CA2286909A1 - 5,7-disubstituted 4-aminopyrido¬2,3-d|pyrimidine compounds and their use as adenosine kinase inhibitors - Google Patents

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

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CA2286909A1
CA2286909A1 CA002286909A CA2286909A CA2286909A1 CA 2286909 A1 CA2286909 A1 CA 2286909A1 CA 002286909 A CA002286909 A CA 002286909A CA 2286909 A CA2286909 A CA 2286909A CA 2286909 A1 CA2286909 A1 CA 2286909A1
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amino
pyrido
pyrimidine
bromophenyl
phenyl
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Shripad S. Bhagwat
Anne Laure Grillot
Chih-Hung Lee
Marlon D. Cowart
Jeffrey Mckie
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    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
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    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
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    • 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
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Abstract

A method for inhibiting adenosine kinase by administering a compound having formula (I) wherein R1 and R2 are independently selected from H, loweralkyl, C1-C6alkoxyC1-C6alkyl, arylC1-C6alkyl, -C(O)C1-C6alkyl, -C(O)aryl, -C(O)heterocyclic or may join together with the nitrogen to which they are attached to form a 5-7 membered ring optionally containing 1-2 additional heteroatoms selected from O, N or S; R3 is selected from the group consisting of loweralkyl, loweralkenyl, loweralkynyl, cycloalkyl, aryl, arylalkyl, heteroaryl, heterocyclic group, heteroarylalkyl or heterocycloalkyl wherein the heteroaryl and heterocyclic groups are linked directly or indirectly by a ring carbon; R4 is selected from the group consisting of loweralkyl, loweralkenyl, loweralkynyl, cycloalkyl, aryl, arylalkyl, heteroaryl, heterocyclic group heteroarylalkyl or heterocycloalkyl; and a dashed line ---indicates that a double bond is optionally present provided that proper valencies are maintained, 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 R1, R2, R3 and R4 are separately defined.

Description

5,7-DISUBSTITUTED 4-AMINOPYRIDO[2,3-D]PYRIMIDINE COMPOUNDS AND THEIR USE AS
ADENOSINE KINASE INHIBITORS
Technical Field The present invention relates to a method of inhibiting adenosine kinase by administering 5,7-disubstituted-4-aminopyrido[2,3-d]pyrimidine compounds, to pharmaceutical compositions containing such compounds, as well as to certain 5,7-disubstituted-4-aminopyrido[2,3-d)pyrimidine compounds.
Background Of The Invention Adenosine kinase (ATP:adenosine 5'-phosphotransferase, EC 2.7.1.20) is a ubiquitous enzyme which catalyzes the phosphorylation of adenosine to AMP, using ATP, preferentially, as the phosphate source. Adenosine kinase has broad tissue and species distribution, and has been isolated from yeast, a variety of mammalian sources and certain microorganisms. It has been found to be present in virtually every human tissue assayed including kidney, liver, brain, spleen, placenta and pancreas. Adenosine kinase is a key enzyme in the control of the cellular concentrations of adenosine.
Adenosine is a purine nucleoside that is an intermediate in the pathways of purine nucleotide degradation and salvage. Adenosine also has many important physiologic 2o effects, many of which are mediated through the activation of specific ectocellular receptors, termed P 1 receptors (Burnstock, in Cell Membrane Receptors for Drugs and Hormones, 1978, (Bobs 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 3o disorders of the central nervous system such as schizophrenia, anxiety, depression and Parkinson's disease. (Williams, M., in Psychopharmacology: The Fourth Generation of Progress; Bloom, Kupfer (eds.), Raven Press, New York, 1995, pp 643-655.
Adenosine has also been implicated in modulating transmission in pain pathways in the spinal cord (Sawynok, et al., Br. J. Pharmacol., 1986, 88: 923-930), and in mediating the analgesic effects of morphine (Sweeney, et al., J. Pharmacol. Exp. Ther.
1987, 243:

657-665). In the immune system, adenosine inhibits certain neutrophil functions and exhibits and-inflammatory effects (Cronstein, J. Appl. Physiol. 1994, 76: 5-13). An AK
inhibitor has been reported to decrease paw swelling in a model of adjuvant arthritis in rats (Firestein, et.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 A1 receptor activation on adipocytes, plays a role in diabetes by inhibiting Iipolysis [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 sites) of excessive cellular activity, trauma or metabolic stress. Once in the extracellular space, adenosine activates specific extracellular receptors to elicit a variety of responses which tend to restore cellular function towards normal (Bruns, Nucleosides Nucleotides, 1991, 10: 931-943;
Miller and Hsu, J. Neurotrauma, 1992, 9: S563-S577). Adenosine has a half life measured in seconds in extracellular fluids (Moser, et al., Am. J. Physiol. 1989, 25: C799-C806), and its endogenous actions are therefore highly localized.
The inhibition of adenosine kinase can result in augmentation of the local adenosine concentrations at foci of tissue injury, further enhancing cytoprotection.
This effect is likely to be most pronounced at tissue sites where trauma results in increased adenosine production. thereby minimizing systemic toxicities.
Pharmacologic compounds directed towards adenosine kinase inhibition provide potentially effective new therapies for disorders benefited by the site- and event-specific potentiation of adenosine. Disorders where such compounds may be useful include ischemic conditions such as cerebral ischemia, myocardial ischemia, angina, coronary artery bypass graft surgery (CABG), percutaneous transluminal angioplasty (PTCA), stroke, other thrombotic and embolic conditions, and neurological disorders such as epilepsy, anxiety, schizophrenia, nociperception including pain perception, neuropathic pain, visceral pain, as well as inflammation, arthritis, immunosuppression, sepsis, diabetes and gastrointestinal disfunctions such as abnormal gastrointestinal motility.
A number of compounds have been reported to inhibit adenosine kinase. The most potent of these include 5'-amino-5'-deoxyadenosine (Miller, et al., J. Biol.
Chem. 1979, 254: 2339-2345), 5-iodotubercidin (Wotring arid Townsend, Cancer Res. 1979, 39: 3018-3023) and 5'-deoxy-5-iodotubercidin (Davies, et al., Biochem. Pharmacol. 1984, 33: 347-355).
Adenosine kinase is also responsible for the activation of many pharmacologically active nucleosides (Miller, et al., J. Biol. Chem. 1979, 254: 2339-2345), including tubercidin, formycin, ribavirin, pyrazofurin and 6-(methylmercapto)purine riboside. These purine nucleoside analogs represent an important group of antimetabolites which possess eytotoxic, anticancer and antivirai 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., 1 l: 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-4-2S 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]pyrimidine compounds having antibacterial activity.
A. Gupta et al., (J. Indian Chem. Soc., 71: 635-636 (1994)) disclose 4-amino-5-(4-fluorophenyl)-7-(4-3o 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-d]pyrinudine, 4-amino-5-{4-methoxyphenyl}-7-(4-aminophenyl)pyrido[2,3-d]pyrimidine, - 35 and 4-amino-5-(4-methoxyphenyl)-7-(4-bromophenyl)pyrido[2,3-d]pyrimidine compounds having antifungal activity. P. Victory et al., Tetrahedron, 51: 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.
Summarv Of The Invention The present invention provides for 5,7-disubstituted-4-aminopyrido[2,3-d)pyrimidine compounds having utility as adenosine ldnase inhibitors.
In one aspect, the present invention provides a method of inhibiting adenosine kinase by administering a compound of formula (n RyN,R2Rs I
H
io ~N N~~ R4 (n wherein R 1 and R2 are independently selected from H, loweralkyl, C 1-C6alkoxyC 1-C6alkyl, arylCl-C6alkyl, -C(O)C1-C6alkyl, -C(O)aryl, -C(O)heterocyclic or may join together with the nitrogen to which they are attached to form a 5-7 membered ring optionally containing 1-2 additional heteroatoms selected from O, N or S;
R3 is selected from the group consisting of loweralkyl, loweralkenyl, loweralkynyl, cycloallcyl, aryl, arylalkyl, heteroaryl, heterocyclic group, heteroarylalkyl or heterocycloalkyl wherein the heteroaryl and heterocyclic groups are linked directly or indirectly by a ring carbon;
R4 is selected from the group consisting of loweralkyl, loweralkenyl, loweralkynyl, cycloallcyl, aryl, arylalkyl, heteroaryl, heterocyclic group heteroarylalkyl or heterocycloalkyl; and a dashed line --- indicates that a double bond is optionally present provided that proper valencies are maintained.
In particular, the method of inhibiting adenosine kinase comprises exposing an adenosine kinase to an effective inhibiting amount of a compound of Formula I
of the present invention. Where the adenosine kinase is located in vivo, the compound is administered to the organism.
In still another aspect, the present invention provides a method of treating ischemia, neurological disorders, nociperception , inflammation, immunosuppression, gastrointestinal disfunctions, diabetes and sepsis in a mammal in need of such treatment, comprising 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) RvN~R2 Rs H
,6 2N i to ~N N'~~ R4 (I) wherein R 1 and R2 are independently selected from H, loweralkyl, C 1-C6alkoxyC 1-C6aikyl, arylC I -C6alkyl, -C(O)C 1-C6alkyl, -C{O)aryl; -C(O)heterocyclic or may join together with the nitrogen to which they are attached to form a 5-7 membered ring optionally 15 containing 1-2 additional heteroatoms selected from O, N or S;
R3 is selected from the group consisting of loweralkyl, loweralkenyl, loweralkynyl, cycloalkyl, aryl, arylalkyl, heteroaryl, heterocyclic group, heteroarylalkyl or heterocycloalkyi wherein the heteroaryl and heterocyclic groups are linked directly or indirectly by a ring carbon;
20 R4 is selected from the group consisting of loweralkyl, loweralkenyl, loweralkynyl, cycloalkyl, aryl, arylalkyl, heteroaryl, heterocyclic group heteroarylalkyl or heterocycloalkyl; and a dashed line --- indicates that a double bond is optionally present provided that proper valencies are maintained;
with the proviso that the compound may not be selected from the group consisting 25 of:
(a) 4-amino-5-(4-chlarophenyl}-7-{4-nitrophenyl)pyrido[2,3-d]pyrimidine;
(b) 4-amino-5-(4-methoxyphenyl)-7-(4-nitrophenyl)pyrido[2,3-d]pyrimidine;
(c) 4-amino-5-(4-fluorophenyl)-7-(4-fluorophenyl)pyrido[2,3-d]pyrimidine;
(d) 4-amino-5-(4-chlorophenyl)-7-(4-fluorophenyl)pyrido[2,3-d]pyrinudine;
30 (e) 4-amino-5-phenyl-7-(4-aminophenyl)pyrido[2,3-d]pyrimidine;
(f) 4-amino-5-phenyl-7-(4-bromophenyl)pyrido[2,3-d]pyrimidine;
(g) 4-amino-5-(4-methoxyphenyl)-7-(4-aminophenyl)pyrido[2,3-d]pyrimidine;
(h) 4-amino-5-(4-methoxyphenyl)-7-(4-bromophenyl)pyrido[2,3-d]pyrimidine; and (i) 4-amino-5,7-diphenylpyrido[2,3-d]pyrimidine.
In another aspect, the present invention provides a pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula I above in combination with a pharmaceutically acceptable carrier.
In another aspect, the present invention provides a process for the preparation of adenosine kinase inhibiting compounds having the formula R~~N, R2 R3 I
3N 4~ \6H
i~ 4 1 N N ~ R , wherein R 1 and RZ are hydrogen, the method comprising (a) contacting 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 NC

(b) contacting the first intermediate compound with formamide at reflux for from about 1 to about 8 hours, and isolating the compound of formula I with double bonds between the 7 and 8 position and the 5 and 6 position and optionally reducing to form a partially saturated right side or a fully saturated right side to form a compound of formula I.
Detailed De, cription 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, and to novel 5,7-disubstituted-4-aminopyrido[2,3-dJpyrimidine 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 3U adenosine kinase comprising administering a compound of formula l R ~~N- R2 R3 H
3 N ~, 2~ i u6 1 N N ~~ R a (I) wherein RI and R2 are independently selected from H, loweralkyl, arylC1-C6alkyl, -C(O)C1-C6allcyl, -C(O)aryl, -C(O)heterocyclic or may join together with the nitrogen to which they are attached to from a 5-7 membered ring optionally containing 1-2 additional heteroatoms selected from O, N or S;
R3 and R4 are independently selected from the group consisting of:
C1-C6~Yl~
C2-C6alkenyl, C2-C~alkynyl, C3-Cgcycloalkyl, heteroarylCp-C6alkyl or substituted heteroarylCp-C6alkyl, optionally substituted cycloalkyl, arylCp-C6alkyl or substituted arylCp-C6alkyl, heteroarylC2-C6alkenyl or substituted heteroarylC2-C6alkenyl, arylC2-C6alkenyl or substituted arylC2-C6alkenyl, heteroarylC2-C6alkynyl or substituted heteroarylC2-C6alkynyl, aryIC2-C6alkynyl or substituted arylC2-C6alkynyl wherein the 1-4 heteroaryl or aryl substituents are independently selected from halogen, oxo, C02R5, cyanoCl-C6alkyl, heteroarylCp-C6alkyl, heterocyclicCp-C6alkyl, Cl-C6alkyloxy, C1-C6alkyloxyCl-C6alkyl, arylCp-C6allcyl, arylCl-C6alkyloxy, RSR6NC(O), cyano, C2-C6alkenyl, C2-C6alkynyl, C 1-C6alkyl, C2-C6allcenyldialkylmalonyl, CF3, HO-, C I-C6alkyloxyCl-C6alkyloxy, CI-C6aIkylSOn wherein n is 1-2, C1-C6alkylthio, Cl-C6alkylacryl, CF30, CF3, C1-C4alkylenedioxy, C1-C~alkylacryl, RSR6N(CO)NRS, N-formyl(heterocyclic), NO2, NRSR6Cp-C6alkyl, (R50)(R60)-P(O)- Cp-C6alkyl, wherein RS and R6 are independently selected from H, C1-C6alkyl, HC(O), Cl-C6alkyloxyCl-C6alkyl, CI-C6allcyloxy, CI-3o C6alkylC(O), CF3C(O), NR~RgCI-C6alkyl, phthalimidoCl-C(C(O), Cl-C6alkylSOn where n is 1-2, CNC1-C6alkyl, R~R8NC(O)NR~-, heteroaryl, NR~RgCI-C6a1ky1C(O), C1-C6allcyloxycarbamidoC 1-C6allcyl, wherein R~ and Rg are independently selected from those variables identified for RS and R6 or RS and R6 or R~ and Rg may join together with the nitrogen atom to which they are attached to form a 5-7 membered unsubstituted or substituted ring optionally containing 1-3 additional heteroatoms selected from O, N or S wherein the substituents are selected from Cl-C6alkyl and a dashed line --- indicates a double bond is optionally present.
The preferred compounds utilized in the above method of inhibiting adenosine kinase are selected from a compound of formula II
RvN,R2 R3 H
\~
2~N N' 'R4 1 (In wherein Rl-Rg and n are as defined above. The present invention also relates to compounds of formula II with Rl-Rg and n as defined above with the proviso that the specific known compounds identified above for a compound of formula I are excluded.
In a preferred embodiment, an adenosine kinase inhibitor of the present invention is a compound of Formula (II) above, wherein R4 is aryl or heteroaryl and substituted versions thereof.
In a more preferred embodiment, an adenosine kinase inhibitor of the present invention is a compound of Formula (II) above, wherein R4 is aryl or heteroaryl and substituted versions thereof and R3 is loweralkyl, aryl, arylalkyl or heteroaryl and substituted versions thereof wherein the substituents are as identified above.
In another preferred embodiment, an adenosine kinase inhibitor of the present invention is a compound of Formula (I) above, wherein R4 is selected from the group consisting of: phenyl; thiophene-2-yl; 3-methyl-2-oxobenzoxazolin-6-yl; 2-(dimethyiamino)-5-pyrimidinyl; 2-(N-formyl-N-methyl amino)-5-pyrimidinyl; 2-(N-methoxyethyl-N-methyl amino)-5-pyrimidinyi; 2-(N-methylamino)-5-pyrimidinyl; 2-(1-morpholinyl)-5-pyrimidinyl;
2-(1-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-_g_ (dimethylamino)phenyl; 4-(imidazol-1-yl)phenyl; 4-(methylthio)phenyl; 4-(morpholinyl)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-morpholinyl)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)ethoxyphenyl; 4-(2-oxo-3-oxazolidinyl)phenyl; 4-(4-methoxy-2-butyl)phenyl;
4-(4-methylpiperidinyl)phenyi; 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-morpholinylphenyl; 4-N-(2-(dimethylamino)ethyl)-N-formylamino)phenyl; 4-N-(3-methoxypropionyl)-N-isopropyl-amino)phenyl; 4-N-ethyl-N-(2-methoxyethyl)amino)phenyl; 4-N-formylpiperazinylphenyl; 4-nitrophenyl; 4-piperidinylphenyl; 4-(3-pyridyl)phenyl; 4-pyrrolidinylphenyl; 4-t-butylacrylphenyl; 5-(dimethylamino)thiophene-2-yl; 5-amino-2-pyridyl; 5-dimethylamino-2-pyrazinyl;

dimethylaminopyridazin-6-yl; 5-dimethylamino-2-pyridyl; 5-pyrimidinylphenyl; 6-(N-methyl-N-formylamino)-3-pyridinyl; 6-(N-methyl-N-methoxyethylamino)-3-pyridinyl; 6-(2-oxo-3-oxazolidinyl)-3-pyridinyl; 6-dimethylamino-3-pyridinyl; 6-imidazolyl-3-pyridinyl; 6-morpholinyl-3-pyridinyl; 6-pyrrolidinyl-3-pyridinyl; 6-(2-propyl)-3-pyridinyl;
and (4-formylamino)phenyl.
In another preferred embodiment, an adenosine ldnase 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-y1; 1-(3-bromophenyl)ethyl; 2-(N-phenylmethoxycarbonyl)aminophenyl; 2-(3-bromophenyl)ethyl; 2-(3-cyanophenyl)methyl; 2-(4-bromophenyl)ethyl; 2-(S-chloro-2-(thiophen-3-yl)phenyl; 2-bromophenyl; 2-furanyl; 2-methylpropyl; 2-phenylethyl;
3s phenylmethyl; 2,3-dimethoxyphenyl; 2,3-methylenedioxyphenyl; 3-(furan-2-yl)phenyl; 3-(thiophen-2-yl)phenyI; 3-(2-pyridyl)phenyl; 3-(3-methoxybenzyl)phenyl; 2-(3-aminopropynyl)phenylmethyl; 3-benzyloxyphenyl; 3-bromo-4-fluorophenyl; 3-bromo-iodophenyl; 3-bromo-5-methoxyphenyl; 3-bromophenyl; 3-bromophenylmethyl; 3-carboxamidophenyl; 3-chlorophenyl;.3-cyanophenyl; 3-diethylmalonylallylphenyl;

dimethylaminophenyl; 3-ethoxyphenyl; 3-fluoro-5-trifluoromethylphenyl; 3-fluoiophenyl; 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-i0 benzyloxyphenyl; 4-bromophenyl; 4-bromothiophene-2-yl; 4-butoxyphenyl; 4-dimethylaminophenyl; 4-fluoro-3-trifluoromethylphenyl; 4-methoxyphenyl; 4-neopentylphenyl; 4-phenoxyphenyl; 5-bromothiophene-2-yl; 5-cyclohexyl; 5-cyclopropyl;
5-hexyl; 5-methyl; 5-phenyl; (2-bromo-5-chlorophenyl)methyl; (2-bromophenyl)methyl; and (5-chloro-2-(3-methoxyphenyl)phenyl)methyl.
Exemplary and preferred adenosine ldnase inhibitor compounds of the invention utilized in the method recited herein include the compounds listed below wherein R1 and R2 in a compound of formula II are selected from H, the groups identified at the 5-position are included within R3 and the groups identified at the 7-position are included within R4, RS-Rg are as described in the specific compound:
4-amino-5-(4-dimethylaminophenyl)-7-(4-bromophenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(4-dimethylaminophenyl)-7-(4-dimethylaminophenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(4-methoxyphenyl)-7-(4-dimethylaminophenyl)pyrido[2,3-d]pyrimidine;
4-amino-S-(4-dimethylaminophenyl)-7-(4-methoxyphenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(4-(2-propyl)phenyl)-7-(4-methoxyphenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(4-neopentylphenyl)-7-(4-methoxyphenyl)pylzdo[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[2,3-d]pyrimidine;
4-amino-5-(4-benzyloxyphenyl)-7-(4-methoxyphenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(4-phenoxyphenyI)-7-(4-methoxyphenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(4-(2-propyl)phenyl)-7-(4-diethylmalonylallylphenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(4-(2-propyl)phenyl)-7-(4-t-butylacrylphenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(4-dimethylaminophenyl)pyrido[2,3-d]pyrimidine;

4-amino-5-(3,4-dimethoxyphenyl)-7-(4-dimethylaminophenyl)pyrido [2,3-d]pyrimidine;
4-amino-5-(3-t-butylacrylphenyl)-7-(4-dimethylaminophenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-methoxyphenyl-7-(4-dimethylaminophenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3,5-dimethoxyphenyl-7-(4-dimethylaminophenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-diethylmalonylallylphenyl)-7-{4-dimethylaminophenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-vinylpyridinylphenyl)-7-(4-dimethylaminophenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-trifluoromethylphenyl)-7-(4-dimethylaminophenyl)pyrido[2,3-d]PY~dine;
4-amino-5-(3-carboxamidophenyl)-7-{4-dimethylaminophenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-cyanophenyl)-7-(4-dimethylaminophenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-benzyloxyphenyl)-7-(4-dimethylaminophenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-methoxyphenyl)-7-(4-methoxyphenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(4-butoxyphenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-(2-pyridyl)phenyl)-7-(4-dimethylaminophenyl)pyrido[2,3-d]pyrimidine;
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[2,3-d]pyrimidine;
4-amino-5-(3-ethoxyphenyl)-7-(4-dimethylaminophenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-trifloromethyoxyphenyl)-7-(4-dimethylaminophenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3,5-dichlorophenyl)-7-(4-dimethylaminophenyl)pyrido[2,3-d]pyrirnidine;

4-amino-5-(3-bromo-4-fluorophenyl)-7-(4-dimethylaminophenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-hydroxyphenyl}-7-(4-dimethylaminophenyl)pyrido [2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(4-morpholinylphenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-{4-piperidinylphenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(4-(imidazol-1-yl)phenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(4-chlorophenyl)pyrido[2,3 ~d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(4-isopropylphenyl)pyrido[2,3-d]pyrimidine;
4-amino-S-(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-S-(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-d]pyrimidine;
'4-amino-5-(3-methoxyethyoxyphenyl)-7-(4-dimethylaminophenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3,4-methylenedioxyphenyl)-7-(4-dimethylaminophenyl)pyrido[2,3-d]PY~dine;
4-amino-5-(3-bromophenyl)-7-(4-ethoxyphenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(2'-thiophene)pyrido[2,3-d]pyrimidine;
4-amino-S-(3-bromophenyl)-7-{4-fluorophenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-dimethylaminophenyl)-7-(4-dimethylaminophenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-phenyl-7-(4-dimethylaminophenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3,4,5-trimethoxyphenyl)-7-(4-dimethylaminophenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(4-nitrophenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-{4-iodophenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-{3-bromophenyl)-7-(3,4-methylenedioxyphenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(thiophen-2-yl)-7-(4-morpholinylphenyl)pyrido [2,3-d]pyrimidine;
4-amino-5-(3,5-dimethoxyphenyl)-7-(thiophen-2-yle)pyrido [2,3-d]pyrimidine;
4-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-d]PY~dine;
4-amino-5-(3,5-dimethoxyphenyl)-7-(4-morpholinylphenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-trifluoromethylphenyl)-7-(thiophene-2-yl)pyrido [2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(4-aminophenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromo-4-fluorophenyl)-7-(thiophene-2-yl)pyrido [2,3-d]pyrimidine;

WO 98!46605 PCT/ITS98/07207 4-amino-5-(3-bromo-4-fluorophenyl)-7-(2-furanyl)pyrido [2,3-d]pyrimidine;
4-amino-5-(3,5-dimethoxyphenyl)-7-(4-iodophenyl)pyrido[2,3-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[2,3-d]pyrimidine;
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-d]pyrimidine;
4-amino-S-(3-bromophenyl)-7-(4-pyrrolidinylphenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(4-bromothiophene-)-7-(4-dimethylaminophenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(4-bromothiophene-2-yl)-7-(4-morpholinylphenyl)pyrido[2,3 d]pyrimidine;
4-morpholinyl-5-(3-bromophenyl)-7-(4-dimethylaminophenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(5-bromothiophene-2-yl)-7-(4-morpholinylphenyl)pyrido[2,3-d]pyrimidine;
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-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(4-dimethylaminophenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3,S-dimethoxyphenyl)-7-(5-pyrimidinylphenyl)pyrido[2,3-d]pyrimidine;
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-d]pyrimidine;
4-amino-5-(4-bromothiophene-2-yl)-7-(thiophene-2-yl)pyrido[2,3-d]pyrimidine;
4-amino-~-(3-bromophenyl)-7-(5-(dirnethylamino)thiophene-2-yl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromo-5-iodophenyl)-7-(4-(dimethylamino)phenyl)pyrido [2,3-d]pyrimidine;
4-amino-5-(3,5-di(trifluorornethyl)phenyl)-7-(4-(dimethylamino)phenyl)pyrido[2,3-d]pyrimidine;
4-amino-S-(3,5-di(trifluoromethyl)phenyl)-7-(4-morpholinylphenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3,5-dibromophenyl)-7-(4-(dimethylamino)phenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3,5-dibromophenyl)-7-(4-morpholinylphenyl)pyrido[2,3-d]pyrimidine;

4-amino-5-(4-bromothiophene-2-yl)-?-(4-(4-methylpiperidinyi)phenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3,5-dibromophenyl)-?-(4-(dimethylamino)phenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-?-(3-(dimethylamino)phenyl}pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-?-(4-methylsulfonylphenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-?-(3-methoxyphenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-?-(4-(methylthio)phenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-?-(3,4-dichlorophenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-?-(4-{N-methyl-N-formylamino)phenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-?-(4-methylaminophenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromo-4-fluorophenyl)-?-(4-methylsulfonylphenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-?-(3-amino-4-methoxyphenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-?-(3-bromo-4-(dimethylamino)phenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-?-(3-methyl-4-(dimethylamino)phenyl)pyrido[2,3-d]pyrimidine;
4-amino-S-(3-bromophenyl)-?-(4-(N-methyl-N-trifluoroacetylamino)phenyl)pyrido [2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-?-(4-(dimethylamino)-3-fluorophenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-?-(4-(N-ethyl-N-formylamino)phenyl)pyrido(2,3-d]pyrimidine;
4,4-bis(acetylamino)-5-(3-bromophenyl)-?-(4-(N-methyl-N-acetylamino)phenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-?-(4-(N-acetyl-N-methylanvno)phenyl)pyrido[2,3-d]pyrinudine;
4-amino-5-(3-bromophenyl)-?-(4-(N-ethylamino)phenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-?-(4-(N-methyl-N-(2-methoxyethyl)amino)phenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-?-(4-(N-isopropylamino)phenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-?-(4-N-ethyl-N-(2-methoxyethyl)amino)phenyl)pyrido[2,3-d]pyrimidine;

WO 98!46605 PCT/US98/07207 4-amino-5-(3-bromophenyl)-7-(4-N-(3-methoxypropionyl)-N-isopropyl-amino)phenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(4-N-(2-(dimethylamino)ethyl)-N-formylamino)phenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(4-(N-(2-(dimethylamino)ethyl)amino)phenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(4-(N-methyl-N-(2-cyano)ethylamino)phenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(4-(N-methyl-N-(3-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;
i5 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-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(3-methyl-4-(N-methyl-N-2o (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-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(6-dimethy!amino-3-pyridinyl)pyrido[2,3-d]pyrimidine;
25 4-amino-5-(3-cyanophenyl)-7-(4-methylsulfonylphenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-cyanophenyl)-7-(4-(N-methyl-N-formylamino)-phenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(6-(N-methyl-N-formylamino)-3-pyridinyl)pyrido[2,3-d]pyrimidine;
30 4-amino-5-(3-bromophenyl)-7-(6-morpholinyl-3-pyridinyl)pyrido[2,3-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-pyrolidinyl-3-pyridinyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(2-(dimethylamino)-5-pyrimidinyl)pyrido[2,3-35 d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(2-(N-methoxyethyl-N-methyl amino)-5-pyrimidinyl)pyrido[2,3-d]pyrimidine;

