza-5-oxa-bicyclo[2.2.1 jheptane. mp: δ 3 180°C;
MS (FAB)* m/z calc'd for C24H25N7O8'Br: 508.1283, found: 508.1285. IR (cm"1) of salt: 3438, 3302, 2974. 1637, 1609, 1588. 1554, 1440. 1374, 11 1 1. Step a. (SVO-ethyl-2-hvdroxymethylpyrrolidine
A suspension of (S)-N-tertbutyloxycarbonyl-2-hydroxymethylpyrrolidine (1006mg) and crushed NaOH (800mg) in DMSO (20ml) was treated with ethyl iodide (560ml). After the suspension had been stirred for 45m. the reaction mixture was partitioned between 0.2M aq KH2P04 and Et2O, worked up as usual, and concentrated. A solution of the intermediate (1.04g) in MeOH (10ml) was treated with cone aq HCl (1.5ml) and stirred over the weekend. The reaction mixture was concentrated and partitioned between 3M aq K3PO4 and Et2O, worked up as usual, and concentrated to give the desired amine
Example 410
4-amino-5-(3-bromophenvπ-7-(6-((2SJS')-2J-dimethyl-l J-dioxa-8-azaspiror4.51decan-
8-yl)-3-pyridazinyl)pyrido[2J-dlpyrimidine
Prepared by the method of Example 327, substituting (2S,3S)-2,3-dimethyl-l,4-dioxa-8- azaspiro[4.5]decane for 4,4-ethylenedioxypiperdine and using 1 ,2,4-trichlorobenzene as cosolvent with formamide at 200°C in the final cyclization. mp: δ >235°C; MS (FAB)* m/z calc'd for C26H27N7O2 81Br: 550.1389, found: 550.1374. IR (cm"1): 3477, 3046, 2968, 1578, 1559, 1460, 1410, 1353, 1251, 1113.
410a. 4.4-( 1 S,2S-dimethylethanedioxy)piperidine
N-tertbutyloxycarbonylpiperidi-N-4-one (2.59g), (2S,3S)-butanediol (1.464g), and a catalytic amount of p-toluenesulphonic acid were dissolved into benzene (25ml) within a flask fitted with a Dean-Stark trap and condenser, and refluxed lday. The reaction mixture was partitioned between aq NaHCO3 and ether, and worked up as usual. Chromatographed (CH3CN/CH2C12). This intermediate (3.78g) was dissolved into CH2C12 (10ml) and treated with TFA (3ml). After 90m more TFA (0.5ml) was added, and after another 90min the reaction mixture was concentrated, then conc'd from CHC13, then from toluene. The intermediate. 6-acetyl-3-chloropyridazine (2.03g), and diisopropylethylamine (9.75ml) were dissolved into methanol (55ml) and heated at 55°C for 2d. The reaction mixture was added to Et2O and IM pH7 aq potassium phosphate buffer and worked up as usual. Purified by column chromatography (EtOAc/Hexanes). Example 41 1 4-amino-5-(3-bromophenyl)-7-(6-(4J-(cis-1.2-dioxycvclopentyl)piperidinyl)-3- pyridazinvPpyrido 2J-d]pyrimidine Prepared by the method of Example 410 (A-312378), substituting cis-1,2- dihydroxycyclopentane for (2S,3S)-butanediol. mp: unmelted at 300°C;
MS (FAB)* m/z calc'd for C27H27N7O2 81Br: 562.1389, found: 562.1382. IR (cm"1): 3478, 3081, 2959, 1578, 1560, 1460, 1406, 1351, 1246, 1109.
Example 412 4-amino-5-(3-bromophenyl -7-(6-(4-acetyl-l-oxa-4.8-diazaspiro[4.5]decan-8-yl)-3- pyridazinvDpyrido'ΣJ-djpyrimidine 4-Acetyl-l-oxa-4,8-diazaspiro[4.5]decane (341mg) was dissolved into CH2C12 (0.5ml) and treated with TFA (lml). After 20m the reaction mixture was concentrated. The intermediate, potassium carbonate (552mg), and 4-amino-5-(3-bromophenyl)-7-(6-chloropyridaz-3- yl)pyrido[2,3-d]pyrimidine (165mg), prepared in Example 367, were suspended in DMSO (2ml) and heated 6h at 120°C. The reaction mixture was partitioned between brine and CH2C12 and worked up as usual. Purification by chromatography (CH3OH/ CH3CN/CH2C12) provided the title compound.. mp: dec 260°C (sweats and turns deep brown 220°C); MS (FAB)* m/z calc'd for C26H26N8O2 81Br:
563.1342, found: 563.1329.
IR (cm"1): 3487, 3308, 1626, 1578, 1553, 1461, 1416, 1353, 1254, 1073.
412a.
N-tertbutyloxycarbonyl-4-oxopiperidine (996mg) and 2-aminoethanol (320ml) were dissolved into ethanol (5ml). After 4h, the reaction mixture was concentrated, and the residue dissolved into CH2C12 (8ml) and pyridine (2ml). Acetyl chloride (360ml) was added and the mixture was stirred overnight. More acetyl chloride (350ml) was added then and the same amount 2h later. After 15m more, the reaction mixture was quenched with aq NaHCO3 and worked up as usual but with NaHC03 and NaCl in each aqueous wash. This intermeadiate was purified by chromatography (EtOAc/Hexanes).
Example 413 4-amino-5-(3-bromophenyl)-7-(6-((2RJR")-2J-bis(methoxymethyl -l J-dioxa-8- azaspiro[4.51decan-8-vD-3-pyridazinyOpyrido 2J-d]pyrimidine Prepared following the procedure according to Example 412 (A-314908). substituting (2R,3R)-2,3-bis(methoxymethyl)-l ,4-dioxa-8-azaspiro[4.5]decane for 412a. mp: δ >130°C; MS (FAB)* m/z calc'd for C28H31N7O4 79Br: 608.1615, found: 608.1614. IR (cm"1): 3486, 3304, 2928, 1578, 1554, 1461, 1407, 1352, 1235, 1 106.
Example 414 4-amino-5-(3-bromophenyl)-7-(6-(4.4-(cis-3J-dioxy-oxacvclopentyl')piperidinyl')-3- pyridazinyl)pyrido[2J-d1pyrimidine Prepared following the procedure of Example 412 (A-314908), substituting 4,4-(cis-3 ,4- dioxy-oxacyclopentane)piperidine for 412a. mp: δ 3 280°C; MS (FAB)* m/z calc'd for C26H25N7O3 79Br: 562.1202, found: 562.1209. IR (cm"1): 3475, 3293, 3094, 1577, 1559, 1461, 1410, 1355, 1229, 1111.
Example 415
4-amino-5-(3-bromophenyl)-7-(6-(3-methoxy-1.5-dioxa-9-azaspiro[5.51undecan-9-yl)-3- pyridazinyl)pyrido[2J-d1pyrimidine Prepared following the procedure of Example 412 (A-314908), substituting 3-methoxy- l,5-dioxa-9-azaspiro[5.5jundecane for 412a. mp: δ 3 2 75°C; MS (FAB)* m/z calc'd for C26H27N7O3 79Br: 564.1359, found: 564.1354. IR (cm '): 3478, 3293, 3070, 1574. 1564, 1462, 1407. 1349, 1227. 1 147, 1101.
Example 416 4-amino-5-(3-bromophenyl)-7-(6-(1.5-dioxa-3-hvdroxymethyl-9-azaspiro[5.51undecan-9- yl)-3-pyridazinyl pyrido"2J-d]pyrimidine Prepared following the procedure of Example 412, substituting l,5-dioxa-3- hydroxymethyl-9-azaspiro[5.5]undecane for 412a. and adding butanol during the work-up. mp: unmelted at 300°C (sweats/shrivels >270°C); MS (ESI)' m/z: 564/566. IR (cm"1): 3475, 3302, 1578. 1554, 1462, 1409. 1354. 1237, 1 146, 1 100.
Example 417 4-amino-5-(3-bromophenyl)-7-(6-(lJJ4-trioxa-l l-azadispiro[4.2.5.21pentadecan-l l-yl)-
3-pyridazinvOpyrido[2.3-d]pyrimidine Prepared following the procedure of Example 412 (A-314908), substituting 1,7,14-trioxa- 1 l-azadispiro[4.2.5.2]pentadecane for 412a. mp: unmelted at 300°C; MS (ESI)* m/z: 590/592.
IR (cm 1): 3476, 3295, 3087, 2968, 1577, 1562, 1465. 1419, 1356, 1149, 1099.
Example 418 4-amino-5-(4-tetrahvdropyranyl)-7-(4J-ethylenedioxypiperdinyl)pyridor2J-d1pyrimidine
Prepared following the procedure according to Example 327, substituting lJ-dicyano-3- (4-tetrahydropyranyl)ethene from Example 292 for 3-bromobenzaldehyde, and 6-acetyl-3- chloropyridazine for 5-acetyl-2-chloropyridine at room temperature rather than reflux, mp: unmelted at 300°C; MS (FAB)* m/z calc'd for C23H27N7O3: 450.2254, found: 450.2266. IR (cm"'): 3544, 3304, 2938, 1579, 1557, 1468, 1415. 1355, 1240, 1104.
Example 419 4-amino-5-(3-bromophenvD-7-f6-(4-moφholinyliminopiperidinyl )-3-pyridyl)pyrido[2, - dlpyrimidine Prepared as described for Example 359; substituting 4-aminomoφholine for ethoxylamine hydrochloride. MS (DCI NHJ m/z 559 (M+H)*; IR (cm"'): 1643, 1602, 1557.
Example 420 4-amino-5-(3-bromophenyl)-7-(6-(4-(N-methylpiperazinyl)iminopiperidinyl )-3- pyridyl)pyrido~2.3-dlpyrimidine Prepared as described for Example 419 except substituting 1 -amino- 4-N- methylpiperazine for 1 -aminomoφholine. MS (DCI) m/e 572 (M+H>J IR 1647, 1602, 1559.
Example 421 4-amino-5-(3-bromophenyl)-7-(6-(4-(1.2.4-triazol-l-yl)iminopiperidinyl )-3- pyridyl)pyrido[2.3-d]pyrimidine
Prepared as described for Example 419 except substituting 4-amino- 1 ,2,4-triazole for 1 -aminomoφholine MS (DCI) m/e 541 (M+H)+; IR 1602, 1580.
Example 422 4-amino-5-(3-indolyl)-7-(6-morpholinyl-3-pyridyl)pyrido[2J-d1pyrimidine The title compound was prepared following the procedure of Example 396 except substituting 3-indolylcarboxaldehyde for 2,5-dichlorobenzaldehyde. MS (DCI), m z 424.
H1 NMR (DMSO-d6) d, 1 1.81 (s, IH), 9.05 (d, IH), 8.5 (s, IH), 8.45 (dd, IH). 7.84 (s, 2H), 7.55 (d, IH), 7.40 (d, IH), 7.25 (t, IH), 7J0 (t, IH), 6.58 (d, IH), 3.72 (m, 4H), 3.6 (m, 4H).
Example 423
4-amino-5-(5-indolylV7-(6-moφholinyl-3-pyridyl pyrido[2J-d]pyrimidine The title compound was prepared following the procedure of Example 422 except substituting 5-indolylcarboxaldehyde for 3-indolylcarboxaldehyde, which was prepared according to the procedure of Moyer et. al. Journal of Organic Chemistry, 51., 5106-51 10, 1986. MS (DCI). m/z 452.
IR (mic. cm"1) 3448, 1557, 1503. 1234. 943.
Example 424 4-amino-5-(3-bromophenyl)-7-(6-(4-ethylpiperidinylcarboxylate)-3-pyridvπpyrido[2J- dlpyrimidine Prepared following the procedures of Example 327 except substituting ethyl 4- piperidinecarboxylate for 4,4-ethlenedioxypiperidine. MS (DCI) m/e 533 (M+H)+; IR (mic.cm"1 1604, 1592, 1560
Example 425 4-amino-5-(3-bromophenyl)-7-(2-phenylmethyl-3(2H -pyridazinone-6-vπpyrido[2J- dlpyrimidine step a 3 -acetyl-6-hvdroxypyridazine
A solution of 3-acetyl-6-chloropyridazine (prepared in Example 246 step b)(6.0 g, 38.4 mmol) and aq. 3N HCl (70 mmol) in THF (100 mL) was heated at 60°C for 4 h, cooled to ambient temperature, concentrated and chromatographed on silica gel (30% EtOAc-hexane) to obtain the desired compound (3.3 g, 62%). Η NMR (CDC13, 300 MHz) δ 12.42 (broad s, IH), 7.98 (d, J=9.0 Hz, IH), 7.02 (d, J=9.0 Hz. IH). 2.58 (s, 3H); MS m/z (DCI) 139 (M+H)*.
step b 6-acetyl-2-phenylmethyl-3(2H)-pyridazinone
A solution of 3-acetyl-6-hydroxypyridazine (2.9 g, 21.0 mmol). benzyl bromide (2.8 mL. 23.0 mmol) and KOH (13 g, 23.0 mmol) in DMF (45 mL) was stirred at ambient temperature for 15 h. The mixture was diluted with EtOAc and washed twice with water. Aqueous layer was extracted with EtOAc and combined organic fractions concentrated and chromatographed (10-25%EtOAc-hexane) to obtain of the desired 6-acetyl-2- phenylmethyl-3(2H)-pyridazinone (3.6 g. 75%) as an oil. Η NMR (CDC1,. 300 MHz) δ 7.80 )d, J=9.2 Hz, IH), 7.48-7.27 (m, 5H), 6.90 (d, J=9.2 Hz. IH). 5.38 (s. 2H). 2.51 (s, 3H); MS m/z (DCI) 229 (M+H)*.
The title compound was prepared as described in Example 327 except substituting 6-acetyl-2-phenylmethyl-3(2H)-pyridazinone for 3-acetyl-(4,4- ethylenedioxypiperidinyl)pyridine MS (DCI) m/e 485 (M+H**; IR 1640, 1618, 1560.
Example 426 4-amino-5-(3-bromophenvD-7-(6-(4-(moφholinylcarboxamide)piperidinyl)-3-
Pyridyl pyrido[2.3-djpyrimidine The title compound was prepared following the procedure of Example 424 except substituting 3-acetyl-6-(4-N-moφholinylcarboxamide)piperidinyl)pyridine for ethyl-4- piperidinecarboxylate derivative. MS (ESI+), m/z 575 (M+H)+;
IR (MIC); cm"1, 3486, 1557, 1211, 933.
3 -acetyl-6-(4-N-moφholiny lcarboxamide)piperidiny l)pyridine :
2-chloro-5-acetylpyridine (6g) and ethyl isonipecotate (6Jg) was relfuxed in ethanol. The volatiles were evaporated to leave 2-(l '-ethyl isonipecoticate)-4- acetylpyridine. This material was treated with aqueous lithium hydroxide, followed by acidification and filtration. The resulting acid (1.5 g) was treated with moφholine (2.4 g), hydroxybenzotriazole (1.3g) and 1 -(3 -Dimethy laminopropyl)-3-carbodiimide. to afford the desired compound . MS (DCI) m/z, 318 (M+H)*.
Example 427 4-amino-5-(3-bromophenyl)-7-(6-(4-(N-moφholinylaminocarboxamide piperidinyl)-3-
Pyridyl)pyrido[2.3-d]pyrimidine Prepared following the procedure of Example 426 except substituting 4- aminomoφholine for moφholine. MS (ESI) m/z 589 (M+H)*; IR (cm 1 ) 3490, 1557, 1351, 1111.
Example 428 4-amino-5-(3-bromophenyl -7-(,6-("4-(N.N-dimethylaminocarboxamide piperidinyl -3- pyridy Dpyrido \23 -djpyrimidine Prepared following the procedure of Example 426 except substituting dimethylamine for moφholine. MS (ESI) mz 532 (M+H)*;
H1 NMR (300 MHz; DMSO-d6. δ 9.05 (d,lH), 8.52 (s, IH), 8.44 (dd, IH), 7.85 (s, 2H), 7.78 (dt, IH), 7.55 (s, IH), 6.99(d, IH), 4.49 (d, 2H), 3.09 (s, 2H), 3.00 (m, 3H), 2.80 (s, 3H), 1.7 (m, 2H), 1.54 (m, 2H).
Example 429 4-amino-5-('3-bromophenyl)-7-(6-(4-(N-methyl-N-methoxyethylcarboxamide)piperidinyl)-
3-pyridyl)pyrido[2.3-d1pyrimidine Prepared following the procedure of Example 426 except substituting N-methyl-N- methoxyethylamine for moφholine.. MS (ESI+) m/z 576, (M+H)*; IR (mic, cm 1) 3489, 1555, 1118, 936.
Example 430
4-amino-5-(4-quinolyl)-7-(6-morpholinyl-3-pyridvπpyrido[2J-djpyrimidine Prepared following the procedure of 392, substituting 4-quinolinecarboxaldehyde for 2,3-dichlorobenzaldehyde. MS (ESI+). m/z 436 (M+H)*; IR (mic. cm"1) 3488, 1580, 1557. 1227, 936. Example 431 4-amino-5-(3-bromophenvπ-7-(6-(4-(N-methoxyethylcarboxamide piperidinyl)-3- pyridvDpyrido [2,3 -dlpyrimidine Prepared following the procedure of Example 426, except substituting N- methoxyethylamine for moφholine... MS (ESI+) M/z 564, (M+H)*; IR (cm "1) 3310, 1560, 1210, 954.
Example 432
4-amino-5-f3-bromophenyl)-7-(6-(4-hvdroxymethylpiperidinyl)-3-pyridyl pyrido[2J- dlpyrimidine Prepared as described for Example 370 except substituting 4- hydroxypiperidnepiperidine for 4-methoxypiperidine, which was prepared as follows: ethyl isonipecotate (lθg)was treated with lithium aluminum hydride (2.53g) in tetrahydrofuran for 36 hours. MS. (ESI+) m/z 491 (M+H)*.
Example 433 4-amino-5-(2-bromophenyl)-7-(6-(lJ-dioxa-8-azaspiro[4.5jdecan-8-yl)-3- pyridyl pyrido[2.3-djpyrimidine Prepared as described for Example 370 except substituting l,4-dioxa-8- azaspiro[4.5]decane for 4-methoxypiperidine and substituting the dicyanostyrene derived from 2-bromobenzaldehyde instead of the 3-bromoderivative. 'H NMR (300 MHz, d6-DMSO) δ 9.05 (d, IH), 8.53 (s. IH), 8.44 (dd, 1 H), 7.91 (d, IH), 7.83 (s. IH), 7.66 (d, 2H), 7.56 (m, IH), 7.04 (d, IH), 3.93 (s, 3H), 3.77 (m, 4H), 1.67 (m, 4H); MS (ESI) m/z 519/521 (M*+H, 79Br/81Br).
Example 434 4-amino-5-(2-bromophenv0-7-f6-(4-hvdroxypiperidinviy3-pyridyl pyrido[2.3- dlpyrimidine Prepared as described for Example 433 except substituting 4-hydroxypiperidine for 4,4-ethylenedioxypiperidine. IR (KBr pellet) vmax 3485, 3298. 3198, 2938, 2848. 1600, 1574, 1557, 1357, 1225, 1024, 766 cm"1; MS (ESI) m/z 477/479 (M*+H, 79Br/81Br).
Example 435 4-amino-5-(3-bromophenyl -7-(6-(4-N-acetylpiperazinyl)-3-pyridyl')pyrido[2J- djpyrimidine
Prepared as described for Example 370 except substituting 1 -acetylpiperazine for 4-methoxypiperidine.
Η NMR (300 MHz, d6-DMSO) δ 9.09 (d, IH), 8.53 (s, IH), 8.48 (dd, IH), 7.86 (s, IH), 7.85 (s, IH), 7.78 (dt, IH), 7.54 (m, 2H), 7.00 (d, IH), 3.63-3.73 (m, 4H), 3.55-3.59 (m, 4H), 2.06 (s, 3H);
MS (ESI) m/z 504/506 (M*+H, 79Br/81Br).
Example 436 4-amino-5-(3-bromophenyl)-7-(6-(4-cvanopiperidinyl)-3-pyridyl)pyrido[2J-d1pyrimidine Prepared as described for Example 370 except substituting 4-cyanopiperidine for
4-methoxypiperidine, which was prepared as follows: isonipecotamide was heated in POClj at reflux for 2 hours and then was cooled to it. Most of the POCl3 was removed in vacuo, and the remaining syrup was carefully quenched with ice. The melted aqueous solution was extracted with CH2C12, and the combined organic extracts were dried over Na2SO4 Removal of the solvent in vacuo afforded 4-cyanopiperidine as a grey-white semi- solid.
Η NMR (300 MHz, d6-DMSO) δ 9.07 (d, IH), 8.53 (s, IH), 8.45 (dd, IH), 7.85 (m, 2H), 7.76-7.80 (m. IH), 7.52 (m, 2H), 7.02 (d. IH), 3.95-4.02 (m, 2H), 3.46-3.55 (m, 2H), 3.17 (m, IH), 1.94-1.99 (m, 2H), 1.74-1.80 (m, 2H); MS (ESI) m/z 486/488 (M*+H, 79Br/81Br). Example 437 4-amino-5-(3-bromophenvπ-7-(6-(4-N-(4-fluorophenvπpiperazinyl)-3-pyridyl)pyrido[2J- dlpyrimidine Prepared as described for Example 370 except substituting l-(4- fluorophenyl)piperazine for 4-methoxypiperidine.
'H NMR (300 MHz, d6-DMSO) δ 9.10 (d, IH), 8.53 (s, IH), 8.48 (dd, IH), 7.85 (m, 2H), 7.78 (dt, IH), 7.55 (m, 2H), 7.00-7.1 1 (m, 5H), 3.81 (m, 4H), 3.21 (m, 4H); MS (ESI) m/z 556/558 (M*+H, 79Br/81Br).
Example 438 4-amino-5-(4-fluorophenyl)-7-(6-moφholinyl-3-pyridyl)pyrido[2.3-djpyrimidine Prepared as described for Example 370 except substituting moφholine for 4- methoxypiperidine and substituting the dicyanostyrene derived from 4-fluorobenzaldehyde instead of the 3-bromoderivative.
'H NMR (300 MHz, d6-DMSO) δ 9.08 (d, IH), 8.53 (s, IH), 8.47 (dd, IH), 7.83 (s, IH), 7.65 (m, 2H), 7.44 (m, 2H), 6.99 (d, IH), 3.59-3.73 (m, 8H); MS (ESI) m z 403 (M++H).
Example 440
4-amino-5-(3-bromophenyl)-7-(4-moφholinylbenzenesulfonamide pyrido[2.3- dlpyrimidine Step a 3-acetyl-6-moφholinylbenzenesulphonamide
A solution of 4-acetylbenzenesulfonyl chloride in CH2C12 at -78° is treated with 2 equivalents of moφholine. The mixture is stirred at -78° for 1 hour and then warmed to rt and stirred for 2 additional hours. After this time, the mixture is diluted with EtOAc and is washed with water and brine. The solution is dried (Na2SO ) and concentrated in vacuo to afford the desired 3-acetyl-6-moφholinylbenzenesulphonamide. Step b 2-amino-3-cvano-4J3-bromophenyl')-6-(6- moφholinylbenzenesulphonamide)pyridine
3-acetyl-6-moφholinylbenzenesulphonamide is then cyclized as described in example 244. using dicyanostyrene derived from 3-bromobenzaldehyde, to the desired 2- amino-3-cyano-4-(3-bromophenyl)-6-( 6-moφholinylbenzenesulphonamide)pyridine
The material prepared in step b is converted to the title compound by cyclization with trisformamide using conditions described in Example 370.
. Η NMR (300 MHz, d6-DMSO) δ 8.62 (s, IH), 8.60 (d, 2H), 8.05 (s, IH), 7.89-7.92 (m, 3H), 7.81 (dt, IH), 7.53-7.63 (m, 2H), 3.65 (m, 4H), 2.94 (m,4H); MS (ESI) m/z 526/528 (M*+H, 79Br/81Br).
Example 441 4-amino-5-(3-bromophenyl -7-('4-N-1.4-dioxa-8-azaspiro[4.51decan-8- ylbenzenesulfonamide)pyrido[2J-djpyrimidine Prepared as described for Example 440 except substituting 1 ,4-dioxa-8- azaspiro[4.5]decane for moφholine in step a.
Η NMR (300 MHz, d6-DMSO) δ 8.62 (s, IH), 8.58 (d, 2H), 8.05 (s, IH), 7.91-7.93 (m, 3H), 7.80 (dt, IH), 7.53-7.63 (m, 2H), 3.80 (s, 4H), 3.06 (m, 4H), 1.69 (m, 4H); MS (ESI) m/z 582/584 (M*+H, 79Br/81Br).
Example 442 4-amino-5-(3-bromophenyl)-7-(4-N-cvclopropylbenzenesulfonamide)pyrido[2J- dlpyrimidine Prepared as described for Example 440 except substituting n-cyclopropylamine for moφholine in step a.
IR (KBr pellet) vm„ 3478. 3301, 3059. 2847, 2761, 2664, 1730, 1696, 1642, 1579, 1567, 1486. 1349, 1327, 1 156, 1094, 887, 844, 828, 798 cm"1; MS (ESI) 496/498 (M*+H, 79Br/81Br).
Example 443 4-amino-5-(3-bromophenv0-7-(4-piperidinebenzenesulfonamide)pyrido[2J-d]pyrimidine
Prepared as described for Example 440 except substituting piperidine for moφholine in step a
Η NMR (300 MHz, d6-DMSO) δ 8.61 (s. IH), 8.57 (d, 2H). 8.02 (s, IH), 7.88-7.90 (m, 3H), 7.80 (dt, IH), 7.53-7.62 (m, 2H), 2.95 (m, 4H), 1.56 (m. 4H). 1.38 (m, 2H); MS (ESI) 524/526 (M*+H, 79Br/81Br).
Example 444 4-amino-5-(3-bromophenyl)-7-(4-(4-cvanopiperidine)benzenesulfonamide')pyrido~2.3- dlpyrimidine
Prepared as described for Example 440 except substituting 4-cyanopiperidine (prepared in Ex. 436) for moφholine in step a.
'H NMR (300 MHz, d6-DMSO) δ 8.62 (s, IH), 8.60 (d, 2H), 8.05 (s, IH), 7.93 (s, IH), 7.90 (m, 2H), 7.81 (dt, IH), 7.53-7.63 (m, 2H), 3.24 (m, 2H), 2.94 (m, IH), 2.80 (m, 2H), 1.95 (m, 2H), 1.77 (m, 2H);
MS (ESI) 549/551 (M*+H, 79Br/81Br).
Example 445 4-amino-5-(3-bromophenyl)-7-(4-N-cvclopropylmethylbenzenesulfonamide pyrido[2J- dlpyrimidine
Prepared as described for Example 440 except substituting cyclopropylmethylamine for moφholine in step a.
Η NMR (300 MHz, d6-DMSO) δ 8.61 (s, IH), 8.52 (d, 2H), 8.01 (d, IH), 7.96 (d, 2H), 7.79-7.90 (m, 3H), 7.56 (m, 2H), 2.73 (m, 2H), 0.81 (m, IH), 0.34 (m, 2H), 0.09 (m, 2H); MS (ESI) m/z 510/512 (M*+H, 79Br/81Br).
Example 446 4-amino-5-(3-bromophenyl)-7-(4-N.N-dimethylaminobenzenesulfonamide pyrido[2.3- dlpyrimidine Prepared as described for Example 440 except substituting dimethylamine for moφholine in step a.
Η NMR (300 MHz, d6-DMSO) δ 8.62 (s, IH), 8.59 (d, 2H). 8.04 (s, IH), 7.90-7.93 (m, 3H), 7.81 (dt, IH), 7.53-7.63 (m, 2H), 2.67 (s. 6H); MS (ESI) m/z 484/486 (M*+H, 79Br/81Br).
Example 447 4-amino-5-(3-bromophenylV7-(4-N-(SV2- hydroxymethylpyrrolidinebenzenesulfonamide pyrido[2J-djpyrimidine Prepared as described for Example 440 except substituting (S-(+)-2- hydroxymethylpyrrolidine for moφholine in step a.
'H NMR (300 MHz, d6-DMSO) δ 8.61 (s, IH), 8.56 (d, 2H), 8.03 (s, IH), 7.99 (d, 2H), 7.90 (m, IH), 7.81 (dt, IH), 7.53-7.62 (m, 2H), 4.87 (t, IH), 3.57 (m, 2H), 3.12 (m, 2H), 1.79 (m, 2H), 1.44 (m, 2H); MS (ESI) m/z 540/542 (M*+H, 79Br/81Br).
Example 448 4-amino-5-f3-bromophenyl)-7-(4-(4-hvdroxypiperidine)benzenesulfonamide)pyrido[2J- djpyrimidine Prepared as described for Example 440 except substituting 4-hydroxypiperidine for moφholine in step a.
Η NMR (d6-DMSO) δ 8.62 (s, IH), 8.59 (d, 2H), 8.04 (s, IH), 7.90-7.94 (m, 3H), 7.81 (dt, IH), 7.52-7.63 (m, 2H), 4.86 (m, IH), 3.06 (m, 4H), 1.91 (m, 2H), 1.69 (m, 2H); MS (ESI )m/z 540/542 (M*+H, 79Br/8lBr).
Example 449 4-amino-5-(3-bromophenyl)-7-f4-(cis-3.5- dimethylmoφholinyl)benzenesulfonamide pyrido[2J-djpyrimidine Prepared as described for Example 440 except substituting cis-2.6- dimethylmoφholine for moφholine in step a. Η NMR (300 MHz, d6-DMSO) δ 8.62 (s, IH). 8.59 (d, 2H). 8.04 (s, IH). 7.90 (m, 3 H), 7.80 (dt. IH), 7.52-7.61 (m, 2H), 3.53-3.66 (m. 4H). 1.89 (m. 2H), 1.05 (d, 6H); MS (ESI) m/z 554/556 (M*+H. 79Br/81Br).
Example 450
4-amino-5-(3-bromophenyl)-7-(3-fluoro-4-thiomoφholinylphenyl)pyrido[2J- djpyrimidine Prepared as described for Example 370 using steps a and b except substituting 3- fluoro-4-thiomoφholinylacetophenone for 5-acety-2-chloropyridine in step a which was prepared as follows 3',4'-difluoroacetophenone and thiomoφholine are stirred in DMSO at 100° for 12 hours. The mixture is cooled and quenched with water. The resulting beige solid. 3'-fluoro-4'thiomoφholino-acetophenone, was collected by filtration and washed with water.
Η NMR (300 MHz, d6-DMSO) δ 8.55 (s, IH), 8.11 (m, IH), 7.91 (s, IH), 7.86 (m, IH), 7.78 (dt, IH), 7.55 (m, 2H), 7.19 (t, IH), 3.41 (m, 4H), 2.77 (m, 4H); MS (ESI) m/z 496/498 (M+H, 79Br/81Br).
Example 451 4-amino-5-("4-fluorophenvπ-7-(6-(thiomoφholinyl -3-pyridyl)pyrido[2J-d1pyrimidine Prepared as described in Example 370 except substituting thiomoφholine for 4- methoxypiperidine component and dicyanostyrene derived from 4-fluorobenzaldehyde for the 3-bromo derivative.
Η NMR (300 MHz, d6-DMSO) δ 9.06 (d, IH), 8.52 (s, IH), 8.44 (dd, IH), 7.82 (s, IH), 7.64 (m, 2H), 7.44 (m, 2H), 7.01 (d, IH), 4.03 (m, 4H), 2.65 (m, 4H); MS (ESI) m/z 419 (M*+H).
Example 452 4-amino-5-(4-fluorophenyl -7-(6-(4J-dioxothiomoφholinyl)-3-pyridyl)pyrido[2J- dlpyrimidine Prepared by substituting Example 451 for Example 331 as described in Example 332.
'H NMR (300 MHz, d6-DMSO) δ 9J0 (d, IH), 8.53 (s, IH). 8.51 (dd, IH), 7.85 (s, IH). 7.65 (m. 2H), 7.44 (m. 2H), 7.18 (d, IH), 4.18 (m, 4H). 3.18 (m. 4H); MS (ESI) m/z 451 (M*+H).
Example 453 4-methoxy-5-("3-bromophenyl)-7-(6-moφholinyl-3-pyridyl)pyrido[2J-dlpyrimidine Step a 4-hvdroxy-5-(3-bromophenyl)-7-(6-moφholinyl-3-pyridyl pyrido[2,3- djpyrimidine
Example 134 was dissloved in 10:1 acetic acid : water. The mixture was heated to reflux for 1 day and cooled. The desired product was collected by filtration.
The 4-hydroxy-5-(3-bromophenyl)-7-(6-moφholinyl-3-pyridyl)pyrido[2,3- d]pyrimidine was treated with K2CO3 (5 eq) and 18-crown-6 (7 eq) in DMF at rt. After 1 hour, methyl iodide (30 eq) added, and the reaction continued to stir at rt. After 3 hours, the reaction was quenched with water, and the resulting solid was collected by filtration and purified by chromatography to afford the the title compound. Η NMR (300 MHz, d6-DMSO) δ 9.07 (d, IH), 8.60 (s, IH), 8.45 (dd, IH), 7.83 (s, IH), 7.60 (m, 2H), 7.39 (m, 2H), 6.98 (d, IH), 3.61-3.73 (m, 8H), 3.38 (s, 3H); MS (ESI) m/z 478/480 (M*+H, 79Br/81Br).
Example 454 4-amino-5-(3-bromophenyl)-7-f4-(4-dioxa-8-azaspiro[4.5]decan-8- ylcarboxamide)phenyl)pyrido [23 -dlpyrimidine step a 4-acetylbenzoylchloride
4-Acetylbenzoic acid is stirred with thionyl chloride at reflux for 90 min. The solution is cooled to roomtemperature. and the thionyl chloride is removed under reduced pressure. Residual SOCl2 is removed by evaporation with CH2C12, and the remaining yellow residue is used without furthur purification. Step b 4-(4'.4'-ethylenedioxypiperidnyl)acetophenone
4-acetylbenzoylchloride prepared in step a is dissolved in CH2C12 and treated with 3 eq. of 4,4-ethylenedioxypiperidine. The reaction mixture is stirred overnight at rt and is then washed with water and brine. The solution is dried (Na2SO4) and concentrated in vacuo to afford the desired amide.
Step c Example 454 was prepared as described forsteps a and b of Example 370 , substituting the 4-(4',4'-ethylenedioxypiperidnyl)acetophenone prepared above for the 5- acetly-2-chloropyridine in step a. Substituting the 4-(4',4'- ethylenedioxypiperidnyl)acetophenone prepared in step b for the 5 acetyl . Η NMR (300 MHz, d6-DMSO) δ 8.59 (s, IH), 8.39 (d, 2H), 7.97 (s, IH), 7.89 (m, IH), 7.80 (dt, IH), 7.52-7.60 (m, 4H), 3.92 (s, 4H), 3.70 (m, 2H), 3.40 (m, 2H), 1.68 (m, 4H); MS (ESI) m/z 548/548 (M*+H, 79Br/81Br).
Example 455 4-amino-5-(3-bromophenyl)-7-(4-(N-cvclopropylcarboxamide phenvπpyrido[2J- dlpyrimidine Prepared as described for Example 454 except substituting cyclopropyl amine for 4,4-ethylenedioxypiperidine.
Η NMR (300 MHz, d6-DMSO) δ 8.60-8.62 (m, 2H). 8.42 (d. 2H), 7.99 (d, IH), 7.98 (d, IH), 7.52-7.62 (m, 2H), 2.89 (m, IH), 0.67-0.75 (m, 2H), 0.58-0.63 (m, 2H); MS (ESI) m/z 460/462 (M*+H, 79Br/81Br).
Example 456
4-amino-5-(3-bromophenyiy7-(4-(moφholinylcarboxamide phenyQpyrido[2,3- dlpyrimidine Prepared as described for Example 454 except substituting moφholine for 4,4- ethylenedioxypiperidine. Η NMR (300 MHz. d6-DMSO) δ 8.74 (s, IH), 8.41 (d, 2H), 7.98 (s, IH), 7.89 (m, IH), 7.80 (dt. 1 h), 7.52-7.61 (m. 4H). 3.52-3.71 (m, 8H); MS (ESI) m/z 490/492 (M*+H, 79Br/81Br).
Example 457
4-amino-5-(3-bromophenyl)-7-(6-N-cvclopropylamino-3-pyridv0pyrido[2J-d]pyrimidine
Prepared as described for Example 370 except substituting cyclopropyl amine for 4-hydroxypiperidine.
Η NMR (300 MHz, d6-DMSO) δ 8.99 (d, IH), 8.52 (s, IH), 8.40 (dd, IH), 7.83 (m, IH), 7.76-780 (m, 2H), 7.51-7.58 (m, 2H), 7.40 (d, IH), 6.73 (d, IH), 2.62 (m, IH), 0.76 (m, 2H), 0.48 (m, 2H); MS (ESI ) m z 433/435 (M*+H, 79Br/81Br).
Example 458 4-amino-5-(3-bromophenyl)-7-(4-(4-hvdroxypiperidinylcarboxamide)phenyls)pyrido[2J- dlpyrimidine Prepared as described for Example 454 except substituting 4-hydroxypiperidine for 4,4-ethylenedioxypiperidine.
Η NMR (300 MHz, d6-DMSO) δ 8.59 (s, IH), 8.40 (d, 2 H), 8.25 (s, IH), 7.97 (s, IH), 7.89 (t, IH), 7.79 (dt, IH), 7.56 (m. 3H), 5.06 (m, IH), 3.96 (m, 2H), 3.48 (m, 2H), 1.93 (m, 2H), 1.64 (m, 2H); MS (ESI) m/z 504/506 (M*+H, 79Br/81Br).
Example 459 4-amino-5-('3-bromophenvπ-7-(6-(S -hvdroxymethylpyrrolidinyl-3- pyridazinyl)pyrido[2J-d]pyrimidine Prepared as described for Example 367 except substituting (S)-(+)-2- hydroxymethlypyrrolidine for (lS,4S)-2-aza-5-oxa-bicyclo[2.2J]heptane Η NMR (300 MHz, d6-DMSO) δ 8.58 (s, IH), 8.38 (d. IH), 8.26 (s. IH), 7.84 (m. IH), 7.81 (dt, IH). 7.57 (2 overlapping m, 2H), 7.16 (br d. 1. H), 4.91 (t, IH), 3.63 (m. 2H), 3.44 (m, 2H), 2.05 (m, 4H); MS (ESI) m/z 478/480 (M*+H, 79Br/81Br).
Example 460 4-amino-5-(3-bromophenyl)-7-(6-(4-(2-ethoxyethoxy)piperidinyl)-3-pyridvπpyrido[2J- d] pyrimidine Prepared as described for Example 370 except substituting 4-(2- ethoxyethoxy)piperidine for 4-methoxypiperidine, which was prepared as follows. 4- Hydroxypiperidine is treated with 1 eq. of Boc2O in CH2C12 and stirred at rt for 5 min. The solution is then washed with water and brine, dried over Na2SO4, and concentrated in vacuo. The protected species is then dissolved in DMF and treated with 7 eq. of NaH. The mixture is stirred for 5 min, then 2-ethoxy- 1 -chloroethane (2 eq) is added, and the reaction is stirred at rt overnight. After this time, it is quenched with water and extracted with 2:1 ether-hexanes. The organic solution is dried (Na2SO4) and concentrated in vacuo. The oil thus obtained is finally stirred in 4M HCl-dioxane for 30 minutes. The solvent was removed in vacuo, then the residue was basified with 50% aq. NaOH solution and extracted with ether. Drying (Na2SO4) of the extracts, followed by removal of the solvent in vacuo, afforded the desired 4-alkoxy-piperidine.
Η NMR (300 MHz, d6-DMSO) δ 9.05 (d, IH), 8.52 (s, IH), 8.43 (dd, 1 H). 7.85 (m, 2H), 7.78 (dt, IH), 7.53 (m, 2H), 6.99 (d, IH), 4.07 (m, 2H), 3.56 (m, 2H), 3.48 (m, 2H), 3.45 (q, 2H), 3.29 (m, 2H), 3.27 (m, IH), 1.92 (m, 2H), 1.45 (m, 2H), 1.10 (t, 3H); MS (ESI) m/z 549/551 (M*+H, 79Br/81Br).
Example 461 4-amino-5-(3-bromophenyl)-7-(6-hexahvdropyrimidine )-3-pyridyl)pyrido[2J- dlpyrimidine Prepared as described for Example 370 except substituting hexahydropyrimidine for 4-methoxypiperidine, which was prepared according to Shustov, et al Tetrahedron 1985. 41. 5719.
'H NMR (300 MHz, d6-DMSO) δ 9.23 (d, IH), 8.89 (s, IH), 8.58 (dd, IH), 8.21 (s, IH), 7.95 (m. IH). 7.83 (m, IH), 7.61 (m, 2H), 7.29 (d, IH), 5J3 (m, IH). 3.91 (m, 2H), 3.69 (m, 2H). 3.32 (m, 2H), 1.83 (m, 2H); MS (ESI) m/z 462/464 (M*+H, 79Br/81Br).
Example 462 4-amino-5-(4,4-difluorocyclohxeyl)-7-(6-(1.4-dioxa-8-azaspiro[4.5]decan-8-yl -3- pyridvDpyrido!2.3-d1pyrimidine
Prepared as described for Example 370 except substituting 4,4- difluorocyclohexylcarboxaldehyde for 3-bromobenzaldehyde and 4,4- ethylenedioxypiperidine for for 4-methoxypiperidine. The 4,4- difluorocyclohexylcarboxaldehyde was prepared as follows: 4-Oxo-cyclohexanecarboxylic acid ethyl ester was stirred with 10 eq of (diethylamino)sulfur trifluoride in benzene at rt for 24 hours. The mixture was diluted with ether and was quenched carefully with saturated NaHCO3 solution. The organic solution was separated, washed with brine, and concentrated in vacuo to afford 4,4-difluoro-cyclohexanecarboxylic acid ethyl ester. This material was treated with 1 eq. of DIBAL-H in dry ether at -78° to afford, after workup, 4,4-difluoro-cyclohexanecarboxaldehyde.
Η NMR (300 MHz, d6-DMSO) δ 9.13 (d, IH), 8.79 (s, IH), 8.44 (dd, IH). 8.06 (s, IH), 7.10 (d. IH), 3.94 (s, 4H), 3.82 (m, 4H), 1.70 (m, 4H); MS (ESI) m/z 483 (M*+H).
Example 463
4-amino-5-(3-bromophenvπ-7-(6-(R)-2-ethoxyethoxypyrrolidinyl)-3-pyridyl pyrido[2J- dlpyrimidine Prepared as described for Example 370 except substituting (S???)-2- ethoxyethoxypyrrolidine for for 4-methoxypiperidine. (R)-2-ethoxyethoxypyrrolidinyl was prepared as follows: (R)-(+)-3-Pyrrolidinol is treated with 1 eq. of Boc20 in CH2C12 and stirred at rt for 5 min. The solution is then washed with water and brine, dried over Na^SO , and concentrated in vacuo. The protected species is then dissolved in DMF and treated with 7 eq. of NaH. The mixture is stirred for 5 min. then 2-ethoxy-l-chloroethane (2 eq) is added, and the reaction is stirred at rt overnight. After this time, it is quenched with water and extracted with 2:1 ether-hexanes. The organic solution is dried (Na2SO4) and concentrated in vacuo. The oil thus obtained is finally stirred in 4M HCl-dioxane for 30 minutes. The solvent was removed in vacuo, then the residue was basified with 50% aq. NaOH solution and extracted with ether. Drying (Na2SO4) of the extracts, followed by removal of the solvent in vacuo, afforded the 3-alkoxy-pyrrolidine derivative.
Η NMR (300 MHz, d6-DMSO) δ 9.06 (d, IH), 8.52 (s, IH), 8.44 (dd, IH). 7.84 (m, 2H), 7.79 (dt, IH), 7.56 (2 overlapping m, 2H), 6.62 (br d, IH). 4.24 (m, IH), 3.58 (m, 4H), 3.48 (m. 4H), 3.42 (q, 2H), 2.10 (m, 2H), 1.09 (t, 3H); MS (ESI) m/z 535/537 (M*+H, 79Br/8lBr).
Example 464 4-amino-5-(3-bromophenviy7-(6-(cis-3.4-dihvdroxypyrolidinvI")-3-pyridyl)pyridor2,3- dlpyrimidine Was prepared from Example 603 by treatment with 0J eq. OsO and 1.2 eq. NMO in 10% MeOH-CH2Cl2 and the mixture was refluxed for 13 hours and was then quenched with water and filtered. The solid thus obtained was purified by recrystallization to afford the title compound.
Η NMR (300 MHz, d6-DMSO) δ 9.05 (d, IH), 8.52 (s, IH), 8.44 (dd, IH), 7.85-7.77 (m, 3H), 7.58-7.5 (m, 2H), 6.58 (d, IH), 5.0 (d, 2H), 4.17 (m. 2H), 3.6 (m, 2H). MS m/z 480 (M+H)*
Example 465 4-amino-5-(3-bromophenyl)-7-(6-((3aR.6aS)-2-oxo-tetrahvdro-3aH-[1.31dioxolo[4.5- c]pyrrol-5-yl)-3-pyridyl)pyrido~2.3-d1pyrimidine Example 464 was stirred with 5 eq. of carbonyl diimidazole and 12 eq. of imidazole in DMSO at 100° for 12 hours. The solution was then cooled, quenched with water, and the resulting solid was collected by filtration and washed with water. Purification by chromatography afforded the title compound. Η NMR (300 MHz, d6-DMSO) δ 9.10 (d, IH). 8.54 (s, IH), 8.51 (dd, IH), 7.87 (m, 2H), 7.78 (dt, 1 H), 7.54 (m, 2H), 6.91 (d, IH), 5.48 (m, 2H), 4.18 (d, 2H), 3.48 (m, 2H); MS (ESI) m/z 505/507 (M*+H, 79Br/81Br).
Example 466 4-amino-5-(3-bromophenyl)-7-(6-(cis-2.3-dihvdroxypyrrolidinyl)-3- pyridazinvDpyrido [2 ,3 -djpyrimidine Prepared as described for Example 370 except substituting pyrroline for for 4- methoxypiperidine and subsequent oxidation of this material by the following procedure: treatment with 0J eq. OsO4 and 1.2 eq. NMO in 10% MeOH-CH2Cl2 containing a few drops of glacial acetic acid. The mixture was refluxed for
13 hours and was then quenched with water and filtered. The solid thus obtained was purified by recrystallization to afford the title compound.
Η NMR (300 MHz, d6-DMSO) δ 8.93 (s, IH), 8.47 (s, IH), 8.31 (d, IH), 7.92 (t, IH), 7.83 (dt, IH), 7.59 (m, 2H), 7.20 (d, IH), 4.23 (m, 2H), 3.55 (m, 4H); MS (ESI) m/z 480/482 (M*+H, 79Br/81Br).
Example 467 4-amino-5-(3-bromophenyl)-7-(6-(S.R-2-hvdroxymethyl-4-hvdroxypyrrolidinyl)-3- pyridvDpyrido 23 -djpyrimidine Prepared as described for Example 370 except substituting (S,R)-2- hydroxymethyl-4-hydroxypyrrolidine for 4-methoxypiperidine, which was prepared as follows: N-Boc-hydroxyproline was treated with BH3-SMe2 (4 eq) in ether at roomtemperature. After 16 hours, the reaction was quenched with water and K2CO3 and was extracted with EtOAc. The combined extracts were dried and concentrated in vacuo to afford N-Boc-hydroxyprolinol. The Boc group was then removed (HCl-dioxane, rt). Η NMR (300 MHz, d6-DMSO) δ 9.05 (d, IH). 8.52 (s, IH), 8.42 (dd, IH), 7.82 (m, 2H), 7.78 (dt, 1 H). 7.54 (m. 2H), 6.66 (d. IH). 5.02 (d. IH). 4.95 (t, IH), 4.47 (m, IH), 4.23 (m, IH), 3.46-3.66 (m. 4H), 2.16 (m. IH). 1.96 (m. IH); MS (ESI) m/z 493/495 (M*+H. 79Br/81Br).