4-amino-5-(3-bromophenyl)-7-(2-(N-formyl-N-methyl amino)-5-pyrimidinyl)pyrido[2,3-d)pyrimidine;
4-amino-5-(3-bromophenyl)-7-(2-(N-methylamino)5-pyrimidinyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(2-( 1-pyrrolidinyl)-5-pyrimidinyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(2-( 1-morpholinyl)-5-pyrimidinyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(6-(2-oxo-3-oxazolidinyl)-3-pyridinyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(2-pyridyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(3-pyridyl)pyrido[2,3-d]pyrimidine;
4-amino-S-(3-(thiophen-2-yl)phenyl)-7-(4-dimethylaminophenyl)pyrido(2,3-d]pyrimidine;
4-amino-5-(3-(furan-2-yl)phenyl)-7-(4-dimethylaminophenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-(3-methoxyphenyl)phenyl)-7-(4-dimethylaminophenyl)pyrido[2,3-d]pylimidine;
4-amino-5-phenyl-7-(4-dimethylaminophenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-chlorophenyl)-7-(4-(morpholinyl)phenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromo-4-fluorophenyl)-7-(4-(morpholinyl)phenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-chlorophenyl)-7-(4-iodophenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-chlorophenyl)-7-(4-(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-d]pyrimidine;
4-amino-5-(2-phenylethyl)-7-(4-diethylaminophenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(2-methylpropyl)-7-(4-diethylaminophenyl)pyrido[2,3-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[2,3-d]pylimidine;
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-d]pyrimidine;
-lb-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-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-d]pyrimidine;
4-amino-5-hexyl-7-(4-diethylaminophenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(2-{3-bromophenyl)ethyl)-7-(4-diethylaminophenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-((2-bromophenyl)methyl)-7-(4-diethylaminophenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-cyclopropyl-7-(4-dimethylaminophenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-cyclohexyl-7-(4-dimethylaminophenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-((2-bromo-5-chlorophenyl)methyl)-7-(4-diethylaminophenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-methyl-7-(4-diethylaminophenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(2,3-methylenedioxyphenyl)-7-(4-dimethylaminophenyl)pyrido[2,3-d]pyrimidirie;
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-d]pyrimidine;
4-amino-5-(3,5-dimethylphenyl)-7-{4-dimethylaminophenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-{3,4-dichlorophenyl)-7-(4-dimethylaminophenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(4-fluoro-3-trifluoromethylphenyl)-7-(4-dimethylaminophenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromo-5-methoxyphenyl)-7-(4-morpholinylphenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromo-5-methoxyphenyl)-7-(4-pyrrolidinylphenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromo-5-methoxyphenyl)-7-(4-piperidinylphenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromo-5-methoxyphenyl)-7-(4-dimethylaminophenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-methylthiophenyl)-7-(4-dimethylaminophenyl)pyrido[2,3-d]pyrimidine;
4-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-d]pyrimidine;
4-amino-5-(3-methylsulfonylphenyl)-7-(4-dimethylaminophenyl)pyrido[2,3-d]pvrimidine;
4-acetylamino-5-(3-bromophenyl)-7-(4-dimethylaminophenyl)pvrido[2,3-d]pyrimidine;
4-formylamino-5-(3-bromophenyl)-7-(4-dimethylaminophenyl)pyrido[2,3-d]pyrimidine;
4-(methoxyacetyl)amino-5-(3-bromophenyl)-7-(4-diethylaminophenyl)pyrido[2,3-d]pyrimidine;
4-trifluoroacetylamino-5-(3-bromophenyl)-7-(4-dimethylaminophenyl)pyrido[2,3-d]pyrimidine;
4-pentanoylamino-5-(3-bromophenyl)-7-(4-dimethylaminophenyl)pyrido[2,3-d]PY~dine;
4-benzoylamino-5-(3-bromophenyl)-7-(4-dimethylaminophenyl)pyrido[2,3-d]PY~dine:
4-(N-BOC-glycyl)amino-5-(3-bromophenyl)-7-(4-dimethylaminophenyl)pyrido[2,3-d]pyrimidine;
4-(N-phthalimidylglycyl)amino-5-(3-bromophenyl)-7-{4-2o dimethylaminophenyl)pyrido[2,3-d]pyrimidine;
4-(ethoxycarbonyl)amino-5-(3-bromophenyl)-7-(4-dimethylaminophenyl)pyrido[2,3-d]pyrimidine;
4-(ethylaminocarbonyl)amino-5-(3-bromophenyl)-7-(4-dimethylaminophenyl)pyrido[2,3-d]pyrimidine;
4-allylamino-S-(3-bromophenyl)-7-(4-dimethylaminophenyl) pyrido[2,3-d]pyrimidine;
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[2,3-d]pyrimidine;
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[2,3-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-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-( 1-methyl-2-oxobenzoxazolin-6-yl)pyrido[2,3-d]pyrimidine;
4-amino-5-((5-chloro-2-(3-methoxyphenyl)phenyl)methyl)-7-(4-dimethylaminophenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-{(thiophene-2-yl)methyl)-7-(4-diethylaminophenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-((thiophene-3-yl)methyl)-7-(4-diethylaminophenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-((2-bromophenyl)methyl)-7-(4-dimethylaminophenyl)pyrido[2,3-d]PY~dine;
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-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(4-{N-methyl-N-((2-dimethylamino)ethyl)amino)phenyl)pyrido[2,3-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[2,3-d]pyrimidine;
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-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-{6-(2-propyl)-3-pyridinyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(3-methyl-4-pyrrolidinylphenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(6-imidazolyl-3-pyridinyl)pyrido(2,3-d]pyrimidine;
4-amino-5-phenylmethyl-7-(4-diethylaminophenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(2-(3-aminopropynyl)phenylmethyl)-7-(4-diethylaminophenyl)pyrido[2,3-d]pyrimidine;
4-amino-~-( 1-(3-bromophenyl)ethyl)-7-(4-diethylaminophenyl)pyrido[2,3-d]pyrimidine;
4-amino-~-(4-dimethylaminophenyl)-7-(4-bromophenyl)pyrido[2,3-d]pyrimidine;
4-amino-~-(2-furanyl)-7-(4-(N-morpholinyl)phenyl)pyrido[2,3-d]pyrimidine;

4-amino-5-(3-bromophenyl)-7-(2-dimethylamino-5-pyrimidinyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(4-(ureido)phenyl)pyrido [2,3-d]pyrimidine;
4-amino-5-( 1-phenylmethyl-3-piperidinyl)-7-(4-diethylaminophenyl)pyrido[2,3-d]pyrimidsne;
4-amino-5-(3-bromophenyl)-7-(6-(3-methyl-5-isoxazolyl))-3-pyridinyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(6-chloro-3-pyridinyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(6-methoxy-3-pyridinyl)pyrido[2,3-d]pyrimidine;
l0 4-amino-5-(3-bromophenyl)-7-(6-(1,2,4-triazol-4-yl)-3-pyridinyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(2-morpholinyl-5-pyrimidinyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(2-thiazolyl}-7-(4-pyrrolidinylphenyl)-pyrido[2,3-d]pyrimidine;
15 4-amino-5-(3-bromophenyl)-7-(6-pyrazolyl-3-pyridinyl))-pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(4-( 1-methyl-ureido)phenyl)-pyridoj2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(4-(N-methyl-N-(2-pyrimidinyl)amino)phenyl)-20 pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(3-fluoro-4-(N-formyl-N-methylamino)phenyl)-pyrido[2,3-d]pyrimidine;
4-formylamino-5-(3-bromophenyl)-7-(3-fluoro-4-(N-formyl-N-methylamino)phenyl)-pyrido[2,3-d]pyrimidine;
25 4-amino-5-(3-bromophenyl)-7-(4-(N-methyl-N-methylsulfonylamino)-phenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(6-(N-methyl-N-methylsulfonylamino)-3-pyridinyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-( 1-methyl-5-indolinyl)pyrido[2,3-d]pyrimidine;
30 4-amino-5-(3-bromophenyl)-7-( 1-methyl-5-benzimidazolyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(6-dimethylamino-3-pyridazinyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3bromophenyl)-7-(6-morphoiinyl-3-pyridazinyl)pyrido[2,3-35 d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(6-pyrrolidinyl-3-pyridazinyl)pyrido[2,3-d]pyrimidine;

4-amino-5-(3-bromophenyl)-7-(5-morpholinyl-2-pyrazinyl)pyrido(2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(5-(N-(2-methoxyethyl)-N-methylamino)-2-pyrazinyl)pyrido [2,3-d]pvrimidine;
4-amino-5-(3-bromophenyl)-7-(4-(morpholinylmethyl)-phenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-{5-(N,N-bis(2-methoxyethyl)amino)-2-pyridinyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(4-(imidazolylmethyl)-phenyl)pyrido[2,3-1o d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(S-( 1-morpholinyl)-2-pyridinyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(4-((dimethylamino)methyl)-phenyl)pyrido[2,3-d]PY~dine:
15 4-amino-5-(3-bromophenyl)-7-(5-(4-hydroxy-1-piperidinyl)-2-pyridinyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(S-(N-formyl-N-methylamino)-2-pyridinyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(5-(2-propenyl)-2-pyridinyl)pyrido[2,3-2o d]pyrimidine;
4-amino-S-(3-bromophenyl)-7-(3-(2-methoxyethyl)-2-oxo-6-benzoxazolyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(4-( 1-(N-formylamino)-ethyl)phenyl)pyrido [2,3-d]pyrimidine;
25 4-(methylamino)-5-(3-bromophenyl)-7-(4-dimethylaminophenyl)pyrido[2,3-d]pyrimidine hydrochloride;
4-(2-methoxyethylamino)-5-(3-bromophenyl)-7-(4-dimethylaminophenyl)pyrido[2,3-d]pyrimidine hydrochloride;
4-amino-5-(3-bromophenyl)-7-(4-( 1-methyl-2-imidazolyl)phenyl)pyrido[2,3-3o d]pyrimidine 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-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(4-(dimethylaminoethyl)phenyl)pyrido[2,3-35 d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(4-(3-(dimethylamino)propynyl)phenyl)pyrido[2,3-d)pyrimidine;

WO 98/46605 PCT/fJS98/07207 4-amino-5-(3-bromophenyl)-7-(4-(3-amino-3-methylbutynyl)phenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(4-dimethylphosphonatophenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(4-(3-(methoxypropynyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(4-carboxyphenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(4-methyl-3-oxo-2H-4H-pyrido[3,2-b]-1,4-oxazin-7-yl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(4-(2-(dimethylamino)ethyl)-3-oxo-2H-4H-to pyrido[3,2-b]-1,4-oxazin-7-yl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(2,3-dihydro-3-(dimethylaminoethyl)-2-oxobenzoxazol-6-yl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(4-methyl-3-oxo-2H-4H-benzo-1,4-oxazin-7-yl)pyrido[2,3-d]pyrimidine;
15 4-amino-5-(3-bromophenyl)-7-(2,2,4-trimethyl-3-oxo-ZH-4H-benzo-1,4-oxazin-7-yl)pyrido[2,3-d]pyrimidine;
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-( 1-methylethyl)-2-pyridyl)pyrido[2,3-20 d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-{S-piperidin-1-ylpyrid-2-yl)pyrido[2,3-d]pyrimidine;
4-amino-5-( 1-(4-bromophenyl)ethyl)-7-(6-morpholinylpyrid-3-yl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-{4-((N-formylamino)methyl)phenyl)pyrido[2,3-25 d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(4-( 1-methyl-1-(N-methylamino)ethyl)phenyl)-pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(4-( 1-(dimethylamino)-1-methylethyl)phenyl)pyrido[2,3-d]pyrimidine;
30 4-amino-5-(3-bromophenyl)-7-(N-acetyl-5-indolinyl)pyrido[2,3-d]pyrimidine;
4-amino-5-cyclohexyl-7-(6-chloro-3-pyridyl)pyrido[2,3-d]pyrimidine:
4-amino-5-( 1-(2-bromophenyl}ethyl)-7-(6-diethylamino-3-pyridyl)pyrido[2,3-d]pyrimidine;
4-amino-5-( 1-(2-bromophenyl)ethyl)-7-(6-morpholinyl-3-pyridyl)pyrido[2,3-35 d]pyrimidine;
4-amino-5-( 1-(2-bromophenyl)ethyl)-7-(4-(N-methyl-N-formyl)amino)-phenyl)pyrido[2,3-d]pyrimidine;

4-amino-5-cyclohexyl-7-(6-morpholinyl-3-pyridyl)pyrido [2,3-d]pyrimidine;
4-amino-5-((2-bromophenyl)methyl)-7-(6-morpholinyl-3-pyridyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(4-tetrahydropyranyl)-7-(6-morphoiinyl-3-pyridyl)pyrido[2,3-d]pyrimidine;
4-amino-5-cyclohexyl-7-(6-dimethylamino-3-pyridyl)pyrido[2,3-d]pyrimidine;
4-amino-5-( 1-ethylpropyl)-7-(6-dimethylamino-3-pyridyl)pyrido[2,3-d]pyrimidine;
4-amino-5-cyclopentyl-7-(6-morpholinyl-3-pyridyl)pyrido[2,3-d]pyrimidine;
4-amino-5-cyclohexyl-7-(2-chloro-3-pyridyl)pyrido[2,3-d]pyrimidine;
l0 4-amino-5-(3,5-dimethylcyclohexyl)-7-(6-dimethylamino-3-pyridyl)pyrido.[2,3-d]pyrimidine;
4-amino-5-((N-(benzyloxycarbonyl)-4-piperidinyl)methyl)-7-(6-morpholinyl-3-pyridyl)pyrido[2,3-d]pyrimidine;
4-amino-5-cyclohexyl-7-(6-bromo-3-pyridyl)pyrido[2,3-d]pyrimidine;
15 4-amino-5-cyclohexyl-7-(3-cyanophenyl)pyrido[2,3-d]pylimidine;
4-amino-5-{ t -(2-bromophenyl)ethyl)-7-(6-dimethylamino-3-pyridazinyl)pyrido [2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(6-imidazolyl-3-pyridazinyl)pyrido(2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-{6-(azacycloheptanyl)-3-pyridazinyi)pyrido[2,3-20 d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(6-(N-methyl-N-( 1-methylethyl))amino)-3-pyridazinyl)pyrido[2,3-d]pyrimidine;
4-amino-5-{ 1-(2-bromophenyl~thyl)-7-(6-morpholinyl-3-pyridazinyl)pyrido[2,3-d]pyrimidine;
25 4-amino-5-cyclohexyl-7-(6-(4-acetylpiperazinyl)-3-pyridyl)pyrido[2,3-d]pyrimidine;
4-amino-5-cyclohexyl-7-(6-(4-acetyl-1,4-diazacycloheptanyl)-3-pyridyl)pyrido[2,3-d]pyrimidine;
4-amino-5-cyclohexyl-7-(b-(4-methyl-1,4-diazacycloheptanyl)-3-pyridyl)pyrido[2,3-d]pyrimidine;
30 4-amino-5-cyclohexyl-7-(6-(N-methyl-N-(2-(2-pyridyl)ethyl)amino)-3-pyridyl)pyrido[2,3-d]pyrimidine;
4-amino-5-cyclohexyl-7-(6-2-(N-(N',N'-dimethylaminoethyl)-N-methylamino)-3-pylidyl)pyrido[2,3-d]pyrimidine;
4-amino-5-cyclohexyl-7-(6-azetidinyl-3-pyridyl)pyrido[2,3-d]pyrimidine;
35 4-amino-5-cyclohexyl-7-(6-{3-(N-methylacetamido)pyrrolidinyl)pyridyl)pyrido[2,3-d]pyrimidine;

4-amino-5-cyclohexyl-?-(6-(3-(formamido)pyrrolidinyl)pyridyl)pyrido[2,3-d]pyrimidine;
4-amino-5-cyclohexyl-?-(4-oxo-1-phenyl-1,3,8-triazaspiro[4.5[decan-8-yl)pyrido[2,3-d]pyrimidine;
4-amino-S-cyclohexyl-?-(6-(2-methoxymethyl)pyrrolidin-1-yl)pvridyl)pyrido[2,3-d]pyrimidine;
4-amino-5-cyclohexyl-?-(6-(N-methoxyethyl-N-propylamino)pyridyl)pyrido[2,3-d]pyrimidine;
4-amino-5-cyclohexyl-?-(N-methyl-N-(2,2-dimethoxyethyl)amino)pyrido[2,3-d]pyrimidine;
4-amino-5-cyclohexyl-?-(6-(4-(dimethylamino)piperidinyl)pyridyl)pyrido[2,3-d]pyrimidine;
4-amino-5-cyclohexyl-?-(6-(4-(aminocarbonyl))piperidinyl)pyridyl)pyrido[2,3-d]pyrimidine;
4-amino-5-cyclohexyl-?-(N-methyl-N-(3-(diethylamino)propyi)aminopyrid-3-yl)pyrido[2,3-d]pyrimidine;
4-amino-5-cyclohexyl-?-(6-(N-methyl-N-(4-pyridyl)ethylamino)pyrid-3-yl)pyrido[2,3-d]pyrimidine;
4-amino-5-cyclohexyl-?-(6-(N-methyl-N-(3-pyridylmethylamino)pyrid-3-yl)pyrido[2,3-d]pyrimidine;
4-amino-5-( 1-{2-bromophenyl)ethyl)-?-( 1-methyl-5-indolyl)pyrido[2,3-d]pyrimidine;
4-amino-5-( 1-(2-bromophenyl)ethyl)-?-{ 1-methyl-2,3-dioxo-5-indolyl)pyrido [2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-?-(3-fluoro-4-(1-morpholinyl)phenyl)pyrido[2,3-d]pyrimidine;
4-amino-~-(3-bromophenyl)-?-(4-hydroxy-3-nitrophenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-?-(6-(4,4-ethylenedioxypiperidinyl)-3-pyridyl)pyrido[2>3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-?-(6-(4-oxopiperidinyl)-3-pyridyl)pyrido[2,3-d]pyrimidine;
4-amino-S-(3-bromophenyl)-?-(6-(4-formylpiperazinyl)-3-pyridyl)pyrido[2,3-d]pyrimidine:
4-amino-5-(3-bromophenyl)-?-(6-(4-methylpiperazinyl)-3-pyridyl)pyrido[2,3-d]pyrimidine:
4-amino-5-(3-bromophenyl)-?-(6-thiomorpholinyl-3-pyridyl)pyrido[2,3-d]pyrimidin;

4-amino-5-(3-bromophenyl)-7-(6-(4,4-dioxothiomorpholinyl)-3-pyridyl)pyrido[2,3-d]pyrimidine;
4-amino-5-{2-bromophenyl)-7-(6-morpholinyl-3-pyridyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromo-4-methoxyphenyl)-7-(6-morpholinyl-3-pyridyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(4-bromophenyl)-7-(6-morpholinyl-3-pyridyl)pyrido(2,3-d]pyrimidine;
4-amino-5-(3-chiorophenyl)-7-(6-morpholinyl-3-pyridyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(5-chloro-6-morpholinyl-3-pyridyl)pyrido[2,3-d]pyrimidine;
l0 4-amino-5-(3-bromophenyl)-7-(6-(N-oxidomorpholinyl)-3-pyridyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(6-(N-(2-hydroxyethoxyethyl)amino)-3-pyridyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(6-(N-(2-hydroxyethoxyethyl)-N-formylamino)-3-15 pyridyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(6-(N-{2-hydroxyethoxyethyl)-3-pyridyl-N-oxide)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(6-(3-hydroxy)morpholinyl)-3-pyridyl)pyrido[2,3-d]pyrimidine;
20 1-(5-(4-amino-5-(3-bromophenyl)pyrido[2,3-d]pyrimidin-7-yl)-2-pyridyl)-piperidine-4-phosphate, disodium salt;
4-amino-5-(3-bromophenyl)-7-(4-methylenylpiperidinyl)-3-pyridyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(4-hydroxy-4-(hydroxymethyl)piperidinyl)-3-25 pyridyl)pyrido[2,3-d]pyrimidine;
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[2,3-3o d]pyrimidine;
4-N-(iminomethyl)amino-5-cyclohexyl-7-(6-dimethylamino-3-pyridyl)pyrido[2,3-d]pyrimidine;
and pharmaceutically acceptable salts and amides thereof. In addition, the and pharmaceutically acceptable salts and amides thereof. The partially saturated and fully 35 saturated versions of the above compounds are also included within the scope of the method of inhibiting adenosine kinase in a patient in need of treatment thereof. The above compounds may be treated with hydrogen and a catalyst to form a compound of formula I

wherein the double bonds on the right side are absent or there is a double bond between the 5,6 carbons; the 6,7 carbons or the 7 carbon, 8 nitrogen.
Exemplary and preferred compounds of the invention, again with the variables Rg as specifically shown below, include:
4-amino-5-(4-dimethylaminophenyl)-7-(4-bromophenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(4-dimethylaminophenyl)-7-(4-dimethylaminophenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(4-methoxyphenyl)-7-(4-dimethylaminophenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(4-dimethylaminophenyl)-7-(4-methoxyphenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(4-(2-propyl)phenyl)-7-(4-methoxyphenyl)pyrido[2,3-d]pyrimidine;
4-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[2,3-d]PY~dine;
4-amino-5-(4-benzyloxyphenyl)-7-(4-methoxyphenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(4-phenoxyphenyl)-7-(4-methoxyphenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(4-(2-propyl)phenyl)-7-(4-diethylmalonylallylphenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(4-(2-propyl)phenyl)-7-(4-t-butylacrylphenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(4-dimethylaminophenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3,4-dimethoxyphenyl)-7-(4-dimethylaminophenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-t-butylacrylphenyl)-7-(4-dimethylaminophenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3- methoxyphenyl-7-(4-dimethylaminophenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3.5-dimethoxyphenyl-7-(4-dimethylaminophenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-diethylmaionylallylphenyl)-7-(4-dimethylaminophenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-vinylpyridinylphenyl)-7-(4-dimethylaminophenyl)pyrido[2,3-d]PY~dine:
4-amino-5-(3-trifluoromethylphenyl)-7-(4-dimethylaminophenyl)pyrido[2,3-d]pyrimidine;

4-amino-5-(3-carboxamidophenyl)-7-(4-dimethylaminophenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-cyanophenyl)-7-(4-dimethylaminophenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-benzyloxyphenyl)-7-(4-dimethylaminophenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-methoxyphenyl)-7-(4-methoxyphenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(4-butoxyphenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-(2-pyridyl)phenyl)-7-(4-dimethylaminophenyl)pyrido[2,3-d]pyrimidine;
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[2,3-d]pyrimidine;
4-amino-5-(3-ethoxyphenyl)-7-(4-dimethylaminophenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-trifloromethyoxyphenyl)-7-(4-dimethylaminophenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3,5-dichlorophenyl)-7-(4-dimethylaminophenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromo-4-fluorophenyl)-7-(4-dimethylaminophenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-hydroxyphenyl)-7-(4-dimethylaminophenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(4-morpholinylphenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(4-piperidinylphenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(4-(imidazol-1-yl)phenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(4-chlorophenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(4-isopropylphenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(4-trifluorophenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(4-diethylaminophenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(3,4,5-trimethoxyphenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-(3-methoxybenzyl)phenyl)-7-(4-dimethylaminophenyl)pyrido[2,3-d]pyrimidine;

4-amino-5-(3-methoxyethyoxyphenyl)-7-(4-dimethylaminophenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3,4-methylenedioxyphenyl)-7-(4-dimethylaminophenyl)pyrido [2,3-d)pyrimidine;
4-amino-5-(3-bromophenyl)-7-(~-ethoxyphenyl)pyrido[2,3-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-dimethylaminophenyi)-7-(4-dimethylaminophenyl)pyrido[2,3-d)pyrimidine;
4-amino-5-phenyl-7-(4-dimethylaminophenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3,4,5-trimethoxyphenyl)-7-(4-dimethylaminophenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(4-nitrophenyl)pyrido[2,3-d)pyrimidine;
4-amino-5-(3-bromophenyl)-7-(4-iodophenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(3,4-methylenedioxyphenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(thiophen-2-yI)-7-(4-morpholinylphenyl)pyrido [2,3-d]pyrimidine;
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-d]pyrimidine;
4-amino-5-(3,5-dimethoxyphenyl)-7-(4-morpholinylphenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-trifluoromethylphenyl)-7-(thiophene-2-yl)pyrido [2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(4-aminophenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromo-4-fluorophenyl)-7-(thiophene-2-yl)pyrido [2,3-d)pyrimidine;
4-amino-5-(3-bromo-4-fluorophenyl)-7-(2-furanyl)pyrido [2,3-d]pylvrudine;
4-amino-5-(3,5-dimethoxyphenyl)-7-(4-iodophenyl)pyrido[2,3-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 [2,3-d]pyrimidine;
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-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(4-pyrrolidinylphenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(4-bromothiophene-)-7-(4-dimethylanunophenyl)pyrido[2,3-d]pyrimidirre;
4-amino-5-(4-bromothiophene-2-yl)-7-(4-morpholinylphenyl)pyrido[2,3-d]pyrimidine;

4-morpholinyl-5-(3-bromophenyl)-7-(4-dimethylaminophenyl)pyrido[2,3-d]pyrimidine;
4-amino=5-(5-bromothiophene-2-yl)-7-{4-morpholinylphenyl)pyrido[2,3-d]pyrimidine;
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-d]pyrimidine;
4-amino-S-(3-bromophenyl}-7-(4-dimethylaminophenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3,5-dimethoxyphenyl)-7-(5-pyrimidinylphenyl)pyrido[2,3-d]pyrimidine;
4-(4-fluorophenyl)amino)-5-(3-bromophenyl)-7-(4-1o dimethylaminophenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(4-bromothiophene-2-yl)-7-(4-pyrrolidinylphenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(4-bromothiophene-2-yl)-7-(thiophene-2-yl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(5-(dimethylamino)thiophene-2-yl)pyrido[2,3-15 d]pyrimidine;
4-amino-5-(3-bromo-5-iodophenyl)-7-(4-(dimethylamino)phenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3,5-di(trifluoromethyl)phenyl)-7-(4-(dimethylamino)phenyl)pyrido[2,3-d]pyrimidine;
20 4-amino-5-(3,5-di(trifluoromethyl)phenyl)-7-(4-morpholinylphenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3,5-dibromophenyl)-7-(4-(dimethylamino)phenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3,5-dibromophenyl)-7-(4-morpholinylphenyl)pyrido[2,3-d]pyrimidine;
25 4-amino-5-(4-bromothiophene-2-yl)-7-(4-(4-methylpiperidinyl)phenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3,5-dibromophenyl)-7-(4-(dimethylamino)phenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(3-{dimethylamino)phenyl)pyrido [2,3-d]pyrimidine;
30 4-amino-5-(3-bromophenyl)-7-(4-methylsulfonylphenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(3-methoxyphenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(4-(methylthio)phenyl)pyrido[2,3-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[2,3-35 d]pyrimidine:
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-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(3-amino-4-methoxyphenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(3-bromo-4-(dimethylamino)phenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(3-methyl-4-(dimethylamino)phenyl)pyrido[2,3-d]pylimidine;
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-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(4-(N-ethyl-N-formylamino)phenyl)pyrido[2,3-d]pyrimidine;
4,4-bis(acetylamino)-5-(3-bromophenyl)-7-(4-(N-methyl-N-acetylamino)phenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(4-(N-acetyl-N-methylamino)phenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(4-(N-ethylamino)phenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(4-(N-methyl-N-(2-methoxyethyl)amino)phenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(4-(N-isopropylamino)phenyl)pyrido[2,3-d]pyrimidine;
4-amino-S-(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-d]pyrimidine;
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[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-S-(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-S-(3-bromophenyl)-7-(4-(N-methyl-N-(2-(N-phthalimidyl)acetyl)amino)phenyl)pyrido(2,3-d]pyrimidine;
4-amino-S-(3-bromophenyl)-7-(3-methyl-4-(N-methyl-N-(trifluoroacetyl)amino)phenyl)pyrido[2,3-d]pyrimidine;
4-amino-S-(3-bromophenyl)-7-(3-methyl-4-(N-acetyl-N-methylamino)phenyl)pyrido[2,3-d]pyrimidine;
4-amino-S-(3-bromophenyl)-7-(6-dimethylamino-3-pyridinyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-cyanophenyl)-7-(4-methylsulfonylphenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-cyanophenyl)-7-(4-{N-methyl-N-formylamino)-phenyl)pyrido[2,3-d]pyrimidine;
4-amino-S-(3-bromophenyl)-7-(6-(N-methyl-N-formylamino)-3-pyridinyl)pyrido[2,3-d]pyrimidine;
4-amino-S-(3-bromophenyl)-7-(6-morpholinyl-3-pyridinyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(6-(N-methyl-N-methoxyethylamino)-3-pyridinyl)pyrido[2,3-d]pyrimidine;
4-amino-S-(3-bromophenyl)-7-(6-pyrrolidinyl-3-pyridinyl)pyrido[2,3-d]pyrimidine;
4-amino-S-(3-bromophenyl)-7-(2-(dimethylamino)-S-pyrimidinyl)pyrido[2,3-d]pyrimidine;
4-amino-S-(3-bromophenyl)-7-(2-(N-methoxyethyl-N-methyl amino)-S-pyrimidinyl)pyrido(2,3-d]pyrimidine;
4-amino-S-(3-bromophenyl)-7-(2-(N-formyl-N-methyl amino)-S-pyrimidinyl)pyrido[2,3-d]pyrimidine;
4-amino-S-(3-bromophenyl)-7-(2-(N-methylamino)S-pyrimidinyl)pyrido[2,3-d]pyrimidine;
4-amino-S-(3-bromophenyl)-7-(2-(1-pyrrolidinyl)-S-pyrimidinyl)pyrido[2,3-d]pyrimidine;
4-amino-S-(3-bromophenyl)-7-(2-( 1-morpholinyl)-S-pyrimidinyl)pyrido(2,3-d]pyrimidine;
4-amino-S-(3-bromophenyl)-7-(6-(2-oxo-3-oxazolidinyl)-3-pyridinyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(2-pyridyl)pyrido[2,3-d]pyrimidine;
4-amino-S-(3-bromophenyl)-7-(3-pyridyl)pyrido(2,3-d]pyrimidine;

4-amino-5-(3-(thiophen-2-yl)phenyl)-7-(4-dimethylaminophenyl)pyrido[2,3-dIPY~~e~
4--amino-5-(3-(furan-2-yl)phenyl)-7-(4-dimethylaminophenyl)pyrido[2,3-d]PY~dine;
4-amino-5-(3-(3-methoxyphenyl jphenyl)-7-(4-dimethylaminophenyl)pyrido[2,3-d]pyrimidine;
4-amino-S-phenyl-7-(4-dimethylaminophenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-chlorophenyl)-7-(4-(morpholinyl)phenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromo-4-fluorophenyl)-7-(4-(morpholinyl)phenyl)pyrido[2,3-l0 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[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;
15 4-amino-S-(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-d]pyrimidine;
4-amino-5-(2-phenylethyl)-7-(4-diethylaminophenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(2-methylpropyl)-7-(4-diethylaminophenyl)pyrido[2,3-d]pyrimidine;
20 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-d]pyrimidine;
4-amino-5-(butyl)-7-(4-dimethylaminophenyl)pyrido [2,3-d]pyrimidine;
4-amino-5-(2-(3-cyanophenyl)methyl)-7-(4-dimethylaminophenyl)pyrido[2,3-25 d]pyrimidine;
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-d]pyrimidine;
4-amino-5-(2-(5-chloro-2-(thiophen-3-yl)phenylmethyl)-7-(4-30 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-d]pyrimidine;
4-amino-5-(2-(3-bromophenyl)ethyl)-7-(4-diethylaminophenyl)pyrido[2,3-d]pyrimidine;
35 4-amino-5-((2-bromophenyl)methyl)-7-(4-diethylaminophenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-cyclopropyl-7-(4-dimethylaminophenyl)pyrido[2,3-d]pyrimidine;

4-amino-5-cyclohexyl-7-(4-dimethylaminophenyl)pyrido [2,3-d]pyrimidine;
4-amino-5-((2-bromo-5-chlorophenyl)methyl)-7-(4-diethylaminophenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-methyl-7-(4-diethylaminophenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(2,3-methylenedioxyphenyl)-7-(4-dimethylaminophenyl)pyrido[2,3-d]pyrimidine;
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-d]pyrimidine;
4-amino-5-(3,5-dimethylphenyl)-7-(4-dimethylaminophenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3,4-dichlorophenyl)-7-(4-dimethylaminophenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(4-fluoro-3-trifluoromethylphenyl)-7-(4-d:methylaminophenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromo-5-methoxyphenyl)-7-(4-morpholinylphenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromo-5-methoxyphenyl)-7-(4-pyrrolidinylphenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromo-5-methoxyphenyl)-7-(4-piperidinylphenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromo-5-methoxyphenyl)-7-(4-dimethylaminophenyl)pyrido[2,3-d]pyrirnidine;
4-amino-5-(3-methylthiophenyl)-7-(4-dimethylaminophenyl)pyrido[2,3-d]pyrimidine;
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-d]pyrimidine;
4-amino-5-(3-methylsulfonylphenyl)-7-(4-dimethylaminophenyl)pyrido[2,3-d]pyrimidine;
4-acetylamino-5-(3-bromophenyl)-7-(4-dimethylaminophenyl)pyrido[2,3-d]pyrimidine;
4-formylamino-5-(3-bromophenyl)-7-(4-dimethylaminophenyl)pyrido[2,3-d]pyrimidine;
4-(methoxyacetyl)amino-5-(3-bromophenyl)-7-(4-diethylaminophenyl)pyrido[2,3-d]pyrimidine;
4-trifluoroacetylamino-5-(3-bromophenyl)-7-(4-dimethylaminophenyl)pyrido[2,3-d]pyrimidine;

4-pentanoylamino-5-(3-bromophenyl)-7-(4-dimethylaminophenyl)pyrido(2,3-d]pyrimidine;
4-benzoylamino-5-(3-bromophenyl)-7-(4-dimethylaminophenyl)pyrido[2,3-d]pyrimidine;
4-(N-BOC-glycyl)amino-5-(3-bromophenyl)-7-(4-dimethylaminophenyl)pyrido[2,3-d]pyrimidine;
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[2,3-1o 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-d]pyrimidine;
15 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(2,3-d]pyrimidine;
4-(N-allyl-N-formylamino)-5-(4-dimethylaminophenyl)-7-(4-2o 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[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(5-dimethylamino-2-pyridyl)pyrido[2,3-d]pyrimidine;
25 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-( 1-methyl-2-oxobenzoxazolin-6-yl)pyrido[2,3-d]pyrimidine;
30 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-d]pyrimidine;
4-amino-5-((thiophene-3-yl)methyl)-7-(4-diethylaminophenyl)pyrido[2,3-35 d]PYi'~dine;
4-amino-5-((2-brornophenyl)methyl)-7-(4-dimethylaminophenyl)pyrido[2,3-d]pyrimidine;

WO 98/46605 PCTlUS98/07207 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-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(4-(N-methyl-N-((2-dimethylamino)ethyl)amino)phenyl)pyrido[2,3-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[2,3-d]pyrimidine;
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-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(6-(2-propyl)-3-pyridinyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(3-methyl-4-pyrrolidinylphenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(6-imidazolyl-3-pyridinyl)pyrido[2,3-d]pyrimidine;
4-amino-5-phenylmethyl-7-(4-diethylaminophenyl)pyrido [2,3-d]pyrimidine;
4-amino-5-(2-(3-aminopropynyl)phenylmethyl)-7-(4-diethylaminophenyl)pyrido[2,3-2o d]pyrimidine;
4-amino-5-( 1-(3-bromophenyl)ethyl)-7-(4-diethylaminophenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(4-dimethylaminophenyl)-7-(4-bromophenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(2-furanyl)-7-(4-(N-morpholinyl)phenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(2-dimethylamino-5-pyrimidinyl)pyrido[2,3-d]pyrimidine;
4-amino-S-(3-bromophenyl)-7-(4-(ureido)phenyl)pyrido [2,3-d]pyrimidine;
4-amino-5-( 1-phenylmethyl-3-piperidinyl)-7-(4-diethylaminophenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-brornophenyl)-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-d]pyrimidine; --4-amino-5-(3-bromophenyl)-7-(6-( 1,2,4-triazol-4-yl)-3-pyridinyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(2-moipholinyl-5-pyrimidinyl)pyrido[2,3-d]pyrimidine;

4-amino-5-(2-thiazolyl)-7-(4-pyrrolidinylphenyl)-pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(6-pyrazolyl-3-pyridinyl))-pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(4-( 1-methyl-ureido)phenyl)-pyrido [2,3-d]pyrimidine:
4-amino-5-(3-bromophenyl)-7-(4-(N-methyl-N-(2-pyrimidinyl)amino)phenyl)-pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(3-fluoro-4-(N-formyl-N-methylamino)phenyl)-pyrido[2,3-d]pyrimidine;
4-formylamino-5-(3-bromophenyl)-7-(3-fluoro-4-{N-formyl-N-methylamino)phenyl)-pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(4-(N-methyl-N-methylsulfonylamino)-phenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(6-(N-methyl-N-methylsulfonylaminol-3-pyridinyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-( 1-methyl-5-indolinyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-( 1-methyl-5-benzimidazolyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(6-dimethylamino-3-pyridazinyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3bromophenyl}-7-(6-morpholinyl-3-pyridazinyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(6-pyrrolidinyl-3-pyridazinyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(5-morphoiinyl-2-pyrazinyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(5-(N-(2-methoxyethyl)-N-methylamino)-2-pyrazinyl)pyrido [2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(4-(morpholinylmethyl}-phenyl}pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(5-(N,N-bis(2-methoxyethyl)amino)-2-pyridinyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(4-(imidazolylmethyl)-phenyl)pyrido[2,3-d]PY~dine;
4-amino-~-(3-bromophenyl)-7-(5-(1-morpholinyl)-2-pyridinyl)pyrido[2,3-d]pyrimidine;

4-amino-5-(3-bromophenyl)-7-(4-((dimethylamino)methyl)-phenyl)pyrido [2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(5-(4-hydroxy-1-piperidinyl)-2-pyridinyl)pyrido[2,3-dJpyrimidine;
4-amino-5-(3-bromophenyl)-7-(5-(N-formyl-N-methylamino)-2-pyridinyl)pyrido(2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(5-(2-propenyl)-2-pyridinyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(3-(2-methoxyethyl)-2-oxo-6-benzoxazolyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(4-( 1-(N-formylamino)-ethyl)phenyl)pyrido[2,3-d]pyrimidine;
4-(methylamino)-5-(3-bromophenyl)-7-(4-dimethylaminophenyl)pyrido[2,3-d]pyrimidine hydrochloride;
:~-(2-methoxyethylamino)-5-(3-bromophenyl)-7-(4-dimethylaminophenyl)pyrido[2,3-d]pyrimidine hydrochloride;
~-amino-5-(3-bromophenyl)-7-(4-( 1-methyl-2-imidazolyl)phenyl)pyrido[2,3-dJpyrimidine trihydrochloride;
4-amino-5-(3-bromophenyl)-7-(4-(aminomethyl)phenyl)pyrido[2,3-d]pyrimidine;
:~-amino-5-(3-bromophenyl)-7-(2-bromo-4-(dimethylamino)phenyl)pyrido[2,3-d]pyrimidine;
-1-amino-5-(3-bromophenyl)-7-(4-(dimethylaminoethyl)phenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-{3-bromophenyl)-7-(4-(3-(dimethylamino)propynyl)phenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(4-(3-amino-3-methylbutynyl)phenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(4-dimethylphosphonatophenyl)pyrido[2,3-d]pyrimidine;
:l-amino-5-(3-bromophenyl)-7-(4-(3-(methoxypropynyl)pyrido[2,3-d]pyrimidine;
-t-amino-5-(3-bromophenyl)-7-(4-carboxyphenyl)pyrido[2;3-d]pyrimidine;
-1-amino-5-(3-bromophenyl)-7-(4-methyl-3-oxo-2H-4H-pyrido[3,2-b]-1,4-oxazin-7-yl)pyrido[2,3-d]pyrimidine;
4-amino-5-{3-bromophenyl)-7-(4-(2-(dimethylamino)ethyl)-3-oxo-2H-4H-pyrido[3,2-b]-1,4-oxazin-7-yl)pyrido[2,3-d]pyrimidine;
~-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-1,4-oxazin-7-yl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(2,2,4-trimethyl-3-oxo-2H-4H-benzo-1,4-oxazin- 7-yl)pyrido[2,3-d]pyrimidine;
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-( 1-methylethyl)-2-pyridyl)pyrido[2,3-d]PY~dine;
4-amino-5-(3-bromophenyl)-7-(5-piperidin-1-ylpyrid-2-yl)pyrido[2,3-d]pyrimidine;
4-amino-5-(1-(4-bromophenyl)ethyl)-7-(6-morpholinylpyrid-3-yl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(4-((N-formylamino)methyl)phenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(4-( 1-methyl-1-(N-methylamino)ethyl)phenyl)-pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(4-( 1-(dimethylamino)-1-methylethyl)phenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(N-acetyl-5-indolinyl)pyrido[2,3-d]pyrimidine;
4-amino-5-cyclohexyl-7-(6-chloro-3-pyridyl)pyrido[2,3-d]pyrimidine;
4-amino-5-( 1-(2-bromophenyl)ethyl)-7-(6-diethylamino-3-pyridyl)pyrido[2,3-d]pyrimidine;
4-amino-5-( 1-{2-bromophenyl)ethyl}-7-(6-morpholinyl-3-pyridyl)pyrido[2,3-d]pyrimidine;
4-amino-5-( 1-(2-bromophenyl)ethyl)-7-(4-(N-methyl-N-formyl}amino)-phenyl)pyrido[2,3-djpyrimidine;
4-amino-5-cyclohexyl-7-(6-morpholinyl-3-pyridyl)pyrido[2,3-d]pyrimidine;
4-amino-5-((2-bromophenyl)methyl)-7-(6-morpholinyl-3-pyridyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(4-tetrahydropyranyl)-7-(6-morpholinyl-3-pyridyl)pyrido[2,3-d]pyrimidine;
4-amino-S-cyclohexyl-7-(6-dimethylamino-3-pyridyl)pyrido[2,3-d]pyrimidine:
4-amino-5-( 1-ethylpropyl)-7-(6-dimethylamino-3-pyridyl)pyrido[2,3-d]pyrimidine;
4-amino-5-cyclopentyl-7-(6-morpholinyl-3-pyridyl)pyrido[2,3-d]pyrimidine;
4-amino-5-cyclohexyl-7-(2-chloro-3-pyridyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3,5-dimethylcyclohexyl)-7-(6-dimethylamino-3-pyridyl)pyrido[2,3-d]pyrimidine:

4-amino-5-((N-{benzyloxycarbonyl)-4-piperidinyl)methyl)-7-(6-morpholinyl-3-pyridyl)pyrido[2,3-d]pyrimidine;
4-amino-5-cyclohexyl-7-(6-bromo-3-pyridyl)pyrido[2,3-d]pyrimidine;
4-amino-5-cyclohexyl-7-(3-cyanophenyl)pyrido[2,3-d]pyrirnidine;
4-amino-5-(1-(2-bromophenyl)ethyl)-7-(6-dimethyIamino-3-pyridazinyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyi)-7-(6-imidazolyl-3-pyridazinyl)pyrido[2,3-d]pyrimidine;
4-amino-S-(3-bromophenyl)-7-(6-(azacycloheptanyl)-3-pyridazinyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl}-7-(6-(N-methyl-N-( 1-methylethyl))amino)-3-pyridazinyl)pyrido[2,3-d]pyrimidine;
4-amino-5-( 1-(2-bromophenyl)ethyl)-7-(b-morpholinyl-3-pyridazinyl)pyrido[2,3-d]pyrimidine;
4-amino-5-cyclohexyl-7-(6-(4-acetylpiperazinyl)-3-pyridyl)pyrido[2,3-d]pyrimidine;
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-1,4-diazacycloheptanyl)-3-pyridyl)pyrido[2,3-d]pyrimidine;
4-amino-5-cyclohexyl-7-{6-(N-methyl-N-(2-(2-pyridyl)ethyl)amino)-3-2o pyridyl)pyrido[2,3-d]pyrimidine;
4-amino-S-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[2,3-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-d]PY~dine;
4-amino-5-cyclohexyl-7-(4-oxo-1-phenyl-1,3,8-triazaspiro[4.5 [decan-8-yl)pyrido[2,3-d]pyrimidine;
4-amino-5-cyclohexyl-7-(6-(2-methoxymethyl)pyrrolidin-1-yl)pyridyl)pyrido[2,3-d]pyrimidine;
4-amino-5-cyclohexyl-7-{6-(N-methoxyethyl-N-propylamino)pyridyl)pyrido[2,3-d]pyrimidine;
4-amino-5-cyclohexyl-7-(N-methyl-N-(2,2-dimethoxyethyl)amino)pyrido[2,3-d]pyrimidine;
4-amino-5-cyclohexyl-7-(6-(4-(dimethylamino)piperidinyl)pyridyl)pyrido[2,3-d]pyrimidine;

4-amino-5-cyclohexyl-7-(6-(4-(aminocarbonyl))piperidinyl)pyridyl)pyrido[2,3-d]pyrimidine;
4-amino-5-cyclohexyl-7-(N-methyl-N-(3-(diethylamino)propyl)aminopyrid-3-yl)pyrido[2,3-d]pylimidine;
4-amino-5-cyclohexyl-7-(6-(N-methyl-N-(4-pyridyl)ethylamino)pyrid-3-yl)pyrido[2,3-d]pyrimidine;
4-amino-5-cyclohexyl-7-(6-(N-methyl-N-(3-pyridylmethylamino)pyrid-3-yl)pyrido[2,3-d]pyrimidine;
4-amino-5-( 1-(2-bromophenyl)ethyl)-7-( 1-methyl-5-indolyl}pyrido[2,3-d]pyrimidine;
4-amino-S-( 1-(2-bromophenyl)ethyl)-7-( 1-methyl-2,3-dioxo-5-indolyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(3-fluoro-4-( 1-morpholinyl)phenyl)pyrido(2,3-d]pyrimidine;
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-pyridyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(6-(4-oxopiperidinyl)-3-pyridyl)pyrido[2,3-d)pyrimidine;
4-amino-5-(3-bromophenyl)-7-(6-(4-formylpiperazinyl)-3-pyridyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(6-(4-methylpiperazinyl)-3-pyridyl}pyrido[2,3-d]pyrimidine;
4-amino-S-(3-bromophenyl)-7-(6-thiomorpholinyl-3-pyridyl)pyrido[2,3-d]pyrimidin;
4-amino-5-{3-bromophenyl)-7-(6-(4,4-dioxothiomorpholinyl)-3-pyridyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(2-bromophenyl)-7-(6-morpholinyl-3-pyridyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromo-4-methoxyphenyl)-7-(6-morpholinyl-3-pyridyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(4-bromophenyl)-7-(6-morpholinyl-3-pyridyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-chlorophenyl)-7-(6-morpholinyl-3-pyridyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(5-chloro-6-morpholinyl-3-pyridyl)pyrido(2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(6-(N-oxidomorpholinyl)-3-pyridyl)pyrido[2,3-d]pyrimidine;

WO 98/46605 PCT/US98l07207 4-amino-5-(3-bromophenyl)-7-(6-(N-(2-hydroxyethoxyethyl)amino)-3-pyridyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(6-(N-(2-hydroxyethoxyethyl)-N-formylamino)-3-pyridyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(6-(N-(2-hydroxyethoxyethyl)-3-pyridyl-N-oxide)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(6-(3-hydroxy)morpholinyl)-3-pyridyl)pyrido[2,3-d]pyrimidine;
1-(5-(4-amino-5-(3-bromophenyl)pyrido[2,3-d]pyrimidin-7-yl)-2-pyridyl)-1o piperidine-4-phosphate, disodium salt;
4-amino-5-(3-bromophenyl)-7-(4-methylenylpiperidinyl)-3-pyridyl)pyrido[2,3-d]pyrimidine;
4-amino-S-(3-bromophenyl)-7-(4-hydroxy-4-(hydroxymethyl)piperidinyl)-3-pyridyl)pyrido[2,3-d]pyrimidine;
1S 4-amino-S-(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[2,3-d]pyrimidine;
2o 4-N-(iminomethyl)amino-5-cyclohexyl-7-(6-dimethylamino-3-pyridyl)pyrido[2,3-d]pyrimidine;
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 25 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 heteroaryl group, is having at least one substituent at the para position. The present invention is therefore directed to compounds of formula I or II with the variables 3o recited as above wherein, in the case of R3 selected from substituted aryl or heteroaryl groups and R4 selected from substituted aryl or heteroaryl 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 convened to the non pro-drug form as exemplified above. The 35 invention is not limited to synthetic versions of the claimed compounds and includes the compounds-per-se or pro-drugs or metabolites thereof regardless of how or where they are manufactured or made.

The term "acyl", as used herein, refers to a moiety attached by a carbonyl linkage, as for example, loweralkyl-carbonyl or aryl-carbonyl, wherein loweralkyl and aryl are as defined herein. Examples of acyl include, for example, acetyl, propionyl, hexanoyl, trifluoroacetyl, benzoyl, 4-methylbenzoyl, methoxyacetyl, pentanoyl, N-Bocglycylimidazoyl, N-phthalimidylglycyl and the like or others as specified herein.
The term "aryl" or "substituted aryl" as used herein, refers to a carbocyclic aromatic radical, including, for example, phenyl and 1- or 2-naphthyl, which may be unsubstituted or substituted respectively by independent replacement of one, two or three of the hydrogen atoms thereon with Cl, Br, F, I, cyano, carboxamido, hydroxy, loweralkoxy, loweralkyl, loweralkenyl, loweralkynyl, amino, loweralkylamino, di(loweralkylamino), N-loweralkyl-N-loweralkoxyamino, trifluoromethyl or methoxymethyl groups. In addition, the term "aryl" refers to a phenyl group substituted with one ureido, methylsulfonyl, pyrimidinyl, pyridinyl, pyridazinyl, morpholinyl, phenyl-loweralkoxy, phenyl-loweralkenyl or cycloalkyl-loweralkyl group. Examples of aryl radicals include, but are not limited to, 3-bromophenyl, 3-chlorophenyl, 4-chlorophenyl, 3-methoxyphenyl, 3-(2-propyl)phenyl, 3,4-dimethoxyphenyl, 3-trifluromethylphenyl, 3-trifluoro-4-fluorophenyl, 4-(N-methyl-N-methoxyl)ethylaminophenyl, 4-dimethylaminophenyl, 3-fluoro-4-methylphenyl, 4-methylphenyl, 4-cyanophenyl, 4-propylmethyl, 3,5-dichlorophenyl, 3,4-methylenedioxyphenyl, 3-cyanopropylphenyl, 4-ureidophenyl, 3-methylsulfonylphenyl, 3-carboxamidopropylphenyl.
The term "arylalkyl" refers to a ioweralkyl radical having appended thereto an aryl group, as defined above, as for example benzyl and phenylethyl.
The term "aryloxy" refers to a aryl radical which is appended to the molecule via an ether linkage (i.e., through an oxygen atom), as for example phenoxy, naphthyloxy, 4-chlorophenoxy, 4-methylphenoxy, 3,5-dimethoxypehenoxy, and the like.
The term "cycloalkyl" refers to a cyclic saturated hydrocarbon radical having from 3 to 7 ring atoms. Examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl. Cycloalkyl is also described as C3-CgcycloalkyL
The term "cycloalkyl-loweralkyl" refers to a loweralkyl radical as defined below substituted with a cycloalkyl group as defined above by replacement of one hydrogen atom.
Examples of cycloalkyl-loweralkyl include cyclopropylmethyl, cycloburylethyl, cyclopentylmethyl, cyclohexylmethyl and cycloheptylbutyl, and the like.
The term "heteroaryl" or "substituted heteroaryl" refers to a monocyclic aromatic radical having from five to seven ring atoms of which one ring atom is nitrogen, oxygen or sulfur; zero, one or two ring atoms are additional heteroatoms independently selected from S, O and N; and the remaining ring atoms are carbon, the radical being joined to the rest of the molecule via any of the ring atoms. A heteroaryl group may be unsubstituted or substituted by independent replacement of one, two or three of the hydrogen atoms thereon with Cl, Br, F, I, cyano, carboxamido, hydroxy, loweralkoxy, lowerallryl, loweralkenyl, loweralkynyl, amino, loweralkylamino, di(loweralkylamino), N-loweralkyl-N-loweralkoxyamino, trifluoromethyl or methoxymethyl groups. In addition, the term "heteroaryl " refers to a heteroaryl group substituted with one ureido, methylsulfonyl, pyrimidinyl, pyridinyl, pyridazinyl, morpholinyl, phenyl-loweralkoxy, phenyl-loweralkenyl or cycloallcyl-loweralkyl group. In addition a heteroaryl group may be substituted by replacement of any two adjacent hydrogen atoms with a grouping of atoms to form a fused benzene ring, e.g., benz derivatives such as indole, benzoxazole and the like.
Examples of heteroaryl include pyridinyl, pyrazinyl, pyrimidinyl, pyrrolyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, isoxazolyl, thiadiazolyl, oxadiazolyl, furanyl, thiophenyl, 5-methylthiophene-2-yl, 5-nitrothiophene-2-yl, 5-methylfuranyl, benzofuranyl, benzothiophenyl, and the like and those additionally described herein.
The term "heterocyclic" refers to a saturated or unsaturated monocyclic ring system radical having from four to seven ring atoms of which one is nitrogen or oxygen; zero, one or two ring atoms are additional heteroatoms independently selected from S, O
and N; and the remainder are carbon, the radical being joined to the rest of the molecule via any of the ring carbon atoms and being optionally substituted, either on a nitrogen or a carbon atom, by an additional radical selected from among aryl(loweralkyl), alkoxycarbonyl, loweralkyl, halo(loweralkyl), amino(loweralkyl), hydroxy-substituted loweralkyl, hydroxy, loweralkoxy, halogen, amino, loweralkylamino, and amino, (loweralkyl)amino or alkanoylamino of from one to eight carbon atoms in which the amino group may be further substituted with alkanoyl of from one to eight carbons, an alpha-amino acid or a polypeptide. Examples of heterocyclic include pyrrolidine, tetrahydrofuran, dihydropyrrole, isoxazolidine, oxazolidine, tetrahydropyridine, piperidine, piperazine, morpholine, thiomorpholine, aziridine and azetidine or those additionally described herein.
The term "heterocyclic-loweralkyl" refers to a loweralkyl radical as defined below substituted with a heterocyclic-group as defined above by replacement of one hydrogen atom. Examples of cycloallcyl-lowerallcyl include pyrrolidinylmethyl, piperidinylethyl, and the like.
The term "loweralkyl", as used herein, refers to saturated, straight- or branched-chain hydrocarbon radicals containing from one to six carbon atoms including, which may be unsubstituted or substituted by independent replacement of one, two or three of the hydrogen atoms thereon with Cl, Br, F, I, cyano, carboxamido, hydroxy, loweralkoxy, amino, loweralkylamino, iminoloweralkylamino,di(loweralkylamino) or N-loweralkyl-N-lowerallcoxyamino groups. Examples of loweralkyl include, but are not limited to, methyl, ethyl, propyl, isopropyl, ~a-butyl, tert-butyl, neopentyl, n-hexyl, hydroxyethyl, methoxymethyl, trifluoromethyl, 3-cyanopropyl, 3-carboxamidopropyi, and the like. In certain cases, the group "Cl-C6alkyl" is described and has a similar meaning as above for loweralkyl but is more specifically recited. Likewise, the term "CO-C6alkyl"
indicates the carbon atoms which may be present in the alkyl chain including zero. These terms are also provided adjacent to aryl or heteroaryl or other generic group and represent or have the same meaning as, for example, "arylalkyl" or "heteroarylalkyl".
The term "loweralkenyl", as used herein, refers to mono-unsaturated straight-or branched-chain hydrocarbon radicals containing from two to six carbon atoms including, but not limited to, vinyl, propenyl, n-butenyl, i-butenyl, n-pentenyl, and n-hexenyl. These variables are also recited as, for example, C2-C(alkenyl.
The term "loweralkoxy" refers to a loweralkyl radical which is appended to the molecule via an ether linkage (i.e., through an oxygen atom), as for example methoxy, ethoxy, propoxy, 2-propoxy, 2-methyl-2-propoxy, tert-butoxy, pentyloxy, hexyloxy, isomeric forms thereof and the like. This term is also described as C1-C(alkyloxy.
The term "loweralkynyl", as used herein, refers to straight- or branched-chain hydrocarbon radicals possessing a single triple bond and containing from two to six carbon atoms including, but not limited to, ethynyl, propynyl, rc-butynyl, n-pentynyl, and n-hexynyl. This term is also described as C2-C6alkynyl.
The term "mammal" has its ordinary meaning and includes human beings.
In a further aspect of the present invention pharmaceutical compositions are disclosed which comprise a compound of the present invention in combination with a pharmaceutically acceptable carrier.
The present invention includes one or more compounds, as set forth above, formulated into compositions together with one or more non-toxic physiologically tolerable or acceptable diluents, carriers, adjuvants or vehicles that are collectively referred to herein as diluents, for parenteral injection, for oral administration in solid or liquid form, for rectal or topical administration, or the like. As is well known in the art, a compound of the present invention can exist in a variety of forms including pharmaceutically-acceptable salts, amides and the like.
Compositions may be prepared that will deliver the correct amount of a compound or compounds of the invention. The following dosages are thought to provide the optimal therapy: iv infusions: 0.1- 250 nmol/kg/minute> preferably from 1-50 nmol/kg/minute; oral:
0.01-250 ~.MoUkg/day, preferably from about 0.1-50 ~.Mol/kg/day; these oral molar dosage ranges correspond to 0.005-125 mg/kg/day, preferably 0.05-25 mg/kg/day. 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.
_q.4_ "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 1-to-6 amino acids joined by amide linkages which may be branched or linear, wherein the amino acids are selected independently from naturally-occurring amino acids, such as for example, glycine, alanine, leucine, valine, phenylalanine, proline, methionine, tryptophan, asparagine, aspartic acid, glutamic acid, glutamine, serine, threonine, lysine, arginine, tyrosine, histidine, ornithine, and the like.
"Pharmaceutically-acceptable salts" refers to the pharmaceutically-acceptable, nontoxic, inorganic or organic acid addition salts of the compounds of the present invention, as described in greater detail below.
The compounds of the present invention can be used in the form of pharmaceutically-acceptable salts derived from inorganic or organic acids.
These salts include, but are not limited to, the following: acetate, adipate, alginate, aspartate, benzoate, 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, 2o 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, dicyclohexyiamine, triethylamine, piperidine, pyrrolidine, benzylamine, and the like, or a quaternary ammonium hydroxide such as tetramethylammonium hydroxide and the like.
Also, the basic nitrogen-containing groups can be quaternized with such agents as loweralkyl halides, such as methyl, ethyl, propyl, and butyl chlorides, bromides, and iodides; dialkyl sulfates; long chain halides such as decyl, lauryl, myristyl, and stearyl chlorides, bromides and iodides; arylalkyl halides like benzyl and phenethyl bromides, and others. Water or oil-soluble or dispersible products are thereby obtained.
The salts of the present invention can be synthesized from the compounds of Formula I which contain a basic or acidic moiety by conventional methods, such as by reacting the free base or acid with stoichiometric amounts or with an excess of the desired salt forming inorganic acid or base in a suitable solvent or various combinations of solvents.