Example 468 4-amino-5-(3-bromophenyl)-7-(6-(R-2-hvdroxymethyl-4-pyrrolidinyl)-3- pyridazinyl)pyrido[2J-dlpyrimidine Prepared as described for Example 367 except substituting R-2- hydroxymethylpyrrolidine for (1 S,4S)-2-aza-5-oxa-bicyclo[2.2J]heptane
Η NMR (300 MHz, d6-DMSO) δ 8.58 (s, IH), 8.38 (d, IH), 8.26 (s, IH), 7.84 (m, IH), 7.80 (dt, IH), 7.56 (2 overlapping m, 2 H), 7.16 (d, IH), 4.89 (t, IH), 4.23 (br, IH), 3.62 (m, 2H), 3.45 (m, 2H), 2.05 (m, 4H); MS (ESI) m/z 478/480 (M*+H, 79Br/81Br).
Example 469
4-amino-5-(3-bromophenyl)-7-('6-((' 1 S.4SV2-oxa-5-azabicvclor2.2.11heptan-5-vIV3- pyridyl)pyridol2.3 -dlpyrimidine Prepared as described for Example 370 except substituting (lS,4S)-2-oxa-5- azabicyclo[2.2J]heptane for 4-methoxypiperidine. which was prepared according to Portoghese. et al j. Med. Chem 1971, 14, 288
'H NMR (300 MHz, d6-DMSO) δ 9.05 (d, IH). 8.52 (s, IH), 8.43 (dd, IH), 7.82 (m, 2H), 7.78 (dt, 1 H). 7.57 (m, 2H), 6.67 (m, IH), 5.01 (s, IH), 4.71 (s, IH), 3.82 (dd, IH), 3.68 (d, IH), 3.54 (dd, IH), 3.38 (d, IH), 1.93 (m, 2H); MS (ESI) m/z 475/477 (M*+H, 79Br/8lBr).
Example 470 4-amino-5-f3-bromophenyl)-7-(6-(2-imidizolidone-l-yl)-3-pyridyl)pyrido[2J- dlpyrimidine Prepared as described for Example 370 except substituting 1 ,2-ethanediamine for 4-methoxypiperidine and the resulting crude product was stirred in DMSO with carbonyl diimidazole (4.7 eq) and imidazole (9 eq) at 100° for 16 hours. Solution quenched with water, then the solvent was removed by lyophilization. Chromatography of the residue afforded the title compound.
IR (KBr pellet) vma 3363, 3201, 3122. 3049. 2941. 1734, 1645, 161 1 , 1566. 1484. 1381, 1270, 1 162, 1058, 808, 781. 767 cm 1; MS (ESI) 462/464 (M=+H, 79Br/81Br).
Example 472 4-amino-5-(l J-dimethyl-3-butenyl)-7-(6-moφholinyl-3-pyridyl)pyrido[2J-d]pyrimidine A mixture of 7.6 mmol of 2,2-dimethyl-4-pentenal (Aldrich Chemical Co.), 24.4 mmol of l-moφholino-5-acetylpyridine. 7.6 mmol of malononitrile. and 29 mmol of ammonium acetate in ethylene dichloride was heated at 120 °C in a sealed tube for 16 hours. The reaction was cooled, poured into dichloromethane, and washed with water. The organic phase was dried over Na2SO4, concentrated in vacuo, and purified by flash chromatography, eluting with ethyl acetate/dichloromethane to give the intermediate product pyridine.
A mixture of 1.7 mmol of this intermediate pyridine, and 45 mg of ammonium sulfate was heated in 10 mL of triethyl ortho formate at 140 °C in a sealed tube for one hour. After cooling, the reaction was poured into 40 mL of 2-M ammonia in ethanol with stirring. After 24 hours, 300 mL of hexane was added, and the solid collected by filtration to give the intermediate amidine. A mixture of 0.87 mmol of this intermediate amidine and 3 mmol of potassium t-butoxide in 10 mL of dioxane was heated at 135 °C in a sealed tube for 16 hours. After cooling, the reaction was poured into dichloromethane, washed with water, and dried over sodium sulfate. The residue was purifed by flash chromatography, eluting with methanol/dichloromethane, to give the title compound as a yellow glass.
CHN analysis calculated for C22H26N6O(0.5 Methanol) C 66.48, H 6.94, N 20.67: found: C 66.18. H 6.83. N 20.65. MS (FAB) calc for C22H27N6O: 391.2246; found: 391.2238. IR 3417. 3340, 2965. 2853. 1603. 1584. 1563, 1533, 1241 cm J Example 473 4-amino-5-(3-bromophenyl -7-(6-(2J-dioxo-(lHJH)-quinazolin-3-yl)-3- A solution of 4-aminoacetophenone and triethylamine in toluene at -78 C was treated with phosgine, warmed to ambient temperature and concentrated under reduced pressure to give 4-isocyanateacetophenone. This product was reacted with ethyl 2- aminobenzoate in refluxing THF for 16 hours, cooled and treated with IM potassium tert- butoxide to give after silica gel purification 3-(4-acetylphenyl)-2,4(lH,3H)- quinazolinedione. Using the procedure in Example 244c except substituting 2,4(1 HJH)- quinazolinedione for N-methyl-5-acetylindoline gave the title compound. MS (APCI +) m/z 537 (M+H)*;
Η NMR (300 MHz, DMSO-d6) δ 8.59 (s, IH), 8.35 (m, 2H), 7.97 (s, IH), 7.91 (t, IH), 7.78 (m, IH), 7.71 (dd, IH), 7.63 (m, IH), 7.55 (t, IH), 7.35-7.24 (m, 3H), 6.92 (d, IH), 6.72 (dt, IH).
Example 474 4-amino-5-(3-bromophenyl -7-(6-carboxamide-3-pyridazinyl)pyridor2J-d1pyrimidine Prepared as described in Example 475 except substituting ammonia for moφholine.
MS (APCI +) m/z 422 (M+H)*;
Η NMR (300 MHz, DMSO-d6) δ 8.87 (d, IH), 8.66 (s, IH), 8.62 (bs, IH), 8.44 (d, IH),
8.42 (s, IH), 8.07 (bs, IH), 7.88 (m, IH), 7.83 (m, IH), 7.63 (m, IH), 7.58 (t, IH).
Example 475
4-amino-5-(3-bromophenyl)-7-(6-morpholinylcarboxamide-3-pyridazinv0pyridof2,3- djpyrimidine A solution of 3-chloro-6-pyridazinoyl chloride (Mourad et al.; J. Heterocycl. Chem., 29 6, (1992), ppl583-1592)) and triethylamine in dichloroethane was treated with moφholine to give 3-chloro-6-moφholinocarboxamide pyridazine. This intermediate was then treated with tributyl ethoxyvinyl tin under Stille conditions to give 3-acetyl-6- moφholinocarboxamide pyridazine. Treatment of thisjntermediate as in Example 246 replacing 3-acetyl-6-dimethylaminopyridazine gave the title compound. MS (APCI +) m/z 492 (M+H)*; 'H NMR (300 MHz, DMSO-d6) δ 8.84 (d, IH), 8.66 (s, IH), 8.42 (s, IH), 8.17 (d, IH), 7.89 (t. IH), 7.84 (m. IH), 7.65 (m, IH), 7.57 (t, IH), 3.74 (s, 4H), 3.61 (m, 2H), 3.51 (m, 2H).
Example 476 4-amino-5-f3-bromophenviy7-(6-methoxy-3-pyridazinv0pyrido[2J-d1pyrimidine
Prepared as described for Example 369 replacing benzyl alcohol with methanol. Treatment with excess 4 M HCl in dioxane followed by lyophilization gave the title compound as the HCL salt. MS (APCI +) m/z 409 (M+H)*; Η NMR (300 MHz, DMSO-d6) δ 9.90 (bs, IH), 8.93 (s, IH), 8.54 (d, IH), 8.52 (s, IH), 7.94 (t, IH), 7.68 (m, IH), 7.67 (m, IH), 7.60 (d, IH), 7.54 (d, IH), 4.15 (s, 3H).
Example 477 4-amino-5-(3-bromophenvπ-7-(6-N.N-diethoxyethylamino-3-pyridazinyl)pyridor2J- djpyrimidine
Prepared following the procedure in Example 246 replacing dimethylamine with bis(2-ethoxyethyl)amine. Treatment with excess 4 M HCl in dioxane followed by lyophilization gave the title compound as the di-HCL salt. MS (APCI +) m z 538 (M+H)*; Η NMR (300 MHz, DMSO-d6) δ 10.11 (bs, IH), 8.89 (s, IH), 8.40 (s, IH), 8.26 (d, IH), 7.89 (m. IH), 7.81 (d, IH), 7.64 (d, IH). 7.58-7.46 (m, 3H), 3.88 (m, 4H). 3.63 (t, 4H). 3.44 (q. 4H). 1.09 (t, 6H).
Example 478 4-amino-5-(3-bromophenyl )-7-(6-(4-ethoxymethylpiperidinvπ-3-pyridazinyl pyridor2,3- dlpyrimidine 4-Hydroxymethyl piperidine was treated sequentially with di-tert-butyl dicarbonate, iodoethane. and trifluoroacetic acid to give 4-ethoxymethyl piperidine which was reacted as in Example 367 replacing (lS,4S)-2-aza-5-oxa-bicyclo[2.2J]heptane. Treatment with excess 4 M HCl in dioxane followed by lyophilization gave the title compound as the di-HCL salt. MS (APCI +) m/z 520 (M+H)*;
'H NMR (300 MHz, DMSO-d6) δ 10.08 (bs, IH), 8.91 (s, IH), 8.40 (s, IH), 8.28 (d, IH), 7.89 (s, IH), 7.82 (d, IH), 7.64 (d, IH), 7.57 (t, IH), 7.48 (bs, IH), 4.56 (bd, 2H), 3.40 (q, 2H), 3.24 (d, 2H). 3.11 (t, 2H), 1.92 (m. IH), 1.81 (d. 2H), 1.22 (m, 2H). 1.18 (t, 3H).
Example 479 4-amino-5-(3-bromophenyl')-7-(6-(4-(4-tetrahvdropyranyloxymethyl)piperidinyl)-3- pyridazinvDpyrido[2J-djpyrimidine
4-Hydroxymethyl piperidine was treated sequentially with di-tert-butyl dicarbonate, methanesulfonyl chloride, sodium 4-tetrahydropyranoxide, and ethereal HCl to give 4-(4-tetrahydropyran)oxymethyl piperidine which was reacted as in Example 367 replacing (lS,4S)-2-aza-5-oxa-bicyclo[2.2J]heptane. Treatment with excess 4 M HCl in dioxane followed by lyophilization gave the title compound as the HCL salt. MS (APCI +) m/z 576 (M+H)*;
Η NMR (300 MHz, DMSO-d6) δ 9.89 (bs, IH), 8.88 (s, IH), 8.44 (s, IH), 8.24 (d, IH), 7.89 (t, IH), 7.81 (m, IH), 7.64 (m, IH), 7.57 (t, IH), 7.50 (d, IH), 7.31 (bs, IH), 4.55 (bd, 2H), 3.78 (m, 2H), 3.52-3.22 (m, 5H), 3.07 (t, 2H), 1.89-1.79 (m, 5H), 1.41-1.16 (m, 4H).
Example 480 4-amino-5-(3-bromophenyl)-7-(6-(4-ethoxyethoxymethylpiperidinyl -3- Pyridazinyl)pyrido[2.3-djpyrimidine 4-Hydroxymethyl piperidine was treated sequentially with di-tert-butyl dicarbonate, 2-chloroethyl ethyl ether and ethereal HCl to give 4-ethoxyethoxymethyl piperidine which was reacted as in Example 367 replacing (l S,4S)-2-aza-5-oxa- bicyclo[2.2J]heptane. Treatment with excess 4 M HCl in dioxane followed by lyophilization gave the title compound as the HCL salt. MS (APCI +) m/z 564 (M+H)*; "H NMR (300 MHz, DMSO-d6) δ 10.13 (bs. IH), 8.90 (s. IH), 8.33 (s, IH), 8.29 (d, IH), 7.88 (s. IH), 7.81 (d, IH), 7.74 (d, IH), 7.63 (d, IH), 7.54 (t, IH), 7.50 (s, IH), 4.55 (bd, 2H), 3.50-3.38 (m, 6H), 3.28 (d, 2H), 3.15 (t, 2H), 1.93 (m, IH), 1.82 (d, 2H), 1.26 (m, 2H), 1.08 (t, 3H).
Example 481
4-amino-5-(3-bromophenyl -7-(6-N-methyl-N-l J-dioxalanemethylamino )-3- pyridazinvDpyrido^J-djpyrimidine Prepared as described for Example 367 replacing (lS,4S)-2-aza-5-oxa- bicyclo[2.2J]heptane with 2-methylaminomethyl- 1,3-dioxolane. MS (APCI +) m/z 494 (M+H)*;
Η NMR (300 MHz, DMSO-d6) δ 8.59 (s, IH), 8.38 (d, IH), 8.27 (s, IH), 7.85-7.77 (m, 2H), 7.62-7.53 (m, 2H), 7.35 (d, IH), 5.10 (t, IH), 3.97-3.77 (m, 6H), 3.24 (s, 3H).
Example 482 4-amino-5-("3-bromophenyl)-7-(6-(l J-dioxaspiro[4.5]decanyl-8-oxy -3- pyridazinyl pyrido~2.3-dlpyrimidine Treatment of l,4-dioxaspiro[4.5]decan-8-one with lithium aluminum hydride in diethyl ether provided l,4-dioxaspiro[4.5]decan-8-ol which was subsequently treated as in Example 369 replacing benzyl alcohol to give the title compound. MS (APCI +) m/z 535 (M+H)*;
Η NMR (300 MHz, DMSO-d6) δ 8.62 (s, IH), 8.60 (d, IH), 8.28 (s, IH), 7.85-7.77 (m, 2H), 7.60 (m. 2H), 7.40 (d, IH), 5.42 (m, IH). 3.90 (s, 4H), 2.10-1.55 (m, 8H).
Example 483 4-amino-5-(3-bromophenyl)-7-(6-dihvdroxymethylmethoxy-3-pyridazinyl)pyrido 2.3- dlpyrimidine Prepared as described for Example 369 replacing benzyl alcohol with cis 1,3-0- benzylidene glycerol. Treatment with excess 4 M HCl in dioxane followed by lyophilization gave the title compound as the HCL salt. MS (APCI +) m/z 469 (M+H)*;
Η NMR (300 MHz, DMSO-d6) δ 10.05 (bs, IH), 8.93 (s, IH), 8.51 (d, IH). 8.50 (s, IH), 7.92 (s, IH), 7.82 (d, IH). 7.66 (d, IH), 7.59 (t, IH), 7.53 (d. IH), 4.59 (dd. 2H), 4.45 (dd, 2H), 3.90 (m, IH), 3.45 (m, 2H).
Example 484 4-amino-5-(3-bromophenyl)-7-(6-(3-pyridyloxy -3-pyridazinyl )pyrido 2J-d]pyrimidine Prepared as described for Example 369 replacing benzyl alcohol with 3- hydroxypyridine. Treatment with excess 4 M HCl in dioxane followed by lyophilization gave the title compound as the di-HCL salt. MS (APCI +) m/z 472 (M+H)+;
Η NMR (300 MHz, DMSO-d6) δ 10.10 (bs, IH), 8.98 (s, IH), 8.69 (d, IH), 8.67 (s, IH), 8.56 (dd, IH), 8.51 (s, IH), 7.93-7.79 (m, 4H), 7.68-7.53 (m, 4H).
Example 485
4-amino-5-(3-bromophenyl)-7-(6-(4J-epoxy-7-methyl-2.3.3AJ.5.6.7Ja-octahydro-lH- isoindolyl)-3-pyridazinvPpyrido[2,3-d1pyrimidine Prepared as described for Example 367 replacing (lS,4S)-2-aza-5-oxa- bicyclo[2.2J]heptane with 4,7-epoxy-7-methyl-2,3JA,4,5,6,7,7a-octahydro-lH-isoindole hydrochloride (SALOR) and adding potassium carbonate. Treatment with excess 4 M HCl in dioxane followed by lyophilization gave the title compound as the di-HCL salt. MS (APCI +) m/z 530 (M+H)*;
Η NMR (300 MHz. DMSO-d6) δ 10.03 (bs, IH), 8.93 (s, IH), 8.46 (s, IH). 8.30 (d, IH), 7.92 (m, IH), 7.83 (dd, IH), 7.67-7.52 (m, 3H), 7.26 (d, IH). 4.33 (d, IH), 3.95-3.32 (m, 4H), 2.78 (m, IH), 2.66 (m, IH), 1.72-1.44 (m, 4H). 1.42 (s, 3H). Example 486 . 4-amino-5-(3-bromophenyl)-7-(6-(4-N-ethyl-N-methoxyethyl)-3-pyridazinvπpyrido[2J- djpyrimidine Boc-piperidine-4-carboxylic acid was coupled with N-ethylmethoxyethylamine using standard amide formation conditions to give Boc-piperidine-4-(N- ethylmethoxyethyl) carboxamide. This material was treated with HCl and the resulting amine was reacted as in Example 367 replacing (lS,4S)-2-aza-5-oxa-bicyclo[2.2J]heptane to give the desired prduct. Treatment with excess 4 M HCl in dioxane followed by lyophilization gave the title compound as the di-HCL salt. MS (APCI +) m/z 591 (M+H)*;
'H NMR (300 MHz, DMSO-d6) δ 10.00 (bs, IH), 8.93 (s, IH), 8.50 (s, IH), 8.27 (d, IH), 7.92 (m, IH), 7.83 (d, IH), 7.67-7.45 (m, 4H), 4.59 (d, 2H), 3.55-2.95 (12H), 1.80-1.52 (m, 4H), 1.05 (t, 3H).
Example 487 4-amino-5-(3-bromophenyl)-7-(6-(4-N-methyl-N-methoxyethyl)-3- pyridazinyl)pyrido[2,3-d1pyrimidine The title compound was preparedfollowing the procedure of Example 486 replacing N-ethylmethoxyethylamine with N-methylmethoxyethylamine. MS (APCI +) m/z 577 (M+H)*;
'H NMR (300 MHz, DMSO-d6) δ 10.07 (bs, 1), 8.91 (s, IH), 8.45 (s, IH), 8.28 (d, IH), 7.90 (m, IH), 7.82 (dd, IH), 7.67-7.53 (m, 3H), 7.48 (bs, IH), 4.56 (bd, IH), 3.62-3.05 (m, 8H), 3.53 (s, 3H), 3.10 (s, 3H), 1.84-1.54 (m, 4H).
Example 488
4-amino-5-(3-bromophenyl)-7-(6-(3.4-dimethoxymethoxypyrrolidinyl)-3- pyridazinv0pyrido[2J-djpyrimidine Prepared as described for Example 367 replacing (l S.4S)-2-aza-5-oxa- bicyclo[2.2J]heptane with cis-3.4-bis(methoxymethoxy) pyrrolidine (Rosenberg et al.; J Med Chem 33, 7 (1990) pp 1962- 1969). MS (APCI +) m/z 568 (M+H)*;
Η NMR (300 MHz, DMSO-d6) δ 8.58 (s, IH). 8.40 (d, IH), 8.26 (s, IH). 7.85-7.76 (m, 2H), 7.62-7.50 (m, 2H), 7J2 (d, IH), 4.72 (m. 4H), 4.37 (m, 2H), 3.80 (bm, 2H), 3.63 (bm, 2H), 3.32 (s, 6H).
Example 489 4-amino-5-(3-bromophenyl -7-(6-('hexahvdro-lH-furo[3.4-cjpyrrol-5-yl)-3- pyridazinyl)pyrido[2J-d1pyrimidine Prepared as described for Example 367 replacing (lS,4S)-2-oxa-5- azabicyclo[2.2Jjheptane with hexahydro-lH-furo[3J-c]pyrrole (US Patent 3910950, ICI United States Inc. 1975). Treatment with excess 4 M HCl in dioxane followed by lyophilization gave the title compound as the di-HCl salt. MS (APCI +) m/z 490 (M+H)+;
•H NMR (300 MHz, DMSO-d6) δ 10.01 (bs, IH), 8.93 (s, IH), 8.48 (s, IH), 8.30 (d, IH), 7.90 (m, IH), 7.84 (m, IH), 7.65 (m, IH), 7.57 (t, IH), 7.48 (bs, IH), 7.20 (d, IH), 3.85 (m, 4H), 3.68-3.45 (m, 4H), 3.12 (m, 2H).
Example 490 4-amino-5-('3-bromophenyl)-7-(6-('hexahvdro-lH-furo[3J-cjpyrrol-5-yl)-3- pyridyl pyrido[2J-d]pyrimidine Prepared as described for Example 370 replacing 4-methoxypiperidine with hexahydro-lH-furo[3,4-c]pyrrole (US Patent 3910950. ICI United States Inc. 1975). Treatment with excess 4 M HCl in dioxane followed by lyophilization gave the title compound as the di-HCL salt. MS (APCI +) m/z 489 (M+H)*; Η NMR (300 MHz, DMSO-d6) δ 9.98 (bs, IH), 9.03 (d, IH), 8.88 (s, IH). 8.67 (dd, IH). 8.22 (s, IH). 7.95 (m, IH), 7.82 (dd. IH). 7.64 (d, 1H)..7.55 (t, IH), 7.34 (bs. IH), 7.03 (d. 1H), 3.90-3J 1 (m. 10H).
Example 491
4-amino-5-(3-bromophenyl)-7-(6-(trans-3-hvdroxy-4-methylpyrrolidinyl)-3- pyridazinyl pyrido[2.3-d]pyrimidine Prepared as described for Example 367 replacing (lS,4S)-2-aza-5-oxa- bicyclo[2.2J]heptane with (anti)- 3-hydroxy-4-methylpyrrolidine hydrochloride (PCT Int.Appl. (1992) WO9210191) and adding potassium carbonate. Treatment with excess 4 M HCl in dioxane followed by lyophilization gave the title compound as the di-HCL salt. MS (APCI +) m/z 478 (M+H)*;
Η NMR (300 MHz, DMSO-d6) δ 10.06 (s, IH), 8.93 (s, IH), 8.42 (s, IH), 8.35 (d, IH), 7.91 (m, IH), 7.84 (dd, IH), 7.65 (dd, IH), 7.57 (t, IH). 7.50 (bs, IH), 7.35 (d, IH), 4.02 (m, IH), 3.95-3.30 (m, 5H), 2.27 (m, IH), 1.05 (d, 3H).
Example 492 4-amino-5-(3-bromophenyl)-7-(6-(trans-3-hydroxy-4-methylpyrrolidinyl -3- pyridyl)pyrido[2J-d]pyrimidine Prepared as described for Example 370 replacing 4-methoxypiperidine with (anti)-
3-hydroxy-4-methylpyrrolidine hydrochloride (PCT Int.Appl. (1992) WO9210191) and potassium carbonate. Treatment with excess 4 M HCl in dioxane followed by lyophilization gave the title compound as the di-HCL salt. MS (APCI +) m/z 477 (M+H)*; Η NMR (300 MHz, DMSO-d5) δ 10.12 (bs, IH), 9.00 (d, IH). 8.90 (s, IH). 8.78 (dd, IH), 8.26 (s, IH), 7.97 (s, IH), 7.82 (d, IH), 7.64 (d, IH), 7.57 (t, IH), 7.42 (s. IH), 7.20 (d, IH). 4.07-3.30 (m, 6H), 2.30 (m, IH), 1.03 (d, 3H).
Example 493 4-amino-5-(3-bromophenyl)-7-(6-(cis-3-hvdroxy-4-methylpyrrolidinyl)-3- pyridazinyl pyrido~2J-d1pyrimidine Prepared as described for Example 367 replacing (lS.4S)-2-aza-5-oxa- bicyclo[2.2J]heptane with (anti)- 3-hydroxy-4-methylpyrrolidine hydrochloride (PCT Int.Appl. ( 1992) WO9210191) and potassium carbonate. Treatment with excess 4 M HCl in dioxane followed by lyophilization gave the title compound as the di-HCL salt. MS (APCI +) m/z 478 (M+H)*;
'H NMR (300 MHz, DMSO-d6) δ 10.18 (bs, IH), 8.92 (s, lH), 8.42 (d, IH), 8.26 (s, IH), 7.91 (s, IH), 7.83 (d, IH), 7.70-7.51 (m, 4H), 4.40-3.64 (m, 5H), 3.30 (t, IH), 2.38 (m, IH), 1.18 (d, 3H).
Example 494 4-amino-5-(3-bromophenyl)-7-(6-(cis-3-hvdroxy-4-methylpyrrolidinyl)-3- pyridyl)pyrido[2.3-d]pyrimidine Prepared as described for Example 370 replacing 4-methoxypiperidine with (syn)-
3-hydroxy-4-methylpyrrolidine hydrochloride (PCT Int.Appl. (1992) WO9210191) and potassium carbonate. Treatment with excess 4 M HCl in dioxane followed by lyophilization gave the title compound as the di-HCL salt. MS (APCI +) m/z 477 (M+H)+; "H NMR (300 MHz, DMSO-d6) δ 10.08 (bs, IH). 8.97 (d, IH), 8.90 (s, IH), 8.78 (dd, IH), 8.26 (s, IH), 7.97 (m, IH), 7.82 (m, IH), 7.65 (dd, IH), 7.57 (t. IH), 7.42 (s, IH), 7.20 (d, IH), 4.26 (s, IH), 4.10-3.22 (m, 5H), 2.38 (m. IH), 1.08 (d, 3H).
Example 495 4-amino-5-(3-bromophenyl)-7-(6-(trans-3-cvano-4-hvdroxylpyrrolidinyl)-3- pyridyl pyrido[2J-d]pyrimidine Prepared as described for Example 370 replacing 4-methoxypiperidine with 3- cyano-4-hydroxypyrrolidine hydrochloride ( Hong et al: J Med Chem. 40. 22. (1997) pp 3584-3593) and potassium carbonate. Treatment with excess 4 M HCl in dioxane followed by lyophilization gave the title compound as the di-HCL salt. MS (ESI +) m/z 488 (M+H)*;
'H NMR (300 MHz, DMSO-d6) δ 10.03 (bs. IH). 9.08. (d, IH), 8.88 (s, IH), 8.65 (t, IH). 8.20 (s, IH), 7.95 (s, IH). 7.82 (d, IH), 7.62 (d, IH). 7.55 (t, IH), 7.32 (d, IH). 7.00 (d, IH), 4.65 (m, IH), 4J5-3.50 (m, 6H).
Example 496 4-amino-5-(3-bromophenviy7-(6-(3-hydroxy-4-tert-butylcarboxamidepyrrolidinyl)-3- pyridyl pyrido[2,3-d]pyrimidine The compound was isolated from the reaction mixture of Example 495. Treatment with excess 4 M HCl in dioxane followed by lyophilization gave the title compound as the di-HCL salt.
MS (ESI +) m/z 562 (M+H)*;
'H NMR (300 MHz, DMSO-d6) δ 10.03 (bs, IH), 9.05 (d, IH), 8.52 (s, IH), 8.44 (dd, IH), 7.85-7.76 (m, 3H), 7.57-7.51 (m, 3H), 7.32 (s, IH), 6.60 (d, IH), 5.28 (d, IH), 4.56 (m, IH), 3.70-3.25 (m, 4H), 3.03 (m, IH), 1.27 (s, 9H).
Example 497 4-amino-5-(3-bromophenyl -7-(6-('S-2-(4-tetrahvdropyranyloxy)methylpyιτolidinyl -3- pyridazinyl)pyrido[2, 3-djpyrimidine A solution of (S) 1 -Boc-2-pyrrolidinemethanol and triethylamine in dichloromethane at 0 °C was treated with methanesulfonyl chloride. The resulting mesylate was treated with 1.5 eq each of 4-hydroxytetrahydropyran and powdered potassium hydroxide in DMSO to afford the tetraydropyranyl ether. Deprotection of the Boc amine with trifluoroacetic acid provided the free base pyrrolidine which was reacted as in Example 367 replacing (lS,4S)-2-aza-5-oxa-bicyclo[2.2J]heptane. Treatment with excess 4 M HCl in dioxane followed by lyophilization gave the title compound as the di- HCL salt. MS (ESI +) m/z 562 (M+H)*; Η NMR (300 MHz, DMSO-d6) δ 10.00 (bs, IH), 8.93 (s, IH), 8.49 (s, IH). 8.30 (d, IH), 7.91 (m. IH), 7.84 (m. IH), 7.64 (m, IH), 7.58 (t, IH). 7.49 (bs, IH), 7.27 (bd, IH), 4.45 (m, IH), 3.78-3.25 (m, 9H). 2.04 (m, 4H). 1.78 (m. 2H), 1.37 (m. 2H).
Example 498
4-amino-5-(3-bromophenyl -7-(6-(3-(4-tetrahvdropyranyloxy iminopyrrolidinyl)-3- pyridazinvDpyridor2J-d]pyrimidine Equimolar amounts of l-N-Boc-3-pyrrolidinone and O-(tetrahydro-2H-pyran-4-yl) hydroxylamine hydrochloride (JP 07173169 Takeda Chemical Industries Ltd (1995)) were heated at reflux in 1 : 1 ethanol/pyridine, cooled and concentrated to give after silica gel chromatography the desired Boc protected oxime. Deprotection with trifluoroacetic acid afforded the free base pyrrolidine which was treated as in Example 367. replacing (lS,4S)-2-aza-5-oxa-bicyclo[2.2.1]heptane. Treatment with excess 4 M HCl in dioxane followed by lyophilization gave the title compound as the di-HCL salt. MS (ESI +) m z 561 (M+H)*;
'H NMR (300 MHz, DMSO-d6) δ 10.11 (bs, IH), 8.92 (s, IH), 8.41 (d, IH), 8.35 (dd, IH), 7.90 (d, IH), 7.83 (m, IH), 7.65-7.33 (m, 4H), 4.38 (d, 2H), 4.25 (m, IH), 4.10-3.72 (m, 4H), 3.44 (m, 2H), 2.93 (m, 2H), 1.93 (m, 2H), 1.55 (m, 2H).
Example 500
4-amino-5-(3-bromophenyl)-7-(5-bromo-2-thienyl)pyrido[2J-d]pyrimidine Procedure as found in Example 357 except substituting 2-acetyl-5-bromothiophene (Lancaster) for 5-acetyl-2-moφholinylthiazole. MS (DCI/NHj) m/z 463/465 (M+H)*; IR (microscope) 3473, 3299. 1580, 1557, 1073 cm"1.
Example 501 4-amino-5-(3-bromophenvπ-7-(2.5-dimethyl-3-thienvπpyrido[2.3-djpyrimidine Procedure as found in Example 357 except substituting 3-acetyl-2.5- dimethylthiophene (Acros) for 5-acetyl-2-moφholinylthiazole. mp: 210-212 °C;
MS (DCI NHJ m/z 41 1/413 (M+H)*;
IR (microscope) 3477, 3058. 1555, 1574. 1 142 cm"'.
Example 502
4-amino-5-(3-bromophenyl)-7-(5-chloro-2-thienyl)pyrido[2J-d1pyrimidine Procedure as found in Example 357 except substituting 2-acetyl-5-chlorothiophene (Acros) for for 5-acetyl-2-moφholinylthiazole. mp: 264-265 °C; MS (DCI NH3) m/z 417/419 (M+H)*;
IR (microscope) 3466. 3290, 1635, 1561, 1 114 cm"1.
Example 503 4-amino-5-(3-bromophenyl)-7-f2J-dimethyl-5-thiazoyl)pyrido~2J-d]pyrimidine Procedure as found in Example 357 except substituting 5-acetyl-2,4- dimethylthiazole (Acros) for 5-acetyl-2-moφholinylthiazole. mp: 254-255 °C; MS (DCI/NH3) m/z 412/414 (M+H)*; IR (microscope) 3477, 3299, 1648, 1563, 1285 cm"1.
Example 504
4-amino-5-(3-bromophenyl)-7-(5-methyl-2-thien\J)pyrido[2.3-d]pyrimidine Procedure as found in 357 except substituting 2-acetyl-5-methylthiophene (Lancaster) for 5-acetyl-2-moφholinylthiazole. MS (DCI/NHJ m/z 397/399 (M+H)*; IR (microscope) 3294, 3218, 1618, 1581, 1065 cm"1.
Example 505 4-amino-5-(3-bromophenyl)-7-(2-furanyl)pyrido[2J-dlpyrimidine Procedure as found in 357 except substituting 2-acetylfuran (Aldrich) for 5-acetyl- 2-moφholinylthiazole. MS (DCI/NHJ m z 367/369 (M+H)*; IR (microscope) 3485. 31 10. 1642. 1563, 1008 cm 1.
Example 506 4-amino-5-(3-bromophenyl)-7-(2-(lJ-dioxa-8-azaspiro[4.5jdecan-8-yl)-5- thiazoyl)pyrido[2, -dlpyrimidine Procedure as found in 357 substituting 4,4-dioxyethylenepiperidine (Aldrich) for moφholine in Example 357a. mp: >285 °C; MS (DCI/NH3) m/z 525/527 (M+H)*; IR (microscope) 3493, 3087, 1648, 1584, 1142 cm"1.
Example 507 4-amino-5-(3-bromophenyl)-7-(3-thienyl)pyrido[2J-dlpyrimidine Procedure as found in Example 357 substituting 3-acetylthiophene (Aldrich) for the product from Example 357b in 357c MS (DCI/NH3) m/z 383/385 (M+H)*; IR (microscope) 3473, 3100, 1638, 1561, 1288 cm 1.
Example 508 4-amino-5-(3-bromophenyl)-7-(3-methyl-2-thienyl)pyrido[2J-djpyrimidine Procedure as found in Example 357 substituting 2-acety 1-3 -methy lthiophene (Lancaster) for the product from Example 357b in Example 357c mp: 271-272 °C; MS (DCI/NH3) m/z 397/399 (M+H)*; IR (microscope) 3470, 3060, 1644, 1560, 1123 cm"1.
Example 509 4-amino-5-(3-bromophenyl)-7-(2-moφholinyl-4-thiazoyl)pyrido[2J-d]pyrimidine Procedure as found in Example 357 substituting the product from Example 509c for the product from 357b in 357c to give the title compound, mp: 278-282 °C; MS (DCI/NHJ m/z 469/471 (M+H)*; IR (microscope) 3468, 3085, 1653, 1559. 1 1 16 cm 1.
509a: 1 -Bromobutane-2.3-dione-3-oxime 2,3-butanedione (30 mL, 355 mmol; Aldrich) at 0 °C was treated with 10 drops of bromine (cautiomdelayed exothermic reaction). After 20 minutes, additional bromine (12.2 mL. 237 mmol) was added dropwise at such a rate as to maintain reaction temperature between 20-30 °C. Vacuum distillation (10 mmHg; fractions between 37-48 °C) provided 16.26 g (41%) of l-bromo-2,3-butanedione compound as a yellow oil. A solution of 1 -bromo-2,3-butanedione (16.26 g, 98.55 mmol) in water at 0 °C was treated dropwise with a solution of hydroxylamine hydrochloride (6.90 g, 99.29 mmol) and sodium carbonate (4.20 g, 39.63 mmol) in water (38 mL). After 1 hour, the reaction was extracted with dichloromethane, concentrated to one fourth the original volume, cooled and filtered to provide 7.08 g (40%) of the desired compound as an unstable (freezer) white solid.
509b: l-(2-Mθφholinothiazol-5-yl ethanoneoxime
A solution of known moφholine-4-carbothioic acid amide (2.66 g, 18.2 mmol; J. Het. Chem. 1987, 24, 1509) and the product from Example 509a (3.29 g, 18.3 mmol) in ethanol (5.5 mL) was heated to reflux for 2 hours. The reaction mixture was cooled to room temperature and the solid filtered, washed with ethanol and dried to provide 4.16 g (99%) of the desired compound as pink solid. MS (DCI/NH3) m/z 228 (M+H)*.
509c: l-(2-MoφholinothiazoI-5-yl)ethanone
A solution of the product from Example 509b (6.00 g, 26.4 mmol) in water (250 mL), sulfuric acid (27 mL) and ethanol (26 mL) at 50 °C was treated dropwise with sodium nitrite (1.97 g, 28.5 mmol) as a solution in water (50 mL). After 2 hours, the mixture was cooled to 0 °C, neutralized with ammonium hydroxide and extracted with dichloromethane. The organic phases were concentrated and purified by silica gel chromatography (elution with 10% ethyl acetate/dichloromethane) to give 1.06 g (19%) the desired compound as a pink solid. MS (DCI NH,) m/z 213 (M+H)*.
Example 510 4-amino-5-(3-bromophenyl)-7-(2-moφholinyl-4-trifluoromethv-5-thiazovπpyrido[2J- dlpyrimidine Procedure as found in Example 357 substituting the product from Example510a for the product from Example 357a in Example 357b to give the title compound, mp: 277- 278 °C; MS (DCI/NH3) m/z 537/539 (M+H)*; IR (microscope) 3481, 3061. 1607. 1544, 1116 cm-'.
step a: 2-Moφholino-4-trifluoromethylthiazole
Procedure as found in Example 509b substituting 3-bromo-lJJ-trifluoroacetone (Aldrich) for the product from Example 509a. MS (DCI NH3) m/z 239 (M+H)*.
Example 511 4-amino-5-(3-bromophenvπ-7-(5-morpholinyl-2-thienvπpyridor2J-d1pyrimidine Procedure as found in 357 substituting the product from Example 51 la for the product from Example 357b in Example 357c mp: 265 °C (dec); MS (ESI) m/z 468/470 (M+H)*; IR (microscope) 3484, 3052, 1647, 1581, 1 1 18 cm"1.
51 la: 5-Acetyl-2-moφholinothiophene A solution of 5-acetyl-2-bromothiophene (8.01 g, 39J mmol; Aldrich) and moφholine (16 mL) was heated to 145 °C overnight. The reaction mixture was cooled and partitioned between water and dichloromethane. The organic phase was concentrated and purified by silica gel chromatography (elution with 30% hexane/ethyl acetate) to give 5.61 g (68%) of the desired compound. MS (DCI/NH3) m/z 212 (M+H)*.
Example 512 4-amino-5-(3-bromophenvπ-7-(4-methyl-2-moφholinyl-5-thiazoyl pyrido[2J- dlpyrimidine Procedure as found in Example 357 substituting the product from Example 357a for the product from Example 357a in Example 357b to provide the title compound, mp: >280 °C: MS (DCI/NHJ m/z 483/485 (M+H)*; IR (microscope) 3481. 3078, 1653, 1510, 1 1 17 cm"1.
512a: 4-Methyl-2-moφhoIinothiazole Procedure as in Example509b substituting chloroacetone (Aldrich) for the product from 509a. MS (DCI/NH3) m/z 185 (M+H)*.
Example 513 4-amino-5-(3-bromophenvI)-7-(2.5-dichloro-3-thienyl)pyrido[2.3-djpyrimidine Procedure as found in Example 357 substituting 3-acetyl-2,5-dichlorothiophene
(Aldrich) for the product from Example 357b in Example357c to provide the title compound, mp: 258-259 °C; MS (DCI/NH3) m/z 451/453 (M+H)*; IR (microscope) 3477, 3060, 1651, 1564, 1044 cm"1.
Example 514
4-amino-5-(3-bromophenyl)-7-(2.5-dimethyl-3-furanyl)pyrido[2J-djpyrimidine Procedure as found in Example 357 substituting 3-acetyl-2,5-dimethylfuran (Lancaster) for the product from Example 357b in Example 357c to provide the title compound. MS (DCI/NH3) m/z 395/397 (M+H)*; IR (microscope) 3492, 3092J641, 1581, 1222 cm"1.
Example 515 4-amino-5-(3-bromophenyl)-7- N-methyl-2-pyrrolyl)pyrido[2.3-d]pyrimidine A solution of the product from Example 515a (3.30 g, 9.34 mmol) and triethylorthoformate (20 mL) was treated with a catalytic amount of ammonium sulfate and heated to 100 °C for 2 hours. The reaction mixture was cooled, treated with ammonia (2 M in ethanol, 50 mL) and stirred overnight. The dark mixture was then treated with sodium methoxide (3 M in methanol. 30 mL) and heated to reflux for 3 hours. The reaction was cooled, concentrated and the residue taken up in water and neutralized with 10% hydrochloric acid. The aqueous phase was extracted with dichloromethane, the organic phase concentrated and purified by silica gel chromatography (elution with 5% methanol/dichloromethane) to provide 830 mg (23%) of the title compound. MS (DCI NHj) m/z 380/382 (M+H)*; IR (microscope) 3482. 3051. 1643, 1580, 1073 cm"1.
515a: 4-(3-Bromophenyl -3-cvano-6-(2-(N-methylpyrrole pyridine-2-amine
Procedure as found in Example 357c substituting 2-acetyl-l -methy lpyrrole for the product from 357b. MS (DCI/NHj) m/z 353/355 (M+H)*.
Example 516
4-amino-5-(3-bromophenyl -7-(2-N,N-dimethylamino-5-thiazoyl)pyrido[2J-djpyrimidine
Procedure as found in Example 357 substituting dimethylamine (40%) in water, Aldrich) for moφholine in Example 357a. mp: >280 °C; MS (DCI/NH3) m/z 427/429 (M+H)*; IR (microscope) 3455, 3054, 1636, 1503, 1035 cm"1.
Example 517 4-amino-5-(3-bromophenyl)-7-(2-morpholinyl-5-thiazoyl)pyridor2.3-djpyrimidine Procedure as found in Example 515 substituting thiomoφholine for moφholine in Example357a to provide the title compound. MS (DCI/NH3) m/z 485/487 (M+H)*; IR (microscope) 3474, 3083, 1641 , 1509, 1 129 cm'1.
Example 518 4-amino-5-(3-bromophenyl)-7-(2-(l J-dioxidothiomoφholinvπ-5-thiazovπpyrido[2J- dlpyrimidine A solution of the product from Example 517 (402 mg, 0.83 mmol) in acetic acid and acetone was treated with potassium permanganate in water until complete consumption of starting material was detected. Reaction mixture poured over ice, the solution made strongly basic with 50% sodium hydroxide. The resulting solid was filtered and purified by silica gel chromatography (elution with 5% methanol/dichloromethane) to provide 231 mg (54%) of the title compound as a yellow solid. MS (DCI/NHJ m/z 517/519 (M+H)*; IR (microscope) 3484. 3056. 1606, 1501. 1 125 cm"1.
Example 519 4-amino-5-(3-bromophenyl)-7-(l-N-methyl-2-moφholinyl-5-imidazovπpyrido[2J- dlpyrimidine Procedure as in Example 515 substituting the product from Example 519a for the product of Example 357b in Example 357c MS (DCI/NH3) m/z 466/468 (M+H)*; IR (microscope) 3479, 3089, 1646, 1587, 1118 cm 1.
519a: 4- Acetyl- 1 -methyl-2-moφholinylimidazole
A solution of 5-acetyl-2-aminooxazole (7.00 g, 55.5 mmol; J. Org. Chem. 1984, 49, 566) and moφholine (20 mL) in water (14 mL) was heated to reflux overnight. The reaction was cooled to room temperature, concentrated and triturated with ethyl acetate, filtered and dried to provide 3.52 g (33%) of the desired compound. A slurry of sodium hydride (60% in oil, 590 mg, 14.7 mmol) and methyliodide (0.86 mL, 13.7 mmol) in tetrahydrofuran (20 mL) at room temperature was added a solution of 4-acetyl-2- moφholinylimidazole (2.44 g, 12.5 mmol) in dimethylformamide (13 mL) and stirring continued for 1.5 hours. Reaction quenched with ethanol, water added and extracted with dichloromethane. The organic phases were combined, dried (Na2SO4), concentrated and the residue purified by silica gel chromatography (elution with 25% dichloromethane/ethyl acetate) to provide 1.27 g (49%) of the desired compound. MS (DCI/NH,) m/z 210 (M+H)*.
Example 520
4-amino-5-(3-bromophenyl)-7-(2-moφholinyl-5-oxazolyl)pyrido[2J-d]pyrimidine Procedure as found in Example 357 substituting the product for Example 520a for the product of Example 357b in Example 357c MS (DCI/NH3) m z 453/455 (M+H)*; IR (microscope) 3502. 3388. 1607. 1575, 1 1 16 cm"'. 520a: 5-Acetyl-2-moφholinooxazole
A solution of 2-bromo-3-oxobutyraldehyde (6.00 g, 36.4 mmol; Bull. Chem. Soc. Jpn. 1965. 38, 1 158) and moφholine-4-carboxylic acid amide (9.01 g, 69.2 mmol; J. Am. Chem. Soc. 1945, 67, 1055) in acetone (40 mL) was stirred at room temperature for 1 hour then at reflux for 1 hour. The solvent removed in vacuo and the residue purified by silica gel chromatography (gradient elution with 10% ethyl acetate/dichloromethane to ethyl acetate) to provide 2.85 g (40%) of the desired compound as a yellow solid. MS (DCI NH3) m/z 197 (M+H)*.
Example 521
4-amino-5-(3-bromophenyl -7-(2-N-methyl-N-methoxyethylamino-5-thiazoylN)pyrido[2J- dlpyrimidine Procedure as found in Example 357 substituting the product from Example 521b for the product from Example 357b in Example 357c MS (DCI/NH3) m/z 471/473 (M+H)*; IR (microscope) 3472, 3051, 1645, 1519, 1090 cm"1.
521a: 2-(N-methyl-N-(2-methoxy)ethylamino)thiazole
Procedure as found in Example 357a substituting (2- methoxyethyl)methylamine (TCI Japan) for moφholine. MS (DCI/NH3) m/z 173 (M+H)+.
521b: 5-Acetyl-2-(N-methyl-N-(2-methoxy)ethylamino)thiazole
A solution of the product from Example 521a (4.98 g, 28.9 mmol) in tetrahydrofuran (150 mL) at -78 °C was treated with n-BuLi (2.3 M in hexanes, 15 mL) and stirring continued for 40 minutes. The light yellow solution was then treated with acetaldehyde (9.00 mL, 161 mmol), stirred for 15 minutes, quenched with saturated aqueous ammonium chloride, extracted with ethyl acetate, dried (Na2SO4) and concentrated. The residue was taken up in dichloromethane (150 mL) and treated with manganese dioxide (5 weight equivalents) and heated to reflux for 20 hours. The reaction mixture was cooled, filtered and concentrated to provide 4.62 g (75%) of the desired compound. MS (DCI/NHJ m/z 215 (M+H)*. Example 522 . 4-amino-5-(3-bromophenyl)-7-(2-N-methyl-N-ethylamino-5-thiazoyl)pyrido[2.3- dlpyrimidine Procedure as found in Example 357 substituting methy lethyl amine (Aldrich) for
(2-methoxyethyl)methylamine in Example 521a. MS (DCI/NH3) m/z 441/443 (M+H)*; IR (microscope) 3493, 3041, 1655, 1524, 1133 cm"1.
Example 523 4-amino-5-(3-bromophenyl -7-(2-N-pyrrolidinyl-5-thiazoyl)pyrido[2.3-d]pyrimidine
Procedure as found in Example 357 substituting pyrrolidine (Aldrich) for (2- methoxyethyl)methylamine in Example 521a. MS (DCI/NH3) m/z 453/455 (M+H)*; IR (microscope) 3483, 3044, 1647, 1511, 1203 cm"1.
Example 524
4-amino-5-(3-bromophenylV7-(2-N-methyl-N-propylamino-5-thiazoyl pyrido[2J- djpyrimidine Procedure as found in Example 357 substituting methylpropyl amine (Aldrich) for (2-methoxyethyl)methylamine in Example 521a to provide the title compound. MS (DCI/NH3) m/z 455/457 (M+H)*; IR (microscope) 3489. 3042, 1646, 1518, 1139 cm"1.
Example 525 4-amino-5-(3-bromophenyπ-7-(2-N.N-diethylamino-5-thiazoyl pyrido[2J-djpyrimidine Procedure as in Example 357 substituting diethylamine (Aldrich) for moφholine in Example 357a to provide the title compound. MS (DCI/NH,) m/z 455/457 (M+H)*; IR (microscope) 3478, 3051, 1582, 1518, 1177 cm"1.
Example 526 4-amino-5-(3-bromophenvD-7-(2-fN-methvpiperazinv0-5-thiazoyl)pyrido[2J- dlpyrimidine Procedure as in Example 515 substituting the product from Example 526a for the product of Example 357b in Example 357c provided the title compound. MS (DCI/NH3) m/z 482/484 (M+H)*; IR (microscope) 3469, 3053, 1645, 1500, 1002 cm"'.