Further included within the scope of the present invention are pharmaceutical compositions comprising one or more of the compounds of formula (I) prepared and formulated in combination with one or more non-toxic pharmaceutically acceptable carriers compositions, in the manner described below.
Compositions suitable for parenteral injection may comprise pharmaceutically acceptable sterile aqueous or nonaqueous solutions, dispersions, suspensions or emulsions and sterile powders for reconstitution into sterile injectable solutions or dispersions.
Examples of suitable aqueous and nonaqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols (propylene glycol, polyethylene glycol, glycerol, and the like), suitable mixtures thereof, vegetable oils {such as olive oil) and injectable organic esters such as ethyl oleate. Proper fluidity may be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants.
These compositions may also contain adjuvants such as preserving, wetting, emulsifying, and dispersing agents. Prevention of the action of microorganisms may be ensured by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, and the like. It may also be desirable to include isotonic agents, for example, sugars, sodium chloride and the like. Prolonged absorption of the injectable pharmaceutical form may be brought about by the use of agents delaying 2o absorption, for example, aluminum monostearate and gelatin.
If desired, and for more effective distribution, the compounds may be incorporated 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 incorporating 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) absorption 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 to 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.
15 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 20 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, 25 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 30 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, 35 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 absorption-retarding agents or barriers. Ophthalmic formulations, 1o 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 I5 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.
20 Methods to form liposomes are known in the art. See, for example, Prescott, Ed., Methods in Cell Bioloev. 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 25 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.

he 1 O CH3 O~,,H ~ NC
Rs + NC CN -R3 NH2 R3 .
NC O
H~NH N~

H2N N R4 ~ N- _R4 3 (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, heteroaryl, or a heterocyclic group may be prepared by a modification of a method of Kambe et al., Synthesis, 1980, 366-368. An appropriately substituted acetophenone (1, the "R4 Reagent"), wherein R4 is aryl, heteroaryl, or a heterocyclic group, an appropriately substituted aldehyde (2, the "R3 Reagent"), R3 is aryl, heteroaryl, or a heterocyclic group, and malononitrile are heated in the presence of ammonium acetate, or another suitable ammonium salt, such as for example, ammonium propionate, ammonium iodide, or the like, in an aprotic solvent to produce compound (3).
The water of the reaction may removed by use of a Dean Stark apparatus or by another suitable means, such as 4 ~ molecular sieves. Suitable aprotic solvents include benzene, toluene, methylene chloride, DMF, THF, dioxane, and the like. The reaction may be performed at from about 40 °C to about 200 °C, and preferably at the reflux temperature of the solvent, for from about 1 hour to about 24 hours, preferably about 4 hours to 8 hours.
The product (3) is preferably purified by chromatography after isolation from the reaction mixture. The above reaction may also proceed by contacting the aldehyde (2) with malononitrile and isolating the resulting dicyano R3substituted alkene which is then reacted with the ketone ( 1 ) to form, upon addition of ammonium and cyclization, compound (3).
Aliphatic aldehydes do not work effectively by this route. The ketone (1) may, however, include 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 versions) (on the right side of the molecule) of the compounds shown in Scheme l or of Formula I. Stereoisomers produced during these reduction steps are included within the scope of the invention.
The present invention also contemplates reductions which produce single bonds between the 5,6 and 7,8 positions and a double bond between the 6,7 carbons. The stereoisomers may be isolated and purified by conventional means.
In accordance with Scheme 2 are prepared compounds of Formula (I) wherein R4 is preferrably an aryl, heteroaryl or heterocyclic group, and R3 is loweralkyl, loweralkenyl, loweralkynyl, or an arylalkyl group. In addition, 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, diisobutylaiuminum 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 3o 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).
,S~heme 2 O red'n O oxid'n R _!( '--~ R3-I( ~--- R3- CH2-OH

..
Br P(Ph)3+ Bi P(Ph)3 R4 ---~ R4 -...,~ Ra P(Ph)3 ~+
O H R4 ~ O R4 NC
+ NC~CN -(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 10 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 HCI, followed by lyophilization.
Scheme 3 O~ CH3 I NC

R + NC CN ----~ ~ ~ a {1) 12 H2 ~N R
(I) 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, anunonium 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 2o from the precursor aldehyde (4) by treatment with malononitrile in 1:1 H20:EtOH in the presence of a catalytic amount of glycine according to the method of Bastus (Tetrahedron Len. , 1963: 955), or alternately Mg0 in dichloromethane or a similar aprotic solvent {cf.
Broekhuis, et al., Recl. J. R. Neth. Chem. Soc., ~9: 6-12 (1980); Moison, et al.
Tetrahedron ( 1987), 43:537-542).
To prepare compounds of formula (I) wherein R1 and R2 are not both hydrogen atoms, it is possible to prepared the desired derivative from the compound of Formula (I) wherein R1 and R2 are both hydrogen atoms. When R1 or R2 is loweralkyl this may be accomplished by reaction of the free amino group with the appropriate allcylatin~ 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 1 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 R1 and R2 are taken together with the nitrogen atom to which they are attached to form a 5-to-7 membered ring optionally containing an additional oxygen or nitrogen atom, the compound may be prepared by reacting a precursor compound having a halogen atom in place of the amino group at the 4-position with a S-7 membered ring compound optionally containing an additional oxygen or nitrogen atom.
Examples of such compounds include, but are not limited to, morpholine, piperidine, pyrrolidine, piperazine, thiomorpholine, 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, is dibutylamine. This reaction takes place readily in a solvent such as methylene chloride, for example, in the presence of a tertiary amine. The precursor compound having a halogen atom in place of the amino group at the 4-position may be prepared by substitution of triethyl orthofonmate for the formamide followed by chlorination of the ring by treatment with phosphorous oxychloride or thionyl chloride in the presence of DMF in Scheme 1 wherein compound (3) is converted to compound (I).
Method of Inhibitin Kinase In yet another aspect of the present invention a process of inhibiting adenosine kinase is disclosed. In accordance with that process, an adenosine kinase enzyme is exposed to an effective inhibiting amount of an adenosine kinase inhibitor compound of the present invention. Preferred such compounds for use in the process are the same as set forth above. Means for determining an effective inhibiting amount are well known in the art.
The adenosine kinase to be inhibited can be located in vitro, in situ or in vivo.
Where the adenosine kinase is located i~: vitro, adenosine kinase is contacted with the inhibitor compound, typically by adding the compound to an aqueous solution containing the enzyme, radiolabeled substrate adenosine, magnesium chloride and ATP. The enzyme can exist in intact cells or in isolated subcellular fractions containing the enzyme. The enzyme is then maintained in the presence of the inhibitor for a period of time and under suitable physiological conditions. Means for determining maintenance times are well known in the art and depend inter 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. Physiol. 1982, 71B: 367-372).
Where the adenosine kinase is located in situ or in vivo, is typically administered to a fluid perfusing the tissue containing the enzyme. That fluid can be a naturally occuring fluid such as blood or plasma or an artificial fluid such as saline, Ringer's solution and the like.
A method of inhibiting adenosine kinase in vivo is particularly useful in mammals such as humans. Administering an inhibitor compound is typically accomplished by the parenteral (e.g., intravenous injection or oral) administration of the compound. The amount 1o administered is an effective inhibiting or therapeutic amount.
By a "therapeutically-effective amount" of the compound of the invention is meant a sufficient amount of the compound to treat adenosine kinase related disorders or those conditions or diseases which are ameliorated or modified by local inhibition of the enzyme which results in an increase in the concentration of adenosine. It will be understood, 15 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;
2o 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.
25 Compounds of the present invention inhibit adenosine kinase activity in vitro and in vivo. In vitro adenosine kinase activity can be measured using any of the standard procedures well known in the art. By way of example, cells containing adenosine kinase, such as IMR-32 human neuroblastoma cells, are cultured in the presence and absence of an inhibitor. Inhibition is measured as the ability to inhibit phosphorylation of endogenous or 3o 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 1 and A2a receptor binding, adenosine deaminase activity and adenosine transport.
Compounds of the present invention are effective in inhibiting adenosine kinase 35 activity in vivo. Numerous animal models for studying adenosine kinase activity and the affects of inhibiting such activity are well known in the art. By way of example, adenosine kinase inhibitors have been reported to protect rodents (e.g., mice and rats) from seizures WO 98/46605 ~'CT/US98/07207 induced by the subcutaneous administration of pentylenetetrazol (PTZ).
Typically the rodents are injected with various doses of a given inhibitor followed at various times by the subcutaneous administration of from about 10 to about 500 milligrams per kilogram of PTZ, The injected animals are then observed for the onset of seizures.
The compounds of the invention were tested in vivo in the hot plate test of analgesia m 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 ~.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 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 Assav 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 warned to 55oC.
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., 2$:410-( 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 unlrnown inhibitors or potential inhibitors.
Table 1 Inhibition of Adenosine Kinase by Representative Compounds of the Invention Com ound of Exam le 1050 (nM) No.

64 g 130 , 1 256 i 272 >100 288 0.3 291 I 0.6 292 i 10 304 ~ 1 306 ' 0.3 308 ~ 2 309 ~ 0.1 315 ; 0.3 319 j 1 338 4.5 Method of Treating Cerebral Ischemia, Epilepsy, Nociperception (Nociception) (Pain), Inflammation including conditions such as Se tip c Sh?ck due to Sepsis Ln~fection 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 Rl-R8 as defined herein. The preferred compounds are those of formula II
with the R
variables as defined previously. In particular, the present invention relates to a method of treating the above disorders comprising administering a compound of formula II
wherein R3 is a substituted aryl or heteroaryl moiety wherein the substituent (preferrably halogen) is at the meta position relative to the ring attachment and R4 is a substituted heteroaryl or aryl moiety wherein the substituent is at the para position relative to the ring attachment. The most preferred use is in the treatment of pain.
Alterations in cellular adenosine kinase activity have been observed in certain disorders. Adenosine kinase activity was found to be decreased, relative to normal liver, in a variety of rat hepatomas: activity of the enzyme giving a negative correlation with tumor growth rate (Jackson, et al., Br. J. Cancer, 1978, 37: 701-713). Adenosine kinase activity was also diminished in regenerating 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: 1 ~-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-(n-dimeth 1"~minophenvl)-7-(n-bromophen~pvridof2 3-dl~,vrimidine 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/CH2CI2 to give the pure title compound. IR (KBr) 3503, 3398, 1731, 1658, 1510, 1467, 1278cm-1; MS m/z 421 (M+H)+.
The 4-(4-bromophenyl)-3-cyano-6-(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)+.
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-X56 ~ Name R4 Reagent R3 Reagent yt~cal I

N (for 7- {for 5- Data o .

osition) osition ~

2 4-amino-5-(4- 1-(4- 4- IR (KBr) 3440, dimethylaminophenyl)-7-dimethylamino-dimethylamino-1615. 1760, ( (4- phenyl)-ethanonebenzaldehyde1210cm-i:
MS m/z dimethylaminophenyl)pyri 385 (M+H)+.

do[2,3-d] 'rrudine;

3 4-amino-5-(4- 1-(4- 4- IR (KBr) 3330, methoxyphenyl)-7-(4-dimethylamino-methoxybenzalde1600, 1640, 1780.

dimethylaminophenyl)pyriphenyl)-ethanonehyde 1200cm-i;
MS m/z do[2,3-d]pyrimidine; 3'72 M+ +

4 4-amino-5-(4- 1-(4- 4- IR (KBr) 3660, dimethylaminophenyl)-7-methoxyphenyl)-dimethylamino-1600, 1620, 1510.

(4- ethanone benzaldehyde1360, 1240 cm-i;

methoxyphenyl)pyrido[2, MS miz 372 3-d]pyrimidine; M+H +

4-amino-5-(4- 1-(4- 4-isopropyl-IR (KBr) 3430, isopropylphenyl)-7-(4-methoxyphenyl)-benzaldehyde3360, 1580, methoxyphenyl)pyrido[2,ethanone cm-i; MS m/z 3'71 3-d]pyrimidine; M+H +

6 4-amino-5-(4- 1-(4- 4-neopentyl-IR (KBr) 3480, neopentylphenyl)-7-(4-methoxyphenyl)-benzaldehyde2960, 1580, 1510, methoxyphenyl)pyrido[2,ethanone 1240 cm-i;
MS m/z 3-d]pyrimidine; 399 M+H +

7 4-amino-5-(4- 1-(4- 4- TR (KBr) butoxyphenyl)-7-(4-methoxyphenyl)-butoxybenzaldeh3480,1600, 1580, methoxyphenyl)pyrido[2,ethanone yde 1510, 1240, 3-d]pyrimidine; cm-i; MS m/z M+H +

8 4-amino-5-(4- 1-(4- 4- Iit (KBr) 3660, methoxyphenyl)-7-(4-bromophenyl)-methoxybenzalde1600, 1680, 1520, bromophenyl)pyrido[2,3-ethanone hyde 1240cm-i;
MS m/z d]pyrimidine; 407 M+ +

9 4-amino-~-(4- 1-(4- 4-isopropoxy-IR (KBr) 3480, isopropoxyphenyi)-7-(4-methoxyphenyl)-benzaldehyde2940, 1600, 1580, methoxyphenyl)pyrido[2,ethanone 1504 cm-i;
MS m/z 3-d]pyrimidine; 386 M+H +

4-amino-5-(4- 1-(4-N- 4-butoxy- IR (KBr) 3480, butoxyphenyl)-7-(4-N-fonmylpiperazinybenzaldehyde2940, 1660, 1600, formylpiperazinylphenyl)pIphenyl)- 1580, 1510 cm-i:

yrido[2,3-d]pyrimidine;ethanone MS mi_ 483 (M+H +
11 4-amino-S-(4- 1-(4- 4-benzyloxy-IR (KBr) 3480, benzyloxyphenyl)-7-(4-methoxyphenyl)-benzaldehyde3040, 1600, 1580, methoxyphenyl)pyrido[2,ethanone 1560 cm-i;
MS m/z 3-d]pynmidine; 435 (M+H +
12 4-amino-5-(4- 1-(4- 4-phenoxy- IR (KBr) 3456, phenoxyphenyl)-7-(4-methoxyphenyl)-benzaldehyde3053, 1580, 1558, methoxyphenyl)pyrido[2,ethanone 1247 cm-1;
MS m/z 3-d]pyrlmidine; 421 M+ +
13 4-amino-5-(4- 1-(4-(3- 4-isopropyl-IR (KBr) 3480, isopropylphenyl)-7-(4-; (diethylmalonyl)benzaldehyde! 2980. 1735.
1580.

diethylinalonylallylphenyl)allyl) phenyl)- 1555 cm-I;
MS m~z pvrido[2,3-d]pyrimidine;ethanone 539 M+H +

l4 4-amino-5-(4- 1-(4-t- 4-isopropyl-IR (KBr) 3471, isopropylphenyl)-7-(4-t-butylacrylphenylbenzaldehyde2957, 1708, 1584, butylacrylphenyl)pyrido[2)-ethanone 1556, 1149 cm'1~

,3-d]pyrimidine; MS m/z 467 M+H +

15 4-amino-5-(3- 1-(4- 3-bromo- IR (KBr) 3480, bromophenyl)-7-(4- dimethylaminophbenzaldehyde1610, 1580, 1560, dimethylaminophenyl)pyrienyl)-ethanone 1360, 1200 cm-1;

do[2,3-d]pyrimidine; MS m/z 421 M+H +

16 4-amino-5-(3,4- 1-(4- 3,4-dimethoxy-IR (KBr) 3450, dimethoxyphenyl)-7-(4-dimethylaminophtxnzaldehyde1610.1580.1560, dimethylaminophenyl)pyrienyl)-ethanone 1510 cm-1;
MS m/z do[2,3-d]pyrirrudine; 402 M+H +

17 4-amino-5-(3-t- 1-(4- 3-(3- IR (KBr) 3480, butylacryiphenyl)-7-(4-dimethylaminophformylphenyl)acr3400, 1700, 1610, dimethylaminophenyl)pyrienyl)-ethanoneylic acid 1580, 1560 t-butyl cm-I;

do[2,3-d]pyrimldine; ester MS m/z 468 M+H +

18 4-amino-5-(3- 1-(4- 3-methoxy- 1It (KBr) 3475, methoxyphenyl-7-(4-dimethylaminophbenzaldehyde1610, 1580, 1560, dimethylaminophenyl)pyrienyl)-ethanone 1200 cm-1;
MS m/z do[2,3-d]pyrimidine; 372 M+H +

19 4-amino-5-(3,5- 1-(4- 3,5-dimethoxy-IR (KBr) 3419, dimethoxyphenyl-7-(4-dimethylaminophbenzaldehyde1637, 1600, 1572, dimethylaminophenyl)pyrienyl)-ethanone 1371, 1202 cm-1;

do[2,3-d]pyrimidine; MS m/z 402 M+H +

20 4-amino-5-(3- 1-(4- 2-[2-(3- IR (KBr) 3480.

diethyhnalonylallylphenyl)dimethylaminophformylphenyl)vi1720, 1610;
1580, -7-(4- enyl)-ethanonenyl]malonic 1558, 1524,1360 acid dimethylaminophenyl)pyri diethyl estercm-1; MS m/z do[2,3-d]pyrimldine; M+H +

21 4-amino-S-(3- 1-(4- 3-vinylpyridinyl-IR (KBr) 3480, vinylpyridinylphenyl)-7-dimethylaminophbenzaldehyde1610, 1580, 1560, (4- enyl)-ethanone 1513, 1360 cm-i;

dimethylaminophenyl)pyri MS m~~ 385 do[2,3-d]pyrimidine; M+H +

22 4-amino-5-(3- 1-(4- 3- IR (KBr) 3480, trifluoromethylphenyl)-7-dimethylaminophtrifluoromethyl-1610, 1580, 1560.

(4- enyl)-ethanonebenzaldehyde1360. 1200 cm-i;

dimethylaminophenyl)pyri MS m~= 410 do[2,3-d]pyrimidine; (M+H +

23 4-amino-5-(3- 1-(4- 3-amido- IR (KBr) 3480, carboxamidophenyl)-7-(4-dimethylaminophbenzaldehyde1610, 1580, 1380, dimethylaminophenyl)pyrienyl)-ethanone 1200 cm 1;
MS m/z do[2,3-dJpyrimidine; ,~6 + +

24 4-amino-5-(3- 1-(4- 3-cyano- IR (KBr) 3460, cyanophenyl)-7-(4- dimethylaminophbenzaldehyde3400, 2210.
1610, dimethylaminophenyl)pyrienyl)-ethanone 1580, 1554.

do[2,3-d]pyrimidine; cm-1; MS m/_ M+H +

25 4-amino-5-(3- 1-(4- 3-benzyloxy-IR (KBr) 3470, benzyloxyphenyl)-7-(4-dimethylaminophbenzaldehyde1640, 1580, 1550, dimethylaminophenyl)pyrienyl)-ethanone 1515, 1357.

do[2,3-d]pyrimidine; cm-1; MS m/z M+H +

26 4-amino-5-(3- 1-(4- 3-methoxy- IR (KBr) 3470, methoxyphenyl)-7-(4-methoxyphenyl)-benzaldehyde1640, 1580.
1550, methoxyphenyl)pyrido[2,ethanone 1515, 1357, 1250, 3-d]pyrimidine; 1240, 1180 cm-1;

MS m/z 359 M+H +

27 4-amino-5-(3- 1-(4- 3-bromo- IR (KBr) 3478, bromophenyl)-7-(4- butoxyphenyl)-benzaldehyde1610, 1580, 1560, butoxyphenyl)pyrido[2,3-ethanone 1515, 1355, 1255.

d]pyrimidine; 1240, 1180 cm-I;

MS m/z 449 M+H +

28 4-amino-5-(3-(2- 1-(4- 3-(2-pyridyl)-IR (microscope) pyridyi)phenyl)-7-(4-dimethylaminophbenzaldehyde3476.1609.
1580, dimethylaminophenyi)pyrienyl)-ethanone 1560, 1358 cm-1;

do[2,3-d]pyrimidine; MS m/z 419 M+H +

29 4-amino-5-(3- I-(4- 3-methyl- Iit (microscope) methylphenyl)-7-(4-dimethylaminophbenzaldehyde3400. 1640,1600.

dimethylaminophenyi)pyrienyl)-ethanone 1580, 1540cm-1;

do[2,3-dJpyrimidine; MS m/z 356 M+H +

30 4-amino-5-(3- 1-(4- 3-chloro- IR (microscope) chlorophenyl)-7-(4-dimethylaminophbenzaldehyde3400, 1600.
1580, dimethylaminophenyl)pyrienyl)-ethanone 1540 cm-1:
MS m/z do[2,3-d]pyrimidine; 376 M+ +

31 4-amino-5-(3- 1-(4- 3-fluoro- IR (microscope) fluorophenyl)-7-(4-dimethylaminophbenzaldehyde3480, 1640, 1580, dimethylaminophenyl)pyrienyl)-ethanone 1560cm-1:
MS m/z do[2,3-d)pyrimidine; 360 M+H +

32 4-amino-5-(3- 1-(4- 3-bromo- IR (microscope) bromophenyl)-7-(4- methoxyphenyl)-benzaldehyde3485.1607.1575, methoxyphenyl)pyrido[2,ethanone 1550, 1515.
1350, 3-d]pyrimidine; 1255. 1240, 1180, 1030 cm-1;
MS m/.

407 M+H +

WO 98/46605 PCT/iJS98/07207 33 4-amino-5-(3- 1-(4- 3-methoxy- iR (microscope) methoxyphenyl)-7-(4.bromophenyl)-benzaldehyde 3450, 1640, 1573, bromophenyl)pyrido[2,3-ethanone 1555, 1496, 1350, d]pyrimidine; 1260 cm-1;
MS m/z 407 M+H +

34 4-amino-5-(3- 1-phenyl- 3-bromo- IR (lcBr) 3480, bromophenyl)-7-phenylethanone benzaldehyde 1640, 1580, 1560, pyrido [2,3-d]pyrimidme; 1480, 1350, cm-1; MS m/z M+H +

35 4-amino-5-(3- 1-(4- 3-bromo- IIt (microscope) bromophenyl)-7-(4- ethylphenyl)-benzaldehyde 3480, 1645, ethylphenyl)pyrido[2,3-ethanone (broad),1490,1380 d]pyrimidine; cm-1; MS mlz M+H +

36 4-amino-5-(3- 1-(4- 3-bromo- lR (KBr) 3480, bromophenyl)-7-(4- bromophenyl)-benzaldehyde 1610, 1575, 1540, bromophenyl)pyrido[2,3-ethanone 1350 cm-1;
MS mlz d]pyrimidine; 455 M+ +

37 4-amino-5-(3- 1-(4- 3-bromo- IR (microscope) bromophenyl)-7-(4- cyanophenyl)-benzaldehyde 3480, 2230, 1618, cyanophenyl)pyrido[2,3-ethanone 1580, 1555, 1545, d]pyrimidine; 1350 cm-1;
MS mh 402 M+H +

38 4-amino-5-(3- 1-(4- 3-bromo- IR (microscope) bromophenyl)-7-(4- hydroxyphenyl)-benzaldehyde 3481, 3060 (broad), hydroxyphenyl)pyrido[2,3ethanone 1645, 1580, 1560, -d]pyrimidine; 1544, 1360, 1155 cm-1;
MS mlz 393 M+H +

39 4-amino-S-(3- 1-(4- 3-iodo- IR (microscope) iodophenyl)-7-(4- dimethylaminophbenzaldehyde 3500, 3040, 1640, dimethylaminophenyl)pyrienyl)-ethanone 1600, 1580, do[2,3-d]pyrimidine; cm-1; MS m/z M+H +

40 4-amino-5-(3- 1-(4- 3-ethoxy- Iit (microscope) ethoxyphenyl)-7-(4-dimethylaminophbenzaldehyde 3460, 3250, 1640, dimethylammophenyl)pyrienyl)-ethanone 1600, 1580.

do[2,3-d]pyrimidine; cm-1; MS m/z M+H +

41 4-amino-5-(3- 1-(4- 3- IR (microscope) trifloromethyoxyphenyl)-dimethylaminophtrifluoromethoxy3480, 1710, 1610, 7-(4- enyl)-ethanone-benzaldehyde1580, 1560, dimethylaminophenyl)pyri cm-1; MS mlz do[2,3-d]pyrimidine; M+H +

42 4-amino-5-(3.5- 1-(4- 3,5-dichloro-IR (microscope) dichlorophenyl)-7-(4-dimethylaminophbenzaldehyde 3500, 3040, 1640.

dimethylaminophenyl)pyrienyl)-ethanone 1600, 1580.

do[2,3-d]pyrimidine; cm-1; MS m/z M+H +

WO 98/4b605 PCT/US98/07207 43 4-amino-5-(3-bromo-4-1-(4- 3-bromo-4- I1t (microscope) fluorophenyl)-7-(4-dimethylaminophfluoro- 3440. 3015, 1633, dimethylaminophenyl)pyrienyl~ethanonebenzaldehyde1607,1583 cm-1;

do[2,3-d]pyrimidine; MS m/z 438 M+ +

44 4-amino-5-(3- 1-(4- 3-hydroxy- llt (microscope) hydroxyphenyl)-7-(4-dimethylaminophbenzaldehyde3450. 1640.
i 1610.

dimethylaminophenyl)pyrienyl)-ethanone 1580,1560 cm-1;

do[2,3-d]pyrimidine; MS m/z 358 M+H +

45 4-amino-5-(3- 1-(4- 3-bromo- IR (microscope) bromophenyl)-7-(4- morpholinylphenbenzaldehyde3483, 1607, 1578, morpholinylphenyl)pyridoyl)-ethanone 1561, 1518, 1355, [2,3-d]pyrimidine; 1228 1120 cm-1;

MS m/z 462 M+H +

46 4-amino-5-(3- 1-(4- 3-bromo- 1R (microscope) bromophenyl)-7-(4- piperidinylphenybenzaldehyde3486, 1606, 1561, piperidinylphenyl)pyrido[1)-ethanone 1540, 1519, 1353, 2,3-d]pyrimidine; 1231, 1199, cm-1; MS m/z M+H +

47 4-amino-5-(3- 1-(4-(imidazol-1-3-bromo- IR (KBr) 3481, bromophenyl)-7-(4- yl)phenyl}- benzaldehyde1580, 1555, 1525, (imidazol-1- ethanone 1482, 1352.
1303, yl)phenyl)pyrido[2,3- 1053 cm-1;
MS m/z d]pyrimidine; 443 M+H +

48 4-amino-5-(3- 1-(4- 3-bromo- IR (KBr) 3470, bromophenyl)-7-(4- chlorophenyl)-benzaldehyde1635, 1580, 1560, chlorophenyl)pyrido[2,3-ethanone 1500, 1350, d]pyrimidine; cm-1; MS m/z M+H +

49 4-amino-5-(3- 1-(4- 3-bromo- IR (KBr) 3484, bromophenyl)-7-(4- isopropylphenyl)benzaldehyde1610, 1579, 1560, isopropylphenyl)pyrido[2,-ethanone 1550. 1483, 3-d]pyrimidine; cm-1; MS m/z M+H +

50 4-amino-5-(3- 1-(4- 3-bromo- Itt (microscope) bromophenyl}-7-(4- trifluorophenyl)-benzaldehyde3481, 3289.
1616, trifluorophenyl)pyrido[2,3ethanone 1579, 1547, 1324, -d]pyrimidine; 1312, 1122, cm-1; MS m/z M+H +

51 4-amino-5-(3- 1-(4- 3-bromo- IR (KBr) 3481, bromophenyl)-7-(4- diethylaminophebenzaldehyde1607, 1578, 1561, diethylaminophenyl)pyridnyl)-ethanone 1533. 1353, 1200, 0[2,3-d]pyrimidine; 1155 cm-1;
MS mlz 448 M+H +

52 4-amino-5-(3- 1-(3,4,5- 3-bromo- IR (KBr) 3485.

bromophenyl)-7-(3,4,5-trimethoxyphenybenzaldehyde1579, 1548, 1507, trimethoxyphenyl)pyrido[1)-ethanone 1340, 1129 cm-1~

2,3-d]pyrimidine; MS ml~ 467 M+H +

WO 98/46b05 PCT/US98/07207 53 4-amino-5-(3-(3- 1-(4- 3-(3- 1R (KBr) 3425, methoxybenzyl)phenyl)-7-dimethylaminophmethoxybenzyl)-1613, 1580, 1558, (4- enyl)-ethanonebenzaldehyde 1537 cm-1;
MS m/z dimethylaminophenyl)pyri 478 ~+~+
' .
do[2,3-d]
midine;

54 4-amino-5-(3- 1-(4- 3- IR (KBr) ~ 3469, methoxyethyoxyphenyl)-dimethylaminophmethoxyethoxy-1610. 1580, 1560, ~-(4- enyl)-ethanonebenzaldehyde 1357 cm-1;
MS m/z dimethylaminophenyl)pyri 416 (M+H)+
' .
do[2,3-d]
midine;

55 4-amino-5-(3,4- 1-(4- 3,4- IR (KBr) 3466, methylenedioxyphenyl)-7-dimethylaminophmethylenedioxy-16245, 1579, (4- enyl)-ethanonebenzaldehyde cm-1; MS
m/z 386 dimethylaminophenyl)pyri (M+~+
' .
do[2,3-d]
midine;

56 4-amino-5-(3- 1-(4- 3-bromo- IR (KBr) 3480, bromophenyl)-7-(4- ethoxyphenyl)-benzaldehyde 160'7, 1579, 1560, ethoxyphenyl)pyrido[2,3-ethanone 1517, 1360, 1238, d]pyrimidine; 1180 cm-1;
MS m/z 421 (M+H)+.
57 4-amino-5-(3- 1-phenyl- 3-bromo- IR (KBr) 3470, bromophenyl)-7-(2'-ethanone benzaldehyde 1579, 1560, 1547, thiophene)pyrido[2,3- 1429, 1361 cm-1~

d]pyrlmldlrie; MS m/z 383 M+H +

58 4-amino-5-(3- 1-(4- 3-bromo- IR (microscope) bromophenyl)-7-(4- fluorophenyl)-benzaldehyde 3476.1600.1580, fluorophenyl)pyrido[2,3-ethanone 1555, 1515, 1350, d]pyrimidine; 1230 cm-1;
MS m/z 395 M+H +

59 4-amino-5-(3- 1-(4- 3- IR (KBr) 3436.

dimethylaminophenyl)-7-dimethylaminophdimethylamino-1601. 1580.
1563, (4- enyl)-ethanonebenzaldehyde 1534, 1200 cm-1;

dimethylaminophenyl)pyri MS m/z 385 do[2,3-d]pyrimidine; M+H +

60 4-amino-5-phenyl-7-(4-1-(4- benzaldehyde IR (K>3r) 3400, dimethylamlnophenyl)pyridimethylaminoph 1600. 1580, 1560, do[2,3-d]pyrimldine;enyl)-ethanone 1530, 1200 cm-1;

MS m/z 342 +H +

61 4-amino-5-(3,4,5- 1-(4- 3,4,5- IR (I~r) 33460, trimethoxyphenyl)-7-(4-dimethylaminophtrimethoxy- 1607.1578, dimethylammophenyl)pyrienyl)-ethanonebenzaldehyde 1127cm-1;
MS m/z do[2,3-d]pyrimldine; 432 M+H +

62 4-amino-5-(3- 1-(4- 3-bromo- IR (microscope) bromophenyl)-7-(4- nitrophenyl)-benzaldehyde 3485.1618.1580, nitrophenyl)pyrido[2,3-ethanone 1550, 1520, 1340, d]pyrimidine; 860 cm-1;
MS m/z 422 M+H +

63 4-amino-5-(3- 1-(4- 3-bromo- 1R (KBr) 3480, bromophenyl)-7-(4- iodophenyl)- benzaldehyde1610, 1575, 1570, iodophenyl~yrido[2,3-ethanone ' 1540. 1350, d]pyrimidine; cm-1; MS.m/z M+ +

64 4-amino-5-(3- 1-(3,4- 3-bromo- IR (KBr) 3485, bromophenyl)-7-(3,4-methylenedioxypbenzaldehyde1607, 1575.
1545, methylenedioxyphenyl)pyrhenyl)-ethanone 1500, 1440, 1350, ido[2,3-d]pyrimidine; 1255. 1038 cm-1;

MS m/z 421 M+H +

65 4-amino-5-{thiophen-2-1-(4- thiophene-2-IR (KBr) 3480, yl)-7-(4- morpholinylphencarboxaldehyde1607, 1580, 1560, morpholinylphenyl)pyridoyl)-ethanone 1226 cm-1;
MS m/z (2,3-d]pyrimidine; 390 M+H +

66 4-amino-5-(3,5- 1-(thiophen-2-3,5-dimethoxy-IR (KBr) 3450, dimethoxyphenyl)-7-yl)-ethanone benzaldehyde1640, 1600, - 1580, (thiophen-2-yle)pyrido 1560 cm-1;
MS m/z [2,3-d]pyrimidine; 365 M+H +

67 4-amino-5-(3- 1-(4- 3-bromo- IIt (KBr) 3481, bromophenyl)-7-(4- carboxamidophebenzaldehyde1674, 1611, 1577, carboxamidophenyl)pyridnyl)-ethanone 1558,1352 cm-1;

0[2,3-d]pyrimidine; MS m/z 420 M+H +

68 4-amino-5-(3- 1-(4-(2- 3-bromo- IR (KBr) 3478, bromophenyl)-7-(4-(2-methoxy)ethoxybenzaldehyde1607, 1580, 1560, methoxy)ethoxyphenyl)pyphenyl)-ethanone 1515, 1357, 1260, rido[2,3-d]pyrimidine; 1235, 1180, cm' 1; MS
m/z 451 M+H +

69 4-amino-5-(3,5- 1-(4- 3,5-dimethoxy-IR (Kgr) 3450, dimethoxyphenyl)-7-(4-morpholinylphenbenzaldehyde1608, 1580, 1555, morpholinylphenyl)pyridoyl)-ethanone 1541, 1230, 1210, [2,3-d]pyrimidine; 1160 cm-i;
MS m/z 444 M+H +

70 4-amino-5-(3- 1-(thiophene-2-3- iit (KBr) 3486, trifluoromethylphenyl)-7-yl)-ethanone trifluoromethyl-1620, 1580, 1560, (thiophene-2-yl)pyrido benzaldehyde1325,1123cm-1;

[2,3-d)pyrimidine; MS m/z 373 M+H +

71 4-amino-5-(3- 1-(4- 3-bromo- Itt (KBr) 3450, bromophenyl)-7-(4- aminophenyl)-benzaldehyde1632, 1605, 1580, aminophenyl)pyrido[2,3-ethanone 1365 cm-i;
MS m/z d]pyrimidine; 393 M+H +

72 4-amino-5-(3-bromo-4-1-(thiophene-2-3-bromo-4- IFt (KBr) 3480, fluorophenyl)-7- yl)-ethanone fluoro- 1640, 1580, ~ 1560, (thiophene-2-yl)pyrido benzaldehyde1500cm-1;
MS m/z [2,3-d]pyrimidine; 401 M+H +

73 4-amino-5-(3-bromo-4-1-(2-furanyl)-3-bromo-4- IR (KBr) 3460, fluorophenyl)-7-{2-ethanone fluoro- 1600. 1580, 1560, furanyl)pyrido [2,3- benzaldehyde1500cm-1;
MS m/z d]pyrirrudine;
385 M+H +

74 4-amino-5-(3,5- 1-(4- 3,5-dimethoxy-llt (KBr) 3460, dimethoxyphenyl~7-(4-iodophenyl)-benzaldehyde 1604, 1575, 1556, iodophenyl)pyrido[2,3-ethanone 1541, 1207, d]pyrimidine; cm-1; MS m/z +H +

75 4-amino-5-(3,5- 1-(4- 3,5-dimethoxy-IR (KBr) 3459.

dimethoxyphenyl)-7-(4-imidazolylphenylbenzaldehyde ~ 1604. 1580, 1556, imidazolylphenyl)pyrido[2)-ethanone 1524, 1484, 1304, ,3-d]pyrimidine; 1159, 1056 cm-1:

MS m/z 425 (M+H +

76 4-amino-5-(3,5- I-(4-(thiophene-3,5-dimethoxy-IR (KBr) 3457, dimethoxyphenyl)-7-(4-2-yl)phenyl)-benzaldehyde 1602, 1579, 1557, (thiophene-2- ethanone 1207, 1159 cm-1~

yl)phenyl)pyrido[2,3- MS m/z 441 d]pyrimidine; M+H +

77 4-amino-5-(3,5- 1-(4-(3- 3,5-dimethoxy-IR (KBr) 3452.

dimethoxyphenyl)-7-(4-pyridyl)phenyl)-benzaldehyde 1604, 1578.
1558, (3- ethanone 1287, 1206, pyridyl)phenyl)pyrido[2,3 cm-1~ MS m/.

-d]pyrimidine; M+H +

78 4-amino-5-(3- I-(4-(4- 3-bromo- IR (KBr) 3475.

bromophenyl)-7-(4.-{4-methylpiperidinybenzaldehyde 1607, 1577, 1558, methylpiperidinyl)phenyl)1)phenyl)- 1540, 1356, pyrido[2,3-d]pyrin-iidine;ethanone cm-1; MS m/_ M+H +

79 4-amino-5-(3- 1-(4- 3-bromo- IR (KBr) 3486.

bromophenyl)-7-(4- pyrrolidinylphenbenzaldehyde 1608, 1577, 1560, pyrrolidinylphenyl)pyrido[yl)-ethanone 1533, 1353.

2,3-d]pyrimidine; cm-1; MS m/.

+H +

80 4-amino-S-(4- 1-(4- 4- IR (KBr) 3327.

bromothiophen-2-yl)-7-{4-dimethylaminophbromothiophene-1604, 1578, 1548, dimethylaminophenyl)pyrienyl)-ethanone2- 1521, 1367, 1350, do[2.3-d]pyrimidine; carboxaldehyde1202, 820 cm-1;

MS m/z 426 M+H +

81 4-amino-5-(4- 1-(4- 4- nt (KBr) 3460, bromothiophene-2-yl)-7-morpholinylphenbromothiophene-1606, 1578, 1558, (4- yl)-ethanone2- 1541, 1517, 1232, morpholinylphenyl)pyrido carboxaldehyde824 cm-1;
MS m/z [2,3-d)pyrimidine; 468 M+H +

82 4-morpholinyl-5-(3-1-(4- 3-bromophenyl-IIt (microscope) bromophenyl)-7-(4- dimethylaminophbenzaldehyde 3340. 1603, 1580, dimethylaminophenyl)pyrienyl)-ethanone 1540 cm-1;
MS m/z do[2,3-d]pyrimldine; 490 M+H +

83 4-amino-5-(5- I-(4- 5- IR (KBr) 3460.

bromothiophene-2-yl)-7-morpholinylphenbromothiophene-1606, 1580.
1558, {4- yl)-ethanone2-yl- 1541, 1517, morpholinylphenyl)pyrido benzaldehyde cm-1; MS m/_ [2,3-d]pyrimidine; M+H +

84 4-amino-5-(4- 1-(4- 4-bromo- 1R (microscope) bromophenyl)-7-(4- dimethylaminophbenzaldehyde 3480, 3320, 1603, dimethylarninophenyl)pyrienyl)-ethanone 1580, 1540, do[2,3-d]pyrimidine; cm-1; MS m/z (M+H +

85 4-amino-~-(3- 1-(4- 3-bromo- ~ llt (microscope) bromophenyl)-7-(4- (acetyiamino)phebenzaldehyde 34801600.1580.

(acetylamino)phenyl)pyridnyl)-ethanone 1520cm-1:
MS rr~:

0[2,3-d)pyrimidine; 434 M+H +

86 4-amino-5-(3- 1-(4- 3-bromo- IR (microscope) bromophenyl)-7-(4- dimethyiaminophbenzaldehyde 3300, 1606.
1600, dimethylaminophenyl)pyrienyl)-ethanone 1580, 1560 cm-1;

do[2,3-d]pyrirrudine; MS m/z 421 (M+H +

87 4-amino-5-(3,5- 1-(5- 3,5-dimethoxy-IR (microscope) dimethoxyphenyl)-7-(5-pyrimidinylphenbenzaldehyde 3458. 1602, 1579, pyrimidinylphenyl)pyrido[yl)-ethanone 1558.1460.1414, 2,3-d]pyrimidine; 1364. 1196.

cm-1; MS m/z M+H +

88 4-(4-fluorophenyl)amino)-1-(4- 3-bromo- IR (KBr) 3410, 5-(3-bromophenyl)-7-(4-dimethylaminophbenzaldehyde 1605, 1570.
1525.

dimethylammophenyl)pyrienyl)-ethanone 1503 cm-1:
MS m/z do[2,3-d]pyrimidine; 514 +H +

89 4-amino-5-(4- 1-(4- 4- llt (KBr) 3470, bromothiophene-2-yl)-7-pyrrolidinylphenbromothiophene-1609. 1577, 1555, (4- yl)-ethanone 2- 1520. 1409, 1386, pyrrolidinylphenyl)pyrido[ carboxaldehyde1350.1196.821 2,3-d]pyrimldine; cm-1; MS m/z M+H +

90 4-amino-5-(4- 1-(thiophene-2-4- IR (KBr) 3308, bromothiophene-2-yl)-7-yl)-ethanone bromothiophene-1606.1578.1543.

(thiophene-2- 2- 1526, 1427, yl)pyrido[2,3- carboxaldehydecm-1; MS m/z d]pyrimidine; M+H +

91 4-amino-5-(3- 1-(5- 3-bromo- IR(microscope) bromophenyl)-7-(5- (dimethylamino)tbenzaldehyde 3490, 1581, 1556, (dimethylamino)thiophenehiophene-2-yl)- 1501, 1481, 1407, -2-yl)pyrido[2,3- ethanone 1373. 1072 cm-1;

d]pylimidine; MS m/z 426 M+H +

92 4-amino-5-(3-bromo-5-1-(4- 3-bromo-5-iodo-IR (KBr) 3493, iodophenyl)-7-(4- (dimethylamino)benzaldehyde 1608, 1562.
1533.

(dimethylamino)phenyl)pyphenyl)-ethanone 1364, 1350, rido[2,3-d]pyrimidine; cm-1: MS mlz M+H +

93 4-amino-5-(3,5- 1-(4- 3,5- IR (KBr) 3484, di(trifluoromethyl)phenyl)(dimethylamino)di(trifluoromethy1607, 1580.
1554.

-7-(4- phenyl)-ethanone1-benzaldehyde1386. 1280 cm-1;

(dimethylamino)phenyl)py MS m/z 478 rido[2,3-d]pyrimidine; M+H i+.

94 4-amino-5-(3,5- 1-(4- 3,5- IR (KBr) 3500 , di(trifluoromethyl)phenyl)morphoiinylphendi(trifluoromethy1643. 1602, 1578, -7-(4- yl)-ethanone 1-benzaldehyde1554,1280 cm-1;

morpholinylphenyl)pyrido MS m~z 520 [2,3-dJpyrimidine; (M+~+.

95 4-amino-~-(3,5- 1-(4- 3,5-dibromo-IR (KBr) 3440 , dibromophenyl)-7-(4-(dimethylamino)benzaldehyde~ 1608. 1570, 1559, (dimethylamino)phenyl)pyphenyl)-ethanone I 1536 cm-1~
MS miz rido[2,3-d]pyrimidine; 475 M+H~+

96 4-amino-5-(3,5- 1-(4- 3>5-dibromo-llt (KBr) 3480 , dibromophenyl)-7-(4-molpholinylphenbenzaldehyde1607, 1560, 1540, morpholinylphenyl)pyridoyl)-ethanone 1225 cm-1~
MS m/z [2,3-d]pyrimidine; ~

_ 540 M+H
97 4-amino-5-(4- 1-(4-{4- 4- +
gz (KBr) 3460 , bromothiophene-2-yl)-7-methylpiperidinybromothiophene-1608. 1576, 1557, (4-(4- 1)phenyl)- 2- 1540, 1513, 1384, methylpiperidinyl)phenyl)ethanone carboxaldehyde1353, 1240, pyrido[2,3-d]pyrimidine; cm-1; MS m/z M+H +

98 4-amino-5-(3,5- 1-(4- 3,5-dibromo-Ilt (KBr) 3486, dibromophenyl)-7-(4-(dimethylamino)benzaldehyde1608, 1570, 1559, (dimethylamino)phenyl)pyphenyl)-ethanone 1536, 1360, 1350, rido[2,3-d]pyrimidine; 1200, 823 cm-1;

MS m/ z 498 + +

99 4-amino-5-(3- 1-(4- 3-bromo- IR
~

bromophenyl)-7-(3- (dimethylamino)benzaldehyde160 579 8 548, (dimethylamino)phenyl)pyphenyl)-ethanone 1483, 1357 cm-1~

rido[2,3-d]pyrimldine; MS miz 420 + +

100 4-amino-5-(3- 1-{4- 3-bromo- .
IR
(KBr) 3486, bromophenyl)-7-(4- methylsulfonylpbenzaldehyde1600, 1580, 1550, methylsulfonylphenyl)pyrihenyl)-ethanone 1490 cm-1~
MS m/z do [2,3-d]pyrimidine; ' 5 M+ +

101 4-amino-5-(3- 1-(3- 3-bromo- .
~
(KBr) 3486, bromophenyl)-7-(3- methoxyphenyl)-benzaldehyde1605, 1578, 1550, methoxyphenyl}pyrido[2,ethanone 1492. 1346, 3-d]pyrimidine; cm-1; MS m/z M+H +

.
102 4-amino-5-(3- 1-(4- 3-bromo- IR (KBr) 3485, bromophenyl)-7-(4- (methylthio)phenbenzaldehyde1607, 1578, 1566, (methylthio)phenyl)pyridoyl)-ethanone 1538, 1350, 1094, [2,3-d]pyrimidine; 795 cm-1; MS
m~z 103 4-amino-5-(3- 1-(3,4- 3-bromo- ~3 M+H +.
(KBr) 3482 , bromophenyl)-7-(3,4-dichlorophenyl)-benzaldehyde1634, 1576, 1545, dichlorophenyl)pyrido[2,3ethanone 1488, 1342 cm-n -d]pyrirrudine; MS mi_ 445 (M+H +

104 4-amino-5-(3- 1-(4-(N-methyl-3-bromo- lIt (I~r) 3478, bramophenyl)-7-(4-(N-N- benzaldehyde1672, 1639, 1603, methyl-N- formylamino)phe 1579, 1547, 84i formylamino)phenyl)pyridnyl)-ethanone cm-1; MS m/z 0[2,3-d]pyrimidine; ~M+~+.

105 4-amino-5-(3- ~ 1-{4- 3-bromo- IR (ICl3r) 3488, bromophenyl)-7-(4-methylaminophebenzaldehyde1637, 1607.
1587.

methylaminophenyl)pyridnyl)-ethanone 1360 cm-1~
MS m~~
.

0[2,3-d]pyrimidine; 480 (Li+H
+

106 4-amino-S-(3-bromo-4-1-(4- 3-bromo-4- IR (KBr) 3489, fluorophenyl)-7-(4-methylsulfonylpfluoro- 1578, 1560, 1496, methylsulfonylphenyl)pyrihenyl)-ethanonebenzaldehyde1311, 1151, do[2,3-d]pyrimidine; cm-1: MS mi_ M+ +

107 4-amino-5-(3- 1-(3-amino-4-3-bromo- IR (microscope) bromophenyl)-7-(3-methoxyphenyl)-benzaldehyde3431, 1629, 1606, amino-4- ethanone 1583, 1274 cm-1;

methoxyphenyl)pyrido[2, MS rr~z 422 3-d]pynmidine; M+ +

108 4-amino-5-(3- 1-(3-bromo-4-3-bromo- >It (microscope) bromophenyl)-7-(3-(dimethylamino)benzaldehyde3470, 1638.
1570, bromo-4- phenyl)-ethanone 1560. 1538, 1480, (dimethylamino)phenyl)py 1345 cm-1;
MS m/z rido[2,3-d]pyrimidine; 498 +H +

109 4-amino-5-(3- 1-(3-bromo-4-3-bromo- IR (microscope) bromophenyl)-7-(3-(dimethylamino)benzaldehyde3438.1640..1605, methyl-4- phenyl)-ethanone 1580. 1555, (dimethylamino)phenyl)py cm-1: MS m~:

rido[2,3-d]pyrimidine; M+ +

110 4-amino-5-(3- 1-(4-(N-methyl-3-bromo- IR (l~r) 3443, bromophenyl)-7-(4-(N-N- benzaldehyde1699. 1635, 1606, methyl-N- trifluoroacetylam 1201 cm-1~
MS m/z trifluoroacetylamino)phenino)phenyl)- 502 (M+H)+

.
yl)pyrido[2,3- ethanone d] ' midine;

I 4-amino-5-(3- 1-(4- 3-bromo- IR (KBr) 3438, bromophenyl)-7-(4-(dimethylamino)-benzaldehyde1638. 1592, (dimethylamino)-3-3-fluorophenyl)- cm-i: MS mn fluorophenyl)pyrido[2,3-ethanone (M+~+
' .
d]
midine;

112 4-amino-5-(3- 1-(4-(N-ethyl-N-3-bromo- IR (l~r) 3477, bromophenyl)-7-(4-(N-formylamino)phebenzaldehyde1672. 1604, 1580, ethyl-N- nyl)-ethanone 1562. 1353 cm-1~

formylamino)phenyl)pyrid MS m;= 448 ' 0[2,3-d]pyrirrudine; M+H)+

.
113 4,4-bis(acetylamino)-5-(3-1-(4-(N-methyl-3-bromo- lIt (KBr) 3434.

bromophenyl)-7-(.~-(N-N- benzaldehyde1667. 1635, 1600, methyl-N- acetylamino)phe 1200 cm-1;
biS m/_ acetylamino)phenyl)pyridonyl)-ethanone 532 (Vi+H)+
' .
[2,3-d]
rrudine;

114 4-amino-5-(3- 1-(4-{N-acetyl-3-bromo- IR (Ki3r) 3443, bromophenyl)-7-(4-(N-N- benzaldehyde 1667, 1635, 1600, acetyl-N- methylamino)phe 1200 cm-1;
Ms m/z methylamino)phenyl)pyridnyl)-ethanone 532 (M+H)+.

0[2,3-d] 'midine;

115 4-amino-5-(3- 1-(4-(N- 3-bromo- Ilt (KBr) 3441, bromophenyl)-7-(4-(N-ethylamino)phenbenzaldehyde 1633.1603.1572, ethylamino)phenyl)pyrido[yl)-ethanone 1368 cm-i;
MS mi=

2,3-d]pyrimidine; 420 M+H +
I

116 4-amino-5-(3- 1-(-(N-methyl-3-bromo- IR (KBr) 3439, bromophenyl)-7-(4-(N-N-(2- benzaldehyde 1636, 1601, 1529, methyl-N-(2- methoxyethyl)am 1361 cm-1:
MS mi_ methoxyethyl)amino)phenino)phenyl)- 464 (M+H)+.

yl)pyrido[2,3- ethanone d] ' midine;

117 4-amino-5-(3- 1-(-(N- 3-bromo- IR (KBr) 3430.

bromophenyl)-7-(4-(N-isopropylamino)benzaldehyde 1632, 1600, 1578.

isopropylamino)phenyl)pyphenyl)-ethanone 1530, 1357 cm-1;

rido[2,3-d]pyrirrudine; MS m~z 434 M+H +

118 4-amino-5-(3- 1-(4-N-ethyl-N-3-bromo- IR(microscope) bromophenyl)-7-(4-N-(2- benzaldehyde 3488, 1657.
1604, ethyl-N-(2- methoxyethyl)am 1579,1552, methoxyethyl)amino)phenino)phenyl)- cm-1; MS m~_ yl)pyrido [2,3- ethanone (M+H)+.

d] 'midine;

119 4-amino-5-(3- 1-(4-N-(3- 3-bromo- IR (KBr) 3201, bromophenyl)-7-(4-N-(3-methoxypropionbenzaldehyde 1679, 1617, methoxypropionyl)-N-yl)-N-isopropyl- 1597,1576, 1539, isopropyl- amino)phenyl)- 1177. 1117 cm-1;

amino)phenyl)pyrido[2,3-ethanone MS miz 521 d] 'midine; M+H +

120 4-amino-5-(3- 1-(4-N-(2- 3-bromo- IIt (KBr) 3475, bromophenyl)-7-(4-N-{2-(dimethylamino)benzaldehyde 1681, 1579, 1351.