526a: 5-Acetyl-2-(4-methylpiperazine thiazole
A solution of silicon tetraisothiocyanate (2.02 g, 7.76 mmol; Can. J. Chem. 1963, 41, 2123) in toluene (30 mL) was treated with a solution of N-methylpiperazine (3.50 mL, 31.6 mmol; Acros) in toluene (10 mL) and the mixture heated to 80 °C for 20 minutes. The resulting mixture was concentrated, taken up in 10% water in isopropanol, refluxed for 20 minutes, cooled and filtered. The filtrate was concentrated and recrystallized from isopropanol to provide 3.89 g (77%) of the desired compound. A solution of the 4- methylpiperazine-1-carbothioic acid amide (3.53 g, 22.2 mmol) and 2-bromo-3- oxobutyraldehyde (3.69 g, 22.2 mmol; Bull. Chem. Soc. Jpn. 1965, 38, 1158) in acetone was refluxed for 30 minutes. The reaction mixture was cooled, quenched with saturated aqueous sodium carbonate and extracted with dichloromethane. The organic layers were combined, dried (Na2SO4), concentrated and the residue purified by silica gel chromatography (gradient elution with 30% acetone/dichloromethane to 5% methanol/dichloromethane) to provide 1.76 g (35%) of the desired compound as a yellow- brown solid.
Example 527 4-amino-5-(3-bromophenyl -7-(2-(N-(2-pyridyl piperazinyl)-5-thiazoyl pyridol2J- dlpyrimidine Procedure as in Example 515 substituting 1 -(2-pyridyl)piperazine (Acros) for N- methylpiperazine in Example 526a. MS (ESI) m/z 545/547 (M+H)*; IR (microscope) 3484, 3049, 1651, 1495, 1053 cm"1.
Example 528 4-amino-5-(3-bromophenyl)-7-(2-N-methv-N-(2-pyridylethyl)-5-thiazoyπpyrido[2J- dlpyrimidine Procedure as in Example 515 substituting 2-(2-(methylamino)ethyl)pyridine dihydrochloride (Acros) for N-methylpiperazine in Example 526a. MS (DCI/NH,) m/z 518/520 (M+H)*; IR (microscope) 3472, 3054, 1648, 1517, 1051 cm"1.
Example 529
4-amino-5-(3-bromophenvπ-7-(2-(4-oxopiperazinyl)-5-thiazoyl pyrido[2J-d1pyrimidine
A solution of the product from Example 506 (900 mg, 1.71 mmol) and tetrahydrofuran (12 mL) at room temperature was treated with 3 N hydrochloric acid (12 mL) and stirring continued for 24 hours. The reaction was made basic with sodium bicarbonate, extracted with dichloromethane, concentrated and the residue purified by silica gel chromatography (elution with 5% methanol/dichloromethane) to provide 263 mg (32%) of the title compound. MS (DCI/NH3) m/z 481/483 (M+H)*; IR (microscope) 3482, 3084, 1716, 1508, 1074 cm"1.
Example 530
4-amino-5-(3-bromophenyl)-7-('2-(4-rN-moφholinyl)iminopiperazinyl)-5- thiazoyl pyridor2.3-d]pyrimidine A solution of Example 529 (200 mg, 0.415 mmol) and 4-aminomoφholine (Aldrich) in ethanol (5 mL) was heated to reflux for 5 hours. The solid was filtered and dried to provide 140 mg (60%) of the title compound. MS (DCI/NH3) m/z 565/567 (M+H)*; IR (microscope) 3485, 3051, 1644. 1506. 1 111 cm"1.
Example 531 4-amino-5-f3-bromophenyl)-7-(6-N-moφholine-3-pyridinesulfonamide pyridor2J- dlpyrimidine
Procedure as found in Example 357 substituting the product from Example 531b for the product from Example 357b in Example 357c MS (DCI/NHJ m/z 527/529 (M+H)*; IR (microscope) 3439, 3058, 1639, 1609. 1072 cm 1.
531a: 5-Acetyl-2-thiopyridine A solution of 5-acetyl-2-chloropyridine (10.11 g, 64.98 mmol; Tetrahedron 1992, 48, 9233) in ethanol was treated with thiourea (5.97 g, 78.4 mmol) and heated to reflux overnight. The reaction was cooled, the solid collected and taken up in 2 M sodium hydroxide. After stirring for 2 hours, the red solid was collected, acidified with glacial acetic acid. The yellow solid was collected and recrystallized from ethanol to provide 3.39 g (34%) of the desired compound. MS (DCI NHj) m/z 154 (M+H)*.
531b: 5-Acetyl-2-moφholinopyridylsulfonamide A suspension of the product from Example 53 la (7.01 g, 45.7 mmol) in 1 M hydrochloric acid (60 mL) was treated with chlorine gas at 0 °C for 1 hour. The resulting solid was filtered, and taken up in dichloromethane (50 mL) and treated with moφholine (15 mL). After 1 hour, the mixture was quenched with 1 N hydrochloric acid and extracted with dichloromethane. The organic phases were combined, dried (Na2SO4) and concentrated. The residue was recrystallized from ethyl acetate to provide 6.31 g (59%) of the desired compound. MS (DCI NH3) m/z 271 (M+H)*.
Example 532 4-amino-5-(3-bromophenyl)-7-(2-(4-oxopiperidinyl)-5-pyrimidyl)pyrido[2J-d1pyrimidine Procedure as found in Example 529 substituting the product from Example533c for the product from Example 506. MS (DCI/NH3) m/z 476/478 (M+H)*; IR (microscope) 3469, 3051, 1644, 1561, 1108 cm"1.
Example 533 4-amino-5-(3-bromophenyl)-7-(2-(4.4-dioxethylenepiperidinyl)-5-pyrimidyl)pyrido[2J- dlpyrimidine Procedure as found in Example 515 substituting the product from Example 533b for the product from Example 357b in Example 357c and formation of the salt by treatment with HCl in diethyl ether to provide the title compound. MS (DCI/NH,) m/z 520/522 (M+H)*; IR (microscope) 3434, 3064, 1645, 1602. 1 105 cm"1. 533a: 5-bromo-2-( 1 J-dioxa-8-azaspiro[4.5]decane)pyrimidine
A solution of 5-bromo-2-chloropyrimidine (3.09 g, 16.0 mmol; J. Chem. Soc. Chem. Commun. 1996. 2719) in ethanol (20 mL) at room temperature was treated with l ,4-dioxa-8-azaspiro[4,5]decane (6.00 mL. 46.8 mmol; Aldrich) and stirring continued overnight. The reaction mixture was neutralized with saturated aqueous sodium bicarbonate and extracted with dichloromethane. The organic phases were combined, dried (Na2SO4), concentrated and the residue purified by silica gel column chromatography (elution with 25% ethyl acetate/hexanes) to provide 4.78 g (99%) of the desired compound as a white solid. MS (DCI NH3) m/z 300/302 (M+H)*.
533b: 5-Acetyl-2-π.4-dioxa-8-azaspiro[4.5]decane)pyrimidine
Procedure as found in Example 521b substituting the product from Example 533a for Example 521a to provide the desired compound. MS (DCI/NH3) m/z 264 (M+H)*.
Example 534 4-amino-5-(3-bromophenyl)-7-(5-(1.4-dioxa-8-azaspiro[4.5]decan-8-yl -2- pyrazinyl)pyrido[2.3-d]pyrimidine Procedure as found in Example 515 substituting the product from Example 534b for the product from Example 357b in Example 357c and formation of the salt by treatment with HCl in diethyl ether to provide the title compound. MS (DCI/NH,) m/z 520/522 (M+H)*; IR (microscope) 3292, 3060, 1634, 1526, 1105 cm"1.
534a: 5 - Acetyl-2-chloropyrazine A solution of 5-hydroxypyrazine-2-carboxylic acid (5.29 g, 37.76 mmol) in toluene was treated with thionyl chloride (9.00 mL, 123 mmol) and the mixture heated to reflux for 16 hours. The reaction mixture was concentrated and the residue taken up in dichloromethane (200 mL) and treated with a solution of N.O-dimethylhydroxylamine hydrochloride in 2 N sodium hydroxide. After 30 minutes, the layers were separated, the organic phase dried (Na2SO ) and concentrated. A portion of the amide (807 mg, 4.00 mmol) was taken up in tetrahydrofuran (20 mL) cooled to -10 °C and treated with methylmagnesium bromide (3 M in diethyl ether, 4.00_mL) and warmed to room temperature. The mixture was quenched with saturated aqueous ammonium chloride and extracted with ethyl acetate. The organic layers were dried (Na2SO4) and concentrated to provide 610 mg (97%) of the desired compound. Η NMR (CDC13, 500 MHz) δ 9.00 (d, J = 1 J Hz. 1 H), 8.63 (d, j = 1 J Hz, 1 H), 2.70 (s, 3 H).
534b: 5-Acetyl-2-(lJ-dioxa-8-azaspiro[4.5jdecane pyrazine
Procedure as found in Example 51 1a substituting the product from Example 534a for 5-acetyl-2-bromothiophene and l,4-dioxa-8-azaspiro[4,5]decane for moφholine. MS (DCI/NH,) m/z 264 (M+H)*.
Example 535 4-amino-5-(3-bromophenyl)-7-(5-(4-oxopiperidinvIV2-pyrazinyl)pyridoI2J-d]pyrimidine Procedure as found in Example 529 substituting the product from Example 534c for the product from Example 506 to provide the title compound. MS (DCI/NH3) m/z 476/478 (M+H)*; IR (microscope) 3470, 3085, 1721, 1542, 1184 cm"1.
Example 536 4-amino-5-(3-bromophenyl -7-(6-N-cvclopropyl-3-pyridinesulfonamide pyrido[2J- dlpyrimidine Procedure as found in Example 534c substituting cyclopropyl amine (Aldrich) for moφholine in Example 534b. MS (DCI/NH3) m/z 497/357 (M+H)*; IR (microscope) 3441, 3059, 1640, 1609, 1177 cm"1.
Example 537
4-amino-5-(3-bromophenyl)-7-(6-(N-1.4-dioxa-8-azaspiro 4.51decan-8-yl)-3- pyridylsulfonamide')pyrido 2J-d]pyrimidine Procedure as found in Example 534 substituting l,4-dioxa-8-azaspiro[4,5]decane (Aldrich) for moφholine in Example 534b. MS (DCI/NH,) m z 583/585 (M+H)*; IR (microscope) 3483, 3060, 1567, 1355. 1 101 cm"'.
Example 538
4-amino-5-(3-bromophenyl)-7-(2-(4-(4-tetrahvdropyranyloxy iminopiperidinyl )-5- pyrazinyl)pyrido[2, -d]pyrimidine Procedure as found in Example 530 substituting the product from 532 for the product from Example 529 and 0-(tertrahydro-2H-pyran-4-yl)hydroxylamine hydrochloride (JP07173169; CAN 123:313629) for 4-aminomoφholine. MS (DCI/NH3) m/z 575/577 (M+H)*; IR (microscope) 3486. 3055, 1601, 1515. 1345 cm"1.
Example 539 4-amino-5-(3-bromophenviy7-(6-(4-ψhenylmethoxy)iminopiperidinvD-3- pyridvDpyrido [2.3 -djpyrimidine
Prepared as described for Example 359, substituting O-Benzylhydroxylamine hydrochloride for ethoxyamine hydrochloride.
MS (DCI NH3) m/z 580/582 (M+H; 79Br/81Br); IR (microscope) 3486, 3297, 3060, 1603, 1579, 1557 cm"1 .
Example 540 4-amino-5 -(3 -bromophenyl)-7-f 6-(4-(tert-butyloxy)iminopiperidinyl)-3 - pyridyl)pyrido[2, -d]pyrimidine Prepared as described for Example 359, substituting O-(tert-butyl)hydroxylamine hydrochloride for ethoxyamine hydrochloride.
MS (DCI/NH3) m/z 546/548 (M+H; 79Br/81Br); IR (microscope) 3488, 3301, 3037. 1602, 1560, 1512 cm"1 .
Example 541 4-amino-5-(3-bromophenyl)-7-(6-(4-(cvclohexyloxy)iminopiperidinyl)-3- pyridyl)pyrido[2J-d]pyrimidine Prepared as described for Example 359, substituting O-Cyclohexylhydroxylamine hydrochloride, synthesized by the procedure of Grochowski, E; Jurczak. J. Synthesis 1976, 682 and starting with cyclohexanol. for ethoxyamine hydrochloride.
MS (DCI NH3) m/z 572/574 (M+H; 79Br/81Br); IR (microscope) 3485. 3297. 2931, 1555, 1517, 1349 cm"1 .
Example 542 4-amino-5-(3-bromophenyl)-7-(6-(4-hvdroxyiminopiperidinv0-3-pyridyl)pyrido[2J- dlpyrimidine Prepared as described for Example 359, substituting Hydroxylamine hydrochloride for ethoxyamine hydrochloride.
MS (DCI NHj) m/z 490/492 (M+H; 79Br/81Br); IR (microscope) 3444, 3020, 2819, 1646, 1605, 1546 cm"1 .
Example 543 4-amino-5-(3-bromophenyl)-7-(6-(4-(4-tetrahvdropyranyloxy)iminopiperidinyl)-3- pyridvDpyrido \23 -djpyrimidine Prepared as described for Example 359, substituting 4-tetrahydropyranyloxyamine hydrochloride, synthesized by the procedure of Grochowski. E; Jurczak. J. Synthesis 1976, 682 and starting with Tetrahydro-4H-pyran-4-ol, for ethoxyamine hydrochloride. MS (DCI/NH3) m/z 574/576 (M+H; 7 Br/8'Br); IR (microscope) 3484, 3297. 3157, 2954, 1582, 1555 cm"1 .
Example 544 4-amino-5-(3-bromophenyl)-7-(6-(4-methoxyethoxyiminopiperidinyl)-3- Pyridyl)pyridor2.3-d1pyrimidine Prepared as described for Example 359. substituting O-(2- methoxyethyl)hydroxylamine hydrochloride, synthesized by the procedure of Grochowski, E; Jurczak. J. Synthesis 1976. 682 and starting with 2-Methoxyethanol. for ethoxyamine hydrochloride.
MS (DCI NHj) m/z 548/550 (M+H; 79Br/81Br); IR (microscope) 3485, 3298. 3042, 1582,
1555, 1517 cm"' .
Example 545 4-amino-5-(3-bromophenyl)-7-(6-(4-(2-thenylmethoxy)iminopiperidinvD-3-
PyridvDpyrido [2,3 -djpyrimidine Prepared as described for Example 359, substituting O-(2- thienylmethyl)hydroxylamine hydrochloride, synthesized by the procedure of Grochowski, E; Jurczak, J. Synthesis 1976, 682 and starting with 2-Thiophenemethanol. for ethoxyamine hydrochloride. MS (DCI NH3) m/z 586/588 (M+H; 79Br/81Br); IR (microscope) 3485, 3298, 3068, 1579,
1556, 1507 cm"' .
Example 546 4-amino-5 -(3 -bromopheny l -7-(6-(4-("4 * -(5 ' H-2-oxyfuranyl)-4-hvdroxy piperidinyl)-3 -
PyridvDpyridoβJ-djpyrimidine Prepared as described for Example 370 except substituting 4-(4'-(5'H-2- oxyfuranyl)-4-hydroxypiperidine for 4-methoxypiperidine, which was made as follows: to a solution of 4-bromo-2-triisopropylsiloxylfuran (5.0 g, 15.7 mmol; made according to G. Jas, Synthesis 1991, 965) in THF (50 mL) at -78 °C, a solution of t-buty lithium (1,7 M, 15 mL, 25.5 mmol) was added dropwise for 40 min. A solution of N-benzylpiperidin-4-one (4.4 mL, 23.8 mmol) was added at -78 °C The reaction mixture was then allowed to warm up over night. Standard work-up. Column chromatographic separation (SiO2, ethyl acetate : hexane = 1 : 2) gave 4.72 g product (70%). The product was then deprotected under H2 in the presence of Pd(OH)2, Et3N in methanol. MS (ESI): 559/561 (M+H; 79Br/81Br).
IR (Mic): Vmax: 3432. 3309, 3204, 2928, 1744, 1634, 1605, 1372 cm"' Example 547 4-amino-5-(3-bromophenyl)-7-(6-(4-(l-(4- tetrahvdropyranyloxy)iminoethyl))-4-hvdroxypiperidinyl)-3-pyridazinv0pyridor2J- dlpyrimidine Prepared as described for Example559 except substituting Example548 for Example 562.
MS (ESI): 619/621 (M+H; 79Br/81Br).
IR (Mic): Vmax: 3485, 3310, 3204, 2955, 2849, 1682, 1615, 1578, 1552, 1461, 1353,
1 135, 1066 cm"1.
Example 548
4-amino-5-(3-bromophenvπ-7-(6-f4-f4,-acetyl-4,-hvdroxypiperidinyl)-3- pyridazinv0pyrido[2J-d]pyrimidine Prepared as described for Example 367 except substituting 4-acetyl-4- hydroxypiperidine for (lS,4S)-2-aza-5-oxa-bicyclo[2.2J]heptane, which was prepared as described in Example 562.
MS (ESI): 520/522 (M+H; 79Br/81Br).
IR (Mic): Vmax: 3472, 3385, 3298, 3090, 2953, 1711, 1644, 1578, 1562, 1483, 1464,
1353 cm"1.
Example 549 4-amino-5-(3-bromophenyl)-7-(6-(4-(l-
(isopropylcaboxymethoxy)iminoethvπ)-4-hvdroxypiperidinyl -3-pyridyl)pyrido[2J- djpyrimidine Prepared from Example 562 as described in Example 559; substituting carboxymethoxylamine (Aldrich) for 4-tetrahydropyranoxyamine hydrochloride in isopropanol as solvent
MS (ESI): 634/636 (M+H; 79Br/81Br).
IR (Mic): Vmax: 3450, 3311, 3174, 3068, 2984. 2937, 1737, 1674, 1647. 1606, 1555,
1440. 1373, 1201, 1136 cm 1. Example 550 4-amino-5-(3-bromophenyl)-7-(6-(4-(l-(ethylcaboxymethoxy)iminoethyl) -4- hvdroxypiperidinyl -3-pyridyl)pyrido[2J-d]pyrimidine Prepared from Example 562 as described in Example 559; substituting carboxymethoxylamine (Aldrich) for 4-tetrahydropyranoxyamine hydrochloride in ethanol as solvent.
MS (ESI): 620/622 (M+H; 79Br/81Br).
IR (Mic): Vmax: 3449, 3313, 3178, 3066, 2985, 1745, 1674, 1648, 1607, 1444, 1371, 1200, 1135 cm"1.
Example 551 4-amino-5-(3-bromophenyl)-7-(6-(4-(l-(methylcaboxymethoxy)iminoethyl )-4- hvdroxypiperidinv l)-3 -pyridyllpyrido '2.3 -dlpyrimidine Prepared from Example 562 as described in Example 559; substituting carboxymethoxylamine (Aldrich) for 4-tetrahydropyranoxyamine hydrochloride in methanol as solvent. MS (ESI): 606/608 (M+H; 79Br/81Br).
IR (Mic): Vmax: 3450, 3309, 3067, 2957, 2933, 1751, 1675, 1647, 1605, 1439, 1368, 1200, 1134 cm"1.
Example 552 4-amino-5-(3-bromophenyl -7-(6-(4-(l-(2-tetrahvdropyranyloxy)iminoethyl -4- hvdroxypiperidinyP-S-pyridvDpyrido ?.3-djpyrimidine Prepared from Example 562 as described in Example 559; substituting O- (tetrahydro-2H-pyran-2-yl)hydroxylamine (Aldrich) for 4-tetrahydropyranoxyamine hydrochloride.
MS (ESI): 618/620 (M+H; 79Br/81Br).
IR (Mic): Vmax: 3449, 3306, 3197, 3066, 2949. 2872, 1675, 1648. 1607, 1442, 1370, 1200, 1135 cm 1. Example 553 4-amino-5-(3-bromophenyl -7-(6-(4-(l-(allyloxy)iminoethv0)-4- hvdroxypiperidinviy3-pyridyl)pyrido[2J-d1pyrimidine Prepared from Example 562 as described in Example 559; substituting 2-propeN- 1-oxylamine (Aldrich) for 4-tetrahydropyranoxyamine hydrochloride. MS (ESI): 574/576 (M+H; 79Br/81Br).
IR (Mic): Vmax: 3450, 3309, 3175, 3071, 2930, 2871. 1673, 1647, 1605. 1515, 1435. 1200. 1134 cm"1.
Example 554 4-amino-5-(3-bromophenyl)-7-(6-(4-(l -(ethoxy iminoethyl -4- hvdroxypiperidinyl -3-pyridyl)pyrido[2J-djpyrimidine
Prepared from Example 562 as described in Example 559; substituting ethoxylamine (Aldrich) for 4-tetrahydropyranoxyamine hydrochloride MS (ESI): 562/564 (M+H; 79Br/81Br).
IR (Mic): Vmax: 3451, 3311, 3063, 2979, 2936, 2881, 1673, 1647, 1606, 1368, 1200, 1 183, 1133 cm"1.
Example 555 0.61 4-amino-5-(3-bromophenyl")-7-(6-(4-(l-(methoxy iminoethvπ)-4-hvdroxypiperidinyl)-3- pyridyl pyrido[2,3-d]pyrimidine Prepared from Example 562 as described in Example 559; substituting methoxylamine (Aldrich) for 4-tetrahydropyranoxyamine hydrochloride. MS (ESI): 548/550 (M+H; 79Br/81Br).
IR (Mic): Vmax: 3450, 3312, 3064, 2965, 2820, 1674, 1646, 1444, 1369, 1 199, 1135, 1045 cm"1.
Example 556 4-amino-5-(3-bromophenyl)-7-(6-(4-( 1 -(hvdroxy iminoethyl))-4- hvdroxypiperidinvD-3-pyridvPpyrido[2.3-d]pyrimidine Prepared from Example 562 as described in Example 559; substituting hydroxylamine (Aldrich) for 4-tetrahydropyranoxyamine hydrochloride. MS (ESI): 534/536 (M+H: 79Br/81Br).
IR (Mic): Vmax: 3448, 33133198, 3070. 2881, 1782. 1676, 1650. 1610. 1448. 1371,
1200, 1137 cm"1.
Example 557
4-amino-5-(3-bromophenvπ-7-(6-(4-(2-tetrahvdropyranyloxy)iminopiperidinyl)-3- pyridyl)pyrido[2.3-d1pyrimidine Prepared from Example 328 as described in Example 559; substituting O- (tetrahydro-2H-pyran-2-yl)hydroxylamine (Aldrich) for 4-tetrahydropyranoxyamine hydrochloride.
MS (ESI): 574/576 (M+H; 79Br/8IBr).
IR (Mic): Vmax: 3437, 3304, 3057, 2955, 2859, 2684, 1639, 1605, 1441, 1368, 1238,
1068 cm 1.
Example 558
4-amino-5-(3-bromophenv0-7-(6-(4-fisopropylcarboxymethoxy)iminopiperidinyl>3- pyridyl)pyrido[2J-djpyrimidine Prepared from Example 328 as described in Example 559; substituting Example 328 for Example 562 and substituting carboxymethoxylamine (Aldrich) for 4- tetrahydropyranoxyamine hydrochloride in isopropanol as solvent. MS (ESI): 590/592 (M+H: 79Br/81Br).
IR (Mic): Vmax: 3487, 3389, 3301, 3152, 3058, 2979, 2928, 2873, 1749, 1603, 1580, 1557, 1508, 1414, 1348, 1233, 1101 cm"1.
Example 559
4-amino-5-(3-bromophenyl)-7-(6-(4-hvdroxy-4-(l-(4-tetrahvdropyranyloxy)iminoethyl))- 4-hvdroxypiperidinyl)-3 -pyridvDpyrido [2.3 -d] pyrimidine Prepared from Example 562 as follows: to a solution of Example 562 (250 mg, 0.48 mmol) in ethanol (10 mL), 4-tetrahydropyranoxyamine hydrochloride (80 mg, 0.5 mmol; made as described from: JP 94-177353 19940729 and prepared in Example543) was added, followed by concentrated HCl (2 drops). The mixture was heated to reflux for about 10 hours. Standard work up, followed by chromatography (SiO2. 5% MeOH in CH2C12) gave 156 mg (53%) of the title compound. MS (ESI): 618/620 (M+H; 79Br/81Br). IR (Mic): Vmax: 3488, 3304, 3199, 2954, 2855, 1603, 1578, 1557, 1509, 1352, 1233, 1066 cm 1.
Example 560 4-amino-5-(3-bromophenyl)-7-(6-(4-(3-butyrolactone)-4-hvdroxypiperidinyl)-3- pyridvDpyrido [23 -dlpyrimidine
Prepared as described for Example 370 except substituting 4-(4-hydroxypiperidin- 4-yl)butarolactone for 4-methoxypiperidine. which was made as follows: to a solution of 3-ethoxycarboxylpropyl triphenylphosphonium bromide (10.0 g, 22 mmol) in THF, a solution of potassium bis(trimethylsilyl)amide (0.5 M, 52 mL, 26 mmol) was added at - 78 °C the reaction mixture was allowed to stir for 40 min at - 78 °C. N-benzyl-4- piperidinone (4.5 mL, 24 mmol) was added. The mixture stirred at -78 °C for 3 hours and then gradually warmed up to room temperature over night. Standard work up followed by chromatography (SiO2, ethyl acetate: hexanes = 1 :4) to give 5.01g product (83%). The product was then dihydroxylated as described in Example 565, and treated with p- toluenesulfonic acid in benzene to give the lactone. Debenzylation via hydrogenation gave the desired amine. MS (ESI): 561/563 (M+H; 79Br/81Br).
IR (Mic): Vmax: 3479, 3311, 3056, 2942, 2853, 2726, 1777, 1654, 1574, 1556, 1503, 1408, 1354 cm"1.
Example 561 4-amino-5-(3-bromophenyl)-7-(6-(4J2-butyrolactone -4-hvdroxypiperidiny0-3- pyridazinyl)pyrido~2J-d]pyrimidine Prepared as described for Example 367 except substituting 2-(4- hydroxypiperidiN-4-yl)butyrolactone for ( 1 S.4S)-2-aza-5-oxa-bicyclo[2.2.1 jheptane, which was made from a-(l-benzyl-4-hydroxy-4-piperidyl)-g-butarolactone (Salor) via hydrogenation.
MS (ESI): 562/564 (M+H; 79Br/81Br).
IR (Mic): Vmax:3484, 3289, 3054. 2928. 1768. 1644, 1575, 1464, 1358, 1264, 1138 cm"1.
Example 562 4-amino-5-(3-bromophenylV7-(6-(4-acetyl-4-hvdroxypiperidinyl)-3-pyridv0pyrido[2J- dlpyrimidine Prepared as described for Example 370 except substituting 4-acetyl-4- hydroxypiperidine for 4-methoxypiperidine, which was prepared as follows: to a solution of ethyl vinyl ether (3.8 mL, 40 mmol) in THF, a solution of t-butyllithium (1.7 M, 24 mL, 40 mmol) was added at - 78 °C. The reaction mixture was warmed up to 0 °C for about 30 min, and cooled down to - 78 °C again before transferred to a slurry of CeCl3 (10 g, 40 mmol) in THF at - 78 °C. The mixture was stirred at -78 °C for about 1 hour, and a cold solution of N-benzyl-4-piperidinone (5.5 mL, 30 mmol) in THF was added. The reaction mixture was then gradually warmed up over night. Standard work up, followed by chromatography (SiO2, 1% MeOH in CH2C12) to give 7J g product (91%). The product was then hydrolysed to ketone product in the presence of MeOH/THF/CH2Cl2 (20:30:5) mixture solvents and HCl (3N, 7 mL) at 0 °C. The product was then deprotected via hydrogenation to give the final keto-amine. MS (ESI): 519/521 (M+H; 79Br/81Br).
IR (Mic): Vmax: 3486, 3312, 3210, 2950, 2923, 2859, 1706, 1604, 1580, 1558, 1508, 1352, 1242 cm"1.
Example 563
4-amino-5-(3-bromophenyl)-7-(6-(3-hvdroxyazetidinvD-3-pyridyDpyrido[2,3- djpyrimidine Prepared as described for Example 370 except substituting 3 -hydroxy azetidine for 4-methoxypiperidine, which was prepared from the N-diphenylmethyl-4-hydroxyaziridine (Maybridge) via hydrogenation. MS (ESI): 449/451 (M+HJ9Br/81Br).
IR (Mic): Vmax: 3471. 3301, 3061, 1602, 1580, 1558- 1354 cm"1.
Example 564 4-amino-5-(3-bromophenyl)-7-(6-((lR.5S)-3-hvdroxy-8-azabicvclor3.2J]octan-8-yl)-3- pyridyl)pyrido[2.3-d1pyrimidine Prepared as described for Example 370 except (lR,5S)-8-azabicyclo[3.2J]octan-3- ol for 4-methoxypiperidine, which was prepared from tropanone as described by A.H. Newman, et al, J. Med. Chem. 1995, 38, 3933. MS (ESI): 503/505 (M+H; 79Br/81Br).
IR (Mic): Vmax: 3480, 3317, 3204, 2918, 1706, 1603, 1580, 1558. 1352, 1243 cm"1.
Example 565 4-amino-5-(3-bromophenyl)-7-(6-(cis-2J-dihvdroxypiperidinyl)-3-pyridyl)pyrido[2J- dlpyrimidine
Prepared from Example567 as follows: to a solution of Example567 (600 mg, 1.31 mmol) in THF/MeOH (55:5), NMO (460 mg, 3.93 mmol) was added followed by OsO4 (35 mg, 0J4 mmol). The reaction mixture was allowed to stir over night. Quenched with sodium thiosulfate. Standard work up, followed by chromatography (SiO2, 10% MeOH in CH2C12) to give 260 mg (40%) of the title compound. MS (ESI): 493/495 (M+H; 79Br/81Br). IR (Mic): Vmax: 3478, 3296, 3082, 2924, 1641, 1604, 1581, 1554, 1513, 1354, 1227 cm"
Example 566 4-amino-5-(3-bromophenyl -7-(6- N-methyl-N-(3-pyridylmethyl)amino)-3- pyridazinyl)pyridor2.3-d]pyrimidine Prepared as described for Example 367 except substituting 3- (methylaminomethyl)pyridine (Maybridge) for (lS,4S)-2-aza-5-oxa- bicyclo[2.2.1 jheptane. MS (ESI): 499/501 (M+H; 79Br/81Br). IR (Mic): Vmax: 3475, 3300, 3151, 3061 , 2928. 1682, 1555, 1484, 1395, 1352 cm"'.
Example 567 4-amino-5-(3-bromophenyl -7-(6-(1.2J.6-tetrahvdropyridyl)-3-pyridyl)pyrido[2.3- dlpyrimidine Prepared as described for Example 370 except substituting 1,2,3,6- tetrahydropyridine (Aldrich) for 4-methoxy piperidine. MS (ESI): 459/461 (M+H; 79Br/81Br). IR (Mic): Vmax: 3473, 3305, 3090, 2928, 1670, 1578, 1558, 1508, 1355, 1244 cm"1.
Example 568 4-amino-5-(3-bromophenvπ-7-(6-(4-(N-4,methoxyphenylcarbamovπpiperidinyl)-3-
PyridazinvDpyrido "2.3 -dlpyrimidine Prepared as described for Example 367 except substituting 4-(N- 4'methoxyphenylcarbamoyl)piperidine for (lS,4S)-2-aza-5-oxa-bicyclo[2.2J]heptane, which was prepared prepared as described in Example570 from N-benzyl-4- hydroxypiperidine. MS (ESI): 459/461 (M+H; 79Br/8iBr).
IR (Mic): Vmax: 3473, 3305, 3090, 2928, 1649, 1581, 1560, 1508, 1355 cm"1.
Example 569 4-amino-5-f3-bromophenyl)-7-(6-(4-f2-butyrolactone)-4-hvdroxypiperidinyl)-3- pyridyl pyrido[2.3-djpyrimidine Prepared as described for Example 370 except substituting 2-(4-hydroxypiperidi- N-4-yl)butyrolactone for 4-methoxypiperidine, which was made from a-(l -benzyl-4- hydroxy-4-piperidyl)-g-butarolactone (Salor) via hydrogenation. MS (ESI): 561/563 (M+H; 79Br/81Br).
IR (Mic): Vmax: 3462, 3392, 3297, 3256, 3108. 2948, 2859, 1765, 1638, 1598, 1579, 1556, 1505, 1355, 1240, 1158 cm"1. Example 570 4-arnino-5-(3-bromophenvD-7-f6-(trans-3.4- bis(N-4'-methoxyphenylcarbamoyl )pyrrolidinyl)-3-pyridyl)pyrido[2J-d]pyrimidine Prepared as described for Example 370 except substituting 3R,4R-bis(N-4'- methoxyphenylcarbamoyl)pyrrolidine for 4-methoxypiperidine, which was madeas follows: N-benzyl-3R,4R-dihydroxypyrrolidine (500 mg, 2.6 mmol) (Digital) was dissolved in CH2C12 (50 mL), 4-methoxyphenylisocyanate was added at room temperature. The reaction mixture was then allowed to stir for about 8 hours. White precipitate was collected, and washed with hexanes to give a pure product (1.23 g, 96%). The benzyl group was then deprotected via hydrogenation. MS (ESI): 777/779 (M+H; 79Br/81Br).
IR (Mic): Vmax: 3481, 3302, 3194, 3057, 2955, 2838, 1726, 1604, 1555, 1514, 1415, 1228, 1076, 1030, 829 cm"1.
Example 571
4-amino-5-(3-bromophenyl)-7-(6-((lS.5R)-3-hvdroxy-8-azabicyclo[3.2J1octan-8-yl)-3- pyridyl)pyrido~2.3-d]pyrimidine Prepared as described for Example 370 except substituting (lS,5R)-8- azabicyclo[3.2J]octan-3-ol for 4-methoxypiperidine, which was made from tropane (Aldrich) as described by A.H. Newman, et al. (j. Med. Chem. 1995, 38, 3933). MS (ESI): 503/505 (M+H; 79Br/81Br). IR (Mic): Vmax: 3472, 3303, 3157, 2939, 1681, 1600, 1580, 1554, 1354 cm"1.
Example 572 4-amino-5-(3-bromophenyl)-7-( 6-('S.S-trans-3J-dihvdroxypyrrolidinyl)-3- pyridvDpyrido [2.3 -dlpyrimidine Prepared as described for Example 370 except substituting 3S,4S- dihydroxypyrrolidine for 4-methoxypiperidine which was prepared from the benzylprotected form (Digital) as described in Example574. MS (ESI): 479/481 (M+H; 79Br/81Br). IR (Mic): Vmax: 3484. 3299, 3193. 2928, 2854. 1629, 1584, 1561, 1536. 1513, 1435, 1078 cm 1.
Example 573 4-amino-5-(3-bromophenyl)-7-( 6-(R,R-trans-3,4-dihvdroxypyrrolidinyl)-3- pyridazinyl')pyrido[2J-djpyrimidine Prepared as described for Example 367 except substituting 3R,4R- dihydrixypyrrolidine for "(lS,4S)-2-aza-5-oxa-bicyclo[2.2J]heptane" which was made as described in Example574 MS (ESI): 480/482 (M+H; 79Br/81Br).
IR (Mic): Vmax: 3484, 3302, 3209, 3077, 2932, 2724, 1628, 1599, 1585, 1562, 1514, 1433 cm"1.
Example 574 4-amino-5-("3-bromophenyl)-7-(6-(R,R-trans-3.4-dihvdroxypyrrolidinyl)-3- pyridvDpyrido [2,3 -djpyrimidine Prepared as described for Example 370 except substituting 3R,4R- dihydroxypyrrolidine for 4-methoxypiperidine and was prepared as follows: To a solution of N- benzyl-3R,4R-dihydroxypyrrolidine (Digital; 1.4 g, 7.25 mmol) in methanol, Pd(OH)2 on carbon (300 mg) was added followed by H2 (1 atom.) at room temperature over night. Standard work up gave 635 mg of the product (85%). MS (ESI): 479/481 (M+H; 79Br/8,Br). IR (Mic): Vmax: 3484, 3303, 3208, 2932, 2861, 1585, 1562, 1538, 1513. 1434, 1078 cm"
1
Example 575 4-amino-5-(3-bromophenyl)-7-(6-(4-oxo-l-phenyl-1.3.8-triazaspiro[4.5]decan-8-yl)-3- pyridyl)pyrido[2J-d]pyrimidine Prepared as described for Example 370 except l-phenyl-1,3,8- triazaspiro[4.5]decan-4-one (Acros) for 4-methoxypiperidine. MS (ESI): 607/609 (M+H; 79Br/81Br).
IR (Mic): Vmax: 3427, 3321, 3055. 1776, 1644, 1607, 1533, 1445. 1373, 1246 cm"1.
Example 576 4-amino-5-(3-bromophenyl)-7-(6-(l-oxa-4-oxo-4-thia-8-azaspiro[4.5jdecan-8-yl -3- pyridyl)pyridor2,3-d]pyrimidine Prepared from Example586 as follows: to a solution of Example586 (250 mg, 0.47 mmol) in CH2C12 at 0 °C, mCPBA was added in small portion. The reaction was monitored by TLC. After reaction completion, quenched with sodium thiosulfate. Standard work-up, followed by chromatography purification (SiO2, 10% MeOH in CH2C12) to give 152 mg of the title compound (59%). MS (ESI):551/553 (M+H; 79Br/81Br).
IR (Mic): Vmax: 3474, 3384, 3305, 3062, 2918, 1603, 1581, 1561, 1511, 1413, 1352, 1228 cm 1.
Example 577 4-amino-5-(3-bromophenyl)-7-(6-(l-oxa-4,4-dioxido-4-thia-8-azaspiro[4.51decan-8-yl)-3- pyridvQpyrido [2.3 -dlpyrimidine Prepared from Example586 as follows: to a solution of Example586 (300 mg, 0.56 mmol) in acetic acid at 0 °C. a solution of KMnO4 in water was added till the color stayed. Quenched with sodium thiosulfate. Standard work up, followed by chromatography separation (SiO2, 5% MeOH in CH2C12) to give 151 mg of the title compound (48%). MS (ESI): 567/569 (M+H; 79Br/81Br).
IR (Mic): Vmax: 3475, 3348, 3210, 3061, 2955, 1694, 1585, 1308, 1235 cm"1.
Example 578 4-amino-5-(3-bromophenyl)-7-(6-("4-oxo-l-phenyl-lJ.8-triazaspiro[4.5jdec-2-en-8-yl)-3- pyridvDpyrido [2.3 -djpyrimidine Prepared as described for Example 370 except substituting l-phenyl-1,3,8- triazaspiro[4.5]dec-2-en-4-one for 4-methoxypiperidine as follows: 1-phenyl- 1,3, 8- triazaspiro[4,5]decaN-4-one (Acros; 350 mg, 1.5 mmol) was used to react with the chloride intermediate (200 mg, 0.48 mmol) in DMSO at 100 °C for over night. There were two major products, one of them was the desired compound (95 mg, 33%). MS (ESI): 605/607 (M+H; 79Br/81Br). IR (Mic): Vmax: 3486, 3325, 3194, 3056, 2957, 2870, 1719, 1602, 1580, 1559, 1533, 1353, 1256 cm"1.
Example 579 4-amino-5-("3-bromophenvπ-7-(6-(4-(2-keto-l-benzimidazolinyl piperidinyl)-3- pyridaziny Dpyrido [2.3 -djpyrimidine
Prepared as described for Example 367 except substituting 4-(2-keto-l- benzimidazolinyl)piperidine (Aldrich) for "(lS,4S)-2-aza-5-oxa-bicyclo[2.2J]heptane". MS (ESI): 594/596 (M+H; 79Br/81Br).
IR (Mic): Vmax: 3435, 3347, 3063, 1690, 1631, 1610, 1554, 1484, 1375 cm"1.
Example 580 4-amino-5-(3-bromophenyl)-7-(6-('4-oxothiomoφholinyl)-3-pyridyl pyrido[2J- djpyrimidine Prepared from Ex. 328 as follows: to a solution of Example328 (400 mg, 0.84 mmol) in acetic acid, H2O2 (30%) was added till all the starting material was converted to the desired product. Standard work up, followed by chromatography (SiO2, 10% MeOH in CH2C12) gave 301 mg of the title compound (72%). MS (ESI): 495/497 (M+H; 79Br/81Br).
IR (Mic): Vmax: 3440, 3060, 2869, 1695, 1645, 1606, 1484, 1372, 1243 cm"1. MS (ESI): 495/497 (M+H; 79Br/81Br).
Example 581 4-amino-5-(3-bromophenvπ-7-(6-(4-(2-keto-l-benzimidazolinyl)piperidinyl)-3- pyridvDpyrido [2.3 -dlpyrimidine Prepared as described for Example 370 except substituting 4-(2-keto-l- benzimidazolinyl)piperidine (Aldrich) for 4-methoxypiperidine. MS (ESI): 593/595 (M+H; 79Br/81Br).
IR (Mic): Vmax: 3473, 3304, 3063, 2918, 1603, 1581, 1512, 1413, 1353, 1228 cm"1.
Example 582 4-amino-5-(3-bromophenyl)-7-(6-(N-methyl-N-r2-pyridylethyl)amino)-3- pyridvDpyrido [2.3 -dlpyrimidine Prepared as described for Example 370 except substituting 2-(2'- methylaminoethyl)pyridine (Aldrich) for 4-methoxypiperidine. MS (ESI): 512/514 (M+H; 79Br/81Br). IR (Mic): Vmax: 3475, 3303, 3046, 2931, 1648, 1583, 1561, 1519, 1405, 1354, 1142 cm"
Example 583
4-amino-5-(3-bromophenyl)-7-(,6-(N-methyl-N-(4-pyridylethyl)amino)-3- pyridyl pyrido~2J-d1pyrimidine Prepared as described for Example 370 except substituting 4- (2'methylaminoethyl)pyridine (Aldrich) for 4-methoxypiperidine. MS (ESI): 512/514 (M+H; 79Br/81Br).
IR (Mic): Vmax: 3480, 3252, 3000, 1600, 1590, 1570, 1350 cm"1.
Example 584 4-amino-5 -(3 -bromophenyl)-7-(6-N-(3 -pyridylmethyl)amino-3 -pyridyl pyrido[2J - dlpyrimidine
Prepared as described for Example 370 except substituting 3- (aminomethyl)pyridine (Aldrich) for 4-methoxypiperidine. MS (ESI):484/486 (M+H; 79Br/81Br).
IR (Mic): Vmax: 3477, 3289, 3233, 3040. 1640, 1610, 1558. 1480, 1392, 1353, 1310, 1145 cm"1. Example 585 , 4-amino-5-(3-bromophenvπ-7-(6-(2-hvdroxymethylpiperidinyl -3-pyridyl pyrido[2J- djpyrimidine Prepared as described for Example 370 except substituting 2- (hydroxymethyl)piperidine (Aldrich) for 4-methoxypiperidine. MS (ESI): 491/493 (M+H; 79Br/81Br).
IR (Mic): Vmax: 3479, 3396, 3299, 3076, 2935, 2858, 1643, 1600, 1580, 1558, 1506, 1418, 1351 cm"1.
Example 586 4-amino-5-(3-bromophenyl -7-(6-(l-oxa-4-thia-8-azaspiro[4.5]decan-8-yl)-3- pyridvDpyrido [2.3 -djpyrimidine Prepared from Ex. 328 as follows: to a slurry of Example328 (1.0 g, 2J mmol) in CH2C12 (220 mL), thioethanol (295 mL, 4.2 mmol) was added followed by BF3 etherate (535 mL, 4.2 mmol). The mixture stirred at room temperature for 1 day, and quenched with NaHCO3 (sat.). Standard work up, the crude product mixture was then recrystahzed from CH2Cl2/MeOH/hexanes to give the title compound (902 mg, 80%). MS (ESI): 535/537 (M+H; 79Br/81Br). IR (Mic): Vmax: 3487, 3471, 3291, 3048, 2949. 2858, 1642, 1603. 1560. 1511, 1418, 1353, 1227, 1085 cm"1.
Example 587 4-amino-5-("3-bromophenyl -7-(6-(4-hydroxy-4-(4-bromophenyl piperidinyl -3- pyridvDpyrido [2.3 -d] pyrimidine
Prepared as described for Example 370 except substituting 4-(4'-bromophenyl)-4- hydroxypiperidine (Aldrich) for 4-methoxypiperidine. MS (ESI): 633/635 (M+H; 79Br/8'Br).
IR (Mic): Vmax: 3483, 3296, 3055, 2944, 1645, 1604, 1561, 1531. 1506, 1430. 1340, 1238 cm"1. Example 588 4-amino-5 -(3 -bromophenyl )-7-(6-f 4-N-(2-pyridnyl)piperazinyl)-3 -pyridyDpyrido [2,3 - djpyrimidine Prepared as described for Example 370 except substituting l-(2'- pyridino)piperazine (Aldrich) for 4-methoxypiperidine. MS (ESI): 539/541 (M+H; 79Br/81Br). IR (Mic): Vmax: 3476, 3289, 3052, 2929, 2843, 1642, 1597, 1559, 1481, 1398, 1231 cm"
Example 589 4-amino-5-(3-bromophenyl)-7-(6-(4-N-(2-hvdroxyethyloxyethyl)piperazinyl -3- pyridv0pyridor2.3-d]pyrimidine Prepared as described for Example 370 except substituting l-(2-(2- hydroxy ethoxy)ethyl)piperazine (Aldrich) for 4-methoxypiperidine.. MS (ESI): 550/552 (M+H; 79Br/81Br).
IR (Mic): Vmax: 3490, 3396, 3279, 3143, 2919, 2852, 1633, 1604, 1582, 1555, 1504, 1424, 1337, 1241, 1119 cm"1.
Example 590
4-amino-5-(3-bromophenyl)-7-(6-(4.4-diacetoxyethylthio)piperidinyl)-3- pyridvDpyrido [23 -d] pyrimidine Prepared as described for Example 370 except substituting 4,4-di(2'-acetoxyethaN- l-thio)piperidine for 4-methoxypiperidine. This amine was prepared was made as follows: to a solution of 4-piperidinone hydrochloride salt (5.0 g, 32.6 mmol) in acetic acid (100 mL), 2-thioethaN-l-ol (3 mL, 42.8 mmol) was added followed by BF3 etherate (9.0 mL, 71.0 mmol) at room temperature. The reaction mixture was allowed to stir at room temperature for 3 days, and standard work-up gave a crude product 8.28 g (86%). MS (ESI): 697/699 (M+H; 79Br/81Br). IR (Mic): Vmax 3482, 3300. 3058, 2944. 2853, 1738, 1602, 1574, 1560, 1508, 1352, 1231 cm"1.
Example 591 4-amino-5-(3-bromophenyl -7-(6-(N-methv-N-(3-pyridylmethyl amino)-3- pyridyl pyrido[2,3-d]pyrimidine Prepared as described for Example 370 except substituting 3- (methylaminomethyl)pyridine (Maybridge) for 4-methoxypiperidine. MS (ESI): 498/500 (M+H; 79Br/81Br). IR (Mic): Vmax: 3477, 3298, 3092, 2923, 1645, 1604, 1559, 1516, 1399, 1356 cm"1.
Example 592 4-amino-5-(3-bromophenyl)-7-(6-(4-pyrrolidinylpiperidinyl)-3-pyridyl')pyrido[2J- djpyrimidine Prepared as described for Example 370 except substituting 4-(l- pyrrolidinyl)piperidine (Aldrich)for 4-methoxypiperidine MS (ESI): 554/556 (M+H; 79Br/81Br). IR (Mic): Vmax: 3474, 3299, 3042, 2807, 1647, 1601, 1574, 1560, 1507, 1231 cm"1.
Example 593 4-amino-5-(3-bromophenyl)-7-(6-(2-(lH-imidazol-4-yl ethylamino)-3- pyridazinyl)pyrido[2.3-d]pyrimidine 4-Amino-5-(3-bromophenyl)-7-(6-chloropyridaz-3-yl)pyrido[2J-d]pyrimidine (165mg), prepared in Example 367, histamine (133mg), and potassium carbonate (166mg) were suspended in pyridine (2ml) and heated at 110°C for 20h. The reaction mixture was then directly chromatographed (TFA/MeOH/CH2Cl2) to give the title compound, mp: δ 3 235°C; MS (ESI)* m/z: 488/490. IR (cm"1): 3475, 3301, 3199, 1721, 1625, 1580. 1553, 1467, 1357, 1133.