(dimethylamino)ethyl)-N-ethyl)-N- cm-1: MS mi_ formylamino)phenyl)pyridformylamino)phe (M+H)+.
' 0[2,3-d] n 1)-ethanone midine;

121 4-amino-5-(3- 1-(4-(N-(2- 3-bromo- IR (KBr) 3431, bromophenyl)-7-(4-(N-(2-(dimethylamino)benzaldehyde 1634, 1601, 1573, (dimethylamino)ethyl)amiethyl)amino)phe 1359 cm-1;
MS m/z no)phenyl)pyrido[2,3-nyl)-ethanone 463 (M+H)+.
' d]
mldine;

122 4-amino-5-(3- 1-(4-(N-methyl-3-bromo- IR (KBr) 3475.

bromophenyl)-7-(4-(N-N-(2- benzaldehyde 2220.1660.1604, methyl-N (2 cyano)ethylamin 1580.1560, cyano)ethylamino)phenyl)o)phenyl}- cm-1; MS mi_ 459 ~

pyrido[2,3-d]pyrimidine;ethanone M+H +

123 4-amino-5-(3- 1-(4-(N-methyl-3-bromo- IR (KBr) 3475.

bromophenyl)-7-(4-{N-N-(3- benzaldehyde 1663, 1604.

methyl-N-(3- methoxy)propion 1578,1559, methoxy)propionylamino)ylamino)phenyl}- 1114 cm-1:
MS m~=

phenyl)pyrido[2,3- ethanone 478 (M+H)+.
' d]
rrudine;

124 4-amino-5-(3- 1-(3-methyl-4-3-bromo- llt (KBr) 3486, bromophenyl)-7-(3-(N-formyl-N- benzaldehyde 1677, 1607, 1579, methyl-4-(N-formyl-N-methylamino)phe 1549,1351 cm-1;

methylamino)phenyl)pyridnyl)-ethanone MS m~z 448 0[2,3-d]pyrimidine: M+H +

12~ 4-amino-5-(3- 1-(3-methyl-4-3-bromo- IR (KBr) 3433.

bromophenyl)-7-(3-(N- benzaldehyde 1635, 1605, 1585, methyl-4-(N- methylamino)phe 1359 cm-1;
MS miz methylamino)phenyl)pyridnyi)-ethanone 420 (M+H)+.
' 0[2,3-d]
midine:

126 4-amino-5-(3- I-(4-(4- 3-bromo- IR (microscope) bromophenyl)-7-(4-(4-methoxy-2- benzaldehyde 3473, 3063, 1710, methoxy-2- butyl)phenyl)- 1671, 1582,1564, butyl)phenyi)pyrido[2,3-ethanone 1352 cm-1;
MS mn d]pyrimidine; 593 M+H +

127 4-amino-5-(3- 1-(4-(N-methyl-3-bromo- IR (microscope) bromophenyl)-7-(4-(N-N-(2-(N- benzaldehyde 3443, 1638, 1606, methyl-N-(2-(N- phthalimidyl)acet 1582,1359cm-1;

phthalimidyl)acetyl)amino)yl)amino)phenyl) MS miz 463 phenyl)pyrido[2,3--ethanone (M+H)+.

d] rrudine;

_ I28 4-amino-5-(3- 1-(3-methyl-4-3-bromo- IR (microscope) bromophenyl)-7-(3-(N-methyl-N- benzaldehyde 3484, 1701, 1610, methyl-4-(N-methyl-N-(trifluoroacetyl)a 1579,1559, 1221, (trifluoroacetyl)amino)phemino)phenyl)- 1205,1151 cm-1;

nyl)pylido[2,3- ethanone MS m~z 516 d] 'midine; M+H +

129 4-amino-5-(3- 1-(3-methyl-4-3-bromo- lit (KBr) 3484, bromophenyl)-7-(3-(N-acetyl-N- benzaldehyde 1663, 1607, methyl-4-(N-acetyl-N-methylarnino)phe 1574,1547, methylamino)phenyl)pyridnyl)-ethanone cm-1; MS m~z 0[2,3-d]pyrimidine; M+H +

130 4-amino-5-(3- 1-(6- 3-bromo- IR (KBr) 3428, bromophenyl)-7-(6-dimethylamino-benzaldehyde 1652. 1635, 1606, dimethylamino-3- 3-pyridinyl)- 1585, 1365 cm-1;

pyridinyl)pyrido[2,3-ethanone MS m~z 421 d]PYTimidine; M+H +

131 4-amino-5-(3- I-(4- 3-cyano- IR (KBr) 3479, cyanophenyl)-7-(4-methylsulfonylpbenzaldehyde 1638, 1576,1559, methylsulfonylphenyl)pyrihenyl)-ethanone 1303,1147 cm-1-' do[2,3-d]pyrimidine; MS miz 402 M+H +

132 4-amino-5-(3- 1-(4-(N-methyl-3- Iit (KBr) 3418, cyanophenyl)-7-(4-(N-N-formylamino)-cyanobenzaldehy2230. 1688, 1674, methyl-N-formylamino)-phenyl)-ethanonede 1584, 1554, phenyl)pyrido[2,3- cm-1; MS m~=

d]PYi'imidine; M+H +

133 4-amino-5-(3- 1-(6-(N-methyl-3-bromo- IR (KBr) 3474, -bromophenyl)-7-(6-(N-N-formylamino)-benzaldehyde 1676. 1577, 1561.

methyl-N-formylamino)-3-pyridinyl)- 1353, 1130cm-1;

3-pyridinyl)pyrido[2,3-ethanone MS m~z 435 d]pyrimidine; M+H +

134 4-amino-5-(3- 1-(6- 3-bromo- IR (KBr) 3487, bromophenyl)-7-(6-morpholinyl-3-benzaldehyde3396, 1601, 1580, morpholinyl-3- pyridinyl)- 1558, 1234cm-i;

p ethanone MS m/
p 463 din y l~yrido[2,3-d] M +
~ +H
n l 135 4-amino-5-(3- 1-(6-(N-methyl-3-bromo- IR (KBr) 3476, bromophenyl)-7-(6-(N-N- benzaldehyde3307, 1702, 1683.

methyl-N- methoxyethylami 1605, 1560, methoxyethylamino)-3-no)-3-pyridinyl)- 1116cm-1; MS
m~z pyridinyl)pyrido[2,3-ethanone 465 (M+H)+.
' d]
midine;

136 4-amino-5-(3- 1-(6- 3-bromo- IR (KBr) 3487, bromophenyl)-7-(6-pyrrolidinyl-3-benzaldehyde3396, 1601, 1580, pyrrolidinyl-3- pyridinyl)- 1558, 1234 cm-l ' pyridinyl)pyrido[2,3-ethanone MS mi2 447 d]pyrimidine; M+H +

137 4-amino-5-(3- 1-(2- 3-bromo- Irt (microscope) bromophenyl)-7-(2-(dimethylamino)-benzaldehyde34421640.1604, (dimethylamino)-5-5-pyrimidinyl)- 1577, 1536, 1408, p ethanone 3 ' ~, 1;
yrimi 'dinyl)pyrido[2,3-] MS m~
y 422 n d midine;

M+ +

138 4-amino-5-(3- 1-(2-(N- 3-bromo- IR (microscope) bromophenyl)-7-(2-(N-methoxyethyl-N-benzaldehyde3439, 1640, 1606, methoxyethyl-N-methylmethyl amino)-5- 1587, 1556.
1537, amino)-5- pyrimidinyl)- 1374, 1347 cm-i~
' pyrimidinyl)pyrido[2,3-ethanone MS miz 466 d} 'midine; (M+H +

139 4-amino-5-(3- 1-(2-(N-formyl-3-bromo- IR (microscope) bromophenyl)-7-(2-(N-N-methyl benzaldehyde3472, 1687, 1583, formyl-N-methyl amino)-5- 1565, 1459, amino)- 1353, 5-pyrimidinyl)pyrido[2,3-pyrimidinyl)- 1142, 988 cm-1;

d]pyrimidine; ethanone MS m/z 436 M+H +

140 4-amino-5-(3- 1-(2-(N- 3-bromo- IR (microscope) bromophenyl)-7-(2-(N-methylamino)5-benzaldehyde3483, 1605, 1550, methylamino)5- pyrimidinyl)- 1346 cm-1;
MS m/z pyrimidinyl)pyrido[2,3-ethanone 408 (M+H)+.
' d]
midine;

141 4-amino-5-(3- 1-(2- 3-bromo- IR (KBr) 3468, bromophenyl)-7-(2-(1-pyrrolidinyl-5-benzaldehyde1600, 1581, 1552, pyrrolidinyl)-5- pyrimidinyl)- 1527, 1482, pyrimidinyl)pyrido[2,3-ethanone cm-1; MS m/Z

d]pyrimidine; M+H +

142 4-amino-5-(3- 1-(2- 3-bromo- IR (microscope) ?

bromophenyl)-7-{2-(1-morpholinyl-5-benzaldehydecm-1~ MS m~z molpholinyl)-5- pyrimidinyl)- (M+H)+

.
pyrlmidinyl)pyrido[2,3-ethanone d] 'midine;

143 4-amino-5-(3- 1-(6-(2-oxo-3-3-bromo- 1R (microscope) bromophenyl)-7-(b-(2-oxazolidinyl)-3-benzaldehyde 3473, 1762, 1583, oxo-3-oxazolidinyl)-3-pyridinyl~ 1571. 1562, 1491, pyridinyl)pyrido[2,3-ethanone 1477, 1402, 1348, d]pyrimidine; 1217 cm-1;
MS m/z 463 (M+H +

144 4-amino-~-(3- 1-(2-pyridyl)-3-bromo- IR (microscope) bromophenyl)-7-(2- ethanone benzaldehyde 3427, 3017, 1601, pyridyl)pvrido[2,3- 783 cm-1;
MS m/z d]pyrittudine; 351/353 M+H
+
.

145 4-amino-~-(3- 1-(3-pyridyl)-3-bromo- IR (microscope) bromophenyl)-7-(3- ethanone benzaldehyde 3434, 3042, 1634, pyridyl)pyrido[2,3- 1372 cm-1;
MS m~z d]pyrimidine; 351/353 M+H
+
.

146 4-amino-5-(3-(thiophen-2-1-(4- 3-(thiophen-2-IR (microscope) yl)phenyl)-7-(4- dimethylaminophyl)-benzaldehyde3482. 2922, 1578, dimethylaminophenyl)pyrienyl)-ethanone 1356 cm-1;
MS m/z do[2,3-d]pyrimidine; 420/422 M+H
+

147 4-amino-5-(3-(furan-2-1-(4- 3-(furan-2-yl)-IR (microscope) yl)phenyl)-7-(4- dimethylaminophbenzaldehyde 3479, 3104, 1559, dimethylaminophenyl)pyrienyl)-ethanone 1356 cm-1;
MS m/z do[2,3-d]pyrimidine; 420/422 M+H
+

148 4-amino-~-(3-(3- 1-(4- 3-(3- IR (microscope) methoxyphenyl)phenyl)-7-dimethylaminophmethoxyphenyl)-3477. 2924, 1579, (4- enyl)-ethanonebenzaldehyde 1356 cm-1;
MS m/z dimethylaminophenyl)pyri 420/422 (M+H)+.
' do[2,3-d rrudine;

149 4-amino-5-phenyl-7-(4-1-(4- benzaldehyde IR (microscope) dimethylammophenyl)pyridimethylaminoph 3477, 3298, 1580, do[2,3-d]pyrimidine;enyl}-ethanone 1355 cm-1;
MS m/z 315 +H +

150 4-amino-~-(3- 1-(4- 3-chloro- IR (microscope) chlorophenyl)-7-(4-(morpholinyl)phbenzaldehyde 3480. 3056, 1579, (morpholinyl)phenyl)pyridenyl)-ethanone 1356 cm-1 ~ MS m/z ~

0[2,3-d]pyrirrudine; 391 M+H
+

151 4-amino-~-(3-bromo-4-1-(4- 3-bromo-4- IR (microscope) fluorophenyl)-7-(4-(morpholinyl)phfluoro- 3491, 3044, 1560, (morpholinyl)phenyl)pyridenyl)-ethanonebenzaldehyde 1230 cm-1;
MS m/z 0(2,3-d]pyrlrrudine; 453 +H +

152 4-amino-5-(3- 1-{4- 3-chloro- liz (microscope) chlorophenyl)-7-(4-iodophenyl)- benzaldehyde 3478. 3280, 1539, iodophenyl)pyrido[2,3-ethanone 1350 cm-1;
MS m/z d]pynmidine; 432 M+H +

153 4-amino-~-(3- 1-(4-(thiophen-3-chloro- IR (microscope) chlorophenyl)-7-(4-2-yl)phenyl)-benzaldehyde 3484.3055.1560, (thiophen-2-ethanone 1354 cm-1;
MS m/z yl)phenyl)pyrido[2,3- 459 (M+H)+:
' d]
midine;

154 4-amino-~-(3- 1-(4-(5- 3-chloro- IR (microscope) chlorophenyl)-7-(4-(5-pyrimidinyl)phenbenzaldehyde 3477. 3040, 1578.

pyrimidinyl)phenyl)pyridoyl)-ethanone 1351 cm-1~
MS m~z .

[2,3-d)pyrimidine; 459 M+H
+

155 4-amino-5-(3-bromo-4-1-(4- 3-bromo-4- IR (microscope) fluorophenyl)-7-(4-iodophenyl)-fluoro- 3444. 3048, 1607, iodophenyl)pyrido[2,3-ethanone benzaldehyde 1356 cm-1;
MS m/z d]pynmidine; 494/496 +
. +

156 4-amino-5-(4- 1-(4- 4- IR (microscope) bromothiophene-2-yl)-7-methoxyphenyl)-bromothiophene-3460. 3300, (4- ethanone 2- 3100, 1700, 1580, methoxyphenyl)pyrido[2, carboxaldehyde1510 cm-1;
MS m~z 3-d] 'midine; 413 (M+H)+.

Example 157 4-amino-S-(3-bromo~henvllmethyl-7-(4-(dimethvlamino,}phenyl)pyridol2 3-dlpyrimidine hydrochloride A mixture of 3-cyano-4-(3-bromophenyl)methyl-6-(4-(dimethyl)aminophenyl)pyridine-2-amine ( 1.58 g) and ammonium sulfate (40 mg) in triethyl orthoformate was heated at reflex 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 reflex 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/HCI, followed by drying to give the title compound.
The 3-cyano-4-(3-bromophenyl)methyl-6-(4-(dimethyl)aminophenyl)pyridine-2-amine was prepared by a four-step procedure as follows:
step 157a: Rret~aration of 3-bromophenylacetaldel~de (the "R3 reagent") To a solution of ethyl 3-bromophenylacetate (10.2 g, US patent 2,624,731 (1950)}
in 230 mL of dichloromethane was added 42 mL of 1M Dibal-H in toluene at -78 °C with stirring. After 40 minutes at -78 °C, 10 mL of methanol was added, and the reaction allowed to warm to room temperature and partitioned between 50 mL of dichloromethane and 1200 mL of saturated aqueous potassium sodium tartrate. The organic layer was dried over sodium sulfate and the aldehyde used immediately in the next step without purification.
step 157b~ preparation of a-(triphenvlnhos~honium)-4-(dimethylamino)phenylethan 1 one chloride Following the procedure of Fukui et al. (J. Org. Chem. 33: 3594-3507 (1968)), a-bromo-(4-dimethylaminophenyl)ethan-1-one (the "R4 reagent", CAS #37904-72-6;
Cherri.
Abst. ( 1956), 864) was treated with triphenylphosphine in triethylamine and acetonitrile.
The a-bromo-(4-dimethylaminophenyl)ethan-1-one was prepared by bromination with bromine in hydrobromic acid according to the method of Suzuki et al (J. Pharm.
Soc. Japan, (1955), X5:54. Removal of solvent and recrystallization from methanol/ethyl acetate/toluene gave the title product as a white powder.
stev 157c: nreoaration of I-(4-(dimethvlamino)nhenvl)-4-l3-bromonhenvl)-but-2-en-1-one 20 g of a-(triphenylphosphonium)-4.(dimethylamino)phenylethan-1-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.
stev 157d: preparation of 3-cyano-4-(3-bromo~henvl)methvl-6-(4-(dimethvl)aminophenyl~pvridine-2-amine A mixture of I-(4-(dimethylamino)phenyl)-4-(3-bromophenyl)-but-2-en-I-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-~4 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 fvrmamide or formamidine acetate (added periodically until the reaction was complete) treatment was replaced by treatment with triethyl orthoformate at reflux in the presence of a catalytic amount of ammonium sulfate, followed by cooling to 25 °C and addition of excess ammonia in ethanol. After 24 hours, the precipitated amidine compound was filtered and washed with hexanes, then dried under vacuum. The amidine compound was then heated in 1,2-dichlorobenzene at 120-180 °C for I-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 Ex. Name R4 Reagent R3 Reagent Analytical Data No.
(for 7- (for 5-osition) osition 158 4-amino-5-(2- 1-(4- 3-phenyl- IR (KBr) 3340,3240-' phenylethyl)-7-(4-diethylaminophepropionaldehyde2800.1600,1580,1540;

diethylaminophenyl)pynyl)-ethanone H. Res. MS mn rido[2,3-d] 'midine 398.2343 (M+H)+.

159 4-amino-5-(2- 1-(4- 3-methyl- IR (KBr) methylpropyl)-7-(4-diethylaminophebutanaldehyde3550,3410,3320, diethylaminophenyl)pynyl)-ethanone 2800,1605,1580,1560 rido[2,3-d]pyrimidine H. Res. MS m/z~

350.2357 M+ +

160 4-amino-5- but 1- 4 pentanaldehyde ( y ) (4- diethylaminophe ~5~300,3200-diethylaminophenyl)pynyl)-ethanone 2800,1660,1610.1580.1 rido[2,3-d]pyrimidine 540 H. Res. MS
m~z 350.2354 M+ +

161 4-amino-5-(2-(4-1-(4- 4-(4- IR (lcBr) bromophenyl)ethyl)-7-diethylaminophebromophenyl)-3500,3300,3200-(4- nyl)-ethanonepropionaldehyde30,1650,1615.1580 diethylaminophenyl)py H. Res. MS m~z rido[2,3-d] 'midine 478.1429 (M+H)+.

162 4-amino-5-(butyl)-'7-* ~ (fir) (4- 3400,3350,3200-dimethylaminophenyl) 2900,1650,1620,1580,1 pyrido[2,3- 570 H. Res. MS
m/z d] dine 322.2032 (M+H)+.

163 4-amino-5-(2-(3-1-(4- 3-cyanophenyl-IR (KBr) 2850-cyanophenyl)methyl)-dimethylaminophacetaldehyde3550,2220,1610,1580,1 ~-(4- enyl)-ethanone 560,1540 MS m/z dimethylaminophenyl) (M+H)+.

pyrido[2,3-d] 'dine 164 4-amino-5-(2-(N-1-(4- 3-(N- IR (KBr) 3000-carbobenzyloxy)aminodimethylaminophcarbobenzyloxy)3500,1710,1690,1650,1 ethyl)-7-(4- enyl)-ethanone- 590 H. Res. MS
m/z dimethylaminophenyl) aminopropionald443.2184 (M+H)+.

pyrido[2,3- ehyde d] 'dine 165 4-amino-5- 1-(4- cycloheptane-IR (KBr) (cycloheptyl)-7-(4-dimethylaminophcarboxaldehyde3500.3250,3100,2950,2 dimethylaminophenyl)enyl)-ethanone 850,1620,1575 H. Res.

pyrido(2,3- MS m/z 362.2349 d] 'dine (M+H)+.

166 4-amino-5-(2-(5-** IR (KBr) 3200-chloro-2-(thiophen-3- 3450,2950-yl)phenylmethyl)-7-(4- 3100,1605.1580,1550 dimethylaminophenyl) H. Res. MS miz pyrido[2,3-472.1363 (M+H)+.

d] 'dine 167 4-amino-5-(pentyl)-7-1-(4- hexanal IR (KBr) (4- diethylaminophe 3430,3320,3240-diethylaminophenyl)-nyl)-ethanone 2800,1580,1560,1540,1 pyrido[2,3- 350; mp. 211-214;
MS

d]pyrimidine mlz 364 (M+H)+;
H.

Res. MS ml~
364.2506 M+H'+
~

168 4-amino-5-hexyl-7-(4-1-(4- _ ~r) heptanal diethylaminophenyl)-diethylaminophe 3440,3310,3240-pyrido [2,3- nyl)-ethanone 2800,1580,1560,1540,1 d]pyrimidine 350; mp. 215-217;
MS

mlz 378 (M+H)+;
H.

Res. MS m/z 378.2654 M+H +

169 4-amino-5-(2-(3-1-(4- 3-(3- 1R (KBr) 3640-bromophenyl}ethyl)-7-diethylaminophebromophenyl}-3240,3200-(4- nyl)-ethanonepropionaldehyde2800,1580,1555.1535,1 diethylaminophenyl)- 345; mp. 201-202;
MS

pyrido[2,3- m/z 476/478 (M+H)+;

d]pyrimidine H. Res. MS m/z 476.1448 M+
+

170 4-amino-5-((2- 1-(4- 2-(2- IR (KBr) 3640-bromophenyl)methyl}-diethylaminophebromophenyl)-3240,3240-7-(4- nyl)-ethanoneacetaldehyde 2800.1580,1555,1540,1 diethylaminophenyl)- 350; mp. 130-133;
MS

pyrido[2,3- m/z 462/464 (M+H)+;

d]pyrimidine H. Res. MS mlz 462.1297 M+
+

171 4-amino-5- 1-(4- cyclopropanecarIR (KBr) cyclopropyl-7-(4-dimethylaminophboxaldehyde 3490,3290,3240-dvnethylaminophenyl)enyl)-ethanone 2760,1610,1580,1540,1 -pyrido[2,3- 375; mp. 235-237;
MS

d] ~dlrie m/z 462/464 (M+H)+;

172 4-amino-5-cyclohexyl-1-(4- cyclohexanecarbIIt (xBr) 3640-7-(4- dimethylaminophoxaldehyde 3000.2980-dimethylaminophenyl)enyl)-ethanone 2760,1610,1580,1540,1 -pyrido[2,3- 345; mp. 231-234;
MS

d] dine m/z 462/464 (M+H)+;

173 4-amino-5-((2-bromo-1-(4- 2-(2-bromo-5-IR (KBr) 3460,3220-5- dirnethylaminophchlorophenyl)-2760,1610,1575,1535,1 chlorophenyl)methyl)-enyl)-ethanoneacetaldehyde 365; mp. 185-187;
MS

7-(4- m/z 462/464 (M+H)+;

diethylaminophenyl)-pyrido[2,3-d] 'dine 174 4-amino-5-methyl-7-1-(4- acetaldehyde 1R (KBr) 3640-(4- dimethylaminoph 3250.3250-diethylaminophenyl)-enyl)-ethanone 2760.1610,1585,1560,1 pyrido[2,3- 350; mp. 238-246:
MS

d] ~dlrie m/z 462/464 (M+H)+;

* prepared from the compound of Example 157 by reaction with Pd(PPh3)4 and zinc cyanide in DMF under Suzuki reaction conditions.
-77_ ** prepared from the compound of Example 173 by reaction with 2-thiopheneboronic acid, Pd(PPh3)4 and aqueous sodium carbonate under Suzuld 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 Ex. Name R4 Reagent R3 Reagent Analytical Data No.
(for 7- (for 5-osition) osition 175 4-amino-5-(2,3- 1-(4- 2,3- IR (KBr) 3500-methylenedioxyphenyldimethylaminophmethylenedioxy-2500,1595,1580,1375;

-7-(4- enyl)-ethanonebenzaldehyde mp.290-305;

dimethylaminophenyl) -pyrido[2,3-d] 'dine _ 176 4-amino-5-(3-fluoro-1-(4- 3-fluoro-5- IR (KBr) 3500,3440-5- dimethylaminophtrifluoromethyl-3240,3200-trifluoromethylphenyl)enyl)-ethanonebenzaldehyde 2800,1610,1580,1560,1 _7_(4- 540,1370; mp.
293-296;

dimethylaminophenyl) MS m/z 428 (M+H)+;

-pyrido[2,3- H. Res. MS mlz d]pyrimidine 428.1509 (M+H)+.

177 4-amino-5-(2- 1-(4- 2-bromo- IR (KBr) 3480,3440-bromophenyl)-7-(4-dimethylaminophbenzaldehyde 3240,3200-dimethylaminophenyl)enyl}-ethanone 2800,1610,1575,1555,1 -pyrido[2,3- 535,1355 d]pyrimidine mp. 261-263;
MS m/z 420/422 (M+H)+;
H.

Res. MS m/z 420.0823 (M+H)+.

178 4-amino-5-(3,5- I-(4- 3,5-dimethyl-IR (KBr) 3480,3440-dimethylphenyl)-7-(4-dimethylaminophbenzaldehyde 3240.3200-dimethylaminophenyl)enyl)-ethanone 2800,1610,1575.1555,1 -pyrido[2,3- 535,1360: mp.
284-286;

d]pyrimidine MS mlz 370 (M+H)+;

H. Res. MS m/z 370.2036 (M+H)+.

_78_ 179 4-amino-5-(3,4- 1-(4- 3,4-dichloro-IR (KBr) 3490,3440-dichlorophenyl)-7-(4-dimethylaminophbenzaldehyde 3240,3200-dimethylaminophenyl)enyl)-ethanone 2800.1610,1575,1560,1 -pyrido[2,3- 535,1355- mp.
288-291;

d]pyrimidine MS mlz 410/412 (M+H)+: H. Res.
MS

m/= 410.0948 !M+H +

180 4-amino-5-(4-fluoro-1-(4- 4-fluoro-3- Bt (KBr) 3500,3440-.

3- dimethylaminophtrifluoromethyl-3240,3200-trifluoromethylphenyl)enyl)-ethanonebenzaldehyde 2800.1610.1580,1560,1 _7_(4_ 540,1505,1360;
mp.

dimethylaminophenyl) 254-257; MS
m/z 428 -pyrido[2,3- (M+H)+: H. Res.
MS

d]pyrimidine m/. 428.1487 {M+H)+.

181 4-amino-5-(3-bromo-1-(4- 3-bromo-5- 1R (KBr) 3470,3440-5-methoxyphenyl)-7-morpholinylphenmethoxy- 3240,3200-(4- yl)-ethanonebenzaldehyde 28001605,15801560;

morpholinylphenyl)- mp. 257-260;
MS m/z pyrido[2,3-492/494 (M+H)+.

d] 'dine 182 4-amino-5-(3-bromo-1-(4- 3-bromo-5- 1R (lc>3r) 3470,3440-5-methoxyphenyl)-7-pyrrolidinylphenmethoxy- 3240,3200-(4- yl)-ethanonebenzaldehyde 28001610,15801560,1 ~

pyrrolidinylphenyl)- 540.1355; mp.
d 250;

pyrido[2,3- MS m/z 476/478 d]pyrimidine (M+H)+.