Example 594 4-amino-5-(3-bromophenyl)-7-(6-(4-N-cvanomethylpiperazinyl)-3-pyridyl)pyrido[2J- djpyrimidine Prepared by deformylation of Example 329 with hydrochloric acid in methanol and followed by treatment with iodoacetylnitrile in dimethy formamide. IR (mic) 3473, 3299, 2822, 1561, 1234 cm"1; MS m/z 502 (M+H)*.
Example 595 4-amino-5-(3-bromophenyl -7-(6-(3-hvdroxypyrroldinyl -3-pyridyl')pyrido[2J- dlpyrimidine
Prepared as described for Example 370 except substituting 3-hydroxypyrrolidine for 4-methoxypiperidine.
IR (microscope) 3480, 3300, 1606, 1559, 1431, 1309cm"1; MS m/z 463 (M+H)*.
Example 596 4-amino-5-(3-bromophenylN)-7-f6-(4-methylpiperidinylV3-pyridyl)pyridof2J- dlpyrimidine Prepared as described for Example 370 except substituting 3 -methy lpiperi dine for 4-methoxypiperidine.
IR (microscope) 3473, 3092, 1558, 1506, 1233 cm"1; MS m/z 476 (M+H)*.
Example 597 4-amino-5-(3-bromophenyl)-7-(6-(cis-3.5-dimethylmoφholinvf)-3-pyridyl)pyrido[2J- dlpyrimidine Prepared as described for Example 370 except substituting cis-3,5- dimethylmoφholine for 4-methoxypiperidine. IR (microscope) 3475, 3090, 1561, 1508, 1239, 1175 cm"1 MS m/z 492 (M+H)*. Example 598 4-amino-5-f3-bromophenyl)-7-(6-(4J-difluoropipridinvπ-3-pyridyl pyrido[2J- djpyrimidine Prepared as described for Example 370 except substituting 4,4-difluoropipridine for 4-methoxypiperidine, 4,4-difluoropipridine was prepared according to Tetrahedron, 1977, 33, 1707. IR (microscope) 3474, 3091, 1507, 1237 cm"1; MS m z 498 (M+H)*.
Example 599
4-amino-5-(3-bromophenyl)-7-(6-(lJ-dioxidovthiomorpholinyl)-3- pyridazinyl)pyrido[2, -d]pyrimidine Prepared by the oxidation of Example 605 using OsO4 in MeOH/CH2Cl2/acetone (1 :1:1) solution. IR(KBr) 3470, 1600, 1564, 1316, 1287, 1122 cm"1 MS m/z 513 (M+H)*.
Example 600 4-amino-5-(3-bromophenyl -7-(6-thiazolidinyl-3-pyridyl')pyrido[2J-dlpyrimidine Prepared according o the procedure of Example 306.
IR (microscope) 3468, 3052, 1557, 1509, 1407, 1289 cm 1; MS m/z 466 (M+H)*.
Example 601 4-amino-5-(3-bromophenvπ-7-(6-(lJ-dioxidovthiazolidin-3-vπ-3-pyridyl)pyrido[2J- dlpyrimidine
Prepared according to the procedure of Example 306. IR (microscope) 3466, 3090. 1563, 1508, 1234 cm"1; MS m/z 498 (M+H)*.
Example 602 4-amino-5-(3-bromophenyl)-7-(6-thiomoφholinyl-3-pyridazinyl pyrido[2J-d1pyrimidine Prepared as described for Example 367 except substituting thiomoφholine for (lS,4S)-2-aza-5-oxa-bicyclo[2.2J]heptane. IR (microscope) 3426, 3063, 1605, 1556, 1442, 1377, 1265 cm"1; MS m/z 481 (M+H)*.
Example 603
4-amino-5-(3-bromophenyl -7-('6-(2.5-dihvdropyrrolyl)-3-pyridyl pyrido[2J-d]pyrimidine
Prepared according to the procedure of Example 306. IR (microscope) 3468, 3060, 1607, 1550, 1443, 1265 cm"1; MS m/z 446 (M+H)*.
Example 604
4-amino-5-(3-bromophenvD-7-(6-(T.3-dioxa-8-azaspiro[4.5]decan-8-yl)-3- pyridyl)pyrido[2J-d]pyrimidine Prepared according to the procedure in Example 346, with potassium-t-butoxide and dibromomethane in dimethylformamide. IR (microscope) 3468, 3052, 1557, 1509, 1407, 1289 cm"1; MS m/z 520 (M+H)*.
Example 605 4-amino-5-(3-bromophenyl)-7-(6-hvdroxy-3-pyridazinyl)pyrido[2J-djpyrimidine Prepared according to the procedure of Example 246c substituting thiomoφholine for dimethylamine.
IR(KBr) 3487, 1601, 1562, 1502, 1128 cm"1 MS m/z 481 (M+H)*
Example 606 4-amino-5-(2J-dichlorophenyl)-7-(6-(1.4-dioxa-8-azaspiro[4.5jdecan-8-yl)-3- pyridy Dpyrido [23 -djpyrimidine The procedure of Example 392 was followed, except substituting 5-acetyl-2-(l,4- dioxa-8-azaspiro[4.5]decan-8-yl)pyridine for 5-acetyl-2-moφholinylpyridine. Treatment with HCl/ethanol to form the hydrochloride salt was omitted, and the free base was obtained instead. IR (MIC) 3480, 3120. 1635. 1605, 1561, 1515. 1429, 1240cm '; MS m/z 507 (M-H)"
Example 607 4-amino-5-isopropyI-7-(6-(l,4-dioxa-8-azaspiro[4.5jdecan-8-yl)-3-pyridyl)pyrido[2J- djpyrimidine
Prepared by the method of Example 327, substituting 2-methylpropanal for 3- bromobenzaldehyde. mp: ~ 205°C;
MS (FAB)* m/z calc'd for C22H27N6O2: 407.2195, found: 407.2186. IR (cm"'): 3318, 3142, 2960, 1586, 1554, 1514, 1425, 1344, 1240, 1105.
Example 608 3 4-amino-5-(3-bromophenylV7-(6-piperidinyl-3-pyridvDpyrido[2J-d]pyrimidine The title compound was prepared as described for Example 370 substituting piperidine for 4-methoxypiperidine, followed by treatment with IM HCl ether MS (APCI+) m/z 461 (M+H)*;
'H NMR (300 MHz, DMSO-d6) δ 10.05 (bs, IH), 9.00 (m, IH), 8.90 (s, IH), 8.70 (m, IH), 8.23 (m, IH), 7.82 (m, IH), 7.60 (m, 2H), 7.40 (m, 2H), 3.87 (m, 4H), 1.68 (m, 6H)
Example 609
4-amino-5-(3-bromophenyl)-7-(6-(3-(4-tetrahvdropyranyloxyimino pyrrolidinyl)-3- pyridvDpyrido \23 -djpyrimidine The title compound was prepared as described for Example 370 substituting 3-(4'- tetrahydropyranyl-oximinyl)pyrrolidine (prepared as in A-321236.3) for 4- methoxypiperidine, followed by treatment with IM HCl ether. MS (ESI+) m/z 560 (M+H)*;
'H NMR (300 MHz, DMSO-d6) δ 10.00 (bs, IH), 9.14 (s, IH), 8.90 (s, IH), 8.65 (m, IH), 7.97 (s, IH), 7.82 (m, IH), 7.60 (m, 2H), 7.38 (m, IH), 7.04 (m, IH) 4.39 (m, 2H), 4.25 (m, IH), 3.84 (m, 4H), 3.42 (m, 2H), 2.94 (m, 2H), 1.94 (m, 2H), 1.57 (m, 2H) Example 610 4-amino-5-(2-trifluorophenvIphenyl -7-(6-moφholinyl-3- pyridyl)pyrido[2.3-d]pyrimidine Prepared as described for Example 395 except substituting 2- trifluoromethylbenzaldehyde for 2,5-dichlorobenzaldehyde. IR (KBr) 3495, 1674, 1634, 1487, 1421, 1321, 1302, 1190cm"1; MS m/z 452.9 (M+H)*.

Claims

WHAT IS CLAIMED IS:
1. A method of inhibiting adenosine kinase by administering to a mammal in need of such treatment a pharmaceutically effective amount of one or more compounds of formula I
Figure imgf000307_0001
I, or a pharmaceutically acceptable salt or amide thereof in vitro or to a mammal wherein,
R1 and R2 are each independently selected from the group consisting of hydrogen, alkenyl, alkoxyalkyl, alkoxyalkylcarbonyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkyl, alkylcarbonyl, aminocarbonyl, aryl, arylalkyl, arylalkylcarbonyl, arylcarbonyl, carboxyalkyl, formyl, haloalkylcarbonyl, heterocycle, heterocyclealkyl, heterocyclecarbonyl, hydroxyalkyl, iminoalkyl, and (NZ,Z2)alkyl, or R1 and R2 may join together with the nitrogen atom to which they are attached to form a 5-7 membered ring optionally containing 1 -2 additional heteroatoms selected from the group consisting of O, N, and S;
Z, and Z2 are each independently selected from the group consisting of hydrogen, alkoxycarbonyl, alkyl, alkylcarbonyl, benzyl, benzyloxycarbonyl, and formyl;
R3 is selected from the group consisting of alkenyl, alkyl, alkynyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, heterocycle, heterocyclealkyl, heterocyclealkylcarbonyl, (NZ,Z2)alkyl, and -RARB;
RA is selected from the group consisting aryl and arylalkyl; RB is selected from the group consiting of aryl, arylalkoxy, arylalkyl, aryloxy, heterocycle, and heterocyclealkyl;
R4 is selected from the group consisting of alkenyl, alkoxyalkynyl, alkyl, alkynyl, cycloalkyl, aryl, arylalkyl, heterocycle, heterocyclealkyl, and -RCRDRE; Rc is selected from the group consiting of aryl. arylalkyl. heterocycle, and heterocyclealkyl;
RD is selected from the group consisting of aryl, arylalkoxy, arylalkoxyimino. arylalkyl, aryloxy, heterocycle, heterocyclealkoxy, heterocyclealkyl, heterocyclecarbonyl, heterocycleimino, heterocycleoxy, heterocycleoxyalkyl, heterocycleoxyimino, heterocycleoxyiminoalkyl, and heterocyclesulfonyl;
RE is absent or selected from the group consiting of aryl, arylalkoxy, arylalkoxyimino, arylalkyl, aryloxy, heterocycle, heterocylealkoxy, heterocyclealkyl, heterocyclecarbonyl, heterocycleimino, heterocycleoxy, heterocycleoxyalkyl, heterocycleoxyimino, heterocycleoxyiminoalkyl, and heterocyclesulfonyl; and a dashed line — indicates that a double bond is optionally present provided that proper valencies are maintained; with the proviso that the following compounds are excluded, 4-amino-5-(4-chorophenyl)-7-(4-nitrophenyl)pyridol[2,3-d]pyrimidine, 4-amino-5-(4-methoxyphenyl)-7-(4-nitrophenyl)pyridol[2,3-d]pyrimidine, 4-amino-5-(4-fluorophenyl)-7-(4-fluorophenyl)pyridol[2,3-d]pyrimidine, 4-amino-5-(4-chlorophenyl)-7-(4-fluoφhenyl)pyridol[2,3-d]pyrimidine, 4-amino-5-phenyl-7-(4-aminophenyl)pyrido[2,3-djpyrimidine, 4-amino-5-phenyl-7-(4-bromphenyl)pyrido[2,3-d]pyrimidine, 4-amino-5-(4-methoxyphenyl)-7-(4-aminophenyl)pyrido[2,3-d]pyrimidine, 4-amino-5-(4-methoxyphenyl)-7-(4-bromphenyl)pyrido[2J-d]pyrimidine, and 4-amino-5,7-diphenylpyrido[2,3-djpyrimidine.
2. A method of inhibiting adenosine kinase according to claim 1 comprising administering a compound of formula I
Figure imgf000308_0001
or a pharmaceutically acceptable salt or amide thereof wherein,
R1 and R2 are each independently selected from the group consisting of hydrogen, alkenyl, alkoxyalkyl, alkoxyalkylcarbonyl, alkoxycarbonyl, alkyl, alkylcarbonyl, aminocarbonyl, aryl, arylcarbonyl, carboxyalkyl, formyl, haloalkylcarbonyl, heterocyclealkyl, hydroxyalkyl, iminoalkyl, and (NZ,Z2)alkyl, or R1 and R2 may join together with the nitrogen atom to which they are attached to form a 6 membered ring optionally containing 1 additional heteroatom selected from the group consisting of O, N, and S;
R3 is selected from the group consisting of alkenyl, alkyl, aryl, arylalkyl, cycloalkyl, heterocycle, heterocyclealkyl, (NZ,Z2)alkyl, and -RARB;
RA is selected from the group consisting of aryl and arylalkyl;
RB is selected from the group consisting of aryl, arylalkoxy, arylalkyl, aryloxy, and heterocycle;
R4 is selected from the group consisting of alkoxyalkynyl, alkynyl, aryl, heterocycle, and -RCRDRE;
Rc is selected from the group consisting of aryl and heterocycle;
RD is selected from the group consisting of aryl, arylalkoxy, arylalkyl, aryloxy, heterocycle, heterocyclealkoxy, heterocyclealkyl, heterocyclecarbonyl, heterocycleoxy, and heterocyclesulfonyl; RE is absent or selected from the group consisting of aryl, arylalkoxy, arylalkoxyimino, arylalkyl, aryloxy, heterocycle, heterocylealkoxy, heterocyclealkyl, heterocyclecarbonyl, heterocycleimino, heterocycleoxy, heterocycleoxyalkyl, heterocycleoxyimino, and heterocycleoxyiminoalkyl;
Z\ and Z2 are each independently selected from the group consisting of hydrogen, alkoxycarbonyl, alkyl, alkylcarbonyl, benzyl, benzyloxycarbonyl, and formyl; and a dashed line — indicates that a double bond is optionally present provided that proper valencies are maintained.
3. A method of inhibiting adenosine kinase according to claim 1 comprising administering a compound of formula II
Figure imgf000310_0001
II, or a pharmaceutically acceptable salt or amide thereof wherein,
R1 and R2 are each independently selected from the group consisting of hydrogen, alkenyl, alkoxyalkyl, alkoxyalkylcarbonyl, alkoxycarbonyl, alkyl, alkylcarbonyl, aminocarbonyl, aryl, arylcarbonyl, carboxyalkyl, formyl, haloalkylcarbonyl, heterocyclealkyl, hydroxyalkyl, iminoalkyl, and (NZ,Z2)alkyl, or R1 and R2 may join together with the nitrogen atom to which they are attached to form a 6 membered ring optionally containing 1 additional heteroatom selected from the group consisting of O, N, and S;
R3 is selected from the group consisting of alkenyl, alkyl, aryl, arylalkyl, cycloalkyl, heterocycle, heterocyclealkyl, (NZ,Z2)alkyl, and -RARB;
RA is selected from the group consisting of aryl and arylalkyl;
RB is selected from the group consisting of aryl, arylalkoxy, arylalkyl, aryloxy, and heterocycle;
R4 is selected from the group consisting of alkoxyalkynyl, alkynyl, aryl, heterocycle, and -RCRDRE;
Rc is selected from the group consisting of aryl and heterocycle;
RD is selected from the group consisting of aryl, arylalkoxy, arylalkyl, aryloxy, heterocycle, heterocyclealkoxy, heterocyclealkyl, heterocyclecarbonyl, heterocycleoxy, and heterocyclesulfonyl;
RE is absent or selected from the group consisting of aryl, arylalkoxy, arylalkoxyimino, arylalkyl, aryloxy, heterocycle. heterocylealkoxy, heterocyclealkyl, heterocyclecarbonyl, heterocycleimino, heterocycleoxy, heterocycleoxyalkyl, heterocycleoxyimino, and heterocycleoxyiminoalkyl; and,
Z] and Z2 are each independently selected from the group consisting of hydrogen, alkoxycarbonyl, alkyl, alkylcarbonyl, benzyl, benzyloxycarbonyl, and formyl.
4. The method 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-(l-moφholinyl)-5- pyrimidinyl; 2-(l-pyrrolidinyl)-5-pyrimidinyl; 2-dimethylamino-5-pyrimidinyl; 2-furanyl; 2-oxobenzoxazolin-6-yl; 2-pyridyl; 3 -(dimethy lamino)phenyl; 3-amino-4-methoxyphenyl; 3-bromo-4-(dimethylamino)phenyl; 3 -methoxyphenyl; 3-methyl-4-(N-acetyl-N- methy lamino)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-(N-(2-(dimethylamino)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-methyl-N-(2-cyano)ethylamino)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- 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-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- diethylaminophenyl; 4-diethylmalonylallylphenyl; 4-dimethylaminophenyl; 4- ethoxyphenyl; 4-ethylphenyl; 4-fluorophenyl; 4-hydroxyphenyl; 4-imidazolylphenyl; 4- iodophenyl; 4-isopropy Ipheny 1; 4-methoxyphenyl; 4-methylaminophenyl; 4- methylsulfo ny Ipheny 1; 4-moφholinylphenyl; 4-N-(2-(dimethylamino)ethyl)-N- formylamino)pheny 1 ; 4-N-(3 -methoxypropionyl)-N-isopropy l-amino)pheny 1 ; 4-N-ethy 1- N-(2-methoxyethyl)amino)phenyl; 4-N-formylpiperazinylphenyl) 4-nitrophenyl; 4- piperidinylphenyl; 4-(3 -pyridy l)phenyl; 4-pyrrolidinylphenyl; 4-t-butylacrylphenyl; 5- (dimethylamino)thiophene-2-yl; 5-amino-2-pyridyl; 5 -dimethy lamino-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-moφholinyl-3-pyridinyl; 6-pyrrolidinyl-3-pyridinyl; 6-(2-propyl)-3-pyridinyl; (4-formylamino)phenyl; 6-(4-oxopiperidinyl)-3-pyridazinyl; 6-(4- moφholinyliminopiperidinyl)-3-pyridazinyl; 6-((lS,4S)-2-oxa-5-azabicyclo[2.2J]heptan- 5-yl)-3-pyridazinyl; 6-(4-methoxyiminopiperidinyl)-3-pyridazinyl; 6-phenylmethoxy-3- pyridazinyl; 6-( 1 J -dioxidoythiazolidin-3-yl)-3-pyridyl; 6-( 1 ,3-dioxa-8- azaspiro[4.5jdecan-8-yl)-3-pyridyl; 6-(l-oxa-4-thia-8-azaspiro[4.5]decan-8-yl)-3-pyridyl; 6-( 1 J -dioxidoythiomoφholinyl)-3-pyridazinyl; 6-( 1 -oxa-4,4-dioxido-4-thia-8- azaspiro[4.5]decan-8-yl)-3-pyridyl; 6-(l-oxa-4-oxo-4-thia-8-azaspiro[4.5]decan-8-yl)-3- pyridyl; 6-(3-hydroxy-8-azabicyclo[3.2J]octan-8-yl)-3-pyridyl; 6-(4-oxo-l-phenyl-l,3,8- triazaspiro[4.5jdecan-8-yl)-3-pyridyl; 6-(4-oxo-l-phenyl-l,3,8-triazaspiro[4.5]dec-2-en-8- yl)-3-pyridyl; 6-(N-l,4-dioxa-8-azaspiro[4.5jdecan-8-yl)-3-pyridylsulfonamide; 2-(lJ- dioxidothiomoφholinyl)-5-thiazoyl; 5-(l,4-dioxa-8-azaspiro[4.5]decan-8-yl)-2-pyrazinyl; 2-(l,4-dioxa-8-azaspiro[4.5]decan-8-yl)-5-thiazoyl; 6-(hexahydro-lH-furo[3,4-c]pyrrol-5- yl)-3-pyridazinyl; 6-(hexahydro-lH-furo[3,4-c]pyrrol-5-yl)-3-pyridyl; 6-(4- methoxypiperidinyl)-3-pyridyl; 6-(4,7-epoxy-7-methyl-2,3,3A,4,5,6,7,7a-octahydro-lH- isoindolyl)-3-pyridazinyl; 6-(4-(4-tetrahydropyranyloxy)iminopiperidinyl)-3-pyridazinyl; 6-isopropoxy-3-pyridazinyl; 6-(2,4-dioxo-(lH,3H)-quinazolin-3-yl)-3-pyridyl; 6-(4-(N- methylpiperazinyl)iminopiperidinyl)-3-pyridazinyl; 6-(4-tetrahydropyranyloxy)-3- pyridazinyl; 6-moφholinylethoxy-3 -pyridazinyl; 6-(4-ethoxypiperidinyl)-3-pyridazinyl; 6- (l,4-dioxa-8-azaspiro[4.5]decan-8-yl)-3-pyridyl; 6-(4-(2-ethoxyethoxy)piperidinyl)-3- pyridazinyl; 6-((3aR,6aS)-2-oxo-tetrahydro-3aH-[l ,3 jdioxolo[4,5-cjpyrrol-5-yl)-3-pyridyl; 6-(4-(4-tetrapyranyloxyethyl)piperidinyl)-3-pyridazinyl; 6-(3-(R)- tetrahydrofuranyloxy)piperidinyl)-3-pyridazinyl; 6-(3-(S)- tetrahydrofuranyloxy)piperidinyl)-3-pyridazinyl; 6-(trans-3-ethoxy-4- hydroxy)pyrrolidinyl)-3 -pyridazinyl; 6-(cis-3-ethoxy-4-hydroxy)pyrrolidinyl)-3- pyridazinyl; 6-(trans-3-ethoxy-4-hydroxy)pyrrolidinyl)-3-pyridyl; 6-(trans-3,4-bis- ethoxy)pyrrolidinyl)-3-pyridazinyl; 6-(trans-3,4-bis-ethoxy)pyrrolidinyl)-3-pyridyl; 6-(cis- 3,4-bis-ethoxy)pyrrolidinyl)-3-pyridyl; 6-(cis-3,4-bis-ethoxy)pyrrolidinyl)-3-pyridazinyl; 6-(cis-3-ethoxy-4-hydroxy)pyrrolidinyl)-3-pyridyl; 6-(cis-3-amino-4- hydroxy)pyrrolidinyl)-3-pyridazinyl; 6-(cis-3-amino-4-hydroxy)pyrrolidinyl)-3-pyridyl; 6- (l,5-dioxa-9-azaspiro[5.5]undecan-9-yl)-3-pyridazinyl; 6-(4-tertbutyl)piperidinyl-3- pyridazinyl; 6-(4-N-formyl)piperidinyl-3-pyridazinyl; 6-moφholinyl-3-pyridazinyl; 4-N- l,4-dioxa-8-azaspiro[4.5]decan-8-ylbenzenesulfonamide; 4-(4-dioxa-8- azaspiro[4.5]decan-8-ylcarboxamide)phenyl; 6-(3-methoxy-l,5-dioxa-9- azaspiro[5.5jundecan-9-yl)-3-pyridazinyl; 6-(l,5-dioxa-3-hydroxymethyl-9- azaspiro [5.5 ]undecan-9-yl)-3 -pyridazinyl; 6-(S-O-ethyl-2-hydroxymethylpyrrolidinyl)-3- pyridazinyl; 6-(4-acetyl-l-oxa-4,8-diazaspiro[4.5]decan-8-yl)-3-pyridazinyl; 6-((2R,3R)- 2,3-bis(methoxymethyl)-l,4-dioxa-8-azaspiro[4.5]decan-8-yl)-3-yridazinyl; 6-((2S,3S)- 2,3-dimethyl-l,4-dioxa-8-azaspiro[4.5jdecan-8-yl)-3-pyridazinyl; 6-(4,4-(cis-l,2- dioxycyclopentane)piperidinyl)-3-pyridazinyl; 6-(4,4-( 1 S,2S- dimethoxymethylethanedioxy)piperidinyl)-3-pyridazinyl; 6-(4,4-(cis-3,4-dioxy- oxacyclopentane)piperidinyl)-3-pyridazinyl; 6-(4,4-(l ,3-dioxy-2- methoxypropylene)piperidinyl)-3 -pyridazinyl; 6-(4,4-(l,3-dioxy-2- hydroxymethylpropylene)piperidinyl)-3-pyridazinyl; 6-(4,4-(2-(2,2-spiro- oxacyclopropane-l,3-dioxypropylene)piperidinyl)-3-pyridazinyl; 6-moφholinyl-3- pyridazinyl; 6-(4-moφholinyliminopiperidinyl)-3-pyridyl; 6-(4-(N- methylpiperazinyl)iminopiperidinyl)-3-pyridyl; 6-(4-( 1 ,2,4-triazol- 1 -yl)iminopiperidinyl)- 3-pyridyl; 6-(4-ethylpiperidinylcarboxylate)-3-pyridyl; 2-phenylmethyl-3(2H)- pyridazinone-6-yl; 6-(4-(moφholinylcarboxamide)piperidinyl)-3-pyridyl; 6-(4-(N- moφholinylaminocarboxamide)piperidinyl)-3-pyridyl; 6-(4-(N,N- dimethylaminocarboxamide)piperidinyl)-3-pyridyl; 6-(4-(N-methyl-N- methoxyethylcarboxamide)piperidinyl)-3-pyridyl; 6-(4-(N- methoxyethylcarboxamide)piperidinyl)-3-pyridyl; 6-(4-hydroxymethylpiperidinyl)-3- pyridyl; 6-(4-hydroxypiperidinyl)-3-pyridyl; 6-(4-N-acetylpiperazinyl)-3-pyridyl; 6-(4- cyanopiperidinyl)-3-pyridyl; 6-(4-N-(4-fluorophenyl)piperazinyl)-3-pyridyl; 4- moφholinylbenzenesulfonamide; 4-N-4,4-ethylenedioxypiperidinylbenzenesulfonamide; 4-N-cyclopropylbenzenesulfonamide; 4-piperidinebenzenesulfonamide; 4-(4- cyanopiperidine)benzenesulfonamide; 4-N-cyclopropylmethylbenzenesulfonamide; 4- N,N-dimethylaminobenzenesulfonamide; 4-N-(S)-2- hydroxymethylpyrrolidinebenzenesulfonamide; 4-(4- hydroxypiperidine)benzenesulfonamide; 4-(cis-3,5- dimethylmoφholinyl)benzenesulfonamide; 3-fluoro-4-thiomoφholinylphenyl; 6- (thiomoφholinyl)-3-pyridyl; 6-(4,4-dioxothiomoφholinyl)-3-pyridyl; 4-(4,4- ethylenedioxypiperidinylcarboxamide)phenyl; 4-(N-cyclopropylcarboxamide)phenyl; 4- (moφholinylcarboxamide)phenyl; 6-N-cyclopropylamino-3 -pyridyl; 4-(4- hydroxypiperidinylcarboxamide)phenyl; 6-(S)-hydroxymethylpyrrolidinyl-3-pyridazinyl; 6-(4-(2-ethoxyethoxy)piperidinyl)-3-pyridyl; 6-hexahydropyrimidine)-3-pyridyl; 6-(S)-2- ethoxyethoxypyrrolidinyl)-3-pyridyl; 6-(R)-2-ethoxyethoxypyrrolidinyl)-3-pyridyl; 6-(cis- 3,4-dihydroxypyrolidinyl)-3-pyridyl; 6-[(3aR,6aS)-tetrahydro-3aH-[l,3]dioxolo[4,5- c]pyrrol-2-one-5-ylj-3-pyridyl; 6-(cis-2,3-dihydroxypyrrolidinyl)-3-pyridazinyl; 6-(S,R-2- hydroxymethyl-4-hydroxypyrrolidinyl)-3-pyridyl; 6-(R-2-hydroxymethyl-4-pyrrolidinyl)- 3 -pyridazinyl; 6-(l S,4S)-2-aza-5-oxa-bicyclo[2.2J]heptane)-3-pyridyl; 6-(2- imidizolidone-l-yl)-3-pyridyl; 4-(2,4-(lH,3H)-quinazolinedion-3-yl)phenyl; 6- moφholinylcarboxamide-3-pyridazinyl; 6-methoxy-3 -pyridazinyl; 6-N,N- diethoxyethylamino-3-pyridazinyl; 6-(4-ethoxymethylpiperidinyl)-3-pyridazinyl; 6-(4-(4- tetrahydropyranylmethyl)piperidinyl)-3-pyridazinyl; 6-(4- ethoxyethoxymethylpiperidinyl)-3 -pyridazinyl ; 6-N-methyl-N- 1,3- dioxalanemethylamino)-3-pyridazinyl; 6-(4,4-dioxyethylenecyclohexyloxy)-3 -pyridazinyl; 6-dihydroxymethylmethoxy-3-pyridazinyl; 6-(3-pyridyloxy)-3-pyridazinyl; 4,7-epoxy-7- methyl-2,3,3A,4,5,6,7,7a-octahydro-lH-isoindolyl; 6-(4-N-methyl-N-methoxyethyl)-3- pyridazinyl; 6-(3,4-dimethoxymethoxypyrrolidinyl)-3-pyridazinyl; 6-(trans-3-hydroxy-4- methylpyrrolidinyl)-3-pyridazinyl; 6-(trans-3-hydroxy-4-methylpyrrolidinyl)-3-pyridyl; 6- (cis-3-hydroxy-4-methylpyrrolidinyl)-3-pyridazinyl; 6-(cis-3-hydroxy-4- methy lpyrrolidiny l)-3 -pyridy 1 ; 6-(trans-3 -cyano-4-hydroxy lpyrrolidiny l)-3 -pyridyl; 6-(3 - hydroxy-4-tert-butylcarboxamidepyrrolidinyl)-3 -pyridyl; 6-(S-2-(4- tetrahy dropyranyloxy)methy lpyrrolidiny l)-3 -pyridazinyl; 6-(2-(4- tetrahydropyranyloxy)iminopyrrolidinyl)-3 -pyridazinyl; 2-moφholinyl-5-thiazoyl; 5- bromo-2-thienyl; 2,5-dimethyl-3-thienyl; 5-chloro-2-thienyl; 2,4-dimethyl-5-thiazoyl; 5- methyl-2-thienyl; 2-furanyl; 2-(4,4-dioxyethylenepiperidinyl)-5-thiazoyl; 3-thienyl; 3- methyl-2-thienyl; 2-moφholinyl-4-thiazoyl; 2-moφholinyl-4-trifluoromethy-5-thiazoyl; 5-moφholinyl-2-thienyl; 4-methyl-2-moφholinyl-5-thiazoyl; 2,5-dichloro-3-thienyl; 2,5- dimethyl-3-furanyl; N-methyl-2-pyrrolyl; 2-N,N-dimethylamino-5-thiazoyl; 2- moφholinyl-5-thiazoyl; 2-(4,4-dioxythiomoφholinyl)-5-thiazoyl; 1 -N-methyl-2- moφholinyl-5-imidazoyl; 2-moφholinyl-5-oxazolyl; 2-N-methyl-N-methoxyethylamino- 5-thiazoyl; 2-N-methyl-N-ethylamino-5-thiazoyl; 2-N-pyrrolidinyl-5-thiazoyl; 2-N- methyl-N-propylamino-5-thiazoyl; 2-N,N-diethylamino-5-thiazoyl; 2-(N- methypiperazinyl)-5-thiazoyl; 2-(N-(2-pyridyl)piperazinyl)-5-thiazoyl; 2-N-methy-N-(2- pyridylethyl)-5-thiazoyl; 2-(4-oxopiperazinyl)-5-thiazoyl; 2-(4-(N- moφholinyl)iminopiperazinyl)-5-thiazoyl; 6-N-moφholine-3-pyridinesulfonamide; 2-(4- oxopiperidinyl)-5-pyrimidyl; 2-(4,4-dioxethylenepiperidinyl)-5-pyrimidyl; 5-(4,4- dioxethylenepiperidinyl)-2-pyriazinyl; 5-(4-oxopiperidinyl)-2-pyrazinyl; 6-N-cyclopropyl- 3-pyridinesulfonamide; 6-N-(4,4-dioxethylenepiperidinyl)-3-pyridinesulfonamide; 2-(4- (4-tetrahydropyranyloxy)iminopiperidinyl)-5-pyrazinyl; 6-(4-
(phenylmethoxy)iminopiperidinyl)-3-pyridyl; 6-(4-(tert-butyloxy)iminopiperidinyl)-3- pyridyl; 6-(4-(cyclohexyloxy)iminopiperidinyl)-3-pyridyl; 6-(4-hydroxyiminopiperidinyl)- 3-pyridyl; 6-(4-(4-tetrahydropyranyloxy)iminopiperidinyl)-3-pyridyl; 6-(4- methoxyethoxyiminopiperidinyl)-3-pyridyl; 6-(4-(2-thenylmethoxy)iminopiperidinyl)-3- pyridy 1 ; 6-(4-(4' -(5 ' H-2-oxyfuranyl)-4-hydroxy)piperidiny l)-3 -pyridyl ; 6-(4-( 1 -(4- tetrahydropyranyloxy)iminoethyl))-4-hydroxypiperidinyl)-3 -pyridaziny 1 ; 6-(4-(4 ' -acety 1- 4'-hydroxypiperidinyl)-3-pyridazinyl; 6-(4-( 1 -(isopropylcaboxymethoxy)iminoethyl))-4- hydroxypiperidinyl)-3-pyridyl; 6-(4-(l -(ethylcaboxymethoxy)iminoethyl))-4- hydroxypiperidinyl)-3-pyridyl; 6-(4-( 1 -(methylcaboxymethoxy)iminoethyl))-4- hydroxypiperidinyl)-3 -pyridyl; 6-(4-( 1 -(2-tetrahydropyranyloxy)iminoethyl))-4- hydroxypiperidiny l)-3 -pyridy 1 ; 6-(4-( 1 -(ally loxy)iminoethy l))-4-hydroxypiperidinyl)-3 - pyridyl; 6-(4-(l-(ethoxy)iminoethyl))-4-hydroxypiperidinyl)-3-pyridyl; 6-(4-(l- (methoxy)iminoethyl))-4-hydroxypiperidinyl)-3-pyridyl; 6-(4-(l-(hydroxy)iminoethyl))-4- hydroxypiperidinyl)-3-pyridyl; 6-(4-(2-tetrahydropyranyloxy)iminopiperidinyl)-3-pyridyl; 6-(4-(isopropylcarboxymethoxy)iminopiperidinyl)-3-pyridyl; 6-(4-hydroxy-4-( 1 -(4- tetrahydropyranyloxy)iminoethyl))-4-hydroxypiperidinyl)-3-yridyl; 6-(4-(3- butyrolactone)-4-hydroxypiperidinyl)-3-pyridyl; 6-(4-(2-butyrolactone)-4- hydroxypiperidinyl)-3-pyridazinyl; 6-(4-acetyl-4-hydroxypiperidinyl)-3-pyridyl; 6-(3- hydroxyazetidinyl)-3 -pyridyl; 6-(cis-3-hydroxytropanyl)-3-pyridyl; 6-(cis-2,3- dihydroxypiperidiny l)-3 -pyridy 1 ; 6-(N-methyl-N-(3 -pyridylmethy l)amino)-3 -pyridazinyl; 6-( 1 ,2,3 ,6-tetrahydropyridyl)-3 -pyridyl; 6-(4-(N-4 ' methoxypheny lcarbamoyl)piperidinyl)- 3 -pyridazinyl; 6-(4-(2-butyrolactone)-4-hydroxypiperidinyl)-3 -pyridyl ; 6-(trans-3 ,4-bis(N- 4'-methoxyphenylcarbamoyl)pyrrolidinyl)-3-pyridyl; 6-(trans-3 -hydroxy tropanyl)-3- pyridyl; 6-(S,S-trans-3,4-dihydroxypyrrolidinyl)-3-pyridyl; 6-(R,R-trans-3,4- dihydroxypyrrolidinyl)-3-pyridazinyl; 6-(R,R-trans-3,4-dihydroxypyrrolidinyl)-3-pyridyl; 6-(8-(l-phenyl-l,3,8-triaza-2-spiro[4,5]deceN-4-one)-3-pyridyl; 6-(8-(l-phenyl-l,3,8- triaza-2-spiro[4,5]deceN-4-one)-3-pyridyl; 6-(4-(2-keto-l-benzimidazolinyl)piperidinyl)- 3-pyridazinyl; 6-(4-oxothiomoφholinyl)-3-pyridyl; 6-(4-(2-keto-l- benzimidazolinyl)piperidinyl)-3-pyridyl; 6-(N-methyl-N-(2-pyridylethyl)amino)-3- pyridyl; 6-(N-methyl-N-(4-pyridylethyl)amino)-3-pyridyl; 6-N-(3-pyridylmethyl)amino-3- pyridyl; 6-(2-hydroxymethylpiperidinyl)-3-pyridyl; 6-(4-hydroxy-4-(4- bromophenyl)piperidinyl)-3-pyridyl; 6-(4-N-(2-pyridnyl)piperazinyl)-3-pyridyl; 6-(4-N- (2 -hydroxyethyloxyethyl)piperazinyl)-3 -pyridyl; 6-(4,4-diacetoxyethylthio)piperidinyl)-3- pyridyl; 6-(N-methy-N-(3-pyridylmethyl)amino)-3-pyridyl; 6-(4-pyrrolidinylpiperidinyl)- 3-pyridyl; 6-(4-N-cyanomethylpiperazinyl)-3-pyridyl; 6-(3-hydroxypyrroldinyl)-3-pyridyl; 6-(4-methylpiperidinyl)-3-pyridyl; 6-(cis-3,5-dimethylmoφholinyl)-3-pyridyl; 6-(4,4- difluoropipridinyl)-3-pyridyl; 6-(4,4-dioxythiomoφholinyl)-3-pyridazinyl; 6- thiazolidinyl-3-pyridyl; 6-(lJ-dioxythiazolidinyl)-3-pyridyl; 6-thiomoφholinyl-3- pyridazinyl; 6-(2.5-dihydropyrrolyl)-3-pyridyl; 6-(hexahydro-l H-furo[3,4-c]pyrrol-5-yl)- 3-pyridyl; 6-hydroxy-3-pyridazinyl; 6-piperidinyl-3-pyridyl; and 6-(4- tetrahydropyranyloxy)iminopyrrolidinyl-3-pyridyl; 6-moφholinyl-3-pyridyl.
5. The method according to claim 3 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 -bromopheny l)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-buty lacry Ipheny 1; 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- neopenty Ipheny 1; 4-phenoxyphenyl; 5-bromothiophene-2-yl; 5-cyclohexyl; 5-cyclopropyl; 5-hexyl; 5-methyl; 5-phenyl; (2-bromo-5-chlorophenyl)methyl; (2-bromophenyl)methyl; (5-chloro-2-(3-methoxyphenyl)phenyl)methyl; 3-bromophenyl; 2-pyridyl; 2- ethoxyphenyl; 5 -ethoxyphenyl; 2.5-dichlorophenyl; 2,5-dimethylphenyl; 3-fluorophenyl; 3-trifluoromethylphenyl; 5-trifluoromethylphenyl; 3,5-diclorophenyl; 4-bromo-2-thienyl; 3-bromo-2-thienyl; 3-cyanophenyl; 4-tetrahydropyranyl; 3-indolyl; 5-indolyl; 4-quinolyl; 2-bromophenyl; 4-fluorophenyl; 4,4-difluorocyclohexyl; 1J -dimethy 1-3 -butenyl; 2,3- dichlorophenyl; isopropyl; and 2-trifluoropheny Ipheny 1.