183 4-amino-5-(3-bromo-1-(4- 3-bromo-5- Ift (KBrj 3470,3440-5-methoxyphenyl)-7-piperidinylphenymethoxy- 3240,3200-2800,1565;

(4-piperidinylphenyl)-1)-ethanone benzaldehyde mp. 224-244;
MS m/z pyrido[2,3- 490/492 (M+H)+;

d] 'dine 184 4-amino-5-(3-bromo-1-(4- 3-bromo-5- IR (KBr) 3470,3420-5-methoxyphenyl)-7-dimethylaminophmethoxy- 3240,3200-(4- enyl)-ethanonebenzaldehyde 2800.1610,157515551 dimethylaminophenyl) 535.1355: mp.
262-266;

-pyrido[2,3- MS m/z 450/452 d]pyrimidine (M+H)+: H. Res.
MS

mlz 450.0944 M+H +

185 4-amino-5-(3- 1-(4- 3-methylthio-IR (KBr) 3460.3420-methylthiophenyl)-7-dimethylaminophbenzaldehyde 3240.3200-(4- enyl)-ethanone 2800,1605.1575,1560.1 dimethylaminophenyl) 535.1355: mp.
184-220;

-pyrldo[2,3- MS m/. 388 (M+H)+;

d]pyrimidine H. Res. MS m/z 388.1586 (M+H)+.

WO 98!46605 pr~rirtcoum~~m 186 4-amino-5-(3-bromo-1-(thiophene-2-3-bromo-5- IIt (KBr) 3470,3350-5-methoxyphenyl)-7-yl)-ethanone methoxy- 2200,1700,1640,1580,1 (thiophene-2-yI)- benzaldehyde 5,1 7o~mp.
~~1 pyrid o ~
[2,3- ~~
~

d]pyrimidine 413/415 (M+H)+;
H.

Res. MS m/z 413.0069 (M+H)+.

187 4-amino-5-(2,3- 1-(4- 2,3-dimethoxy-IR (KBr) 3480,3440-dimethoxyphenyl)-7-dimethylaminophbenzaldehyde 3240,3200-(4- enyl)-ethanone 2800,1610,1580,1550,1 dimethylaminophenyl) 530,1360; mp.
222-225;

-pyrido[2,3- MS m/z 402 (M+H)+;

d]pyrimidine H. Res. MS m/z ***

402.1922 (M+H)+.

188 4-amino-5-(3- 1-(4- 3- IR (KBr)3490,3400-methylsulfonylphenyl)dimethylaminophmethylsulfonyl-2800.1610,1580,1555,1 -7-(4- enyl)-ethanonebenzaldehyde 535,1355; mp.

dimethylaminophenyl) 245270; MS m/z -pyrido[2,3- (M+H)+; H. Res.
MS

d 'dine m/z 420.1493 M+ +

Exam lp a 189 4-acetylamino-5-f3-bromophenyl)-7-f4-dimeth ly aminonhenyl)gyridol2 3-dluyrimidine A suspension of 4-amino-5-(3-bromophenyl)-7-(4-dimethylaminophenyl)pyrido[2,3-d)pyrimidine (from Example 15, 0.28 g, 0.67 mole) in pyridine (3 mL) was treated with acetic anhydride {0.10 g, 1.0 mmol) and the reaction mixture was stirred for 4 hours at 25 °C. The volatiles were removed under reduced pressure, and the residue was purified by flash chromatography (Si02, EtOAc/hexanes) to provide the title compound (0.23 g, 73% theoretical): IR (ICBr) 3368, 3048, 1695, 1567;
MS mlz 462/464 (M+H)+.
Examples 190-198 Following the procedures of Example 189, except substituting the appropriate acylating reagent for the acetic anhydride of Example 189 as indicated in Table 5 below, compounds of Examples 190-198 were prepared.
Table 5 Examples 190-198 fix. ivame Acylating Analytical Data N o . I ( Reagent 190 4-formylamino-5-(3- acetic anhydrideIR (KBr) 3382, and 3047, bromophenyl)-7-(4- formic acid 1704.1570;

dimethylaminophenyl~ MS m/z 448/450 'do[2,3-d 'dine--190 (M+I~+.

191 4-(methoxyacetyl)amino-5-(3-methoxyacetyl IR (KBr) 3344, 3044, bromophenyl)-7-(4- chloride 1731, 1561:
MS min diethylaminophenyl)-pyrido[2,3- 492/494 (M+1~+.

p d] 'dine 192 4-trifluoroacetylamino-5-(3-trifluoroaceticIR (KBr) 3426, 3072, bromophenyl)-7-(4- anhydride 1610, 1578:
MS m~z dimethylaminophenyl)- 516/518 (M+1~+.

ido[2,3-d] 'dine 193 4-pentanoylamino-5-(3- pentanoyl chlorideIlt (KBr) 3408, 2954, bromophenyl)-7-(4- 1699, 1569;
MS miz dimethylaminophenyl)- 504/506 (M+1-0+.

ido[2,3-d] 'dine 194 4-benzoylamino-5-(3- benzoic anhydrideIR (KBr) 3420, 3056, bromophenyl)-7-(4- 1606, 1583;
MS miz dimethylaminophenyl)- 524/526 (M+I~+.

'do[2,3-d] imidine 195 4-(N-BOC-glycyl)amino-5-(3-N-BOC-glycyl- iZt (KBr) 3362, 2975, bromophenyl)-7-(4- imidazole 1719, 1570:
MS m/z dimethylaminophenyl)- 577/579 (M+1-0+.

'do[2,3-d] 'dine 196 4-(N-phthalimidylglycyl)amino-5-N-phthalimidyl-Iit (KBr) 3408, 2927, (3-bromophenyl)-7-(4- glycyl-chloride1719, 1570;
MS m~z dimethylaminophenyl)- 607/609 (M+I~+.

'do[2,3-d] 'dine 197 4-(ethoxycarbonyl)amino-5-(3-diethyl dicarbonatelIt (KBr) 3405, 2987, bromophenyl)-7-(4- 1738, 1569:
MS m/z dimethylaminophenyl)- 492/494 (M+~+.

'do[2,3-d 'dine 198 4-(ethylaminocarbonyl)amino-5-ethyl isocyanateIR (KBr) 3405, 3053, (3-bromophenyl)-7-(4- 1701, 1548:
MS m/z dimethylaminophenyl)- 491/493 (M+I~+.

ido[2,3-d] imidine Exam lp a 199 4-allvlamino-~-(3-bromophenyl)-7-l4-dimethylaminophenylZpyrido f2 3-dl pyrimidine The product was prepared by treating a solution of 4-chloro-5-(p-dimethylaminophenyl)-7-(p-bromophenyl)pyrido[2,3-d]pyrimidine in CH2Cl2-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 (Si02, EtOAc/hexanes) to provide the title compound IR (KBr) 3437, 1564, 1355, 1195;
l0 MS m/z 460/462 (M+H)+.
The 4-chloro-5-(p-dimethylaminophenyl)-7-(p-bromophenyl)pyrido [2.3-d]pyrimidine was prepared as follows.

A sample of 4-(4-bromophenyl)-3-cyano-6-(4-(dimethylamino)phenyl)pyridine-2-amine (from Example 1, S.0 g, 12.7 mmol) in 20 mL of H2S04 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-S 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 POC13 was removed under reduced pressure to provide crude 4-chloro-5-(p-dimethylaminophenyl)-7-(p-bromophenyl)pyrido[2,3-d]pyrimidine.
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-dimethvlamino)ethvlamino)-5-(4-bromophenvl)-7-(4-dimethvlaminophenvl) pyrido 12.3-dl pvrimidine 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 (Si02, 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, 1197; MS m/z 491/493 (M+H)+.
Example 201 4-(4-(N.N-dimethvlaminolbut~rlamino)-5-(3-bromophenvl)-7 ~4 dimethvlaminonhenvl) pyrido f 2 3-dl pvrimidine tetrahvdrochloride The product was prepared by treating a solution of 4-amino-5-(p-dimethylaminophenyl)-7-(p-bromophenyl)pyrido[2,3-d]pyrimidine 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 (Si02, EtOAc/hexanes). The product was treated with excess 2M HCl (aq) followed by lyophilization to give the product as the tetrahydrochloride salt; IR (KBr) 3439, 1567, 1356, 1196; MS m/z 519/521 (M+H)+.
Example 202 4-(N-allvl-N-formvlamino)-5-l4-dimethvlaminophenvl)-7-~p-bromophenvl)pyrido12,3-d]pyrimidine A sample of the compound from Example 190 above, 4-formylamino-5-(2-phenylethyl)-7-(4-diethylaminophenyl)-pyrido[2,3-d]pyrimidine (0.27 g, 0.6 mmol) in 3 mL of a 4:1 mixture of THF and DMF at 0°C was treated with NaH
(60%
dispersion, 36 mg, 0.9 mmol) and the solution was stirred for 0.5 hour. Allyl bromide (0.29 g, 2.4 mmol) was added, and the reaction mixture was stirred for an additional 0.5 hour. Aqueous workup followed by flash chromatography provided the title compound: LRMS m/z 488/490. IR (cm') 3428, 2910, 1696, 1551, 1362, IS
1193.
Example 203 4-diacetylamino-5-(4-dimethvlamino~henyl)-7-(p-bromophenyl) pvridof 2.3-d]pvrimidine This compound was isolated as a minor product from the reaction mixture of Example 190 above: LRMS m/z 504/506. IR (crri') 2922, 1726, 1550, 1360, 1197.
Example 204 4-amino-5-(3-bromophenyl)-7-(5-amino-2-~,vridyl)nvridof 2.3-dlwrimidine A solution of 5-aminopyridine-2-ethanone ( 1.15 g, 8.45 mmol), 3-bromobenzaldehyde ( 1.70 g, 9.2 mmol), malononitrile (0.61 g, 9.2 mmol), and ammonium acetate ( 1.15 g, 15 mmol) in 25 mL of benzene was heated at reflux with azeotropic removal of water. After 6 hours the reaction mixture was concentrated, and the desired intermediate (1.82 g, 49%) was isolated following flash chromatography (Si02, 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-1 ) 3481, 3161, 1620, 1573, 1483, 1359.
The 5-aminopyridine-2-carboxaldehyde starting material was prepared as follows:

204a. 5-amino-2-bromogyridine A solution of 2-bromo-5-nitropyridine (5.1 g, 25 mmol) in 50 mL of a 10:1 mixture of acetic acid and water was treated with iron powder (7.8 g, 140 mmol) in several portions over 20 minutes. After an additional 30 minutes the volatiles were removed under reduced S 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-aminopvridine-2-ethanone A sample of 5-amino-2-bromopyridine (4.25 g, 24 mmol), PdCl2(PPh3)2 (0.34 g, 2 mole%), CuI (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 IS residue was dissolved in 100 mL of a 10:1 mixture of acetone and water.
Hg(02CCF3)2 ( 11.1 g, 26 mmol) and H2S04 (72 mmol) were added to the reaction mixture, and the solution was heated at reflux for 2 hours. The reaction mixture wac cnniP~i m 7S °r anrt neutralized with saturated aqueous sodium carbonate. The aqueous layer was extracted with methylene chloride, then the combined organic layer was dried (Na2S04) and concentrated in vacuo. Flash chromatography (Si02, EtOAc-Hexanes) provided the title compound:
LRMS m/z 137 (M = H+); IR (cm-1) 3428, 1668, 1646, 1582, 1358, 1274.
Example 205 Following the procedure of Example 204, 5-dimethylaminopyridine-2-ethanone was reacted with bromobenzaldehyde, malononitrile, and ammonium acetate to give the title compound. The residue was triturated with excess HCl/ether, the volatiles were removed under reduced pressure, and the title compound was dried under high vacuum: LRMS m/z 421/423. IR (cm-1) 3245, 1664, 1545, 1395.
The 5-dimethylaminopyridine-2-carboxaldehyde starting material was prepared as follows:
205a..3-N,N-dimethvlaminopyridine A solution of 3-aminopyridine (9.4 g, 0.10 mol) in a l: l 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 NaHC03. The aqueous layer was extracted with CH2C12, then the combined organic layer was dried (Na2S04) and concentrated under reduced pressure. Flash chromatography (Si02, EtOAc-Hexanes) provided the title compound: ( 11.1 g, 91 %), LRMS m/z 123 (M + H+).
- 205b. 2-bromo-5-N . N-dimethxlamin~ '~mdine A solution of 3-N,N-dimethylaminopyridine (5.88 g, 48.1 mmol) in 150 mL
of CH2C12 at 0 °C was treated with 2,4,4,6-tetrabromo-2,5-cyclohexadienone (20.7 g, 50 mmol) in several portions over 30 minutes. After 2 hours at 0 °C
the reaction mixture was concentrated, and the desired 2-bromo-5-N,N-dimethylaminopyridine was isolated following flash chromatography (16.5 g, 82%): LRMS m/z 201/203.
204c. 5-N . N-dimethyjar~n' pyridine-2-ethanone Following the procedure of Example 203b, 2-bromo-5-N,N-dimethyiaminopyridine, 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-1) 3480, 1666, 1581, 1368, 1272.
Exam In a 206 4-amino-5-(3-bromonhenyl)-7-(5-dimethylamino-2-R azinyi~
pxridof2.3-dl~"vrimidine hydrochloride Following the procedure of Example 204, 5-dimethylaminopyrazine-2 ethanone was reacted with bromobenzaldehyde, malononitrile, and ammonium acetate to give the title compound. The residue was triturated with excess HCl/ether, the volatiles were removed under reduced pressure, and the title compound was dried under high vacuum: LRMS m/z 422/424. IR (cm ') 3310, 1630, 1525, 1444, 1375.
The 5-dimethylaminopyrazine-2-carboxaldehyde starting material was prepared as follows:
206a. 5-dimethylaminoRyrazine-2-eth~~one A solution of 5-hydroxypyrazine-2-carboxylic acid (4.0 g, 28.5 mmol) in 50 mL of thionyl chloride and 0.1 mL of DMF was heated at reflux for 8 hours. The volatiles were removed under reduced pressure, and the residue was dissolved in 20 mL of toluene. This solution was added to a solution of dimethyl malonate (4.75 g, 36 mmol), MgCI, (2.09 g, 22 mmol) and tziethyl amine .(7.08 g, 70 mmol) in 100 mL
of toluene. The reaction mixture was stirred for 1 hour at 25 °C, quenched by addition of water, and the product was extracted with methylene chloride. The solvent was removed, the crude intermediate was dissolved in 25 mL of a 25:1 mixture of DMSO
and water, and the resulting solution was warmed at 150 °C for 2 hours.
The reaction was quenched by addition of water, and the product was extracted with methylene chloride to provide 2-acetyl-5-chloropyrazine (LRMS mlz 156). This intermediate was treated with aqueous dimethylamine at room temperature for 30 minutes to afford 5-dimethylaminopyrazine-2-ethanone-(LRMS m/z 166): LRMS m/z 422/424; IR (cm-') 3310, 1630, 1525, 1444, 1375.
Example 207 4-amino-5-f3-bromonhenvl)-7-(2-oxobenzoxazolin-6-yI)pyridof2 3-dlpyrimidine Following the procedure of Example 204, 2-oxobenzoxazolin-6-ethanone_was reacted with bromobenzaldehyde, malononitrile, and ammonium acetate to prepare the title compound: LRMS m/z 434/436; IR (crri') 3095, 1760, 1579, 1481, 1350.
The 2-oxobenzoxazolin-5-ethanone_starting material was prepared as follows:
207a. 2-oxobenzoxazolin-6-ethanone DMF (9 mL) was added dropwise to A1C13 (58.7 g, 440 mmol) over 20 minutes and the resulting suspension was stirred 15 minutes at 25 °C.
Acetic anhydride (7.14 g, 70 mmol) and 2-benzoxazolinone (6.0 g, 44. mmol) were added and the reaction mixture was warmed at 80 °C and stirred for 4 hours.
The mixture was cooled to 25 °C and poured into ice/HzO. 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-f3-bromophenyl)-7-f 1-methyl-2-oxobenzoxazolin-6-, pvridoT2.3-dlpyrimidine Following the procedure of Example 204, 1-methyl-2-oxobenzoxazolin-5-ethanone was reacted with bromobenzaldehyde, malononitrile, and ammonium acetate to prepare the title compound: LRMS m/z 448/450; IR (crri') 3440, 1782, 1605, 1458, 1350.
The 1-methyl-2-oxobenzoxazolin-5-ethanone-starting material was prepared as follows:
208x. 1-methyl-2-oxobenzoxazolin-5-ethanone A solution of 2-oxobenzoxazolin-5-ethanone_(from Example 206x, 2.50 g, 14.1 mmol) in 20 mL of a 4:1 mixture of THF and DMF at 0 °C was treated with NaH
(60 % dispersion, 0.8 g, 20 mmol) and the mixture was stirred 20 minutes at 0 °C.
Methyl iodide (3.97 g, 28 mmol) was added and the reaction mixture was warmed to 25 °C and stirred for 15 minutes. Saturated aqueous NaHC03 was added and the aqueous layer was extracted with CH,CI=. The desired product (2.55 g, 94%, LRMS
m/z 191), was isolated following flash chromatography (Si02, EtOAc-CHZCIz).
Example 209 4-amino-5-((5-chloro-2-(3-methoxyphenvl'phenvl)methvl)-7-(4-dimethylaminophenyllyvridof 2.3-dlpvrimidine The title compound was prepared from the compound of Example 173 by reaction with 3-methoxyphenylboronic acid, Pd(PPh3)4 and aqueous sodium carbonate under Suzuki reaction conditions. IR (KBr) 3550-3250,3240-2760,1580,1560,1540,1350; H. Res. MS m/z 496.1902 (M+H)+.
Example 210 4-amino-5-((2-bromophenyi)methyl)-7-(4-dimethylaminophenvl)pvridof2 3-dlpvri_midine Following the procedures of Example 157, except substituting 1-(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.
Tahle. fi Ex. Name R4 Reagent R3 Reagent Analytical No. (for (for Data 7- osition) 5- osition 210 _ 1-(4- 2-(2- IR (KBr);
4-amino-5-((2- MS

bromophenyl)methyl)-dimethylaminophebromophenyl)- m/z 434,436 7-(4- nyl)-ethanoneacetaldehyde (M+H)+, dimethylaminophenyl) pyrido[2,3-d] 'dine Example 211 4-amino-5-(2-((thiophene-2-yl)phenyl)meth.,yl)-7-(4-diethvlaminophenyl)pyridof2 3 dlpvrimidine 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)+.
_87_ Example 212 4-amino-5-(2-((thio~hene-3-vl)phenyl)methyl)-7-(4-diethylaminophenvl)pyridof2 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.
1 s Table 7 Examples 213-222 Ex. Name R4 Reagent R3 Reagent Analytical (for (for No. 7- osition) 5- osition Data 213 4-amino-5-(3- 1-(4-(N-formyl-N-3-bromo- IR (KBr) 3490, bromophenyl)-7-(4-(2- benzaldehyde 1689, 1120, (N-formyl-N-(2- methoxy)ethylamin cm-1; MS m/z methoxyethyl)amino)po)phenyl)- 478/480 (M+H)+.

henyl)pyrido[2,3-ethanone d] 'midine;

214 4-amino-S-(3- * ~ fir) bromophenyl)-7-(4- 3330,2925, 1675, (N-(2- 800 cm-1;
MS m/z methoxyethyl)amino)p +
451/453 (M+H) henyl)pyrido[2,3- .

d] 'midine;

215 4-amino-5-(3- 1-(4-(N-methyl-N-3-bromo- IR (KBr) 3440, bromophenyl)-7-{4-((2- benzaldehyde 1600, 1160, (N-methyl-N-((2- dimethylamino)eth cm-1; MS m/z dimethylamino)ethyl)ayl}amino)phenyl)- 477/479 (M+H)+

.
mino)phenyl)pyrido[2,ethanone 3-d] 'midine;

216 4-amino-5-(3- ** IR (KBr) 3480.

bromophenyl)-7-(4-{2- 1520. 710 cm-1~

methoxy)acetylamino) MS m/. 464,466 ethyl)amino)phenyl)py (M+H)+.

rido[2,3-d] imidine;

_88_ 217 4-amino-5-(3- *** IR (KBr) 3475, bromophenyl)-7-((4- 1690, 1355, formylamino)phenyl)p cm-1; MS m/z yrido[2,3- 420/422 (M+H)+.

d] mldine;

218 4-amino-5-(3- **** IR (KBr) 3452.
~

bromophenyl)-7-(4-(2- 1605, 1250, (dimethylamino)acetyl cm-1; MS m!z amino)phenyl)pyrido[ 477/479 (M+H)+.

2,3-d] dine;

219 4-amino-5-(3- 1-(4-(2-oxo-3-3-bromo- IR (KBr) 3480, bromophenyl)-7-(4-(2-oxazolidinyl)phenybenzaldehyde 1750, 1400, oxo-3- 1)-ethanone cm-1; MS m!z oxazolidinyl)phenyl)p 462/464 (M+H)+.

yrido[2,3-d] 'midine;

220 4-amino-5-(3- 1-(6-(2-propyl)-3-3-bromo- IR (KBr) 3474, bromophenyl)-7-(6-(2-pyridinyl)- benzaldehyde 3098, 1636, 1566, propyl)-3- ethanone 1499, 1352, pyridinyl)pvrido[2,3- cm-1:MS m!z d]pyrimidine (M+H)+.

trip drochloride 221 4-amino-5-(3- 1-{3-methyl-4-3-bromo- IR (KBr) 3440, bromophenyl)-7-(3-pyrrolidinylphenylbenzaldehyde 1640, 1607, 1586, methyl-4- )-ethanone 1370 cm-1;
MS m/z pyrrolidinylphenyl)pyr 433 (M+H)+.

ldo[2,3-d]pyrimidine dih drochloride 222 4-amino-5-(3- 1-{6-imidazolyl-3-3-bromo- ilt (KBr) 3028, bromophenyl)-7-(6-pyridinyl)- benzaldehyde 1641, 1607.
1595, imidazolyl-3- ethanone 1375cm-1;
MS m/z p 417 (M+H)+.
Pid ~la~yrido[2,3-d y trih drochloride *prepared by deformylation of Example 213 with dilute HCl in methanol.
**prepared by acylation of Example 213 with 2-methoxyacetyl chloride/pyridine.
***prepared by formylation of the 7-(3-bromophenyl)-2-cyano-5-(4-aminophenyl)pyridine-2-amine intermediate.
****prepared by acylation of Example 213 with the 2-(dimethylamino)acetyl chloride.
Examples 223-225 Following the procedures of Example 157, except substituting the appropriate reagents for the R4 and R3 reagents of Example 157 as indicated in Table 8 below, compounds of Examples 223-225 were prepared.

Table 8 Examples 223-225 Ex. Name R4 Reagent R3 Reagent Analytical Data No.
(for 7- (for 5-osition) osition 223 4-amino-5- 1-(4- 2-phenyl- IR (KBr) phenylmethyl-7-(.~-diethylaminopheacetaldehyde3450.3380,2850-diethylaminophenyl)pynyl)-ethanone 3200,1605,1580,1560,1 rido[2,3-dJpyrimidine 540; H. Res.
MS mi_ 384.2176 M+H)+.
224 4-amino-5-(2-{3-* gt mgr) X00_ aminopropynyl)phenyl 3450.2050,2120,1650,1 methyl)-7-{4- 605.1540; MS
miz 437 diethylaminophenyl)py (M+H)+.

rido[2,3-dJ 'midine 225 4-amino-5-(1-{2-1-(4- 2-(2- 1R (KBr) 3520,3250-bromophenyl)ethyl)-7-dimethylaminophbromophenyl)-3500,2850-(4- enyl)-ethanone)propionaldehyd3150,1605,1580,1560,1 dimethylaminophenyl) a 540; H. Res.
MS miz 3 448.1137 (M+F-0+.
p yrido[2 -'me d a *prepared from the compound of Example 170 by reaction with propargylamine, CuI and Pd(PPh3)4 under Suzulci 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.
Ta le 9 Examples 226-228 Ex. Name R4 Reagent R3 Reagent Analytical No. (for (for Data 7-position) 5- osition 226 4-amino-5-(4- 1-(4- 3-bromo- 1R (1c13r) 3456, dimethylaminophenyl)bromophenyl)- benzaldehyde 3053, 16600.

-7-(4- ethanone cm-1; MS mi=

bromophenyl)pyrido[2 (M+H)+.
' ,3-d]
midine 227 4-amino-5-(2-furanyl)-1-(4-(N- furan-2- IR (KBr) 3460.

7-(4-(N- molpholinyl)phenycarboxaldehyde1600, 1580.

morpholinyl)phenyl)-1)ethanone cm-1~ MS mi=

pyrldo[2,3- (M+H)+.
' d]
dine WO 98/46605 PCTlUS98/07207 228 4-amino-5-(3- 1-(5-(2- 3-bromo- IR (KBr) 3442 bromophenyl)-7-(2-(dimethylamino)pybenzaldehyde 1640. 1604, 1577, dimethylamino-5-rimidinyl)~thanon 1536, 1408, 1367, pyrimidinyl)pyrido[2,a 1348 cm-1;
MS m/z 3-d]pyrimidine 422 M+ -~

Exam lp a 229 4-amino-~-(3-bromophenyl)-7-(4-(ureido),phenyl)~yridof2 3-dlnvrimidine A solution of 4-amino-5-(3-bromophenyl)-7-(4-aminophenyl)pyrido[2,3-d]pyrimidine (Example 71, 310 mg, 0.79 mmol) in 2 mL of acetic acid was treated with sodium cyanate (~6 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 NaHC03.
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') 3442, 2212, 3186, 3059, 1681, 1582, 1525, 1358.
Examvle 230 4-amino-5-( 1-phenylmethvl-3-3-~iperidin~l)-7-(4-dieth~laminophen~?pyridof 2 3 dl~yrimidine Following the procedures of Example 157, except substituting 1-(4-diethylamino-phenyl)-ethanone for the R4 reagent and 1-phenylmethylpiperidine-3-carboxaldehyde (prepared as described by Gilligan et al., J. Med. Chem., ,x: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 crri l; 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.

WO 98!46605 PCT/US98/07207 E~camnles 231-243 Ex. Name R4 Reagent R3 Reagent Analytical N (for 7- Data o (for 5-.

osition) osition 231 4-amino-5-(3- I-(6-(3-methyl-3-bromo- IR (KBr) 3484, 163s , bromophenyl)-7-(6-(3-5-isoxazolyl))-3-benzaldehyde ls~a, 1s62.

methyl-5-isoxazolyl))-3-pyridin 1 ~m-1; Ms m/Z
) 4s9 pyridinyl)pyrido[2,3-ethano a (M+H)+.

d] 'midine;

232 4-amino-5-(3- 1-(6-chloro-3-3-bromo- ~ (tcl3r) 34~s, 1608, bromophenyl)-7-(6- pyridinyl)- benzaldehyde 1s~4, 1s42 om-1;

chloro-3- ethanone Ms m/z 414 pyridinyl)pyrido[2,3- (M+H)+.

d] 'midine;

233 4-amino-5-(3- 1-(6-methoxy-3-3-bromo- 1R (tcBr) 3484, 163s, bromophenyl)-7-(6- pyridinyl)- benzaldehyde ls6o. 1348 cm-1;

methoxy-3- ethanone MS m/z 409 pyridinyl)pyrido[2,3- (M+H)+.

d] 'midine;

234 4-amino-5-(3- 1-(6-(1,2,4- 3-bromo- IR (KBr) 3494, 1612, brornophenyl)-7-(6-triazol-4-yl)-3-benzaldehyde 159, 1467, 1359, (1,2,4-triazol-4-yl)-3-pyridinyl)- 121, 1233 cm-1;

pyridinyl)pyrido[2,3-ethanone Ms .nrz aas d] 'midine; (M+H)+.

235 4-amino-5-(3- I-(2- 3-bromo- IR (KBr) 3434, 1637, bromophenyl)-7-(2- morpholinyl-5-benzaldehyde l6os, lsgs, 133s.

morpholinyl-5- pyrlmidinyl)- cm-1; MS m/z pyrimidinyl)pyrido[2,3-ethanone (M+H)+.

d] 'midine;

236 4-amino-S-(2-thiazolyl)-7-1-(4- 2-thiazole- IR (KBr) 3400, 1637.