6. The method according to claim 1 wherein the compound is selected from the group consisting of:
4-(N-(2,3-dihydroxypropyl)amino)-5-(3-bromophenyl)-7-(6-moφholinyl-3- pyridiny l)pyrido [2,3-djpyrimidine;
4-(N-(3-moφholinylpropyl)amino)-5-(3-bromophenyl)-7-(6-moφholinyl-3- pyridinyl)pyrido[2,3-d]pyrimidine; 4-(N-(2-(4-imidazolyl)ethyl)amino)-5-(3-bromophenyl)-7-(6-moφholinyl-3- pyridinyl)pyrido[2J-d]pyrimidine;
4-(N-(3-carboxypropyl)amino)-5-(3-bromophenyl)-7-(6-moφholinyl-3- pyridinyl)pyrido[2,3-d]pyrimidine;
(S)-4-amino-5-(3-bromophenyl)-7-(6-(O-methyl-2-hydroxymethylpyrrolidinyl)-3- pyridinyl)pyrido[2,3-d]pyrimidine;
(S)-4-amino-5-(3-bromophenyl)-7-(6-(2-hydroxymethylpyrrolidinyl)-3- pyridiny l)pyrido [2 ,3 -djpyrimidine ;
4-amino-5-(2-bromophenyl)-7-(6-(4-hydroxypiperidinyl)-3-pyridinyl)pyrido[2,3- d]pyrimidine; 4-amino-5-(4-fluorophenyl)-7-(6-(4,4-ethylenedioxypiperidinyl)-3- pyridinyl)pyrido[2J-d]pyrimidine;
4-amino-5-(2-bromophenyl)-7-(6-(4-hydroxypiperidinyl)-3-pyridazyl)pyrido[2,3- djpyrimidine;
4-amino-5 -(3 -bromopheny l)-7-(6-(4,4-ethylenedioxypiperidinyl)-3 - pyridazyl)pyrido[2J-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(2-moφholinyl-4-thiazolyl)pyrido[2,3- djpyrimidine;
4-amino-5-(N-methyl-3-indolyl)-7-(6-moφholinyl-3-pyridinyl)pyrido[2,3- djpyrimidine; 4-amino-5-(3-bromophenyl)-7-(6-(4-ethoxyiminopiperidinyl)-3- pyridinyl)pyrido[2,3-d]pyrimidine;
4-amino-5 -(3 -bromopheny l)-7-(6-(4-ethoxycarbony lmethoxy iminopiperidinyl)-3 - pyridinyl)pyrido[2,3-d]pyrimidine; 4-amino-5-(4-dimethylaminophenyl)-7-(4-bromophenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(4-dimethylaminophenyl)-7-(4-dimethylaminophenyl)pyrido[2,3- djpyrimidine;
4-amino-5-(4-methoxyphenyl)-7-(4-dimethylaminophenyl)pyrido[2,3- djpyrimidine; 4-amino-5-(4-dimethylaminophenyl)-7-(4-methoxyphenyl)pyrido[2,3- d]pyrimidine;
4-amino-5-(4-(2-propyl)phenyl)-7-(4-methoxyphenyl)pyrido[2J-d]pyrimidine;
4-amino-5-(4-neopentylphenyl)-7-(4-methoxyphenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(4-butyloxyphenyl)-7-(4-methoxyphenyl)pyrido[2,3-d]pyrimidine; 4-amino-5-(4-methoxyphenyl)-7-(4-bromophenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(4-(2-propyl)oxyphenyl)-7-(4-methoxyphenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(4-butoxyphenyl)-7-(4-N-formylpiperazinylphenyl)pyrido[2J- djpyrimidine;
4-amino-5-(4-benzyloxyphenyl)-7-(4-methoxyphenyl)pyrido[2,3-d]pyrimidine; 4-amino-5-(4-phenoxyphenyl)-7-(4-methoxyphenyl)pyrido[2J-d]pyrimidine;
4-amino-5-(4-(2-propyl)phenyl)-7-(4-diethylmalonylallylphenyl)pyrido[2J- djpyrimidine;
4-amino-5-(4-(2-propyl)phenyl)-7-(4-t-butylacylphenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(4-dimethylaminophenyl)pyrido[2,3-d]pyrimidine; 4-amino-5-(3,4-dimethoxyphenyl)-7-(4-dimethylaminophenyl)pyrido[2J- djpyrimidine;
4-amino-5-(3-t-butylacrylphenyl)-7-(4-dimethylaminophenyl)pyrido[2,3- djpyrimidine;
4-amino-5-(3-methoxyphenyl-7-(4-dimethylaminophenyl)pyrido[2J-d]pyrimidine; 4-amino-5-(3,5-dimethoxyphenyl-7-(4-dimethylaminophenyl)pyrido[2J- djpyrimidine;
4-amino-5-(3-diethylmalonylallylphenyl)-7-(4-dimethylaminophenyl)pyrido[2,3- djpyrimidine; 4-amino-5-(3-vinylpyridinylphenyl)-7-(4-dimethylaminophenyl)pyrido[2,3- djpyrimidine;
4-amino-5-(3-trifluoromethylphenyl)-7-(4-dimethylaminophenyl)pyrido[2,3- djpyrimidine;
4-amino-5-(3-carboxamidophenyl)-7-(4-dimethylaminophenyl)pyrido[2,3- djpyrimidine;
4-amino-5 -(3 -cyanophenyl)-7-(4-dimethylaminopheny l)pyrido [2,3 -djpyrimidine;
4-amino-5-(3-benzyloxyphenyl)-7-(4-dimethylaminophenyl)pyrido[2,3- djpyrimidine;
4-amino-5-(3-methoxyphenyl)-7-(4-methoxyphenyl)pyrido[2,3-d]pyrimidine; 4-amino-5-(3-bromophenyl)-7-(4-butoxyphenyl)pyrido[2,3-djpyrimidine;
4-amino-5-(3-(2-pyridyl)phenyl)-7-(4-dimethylaminophenyl)pyrido[2,3- djpyrimidine;
4-amino-5-(3-methylphenyl)-7-(4-dimethylaminophenyl)pyrido[2J-djpyrimidine;
4-amino-5-(3-chlorophenyl)-7-(4-dimethylaminophenyl)pyrido[2J-d]pyrimidine; 4-amino-5-(3-fluorophenyl)-7-(4-dimethylaminophenyl)pyrido[2J-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(4-methoxyphenyl)pyrido[2J-djpyrimidine;
4-amino-5-(3-methoxyphenyl)-7-(4-bromophenyl)pyrido[2J-djpyrimidine;
4-amino-5-(3-bromophenyl)-7-phenylpyrido [2,3-djpyrimidine;
4-amino-5-(3-bromophenyl)-7-(4-ethylphenyl)pyrido[2J-dJpyrimidine; 4-amino-5-(3-bromophenyl)-7-(4-bromophenyl)pyrido[2J-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(4-cyanophenyl)pyrido[2J-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(4-hydroxyphenyl)pyrido[2,3-dJpyrimidine;
4-amino-5-(3-iodophenyl)-7-(4-dimethylaminophenyl)pyrido[2J-d]pyrimidine;
4-amino-5-(3-ethoxyphenyl)-7-(4-dimethylaminophenyl)pyrido[2,3-d]pyrimidine; 4-amino-5-(3-trifloromethyoxyphenyl)-7-(4-dimethylaminophenyl)pyrido[2J- d]pyrimidine;
4-amino-5-(3,5-dichlorophenyl)-7-(4-dimethylaminophenyl)pyrido[2,3- djpyrimidine; 4-amino-5-(3-bromo-4-fluorophenyl)-7-(4-dimethylaminophenyl)pyrido[2,3- djpyrimidine;
4-amino-5-(3-hydroxyphenyl)-7-(4-dimethylaminophenyl)pyrido[2,3-d]pyrimidine; 4-amino-5-(3-bromophenyl)-7-(4-moφholinylphenyl)pyrido[2,3-djpyrimidine; 4-amino-5-(3-bromophenyl)-7-(4-piperidinylphenyl)pyrido[2,3-dJpyrimidine; 4-amino-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[2J-d]pyrimidine; 4-amino-5-(3-bromophenyl)-7-(4-trifluorophenyl)pyrido[2,3-d]pyrimidine; 4-amino-5-(3-bromophenyl)-7-(4-diethylaminophenyl)pyrido[2,3-djpyrimidine; 4-amino-5-(3-bromophenyl)-7-(3,4,5-trimethoxyphenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-(3-methoxybenzyl)phenyl)-7-(4-dimethylaminophenyl)pyrido[2,3- djpyrimidine;
4-amino-5-(3-methoxyethyoxyphenyl)-7-(4-dimethylaminophenyl)pyrido[2,3- djpyrimidine; 4-amino-5-(3,4-methylenedioxyphenyl)-7-(4-dimethylaminophenyl)pyrido[2,3- d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(4-ethoxyphenyl)pyrido[2J-d]pyrimidine; 4-amino-5-(3-bromophenyl)-7-(2'-thiophene)pyrido[2,3-d]pyrimidine; 4-amino-5 -(3 -bromophenyl)-7-(4-fluorophenyl)pyrido [2,3-djpyrimidine; 4-amino-5-(3-dimethylaminophenyl)-7-(4-dimethylaminophenyl)pyrido[2,3- d]pyrimidine;
4-amino-5-phenyl-7-(4-dimethylaminophenyl)pyrido[2J-d]pyrimidine; 4-amino-5-(3,4,5-trimethoxyphenyl)-7-(4-dimethylaminophenyl)pyrido[2,3- djpyrimidine; 4-amino-5-(3-bromophenyl)-7-(4-nitrophenyl)pyrido[2J-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[2J- d]pyrimidine;
4-amino-5-(thiophen-2-yl)-7-(4-moφholinylphenyl)pyrido [2,3-djpyrimidine; 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-d]pyrimidine; 4-amino-5-(3-bromophenyl)-7-(4-(2-methoxy)ethoxyphenyl)pyrido[2,3- djpyrimidine;
4-amino-5-(3,5-dimethoxyphenyl)-7-(4-moφholinylphenyl)pyrido[2,3- djpyrimidine;
4-amino-5-(3-trifluoromethylphenyl)-7-(thiophene-2-yl)pyrido [2,3-djpyrimidine; 4-amino-5-(3-bromophenyl)-7-(4-aminophenyl)pyrido[2J-d]pyrimidine; 4-amino-5-(3-bromo-4-fluorophenyl)-7-(thiophene-2-yl)pyrido [2,3-djpyrimidine; 4-amino-5-(3-bromo-4-fluorophenyl)-7-(2-furanyl)pyrido [2,3-djpyrimidine; 4-amino-5-(3,5-dimethoxyphenyl)-7-(4-iodophenyl)pyrido[2J-d]pyrimidine;
4-amino-5-(3,5-dimethoxyphenyl)-7-(4-imidazolylphenyl)pyrido[2,3-d]pyrimidine; 4-amino-5-(3,5-dimethoxyphenyl)-7-(4-(thiophene-2-yl)phenyl)pyrido[2J- djpyrimidine;
4-amino-5-(3,5-dimethoxyphenyl)-7-(4-(3-pyridyl)phenyl)pyrido[2J-d]pyrimidine; 4-amino-5-(3-bromophenyl)-7-(4-(4-methylpiperidinyl)phenyl)pyrido[2J- djpyrimidine;
4-amino-5-(3-bromophenyl)-7-(4-pyrrolidinylphenyl)pyrido[2J-djpyrimidine; 4-amino-5-(4-bromothiophene-)-7-(4-dimethylaminophenyl)pyrido[2J- djpyrimidine; 4-amino-5-(4-bromothiophene-2-yl)-7-(4-moφholinylphenyl)pyrido[2,3- djpyrimidine;
4-moφholinyl-5-(3-bromophenyl)-7-(4-dimethylaminophenyl)pyrido[2,3- djpyrimidine;
4-amino-5-(5-bromothiophene-2-yl)-7-(4-moφholinylphenyl)pyrido[2J- djpyrimidine; 4-amino-5-(4-bromophenyl)-7-(4-dimethylaminophenyl)pyrido[2J-d]pyrimidine; 4-amino-5-(3-bromophenyl)-7-(4-(acetylamino)phenyl)pyrido[2J-d]pyrimidine; 4-amino-5-(3-bromophenyl)-7-(4-dimethylaminophenyl)pyrido[2J-d]pyrimidine; 4-amino-5-(3,5-dimethoxyphenyl)-7-(5-pyrimidinylphenyl)pyrido[2J- d]pyrimidine;
4-(4-fluorophenyl)amino)-5-(3-bromophenyl)-7-(4- dimethylaminophenyl)pyrido[2,3 -djpyrimidine;
4-amino-5-(4-bromothiophene-2-yl)-7-(4-pyrrolidinylphenyl)pyrido[2,3- djpyrimidine; 4-amino-5-(4-bromothiophene-2-yl)-7-(thiophene-2-yl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(5-(dimethylamino)thiophene-2-yl)pyrido[2,3- djpyrimidine;
4-amino-5-(3-bromo-5-iodophenyl)-7-(4-(dimethylamino)phenyl)pyrido[2,3- djpyrimidine; 4-amino-5-(3,5-di(trifluoromethyl)phenyl)-7-(4-(dimethylamino)phenyl)pyrido[2J- djpyrimidine;
4-amino-5-(3,5-di(trifluoromethyl)phenyl)-7-(4-moφholinylphenyl)pyrido[2J- djpyrimidine;
4-amino-5-(3,5-dibromophenyl)-7-(4-(dimethylamino)phenyl)pyrido[2J- djpyrimidine;
4-amino-5-(3,5-dibromophenyl)-7-(4-moφholinylphenyl)pyrido[2.3-djpyrimidine; 4-amino-5-(4-bromothiophene-2-yl)-7-(4-(4-methylpiperidinyl)phenyl)pyrido[2,3- djpyrimidine;
4-amino-5-(3,5-dibromophenyl)-7-(4-(dimethylamino)phenyl)pyrido[2,3- djpyrimidine;
4-amino-5-(3-bromophenyl)-7-(3-(dimethylamino)phenyl)pyrido[2,3-d]pyrimidine; 4-amino-5-(3-bromophenyl)-7-(4-methylsulfonylphenyl)pyrido[2J-d]pyrimidine; 4-amino-5-(3-bromophenyl)-7-(3-methoxyphenyl)pyrido[2,3-d]pyrimidine; 4-amino-5 -(3 -bromophenyl)-7-(4-(methy lthio)pheny l)pyrido [2,3-djpyrimidine; 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- djpyrimidine;
4-amino-5-(3-bromophenyl)-7-(4-methylaminophenyl)pyrido[2J-d]pyrimidine;
4-amino-5-(3-bromo-4-fluorophenyl)-7-(4-methylsulfonylphenyl)pyrido[2,3- djpyrimidine;
4-amino-5-(3-bromophenyl)-7-(3-amino-4-methoxyphenyl)pyrido[2,3- djpyrimidine;
4-amino-5-(3-bromophenyl)-7-(3-bromo-4-(dimethylamino)phenyl)pyrido[2,3- d]pyrimidine; 4-amino-5-(3-bromophenyl)-7-(3-methyl-4-(dimethylamino)phenyl)pyrido[2,3- djpyrimidine;
4-amino-5-(3-bromophenyl)-7-(4-(N-methyl-N- trifluoroacetylamino)phenyl)pyrido[2,3-dJpyrimidine;
4-amino-5-(3 -bromopheny l)-7-(4-(dimethylamino)-3 -fluorophenyl)pyrido [2,3 - djpyrimidine;
4-amino-5-(3-bromophenyl)-7-(4-(N-ethyl-N-formylamino)phenyl)pyrido[2,3- djpyrimidine;
4,4-bis(acetylamino)-5-(3-bromophenyl)-7-(4-(N-methyl-N- acetylamino)phenyl)pyrido[2J-d]pyrimidine; 4-amino-5-(3-bromophenyl)-7-(4-(N-acetyl-N-methylamino)phenyl)pyrido[2,3- djpyrimidine;
4-amino-5-(3-bromophenyl)-7-(4-(N-ethylamino)phenyl)pyrido[2J-djpyrimidine;
4-amino-5-(3-bromophenyl)-7-(4-(N-methyl-N-(2- methoxyethyl)amino)phenyl)pyrido[2J-d]pyrimidine; 4-amino-5 -(3 -bromopheny l)-7-(4-(N-isopropylamino)phenyl)pyrido [2,3- djpyrimidine;
4-amino-5-(3-bromophenyl)-7-(4-N-ethyl-N-(2- methoxyethyl)amino)phenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(4-N-(3-methoxypropionyl)-N-isopropyl- amino)phenyl)pyrido[2,3-djpyrimidine; 4-amino-5-(3-bromophenyl)-7-(4-N-(2-(dimethylamino)ethyl)-N- formylamino)phenyl)pyrido[2J-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(4-(N-(2- (dimethylamino)ethyl)amino)phenyl)pyrido[2J-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- methoxy)propionylamino)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- 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- phthalimidyl)acetyl)amino)phenyl)pyrido[2,3-djpyrimidine;
4-amino-5-(3-bromophenyl)-7-(3-methyl-4-(N-methyl-N- (trifluoroacetyl)amino)phenyl)pyrido[2,3 -djpyrimidine;
4-amino-5-(3-bromophenyl)-7-(3-methyl-4-(N-acetyl-N- methylamino)pheny l)pyrido [2 ,3 -djpyrimidine;
4-amino-5-(3-bromophenyl)-7-(6-dimethylamino-3-pyridinyl)pyrido[2.3- d]pyrimidine;
4-amino-5-(3-cyanophenyl)-7-(4-methylsulfonylphenyl)pyrido[2J-d]pyrimidine;
4-amino-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-amino-5-(3-bromophenyl)-7-(6-moφholinyl-3-pyridinyl)pyrido[2J- d]pyrimidine; 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-pyrrolidinyl-3-pyridinyl)pyrido[2J-d]pyrimidine; 4-amino-5-(3-bromophenyl)-7-(2-(dimethylamino)-5-pyrimidinyl)pyrido[2,3- djpyrimidine;
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 -djpyrimidine; 4-amino-5-(3-bromophenyl)-7-(2-(N-methylamino)5-pyrimidinyl)pyrido[2,3- djpyrimidine;
4-amino-5-(3-bromophenyl)-7-(2-(l-pyrrolidinyl)-5-pyrimidinyl)pyrido[2J- djpyrimidine;
4-amino-5-(3-bromophenyl)-7-(2-(l-moφholinyl)-5-pyrimidinyl)pyrido[2,3- djpyrimidine;
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-dJpyrimidine; 4-amino-5-(3-bromophenyl)-7-(3-pyridyl)pyrido[2J-dJpyrimidine; 4-amino-5-(3-(thiophen-2-yl)phenyl)-7-(4-dimethylaminophenyl)pyrido[2,3- djpyrimidine;
4-amino-5-(3-(furan-2-yl)phenyl)-7-(4-dimethylaminophenyl)pyrido[2,3- djpyrimidine;
4-amino-5-(3-(3-methoxyphenyl)phenyl)-7-(4-dimethylaminophenyl)pyrido[2,3- djpyrimidine;
4-amino-5-phenyl-7-(4-dimethylaminophenyl)pyrido[2,3-d]pyrimidine; 4-amino-5-(3-chlorophenyl)-7-(4-(moφholinyl)phenyl)pyrido[2J-d]pyrimidine; 4-amino-5-(3-bromo-4-fluorophenyl)-7-(4-(moφholinyl)phenyl)pyrido[2J- d]pyrimidine; 4-amino-5-(3-chlorophenyl)-7-(4-iodophenyl)pyrido[2,3-d]pyrimidine; 4-amino-5-(3-chlorophenyl)-7-(4-(thiophen-2-yl)phenyl)pyrido[2J-d]pyrimidine; 4-amino-5-(3-chlorophenyl)-7-(4-(5-pyrimidinyl)phenyl)pyrido[2J-djpyrimidine; 4-amino-5-(3-bromo-4-fluorophenyl)-7-(4-iodophenyl)pyrido[2J-d]pyrimidine; 4-amino-5-(4-bromothiophene-2-yl)-7-(4-methoxyphenyl)pyrido[2J-dJpyrimidine; 4--ιmino-5-(3-bromophenyl)methyl-7-(4-(dimethylamino)phenyl)pyrido[2,3- djpyrimidine;
4-amino-5-(2-phenylethyl)-7-(4-diethylaminophenyl)pyrido[2,3-djpyrimidine; 4-amino-5-(2-methylpropyl)-7-(4-diethylaminophenyl)pyrido[2,3-dJpyrimidine; 4-amino-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-amino-5-(butyl)-7-(4-dimethylaminophenyl)pyrido[2J-d]pyrimidine; 4-amino-5-(2-(3-cyanophenyl)methyl)-7-(4-dimethylaminophenyl)pyrido[2,3- djpyrimidine; 4-amino-5-(2-(N-phenylmethoxycarbonyl)aminoethyl)-7-(4- dimethylaminophenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(cycloheptyl)-7-(4-dimethylaminophenyl)pyrido[2,3-djpyrimidine; 4-amino-5-(2-(5-chloro-2-(thiophen-3-yl)phenylmethyl)-7-(4- dimethylaminophenyl)pyrido[2,3-d]pyrimidine; 4-amino-5-(pentyl)-7-(4-diethylaminophenyl)pyrido[2J-djpyrimidine;
4-amino-5-hexyl-7-(4-diethylaminophenyl)pyrido[2J-d]pyrimidine; 4-amino-5-(2-(3-bromophenyl)ethyl)-7-(4-diethylaminophenyl)pyrido[2J- djpyrimidine;
4-amino-5-((2-bromophenyl)methyl)-7-(4-diethylaminophenyl)pyrido[2,3- djpyrimidine;
4-amino-5-cyclopropyl-7-(4-dimethylaminophenyl)pyrido[2J-d]pyrimidine; 4-amino-5-cyclohexyl-7-(4-dimethylaminophenyl)pyrido[2J-d]pyrimidine; 4-amino-5-((2-bromo-5-chlorophenyl)methyl)-7-(4-diethylaminophenyl)pyrido[2,3- djpyrimidine; 4-amino-5-methyl-7-(4-diethylaminophenyl)pyrido[2,3-d]pyrimidine; 4-amino-5-(2,3-methylenedioxyphenyl)-7-(4-dimethylaminophenyl)pyrido[2,3- djpyrimidine;
4-amino-5-(3-fluoro-5-trifluoromethylphenyl)-7-(4- dimethylaminophenyl)pyrido[2J-d]pyrimidine; 4-amino-5-(2-bromophenyl)-7-(4-dimethylaminophenyl)pyrido[2J-djpyrimidine;
4-amino-5-(3,5-dimethylphenyl)-7-(4-dimethylaminophenyl)pyrido[2,3- djpyrimidine;
4-amino-5-(3,4-dichlorophenyl)-7-(4-dimethylaminophenyl)pyrido[2J- djpyrimidine; 4-amino-5-(4-fluoro-3-trifluoromethylphenyl)-7-(4- dimethylaminophenyl)pyrido[2,3-djpyrimidine;
4-amino-5-(3-bromo-5-methoxyphenyl)-7-(4-moφholinylphenyl)pyrido[2,3- djpyrimidine;
4-amino-5-(3-bromo-5-methoxyphenyl)-7-(4-pyrrolidinylphenyl)pyrido[2,3- djpyrimidine;
4-amino-5-(3-bromo-5-methoxyphenyl)-7-(4-piperidinylphenyl)pyrido[2,3- djpyrimidine;
4-amino-5-(3-bromo-5-methoxyphenyl)-7-(4-dimethylaminophenyl)pyrido[2,3- djpyrimidine; 4-amino-5-(3-methylthiophenyl)-7-(4-dimethylaminophenyl)pyrido[2.3- djpyrimidine;
4-amino-5-(3-bromo-5-methoxyphenyl)-7-(thiophene-2-yl)pyrido[2J-d]pyrimidine;
4-amino-5-(2,3-dimethoxyphenyl)-7-(4-dimethylaminophenyl)pyrido[2J- djpyrimidine; 4-amino-5-(3-methylsulfonylphenyl)-7-(4-dimethylaminophenyl)pyrido[2,3- djpyrimidine;
4-acetylamino-5-(3-bromophenyl)-7-(4-dimethylaminophenyl)pyrido[2,3- djpyrimidine;
4-formylamino-5-(3-bromophenyl)-7-(4-dimethylaminophenyl)pyrido[2J- d]pyrimidine; 4-(methoxyacetyl)amino-5-(3-bromophenyl)-7-(4-diethylaminophenyl)pyrido[2J- djpyrimidine;
4-trifluoroacetylamino-5-(3-bromophenyl)-7-(4-dimethylaminophenyl)pyrido[2J- djpyrimidine; 4-pentanoylamino-5-(3-bromophenyl)-7-(4-dimethylaminophenyl)pyrido[2,3- djpyrimidine;
4-benzoylamino-5-(3-bromophenyl)-7-(4-dimethylaminophenyl)pyrido[2,3- djpyrimidine;
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 -bromopheny l)-7-(4- dimethylaminophenyl)pyrido[2,3-d]pyrimidine;
4-allylamino-5-(3-bromophenyl)-7-(4-dimethylaminophenyl) pyrido[2,3- djpyrimidine;
4-(2-(N,N-dimethylamino)ethylamino)-5-(4-bromophenyl)-7-(4- dimethylaminophenyl) pyrido[2,3-d]pyrimidine;
4-(4-(N,N-dimethylamino)butylamino)-5-(3-bromophenyl)-7-(4- dimethylaminophenyl) pyrido[2J-djpyrimidine;
4-(N-allyl-N-formylamino)-5-(4-dimethylaminophenyl)-7-(4- bromophenyl)pyrido[2J-djpyrimidine; 4-diacetylamino-5-(p-dimethylaminophenyl)-7-(4- bromopheny l)pyrido [2,3-djpyrimidine ;
4-amino-5-(3-bromophenyl)-7-(5--imino-2-pyridyl)pyrido[2J-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(5-dimethylamino-2- pyridyl)pyrido[2,3-dJpyrimidine; 4-amino-5-(3-bromophenyl)-7-(5-dimethylamino-2- pyrazinyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(2-oxobenzoxazolin-6-yl)pyrido[2J-djpyrimidine; 4-amino-5-(3-bromophenyl)-7-(l-methyl-2-oxobenzoxazolin-6- yl)pyrido [2,3 -djpyrimidine;
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- djpyrimidine; 4-amino-5-((thiophene-3-yl)methyl)-7-(4-diethylaminophenyl)pyrido[2,3- djpyrimidine;
4-amino-5-((2-bromophenyl)methyl)-7-(4-dimethylaminophenyl)pyrido[2J- djpyrimidine;
4-amino-5-(3-bromophenyl)-7-(4-(N-formyl-N-(2- methoxyethyl)amino)phenyl)pyrido[2,3-djpyrimidine;
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- dimethylamino)ethyl)amino)phenyl)pyrido[2,3-d]pyrimidine; 4-amino-5 -(3 -bromopheny l)-7-(4-(2- methoxy)acetylamino)ethyl)amino)phenyl)pyrido[2J-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-((4-formylamino)phenyl)pyrido[2J-dJpyrimidine; 4-amino-5-(3-bromophenyl)-7-(4-(2- (dimethylamino)acetylamino)phenyl)pyrido[2J-d]pyrimidine; 4-amino-5-(3-bromophenyl)-7-(4-(2-oxo-3-oxazolidinyl)phenyl)pyrido[2,3- djpyrimidine;
4-amino-5-(3-bromophenyl)-7-(6-(2-propyl)-3-pyridinyl)pyrido[2J-dJpyrimidine; 4-amino-5-(3-bromophenyl)-7-(3-methyl-4-pyrrolidinylphenyl)pyrido[2,3- djpyrimidine; 4-amino-5-(3-bromophenyl)-7-(6-imidazolyl-3-pyridinyl)pyrido[2J-d]pyrimidine; 4-amino-5-phenylmethyl-7-(4-diethylaminophenyl)pyrido[2J-d]pyrimidine;
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[2J- djpyrimidine;
4-amino-5-(4-dimethylaminophenyl)-7-(4-bromophenyl)pyrido[2,3-djpyrimidine;
4-amino-5-(2-furanyl)-7-(4-(N-moφholinyl)phenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(2-dimethylamino-5-pyrimidinyl)pyrido[2,3- djpyrimidine; 4-amino-5-(3-bromophenyl)-7-(4-(ureido)phenyl)pyrido[2,3 -djpyrimidine;
4-amino-5-(l-phenylmethyl-3-piperidinyl)-7-(4- diethylaminophenyl)pyrido[2J-d]pyrimidine;
4-amino-5 -(3 -bromopheny l)-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-amino-5-(3-bromophenyl)-7-(6-methoxy-3-pyridinyl)pyrido[2,3- djpyrimidine;
4-amino-5-(3-bromophenyl)-7-(6-(l,2,4-triazol-4-yl)-3-pyridinyl)pyrido[2J- djpyrimidine; 4-amino-5-(3-bromophenyl)-7-(2-moφholinyl-5-pyrimidinyl)pyrido[2J- djpyrimidine;
4-amino-5-(2-thiazolyl)-7-(4-pyrrolidinylphenyl)-pyrido[2J-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(6-pyrazolyl-3-pyridinyl))-pyrido[2J- djpyrimidine; 4-amino-5-(3-bromophenyl)-7-(4-(l-methyl-ureido)phenyl)-pyrido[2J- djpyrimidine;
4-amino-5-(3-bromophenyl)-7-(4-(N-methyl-N-(2-pyrimidinyl)amino)phenyl)- pyrido[2J-d]pyrimidine;
4-amino-5 -(3 -bromopheny l)-7-(3 -fluoro-4-(N-formy l-N-methylamino)pheny 1)- pyrido[2,3-d]pyrimidine; 4-formylamino-5-(3-bromophenyl)-7-(3-fluoro-4-(N-formyl-N- methylamino)phenyl)-pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(4-(N-methyl-N-methylsulfonylamino)- phenyl)pyrido[2J-d]pyrimidine; 4-amino-5-(3-bromophenyl)-7-(6-(N-methyl-N-methylsulfonylamino)-3- pyridinyl)pyrido[2J-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(l-methyl-5-indolinyl)pyrido[2J-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(l-methyl-5-benzimidazolyl)pyrido[2,3- djpyrimidine; 4-amino-5-(3-bromophenyl)-7-(6-dimethylamino-3-pyridazinyl)pyrido[2,3- djpyrimidine;
4-amino-5-(3bromophenyl)-7-(6-moφholinyl-3-pyridazinyl)pyrido[2.3- djpyrimidine;
4-amino-5-(3-bromophenyl)-7-(6-pyrrolidinyl-3-pyridazinyl)pyrido[2,3- djpyrimidine;
4-amino-5-(3-bromophenyl)-7-(5-moφholinyl-2-pyrazinyl)pyrido[2,3- djpyrimidine;
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- djpyrimidine;
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- djpyrimidine;
4-amino-5-(3-bromophenyl)-7-(5-(l-moφholinyl)-2-pyridinyl)pyrido[2J- djpyrimidine;
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[2J-dJpyrimidine;
4-amino-5-(3-bromophenyl)-7-(5-(N-formyl-N-methylamino)-2- pyridiny l)pyrido [2,3-djpyrimidine ; 4-amino-5-(3-bromophenyl)-7-(5-(2-propenyl)-2-pyridinyl)pyrido[2,3- djpyrimidine;
4-amino-5-(3-bromophenyl)-7-(3-(2-methoxyethyl)-2-oxo-6- benzoxazolyl)pyrido [2,3-djpyrimidine;
4--ιmino-5-(3-bromophenyl)-7-(4-(l-(N-formylamino)-ethyl)phenyl)pyrido[2,3- djpyrimidine;
4-(methylamino)-5 -(3 -bromopheny l)-7-(4-dimethylaminophenyl)pyri do [2,3- djpyrimidine hydrochloride;
4-(2-methoxyethylamino)-5-(3-bromophenyl)-7-(4- dimethylaminophenyl)pyrido[2J-d]pyrimidine hydrochloride; 4-amino-5-(3-bromophenyl)-7-(4-(l-methyl-2-imidazolyl)phenyl)pyrido[2,3- djpyrimidine trihydrochloride;
4-amino-5 -(3 -bromopheny l)-7-(4-(aminomethyl)phenyl)pyrido [2,3-djpyrimidine; 4-amino-5-(3-bromophenyl)-7-(2-bromo-4-(dimethylamino)phenyl)pyrido[2,3- djpyrimidine; 4-amino-5-(3-bromophenyl)-7-(4-(dimethylaminoethyl)phenyl)pyrido[2J- djpyrimidine;
4-amino-5-(3-bromophenyl)-7-(4-(3-(dimethylamino)propynyl)phenyl)pyrido[2J- djpyrimidine;
4-amino-5-(3 -bromopheny l)-7-(4-(3 -amino-3 -methy lbutyny l)pheny l)pyrido [2,3 - djpyrimidine;
4-amino-5-(3-bromophenyl)-7-(4-dimethylphosphonatophenyl)pyrido[2,3- djpyrimidine;
4-amino-5-(3-bromophenyl)-7-(4-(3-(methoxypropynyl)pyrido[2J-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-bj-1.4-oxazin- 7-yl)pyrido[2J-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(4-(2-(dimethylamino)ethyl)-3-oxo-2H-4H- pyrido[3,2-b]-l,4-oxazin-7-yl)pyrido[2J-d]pyrimidine; 4-amino-5 -(3 -bromopheny l)-7-(2,3 -dihydro-3 -(dimethy laminoethy l)-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-djpyrimidine;
4-amino-5-(3-bromophenyl)-7-(2,2,4-trimethyl-3-oxo-2H-4H-benzo-l,4-oxazin-7- yl)pyrido[2,3-dJpyrimidine;
4-amino-5-cyclohexyl-7-(4-(2-dimethylamino)ethyl)-2H-4H-benzo-3-oxo-l,4- oxazin-7-yl)pyrido[2J-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(5-(l-methylethyl)-2-pyridyl)pyrido[2,3- djpyrimidine; 4-amino-5-(3-bromophenyl)-7-(5-piperidin-l-ylpyrid-2-yl)pyrido[2,3- djpyrimidine;
4-amino-5-(l-(4-bromophenyl)ethyl)-7-(6-moφholinylpyrid-3-yl)pyrido[2J- djpyrimidine;
4-amino-5-(3-bromophenyl)-7-(4-((N-formylamino)methyl)phenyl)pyrido[2,3- djpyrimidine;
4-amino-5-(3-bromophenyl)-7-(4-(l-methyl-l-(N-methylamino)ethyl)phenyl)- pyrido[2, 3-djpyrimidine;
4-amino-5-(3-bromophenyl)-7-(4-(l-(dimethylamino)-l- methylethyl)phenyl)pyrido[2,3-djpyrimidine; 4-amino-5-(3-bromophenyl)-7-(N-acetyl-5-indolinyl)pyrido[2J-d]pyrimidine;
4-amino-5-cyclohexyl-7-(6-chloro-3-pyridyl)pyrido[2,3-dJpyrimidine;
4-amino-5-(l-(2-bromophenyl)ethyl)-7-(6-diethylamino-3-pyridyl)pyrido[2,3- djpyrimidine;
4-amino-5-(l-(2-bromophenyl)ethyl)-7-(6-moφholinyl-3-pyridyl)pyrido[2,3- djpyrimidine; 4-amino-5-(l-(2-bromophenyl)ethyl)-7-(4-(N-methyl-N-formyl)amino)- phenyl)pyrido[2J-d]pyrimidine;
4-amino-5-cyclohexyl-7-(6-moφholinyl-3-pyridyl)pyrido[2,3-d]pyrimidine; 4-amino-5-((2-bromophenyl)methyl)-7-(6-moφholinyl-3-pyridyl)pyrido[2,3- djpyrimidine;
4-amino-5-(4-tetrahydropyranyl)-7-(6-moφholinyl-3-pyridyl)pyrido[2J- djpyrimidine;
4-amino-5-cyclohexyl-7-(6-dimethylamino-3-pyridyl)pyrido[2J-d]pyrimidine; 4-amino-5-(l-ethylpropyl)-7-(6-dimethylamino-3-pyridyl)pyrido[2J-d]pyrimidine; 4-amino-5-cyclopentyl-7-(6-moφholinyl-3-pyridyl)pyrido[2,3-d]pyrimidine;
4-amino-5-cyclohexyl-7-(2-chloro-3-pyridyl)pyrido[2, 3-djpyrimidine; 4-amino-5-(3,5-dimethylcyclohexyl)-7-(6-dimethylamino-3-pyridyl)pyrido[2,3- djpyrimidine;
4-amino-5-((N-(benzyloxycarbonyl)-4-piperidinyl)methyl)-7-(6-moφholinyl-3- pyridyl)pyrido[2,3-djpyrimidine;
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-amino-5-( 1 -(2-bromophenyl)ethyl)-7-(6-dimethylamino-3- pyridazinyl)pyrido[2J-d]pyrimidine; 4-amino-5-(3-bromophenyl)-7-(6-imidazolyl-3-pyridazinyl)pyrido[2,3- djpyrimidine;
4-amino-5-(3-bromophenyl)-7-(6-(azacycloheptanyl)-3-pyridazinyl)pyrido[2J- djpyrimidine;
4-amino-5-(3-bromophenyl)-7-(6-(N-methyl-N-(l-methylethyl))amino)-3- pyridazinyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(l-(2-bromophenyl)ethyl)-7-(6-moφholinyl-3-pyridazinyl)pyrido[2,3- djpyrimidine;
4-amino-5-cyclohexyl-7-(6-(4-acetylpiperazinyl)-3-pyridyl)pyrido[2J- djpyrimidine; 4-amino-5-cyclohexyl-7-(6-(4-acetyl-1.4-diazacycloheptanyl)-3- pyridyl)pyrido[2,3-d]pyrimidine;
4-amino-5-cyclohexyl-7-(6-(4-methyl-l ,4-diazacycloheptanyl)-3- pyridyl)pyrido[2J-d]pyrimidine; 4-amino-5-cyclohexyl-7-(6-(N-methyl-N-(2-(2-pyridyl)ethyl)amino)-3- pyridyl)pyrido[2J-d]pyrimidine;
4-amino-5-cyclohexyl-7-(6-2-(N-(N',N'-dimethylaminoethyl)-N-methylamino)-3- pyridyl)pyrido[2,3-d]pyrimidine;
4-amino-5-cyclohexyl-7-(6-azetidinyl-3-pyridyl)pyrido[2J-dJpyrimidine; 4-amino-5-cyclohexyl-7-(6-(3-(N- methylacetamido)pyrrolidinyl)pyridyl)pyrido[2,3-d]pyrimidine;
4-amino-5-cyclohexyl-7-(6-(3-(formamido)pyrrolidinyl)pyridyl)pyrido[2J- djpyrimidine;
4-amino-5-cyclohexyl-7-(4-oxo-l-phenyl-l,3,8-triazaspiro[4.5[decan-8- yl)pyrido[2,3-dJpyrimidine;
4-amino-5-cyclohexyl-7-(6-(2-methoxymethyl)pyrrolidin-l-yl)pyridyl)pyrido[2,3- djpyrimidine;
4-amino-5-cyclohexyl-7-(6-(N-methoxyethyl-N-propylamino)pyridyl)pyrido[2J- djpyrimidine; 4-amino-5-cyclohexyl-7-(N-methyl-N-(2,2-dimethoxyethyl)amino)pyrido[2,3- djpyrimidine;
4-amino-5-cyclohexyl-7-(6-(4-(dimethylamino)piperidinyl)pyridyl)pyrido[2,3- djpyrimidine;
4-amino-5-cyclohexyl-7-(6-(4-(aminocarbonyl))piperidinyl)pyridyl)pyrido[2,3- djpyrimidine;
4-amino-5-cyclohexyl-7-(N-methyl-N-(3-(diethylamino)propyl)aminopyrid-3- yl)pyrido[2,3-d]pyrimidine;
4-amino-5-cyclohexyl-7-(6-(N-methyl-N-(4-pyridyl)ethylamino)pyrid-3- y l)pyrido [2 , 3 -djpyrimidine ; 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[2J- djpyrimidine; 4-amino-5-(l-(2-bromophenyl)ethyl)-7-(l-methyl-2,3-dioxo-5-indolyl)pyrido[2J- djpyrimidine;
4-amino-5-(3-bromophenyl)-7-(3-fluoro-4-(l-moφholinyl)phenyl)pyrido[2,3- djpyrimidine;
4-amino-5-(3 -bromopheny l)-7-(4-hydroxy-3 -nitropheny l)pyrido [2,3 -djpyrimidine; 4-amino-5-(3-bromophenyl)-7-(6-(4,4-ethylenedioxypiperidinyl)-3- pyridyl)pyrido[2,3-dJpyrimidine;
4-amino-5-(3-bromophenyl)-7-(6-(4-oxopiperidinyl)-3-pyridyl)pyrido[2,3- djpyrimidine;
4-amino-5-(3-bromophenyl)-7-(6-(4-formylpiperazinyl)-3-pyridyl)pyrido[2,3- djpyrimidine;
4-amino-5 -(3 -bromophenyl)-7-(6-(4-methylpiperazinyl)-3 -pyridyl)pyrido[2,3 - djpyrimidine;
4-amino-5 -(3 -bromophenyl)-7-(6-thiomoφholinyl-3-pyridyl)pyrido [2,3 - djpyrimidin; 4-amino-5-(3-bromophenyl)-7-(6-(4,4-dioxothiomoφholinyl)-3- pyridyl)pyri do [2,3 -djpyrimidine;
4-amino-5-(2-bromophenyl)-7-(6-moφholinyl-3-pyridyl)pyrido[2J-djpyrimidine;
4-amino-5-(3-bromo-4-methoxyphenyl)-7-(6-moφholinyl-3-pyridyl)pyrido[2,3- djpyrimidine; 4-amino-5-(4-bromophenyl)-7-(6-moφholinyl-3-pyridyl)pyrido[2J-djpyrimidine;
4-amino-5-(3-chlorophenyl)-7-(6-moφholinyl-3-pyridyl)pyrido[2J-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(5-chloro-6-moφholinyl-3-pyridyl)pyrido[2,3- djpyrimidine;
4-amino-5-(3-bromophenyl)-7-(6-(N-oxidomoφholinyl)-3-pyridyl)pyrido[2,3- djpyrimidine; 4-amino-5-(3-bromophenyl)-7-(6-(N-(2-hydroxyethoxyethyl)amino)-3- pyridyl)pyrido[2J-d]pyrimidine,
4-amino-5-(3-bromophenyl)-7-(6-(N-(2-hydroxyethoxyethyl)-N-formylamino)-3- pyridyl)pyrido[2J-d]pyrimidine; 4-amino-5 -(3 -bromopheny l)-7-(6-(N-(2-hydroxyethoxyethyl)-3 -pyridy 1-N- oxide)pyrido [2 ,3 -djpyrimidine ;
4-amino-5-(3-bromophenyl)-7-(6-(3-hydroxy)moφholinyl)-3-pyridyl)pyrido[2,3- djpyrimidine; l-(5-(4-amino-5-(3-bromophenyl)pyrido[2J-d]pyrimidin-7-yl)-2-pyridyl)- piperidine-4-phosphate, disodium salt;
4-amino-5-(3-bromophenyl)-7-(4-methylenylpiperidinyl)-3-pyridyl)pyrido[2,3- djpyrimidine;
4-amino-5 -(3 -bromopheny l)-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-dJpyrimidine;
4-amino-5-cyclohexyl-7-(6-(4-oxo-piperidinyl)-3-pyridyl)pyrido[2J-d]pyrimidine;
4-amino-5-cyclohexyl-7-(6-(4-methylenylpiperidinyl)-3-pyridyl)pyrido[2J- djpyrimidine; 4-N-(iminomethy l)amino-5 -cyclohexy l-7-(6-dimethy lamino-3 -pyridy l)pyrido [2.3 - djpyrimidine;
4-allylamino-5-(4-bromophenyl)-7-(4-dimethylaminophenyl) pyrido[2,3- djpyrimidine;
4-amino-5-(3-bromophenyl)-7-(6-(4-hydroxypiperdinyl)-3-pyridyl)pyrido[2,3- djpyrimidine;
4-amino-5-(cyclohexyl)-7-(6-(4,4-ethylenedioxypiperidinyl)-3-pyridyl)pyrido[2,3- djpyrimidine;
4-amino-5-(3-bromophenyl)-7-(2-moφholinyl-5-thiazolyl)pyrido[2,3- djpyrimidine; 4-(N-(2.3-dihydroxypropyl)amino)-5-(3-bromophenyl)-7-(6-moφholinyl-3- pyridinyl)pyrido[2,3-d]pyrimidine;
4-(N-(3-moφholinylpropyl)amino)-5-(3-bromophenyl)-7-(6-moφholinyl-3- pyridinyl)pyrido[2J-dJpyrimidine; 4-(N-(2-(4-imidazolyl)ethyl)amino)-5-(3-bromophenyl)-7-(6-moφholinyl-3- pyridinyl)pyrido[2,3-djpyrimidine;
4-(N-(3-carboxypropyl)amino)-5-(3-bromophenyl)-7-(6-moφholinyl-3- pyridinyl)pyrido[2J-d]pyrimidine;
(S)-4-amino-5-(3-bromophenyl)-7-(6-(O-methyl-2-hydroxymethylpyrrolidinyl)-3- pyridinyl)pyrido[2,3-d]pyrimidine;
(S)-4-amino-5-(3-bromophenyl)-7-(6-(2-hydroxymethylpyrrolidinyl)-3- pyridinyl)pyrido[2J-d]pyrimidine;
4-amino-5-(2-bromophenyl)-7-(6-(4-hydroxypiperidinyl)-3-pyridinyl)pyrido[2,3- djpyrimidine; 4-amino-5-(4-fluorophenyl)-7-(6-(4,4-ethylenedioxypiperidinyl)-3- pyridinyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(2-bromophenyl)-7-(6-(4-hydroxypiperidinyl)-3-pyridazyl)pyrido[2J- djpyrimidine;
4-amino-5-(3-bromophenyl)-7-(6-(4,4-ethylenedioxypiperidinyl)-3- pyridazyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(2-moφholinyl-4-thiazolyl)pyrido[2,3- djpyrimidine;
4-amino-5 -(N-methy 1-3 -indolyl)-7-(6-moφholiny 1-3 -pyridiny l)pyrido [2,3- djpyrimidine; 4-amino-5-(3-bromophenyl)-7-(6-(4-ethoxyiminopiperidinyl)-3- pyridinyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(6-(4-ethoxycarbonylmethoxyiminopiperidinyl)-3- pyridinyl)pyrido[2J-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(-6-(4-oxopiperidinyl)-3-pyridazinyll)pyrido[2J- djpyrimidine; 4-amino-5-(3-bromophenyl)-7-(6-(4-moφholinyliminopiperidinyl )-3- pyridazinyll)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(6-((l S,4S)-2-oxa-5-azabicyclo[2.2J]heptan-5-yl)-3- pyridazyl)pyrido[2,3-d]pyrimidine; 4-amino-5-(3-bromophenyl)-7-(6-(4-methoxyiminopiperidinyl )-3- pyridaziny ll)pyrido [2,3-djpyrimidine;
4-amino-5-(3-bromophenyl)-7-(6-phenylmethoxy-3-pyridazinyll)pyrido[2J-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(6-(4-methoxypiperidinyl)-3-pyridyl)pyrido[2,3- djpyrimidine; 4-amino-5-(3-bromophenyl)-7-(6-(4-(4-tetrahydropyranyloxy)iminopiperidinyl )-3- pyridazinyll)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(6-isobutoxy-3-pyridazinyl)pyrido[2J-djpyrimidine;
4-amino-5-(3-bromophenyl)-7-(6-(4-(N-methylpiperazinyl)iminopiperidinyl )-3- pyridazinyll)pyrido [2,3-djpyrimidine; 4-amino-5-(3-bromophenyl)-7-(6-(4-tetrahydropyranyloxy)-3-pyridazinyll)pyrido[2J- djpyrimidine;
4-amino-5-(3-bromophenyl)-7-(6-moφholinylethoxy-3-pyridazinyll)pyrido[2J- djpyrimidine;
4-amino-5-(3-bromophenyl)-7-(6-(4-ethoxypiperidinyl)-3-pyridazinyll)pyrido[2,3- djpyrimidine;
4-amino-5-(3-bromophenyl)-7-(6-(4-(2-ethoxyethoxy)piperidinyl)-3- pyridazinyll)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(6-(4-(4-tetrapyranyloxyethyl)piperidinyl)-3- pyridazinyll)pyrido[2J-d]pyrimidine; 4-amino-5-(3-bromophenyl)-7-(6-(3-(R)-tetrahydrofuranyloxy)piperidinyl)-3- pyridazinyll)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(6-(3-(S)-tetrahydrofuranyloxy)piperidinyl)-3- pyridazinyll)pyrido[2J-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(6-(trans-3-ethoxy-4-hydroxy)pyrrolidinyl)-3- pyridazinyll)pyrido[2,3-d]pyrimidine; 4-amino-5-(3-bromophenyl)-7-(6-(cis-3-ethoxy-4-hydroxy)pyrrolidinyl)-3- pyridazinyll)pyrido[2J-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(6-(trans-3-ethoxy-4-hydroxy)pyrrolidinyl)-3- pyridyl)pyrido[2J-d]pyrimidine; 4-amino-5-(3-bromophenyl)-7-(6-(trans-3,4-bis-ethoxy)pyrrolidinyl)-3- pyridazinyll)pyrido[2J-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(6-(trans-3,4-bis-ethoxy)pyrrolidinyl)-3-pyridyl)pyrido[2,3- djpyrimidine;
4-amino-5 -(3-bromophenyl)-7-(6-(cis-3 ,4-bis-ethoxy)pyrrolidinyl)-3 -pyridy l)pyrido [2,3 - djpyrimidine;
4-amino-5-(3-bromophenyl)-7-(6-(cis-3,4-bis-ethoxy)pyrrolidinyl)-3- pyridazinyll)pyrido[2J-dJpyrimidine;
4-amino-5-(3-bromophenyl)-7-(6-(cis-3-ethoxy-4-hydroxy)pyrrolidinyl)-3- pyridyl)pyrido [2,3-djpyrimidine; 4-amino-5-(3-bromophenyl)-7-(6-(cis-3-amino-4-hydroxy)pyrrolidinyl)-3- pyridaziny ll)pyrido [2,3-djpyrimidine;
4--ιmino-5-(3-bromophenyl)-7-(6-(cis-3-amino-4-hydroxy)pyrrolidinyl)-3- pyridyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(2-pyridyl)-7-(6-(l,4-dioxa-8-azaspiro[4.5]decan-8-yl)-3-pyridyl)pyrido[2J- djpyrimidine;
4-amino-5-(2J-dichlorophenyl)-7-(6-moφholinyl-3-pyridyl)pyrido[2J-d]pyrimidine;
4-amino-5-(2-pyridyl)-7-(6-moφholinyl-3-pyridyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(2-ethoxyphenyl)-7-(6-(l,4-dioxa-8-azaspiro[4.5]decan-8-yl)-3- pyridyl)pyrido[2,3-dJpyrimidine; 4-amino-5-(2-bromo-5-ethoxyphenyl)-7-(6-moφholinyl-3-pyridyl)pyrido[2,3- djpyrimidine;
4-amino-5-(2,5-dichlorophenyl)-7-(6-moφholinyl-3-pyridyl)pyrido[2J-dJpyrimidine;
4-amino-5-(2,5-dimethylphenyl)-7-(6-moφholinyl-3-pyridyl)pyrido[2J-djpyrimidine
4-amino-5-(3 -fluoropheny l)-7-(6-moφholiny 1-3 -pyridy l)pyrido [2,3-djpyrimidine; 4-amino-5-(3-trifluoromethylphenyl)-7-(6-moφholinyl-3-pyridyl)pyrido[2J- djpyrimidine;
4-amino-5-(3-fluoro-5-trifluoromethylphenyl)-7-(6-(l ,4-dioxa-8-azaspiro[4.5]decan-8-yl)-
3-pyridyl)pyrido[2J-dJpyrimidine; 4-amino-5-(3,5-diclorophenyl)-7-(6-(l,4-dioxa-8-azaspiro[4.5]decan-8-yl)-3- pyridyl)pyrido [2 ,3 -djpyrimidine ;
4-amino-5-(3-bromophenyl)-7-(6-(l,5-dioxa-9-azaspiro[5.5]undecan-9-yl)-3- pyridazinyll)pyrido[2,3-d]pyrimidine;
4-amino-5-(4-bromo-2-thienyl)-7-(6-(l,4-dioxa-8-azaspiro[4.5Jdecan-8-yl)-3- pyridyl)pyrido[2J-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(6-(4-tertbutyl)piperidinyl-3-pyridazinyll)pyrido[2,3- djpyrimidine;
4-amino-5-(3-bromophenyl)-7-(6-(4-N-formyl)piperidinyl-3-pyridazinyll)pyrido[2,3- djpyrimidine; 4-amino-5-(3-bromo-2-thienyl)-7-(6-(4,4-ethylenedioxypiperidinyl)-3-pyridyl)pyrido[2,3- djpyrimidine;
4-amino-5-(3-cyanophenyl)-7-(6-moφholinyl-3-pyridazinyll)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-Bromophenyl)-7-(6-(S-O-ethyl-2-hydroxymethylpyrrolidinyl)-3- pyridazinyll)pyrido[2,3, djpyrimidine;
4-amino-5-(3-bromophenyl)-7-(6-((2SJS)-2.3-dimethyl-l,4-dioxa-8-azaspiro[4.5]decan-
8-yl)-3-pyridazinyl)pyrido[2J-dJpyrimidine;
4-amino-5-(3-bromophenyl)-7-(6-(4,4-(cis-l,2-dioxycyclopentyl)piperidinyl)-3- pyridazinyl)pyrido[2J-dJpyrimidine; 4-amino-5-(3-bromophenyl)-7-(6-(4-acetyl-l-oxa-4,8-diazaspiro[4.5Jdecan-8-yl)-3- pyridazinyl)pyrido[2J-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(6-((2RJR)-2,3-bis(methoxymethyl)-l,4-dioxa-8- azaspiro[4.5]decan-8-yl)-3-pyridazinyl)pyrido[2J-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(6-(4,4-(cis-3,4-dioxy-oxacyclopentyl)piperidinyl)-3- pyridazinyl)pyrido[2J-d]pyrimidine; 4-amino-5-(3-bromophenyl)-7-(6-(3-methoxy-1.5-dioxa-9-azaspiro[5.5Jundecan-9-yl)-3- pyridazinyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(6-(l,5-dioxa-3-hydroxymethyl-9-azaspiro[5.5Jundecan-9- yl)-3-pyridazinyl)pyrido[2J-d]pyrimidine; 4-amino-5-(3-bromophenyl)-7-(6-(l,7J4-trioxa-l l-azadispiro[4.2.5.2]pentadecan-l 1-yl)-
3-pyridazinyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(4-tetrahydropyranyl)-7-(6-moφholinyl-3-pyridazinyll)pyrido[2,3- djpyrimidine;
4-amino-5-(3-bromophenyl)-7-(6-(4-moφholinyliminopiperidinyl )-3-pyridyl)pyrido[2,3- djpyrimidine;
4-amino-5-(3-bromophenyl)-7-(6-(4-(N-methylpiperazinyl)iminopiperidinyl )-3- pyridyl)pyrido[2J-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(6-(4-( 1 ,2,4-triazol- 1 -yl)iminopiperidinyl )-3- pyridyl)pyrido [2,3-djpyrimidine; 4-amino-5-(3-indolyl)-7-(6-moφholinyl-3-pyridyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(5-indolyl)-7-(6-moφholinyl-3-pyridyl)pyrido[2J-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(6-(4-ethylpiperidinylcarboxylate)-3-pyridyl)pyrido[2,3- djpyrimidine;
4-amino-5-(3-bromophenyl)-7-(2-phenylmethyl-3(2H)-pyridazinone-6-yl)pyrido[2,3- djpyrimidine;
4-amino-5-(3-bromophenyl)-7-(6-(4-(moφholinylcarboxamide)piperidinyl)-3- pyridyl)pyrido[2J-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(6-(4-(N-moφholinylaminocarboxamide)piperidinyl)-3- pyridyl)pyrido [2,3 -djpyrimidine; 4-amino-5-(3-bromophenyl)-7-(6-(4-(N,N-dimethylaminocarboxamide)piperidinyl)-3- pyridyl)pyrido[2,3 -djpyrimidine;
4-amino-5-(3-bromophenyl)-7-(6-(4-(N-methyl-N-methoxyethylcarboxamide)piperidinyl)-
3-pyridyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(4-quinolyl)-7-(6-moφholinyl-3-pyridyl)pyrido[2J-d]pyrimidine; 4-amino-5-(3-bromophenyl)-7-(6-(4-(N-methoxyethylcarboxamide)piperidinyl)-3- pyridyl)pyrido[2.3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(6-(4-hydroxymethylpiperidinyl)-3-pyridyl)pyrido[2,3- djpyrimidine; 4-amino-5-(2-bromophenyl)-7-(6-(l,4-dioxa-8-azaspiro[4.5jdecan-8-yl)-3- pyridyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(2-bromophenyl)-7-(6-(4-hydroxypiperidinyl)-3-pyridyl)pyrido[2,3- djpyrimidine;
4-amino-5-(3-bromophenyl)-7-(6-(4-N-acetylpiperazinyl)-3-pyridyl)pyrido[2,3- djpyrimidine;
4-amino-5-(3-bromophenyl)-7-(6-(4-cyanopiperidinyl)-3-pyridyl)pyrido[2J-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(6-(4-N-(4-fluorophenyl)piperazinyl)-3-pyridyl)pyrido[2,3- djpyrimidine;
4-amino-5-(4-fluorophenyl)-7-(6-moφholinyl-3-pyridyl)pyrido[2J-d]pyrimidine; 4-amino-5-(3-bromophenyl)-7-(4-moφholinylbenzenesulfonamide)pyrido[2,3- djpyrimidine;
4-amino-5-(3-bromophenyl)-7-(4-N-l,4-dioxa-8-azaspiro[4.5]decan-8- ylbenzenesulfonamide)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(4-N-cyclopropylbenzenesulfonamide)pyrido[2,3- djpyrimidine;
4-amino-5-(3-bromophenyl)-7-(4-piperidinebenzenesulfonamide)pyrido[2J-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(4-(4-cyanopiperidine)benzenesulfonamide)pyrido[2,3- djpyrimidine;
4-amino-5-(3-bromophenyl)-7-(4-N-cyclopropylmethylbenzenesulfonamide)pyrido[2,3- djpyrimidine;
4-amino-5-(3-bromophenyl)-7-(4-N,N-dimethylaminobenzenesulfonamide)pyrido[2,3- djpyrimidine;
4-amino-5-(3-bromophenyl)-7-(4-N-(S)-2- hydroxymethylpyrrolidinebenzenesulfonamide)pyrido[2J-d]pyrimidine; 4-amino-5-(3-bromophenyl)-7-(4-(4-hydroxypiperidine)benzenesulfonamide)pyrido[2J- djpyrimidine;
4-amino-5-(3-bromophenyl)-7-(4-(cis-3,5- dimethylmoφholinyl)benzenesulfonamide)pyrido[2J-d]pyrimidine; 4-amino-5-(3-bromophenyl)-7-(3-fluoro-4-thiomoφholinylphenyl)pyrido[2J- djpyrimidine;
4-amino-5-(4-fluorophenyl)-7-(6-(thiomoφholinyl)-3-pyridyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(4-fluorophenyl)-7-(6-(4,4-dioxothiomoφholinyl)-3-pyridyl)pyrido[2,3- djpyrimidine; 4-methoxy-5-(3-bromophenyl)-7-(6-moφholinyl-3-pyridyl)pyrido[2J-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(4-(4-dioxa-8-azaspiro[4.5]decan-8- ylcarboxamide)phenyl)pyrido[2J-djpyrimidine;
4-amino-5-(3-bromophenyl)-7-(4-(N-cyclopropylcarboxamide)phenyl)pyrido[2,3- djpyrimidine; 4-amino-5-(3-bromophenyl)-7-(4-(moφholinylcarboxamide)phenyl)pyrido[2,3- djpyrimidine;
4-amino-5-(3-bromophenyl)-7-(6-N-cyclopropylamino-3-pyridyl)pyrido[2J-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(4-(4-hydroxypiperidinylcarboxamide)phenyl)pyrido[2,3- djpyrimidine; 4-amino-5-(3-bromophenyl)-7-(6-(S)-hydroxymethylpyrrolidinyl-3- pyridazinyll)pyrido[2J-d]pyrimidine;
4-amino-5 -(3 -bromopheny l)-7-(6-(4-(2-ethoxyethoxy)piperidinyl)-3 -pyridy l)pyrido [2,3- djpyrimidine;
4-amino-5-(3-bromophenyl)-7-(6-hexahydropyrimidine )-3-pyridyl)pyrido[2,3- djpyrimidine;
4-amino-5-(4,4-difluorocyclohxeyl)-7-(6-(l,4-dioxa-8-azaspiro[4.5]decan-8-yl)-3- pyridyl)pyrido [2,3 -djpyrimidine ;
4-amino-5-(3-bromophenyl)-7-(6-(S)-2-ethoxyethoxypyrrolidinyl)-3-pyridyl)pyrido[2,3- djpyrimidine; 4-amino-5-(3-bromophenyl)-7-(6-(R)-2-ethoxyethoxypyrrolidinyl)-3- pyridyl)pyri do [2 ,3 -djpyrimidine;
4-amino-5 -(3 -bromopheny l)-7-(6-(cis-3 ,4-dihydroxypyrolidiny l)-3 -pyridyl)pyrido [2,3- djpyrimidine; 4-amino-5-(3-bromophenyl)-7-(6-((3aR,6aS)-2-oxo-tetrahydro-3aH-[l,3jdioxolo[4,5- c]pyrrol-5-yl)-3-pyridyl)pyrido[2,3-djpyrimidine;
4-amino-5-(3-bromophenyl)-7-(6-(cis-2,3-dihydroxypyrrolidinyl)-3- pyridazinyll)pyrido[2J-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(6-(S,R-2-hydroxymethyl-4-hydroxypyrrolidinyl)-3- pyridyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(6-(R-2-hydroxymethyl-4-pyrrolidinyl)-3- pyridazinyll)pyrido[2J-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(6-((lS,4S)-2-oxa-5-azabicyclo[2.2J]heptan-5-yl)-3- pyridyl)pyrido [2,3-djpyrimidine; 4-amino-5-(3-bromophenyl)-7-(6-(2-imidizolidone-l-yl)-3-pyridyl)pyrido[2,3- djpyrimidine;
4-amino-5-(lJ-dimethyl-3-butenyl)-7-(6-moφholinyl-3-pyridyl)pyrido[2J-djpyrimidine;
4-amino-5-(3-bromophenyl)-7-(6-(2,4-dioxo-(lH,3H)-quinazolin-3-yl)-3- pyridyl)pyrido[2,3-d]pyrimidine; 4-amino-5-(3-bromophenyl)-7-(6-carboxamide-3-pyridazinyll)pyrido[2J-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(6-moφholinylcarboxamide-3-pyridazinyll)pyrido[2J- djpyrimidine;
4-amino-5-(3-bromophenyl)-7-(6-methoxy-3-pyridazinyll)pyrido[2J-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(6-N,N-diethoxyethylamino-3-pyridazinyll)pyrido[2,3- djpyrimidine;
4-amino-5-(3-bromophenyl)-7-(6-(4-ethoxymethylpiperidinyl)-3-pyridazinyll)pyrido[2,3- djpyrimidine;
4-amino-5-(3-bromophenyl)-7-(6-(4-(4-tetrahydropyranyloxymethyl)piperidinyl)-3- pyridazinyll)pyrido[2J-d]pyrimidine; 4-amino-5-(3-bromophenyl)-7-(6-(4-ethoxyethoxymethylpiperidinyl)-3- pyridazinyll)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(6-N-methyl-N-l,3-dioxalanemethylamino )-3- pyridazinyll)pyrido[2J-dJpyrimidine; 4-amino-5-(3-bromophenyl)-7-(6-(l,4-dioxaspiro[4.5Jdecanyl-8-oxy)-3- pyridazinyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(6-dihydroxymethylmethoxy-3-pyridazinyll)pyrido[2,3- djpyrimidine;
4-amino-5-(3-bromophenyl)-7-(6-(3-pyridyloxy)-3-pyridazinyll)pyrido[2,3-d]pyrimidine; 4-amino-5-(3-bromophenyl)-7-(6-(4,7-epoxy-7-methyl-2,3,3A,4,5,6,7,7a-octahydro-lH- isoindolyl)-3-pyridazinyl)pyrido[2J-d]pyrimidine;
4-amino-5 -(3 -bromopheny l)-7-(6-(4-N-ethy l-N-methoxyethyl)-3 -pyridazinyll)pyrido [2,3- djpyrimidine;
4-amino-5-(3-bromophenyl)-7-(6-(4-N-methyl-N-methoxyethyl)-3- pyridazinyll)pyrido[2,3-djpyrimidine;
4-amino-5 -(3 -bromopheny l)-7-(6-(3 ,4-dimethoxymethoxypyrrolidiny l)-3 - pyridazinyll)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(6-(hexahydro-lH-furo[3,4-c]pyrrol-5-yl)-3- pyridazinyl)pyrido[2,3-d]pyrimidine; 4-amino-5 -(3 -bromopheny l)-7-(6-(hexahydro- 1 H-furo [3 ,4-c]pyrrol-5 -y l)-3 - pyridyl)pyri do [2,3 -djpyrimidine;
4-amino-5-(3-bromophenyl)-7-(6-(trans-3-hydroxy-4-methylpyrrolidinyl)-3- pyridazinyll)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(6-(trans-3-hydroxy-4-methylpyrrolidinyl)-3- pyridy l)pyrido [2 ,3 -djpyrimidine ;
4-amino-5-(3-bromophenyl)-7-(6-(cis-3-hydroxy-4-methylpyrrolidinyl)-3- pyridazinyll)pyrido[2, 3-djpyrimidine;
4-amino-5-(3-bromophenyl)-7-(6-(cis-3-hydroxy-4-methylpyrrolidinyl)-3- pyridyl)pyrido[2J-dJpyrimidine; 4-amino-5-(3-bromophenyl)-7-(6-(trans-3-cyano-4-hydroxylpyrrolidinyl)-3- pyridyl)pyrido[2J-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(6-(3-hydroxy-4-tert-butylcarboxamidepyrrolidinyl)-3- pyridyl)pyrido[2,3-dJpyrimidine; 4-amino-5-(3-bromophenyl)-7-(6-(S-2-(4-tetrahydropyranyloxy)methylpyrrolidinyl)-3- pyridazinyll)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(6-(3-(4-tetrahydropyranyloxy)iminopyrrolidinyl)-3- pyridazinyll)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(2-moφholinyl-5-thiazoyl)pyrido[2J-d]pyrimidine; 4-amino-5-(3-bromophenyl)-7-(5-bromo-2-thienyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(2,5-dimethyl-3-thienyl)pyrido[2,3-dJpyrimidine;
4-amino-5-(3-bromophenyl)-7-(5-chloro-2-thienyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(2,4-dimethyl-5-thiazoyl)pyrido[2,3-dJpyrimidine;
4-amino-5-(3-bromophenyl)-7-(5-methyl-2-thienyl)pyrido[2,3-d]pyrimidine; 4-amino-5-(3-bromophenyl)-7-(2-furanyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(2-(l,4-dioxa-8-azaspiro[4.5]decan-8-yl)-5- thiazoyl)pyrido[2,3-djpyrimidine;
4-amino-5-(3-bromophenyl)-7-(3-thienyl)pyrido[2J-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(3-methyl-2-thienyl)pyrido[2J-d]pyrimidine; 4-amino-5-(3-bromophenyl)-7-(2-moφholinyl-4-thiazoyl)pyrido[2J-djpyrimidine;
4-amino-5-(3-bromophenyl)-7-(2-moφholinyl-4-trifluoromethy-5-thiazoyl)pyrido[2J- djpyrimidine;
4-amino-5-(3-bromophenyl)-7-(5-moφholinyl-2-thienyl)pyrido[2J-djpyrimidine;
4-amino-5-(3-bromophenyl)-7-(4-methyl-2-moφholinyl-5-thiazoyl)pyrido[2,3- djpyrimidine;
4-amino-5-(3-bromophenyl)-7-(2,5-dichloro-3-thienyl)pyrido[2J-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(2,5-dimethyl-3-furanyl)pyrido[2J-djpyrimidine;
4-amino-5-(3-bromophenyl)-7-(N-methyl-2-pyrrolyl)pyrido[2J-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(2-N.N-dimethylamino-5-thiazoyl)pyrido[2J- djpyrimidine; 4-amino-5-(3-bromophenyl)-7-(2-moφholinyl-5-thiazoyl)pyrido[2J-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(2-(4,4-dioxythiomoφholinyl)-5-thiazoyl)pyrido[2J- djpyrimidine;
4-amino-5 -(3 -bromopheny l)-7-(2-( 1 , 1 -dioxidothiomoφholiny l)-5-thiazoy l)pyrido [2,3 - djpyrimidine;
4-amino-5-(3-bromophenyl)-7-(2-moφholinyl-5-oxazolyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(2-N-methyl-N-methoxyethylamino-5-thiazoyl)pyrido[2,3- djpyrimidine;
4-amino-5-(3-bromophenyl)-7-(2-N-methyl-N-ethylamino-5-thiazoyl)pyrido[2J- djpyrimidine;
4-amino-5-(3-bromophenyl)-7-(2-N-pyrrolidinyl-5-thiazoyl)pyrido[2J-d]pyrimidine;
4- imino-5-(3-bromophenyl)-7-(2-N-methyl-N-propylamino-5-thiazoyl)pyrido[2J- djpyrimidine;
4-amino-5-(3-bromophenyl)-7-(2-N,N-diethylamino-5-thiazoyl)pyrido[2,3-dJpyrimidine; 4-amino-5-(3-bromophenyl)-7-(2-(N-methypiperazinyl)-5-thiazoyl)pyrido[2,3- djpyrimidine;
4-amino-5-(3-bromophenyl)-7-(2-(N-(2-pyridyl)piperazinyl)-5-thiazoyl)pyrido[2,3- djpyrimidine;
4-amino-5-(3-bromophenyl)-7-(2-N-methy-N-(2-pyridylethyl)-5-thiazoyl)pyrido[2,3- djpyrimidine;
4-amino-5-(3-bromophenyl)-7-(2-(4-oxopiperazinyl)-5-thiazoyl)pyrido[2J-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(2-(4-(N-moφholinyl)iminopiperazinyl)-5- thiazoyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(6-N-moφholine-3-pyridinesulfonamide)pyrido[2,3- djpyrimidine;
4-amino-5-(3-bromophenyl)-7-(2-(4-oxopiperidinyl)-5-pyrimidyl)pyrido[2,3- djpyrimidine;
4-amino-5 -(3 -bromopheny l)-7-(2-(4,4-dioxethy lenepiperidiny l)-5-pyrimidyl)pyrido [2,3 - djpyrimidine; 4-amino-5-(3-bromophenyl)-7-(5-(l,4-dioxa-8-azaspiro[4.5Jdecan-8-yl)-2- pyrazinyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(5-(4-oxopiperidinyl)-2-pyrazinyl)pyrido[2J-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(6-N-cyclopropyl-3-pyridinesulfonamide)pyrido[2,3- d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(6-(N-l,4-dioxa-8-azaspiro[4.5Jdecan-8-yl)-3- pyridylsulfonamide)pyrido [2,3-djpyrimidine;
4-amino-5-(3-bromophenyl)-7-(2-(4-(4-tetrahydropyranyloxy)iminopiperidinyl )-5- pyrazinyl)pyrido[2,3-dJpyrimidine; 4-amino-5-(3-bromophenyl)-7-(6-(4-(phenylmethoxy)iminopiperidinyl)-3- pyridyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(6-(4-(tert-butyloxy)iminopiperidinyl)-3- pyridyl)pyrido[2,3-dJpyrimidine;
4-amino-5-(3-bromophenyl)-7-(6-(4-(cyclohexyloxy)iminopiperidinyl)-3- pyridyl)pyrido[2,3-dJpyrimidine;
4-amino-5-(3-bromophenyl)-7-(6-(4-hydroxyiminopiperidinyl)-3-pyridyl)pyrido[2,3- djpyrimidine;
4-amino-5-(3-bromophenyl)-7-(6-(4-(4-tetrahydropyranyloxy)iminopiperidinyl)-3- pyridyl)pyrido[2,3-d]pyrimidine; 4-amino-5-(3-bromophenyl)-7-(6-(4-methoxyethoxyiminopiperidinyl)-3- pyridyl)pyrido[2,3-dJpyrimidine;
4-amino-5 -(3 -bromopheny l)-7-(6-(4-(2-thenylmethoxy)iminopiperidinyl)-3 - pyridyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(6-(4-(4'-(5'H-2-oxyfuranyl)-4-hydroxy)piperidinyl)-3- pyridy l)pyrido [2 ,3 -djpyrimidine ;
4-amino-5-(3-bromophenyl)-7-(6-(4-(l-(4-tetrahydropyranyloxy)iminoethyl))-4- hydroxypiperidiny l)-3 -pyridaziny ll)pyrido [2,3-djpyrimidine;
4-amino-5-(3-bromophenyl)-7-(6-(4-(4'-acetyl-4'-hydroxypiperidinyl)-3- pyridazinyll)pyrido[2,3-d]pyrimidine; 4-amino-5-(3-bromophenyl)-7-(6-(4-(l-(isopropylcaboxymethoxy)iminoethyl))-4- hydroxypiperidinyl)-3-pyridyl)pyrido[2J-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(6-(4-(l-(ethylcaboxymethoxy)iminoethyl))-4- hydroxypiperidinyl)-3-pyridyl)pyrido[2,3-dJpyrimidine; 4-amino-5 -(3 -bromopheny l)-7-(6-(4-( 1 -(methy lcaboxymethoxy )iminoethyl))-4- hydroxypiperidinyl)-3-pyridyl)pyrido[2,3-dJpyrimidine;
4-amino-5-(3-bromophenyl)-7-(6-(4-(l-(2-tetrahydropyranyloxy)iminoethyl))-4- hydroxypiperidinyl)-3-pyridyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(6-(4-(l-(allyloxy)iminoethyl))-4-hydroxypiperidinyl)-3- pyridyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(6-(4-(l-(ethoxy)iminoethyl))-4-hydroxypiperidinyl)-3- pyridy l)pyrido [2,3-djpyrimidine;
4-amino-5-(3-bromophenyl)-7-(6-(4-(l-(methoxy)iminoethyl))-4-hydroxypiperidinyl)-3- pyridyl)pyrido[2,3-dJpyrimidine; 4-amino-5-(3-bromophenyl)-7-(6-(4-(l-(hydroxy)iminoethyl))-4-hydroxypiperidinyl)-3- pyridyl)pyrido[2,3-dJpyrimidine;
4-amino-5-(3-bromophenyl)-7-(6-(4-(2-tetrahydropyranyloxy)iminopiperidinyl)-3- pyridyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(6-(4-(isopropylcarboxymethoxy)iminopiperidinyl)-3- pyridyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(6-(4-hydroxy-4-(l-(4-tetrahydropyranyloxy)iminoethyl))-
4-hydroxypiperidinyl)-3-pyridyl)pyrido[2J-dJpyrimidine;
4-amino-5-(3-bromophenyl)-7-(6-(4-(3-butyrolactone)-4-hydroxypiperidinyl)-3- pyridyl)pyrido [2,3-djpyrimidine; 4-amino-5-(3-bromophenyl)-7-(6-(4-(2-butyrolactone)-4-hydroxypiperidinyl)-3- pyridazinyll)pyrido[2,3-d]pyrimidine;
4-amino-5 -(3 -bromophenyl)-7-(6-(4-acety 1-4-hydroxypiperidiny l)-3 -pyridy l)pyrido [2,3- djpyrimidine;
4-amino-5-(3-bromophenyl)-7-(6-(3-hydroxyazetidinyl)-3-pyridyl)pyrido[2,3- djpyrimidine; 4-amino-5-(3-bromophenyl)-7-(6-(( 1 R,5S)-3-hydroxy-8-azabicyclo[3.2.1 ]octan-8-yl)-3- pyridyl)pyrido[2J-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(6-(cis-2J-dihydroxypiperidinyl)-3-pyridyl)pyrido[2,3- djpyrimidine; 4-amino-5-(3-bromophenyl)-7-(6-(N-methyl-N-(3-pyridylmethyl)amino)-3- pyridazinyll)pyrido[2,3-dJpyrimidine;
4-amino-5-(3-bromophenyl)-7-(6-(l,2,3,6-tetrahydropyridyl)-3-pyridyl)pyrido[2,3- djpyrimidine;
4-amino-5-(3-bromophenyl)-7-(6-(4-(N-4'methoxyphenylcarbamoyl)piperidinyl)-3- pyridazinyll)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(6-(4-(2-butyrolactone)-4-hydroxypiperidinyl)-3- pyridy l)pyrido [2 ,3 -d] pyrimidine ;
4-amino-5-(3-bromophenyl)-7-(6-(trans-3,4- bis(N-4'- methoxyphenylcarbamoyl)pyrrolidinyl)-3-pyridyl)pyrido[2,3-dJpyrimidine; 4-amino-5-(3-bromophenyl)-7-(6-(( 1 S,5R)-3-hydroxy-8-azabicyclo[3.2.1 Joctan-8-yl)-3- pyridyl)pyrido [2,3-djpyrimidine;
4-amino-5-(3-bromophenyl)-7-( 6-(S,S-trans-3,4-dihydroxypyrrolidinyl)-3- pyridy l)pyrido [2 ,3 -djpyrimidine ;
4-amino-5-(3-bromophenyl)-7-( 6-(R,R-trans-3,4-dihydroxypyrrolidinyl)-3- pyridazinyll)pyrido[2,3-dJpyrimidine;
4-amino-5-(3-bromophenyl)-7-( 6-(R,R-trans-3,4-dihydroxypyrrolidinyl)-3- pyridy l)pyrido [2 ,3 -djpyrimidine ;
4-amino-5-(3-bromophenyl)-7-(6-(4-oxo-l-phenyl-l,3,8-triazaspiro[4.5]decan-8-yl)-3- pyridyl)pyrido[2,3-d]pyrimidine; 4-amino-5-(3-bromophenyl)-7-(6-(l-oxa-4-oxo-4-thia-8-azaspiro[4.5Jdecan-8-yl)-3- pyridyl)pyrido [2,3-djpyrimidine;
4-amino-5-(3-bromophenyl)-7-(6-(l-oxa-4,4-dioxido-4-thia-8-azaspiro[4.5]decan-8-yl)-3- pyridyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(6-(4-oxo-l-phenyl-l,3,8-triazaspiro[4.5]dec-2-en-8-yl)-3- pyridyl)pyrido[2,3-dJpyrimidine; 4-amino-5-(3-bromophenyl)-7-(6-(4-(2-keto-l-benzimidazolinyl)piperidinyl)-3- pyridazinyll)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(6-(4-oxothiomoφholinyl)-3-pyridyl)pyrido[2,3- djpyrimidine; 4-amino-5-(3-bromophenyl)-7-(6-(4-(2-keto-l-benzimidazolinyl)piperidinyl)-3- pyridyl)pyrido[2,3-dJpyrimidine;
4-amino-5-(3-bromophenyl)-7-(6-(N-methyl-N-(2-pyridylethyl)amino)-3- pyridyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(6-(N-methyl-N-(4-pyridylethyl)amino)-3- pyridyl)pyrido[2,3-dJpyrimidine;
4-amino-5-(3-bromophenyl)-7-(6-N-(3-pyridylmethyl)amino-3-pyridyl)pyrido[2,3- djpyrimidine;
4-amino-5-(3-bromophenyl)-7-(6-(2-hydroxymethylpiperidinyl)-3-pyridyl)pyrido[2,3- djpyrimidine; 4-amino-5-(3-bromophenyl)-7-(6-(l -oxa-4-thia-8-azaspiro[4.5]decan-8-yl)-3- pyridyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(6-(4-hydroxy-4-(4-bromophenyl)piperidinyl)-3- pyridyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(6-(4-N-(2-pyridnyl)piperazinyl)-3-pyridyl)pyrido[2,3- djpyrimidine;
4-amino-5-(3-bromophenyl)-7-(6-(4-N-(2-hydroxyethyloxyethyl)piperazinyl)-3- pyridyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(6-(4,4-diacetoxyethylthio)piperidinyl)-3- pyridy l)pyrido [2 ,3 -djpyrimidine ; 4-amino-5-(3-bromophenyl)-7-(6-(N-methy-N-(3-pyridylmethyl)amino)-3- pyridyl)pyrido [2 ,3 -djpyrimidine ;
4-amino-5 -(3 -bromopheny l)-7-(6-(4-pyrrolidinylpiperidiny l)-3 -pyridy l)pyrido [2,3- djpyrimidine;
4-amino-5-(3-bromophenyl)-7-(6-(2-(lH-imidazol-4-yl)ethylamino)-3- pyridazinyl)pyrido[2,3-d]pyrimidine; 4-amino-5-(3-bromophenyl)-7-(6-(4-N-cyanomethylpiperazinyl)-3-pyridyl)pyrido[2,3- djpyrimidine;
4-amino-5-(3 -bromopheny l)-7-(6-(3 -hydroxypyrroldiny l)-3 -pyridy l)pyri do [2,3 - djpyrimidine; 4-amino-5 -(3 -bromopheny l)-7-(6-(4-methy lpiperidiny l)-3 -pyridy l)pyrido [2,3- djpyrimidine;
4-amino-5-(3-bromophenyl)-7-(6-(cis-3,5-dimethylmoφholinyl)-3-pyridyl)pyrido[2,3- djpyrimidine;
4-amino-5-(3-bromophenyl)-7-(6-(4,4-difluoropipridinyl)-3-pyridyl)pyrido[2,3- djpyrimidine;
4-amino-5-(3-bromophenyl)-7-(6-(lJ-dioxidoythiomoφholinyl)-3- pyridazinyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(6-thiazolidinyl-3-pyridyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(6-(lJ-dioxidoythiazolidin-3-yl)-3-pyridyl)pyrido[2,3- djpyrimidine;
4-amino-5-(3-bromophenyl)-7-(6-thiomoφholinyl-3-pyridazinyll)pyrido[2J- djpyrimidine;
4-amino-5 -(3 -bromophenyl)-7-(6-(2,5-dihydropyrrolyl)-3 -pyridyl)pyrido [2,3 - djpyrimidine; 4-amino-5-(3-bromophenyl)-7-(6-(l,3-dioxa-8-azaspiro[4.5]decan-8-yl)-3- pyridyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(6-hydroxy-3-pyridazinyll)pyrido[2J-djpyrimidine; amino-5-(2,3-dichlorophenyl)-7-(6-(l,4-dioxa-8-azaspiro[4.5]decan-8-yl)-3- pyridyl)pyrido[2,3-d]pyrimidine; 4-amino-5-isopropyl-7-(6-(l,4-dioxa-8-azaspiro[4.5]decan-8-yl)-3-pyridyl)pyrido[2,3- djpyrimidine;
4-amino-5-(3-bromophenyl)-7-(6-piperidinyl-3-pyridyl)pyrido[2J-dJpyrimidine;
4-amino-5 -(3 -bromopheny l)-7-(6-(3 -(4-tetrahydropyranyloxyimino)pyrrolidinyl)-3 - pyridyl)pyrido[2,3-d]pyrimidine; and 4-amino-5-(2-trifluorophenylphenyl)-7-(6-moφholinyl-3-pyridyl)pyrido[2,3- djpyrimidine.
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 treating 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 transluminal angioplasty, stroke, thrombotic and embolic conditions, epilepsy, anxiety, schizophrenia, pain perception, neuropathic pain, visceral pain, arthritis, sepsis, diabetes and abnormal gastrointestinal motility.
10. A compound of formula I
Figure imgf000355_0001
I, or a pharmaceutically acceptable salt or amide thereof wherein, R1 and R2 are each independently selected from the group consisting of hydrogen, alkenyl, alkoxyalkyl, alkoxyalkylcarbonyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkyl, alkylcarbonyl, aminocarbonyl, aryl, arylalkyl, arylalkylcarbonyl, arylcarbonyl, carboxyalkyl, formyl, haloalkylcarbonyl, heterocycle, heterocyclealkyl, heterocyclecarbonyl, hydroxyalkyl, iminoalkyl, and (NZ,Z2)alkyl, or R1 and R2 may join together with the nitrogen atom to which they are attached to form a 5-7 membered ring optionally containing 1-2 additional heteroatoms selected from the group consisting of O, N, and S;
Z, and Z2 are each independently selected from the group consisting of hydrogen, alkoxycarbonyl, alkyl, alkylcarbonyl, benzyl, benzyloxycarbonyl, and formyl;
R3 is selected from the group consisting of alkenyl, alkyl, alkynyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, heterocycle, heterocyclealkyl, heterocyclealkylcarbonyl, (NZ,Z2)alkyl, and -RARB;
RA is selected from the group consisting aryl and arylalkyl; RB is selected from aryl, arylalkoxy, arylalkyl, aryloxy, heterocycle, and heterocyclealkyl;
R4 is selected from the group consisting of alkenyl, alkoxyalkynyl, alkyl, alkynyl, cycloalkyl, aryl, arylalkyl, heterocycle, heterocyclealkyl, and -RCRDRE;
Rc is selected from aryl, arylalkyl, heterocycle, and heterocyclealkyl; RD is selected from aryl, arylalkoxy, arylalkoxyimino, arylalkyl, aryloxy, heterocycle, heterocyclealkoxy, heterocyclealkyl, heterocyclecarbonyl, heterocycleimino, heterocycleoxy, heterocycleoxyalkyl, heterocycleoxyimino, heterocycleoxyiminoalkyl, and heterocyclesulfonyl;
RE is absent or selected from aryl, arylalkoxy, arylalkoxyimino, arylalkyl, aryloxy, heterocycle, heterocylealkoxy, heterocyclealkyl, heterocyclecarbonyl, heterocycleimino, heterocycleoxy, heterocycleoxyalkyl, heterocycleoxyimino, heterocycleoxyiminoalkyl, and heterocyclesulfonyl; and a dashed line — indicates that a double bond is optionally present provided that proper valencies are maintained; with the proviso that the following compounds are excluded,
4-amino-5-(4-chorophenyl)-7-(4-nitrophenyl)pyridol[2J-d]pyrimidine, 4-amino-5-(4-methoxyphenyl)-7-(4-nitrophenyl)pyridol[2,3 -djpyrimidine, 4-amino-5-(4-fluorophenyl)-7-(4-fluorophenyl)pyridol[2,3-d]pyrimidine, 4-amino-5-(4-chlorophenyl)-7-(4-fluoφhenyl)pyridol[2,3-d]pyrimidine, 4-amino-5-phenyl-7-(4-aminophenyl)pyrido[2,3-d]pyrimidine, -amino-5 -pheny l-7-(4-brompheny l)pyrido [2,3-djpyrimidine, -amino-5-(4-methoxyphenyl)-7-(4-aminophenyl)pyrido[2,3-d]pyrimidine, -amino-5-(4-methoxyphenyl)-7-(4-bromphenyl)pyrido[2J-dJpyrimidine, and -amino-5,7-diphenylpyrido[2,3 -djpyrimidine.
11. A compound according to claim 10 of formula II
Figure imgf000357_0001
11, or a pharmaceutically acceptable salt or amide thereof wherein, R1 and R2 are independently selected from the group consisting of hydrogen, alkenyl, alkoxyalkyl, alkoxyalkylcarbonyl, alkoxycarbonyl, alkyl, alkylcarbonyl, aminocarbonyl, aryl, arylcarbonyl, carboxyalkyl, formyl, haloalkylcarbonyl, heterocyclealkyl, hydroxyalkyl, iminoalkyl, and (NZ,Z2)alkyl, or R1 and R2 may join together with the nitrogen atom to which they are attached to form a 6 membered ring optionally containing 1 additional heteroatom selected from the group consisting of O, N, and S;
Z, and Z2 are each independently selected from the group consisting of hydrogen, alkoxycarbonyl, alkyl, alkylcarbonyl, benzyl, benzyloxycarbonyl, and formyl; R3 is selected from the group consisting of alkenyl, alkyl, aryl, arylalkyl, cycloalkyl, heterocycle, heterocyclealkyl, (NZ,Z2)alkyl, and -RARB; RA is selected from the group consisting of aryl and arylalkyl; RB is selected from the group consisting of aryl, arylalkoxy, arylalkyl, aryloxy, and heterocycle;
R4 is selected from the group consisting of alkoxyalkynyl, alkynyl, aryl, heterocycle, and -RCRDRE;
Rc is selected from the group consisting of aryl and heterocycle; RD is selected from the group consisting of aryl, arylalkoxy, arylalkyl, aryloxy, heterocycle, heterocyclealkoxy, heterocyclealkyl, heterocyclecarbonyl, heterocycleoxy, and heterocyclesulfonyl; and
RE is absent or selected from the group consisting of aryl, arylalkoxy, arylalkoxyimino, arylalkyl, aryloxy, heterocycle, heterocylealkoxy, heterocyclealkyl, heterocyclecarbonyl, heterocycleimino, heterocycleoxy, heterocycleoxyalkyl, heterocycleoxyimino, and heterocycleoxyiminoalkyl.
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-(l-moφholinyl)-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-(N-(2-(dimethylamino)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- dimethy lamino)ethy l)amino)phenyl ; 4-(N-methyl-N-(2-(N- phthalimidyl)acetyl)amino)phenyl; 4-(N-methyl-N-(2-cyano)ethylamino)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- formy lamino)phenyl; 4-(N-methyl-N-trifluoroacetylamino)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-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- 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-moφholiny Ipheny 1; 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-formylpiperaziny Ipheny 1) 4-nitrophenyl; 4- piperidiny Ipheny 1; 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 -oxazolidiny l)-3 -pyridinyl ; 6-dimethy lamino-3 -pyridinyl ; 6-imidazoly 1-3 - pyridinyl; 6-moφholinyl-3-pyridinyl; 6-pyrrolidinyl-3-pyridinyl; 6-(2-propyl)-3-pyridinyl; (4-formylamino)phenyl; 6-(4-oxopiperidinyl)-3 -pyridazinyl; 6-(4- moφholinyliminopiperidinyl)-3-pyridazinyl; 6-((lS,4S)-2-oxa-5-azabicyclo[2.2JJheptan- 5-yl)-3-pyridazinyl; 6-(4-methoxyiminopiperidinyl)-3-pyridazinyl; 6-phenylmethoxy-3- pyridazinyl; 6-(l J -dioxidoythiazolidin-3-yl)-3-pyridyl; 6-(l ,3-dioxa-8- azaspiro[4.5jdecan-8-yl)-3-pyridyl; 6-(l-oxa-4-thia-8-azaspiro[4.5]decan-8-yl)-3-pyridyl; 6-( 1 J -dioxidoythiomoφholinyl)-3-pyridazinyl; 6-( 1 -oxa-4,4-dioxido-4-thia-8- azaspiro[4.5]decan-8-yl)-3-pyridyl; 6-(l-oxa-4-oxo-4-thia-8-azaspiro[4.5jdecan-8-yl)-3- pyridyl; 6-(3-hydroxy-8-azabicyclo[3.2J]octan-8-yl)-3-pyridyl; 6-(4-oxo- 1-phenyl- 1,3,8 - triazaspiro[4.5jdecan-8-yl)-3-pyridyl; 6-(4-oxo-l-phenyl-l,3,8-triazaspiro[4.5]dec-2-en-8- y l)-3 -pyridyl ; 6-(N- 1 ,4-dioxa-8-azaspiro [4.5 jdecan- 8 -y l)-3 -pyridy lsulfonamide ; 2-( 1 , 1 - dioxidothiomoφholinyl)-5-thiazoyl; 5-(l,4-dioxa-8-azaspiro[4.5]decan-8-yl)-2-pyrazinyl; 2-(l,4-dioxa-8-azaspiro[4.5jdecan-8-yl)-5-thiazoyl; 6-(hexahydro-lH-furo[3,4-c]pyrrol-5- yl)-3 -pyridazinyl; 6-(hexahydro-lH-furo[3,4-c]pyrrol-5-yl)-3-pyridyl; 6-(4- methoxypiperidinyl)-3-pyridyl; 6-(4.7-epoxy-7-methyl-2.3.3A.4,5,6,7.7a-octahydro-lH- isoindoly l)-3 -pyridazinyl ; 6-(4-(4-tetrahydropyrany lqxy)iminopiperidiny l)-3 -pyridaziny 1 ; 6-isopropoxy-3 -pyridazinyl; 6-(2,4-dioxo-( 1 H,3H)-quinazolin-3-yl)-3-pyridyl; 6-(4-(N- methylpiperazinyl)iminopiperidinyl)-3 -pyridazinyl; 6-(4-tetrahydropyranyloxy)-3- pyridazinyl; 6-moφholinylethoxy-3-pyridazinyl; 6-(4-ethoxypiperidinyl)-3-pyridazinyl; 6- (l,4-dioxa-8-azaspiro[4.5Jdecan-8-yl)-3-pyridyl; 6-(4-(2-ethoxyethoxy)piperidinyl)-3- pyridazinyl; 6-((3aR,6aS)-2-oxo-tetrahydro-3aH-[l,3]dioxolo[4,5-c]pyrrol-5-yl)-3-pyridyl; 6-(4-(4-tetrapyranyloxyethyl)piperidinyl)-3-pyridazinyl; 6-(3-(R)- tetrahydrofuranyloxy)piperidinyl)-3-pyridazinyl; 6-(3-(S)- tetrahydrofuranyloxy)piperidinyl)-3-pyridazinyl; 6-(trans-3-ethoxy-4- hydroxy)pyrrolidinyl)-3-pyridazinyl; 6-(cis-3-ethoxy-4-hydroxy)pyrrolidinyl)-3- pyridazinyl; 6-(trans-3-ethoxy-4-hydroxy)pyrrolidinyl)-3-pyridyl; 6-(trans-3,4-bis- ethoxy)pyrrolidinyl)-3-pyridazinyl; 6-(trans-3,4-bis-ethoxy)pyrrolidinyl)-3-pyridyl; 6-(cis- 3,4-bis-ethoxy)pyrrolidinyl)-3-pyridyl; 6-(cis-3,4-bis-ethoxy)pyrrolidinyl)-3-pyridazinyl; 6-(cis-3-ethoxy-4-hydroxy)pyrrolidinyl)-3-pyridyl; 6-(cis-3-amino-4- hydroxy)pyrrolidinyl)-3-pyridazinyl; 6-(cis-3-amino-4-hydroxy)pyrrolidinyl)-3-pyridyl; 6- (l,5-dioxa-9-azaspiro[5.5]undecan-9-yl)-3-pyridazinyl; 6-(4-tertbutyl)piperidinyl-3- pyridazinyl; 6-(4-N-formyl)piperidinyl-3-pyridazinyl; 6-moφholinyl-3-pyridazinyl; 4-N- l,4-dioxa-8-azaspiro[4.5Jdecan-8-ylbenzenesulfonamide; 4-(4-dioxa-8- azaspiro[4.5Jdecan-8-ylcarboxamide)phenyl; 6-(3-methoxy-l ,5-dioxa-9- azaspiro [5.5]undecan-9-yl)-3 -pyridazinyl ; 6-( 1 ,5 -dioxa-3 -hy droxymethy 1-9- azaspiro[5.5]undecan-9-yl)-3-pyridazinyl; 6-(S-O-ethyl-2-hydroxymethylpyrrolidinyl)-3- pyridazinyl; 6-(4-acetyl-l-oxa-4,8-diazaspiro[4.5]decan-8-yl)-3-pyridazinyl; 6-((2R,3R)- 2J-bis(methoxymethyl)-l,4-dioxa-8-azaspiro[4.5]decan-8-yl)-3-yridazinyl; 6-((2S,3S)- 2,3-dimethyl-l,4-dioxa-8-azaspiro[4.5]decan-8-yl)-3-pyridazinyl; 6-(4,4-(cis-l,2- dioxycyclopentane)piperidinyl)-3 -pyridazinyl; 6-(4,4-(lS,2S- dimethoxymethy lethanedi oxy )piperidiny l)-3 -pyridaziny 1 ; 6-(4,4-(cis-3 J-dioxy- oxacyclopentane)piperidinyl)-3-pyridazinyl; 6-(4,4-(l ,3-dioxy-2- methoxypropylene)piperidinyl)-3-pyridazinyl; 6-(4,4-( 1 ,3-dioxy-2- hydroxymethylpropylene)piperidinyl)-3-pyridazinyl; 6-(4,4-(2-(2,2-spiro- oxacyclopropane-l,3-dioxypropylene)piperidinyl)-3-pyridazinyl; 6-moφholinyl-3- pyridazinyl; 6-(4-moφholinyliminopiperidinyl)-3-pyridyl; 6-(4-(N- methylpiperazinyl)iminopiperidinyl)-3-pyridyl; 6-(4-(l,2,4-triazol-l-yl)iminopiperidinyl)- 3-pyridyl; 6-(4-ethylpiperidinylcarboxylate)-3-pyridyl; 2-phenylmethyl-3(2H)- pyridazinone-6-yl; 6-(4-(moφholinylcarboxamide)piperidinyl)-3 -pyridyl; 6-(4-(N- moφholiny laminocarboxamide)piperidinyl)-3 -pyridyl ; 6-(4-(N,N- dimethy laminocarboxamide)piperidinyl)-3 -pyridyl ; 6-(4-(N-methy 1-N- methoxyethy lcarboxamide)piperidinyl)-3 -pyridy 1 ; 6-(4-(N- methoxyethylcarboxamide)piperidinyl)-3-pyridyl; 6-(4-hydroxymethylpiperidinyl)-3- pyridyl; 6-(4-hydroxypiperidinyl)-3 -pyridyl; 6-(4-N-acetylpiperazinyl)-3-pyridyl; 6-(4- cyanopiperidinyl)-3-pyridyl; 6-(4-N-(4-fluorophenyl)piperazinyl)-3-pyridyl; 4- moφholinylbenzenesulfonamide; 4-N-4,4-ethylenedioxypiperidinylbenzenesulfonamide; 4-N-cyclopropylbenzenesulfonamide; 4-piperidinebenzenesulfonamide; 4-(4- cyanopiperidine)benzenesulfonamide; 4-N-cyclopropylmethylbenzenesulfonamide; 4- N,N-dimethylaminobenzenesulfonamide; 4-N-(S)-2- hydroxymethylpyrrolidinebenzenesulfonamide; 4-(4- hydroxypiperidine)benzenesulfonamide; 4-(cis-3,5- dimethylmoφholinyl)benzenesulfonamide; 3-fluoro-4-thiomoφholinylphenyl; 6- (thiomoφholinyl)-3-pyridyl; 6-(4,4-dioxothiomoφholinyl)-3-pyridyl; 4-(4,4- ethylenedioxypiperidinylcarboxamide)phenyl; 4-(N-cyclopropylcarboxamide)phenyl; 4- (moφholiny lcarboxamide)pheny 1 ; 6-N-cyclopropylamino-3 -pyridy 1 ; 4-(4- hydroxypiperidinylcarboxamide)phenyl; 6-(S)-hydroxymethylpyrrolidinyl-3-pyridazinyl; 6-(4-(2-ethoxyethoxy)piperidiny l)-3 -pyridyl ; 6-hexahydropyrimidine)-3 -pyridy 1 ; 6-(S)-2- ethoxyethoxypyrrolidinyl)-3-pyridyl; 6-(R)-2-ethoxyethoxypyrrolidinyl)-3-pyridyl; 6-(cis- 3, 4-dihydroxypyrolidinyl)-3 -pyridyl; 6-[(3aR,6aS)-tetrahydro-3aH-[l,3]dioxolo[4,5- cJpyrrol-2-one-5-yl]-3-pyridyl; 6-(cis-2,3-dihydroxypyrrolidinyl)-3-pyridazinyl; 6-(S,R-2- hydroxymethyl-4-hydroxypyrrolidinyl)-3-pyridyl; 6-(R-2-hydroxymethyl-4-pyrrolidinyl)- 3-pyridazinyl; 6-(lS,4S)-2-aza-5-oxa-bicyclo[2.2J]heptane)-3-pyridyl; 6-(2- imidizolidone-l-yl)-3 -pyridyl; 4-(2,4-(lH,3H)-quinazolinedion-3-yl)phenyl; 6- moφholinylcarboxamide-3 -pyridazinyl; 6-methoxy-3-pyridazinyl; 6-N,N- diethoxyethylamino-3-pyridazinyl; 6-(4-ethoxymethylpiperidinyl)-3-pyridazinyl; 6-(4-(4- tetrahydropyranylmethyl)piperidinyl)-3-pyridazinyl; _6-(4- ethoxyethoxymethylpiperidinyl)-3-pyridazinyl; 6-N-methyl-N-lJ- dioxalanemethy lamino)-3 -pyridazinyl ; 6-(4,4-dioxyethy lenecyclohexy loxy)-3 -pyridaziny 1 ; 6-dihydroxymethylmethoxy-3-pyridazinyl; 6-(3-pyridyloxy)-3 -pyridazinyl; 4,7-epoxy-7- methyl-2,3,3A,4,5,6,7,7a-octahydro-lH-isoindolyl; 6-(4-N-methyl-N-methoxyethyl)-3- pyridazinyl; 6-(3 ,4-dimethoxymethoxypyrrolidinyl)-3 -pyridazinyl ; 6-(trans-3 -hydroxy-4- methylpyrrolidinyl)-3-pyridazinyl; 6-(trans-3-hydroxy-4-methylpyrrolidinyl)-3-pyridyl; 6- (cis-3-hydroxy-4-methylpyrrolidinyl)-3-pyridazinyl; 6-(cis-3-hydroxy-4- methylpyrrolidinyl)-3-pyridyl; 6-(trans-3-cyano-4-hydroxylpyrrolidinyl)-3-pyridyl; 6-(3- hydroxy-4-tert-butylcarboxamidepyrrolidinyl)-3-pyridyl; 6-(S-2-(4- tetrahydropyranyloxy)methylpyrrolidinyl)-3-pyridazinyl; 6-(2-(4- tetrahydropyranyloxy)iminopyrrolidinyl)-3-pyridazinyl; 2-moφholinyl-5-thiazoyl; 5- bromo-2-thienyl; 2,5-dimethyl-3-thienyl; 5-chloro-2-thienyl; 2,4-dimethyl-5-thiazoyl; 5- methyl-2-thienyl; 2-furanyl; 2-(4,4-dioxyethylenepiperidinyl)-5-thiazoyl; 3-thienyl; 3- methyl-2-thienyl; 2-moφholinyl-4-thiazoyl; 2-moφholinyl-4-trifluoromethy-5-thiazoyl; 5-moφholinyl-2-thienyl; 4-methyl-2-moφholinyl-5-thiazoyl; 2,5-dichloro-3-thienyl; 2,5- dimethyl-3-furanyl; N-methyl-2-pyrrolyl; 2-N,N-dimethylamino-5-thiazoyl; 2- moφholinyl-5-thiazoyl; 2-(4,4-dioxythiomoφholinyl)-5-thiazoyl; 1 -N-methyl-2- moφholinyl-5-imidazoyl; 2-moφholinyl-5-oxazolyl; 2-N-methyl-N-methoxyethylamino- 5-thiazoyl; 2-N-methyl-N-ethylamino-5-thiazoyl; 2-N-pyrrolidinyl-5-thiazoyl; 2-N- methyl-N-propylamino-5-thiazoyl; 2-N,N-diethylamino-5-thiazoyl; 2-(N- methypiperazinyl)-5-thiazoyl; 2-(N-(2-pyridyl)piperazinyl)-5-thiazoyl; 2-N-methy-N-(2- pyridylethyl)-5-thiazoyl; 2-(4-oxopiperazinyl)-5-thiazoyl; 2-(4-(N- moφholinyl)iminopiperazinyl)-5-thiazoyl; 6-N-moφholine-3-pyridinesulfonamide; 2-(4- oxopiperidinyl)-5-pyrimidyl; 2-(4,4-dioxethylenepiperidinyl)-5-pyrimidyl; 5-(4,4- dioxethylenepiperidinyl)-2-pyriazinyl; 5-(4-oxopiperidinyl)-2-pyrazinyl; 6-N-cyclopropyl- 3-pyridinesulfonamide; 6-N-(4,4-dioxethylenepiperidinyl)-3-pyridinesulfonamide; 2-(4- (4-tetrahydropyrany loxy)iminopiperidinyl)-5 -pyraziny 1 ; 6-(4- (phenylmethoxy)iminopiperidinyl)-3-pyridyl; 6-(4-(tert-butyloxy)iminopiperidinyl)-3- pyridyl; 6-(4-(cyclohexyloxy)iminopiperidinyl)-3-pyridyl; 6-(4-hydroxyiminopiperidinyl)- 3 -pyridyl ; 6-(4-(4-tetrahydropyranyloxy)iminopiperidjnyl)-3 -pyridy 1 ; 6-(4- methoxyethoxyiminopiperidiny l)-3 -pyridy 1 ; 6-(4-(2-theny lmethoxy )iminopiperidiny l)-3 - pyridyl; 6-(4-(4,-(5'H-2-oxyfuranyl)-4-hydroxy)piperidinyl)-3-pyridyl; 6-(4-(l-(4- tetrahydropyranyloxy)iminoethyl))-4-hydroxypiperidinyl)-3-pyridazinyl; 6-(4-(4'-acetyl- 4'-hydroxypiperidinyl)-3-pyridazinyl; 6-(4-(l-(isopropylcaboxymethoxy)iminoethyl))-4- hydroxypiperidinyl)-3-pyridyl; 6-(4-( 1 -(ethylcaboxymethoxy)iminoethyl))-4- hydroxypiperidinyl)-3-pyridyl; 6-(4-( 1 -(methylcaboxymethoxy)iminoethyl))-4- hydroxypiperidinyl)-3-pyridyl; 6-(4-( 1 -(2-tetrahydropyranyloxy)iminoethyl))-4- hydroxypiperidinyl)-3-pyridyl; 6-(4-(l-(allyloxy)iminoethyl))-4-hydroxypiperidinyl)-3- pyridyl; 6-(4-(l -(ethoxy)iminoethyl))-4-hydroxypiperidinyl)-3 -pyridyl; 6-(4-( 1 - (methoxy)iminoethyl))-4-hydroxypiperidinyl)-3 -pyridyl ; 6-(4-( 1 -(hydroxy)iminoethy l))-4- hydroxypiperidinyl)-3-pyridyl; 6-(4-(2-tetrahydropyranyloxy)iminopiperidinyl)-3-pyridyl; 6-(4-(isopropylcarboxymethoxy)iminopiperidinyl)-3-pyridyl; 6-(4-hydroxy-4-( 1 -(4- tetrahydropyranyloxy)iminoethyl))-4-hydroxypiperidinyl)-3-yridyl; 6-(4-(3- butyrolactone)-4-hydroxypiperidinyl)-3-pyridyl; 6-(4-(2-butyrolactone)-4- hydroxypiperidinyl)-3-pyridazinyl; 6-(4-acetyl-4-hydroxypiperidinyl)-3 -pyridyl; 6-(3- hydroxyazetidinyl)-3-pyridyl; 6-(cis-3-hydroxytropanyl)-3-pyridyl; 6-(cis-2,3- dihydroxypiperidinyl)-3-pyridyl; 6-(N-methyl-N-(3-pyridylmethyl)amino)-3-pyridazinyl; 6-(l ,2J,6-tetrahydropyridyl)-3-pyridyl; 6-(4-(N-4'methoxyphenylcarbamoyl)piperidinyl)- 3-pyridazinyl; 6-(4-(2-butyrolactone)-4-hydroxypiperidinyl)-3-pyridyl: 6-(trans-3.4-bis(N- 4 ' -methoxypheny lcarbamoy l)pyrrolidiny l)-3 -pyridy 1 ; 6-(trans-3 -hydroxytropanyl)-3 - pyridyl; 6-(S,S-trans-3,4-dihydroxypyrrolidinyl)-3-pyridyl; 6-(R,R-trans-3,4- dihydroxypyrrolidinyl)-3-pyridazinyl; 6-(R,R-trans-3,4-dihydroxypyrrolidinyl)-3-pyridyl; 6-(8-(l-phenyl-lJ,8-triaza-2-spiro[4,5JdeceN-4-one)-3-pyridyl; 6J8-(l-phenyl-1.3,8- triaza-2-spiro[4,5]deceN-4-one)-3-pyridyl; 6-(4-(2-keto- 1 -benzimidazolinyl)piperidinyl)- 3-pyridazinyl; 6-(4-oxothiomoφholinyl)-3-pyridyl; 6-(4-(2-keto-l - benzimidazolinyl)piperidinyl)-3-pyridyl; 6-(N-methyl-N-(2-pyridylethyl)amino)-3- pyridyl; 6-(N-methyl-N-(4-pyridylethyl)amino)-3-pyridyl; 6-N-(3-pyridylmethyl)amino-3- pyridyl; 6-(2-hydroxymethylpiperidinyl)-3-pyridyl; 6-(4-hydroxy-4-(4- bromophenyl)piperidinyl)-3-pyridyl; 6-(4-N-(2-pyridnyl)piperazinyl)-3-pyridyl: 6-(4-N- (2-hydroxyethyloxyethyl)piperazinyl)-3 -pyridyl; 6-(4.4-diacetoxyethylthio)piperidinyl)-3- pyridyl; 6-(N-methy-N-(3-pyridylmethyl)amino)-3-pyridyl; 6-(4-pyrrolidinylpiperidinyl)- 3 -pyridyl ; 6-(4-N-cyanomethy lpiperaziny l)-3 -pyridyl ; 6-(3 -hydroxypyrroldiny l)-3 -pyridyl; 6-(4-methylpiperidinyl)-3-pyridyl; 6-(cis-3,5-dimethylmoφholinyl)-3-pyridyl; 6-(4,4- difluoropipridinyl)-3 -pyridyl; 6-(4,4-dioxythiomoφholinyl)-3-pyridazinyl; 6- thiazolidinyl-3-pyridyl; 6-(lJ-dioxythiazolidinyl)-3 -pyridyl; 6-thiomoφholinyl-3- pyridazinyl; 6-(2,5-dihydropyrrolyl)-3-pyridyl; 6-hydroxy-3-pyridazinyl; 6-piperidinyl-3- pyridyl; and 6-(4-tetrahydropyranyloxy)iminopyrrolidinyl-3-pyridyl; 6-moφholinyl-3- pyridyl.
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 -methy lenedioxyphenyl; 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 -bromopheny l)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- 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 -dimethy Ipheny 1; 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; (5-chloro-2-(3-methoxyphenyl)phenyl)methyl; 3-bromophenyl; 2-pyridyl; 2- ethoxyphenyl; 5-ethoxyphenyl; 2,5-dichlorophenyl; 2,5-dimethylphenyl; 3-fluorophenyl; 3-trifluoromethylphenyl; 5-trifluoromethylphenyl; 3,5-diclorophenyl; 4-bromo-2-thienyl; 3-bromo-2-thienyl; 3-cyanophenyl; 4-tetrahydropyranyl; 3-indolyl; 5-indolyl; 4-quinolyl; 2-bromophenyl; 4-fluorophenyl; 4,4-difluorocyclohexyl; 1J -dimethy 1-3 -butenyl; 2,3- dichlorophenyl; isopropyl; and 2-trifluorophenylphenyl.
14. A compound according to claim 10 selected from the group consisting of:
4-(N-(2,3-dihydroxypropyl)amino)-5-(3-bromophenyl)-7-(6-moφholinyl-3- pyridinyl)pyrido[2,3-d]pyrimidine;
4-(N-(3-moφholinylpropyl)amino)-5-(3-bromophenyl)-7-(6-moφholinyl-3- pyridiny l)pyrido [2,3-djpyrimidine;
4-(N-(2-(4-imidazolyl)ethyl)amino)-5-(3-bromophenyl)-7-(6-moφholinyl-3- pyridinyl)pyrido[2,3-d]pyrimidine;
4-(N-(3-carboxypropyl)amino)-5-(3-bromophenyl)-7-(6-moφholinyl-3- pyridinyl)pyrido[2J-d]pyrimidine; (S)-4-amino-5-(3-bromophenyl)-7-(6-(O-methyl-2-hydroxymethylpyrrolidinyl)-3- pyridinyl)pyrido[2,3-d]pyrimidine;
(S)-4-amino-5-(3-bromophenyl)-7-(6-(2-hydroxymethylpyrrolidinyl)-3- pyridinyl)pyrido[2J-d]pyrimidine;
4-amino-5-(2-bromophenyl)-7-(6-(4-hydroxypiperidinyl)-3-pyridinyl)pyrido[2,3- djpyrimidine;
4-amino-5-(4-fluorophenyl)-7-(6-(4,4-ethylenedioxypiperidinyl)-3- pyridinyl)pyrido[2J-djpyrimidine;
4-amino-5-(2-bromophenyl)-7-(6-(4-hydroxypiperidinyl)-3-pyridazyl)pyrido[2J- djpyrimidine; 4-amino-5-(3-bromophenyl)-7-(6-(4.4-ethylenedioxypiperidinyl)-3- pyridazyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(2-moφholinyl-4-thiazolyl)pyrido[2,3- djpyrimidine; 4-amino-5-(N-methy 1-3 -indoly l)-7-(6-moφholiny 1-3 -pyridiny l)pyrido [2,3- djpyrimidine;
4-amino-5-(3-bromophenyl)-7-(6-(4-ethoxyiminopiperidinyl)-3- pyridinyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(6-(4-ethoxycarbonylmethoxyiminopiperidinyl)-3- pyridinyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(4-dimethylaminophenyl)-7-(4-bromophenyl)pyrido[2J-d]pyrimidine; 4-amino-5-(4-dimethylaminophenyl)-7-(4-dimethylaminophenyl)pyrido[2,3- djpyrimidine;
4-amino-5-(4-methoxyphenyl)-7-(4-dimethylaminophenyl)pyrido[2,3- djpyrimidine;
4-amino-5-(4-dimethylaminophenyl)-7-(4-methoxyphenyl)pyrido[2,3- djpyrimidine;
4-amino-5-(4-(2-propyl)phenyl)-7-(4-methoxyphenyl)pyrido[2J-d]pyrimidine; 4-amino-5-(4-neopentylphenyl)-7-(4-methoxyphenyl)pyrido[2J-djpyrimidine; 4-amino-5-(4-butyloxyphenyl)-7-(4-methoxyphenyl)pyrido[2J-d]pyrimidine;
4-amino-5-(4-methoxyphenyl)-7-(4-bromophenyl)pyrido[2.3-djpyrimidine; 4-amino-5-(4-(2-propyl)oxyphenyl)-7-(4-methoxyphenyl)pyrido[2J-d]pyrimidine; 4-amino-5-(4-butoxyphenyl)-7-(4-N-formylpiperazinylphenyl)pyrido[2,3- djpyrimidine; 4-amino-5-(4-benzyloxyphenyl)-7-(4-methoxyphenyl)pyrido[2J-d]pyrimidine;
4-amino-5-(4-phenoxyphenyl)-7-(4-methoxyphenyl)pyrido[2J-djpyrimidine; 4-amino-5-(4-(2-propyl)phenyl)-7-(4-diethylmalonylallylphenyl)pyrido[2J- djpyrimidine;
4-amino-5-(4-(2-propyl)phenyl)-7-(4-t-butylacylphenyl)pyrido[2J-d]pyrimidine; 4-amino-5-(3-bromophenyl)-7-(4-dimethylaminophenyl)pyrido[2,3-d]pyrimidine; 4-amino-5-(3,4-dimethoxyphenyl)-7-(4-dimethylaminophenyl)pyrido[2J- djpyrimidine;
4-amino-5-(3-t-butylacrylphenyl)-7-(4-dimethylaminophenyl)pyrido[2,3- djpyrimidine; 4-amino-5-(3-methoxyphenyl-7-(4-dimethylaminophenyl)pyrido[2J-d]pyrimidine;
4-amino-5-(3,5-dimethoxyphenyl-7-(4-dimethylaminophenyl)pyrido[2,3- djpyrimidine;
4-amino-5-(3-diethylmalonylallylphenyl)-7-(4-dimethylaminophenyl)pyrido[2,3- djpyrimidine; 4-amino-5-(3-vinylpyridinylphenyl)-7-(4-dimethylaminophenyl)pyrido[2,3- djpyrimidine;
4-amino-5-(3-trifluoromethylphenyl)-7-(4-dimethylaminophenyl)pyrido[2,3- djpyrimidine;
4-amino-5-(3-carboxamidophenyl)-7-(4-dimethylaminophenyl)pyrido[2,3- djpyrimidine;
4-amino-5-(3-cyanophenyl)-7-(4-dimethylaminophenyl)pyrido[2,3-d]pyrimidine; 4-amino-5-(3-benzyloxyphenyl)-7-(4-dimethylaminophenyl)pyrido[2,3- djpyrimidine;
4-amino-5-(3-methoxyphenyl)-7-(4-methoxyphenyl)pyrido[2J-d]pyrimidine; 4-amino-5-(3-bromophenyl)-7-(4-butoxyphenyl)pyrido[2J-d]pyrimidine;
4-amino-5 -(3 -(2-pyridyl)pheny l)-7-(4-dimethylaminopheny l)pyrido [2,3- djpyrimidine;
4-amino-5-(3-methylphenyl)-7-(4-dimethylaminophenyl)pyrido[2,3-d]pyrimidine; 4-amino-5-(3-chlorophenyl)-7-(4-dimethylaminophenyl)pyrido[2J-d]pyrimidine; 4-amino-5-(3-fluorophenyl)-7-(4-dimethylaminophenyl)pyrido[2,3-d]pyrimidine;
4-amino-5 -(3 -bromophenyl)-7-(4-methoxypheny l)pyrido [2,3-djpyrimidine; 4-amino-5-(3-methoxyphenyl)-7-(4-bromophenyl)pyrido[2J-d]pyrimidine; 4-amino-5-(3-bromophenyl)-7-phenylpyrido [2,3-djpyrimidine; 4-amino-5 -(3 -bromopheny l)-7-(4-ethylphenyl)pyri do [2,3-djpyrimidine; 4-amino-5-(3-bromophenyl)-7-(4-bromophenyl)pyrido[2J-d]pyrimidine; 4-amino-5-(3-bromophenyl)-7-(4-cyanophenyl)pyrido[2.3-dJpyrimidine;
4-amino-5-(3-bromophenyl)-7-(4-hydroxyphenyl)pyrido[2J-d]pyrimidine;
4-amino-5-(3-iodophenyl)-7-(4-dimethylaminophenyl)pyrido[2J-d]pyrimidine;
4-amino-5-(3-ethoxyphenyl)-7-(4-dimethylaminophenyl)pyrido[2J-d]pyrimidine; 4-amino-5-(3-trifloromethyoxyphenyl)-7-(4-dimethylaminophenyl)pyrido[2,3- djpyrimidine;
4-amino-5-(3,5-dichlorophenyl)-7-(4-dimethylaminophenyl)pyrido[2J- djpyrimidine;
4-amino-5-(3-bromo-4-fluorophenyl)-7-(4-dimethylaminophenyl)pyrido[2,3- djpyrimidine;
4-amino-5-(3-hydroxyphenyl)-7-(4-dimethylaminophenyl)pyrido[2J-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(4-moφholinylphenyl)pyrido[2J-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(4-piperidinylphenyl)pyrido[2J-d]pyrimidine;
4-amino-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-djpyrimidine;
4-amino-5-(3-bromophenyl)-7-(4-isopropylphenyl)pyrido[2J-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(4-trifluorophenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(4-diethylaminophenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(3,4,5-trimethoxyphenyl)pyrido[2,3-dJpyrimidine; 4-amino-5-(3-(3-methoxybenzyl)phenyl)-7-(4-dimethylaminophenyl)pyrido[2J- djpyrimidine;
4-amino-5-(3-methoxyethyoxyphenyl)-7-(4-dimethylaminophenyl)pyrido[2,3- djpyrimidine;
4-amino-5-(3,4-methylenedioxyphenyl)-7-(4-dimethylaminophenyl)pyrido[2,3- djpyrimidine;
4-amino-5-(3-bromophenyl)-7-(4-ethoxyphenyl)pyrido[2J-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(2'-thiophene)pyrido[2J-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(4-fluorophenyl)pyrido[2J-d]pyrimidine;
4-amino-5-(3-dimethylaminophenyl)-7-(4-dimethylaminophenyl)pyrido[2,3- djpyrimidine; 4-amino-5-phenyl-7-(4-dimethylaminophenyl)pyrido[2.3-d]pyrimidine; 4-amino-5-(3,4,5-trimethoxyphenyl)-7-(4-dimethylaminophenyl)pyrido[2J djpyrimidine;
4-amino-5-(3-bromophenyl)-7-(4-nitrophenyl)pyrido[2J-d]pyrimidine; 4-amino-5-(3-bromophenyl)-7-(4-iodophenyl)pyrido[2J-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(3,4-methylenedioxyphenyl)pyrido[2,3- djpyrimidine;
4-amino-5- thiophen-2-yl)-7-(4-moφholinylphenyl)pyrido [2,3-djpyrimidine;
4-amino-5- 3,5-dimethoxyphenyl)-7-(thiophen-2-yle)pyrido [2,3-djpyrimidine; 4-amino-5-ι 3-bromophenyl)-7-(4-carboxamidophenyl)pyrido[2,3-d]pyrimidine;
4-amino-5- 3 -bromophenyl)-7-(4-(2-methoxy)ethoxypheny l)pyrido [2,3 - djpyrimidine;
4-amino-5- 3 ,5 -dimethoxyphenyl)-7-(4-moφholiny Ipheny l)pyrido [2,3 - djpyrimidine; 4-amino-5-ι 3-trifluoromethylphenyl)-7-(thiophene-2-yl)pyrido [2,3-djpyrimidine;
4-amino-5- 3-bromophenyl)-7-(4-aminophenyl)pyrido[2J-d]pyrimidine; 4-amino-5- 3-bromo-4-fluorophenyl)-7-(thiophene-2-yl)pyrido [2,3-djpyrimidine; 4-amino-5-ι 3 -bromo-4-fluorophenyl)-7-(2-furany l)pyrido [2,3-djpyrimidine; 4-amino-5-ι 3,5-dimethoxyphenyl)-7-(4-iodophenyl)pyrido[2,3-d]pyrimidine; 4-amino-5' 3,5-dimethoxyphenyl)-7-(4-imidazolylphenyl)pyrido[2J-d]pyrimidine;
4-amino-5 3,5-dimethoxyphenyl)-7-(4-(thiophene-2-yl)phenyl)pyrido[2,3- djpyrimidine;
4-amino-5 3,5-dimethoxyphenyl)-7-(4-(3-pyridyl)phenyl)pyrido[2J-d]pyrimidine; 4-amino-5 3-bromophenyl)-7-(4-(4-methylpiperidinyl)phenyl)pyrido[2,3- djpyrimidine;
4-amino-5 3-bromophenyl)-7-(4-pyrrolidinylphenyl)pyrido[2,3-dJpyrimidine; 4-amino-5 4-bromothiophene-)-7-(4-dimethy laminophenyl)pyrido [2,3 - djpyrimidine;
4-amino-5-(4-bromothiophene-2-yl)-7-(4-moφholinylphenyl)pyrido[2,3 djpyrimidine; 4-moφholinyl-5-(3-bromophenyl)-7-(4-dimethylaminophenyl)pyrido[2,3- djpyrimidine;
4-amino-5-(5-bromothiophene-2-yl)-7-(4-moφholinylphenyl)pyrido[2,3- djpyrimidine; 4-amino-5-(4-bromophenyl)-7-(4-dimethylaminophenyl)pyrido[2J-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(4-(acetylamino)phenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(4-dimethylaminophenyl)pyrido[2J-d]pyrimidine;
4-amino-5-(3,5-dimethoxyphenyl)-7-(5-pyrimidinylphenyl)pyrido[2,3- djpyrimidine; 4-(4-fluorophenyl)amino)-5-(3-bromophenyl)-7-(4- dimethylaminophenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(4-bromothiophene-2-yl)-7-(4-pyrrolidinylphenyl)pyrido[2,3- djpyrimidine;
4-amino-5-(4-bromothiophene-2-yl)-7-(thiophene-2-yl)pyrido[2,3-d]pyrimidine; 4-amino-5-(3-bromophenyl)-7-(5-(dimethylamino)thiophene-2-yl)pyrido[2,3- djpyrimidine;
4-amino-5-(3-bromo-5-iodophenyl)-7-(4-(dimethylamino)phenyl)pyrido[2,3- djpyrimidine;
4-amino-5-(3,5-di(trifluoromethyl)phenyl)-7-(4-(dimethylamino)phenyl)pyrido[2J- djpyrimidine;
4-amino-5-(3,5-di(trifluoromethyl)phenyl)-7-(4-moφholinylphenyl)pyrido[2J- djpyrimidine;
4-amino-5-(3,5-dibromophenyl)-7-(4-(dimethylamino)phenyl)pyrido[2J- djpyrimidine; 4-amino-5-(3,5-dibromophenyl)-7-(4-moφholinylphenyl)pyrido[2J-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-(4-(dimethylamino)phenyl)pyrido[2J- djpyrimidine; 4-amino-5-(3-bromophenyl)-7-(3-(dimethylamino)phenyl)pyrido[2J-d]pyrimidine; 4-amino-5-(3-bromophenyl)-7-(4-methylsulfonylphenyl)pyrido[2J-dJpyrimidine; 4-amino-5 -(3 -bromopheny l)-7-(3 -methoxypheny l)pyri do [2,3-djpyrimidine; 4-amino-5-(3-bromophenyl)-7-(4-(methylthio)phenyl)pyrido[2J-d]pyrimidine; 4-amino-5-(3-bromophenyl)-7-(3,4-dichlorophenyl)pyrido[2J-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-methylaminophenyl)pyrido[2,3-d]pyrimidine; 4-amino-5-(3-bromo-4-fluorophenyl)-7-(4-methylsulfonylphenyl)pyrido[2,3- djpyrimidine; 4---mino-5-(3-bromophenyl)-7-(3-amino-4-methoxyphenyl)pyrido[2J- djpyrimidine;
4-amino-5-(3-bromophenyl)-7-(3-bromo-4-(dimethylamino)phenyl)pyrido[2,3- djpyrimidine;
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- trifluoroacetylamino)phenyl)pyrido[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- djpyrimidine;
4,4-bis(acetylamino)-5-(3-bromophenyl)-7-(4-(N-methyl-N- acetylamino)phenyl)pyrido[2J-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(4-(N-acetyl-N-methylamino)phenyl)pyrido[2,3- djpyrimidine;
4-amino-5-(3-bromophenyl)-7-(4-(N-ethylamino)phenyl)pyrido[2J-d]pyrimidine; 4-amino-5-(3-bromophenyl)-7-(4-(N-methyl-N-(2- methoxyethyl)amino)phenyl)pyrido[2,3-dJpyrimidine;
4-amino-5-(3-bromophenyl)-7-(4-(N-isopropylamino)phenyl)pyrido[2J- djpyrimidine; 4-amino-5-(3-bromophenyl)-7-(4-N-ethyl-N-(2- methoxyethyl)amino)phenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(4-N-(3-methoxypropionyl)-N-isopropyl- amino)phenyl)pyrido[2J-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)ethyl)amino)phenyl)pyrido[2,3-dJpyrimidine;
4-amino-5-(3-bromophenyl)-7-(4-(N-methyl-N-(2- cyano)ethylamino)phenyl)pyrido[2J-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(4-(N-methyl-N-(3- methoxy)propionylamino)phenyl)pyrido[2,3-djpyrimidine;
4-amino-5-(3-bromophenyl)-7-(3-methyl-4-(N-formyl-N- methylamino)phenyl)pyrido[2,3-djpyrimidine; 4-amino-5-(3-bromophenyl)-7-(3-methyl-4-(N-methylamino)phenyl)pyrido[2,3- djpyrimidine;
4-amino-5-(3-bromophenyl)-7-(4-(4-methoxy-2-butyl)phenyl)pyrido[2,3- djpyrimidine;
4-amino-5 -(3 -bromophenyl)-7-(4-(N-methyl-N-(2-(N- phthalimidyl)acetyl)amino)phenyl)pyrido[2,3-dJpyrimidine;
4-amino-5-(3-bromophenyl)-7-(3-methyl-4-(N-methyl-N- (trifluoroacetyl)amino)phenyl)pyrido[2J-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(3-methyl-4-(N-acetyl-N- methylamino)phenyl)pyrido[2,3-dJpyrimidine; 4-amino-5-(3-bromophenyl)-7-(6-dimethylamino-3-pyridinyl)pyrido[2,3- djpyrimidine;
4-amino-5-(3-cyanophenyl)-7-(4-methylsulfonylphenyl)pyrido[2J-djpyrimidine;
4-amino-5-(3-cyanophenyl)-7-(4-(N-methyl-N-formylamino)-phenyl)pyrido[2,3- djpyrimidine; 4-amino-5-(3-bromophenyl)-7-(6-(N-methyl-N-formylamino)-3- pyridinyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(6-moφholinyl-3-pyridinyl)pyrido[2,3- djpyrimidine; 4-amino-5 -(3 -bromopheny l)-7-(6-(N-methy 1-N-methoxyethy lamino)-3 - pyridinyl)pyrido[2,3-dJpyrimidine;
4-amino-5-(3-bromophenyl)-7-(6-pyπOlidinyl-3-pyridinyl)pyrido[2J-d]pyrimidine; 4-amino-5-(3-bromophenyl)-7-(2-(dimethylamino)-5-pyrimidinyl)pyrido[2,3- djpyrimidine; 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- pyrimidiny l)pyrido [2 ,3 -djpyrimidine ;
4-amino-5-(3-bromophenyl)-7-(2-(N-methylamino)5-pyrimidinyl)pyrido[2,3- djpyrimidine;
4-amino-5-(3-bromophenyl)-7-(2-(l-pyrrolidinyl)-5-pyrimidinyl)pyrido[2,3- djpyrimidine;
4-amino-5-(3-bromophenyl)-7-(2-(l-moφholinyl)-5-pyrimidinyl)pyrido[2,3- djpyrimidine; 4-amino-5-(3-bromophenyl)-7-(6-(2-oxo-3-oxazolidinyl)-3-pyridinyl)pyrido[2J- djpyrimidine;
4-amino-5-(3-bromophenyl)-7-(2-pyridyl)pyrido[2, 3-djpyrimidine; 4-amino-5-(3-bromophenyl)-7-(3-pyridyl)pyrido[2J-d]pyrimidine; 4-amino-5-(3-(thiophen-2-yl)phenyl)-7-(4-dimethylaminophenyl)pyrido[2,3- djpyrimidine;
4-amino-5-(3-(furan-2-yl)phenyl)-7-(4-dimethylaminophenyl)pyrido[2,3- djpyrimidine;
4-amino-5-(3-(3-methoxyphenyl)phenyl)-7-(4-dimethylaminophenyl)pyrido[2,3- djpyrimidine; 4-amino-5-phenyl-7-(4-dimethylaminophenyl)pyrido[2J-d]pyrimidine; 4-amino-5-(3-chlorophenyl)-7-(4-(moφholinyl)phenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromo-4-fluorophenyl)-7-(4-(mpφholinyl)phenyl)pyrido[2,3- djpyrimidine;
4-amino-5-(3-chlorophenyl)-7-(4-iodophenyl)pyrido[2J-d]pyrimidine; 4-amino-5-(3-chlorophenyl)-7-(4-(thiophen-2-yl)phenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-chlorophenyl)-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- djpyrimidine;
4-amino-5-(2-phenylethyl)-7-(4-diethylaminophenyl)pyrido[2.3 -djpyrimidine;
4-amino-5-(2-methylpropyl)-7-(4-diethylaminophenyl)pyrido[2J-d]pyrimidine;
4-amino-5-(butyl)-7-(4-diethylaminophenyl)pyrido[2,3-djpyrimidine;
4-amino-5-(2-(4-bromophenyl)ethyl)-7-(4-diethylaminophenyl)pyrido[2,3- djpyrimidine;
4-amino-5-(butyl)-7-(4-dimethylaminophenyl)pyrido[2J-d]pyrimidine;
4-amino-5-(2-(3-cyanophenyl)methyl)-7-(4-dimethylaminophenyl)pyrido[2,3- djpyrimidine;
4-amino-5-(2-(N-phenylmethoxycarbonyl)aminoethyl)-7-(4- dimethylaminophenyl)pyrido[2J-d]pyrimidine;
4-amino-5-(cycloheptyl)-7-(4-dimethylaminophenyl)pyrido[2J-d]pyrimidine;
4-amino-5-(2-(5-chloro-2-(thiophen-3-yl)phenylmethyl)-7-(4- dimethylaminophenyl)pyrido[2.3-d]pyrimidine;
4-amino-5-(pentyl)-7-(4-diethylaminophenyl)pyrido[2,3-dJpyrimidine; 4-amino-5-hexyl-7-(4-diethylaminophenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(2-(3-bromophenyl)ethyl)-7-(4-diethylaminophenyl)pyrido[2J- djpyrimidine;
4-amino-5-((2-bromophenyl)methyl)-7-(4-diethylaminophenyl)pyrido[2,3- djpyrimidine; 4-amino-5-cyclopropyl-7-(4-dimethylaminophenyl)pyrido[2J-djpyrimidine; 4-amino-5-cyclohexyl-7-(4-dimethylaminophenyl)pyrido[2.3-d]pyrimidine; 4-amino-5-((2-bromo-5-chlorophenyl)methyl):7-(4-diethylaminophenyl)pyrido[2J- djpyrimidine;
4-amino-5-methyl-7-(4-diethylaminophenyl)pyrido[2J-d]pyrimidine; 4-amino-5-(2J-methylenedioxyphenyl)-7-(4-dimethylaminophenyl)pyrido[2,3- djpyrimidine;
4-amino-5-(3-fluoro-5-trifluoromethylphenyl)-7-(4- dimethylaminophenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(2-bromophenyl)-7-(4-dimethylaminophenyl)pyrido[2,3-djpyrimidine; 4-amino-5-(3,5-dimethylphenyl)-7-(4-dimethylaminophenyl)pyrido[2,3- djpyrimidine;
4-amino-5-(3,4-dichlorophenyl)-7-(4-dimethylaminophenyl)pyrido[2,3- djpyrimidine;
4-amino-5-(4-fluoro-3-trifluoromethylphenyl)-7-(4- dimethylaminophenyl)pyrido[2,3-dJpyrimidine;
4-amino-5-(3-bromo-5-methoxyphenyl)-7-(4-moφholinylphenyl)pyrido[2,3- djpyrimidine;
4-amino-5-(3-bromo-5-methoxyphenyl)-7-(4-pyrrolidinylphenyl)pyrido[2,3- djpyrimidine; 4-amino-5-(3-bromo-5-methoxyphenyl)-7-(4-piperidinylphenyl)pyrido[2J- djpyrimidine;
4-amino-5-(3 -bromo-5 -methoxyphenyl)-7-(4-dimethylaminopheny l)pyrido [2,3- djpyrimidine;
4-amino-5 -(3 -methy lthiopheny l)-7-(4-dimethylaminophenyl)pyrido [2,3 - djpyrimidine;
4-amino-5-(3-bromo-5-methoxyphenyl)-7-(thiophene-2-yl)pyrido[2J-d]pyrimidine; 4-amino-5-(2J-dimethoxyphenyl)-7-(4-dimethylaminophenyl)pyrido[2J- djpyrimidine;
4-amino-5-(3-methylsulfonylphenyl)-7-(4-dimethylaminophenyl)pyrido[2J- djpyrimidine; 4-acetylamino-5-(3-bromophenyl)-7-(4-dimethylaminophenyl)pyrido[2,3- djpyrimidine;
4-formylamino-5-(3-bromophenyl)-7-(4-dimethylaminophenyl)pyrido[2,3- djpyrimidine; 4-(methoxyacetyl)amino-5-(3-bromophenyl)-7-(4-diethylaminophenyl)pyrido[2,3- djpyrimidine;
4-trifluoroacetylamino-5-(3-bromophenyl)-7-(4-dimethylaminophenyl)pyrido[2J- djpyrimidine;
4-pentanoylamino-5-(3-bromophenyl)-7-(4-dimethylaminophenyl)pyrido[2,3- djpyrimidine;
4-benzoylamino-5-(3-bromophenyl)-7-(4-dimethylaminophenyl)pyrido[2,3- djpyrimidine;
4-(N-BOC-glycyl)amino-5-(3-bromophenyl)-7-(4- dimethylaminophenyl)pyrido[2J-dJpyrirnidine; 4-(N-phthalimidylglycyl)amino-5-(3-bromophenyl)-7-(4- dimethylaminophenyl)pyrido[2J-dJpyrimidine;
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-(N,N-dimethylamino)ethylamino)-5-(4-bromophenyl)-7-(4- dimethylaminophenyl) pyrido[2J-d]pyrimidine; 4-(4-(N,N-dimethylamino)butylamino)-5-(3-bromophenyl)-7-(4- dimethylaminophenyl) pyrido[2J-d]pyrimidine;
4-(N-allyl-N-formylamino)-5-(4-dimethylaminophenyl)-7-(4- bromophenyl)pyrido[2J-d]pyrimidine;
4-diacetylamino-5-(p-dimethylaminophenyl)-7-(4- bromophenyl)pyrido[2J-d]pyrimidine; 4-amino-5-(3-bromophenyl)-7-(5-amino-2-pyridyl)pyrido[2.3-d]pyrimidine; 4-amino-5-(3-bromophenyl)-7-(5-dimethylamino-2- pyridyl)pyrido[2,3-dJpyrimidine;
4-amino-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-djpyrimidine;
4-amino-5-((5-chloro-2-(3-methoxyphenyl)phenyl)methyl)-7-(4- dimethylaminophenyl)pyrido[2,3-djpyrimidine;
4-amino-5-((thiophene-2-yl)methyl)-7-(4-diethylaminophenyl)pyrido[2,3- djpyrimidine;
4-amino-5-((thiophene-3-yl)methyl)-7-(4-diethylaminophenyl)pyrido[2,3- djpyrimidine; 4-amino-5-((2-bromophenyl)methyl)-7-(4-dimethylaminophenyl)pyrido[2,3- djpyrimidine;
4-amino-5-(3-bromophenyl)-7-(4-(N-formyl-N-(2- methoxyethyl)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- dimethylamino)ethyl)amino)phenyl)pyrido[2J-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(4-(2- methoxy)acetylamino)ethyl)amino)phenyl)pyrido[2,3-d]pyrimidine; 4-amino-5-(3-bromophenyl)-7-((4-formylamino)phenyl)pyrido[2J-djpyrimidine;
4-amino-5-(3-bromophenyl)-7-(4-(2- (dimethylamino)acetylamino)phenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(4-(2-oxo-3-oxazolidinyl)phenyl)pyrido[2.3- djpyrimidine; 4-amino-5-(3-bromophenyl)-7-(6-(2-propyl)-3-pyridinyl)pyrido[2J-dJpyrimidine; 4-amino-5-(3-bromophenyl)-7-(3-methyl-4-pyrrolidinylphenyl)pyrido[2.3- djpyrimidine;
4-amino-5-(3-bromophenyl)-7-(6-imidazolyl-3-pyridinyl)pyrido[2.3-d]pyrimidine; 4-amino-5-phenylmethyl-7-(4-diethylaminophenyl)pyrido[2J-d]pyrimidine; 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- djpyrimidine;
4-amino-5-(4-dimethylaminophenyl)-7-(4-bromophenyl)pyrido[2J-dJpyrimidine; 4-amino-5-(2-furanyl)-7-(4-(N-moφholinyl)phenyl)pyrido[2J-dJpyrimidine;
4-amino-5-(3-bromophenyl)-7-(2-dimethylamino-5-pyrimidinyl)pyrido[2,3- djpyrimidine;
4-amino-5-(3-bromophenyl)-7-(4-(ureido)phenyl)pyrido[2J-d]pyrimidine; 4-amino-5-(l-phenylmethyl-3-piperidinyl)-7-(4- diethylaminophenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(6-(3-methyl-5-isoxazolyl))-3- pyridinyl)pyrido[2J-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(6-chloro-3-pyridinyl)pyrido[2J-d]pyrimidine; 4-amino-5 -(3 -bromopheny l)-7-(6-methoxy-3 -pyridiny l)pyri do [2,3 - djpyrimidine;
4-amino-5-(3-bromophenyl)-7-(6-(l,2,4-triazol-4-yl)-3-pyridinyl)pyrido[2,3- djpyrimidine;
4-amino-5-(3-bromophenyl)-7-(2-moφholinyl-5-pyrimidinyl)pyrido[2J- djpyrimidine; 4-amino-5-(2-thiazolyl)-7-(4-pyrrolidinylphenyl)-pyrido[2.3-djpyrimidine;
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- djpyrimidine; 4-amino-5-(3-bromophenyl)-7-(4-(N-methyl-N-(2-pyrimidinyl)amino)phenyl)- pyrido[2J-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(3-fluoro-4-(N-formyl-N-methylamino)phenyl)- pyrido[2J-djpyrimidine; 4-formylamino-5-(3-bromophenyl)-7-(3-fluoro-4-(N-formyl-N- methylamino)phenyl)-pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(4-(N-methyl-N-methylsulfonylamino)- phenyl)pyrido[2,3-dJpyrimidine;
4-amino-5-(3-bromophenyl)-7-(6-(N-methyl-N-methylsulfonylamino)-3- pyridinyl)pyrido[2,3-dJpyrimidine;
4-amino-5-(3-bromophenyl)-7-(l-methyl-5-indolinyl)pyrido[2J-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(l-methyl-5-benzimidazolyl)pyrido[2J- djpyrimidine;
4-amino-5-(3 -bromophenyl)-7-(6-dimethylamino-3 -pyridazinyl)pyrido [2,3 - djpyrimidine;
4-amino-5-(3bromophenyl)-7-(6-moφholinyl-3-pyridazinyl)pyrido[2,3- djpyrimidine;
4-amino-5-(3-bromophenyl)-7-(6-pyrrolidinyl-3-pyridazinyl)pyrido[2,3- djpyrimidine; 4-amino-5-(3-bromophenyl)-7-(5-moφholinyl-2-pyrazinyl)pyrido[2,3- djpyrimidine;
4-amino-5-(3-bromophenyl)-7-(5-(N-(2-methoxyethyl)-N-methylamino)-2- pyrazinyl)pyrido[2J-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(4-(moφholinylmethyl)-phenyl)pyrido[2,3- djpyrimidine;
4-amino-5-(3-bromophenyl)-7-(5-(N,N-bis(2-methoxyethyl)amino)-2- pyridinyl)pyrido[2J-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(4-(imidazolylmethyl)-phenyl)pyrido[2,3- djpyrimidine; 4-amino-5-(3-bromophenyl)-7-(5-(l-moφholinyl)-2-pyridinyl)pyrido[2J- djpyrimidine;
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- pyridiny l)pyrido [2 ,3 -d] pyrimidine ;
4-amino-5-(3-bromophenyl)-7-(5-(N-formyl-N-methylamino)-2- pyridinyl)pyrido [2,3-djpyrimidine;
4-amino-5-(3-bromophenyl)-7-(5-(2-propenyl)-2-pyridinyl)pyrido[2,3- djpyrimidine;
4-amino-5-(3-bromophenyl)-7-(3-(2-methoxyethyl)-2-oxo-6- benzoxazolyl)pyrido[2J-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(4-(l-(N-formylamino)-ethyl)phenyl)pyrido[2,3- djpyrimidine; 4-(methylamino)-5-(3-bromophenyl)-7-(4-dimethylaminophenyl)pyrido[2,3- djpyrimidine hydrochloride;
4-(2-methoxyethylamino)-5-(3-bromophenyl)-7-(4- dimethylaminophenyl)pyrido[2,3-d]pyrimidine hydrochloride;
4-amino-5-(3-bromophenyl)-7-(4-(l-methyl-2-imidazolyl)phenyl)pyrido[2,3- djpyrimidine trihydrochloride;
4-amino-5-(3-bromophenyl)-7-(4-(aminomethyl)phenyl)pyrido[2,3-dJpyrimidine; 4-amino-5-(3-bromophenyl)-7-(2-bromo-4-(dimethylamino)phenyl)pyrido[2,3- djpyrimidine;
4-amino-5-(3-bromophenyl)-7-(4-(dimethylaminoethyl)phenyl)pyrido[2,3- djpyrimidine;
4-amino-5-(3-bromophenyl)-7-(4-(3-(dimethylamino)propynyl)phenyl)pyrido[2,3- djpyrimidine;
4-amino-5-(3 -bromopheny l)-7-(4-(3 -amino-3 -methy lbutyny l)pheny l)pyrido [2,3- djpyrimidine; 4-amino-5-(3-bromophenyl)-7-(4-dimethylphosphonatophenyl)pyrido[2,3- djpyrimidine;
4-amino-5-(3-bromophenyl)-7-(4-(3-(methoxypropynyl)pyrido[2J-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(4-carboxyphenyl)pyrido[2J-djpyrimidine; 4-amino-5 -(3 -bromophenyl)-7-(4-methy 1-3 -oxo-2H-4H-pyrido [3 ,2-b]- 1 ,4-oxazin-
7-yl)pyrido [2,3-djpyrimidine;
4-amino-5-(3-bromophenyl)-7-(4-(2-(dimethylamino)ethyl)-3-oxo-2H-4H- pyrido[3,2-bJ-l,4-oxazin-7-yl)pyrido[2,3-dJpyrimidine;
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- y l)pyrido [2,3-djpyrimidine;
4-amino-5-(3-bromophenyl)-7-(2,2,4-trimethyl-3-oxo-2H-4H-benzo-l,4-oxazin-7- y l)pyrido [2 ,3 -djpyrimidine; 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- djpyrimidine;
4-amino-5-(3-bromophenyl)-7-(5-piperidin-l-ylpyrid-2-yl)pyrido[2,3- djpyrimidine;
4-amino-5-(l-(4-bromophenyl)ethyl)-7-(6-moφholinylpyrid-3-yl)pyrido[2J- djpyrimidine;
4-amino-5 -(3 -bromopheny l)-7-(4-((N-formylamino)methyl)phenyl)pyri do [2,3- djpyrimidine; 4-amino-5-(3-bromophenyl)-7-(4-(l-methyl-l-(N-methylamino)ethyl)phenyl)- pyrido [2,3-djpyrimidine;
4-amino-5-(3-bromophenyl)-7-(4-(l-(dimethylamino)-l- methylethyl)phenyl)pyrido[2J-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(N-acetyl-5-indolinyl)pyrido[2J-d]pyrimidine; 4-amino-5-cyclohexy l-7-(6-chloro-3 -pyridyl)pyrido [2,3-djpyrimidine; 4-amino-5-(l-(2-bromophenyl)ethyl)-7-(6-diethylamino-3-pyridyl)pyrido[2,3- djpyrimidine;
4-amino-5-(l-(2-bromophenyl)ethyl)-7-(6-moφholinyl-3-pyridyl)pyrido[2,3- djpyrimidine; 4-amino-5-(l-(2-bromophenyl)ethyl)-7-(4-(N-methyl-N-formyl)amino)- phenyl)pyrido [2,3 -djpyrimidine;
4-amino-5-cyclohexyl-7-(6-moφholinyl-3-pyridyl)pyrido[2,3 -djpyrimidine;
4-amino-5-((2-bromophenyl)methyl)-7-(6-moφholinyl-3-pyridyl)pyrido[2,3- djpyrimidine; 4-amino-5-(4-tetrahydropyranyl)-7-(6-moφholinyl-3-pyridyl)pyrido[2J- djpyrimidine;
4-amino-5-cyclohexyl-7-(6-dimethylamino-3-pyridyl)pyrido[2J-d]pyrimidine;
4-amino-5-(l-ethylpropyl)-7-(6-dimethylamino-3-pyridyl)pyrido[2,3-d]pyrimidine;
4-amino-5-cyclopentyl-7-(6-moφholinyl-3-pyridyl)pyrido[2,3-djpyrimidine; 4-amino-5-cyclohexyl-7-(2-chloro-3-pyridyl)pyrido[2,3-dJpyrimidine;
4-amino-5-(3,5-dimethylcyclohexyl)-7-(6-dimethylamino-3-pyridyl)pyrido[2,3- djpyrimidine;
4-amino-5-((N-(benzyloxycarbonyl)-4-piperidinyl)methyl)-7-(6-moφholinyl-3- pyridyl)pyrido[2,3-d]pyrimidine; 4-amino-5 -cyclohexy l-7-(6-bromo-3 -pyridyl)pyrido [2,3-djpyrimidine;
4-amino-5 -cyclohexy l-7-(3 -cy anophenyl)pyrido [2,3-djpyrimidine;
4-amino-5-( 1 -(2-bromophenyl)ethyl)-7-(6-dimethylamino-3- pyridazinyl)pyrido[2,3-dJpyrimidine;
4-amino-5-(3-bromophenyl)-7-(6-imidazolyl-3-pyridazinyl)pyrido[2,3- djpyrimidine;
4-amino-5-(3-bromophenyl)-7-(6-(azacycloheptanyl)-3-pyridazinyl)pyrido[2,3- djpyrimidine;
4-amino-5-(3-bromophenyl)-7-(6-(N-methyl-N-(l-methylethyl))amino)-3- pyridazinyl)pyrido[2,3-d]pyrimidine; 4-amino-5-(l-(2-bromophenyl)ethyl)-7-(6-moφholinyl-3-pyridazinyl)pyrido[2J- djpyrimidine;
4-amino-5 -cyclohexy l-7-(6-(4-acetylpiperazinyl)-3 -pyridy l)pyrido [2,3 - djpyrimidine; 4-amino-5-cyclohexyl-7-(6-(4-acetyl-l ,4-diazacycloheptanyl)-3- pyridyl)pyrido[2,3-d]pyrimidine;
4-amino-5-cyclohexyl-7-(6-(4-methyl- 1 ,4-diazacycloheptanyl)-3- pyridyl)pyrido[2,3 -djpyrimidine;
4-amino-5-cyclohexyl-7-(6-(N-methyl-N-(2-(2-pyridyl)ethyl)amino)-3- pyridyl)pyrido [2,3 -djpyrimidine;
4-amino-5-cyclohexyl-7-(6-2-(N-(N',N'-dimethylaminoethyl)-N-methylamino)-3- pyridy l)pyrido [2,3-djpyrimidine;
4-amino-5-cyclohexyl-7-(6-azetidinyl-3-pyridyl)pyrido[2J-d]pyrimidine;
4-amino-5-cyclohexyl-7-(6-(3-(N- methylacetamido)pyrrolidinyl)pyridyl)pyrido[2,3-d]pyrimidine;
4-amino-5-cyclohexyl-7-(6-(3-(formamido)pyrrolidinyl)pyridyl)pyrido[2,3- djpyrimidine;
4-amino-5-cyclohexyl-7-(4-oxo-l-phenyl-l,3,8-triazaspiro[4.5[decan-8- y l)pyrido [2 ,3 -djpyrimidine ; 4-amino-5-cyclohexyl-7-(6-(2-methoxymethyl)pyrrolidin-l-yl)pyridyl)pyrido[2,3- djpyrimidine;
4-amino-5-cyclohexyl-7-(6-(N-methoxyethyl-N-propylamino)pyridyl)pyrido[2,3- djpyrimidine;
4-amino-5-cyclohexyl-7-(N-methyl-N-(2,2-dimethoxyethyl)amino)pyrido[2,3- djpyrimidine;
4-amino-5-cyclohexyl-7-(6-(4-(dimethylamino)piperidinyl)pyridyl)pyrido[2,3- djpyrimidine;
4-amino-5-cyclohexyl-7-(6-(4-(aminocarbonyl))piperidinyl)pyridyl)pyrido[2,3- djpyrimidine; 4-amino-5-cyclohexyl-7-(N-methyl-N-(3-(diethylamino)propyl)aminopyrid-3- yl)pyrido[2J-d]pyrimidine;
4-amino-5-cyclohexyl-7-(6-(N-methyl-N-(4-pyridyl)ethylamino)pyrid-3- y l)pyrido [2,3-djpyrimidine; 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- djpyrimidine;
4-amino-5-(l-(2-bromophenyl)ethyl)-7-(l-methyl-2,3-dioxo-5-indolyl)pyrido[2,3- djpyrimidine;
4-amino-5-(3-bromophenyl)-7-(3-fluoro-4-(l-moφholinyl)phenyl)pyrido[2,3- djpyrimidine;
4-amino-5-(3-bromophenyl)-7-(4-hydroxy-3-nitrophenyl)pyrido[2J-d]pyrimidine; 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- djpyrimidine;
4-amino-5-(3-bromophenyl)-7-(6-(4-formylpiperazinyl)-3-pyridyl)pyrido[2,3- djpyrimidine; 4-amino-5-(3-bromophenyl)-7-(6-(4-methylpiperazinyl)-3-pyridyl)pyrido[2,3- djpyrimidine;
4-amino-5-(3 -bromopheny l)-7-(6-thiomoφholinyl-3 -pyridyl)pyrido [2,3 - djpyrimidin;
4-amino-5-(3-bromophenyl)-7-(6-(4,4-dioxothiomoφholinyl)-3- pyridyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(2-bromophenyl)-7-(6-moφholinyl-3-pyridyl)pyrido[2J-djpyrimidine; 4-amino-5-(3-bromo-4-methoxyphenyl)-7-(6-moφholinyl-3-pyridyl)pyrido[2J- djpyrimidine;
4-amino-5-(4-bromophenyl)-7-(6-moφholinyl-3-pyridyl)pyrido[2J-d]pyrimidine; 4-amino-5-(3-chlorophenyl)-7-(6-moφholinyl-3-pyridyl)pyrido[2J-d]pyrimidine; 4-amino-5-(3-bromophenyl)-7-(5-chloro-6-moφholinyl-3-pyridyl)pyrido[2J- djpyrimidine;
4-amino-5-(3-bromophenyl)-7-(6-(N-oxidomoφholinyl)-3-pyridyl)pyrido[2J- djpyrimidine; 4-amino-5-(3-bromophenyl)-7-(6-(N-(2-hydroxyethoxyethyl)amino)-3- pyridy l)pyri do [2 ,3 -djpyrimidine ;
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 -djpyrimidine;
4-amino-5-(3-bromophenyl)-7-(6-(3-hydroxy)moφholinyl)-3-pyridyl)pyrido[2J- djpyrimidine; l-(5-(4-amino-5-(3-bromophenyl)pyrido[2,3-d]pyrimidin-7-yl)-2-pyridyl)- piperidine-4-phosphate, disodium salt; 4-amino-5-(3 -bromopheny l)-7-(4-methy lenylpiperidinyl)-3 -pyridy l)pyrido [2,3- djpyrimidine;
4-amino-5-(3-bromophenyl)-7-(4-hydroxy-4-(hydroxymethyl)piperidinyl)-3- pyridyl)pyrido [2,3-djpyrimidine;
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-piperidinyl)-3-pyridyl)pyrido[2.3-d]pyrimidine;
4-amino-5-cyclohexyl-7-(6-(4-methylenylpiperidinyl)-3-pyridyl)pyrido[2J- djpyrimidine;
4-N-(iminomethyl)amino-5-cyclohexyl-7-(6-dimethylamino-3-pyridyl)pyrido[2,3- djpyrimidine;
4-allylamino-5 -(4-bromophenyl)-7-(4-dimethylaminopheny 1) pyrido [2,3- djpyrimidine;
4-amino-5-(3-bromophenyl)-7-(6-(4-hydroxypiperdinyl)-3-pyridyl)pyrido[2,3- djpyrimidine; 4-amino-5-(cyclohexyl)-7-(6-(4,4-ethylenedioxypiperidinyl)-3-pyridyl)pyrido[2,3- djpyrimidine;
4-amino-5-(3-bromophenyl)-7-(2-moφholinyl-5-thiazolyl)pyrido[2,3- djpyrimidine; 4-(N-(2,3-dihydroxypropyl)amino)-5-(3-bromophenyl)-7-(6-moφholinyl-3- pyridinyl)pyrido[2,3 -djpyrimidine;
4-(N-(3-moφholinylpropyl)amino)-5-(3-bromophenyl)-7-(6-moφholinyl-3- pyridinyl)pyrido[2,3-d]pyrimidine;
4-(N-(2-(4-imidazolyl)ethyl)amino)-5-(3-bromophenyl)-7-(6-moφholinyl-3- pyridinyl)pyrido[2,3-d]pyrimidine;
4-(N-(3-carboxypropyl)amino)-5-(3-bromophenyl)-7-(6-moφholinyl-3- pyridinyl)pyrido [2,3-djpyrimidine ;
(S)-4-amino-5-(3-bromophenyl)-7-(6-(O-methyl-2-hydroxymethylpyrrolidinyl)-3- pyridinyl)pyrido[2,3-d]pyrimidine; (S)-4-amino-5-(3-bromophenyl)-7-(6-(2-hydroxymethylpyrrolidinyl)-3- pyridinyl)pyrido[2,3-dJpyrimidine;
4-amino-5-(2-bromophenyl)-7-(6-(4-hydroxypiperidinyl)-3-pyridinyl)pyrido[2,3- djpyrimidine;
4-amino-5-(4-fluorophenyl)-7-(6-(4,4-ethylenedioxypiperidinyl)-3- pyridinyl)pyrido[2,3-dJpyrimidine;
4-amino-5-(2-bromophenyl)-7-(6-(4-hydroxypiperidinyl)-3-pyridazyl)pyrido[2,3- djpyrimidine;
4-amino-5-(3-bromophenyl)-7-(6-(4,4-ethylenedioxypiperidinyl)-3- pyridazyl)pyrido [2,3-djpyrimidine; 4-amino-5-(3-bromophenyl)-7-(2-moφholinyl-4-thiazolyl)pyrido[2,3- djpyrimidine;
4-amino-5-(N-methyl-3-indolyl)-7-(6-moφholinyl-3-pyridinyl)pyrido[2,3- djpyrimidine;
4-amino-5-(3-bromophenyl)-7-(6-(4-ethoxyiminopiperidinyl)-3- pyridinyl)pyrido[2,3-d]pyrimidine; 4-amino-5-(3-bromophenyl)-7-(6-(4-ethoxycarbonylmethoxyiminopiperidinyl)-3- pyridinyl)pyrido[2J-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(-6-(4-oxopiperidinyl)-3-pyridazinyll)pyrido[2J- djpyrimidine; 4-amino-5 -(3 -bromopheny l)-7-(6-(4-moφholinyliminopiperidinyl )-3 - pyridazinyll)pyrido[2,3-dJpyrimidine;
4-amino-5-(3-bromophenyl)-7-(6-((lS,4S)-2-oxa-5-azabicyclo[2.2JJheptan-5-yl)-3- pyridazyl)pyrido [2,3-djpyrimidine;
4-amino-5-(3-bromophenyl)-7-(6-(4-methoxyiminopiperidinyl )-3- pyridazinyll)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(6-phenylmethoxy-3-pyridazinyll)pyrido[2J-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(6-(4-methoxypiperidinyl)-3-pyridyl)pyrido[2,3- djpyrimidine;
4-amino-5-(3-bromophenyl)-7-(6-(4-(4-tetrahydropyranyloxy)iminopiperidinyl )-3- pyridazinyll)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(6-isobutoxy-3-pyridazinyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(6-(4-(N-methylpiperazinyl)iminopiperidinyl )-3- pyridazinyll)pyrido[2J-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(6-(4-tetrahydropyranyloxy)-3-ρyridazinyll)pyrido[2,3- djpyrimidine;
4-amino-5-(3-bromophenyl)-7-(6-moφholinylethoxy-3-pyridazinyll)pyrido[2J- djpyrimidine;
4-amino-5-(3-bromophenyl)-7-(6-(4-ethoxypiperidinyl)-3-pyridazinyll)pyrido[2J- djpyrimidine; 4-amino-5-(3-bromophenyl)-7-(6-(4-(2-ethoxyethoxy)piperidinyl)-3- pyridazinyll)pyrido[2J-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(6-(4-(4-tetrapyranyloxyethyl)piperidinyl)-3- pyridazinyll)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(6-(3-(R)-tetrahydrofuranyloxy)piperidinyl)-3- pyridaziny ll)pyrido [2,3-djpyrimidine; 4-amino-5-(3-bromophenyl)-7-(6-(3-(S)-tetrahydrofuranyloxy)piperidinyl)-3- pyridazinyll)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(6-(trans-3-ethoxy-4-hydroxy)pyrrolidinyl)-3- pyridazinyll)pyrido[2J-d]pyrimidine; 4-amino-5-(3-bromophenyl)-7-(6-(cis-3-ethoxy-4-hydroxy)pyrrolidinyl)-3- pyridazinyll)pyrido[2J-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(6-(trans-3-ethoxy-4-hydroxy)pyrrolidinyl)-3- pyridyl)pyrido [2,3-djpyrimidine;
4-amino-5-(3-bromophenyl)-7-(6-(trans-3,4-bis-ethoxy)pyrrolidinyl)-3- pyridazinyll)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(6-(trans-3,4-bis-ethoxy)pyrrolidinyl)-3-pyridyl)pyrido[2,3- djpyrimidine;
4-amino-5-(3-bromophenyl)-7-(6-(cis-3,4-bis-ethoxy)pyrrolidinyl)-3-pyridyl)pyrido[2,3- djpyrimidine; 4-amino-5-(3-bromophenyl)-7-(6-(cis-3,4-bis-ethoxy)pyrrolidinyl)-3- pyridazinyll)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(6-(cis-3-ethoxy-4-hydroxy)pyrrolidinyl)-3- pyridyl)pyrido [2,3 -djpyrimidine;
4-amino-5-(3-bromophenyl)-7-(6-(cis-3-amino-4-hydroxy)pyrrolidinyl)-3- pyridazinyll)pyrido[2J-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(6-(cis-3-amino-4-hydroxy)pyrrolidinyl)-3- pyridyl)pyrido[2,3-dJpyrimidine;
4-amino-5-(2-pyridyl)-7-(6-(l,4-dioxa-8-azaspiro[4.5]decan-8-yl)-3-pyridyl)pyrido[2J- djpyrimidine; 4-amino-5-(2,3-dichlorophenyl)-7-(6-moφholinyl-3-pyridyl)pyrido[2J-djpyrimidine;
4-amino-5-(2-pyridyl)-7-(6-moφholinyl-3-pyridyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(2-ethoxyphenyl)-7-(6-(l,4-dioxa-8-azaspiro[4.5]decan-8-yl)-3- pyridyl)pyri do [2,3 -djpyrimidine;
4-amino-5-(2-bromo-5-ethoxyphenyl)-7-(6-moφholinyl-3-pyridyl)pyrido[2J- djpyrimidine; 4-amino-5-(2,5-dichlorophenyl)-7-(6-moφholinyl-3-pyridyl)pyrido[2J-djpyrimidine;
4-amino-5-(2,5-dimethylphenyl)-7-(6-moφholinyl-3-pyridyl)pyrido[2J-djpyrimidine
4-amino-5-(3-fluorophenyl)-7-(6-moφholinyl-3-pyridyl)pyrido[2,3-djpyrimidine;
4-amino-5-(3-trifluoromethylphenyl)-7-(6-moφholinyl-3-pyridyl)pyrido[2J- djpyrimidine;
4-amino-5-(3-fluoro-5-trifluoromethylphenyl)-7-(6-(l,4-dioxa-8-azaspiro[4.5]decan-8-yl)-
3-pyridyl)pyrido[2,3-dJpyrimidine;
4-amino-5-(3,5-diclorophenyl)-7-(6-(l,4-dioxa-8-azaspiro[4.5Jdecan-8-yl)-3- pyridyl)pyrido[2,3-d]pyrimidine; 4-amino-5-(3-bromophenyl)-7-(6-(l,5-dioxa-9-azaspiro[5.5]undecan-9-yl)-3- pyridazinyll)pyrido[2,3-dJpyrimidine;
4-amino-5-(4-bromo-2-thienyl)-7-(6-(l,4-dioxa-8-azaspiro[4.5]decan-8-yl)-3- pyridyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3 -bromophenyl)-7-(6-(4-tertbutyl)piperidinyl-3 -pyridaziny ll)pyri do [2,3 - djpyrimidine;
4-amino-5-(3-bromophenyl)-7-(6-(4-N-formyl)piperidinyl-3-pyridazinyll)pyrido[2,3- djpyrimidine;
4-amino-5-(3-bromo-2-thienyl)-7-(6-(4,4-ethylenedioxypiperidinyl)-3-pyridyl)pyrido[2J- djpyrimidine; 4-amino-5-(3-cyanophenyl)-7-(6-moφholinyl-3-pyridazinyll)pyrido[2J-dJpyrimidine;
4-amino-5-(3-Bromophenyl)-7-(6-(S-O-ethyl-2-hydroxymethylpyrrolidinyl)-3- pyridazinyll)pyrido[2,3 , djpyrimidine;
4-amino-5-(3-bromophenyl)-7-(6-((2S,3S)-2,3-dimethyl-l,4-dioxa-8-azaspiro[4.5]decan- 8-yl)-3-pyridazinyl)pyrido[2,3-d]pyrimidine;
4--ιmino-5-(3-bromophenyl)-7-(6-(4,4-(cis-l,2-dioxycyclopentyl)piperidinyl)-3- pyridazinyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(6-(4-acetyl-l-oxa-4,8-diazaspiro[4.5Jdecan-8-yl)-3- pyridazinyl)pyrido[2J-dJpyrimidine; 4-amino-5-(3-bromophenyl)-7-(6-((2RJR)-2J-bis(methoxymethyl)-l ,4-dioxa-8- azaspiro[4.5Jdecan-8-yl)-3-pyridazinyl)pyrido[2J-djpyrimidine;
4-amino-5-(3-bromophenyl)-7-(6-(4,4-(cis-3.4-dioxy-oxacyclopentyl)piperidinyl)-3- pyridazinyl)pyrido[2J-dJpyrimidine; 4-amino-5-(3-bromophenyl)-7-(6-(3-methoxy-l,5-dioxa-9-azaspiro[5.5Jundecan-9-yl)-3- pyridazinyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(6-(l,5-dioxa-3-hydroxymethyl-9-azaspiro[5.5Jundecan-9- yl)-3-pyridazinyl)pyrido[2,3-dJpyrimidine;
4-amino-5-(3-bromophenyl)-7-(6-(l,7J4-trioxa-l l-azadispiro[4.2.5.2Jpentadecan-l l-yl)- 3-pyridazinyl)pyrido[2,3-djpyrimidine;
4-amino-5-(4-tetrahydropyranyl)-7-(6-moφholinyl-3-pyridazinyll)pyrido[2,3- djpyrimidine;
4-amino-5-(3-bromophenyl)-7-(6-(4-moφholinyliminopiperidinyl )-3-pyridyl)pyrido[2J- djpyrimidine; 4-amino-5-(3-bromophenyl)-7-(6-(4-(N-methylpiperazinyl)iminopiperidinyl )-3- pyridyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(6-(4-(l,2,4-triazol-l-yl)iminopiperidinyl )-3- pyridy l)pyrido [2,3 -djpyrimidine;
4-amino-5-(3-indolyl)-7-(6-moφholinyl-3-pyridyl)pyrido[2,3-d]pyrimidine; 4-amino-5-(5-indolyl)-7-(6-moφholinyl-3-pyridyl)pyrido[2,3-dJpyrimidine;
4-amino-5-(3-bromophenyl)-7-(6-(4-ethylpiperidinylcarboxylate)-3-pyridyl)pyrido[2,3- djpyrimidine;
4-amino-5-(3-bromophenyl)-7-(2-phenylmethyl-3(2H)-pyridazinone-6-yl)pyrido[2,3- djpyrimidine; 4-amino-5-(3-bromophenyl)-7-(6-(4-(moφholinylcarboxamide)piperidinyl)-3- pyridyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(6-(4-(N-moφholinylaminocarboxamide)piperidinyl)-3- pyridyl)pyrido [2,3 -djpyrimidine;
4-amino-5-(3-bromophenyl)-7-(6-(4-(N,N-dimethylaminocarboxamide)piperidinyl)-3- pyridy l)pyrido [2,3-djpyrimidine; 4-amino-5-(3-bromophenyl)-7-(6-(4-(N-methyl-N-methoxyethylcarboxamide)piperidinyl)-
3-pyridyl)pyrido[2J-dJpyrimidine;
4-amino-5-(4-quinolyl)-7-(6-moφholinyl-3-pyridyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(6-(4-(N-methoxyethylcarboxamide)piperidinyl)-3- pyridyl)pyrido[2J-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(6-(4-hydroxymethylpiperidinyl)-3-pyridyl)pyrido[2,3- djpyrimidine;
4-amino-5-(2-bromophenyl)-7-(6-(l,4-dioxa-8-azaspiro[4.5jdecan-8-yl)-3- pyridyl)pyrido [2 ,3 -djpyrimidine ; 4-amino-5-(2-bromophenyl)-7-(6-(4-hydroxypiperidinyl)-3-pyridyl)pyrido[2J- djpyrimidine;
4-amino-5-(3-bromophenyl)-7-(6-(4-N-acetylpiperazinyl)-3-pyridyl)pyrido[2J- djpyrimidine;
4-amino-5-(3-bromophenyl)-7-(6-(4-cyanopiperidinyl)-3-pyridyl)pyrido[2,3-d]pyrimidine; 4-amino-5-(3-bromophenyl)-7-(6-(4-N-(4-fluorophenyl)piperazinyl)-3-pyridyl)pyrido[2,3- djpyrimidine;
4-amino-5-(4-fluorophenyl)-7-(6-moφholinyl-3-pyridyl)pyrido[2J-dJpyrimidine;
4-amino-5-(3-bromophenyl)-7-(4-moφholinylbenzenesulfonamide)pyrido[2,3- djpyrimidine; 4-amino-5-(3-bromophenyl)-7-(4-N-l,4-dioxa-8-azaspiro[4.5]decan-8- y lbenzenesulfonamide)pyrido [2,3 -djpyrimidine ;
4-amino-5-(3-bromophenyl)-7-(4-N-cyclopropylbenzenesulfonamide)pyrido[2,3- djpyrimidine;
4-amino-5-(3-bromophenyl)-7-(4-piperidinebenzenesulfonamide)pyrido[2J-d]pyrimidine; 4-amino-5-(3-bromophenyl)-7-(4-(4-cyanopiperidine)benzenesulfonamide)pyrido[2,3- djpyrimidine;
4-amino-5-(3-bromophenyl)-7-(4-N-cyclopropylmethylbenzenesulfonamide)pyrido[2,3- djpyrimidine;
4-amino-5-(3-bromophenyl)-7-(4-N,N-dimethylaminobenzenesulfonamide)pyrido[2,3- djpyrimidine; 4-amino-5-(3-bromophenyl)-7-(4-N-(S)-2- hydroxymethylpyrrolidinebenzenesulfonamide)pyrido[2J-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(4-(4-hydroxypiperidine)benzenesulfonamide)pyrido[2,3- djpyrimidine; 4-amino-5-(3-bromophenyl)-7-(4-(cis-3,5- dimethylmoφholinyl)benzenesulfonamide)pyrido [2,3-djpyrimidine;
4-amino-5-(3-bromophenyl)-7-(3-fluoro-4-thiomoφholinylphenyl)pyrido[2,3- djpyrimidine;
4-amino-5-(4-fluorophenyl)-7-(6-(thiomoφholinyl)-3-pyridyl)pyrido[2,3-d]pyrimidine; 4-amino-5-(4-fluorophenyl)-7-(6-(4,4-dioxothiomoφholinyl)-3-pyridyl)pyrido[2J- djpyrimidine;
4-methoxy-5-(3-bromophenyl)-7-(6-moφholinyl-3-pyridyl)pyrido[2J-dJpyrimidine;
4-amino-5-(3-bromophenyl)-7-(4-(4-dioxa-8-azaspiro[4.5]decan-8- ylcarboxamide)phenyl)pyrido[2,3-d]pyrimidine; 4-amino-5-(3-bromophenyl)-7-(4-(N-cyclopropylcarboxamide)phenyl)pyrido[2,3- djpyrimidine;
4-amino-5-(3-bromophenyl)-7-(4-(moφholinylcarboxamide)phenyl)pyrido[2,3- djpyrimidine;
4-amino-5-(3-bromophenyl)-7-(6-N-cyclopropylamino-3-pyridyl)pyrido[2J-d]pyrimidine; 4-amino-5-(3-bromophenyl)-7-(4-(4-hydroxypiperidinylcarboxamide)phenyl)pyrido[2,3- djpyrimidine;
4-amino-5-(3-bromophenyl)-7-(6-(S)-hydroxymethylpyrrolidinyl-3- pyridazinyll)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(6-(4-(2-ethoxyethoxy)piperidinyl)-3-pyridyl)pyrido[2,3- djpyrimidine;
4-amino-5 -(3 -bromopheny l)-7-(6-hexahydropyrimidine )-3 -pyridyl)pyrido [2,3- djpyrimidine;
4-amino-5-(4,4-difluorocyclohxeyl)-7-(6-(l,4-dioxa-8-azaspiro[4.5]decan-8-yl)-3- pyridyl)pyrido[2J-d]pyrimidine; 4-amino-5-(3-bromophenyl)-7-(6-(S)-2-ethoxyethoxypyrrolidinyl)-3-pyridyl)pyrido[2,3- djpyrimidine;
4-amino-5-(3-bromophenyl)-7-(6-(R)-2-ethoxyethoxypyrrolidinyl)-3- pyridy l)py rido [2 ,3 -d] py rimidine ; 4-amino-5-(3-bromophenyl)-7-(6-(cis-3,4-dihydroxypyrolidinyl)-3-pyridyl)pyrido[2,3- djpyrimidine;
4-amino-5-(3-bromophenyl)-7-(6-((3aR,6aS)-2-oxo-tetrahydro-3aH-[l,3]dioxolo[4,5- c]pyrrol-5-yl)-3-pyridyl)pyrido[2, 3-djpyrimidine;
4-amino-5-(3-bromophenyl)-7-(6-(cis-2,3-dihydroxypyrrolidinyl)-3- pyridazinyll)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(6-(S,R-2-hydroxymethyl-4-hydroxypyrrolidinyl)-3- pyridyl)pyrido[2J-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(6-(R-2-hydroxymethyl-4-pyrrolidinyl)-3- pyridazinyll)pyrido[2,3 -djpyrimidine; 4-amino-5-(3-bromophenyl)-7-(6-((lS,4S)-2-oxa-5-azabicyclo[2.2J]heptan-5-yl)-3- pyridyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(6-(2-imidizolidone-l-yl)-3-pyridyl)pyrido[2,3- djpyrimidine;
4-amino-5-(lJ-dimethyl-3-butenyl)-7-(6-moφholinyl-3-pyridyl)pyrido[2J-d]pyrimidine; 4-amino-5-(3-bromophenyl)-7-(6-(2,4-dioxo-(lH,3H)-quinazolin-3-yl)-3- pyridyl)pyrido [2,3 -djpyrimidine;
4-amino-5-(3-bromophenyl)-7-(6-carboxamide-3-pyridazinyll)pyrido[2J-djpyrimidine;
4-amino-5-(3-bromophenyl)-7-(6-moφholinylcarboxamide-3-pyridazinyll)pyrido[2J- djpyrimidine; 4-amino-5-(3-bromophenyl)-7-(6-methoxy-3-pyridazinyll)pyrido[2J-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(6-N,N-diethoxyethylamino-3-pyridazinyll)pyrido[2,3- djpyrimidine;
4-amino-5-(3-bromophenyl)-7-(6-(4-ethoxymethylpiperidinyl)-3-pyridazinyll)pyrido[2J- djpyrimidine; 4-amino-5-(3-bromophenyl)-7-(6-(4-(4-tetrahydropyranyloxymethyl)piperidinyl)-3- pyridazinyll)pyrido[2J-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(6-(4-ethoxyethoxymethylpiperidinyl)-3- pyridazinyll)pyrido[2,3-d]pyrimidine; 4-amino-5-(3-bromophenyl)-7-(6-N-methyl-N-l ,3-dioxalanemethylamino )-3- pyridazinyll)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(6-(l,4-dioxaspiro[4.5]decanyl-8-oxy)-3- pyridazinyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(6-dihydroxymethylmethoxy-3-pyridazinyll)pyrido[2,3- djpyrimidine;
4-amino-5-(3-bromophenyl)-7-(6-(3-pyridyloxy)-3-pyridazinyll)pyrido[2J-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(6-(4,7-epoxy-7-methyl-2,3,3A,4,5,6,7,7a-octahydro-lH- isoindolyl)-3-pyridazinyl)pyrido[2,3-dJpyrimidine;
4-amino-5-(3-bromophenyl)-7-(6-(4-N-ethyl-N-methoxyethyl)-3-pyridazinyll)pyrido[2,3- djpyrimidine;
4-amino-5-(3-bromophenyl)-7-(6-(4-N-methyl-N-methoxyethyl)-3- pyridazinyll)pyrido[2J-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(6-(3,4-dimethoxymethoxypyrrolidinyl)-3- pyridazinyll)pyrido[2J-dJpyrimidine; 4-amino-5-(3-bromophenyl)-7-(6-(hexahydro-lH-furo[3,4-c]pyrrol-5-yl)-3- pyridazinyl)pyrido[2J-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(6-(hexahydro-lH-furo[3,4-cjpyrrol-5-yl)-3- pyridy l)pyrido [2,3 -djpyrimidine;
4-amino-5-(3-bromophenyl)-7-(6-(trans-3-hydroxy-4-methylpyrrolidinyl)-3- pyridazinyll)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(6-(trans-3-hydroxy-4-methylpyrrolidinyl)-3- pyridyl)pyri do [2,3 -djpyrimidine;
4-amino-5-(3-bromophenyl)-7-(6-(cis-3-hydroxy-4-methylpyrrolidinyl)-3- pyridazinyll)pyrido[2J-dJpyrimidine; 4-amino-5-(3-bromophenyl)-7-(6-(cis-3-hydroxy-4-methylpyrrolidinyl)-3- pyridyl)pyrido[2J-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(6-(trans-3-cyano-4-hydroxylpyrrolidinyl)-3- pyridyl)pyrido[2J-d]pyrimidine; 4-amino-5-(3-bromophenyl)-7-(6-(3-hydroxy-4-tert-butylcarboxamidepyrrolidinyl)-3- pyridy l)pyrido [2,3-djpyrimidine;
4-amino-5-(3-bromophenyl)-7-(6-(S-2-(4-tetrahydropyranyloxy)methylpyrrolidinyl)-3- pyridaziny ll)pyrido [2 ,3 -djpyrimidine ;
4-amino-5-(3-bromophenyl)-7-(6-(3-(4-tetrahydropyranyloxy)iminopyrrolidinyl)-3- pyridazinyll)pyrido[2,3-dJpyrimidine;
4-amino-5-(3-bromophenyl)-7-(2-moφholinyl-5-thiazoyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(5-bromo-2-thienyl)pyrido[2,3-d]pyrimidine;
4-amino-5 -(3-bromophenyl)-7-(2,5 -dimethy 1-3 -thienyl)pyrido [2,3 -djpyrimidine;
4-amino-5-(3-bromophenyl)-7-(5-chloro-2-thienyl)pyrido[2,3-d]pyrimidine; 4-amino-5-(3-bromophenyl)-7-(2,4-dimethyl-5-thiazoyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(5-methyl-2-thienyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(2-furanyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(2-(l,4-dioxa-8-azaspiro[4.5Jdecan-8-yl)-5- thiazoyl)pyrido[2,3-d]pyrimidine; 4-amino-5-(3-bromophenyl)-7-(3-thienyl)pyrido[2J-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(3-methyl-2-thienyl)pyrido[2J-dJpyrimidine;
4-amino-5-(3-bromophenyl)-7-(2-moφholinyl-4-thiazoyl)pyrido[2J-d]pyrimidine;
4-amino-5-(3 -bromopheny l)-7-(2-moφholiny l-4-trifluoromethy-5 -thiazoyl)pyri do [2,3- djpyrimidine; 4-amino-5-(3-bromophenyl)-7-(5-moφholinyl-2-thienyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(4-methyl-2-moφholinyl-5-thiazoyl)pyrido[2J- djpyrimidine;
4-amino-5-(3-bromophenyl)-7-(2,5-dichloro-3-thienyl)pyrido[2J-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(2,5-dimethyl-3-furanyl)pyrido[2J-d]pyrimidine; 4-amino-5-(3-bromophenyl)-7-(N-methyl-2-pyrrolyl)pyrido[2,3-d]pyrimidine; 4-amino-5-(3-bromophenyl)-7-(2-N,N-dimethylamino-5-thiazoyl)pyrido[2J- djpyrimidine;
4-amino-5-(3-bromophenyl)-7-(2-moφholinyl-5-thiazoyl)pyrido[2J-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(2-(4,4-dioxythiomoφholinyl)-5-thiazoyl)pyrido[2,3- djpyrimidine;
4-amino-5-(3-bromophenyl)-7-(2-(lJ-dioxidothiomoφholinyl)-5-thiazoyl)pyrido[2,3- djpyrimidine;
4-amino-5 -(3 -bromophenyl)-7-(2-moφholinyl-5 -oxazoly l)pyrido [2,3-djpyrimidine;
4-amino-5-(3-bromophenyl)-7-(2-N-methyl-N-methoxyethylamino-5-thiazoyl)pyrido[2,3- djpyrimidine;
4-amino-5-(3-bromophenyl)-7-(2-N-methyl-N-ethylamino-5-thiazoyl)pyrido[2,3- djpyrimidine;
4-amino-5-(3-bromophenyl)-7-(2-N-pyrrolidinyl-5-thiazoyl)pyrido[2,3-dJpyrimidine;
4-amino-5-(3-bromophenyl)-7-(2-N-methyl-N-propylamino-5-thiazoyl)pyrido[2,3- djpyrimidine;
4-amino-5-(3-bromophenyl)-7-(2-N,N-diethylamino-5-thiazoyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(2-(N-methypiperazinyl)-5-thiazoyl)pyrido[2,3- djpyrimidine;
4-amino-5-(3-bromophenyl)-7-(2-(N-(2-pyridyl)piperazinyl)-5-thiazoyl)pyrido[2,3- djpyrimidine;
4-amino-5-(3-bromophenyl)-7-(2-N-methy-N-(2-pyridylethyl)-5-thiazoyl)pyrido[2J- djpyrimidine;
4-amino-5-(3-bromophenyl)-7-(2-(4-oxopiperazinyl)-5-thiazoyl)pyrido[2J-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(2-(4-(N-moφholinyl)iminopiperazinyl)-5- thiazoyl)pyrido[2J-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(6-N-moφholine-3-pyridinesulfonamide)pyrido[2J- djpyrimidine;
4-amino-5-(3-bromophenyl)-7-(2-(4-oxopiperidinyl)-5-pyrimidyl)pyrido[2,3- djpyrimidine; 4-amino-5-(3-bromophenyl)-7-(2-(4J-dioxethylenepiperidinyl)-5-pyrimidyl)pyrido[2,3- djpyrimidine;
4-amino-5-(3-bromophenyl)-7-(5-(l,4-dioxa-8-azaspiro[4.5]decan-8-yl)-2- pyrazinyl)pyrido[2,3-d]pyrimidine; 4-amino-5-(3-bromophenyl)-7-(5-(4-oxopiperidinyl)-2-pyrazinyl)pyrido[2J-dJpyrimidine;
4-amino-5-(3 -bromopheny l)-7-(6-N-cyclopropy 1-3 -pyridinesulfonamide)pyrido [2,3- djpyrimidine;
4-amino-5-(3-bromophenyl)-7-(6-(N-l,4-dioxa-8-azaspiro[4.5Jdecan-8-yl)-3- pyridylsulfonamide)pyrido[2,3-dJpyrimidine; 4-amino-5-(3-bromophenyl)-7-(2-(4-(4-tetrahydropyranyloxy)iminopiperidinyl )-5- pyrazinyl)pyrido [2,3-djpyrimidine;
4-amino-5 -(3 -bromophenyl)-7-(6-(4-(pheny lmethoxy)iminopiperidiny l)-3 - pyridyl)pyrido[2,3-dJpyrimidine;
4-amino-5-(3-bromophenyl)-7-(6-(4-(tert-butyloxy)iminopiperidinyl)-3- pyridyl)pyrido [2,3-djpyrimidine;
4-amino-5-(3-bromophenyl)-7-(6-(4-(cyclohexyloxy)iminopiperidinyl)-3- pyridyl)pyrido [2,3-djpyrimidine;
4-amino-5-(3-bromophenyl)-7-(6-(4-hydroxyiminopiperidinyl)-3-pyridyl)pyrido[2,3- djpyrimidine; 4-amino-5-(3-bromophenyl)-7-(6-(4-(4-tetrahydropyranyloxy)iminopiperidinyl)-3- pyridyl)pyrido[2,3 -djpyrimidine;
4-amino-5-(3-bromophenyl)-7-(6-(4-methoxyethoxyiminopiperidinyl)-3- pyridyl)pyrido[2,3-dJpyrimidine;
4-amino-5-(3-bromophenyl)-7-(6-(4-(2-thenylmethoxy)iminopiperidinyl)-3- pyridyl)pyrido[2, 3-djpyrimidine;
4-amino-5-(3 -bromopheny l)-7-(6-(4-(4 ' -(5 'H-2-oxyfuranyl)-4-hydroxy)piperidiny l)-3 - pyridyl)pyrido[2,3-dJpyrimidine;
4-amino-5-(3-bromophenyl)-7-(6-(4-(l-(4-tetrahydropyranyloxy)iminoethyl))-4- hydroxypiperidinyl)-3-pyridazinyll)pyrido[2,3-d]pyrimidine; 4-amino-5-(3-bromophenyl)-7-(6-(4-(4'-acetyl-4'-hydroxypiperidinyl)-3- pyridaziny ll)pyrido [2,3-djpyrimidine ;
4-amino-5-(3-bromophenyl)-7-(6-(4-(l-(isopropylcaboxymethoxy)iminoethyl))-4- hydroxypiperidinyl)-3-pyridyl)pyrido[2J-d]pyrimidine; 4-amino-5-(3-bromophenyl)-7-(6-(4-( 1 -(ethylcaboxymethoxy)iminoethyl))-4- hydroxypiperidinyl)-3-pyridyl)pyrido[2,3-dJpyrimidine;
4-amino-5-(3-bromophenyl)-7-(6-(4-(l-(methylcaboxymethoxy)iminoethyl))-4- hydroxypiperidinyl)-3-pyridyl)pyrido[2,3-dJpyrimidine;
4-amino-5-(3-bromophenyl)-7-(6-(4-(l-(2-tetrahydropyranyloxy)iminoethyl))-4- hydroxypiperidinyl)-3-pyridyl)pyrido[2,3-dJpyrimidine;
4-amino-5-(3-bromophenyl)-7-(6-(4-(l-(allyloxy)iminoethyl))-4-hydroxypiperidinyl)-3- pyridyl)pyrido [2 ,3 -djpyrimidine ;
4-amino-5-(3 -bromophenyl)-7-(6-(4-( 1 -(ethoxy)iminoethy l))-4-hydroxypiperidinyl)-3 - pyridyl)pyrido [2 ,3 -djpyrimidine ; 4-amino-5-(3-bromophenyl)-7-(6-(4-( 1 -(methoxy)iminoethyl))-4-hydroxypiperidinyl)-3- pyridyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(6-(4-(l-(hydroxy)iminoethyl))-4-hydroxypiperidinyl)-3- pyridyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(6-(4-(2-tetrahydropyranyloxy)iminopiperidinyl)-3- pyridyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(6-(4-(isopropylcarboxymethoxy)iminopiperidinyl)-3- pyridyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(6-(4-hydroxy-4-(l-(4-tetrahydropyranyloxy)iminoethyl))-
4-hydroxypiperidinyl)-3 -pyridy l)pyrido [2,3-djpyrimidine; 4-amino-5-(3-bromophenyl)-7-(6-(4-(3-butyrolactone)-4-hydroxypiperidinyl)-3- pyridy l)pyrido [2,3-djpyrimidine;
4-amino-5-(3-bromophenyl)-7-(6-(4-(2-butyrolactone)-4-hydroxypiperidinyl)-3- pyridazinyll)pyrido[2,3-dJpyrimidine;
4-amino-5-(3-bromophenyl)-7-(6-(4-acetyl-4-hydroxypiperidinyl)-3-pyridyl)pyrido[2J- djpyrimidine; 4-amino-5-(3-bromophenyl)-7-(6-(3-hydroxyazetidinyl)-3-pyridyl)pyrido[2,3- djpyrimidine;
4-amino-5-(3-bromophenyl)-7-(6-((lR,5S)-3-hydroxy-8-azabicyclo[3.2J]octan-8-yl)-3- pyridyl)pyrido[2,3-d]pyrimidine; 4-amino-5-(3-bromophenyl)-7-(6-(cis-2,3-dihydroxypiperidinyl)-3-pyridyl)pyrido[2,3- djpyrimidine;
4-amino-5-(3-bromophenyl)-7-(6-(N-methyl-N-(3-pyridylmethyl)amino)-3- pyridazinyll)pyrido[2,3-djpyrimidine;
4-amino-5-(3-bromophenyl)-7-(6-(l,2,3,6-tetrahydropyridyl)-3-pyridyl)pyrido[2,3- djpyrimidine;
4-amino-5-(3-bromophenyl)-7-(6-(4-(N-4'methoxyphenylcarbamoyl)piperidinyl)-3- pyridazinyll)pyrido[2,3-djpyrimidine;
4-amino-5-(3-bromophenyl)-7-(6-(4-(2-butyrolactone)-4-hydroxypiperidinyl)-3- pyridyl)pyrido[2,3-d]pyrimidine; 4-amino-5-(3-bromophenyl)-7-(6-(trans-3,4- bis(N-4'- methoxyphenylcarbamoyl)pyrrolidinyl)-3-pyridyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(6-((lS,5R)-3-hydroxy-8-azabicyclo[3.2J]octan-8-yl)-3- pyridyl)pyrido [2,3-djpyrimidine;
4-amino-5-(3-bromophenyl)-7-( 6-(S,S-trans-3,4-dihydroxypyrrolidinyl)-3- pyridyl)pyrido [2,3-djpyrimidine;
4-amino-5-(3-bromophenyl)-7-( 6-(R,R-trans-3,4-dihydroxypyrrolidinyl)-3- pyridazinyll)pyrido[2J-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-( 6-(R,R-trans-3,4-dihydroxypyrrolidinyl)-3- pyridy l)pyrido [2 , 3 -djpyrimidine ; 4-amino-5-(3-bromophenyl)-7-(6-(4-oxo-l-phenyl-l,3,8-triazaspiro[4.5]decan-8-yl)-3- pyridyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(6-(l-oxa-4-oxo-4-thia-8-azaspiro[4.5jdecan-8-yl)-3- pyridyl)pyrido[2,3-dJpyrimidine;
4-amino-5-(3-bromophenyl)-7-(6-(l-oxa-4,4-dioxido-4-thia-8-azaspiro[4.5]decan-8-yl)-3- pyridyl)pyrido [2,3-djpyrimidine; 4-amino-5-(3-bromophenyl)-7-(6-(4-oxo- 1-phenyl- 1,3, 8-triazaspiro[4.5]dec-2-en-8-yl)-3- pyridyl)pyri do [2,3 -djpyrimidine;
4-amino-5-(3-bromophenyl)-7-(6-(4-(2-keto-l-benzimidazolinyl)piperidinyl)-3- pyridazinyll)pyrido[2,3-dJpyrimidine; 4-amino-5-(3-bromophenyl)-7-(6-(4-oxothiomoφholinyl)-3-pyridyl)pyrido[2,3- djpyrimidine;
4-amino-5-(3-bromophenyl)-7-(6-(4-(2-keto-l-benzimidazolinyl)piperidinyl)-3- pyridyl)pyrido [2 ,3 -djpyrimidine ;
4-amino-5-(3-bromophenyl)-7-(6-(N-methyl-N-(2-pyridylethyl)amino)-3- pyridyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(6-(N-methyl-N-(4-pyridylethyl)amino)-3- pyridyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(6-N-(3-pyridylmethyl)amino-3-pyridyl)pyrido[2,3- djpyrimidine; 4-amino-5-(3-bromophenyl)-7-(6-(2-hydroxymethylpiperidinyl)-3-pyridyl)pyrido[2,3- djpyrimidine;
4-amino-5-(3-bromophenyl)-7-(6-(l-oxa-4-thia-8-azaspiro[4.5]decan-8-yl)-3- pyridy l)pyrido [2 ,3 -djpyrimidine ;
4-amino-5-(3-bromophenyl)-7-(6-(4-hydroxy-4-(4-bromophenyl)piperidinyl)-3- pyridyl)pyrido [2,3-djpyrimidine;
4-amino-5-(3-bromophenyl)-7-(6-(4-N-(2-pyridnyl)piperazinyl)-3-pyridyl)pyrido[2J- djpyrimidine;
4-amino-5-(3-bromophenyl)-7-(6-(4-N-(2-hydroxyethyloxyethyl)piperazinyl)-3- pyridyl)pyrido[2,3-d]pyrimidine; 4-amino-5-(3-bromophenyl)-7-(6-(4,4-diacetoxyethylthio)piperidinyl)-3- pyridy l)pyrido [2 ,3 -djpyrimidine ;
4-amino-5-(3-bromophenyl)-7-(6-(N-methy-N-(3-pyridylmethyl)amino)-3- pyridyl)pyrido [2,3-djpyrimidine;
4-amino-5-(3-bromophenyl)-7-(6-(4-pyrrolidinylpiperidinyl)-3-pyridyl)pyrido[2J- djpyrimidine; 4-amino-5-(3-bromophenyl)-7-(6-(2-(lH-imidazol-4-yl)ethylamino)-3- pyridazinyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(6-(4-N-cyanomethylpiperazinyl)-3-pyridyl)pyrido[2,3- djpyrimidine; 4-amino-5 -(3-bromopheny l)-7-(6-(3 -hydroxypyrroldinyl)-3 -pyridy l)pyrido [2,3- djpyrimidine;
4-amino-5-(3-bromophenyl)-7-(6-(4-methylpiperidinyl)-3-pyridyl)pyrido[2,3- djpyrimidine;
4-amino-5-(3-bromophenyl)-7-(6-(cis-3,5-dimethylmoφholinyl)-3-pyridyl)pyrido[2,3- djpyrimidine;
4-amino-5-(3-bromophenyl)-7-(6-(4,4-difluoropipridinyl)-3-pyridyl)pyrido[2,3- djpyrimidine;
4-amino-5-(3-bromophenyl)-7-(6-(l J -dioxidoythiomoφholinyl)-3- pyridazinyl)pyrido[2,3-d]pyrimidine; 4-amino-5-(3-bromophenyl)-7-(6-thiazolidinyl-3-pyridyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(6-( 1 J -dioxidoythiazolidin-3-yl)-3-pyridyl)pyrido[2,3- djpyrimidine;
4-amino-5-(3-bromophenyl)-7-(6-thiomoφholinyl-3-pyridazinyll)pyrido[2,3- djpyrimidine; 4-amino-5-(3-bromophenyl)-7-(6-(2,5-dihydropyrrolyl)-3-pyridyl)pyrido[2,3- djpyrimidine;
4-amino-5 -(3 -bromopheny l)-7-(6-( 1 ,3 -dioxa-8-azaspiro [4.5]decan-8-yl)-3 - pyridyl)pyrido[2,3-dJpyrimidine;
4-amino-5-(3-bromophenyl)-7-(6-hydroxy-3-pyridazinyll)pyrido[2J-djpyrimidine; amino-5-(2,3-dichlorophenyl)-7-(6-(l,4-dioxa-8-azaspiro[4.5jdecan-8-yl)-3- pyridy l)pyrido [2,3-djpyrimidine ;
4-amino-5-isopropyl-7-(6-(l,4-dioxa-8-azaspiro[4.5]decan-8-yl)-3-pyridyl)pyrido[2,3- djpyrimidine;
4-amino-5-(3-bromophenyl)-7-(6-piperidinyl-3-pyridyl)pyrido[2,3-d]pyrimidine; 4-amino-5-(3-bromophenyl)-7-(6-(3-(4-tetrahydropyranyloxyimino)pyrrolidinyl)-3- pyridyl)pyrido[2,3-dJpyrimidine; and
4-amino-5-(2-trifluorophenylphenyl)-7-(6-moφholinyl-3-pyridyl)pyrido[2J- djpyrimidine.
15. A pharmaceutical composition comprising a compound according to Claim 10 and a pharmaceutically acceptable carrier.
16. A compound of formula III
Figure imgf000402_0001
in, wherein X is selected from the group consisting of hydroxy and halogen;
R3 is selected from the group consisting of alkenyl, alkyl, alkynyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, heterocycle, heterocyclealkyl, heterocyclealkylcarbonyl, (NZ,Z2)alkyl, and -RARB;
Z, and Z2 are each independently selected from the group consisting of hydrogen, alkoxycarbonyl, alkyl, alkylcarbonyl, benzyl, benzyloxycarbonyl, and formyl;
RA is selected from the group consisting of aryl and arylalkyl;
RB is selected from aryl, arylalkoxy, arylalkyl, aryloxy, heterocycle, and heterocyclealkyl;
R4 is selected from the group consisting of alkenyl, alkoxyalkynyl, alkyl, alkynyl, cycloalkyl, aryl, arylalkyl, heterocycle, heterocyclealkyl, and -RCRDRE;
Rc is selected from the group consiting of aryl, arylalkyl, heterocycle, and heterocyclealkyl; RD is selected from the group consisting of aryl, arylalkoxy, arylalkoxyimino, arylalkyl, aryloxy, heterocycle, heterocyclealkoxy, heterocyclealkyl, heterocyclecarbonyl, heterocycleimino, heterocycleoxy, heterocycleoxyalkyl, heterocycleoxyimino, heterocycleoxyiminoalkyl, and heterocyclesulfonyl; and RE is absent or selected from aryl, arylalkoxy, arylalkoxyimino. arylalkyl, aryloxy, heterocycle, heterocylealkoxy, heterocyclealkyl, heterocyclecarbonyl, heterocycleimino, heterocycleoxy, heterocycleoxyalkyl, heterocycleoxyimino, heterocycleoxyiminoalkyl, and heterocyclesulfonyl; and a dashed line — indicates that a double bond is optionally present provided that proper valencies are maintained.
17. A compound according to claim 15 wherein said compound is an intermediate in a process to produce a compound according to claim 10.
18. A process for the preparation of an adenosine kinase inhibiting compound of formula I
Figure imgf000403_0001
I, wherein: R1 and R2 are hydrogen;
R3 is selected from the group consisting of alkenyl, alkyl, alkynyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl. heterocycle, heterocyclealkyl, heterocyclealkylcarbonyl, (NZ,Z2)alkyl, and -RARB;
Z, and Z2 are each independently selected from the group consisting of hydrogen, alkoxycarbonyl, alkyl, alkylcarbonyl, benzyl, benzyloxycarbonyl, and formyl; RA is selected from the group consisting aryl and arylalkyl; RB is selected from aryl, arylalkoxy, arylalkyl, aryloxy, heterocycle, and heterocyclealkyl;
R4 is selected from the group consisting of alkenyl, alkoxyalkynyl, alkyl, alkynyl, cycloalkyl, aryl, arylalkyl, heterocycle, heterocyclealkyl, and -RCRDRE;
Rc is selected from aryl, arylalkyl, heterocycle, and heterocyclealkyl; RD is selected from aryl, arylalkoxy, arylalkoxyimino. arylalkyl, aryloxy, heterocycle, heterocyclealkoxy, heterocyclealkyl, heterocyclecarbonyl, heterocycleimino, heterocycleoxy, heterocycleoxyalkyl, heterocycleoxyimino, heterocycleoxyiminoalkyl, and heterocyclesulfonyl; and RE is absent or selected from aryl, arylalkoxy, arylalkoxyimino, arylalkyl, aryloxy, heterocycle, heterocylealkoxy, heterocyclealkyl, heterocyclecarbonyl, heterocycleimino, heterocycleoxy, heterocycleoxyalkyl, heterocycleoxyimino, heterocycleoxyiminoalkyl, and heterocyclesulfonyl; and a dashed line — indicates that a double bond is optionally present provided that proper valencies are maintained; the method comprising:
(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 imgf000404_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 the 8 nitrogen and then,
(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 imgf000405_0001
(I), wherein:
R1 and R2 are hydrogen;
R3 is selected from the group consisting of alkenyl, alkyl, alkynyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, heterocycle, heterocyclealkyl, heterocyclealkylcarbonyl, (NZ,Z2)alkyl, and -RARB; Z, and Z2 are each independently selected from the group consisting of hydrogen, alkoxycarbonyl, alkyl, alkylcarbonyl, benzyl, benzyloxycarbonyl, and formyl; RA is selected from the group consisting of aryl and arylalkyl; RB is selected from aryl, arylalkoxy, arylalkyl, aryloxy, heterocycle, and heterocyclealkyl; R4 is selected from the group consisting of alkenyl, alkoxyalkynyl, alkyl, alkynyl, cycloalkyl, aryl, arylalkyl, heterocycle, heterocyclealkyl, and -RCRDRE;
Rc is selected from aryl, arylalkyl, heterocycle, and heterocyclealkyl; RD is selected from aryl, arylalkoxy, arylalkoxyimino, arylalkyl, aryloxy, heterocycle, heterocyclealkoxy, heterocyclealkyl, heterocyclecarbonyl, heterocycleimino, heterocycleoxy, heterocycleoxyalkyl, heterocycleoxyimino, heterocycleoxyiminoalkyl, and heterocyclesulfonyl; and
RE is absent or selected from aryl, arylalkoxy, arylalkoxyimino, arylalkyl, aryloxy, heterocycle, heterocylealkoxy, heterocyclealkyl, heterocyclecarbonyl, heterocycleimino, heterocycleoxy, heterocycleoxyalkyl, heterocycleoxyimino, heterocycleoxyiminoalkyl, and heterocyclesulfonyl; and a dashed line — indicates that a double bond is optionally present provided that proper valencies are maintained; the method comprising
(a) reacting a ketone having the formula R4C(O)CH3, wherein R4 is as defined above, with an dicyanoalkene compound having the formula R3CH=C(CN)2, wherein R3 is as defined above by heating at reflux and isolating a first intermediate compound having the structure
Figure imgf000406_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 and 6 carbons and a double bond between the 7 carbon and the 8 nitrogen 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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