(4-pyrroiidinylphenyl)-pyrrolidinylphencarboxaldehydel6og, 1s32.
~m-1 pyrido[2,3-d]pyrimidine;yl)-ethanone Ms mlz 3~6 M+H +.

237 4-amino-5-(3- I-(6-pyrazolyl-3-3-bromo- at (tcsr) 344, ts8o, bromophenyl)-7-(6- pyridinyl)- benzaldehyde ts6~, 1492, 139s, pyrazolyl-3-pyridinyl))-ethanone ~m-1: Ms m/z 'do[2,3-d] 'midine; (M+H)+.

238 4-amino-5-(3- 1-(4-(1-methyl-3-bromo- 1R (r) 3400, 166s, bromophenyl)-7-(4-(1-ureido)phenyl)-benzaldehyde l3so cm-1;
Ms miZ

methyl-ureido)phenyl)-ethanone 450 (M+H)+
' do[2,3-d) 'midine;

239 4-amino-5-(3- 1-(4-(N-methyl-3-bromo- IR (ICBr) 347s, 1s78, bromophenyl)-7-(4-(N-N-(2- benzaldehyde lss3. 1482, ~ 1396.

~ methyl-N-(2- pyrirru~yl)~ cm-1; Ms m/z pyrimidinyl)amino)phenylo)phenyl)- (M+H)+.

i )- rido[2,3-d] imidine;ethanone 240 4-amino-5-(3- 1-(3-fluoro-4-3-bromo- IR (KBr) 3448, 1600, bromophenyl)-7-(3- (N- benzaldehydets2s, 1476, cm-1;

fluoro-4-(N-formyl-N-methylamino)phe Ms rnz 4s4 methylamino)phenyl)-nyl)-ethanone (Ht+H)+.

pyrido[2,3-d]pyrimidine;

241 4-formylamino-5-(3-1-(3-fluoro-4-3-bromo- ttt (KBr) 3465, 1607, bromophenyl)-7-(3- (N- benzaldehydets46, l3so, om-1;

fluoro-4-(N-formyl-N-methylamino)phe vts miz 481 methylamino)phenyl)-nyl)-ethanone (M+H)+.

pyrido[2,3-d]pyrimidine;

242 4-amino-5-(3- 1-(4-(N-methyl-3-bromo- IR (lCBr) 3470, 16s0, bromophenyl)-7-(4-(N-N- benzaldehydets7o, 1338, cm-1;

methyl-N- methylsulfonyl- ncs miz 4a4 methylsulfonylamino)-amino)phenyl)- yvt+H)+.

phenyl)pyrido[2,3- ethanone d] 'midine;

243 4-amino-5-{3- 1-(6-(N-methyl-3-bromo- IR (KBr) 3460, 1680, bromophenyl)-7-{6-(N-N- benzaldehydets8o, 1330 cm-1;

methyl-N- methylsulfonyl- nts miz 4gs methylsulfonylamino)-3-amino)-3- (M+H)+.

pyridinyl)pyrido[2,3-pyridinyl)-d] ' midine; ethanone ~~ separated dy ctiromatograpny nom the same reaction mixture; tormylatlon occurs dunr~g the cyclization step Exam lp a 244 4-amino-5-(3-bromophenyl)-7-(1-methyl-5-indolinyl)pyrido12.3-dl~~rimidine dihydrochloride A sample of 4-(3-bromophenyl)-3-cyano-6-(1-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/CHZC12 and converted to the hydrochloride salt by treatment with ether/HCI. The salt was isolated and dried under vacuum to give the title compound. LRMS m/z 432/434; IR (crri') 3500, 3400, 3300, 3200-2800, 1610, 1580, 1560, 1540.
The 4-(3-bromophenyl)-3-cyano-6-(1-methyl-5-indoiyl)pyridine-2-amine starting material was prepared as follows:
244a. 5-bromo-1-methylindoline Acetic acid (60 mL) was added to a mixture of 5-bromo-1-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 MgS04 and concentrated to a powder under vacuum. This material was purified by flash chromatography to give the title compound, 8.62 g (82 %): MS
212, 214 [M+H]+.
244b. 5-acetyl-1-methvlindoline A mixture of 5-bromo-1-methylindoline (8.6 g, 40.7 mmol), to trimethylsilylacetylene ( 12 mL), palladium bis-triphenylphosphine dichloride (600 mg), CuI (620 mg) and triethylamine (16 mL) in acetonitrile (20 mL) was heated at 75 °C for 3 days, then cooled and concentrated in vacuo. The residue was dissolved in 120 mL of 1:1 ethyl acetate/hexane, and the solids were removed by filtration.
The solvent was removed and a sample of the residue (5 g) was dissolved in 90%
aqueous 15 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 MgS04 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-bromophen lY )-,3:,c~rano-6-ll-methyl-5-indolinvl)Ryridine-2-amine Prepared by condensation of 1',1'-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-1-methylindoline (the R4 reagent) with . ammonium acetate in ethanol. The reaction mixture was heated to reflux in a vessel fitted with a Dean-Stark apparatus. After 3.5 hours, the mixture was cooled, and the solvent was removed. The residue was purified by flash chromatography, eluting with methylene chloride, to give the title compound (588 mg, 30% yield; MS m/z (M+H)+.
Example 245 4-amino-5-(3-bromophenvl)-7-( 1-methyl-5-benzimidazol~l~pvridof2 3-dlp, rimidine tetrahydrochloride The title compound was prepared according to the procedure of Example 1, except substituting 1-methyl-5-acetyl-benzimidazole (prepared according to the procedure of D. J.
Evans et. al., J. Chem. Soc. Perkin Trans. Il, 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 4-amino-5-(3-bromophenvll-7-l6-dimethvlamino-3-pyridazinyl)pyrido12,3-dlvvrimidine tetrahvdrochloride 246a. 6-( I -butoxy~ethenyl)-3-chlorop~rridazine l0 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(PPh3)4, and 200 mL of 2 M- aqueous sodium carbonate was added. The reaction was heated to reflux over one hour, then cooled and filtered to remove solids. The filtrate was concentrated in vacuo and partitioned between ethyl acetate and 1 M sodium hydroxide. The organic phase was dried over Na2S04, 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-chlorQpvridazin-3-yllethanone 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 NaHC03. The reaction was extracted with ethyl acetate, dried over Na2S04, and concentrated in vacuo to give a yellow solid, 4.7 g.
246c. 1-(3-(6-ldimeth~lamino,~vridazin-3-xl))ethanone (the R4 rea ent A solution of 1.57 g (10 mmol) of 1-(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 CH2Cl2 and water.
The organic phase was dried over CH2C12 , and concentrated in vacuo to give the title compound.

246d. 3-acetyl-6-~ylami no~pvridazine The title compound was prepared by condensing l,l-dicyano-(3-(3-bromophenyl)propene (the R3 reagent) with the compound from Step 246c (the R~
reagent) and ammonium acetate in ethanol according to the procedure of Example 1574.
246e. 4-amino-5-f3-bromophenyl)-7-f6-dimethvlamino-3=pvridazinvl,~pvridof2 3 dlnvrimidine tetrahydrochloride The title compound was prepared from the compound of Step 246d according to the procedure of Example I57, 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 1 IA below, compounds of Examples 247-248 were prepared.
Table 11 A
Exam les 247-248 Ex. Name reagent of Analytical N ste c Data o , 247 4-amino-5- morpholine IR (KBr) 3600-3200, (3bromophenyl)-7-(6- 3000, 1630, 1605, mOrphOhriyl-3- 1590, 1550 cm-1;

pyridazinyl)pyrido[2,3- MS miz 464/466, d~pyrilriidlne 464.0829 (M+H)+;

dih drochloride 248 4-amino-5-(3- pyrrolidine IR (KBr) 3600-3250.

bromophenyl)-7-{6- 3100-2800, 1640, pyrrolidinyl-3- 1605. 1560 cm-I;

pyridazinyl)pyrido(2,3- Ms miz 448/450.

d]Pyt irnidine (M+H)+;

dih drochloride Examples 249-251 Following the procedures of Example 244, except in step (c) first substituting the appropriate reagent for R4 as indicated in Table 11B 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 11 B
Examples 249-260 ~ ~ Name R4 Reagent a~Yt~cal D

, (for 7- a N
o osition) 249 4-amino-5-(3- 2-acetyl-5- IR (KBr) 348, 3os8.

bromophenyl)-7-(S- morpholinyl- Is62. 1542.
I3~8.

morpholinyl-2- pyrazine 1306 ~m-I:
Ms Min pyrazinyl)pyrido[2,3- 464/466, (M+H)+;

d]pyrimidine dih drochloride 250 4-amino-S-(3- 2-acetyl-5-(N-(2-IR (KBr) 3482, 3299, bromophenyl)-7-(S-(N-(2-methoxyethyl)-3053, 1612, 1540, methoxyethyl)-N- N-methylamino)-1310 ~m-1;
Ms m methylamino)-2- pyrazine 466/46s, (M+H)+;

pyrazinyl)pyrido[2,3-d]pyrimidine dih drochloride 2S 4-amino-S-(3- 1-((4- nt (KBr) 1 3040, 1680, ' bromophenyl)-7-(4- acetylphenyl)-1640, 1605, 1580, (morpholinylmethyl)-methyl)- 1400 cm-1;
MS m~Z

phenyl)pyrido[2,3- morpholine 466/468, (M+H)+;

d]pyrimidine h drochloride Example 252 4-amino-S-(3-bromophenyl)-7-lS-IN.N-bisf2-methox~vl)amino)-2-pvridinyl)Ryridof2 3 dlpyrimidine trih3rdrochloride step 2S2a. 1-(S-bromo-2-p~ric~yl)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 SO
mL of toluene/THF (S: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, ethylene glycol (2.79 g, 4S mmol), and p-toluene sulfonic acid (0.1 g) were dissolved in SO mL of toluene and the solution was warmed at reflux for 10 hours. The reaction mixture was quenched by the addition of saturated aqueous NaHC03, and the aqueous layer was extracted with CH2C12. The combined organic layer was dried (Na2S04), concentrated under reduced pressure, and the resulting crude product was purified by flash chromatography to provide the title compound (3.68 g, 79%).

Stew 252b. 1-(5-lbis(2-methoxvethyl)amino)-2-g r~'idyl)ethanone Following literature procedure (J. Org. Chem. 1996, 61, 720), a suspension of the compound from step 252a, bis(2-methoxyethyl)amine, t BuONa, Pd2(dba)3, and BINAP
toluene was warmed at 80 °C for 8 hours. The reaction mixture was quenched by the addition of saturated aqueous NaHC03 and the aqueous layer was extracted with CH2Cl2.
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 CH2C1~. The combined organic layer was dried, concentrated under reduced pressure, and the crude product was purified by flash chromatography to provide the title compound Sten 252c. 4-amino-5-(3-bromophenyl)-7-(5-(N N-bis(2-methoxyethvl)aminol-2-p~ridinvl)pvridof2.3-dl~,vrimidine trihvdrochloride Following the procedures of Example 244, except in step (c) first substituting the t5 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 11B 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.
E Name R4 Reagent Analytical x.

No.
(for 7- Data osition) 253 4-amino-5-(3- 1-((4- IR (IC.Br) 3105, bromophenyl)-7-(4- acetylphenyl)-1645, 1620, (imidazolylmethyl)-methyl)imidazole1570, 1350 phenyl)pyrido[2,3- crri l; MS
m =

dJpyrirrudine 466/468, trihydrochloride (M+H)+;

Z$4 4-amino-$-(3- 1-($- IR (KBr) 3297, 3081, bromophenyl)-7-(S-(1-morpholinyl-2-1646, 1564, 1494, morpholinyl)-2- pyridyl~thanone1362 om-1;
Ms miz pyndinyl)pyrido[2,3-* 463/465, (M+H)*;

d]pyrimidine trih drochloride 2$$ 4-amino-$-(3- 1-(4- IR (KBr) 3308.
1645, bromophenyl)-7-(4- ((dimethylamino)1590, 1560, ((dimethylamino)methyl)-methyl)phenyl)-~m-1: Ms miz phenyl)pyrido[2,3- ethanone 509/511, (M+H)+;

d]pyrimidine dih drochloride 2$6 4-amino-$-(3- 1-{$-(4- IR (KBr) 3000, 1650.

bromophenyl)-7-($-(4-hydroxypiperidin1600. 1580, lsso.

hydroxy-1-piperidinyl)-2-yl)-2- 1400 om-1;
Ms miz pyridinyl)pyrido[2,3-pyridyl)ethanone477/479, (M+H)+;

d]pyrimidine **

dih drochloride 2$7 4-amino-$-(3- - $-acetyl-2- IR (KBr) 3477, 3060, bromophenyl)-7-($-(N-pyridinemethana1678, 1638, 1566, formyl-N-methylamino)-mine 1495, 1319 cm-1;

2-pyridinyl)pyrido[2,3- MS miz 435/437, d]pyrimidine (M+H)'';

dih drochloride 2$8 4-amino-S-(3- 2-acetyl-$-(2-IR (KBr) 3085, 1562, bromophenyl)-7-($-(2-propenyl)- 1485, 1357 cm-1;

propenyl)-2- pyridine Ms miz 41s/42o.

pyridinyl)pyrido[2,3- (M+H)+;

d] 'dine 2$9 4-amino-$-(3- 6-acetyl-3-(2-IR (KBr) 3440, 1770, bromophenyl)-7-(3-(2-methoxyethyl)-1625.1605.1580, methoxyethyl)-2-oxo-6-benzoxazol-2-1360 cm-1:
Ms m/z benzoxazolyl)pyrido[2,3-one 492/494, (M+H)+;

d]pyrimidine h drochloride 260 4-amino-$-(3- 4- IR (KBr) 3283, 3054, bromophenyl)-7-(4-(1-(N-acetylbenzeneeth1678, 1631, 1647.

formylamino)- anar~ne 1352 cm-1:
MS m/z ethyl)phenyl)pyrido[2,3- aas/4so, (M+H)+;

d] 'dine rucpa.rea as m ~x. ~o~o, except sunsatunng morpnollne for the bls(Z-methoxyethyl)amine thereof.
** Prepared as in Ex. 2$2b, except substituting 4-hydroxypiperidine for the bis(2-methoxyethyl)amine thereof.
Exam l 4-amino-$-(3-pyg~yl)-7-(4-dimethvlamino)vhen~RvridQj2 3-dlp«rimidine 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 l0 reagent (7-position) and nicotinaldehyde as the R3 reagent ($-position). IR
(cm-1) 330$.8, 2922, 1606, 1$78, 1$3$, 1360. MS (M+H) 342.

Example 262 4-(methvlamino)-5-(3-bromonhenvl)-7-l4-dimethylaminophenvl)~,vridof2 3 d~,pyru hydrochloride The title compound was prepared by using the method described in Example 200, except substituting methyIamine for the 2-(dimethylamino)ethylamine thereof.
MS (M+H), 478 (1Br); IR (cm-1) 345, 3047, 2959, 1580, 1351, 1234.
Example 263 l0 4-(2-methoxvethvlamino)-5-(3-bromophenvl)-7-(4-dimethvlaminonhenyl~yridof2 3-d~pvrimidine 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 ( 1 Br); IR (cm-1 ) 34I 5, 2920, 1569, 1321, 1234.
Example 264 4-amino-5-(3-bromonhenvl)-7-(4-(I-methyl-2-imidazolyl?phenvl)pyridoT2 3 dlpvri_midine trip vdrochloride Step 264a. 1-(4-(1-Methylimidazol-2-yl)phenyl)ethanone A solution of N-methyl imidazole (0.90 g, 11.0 mmol) in I2 mL of THF at -78 °C
was treated with n-BuLi (7.5 mL, 1.6 M solution in hexanes, 12.0 mmol) for 0.5 hours at -78 °C. Next, ZnCl2 (20 mL, 1.0 M solution in Et20, 20 mmol) was added, and the solution was warmed to 25°C. To this solution was added Pd(PPh3)4 (70 mg, 0.06 mmol) followed by 4-iodoacetophenone ethylene acetal (prepared from iodoacetophenone and ethylene glycol in the presence of an acid catalyst by standard procedures), and the reaction mixture was heated at reflux for 4 hours. The solution was then cooled to 25 °C and quenched by the addition of saturated aqueous NaHC03 ( 10 mL). The aqueous layer was extracted with CH2C12, 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 NaHC03, and the aqueous layer was extracted with CH2CI2.
The combined organic layer was dried (MgS04) then concentrated under reduced pressure.
The crude product was purified by flash chromatography to provide the title compound 3~ (0.89 g, 64%).

Step 264b. 4-amino-5-(3-bromoR,henyl)-7-(4-(1-methyl-2-imidazolvhghenvl)pyridof2.3-dlpvrimidine trihvdrochloride 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 ( 1 Br); IR (cm-1 ) 305 l, 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.
Ex. Name R4 Reagent Analytical No.
(for 7- Data osition) 265 '1'~-5-(3- 1-(4- Ms (M+H), 460: >It bromophenyl)-7-(4- (aminomethyl)ph(gym-1) 3024 2933, (aminomethyl)phenyl)pyrienyl)ethanone1550, 1493, do[2,3-d) 'midine 266 4-'ammo-5-(3- 1-(2-bromo-4-Ives (M+H), soo (2 bromophenyl)-7-(2- (dimethylamino)Br): >It (~,r~-1) 3049, bromo-4- phenyl)ethanone29x9, 1536, 1468, (dirnethylamino)phenyl)py 13 20 rido[2,3-d] 'dine 267 4-amino-5-(3- 1-(4- Ivts (M+H), 44s (1 bromophenyl)-7-(4- (dimethylaminoetBr)~ ~ (~-1) 3420, (dimethylaminoethyl)phenhyl)phenyl)ethan3~0, 2980, 1635, 1) rid0 2,3- one 1610, 1590, a 1435, py 1415 a ]
' a 4-amino-5-(3-bromophenyl)-7-(4-(3-(dime~ylamino)proRynyl henyl)~,3rridof2 '~-A suspension of the compound of Example 63 (0.80 g, 1.59 mmol), PdCl2(PPh3)2, CuI, and 3-dimethylaminoprop-1-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 (1Br); IR (cm-1) 3027, 2964, 1513, 1470, 1360.
Examples 269-271 Following the procedures of Example 268, except substituting the reagent compound shown in the table below for the 3-dimethylaminoprop-1-yne of Example 268, the compounds shown in the table below were prepared.
Ex. Name Reagent Analytical N Data o .

269 4-amino-5-(3- l, l-dimethyl-ms (lvt+H), 4s9 bromophenyl)-7-(4-(3-propargyl (1Br); ttt amine (om-1) amino-3- 3041, 2967, 1562, methylbutynyl)phenyl)pyri 1484, 1319 do[2,3-dJ imidine 270 4-amino-5-(3- dimethyl ms (M+H), bromophenyl)-7-(4- phosphite (1Br); IR
(cm-1) dimethylphosphonatophen 3105, 2912, 162s, yl)pyrld0[2,3- 1437, 1350 d] 'dine 271 4-amino-5-(3- methyl propargyltuts (M+H), bromophenyl)-7-(4-(3-ether (1Br);1Ft (m-1) (methoxypropynyl)pyrido[ 3053, 2929, 1560, 2,3-dJ 'midine 1484, 1352 Exam In a 272 4-amino-5-(3-bromo henyl)-7-(4-carboxyphenyl)pyridof2 3-dlnvrimidine A solution of 4-amino-5-(3-bromophenyl)-7-(4-cyanophenyl)pyrido[2,3-d)pyrimidine (the compound of Example 37, (0.47 g, 1.17 mmol) in 15 mL of 6 M
HCl (aqueous) was heated at 60 °C for 8 hours. The mixture was lyophilized and the crude product was purified by flash chromatography to provide the title compound (0.14 g, 28%).
MS (M+H), 422 (1Br); IR (cm-1) 3064, 2628, 1692, 1403, 1273.
Example 273 4-amino-5-l3-bromophenvl)-7-(4-methyl-3-oxo-2H-4H-~vridof3 2-bl 1 4 oxazinyl)p3rridof2 3-d]pvrimidine Sten 273a. 7-acet 1-~ 2H-pyridof3 2-bl-I 4-oxazin-3(4H)-one A solution of 2H-pyrido[3,2-b]-1,4-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 HCI
(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 NaHS03. The aqueous layer was extracted with CH2CI2 and the combined organic layer was dried (Na2S04), concentrated under reduced pressure, and purified by flash chromatography to provide 7-bromo-2H-pyrido[3,2-b)-1,4-oxazin-3(4H)-one (8.4 g, 56%). A mixture of 7-bromo-2H-pyrido[3,2-b]-1,4-oxazin-3(4H)-one (3.2 g, 14 mmol), tributyl(1-ethoxyvinyl)tin (6.1 g, 17 mmolj, Pd2(dba)3 (0.5 g, 0.56 mmol), and (2-furyl)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 NaHC03 (aqueous), and the aqueous layer was extracted with CH2C12. The combined organic layer was dried (Na2S0~, concentrated, and the crude product was purified by flash chromatography to provide 7-acetyl-2H-pyrido[3,2-b]-1,4-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.
Sten 273b. 7-acetvl-4-methyl-2H-pyridof~ 2-bl-1 4-oxazin 3(4H1 one The compound from step 273 a was treated with methyl iodide and NaH in l:l 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.
Sten 273c. 4-amino-5-(3-bromophenyl)-7-(4-metal 3 oxo 2H 4H pyridof~ 2 bl 1 4 oxazin~pyridof2 3-dlpyrimidine Following the procedure of Example 244 Step c, except first substituting 7-acetyl-4-methyl-2H-pyrido[3,2-b]-1,4-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.
Exam lp a 274 4-amino-5-l3-bromonhenvll-7-(4-(2 (dimethvIaminolethyll ~ oxo 2H 4H pyridof3 2 bl l~xazin-7-yllpyridof2 3-dlpvrimidine S~t p 274a. 7-acetyl-4-dimethylaminoeth ly 2H ny~j3 2 bl 1 4 oxazin 3(4H) .one WO 98/4bb05 PCT/US98/07207 The compound from Example 273 Step a was treated with 2-chloro-(N,N-dimethyl)ethylamine HCl and K2C03 in aqueous acetone at reflux. The mixture was diluted with water and extracted with dichlorometttane, and the residue was purified by chromatogaphy to give the title compound.
Step 274b. 4-amino-5-(3-bromophenyl)-7-(4-(2-(dimethvlamino)ethyl)-3-oxo 2H 4H
pVIld013.2-bl-1 4-oxazin-7-vl)pyridof2 3-dlpvrimidine Following the procedures of Example 244 Step c, except in step c first substituting 7-acetyl-4-dimethylaminoethyl -2H-pyrido[3,2-b]-I,4-oxazin-3(41-x-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-bromonhenyl)-7-(2 3-dihvdro-3-(dimethylaminoethyl)-2-oxobenzoxazol 6 yl~pvridoT2.3-dlpyrimidine Step 275a. 6-acet~rl-2-benzoxazohnone Following the procedures of Example 273 Step a, except substituting 2-benzoxazolinone (Aldrich) for the 2H-pyrido[3,2-b]-1,4-oxazin-3(41-x-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 K2C03 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.
3o Sten 275c. 4-amino-5-(3-bromophenvl)-7-(2 3-dihydro-3-(dimethylaminoethyl) oxobenzoxazol-6=yl)pvrido~2 3-dlpyrimidine Following the procedures of Example 244 Step c, except in step c first substituting the compound from Step 275a for the R4 reagent of Example 244 Step c, and secondly performing the condensation with ammonium acetate substituting dichloroethane as the solvent in place of the ethanol solvent in Example 244 step c, the title compound was prepared. MS (M+H), 506 ( 1 Br); IR (cm-1 ) 3400, 3050, 1630, 1610, 1360.

Exampl 76 4-amino-5-l3-bromonhenyl_)-7-(4-methyl-3-oxo-2H-4H-benzo-1.4-oxazin_-7-vl)pvridof2 3 dlpvrimidine Step 276a. 6-acedvl-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. 1-(3-h~droxv-4-methvlaminQphenvl)-ethanone The compound from Step 276a ( 1.60 g, 8.37 mmol) was dissolved in acetone (70 mL) and treated with 1 M aqueous K2C03 solution (25 mL) with heating at reflux overnight.
The mixture was neutralized with acid, then extracted with diethyl ether. The solvent was dried (MgS04) 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-(3-bromophenyl)-7-(4-methyl-3-oxo-2H-H-benzo-1,4-oxazin-7-vl)pvridof 2.3-dlpvrimidine 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-S-(3-bromophenyl)-7-(2 2 4-trimethyl-3-oxo-2H-4H-benzo-1 4-oxazin-7-vl)pyridof 2.3-dlpyrimidine Steg 277a. 7-acetyl-2.2 4-trimethyl-2H-4H-benzo-1 4-oxazin-3-one The compound from Step 276b (2.25 g, 9 mmol) was dissolved in DMSO and 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 (MgS04), 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-l3-bromophenyl)-7-(2.2,4-trimethyl-3-oxo-2H-4H-benzo-1 4-oxazin-7-vl)pyridof2,3-dlpyrimidine Following the procedures of Example 244. Step c, except in step c first substituting the compound from Step 277a for the R4 reagent of Example 244 Step c, and secondly performing the condensation with ammonium acetate substituting dichloroethane as 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 2?8 4-amino-5-cvclohexyl-7-(4-(2-dimethvlamino)ethyl)-2H-4H-benzo-3-oxo-1 4-oxazin-vl)pvrido~2.3-dlpyrimidine Step 278a. 1-(3-hydroxv-4-f2-(dimethylamino)ethyl,)phenyi)-ethanone A sample of 6-acetyl-3-(dimethylaminoethyl)-2-benzoxazolinone (from Example 27~
Step b) was dissolved in acetone and treated with 1M aqueous K2C03 solution with heating at reflux overnight. The mixture was neutralized with acid, then extracted with diethyl ether.
The solvent was dried (MgS04) and removed under vacuum to give the title compound.
Step 278b. 7-acet~rl-4-ldimethvlamino)ethyl)-2H-4H-benzo-14-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, mmol) at room temperature for 2 days. The mixture was diluted with water then extracted with ether. The extract was dried (MgS04), 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.

Sten 278c. 4-amino-5-cvclohexvl-7-(4-(dimethvlamino)ethyl)-2H-4H-benzo-3-oxo-1.4-oxazin-7-vl)pvridof 2.3-dlpyn~idine Following the procedures of Example 244 Step c, except in step c first substituting 1.1-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-1) 3400, 2900, 1690, 1610, 1590, 1395.
Example 279 4-amino-5-(3-bromophenvl)-7-(5-( 1-methvlet~l)-2-gvridvl)~,vrido f 2,3-dlpyrimidine Step 279a. 1-(5-meth~vl-2-pyridvl)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 tide compound, 2, ( 1.04 g, 84%) was isolated following flash chromatography.
Step 279b. 4-amino-5-(3-bromophenvl)-7-(5-( 1-methvlethyl)-2-~yridyl~pvridof 2 dlpyrimidine Following the procedures of Example 244 Step c, except in step c substituting the compound from Step 279a for the R4 reagent of Example 244 Step c, and performing the condensation with ammonium acetate and also substituting dichloroethane as the solvent in place of the ethanol solvent in Example 244 step c, the title compound was prepared. MS
(M+H) 421 (1Br); 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 WO 98/46b05 PCT/IJS98/07207 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.
Ex. I Name R4 Reagent Analytical No.
(for 7- Data osition) 280 4-amino-5-(3- I-(5-piperidinyl-Ms (M+H), bromophenyl)-7-(5- 2- (1Br); llt (cm-1) piperidin-I-ylpyrid-2-pyridyl)ethanone3064, 2937, 1556, yi)pyrido[2,3-* 1493, 1358 d] 'dine 281 4-amino-J-(1-(4- 1-(2- MS (M+H), 491 (i bromophenyl)ethyl)-7-(6-morpholinyl-5-BTO IR (cm-1) 1685, morpholinylpyrid-3-pyridyl)ethanonelsss, lsos, 1240, yl)pyrido[2,3- ** lllo, 940 d] 'dine * Prepared as in Ex. 252b, except substituting morpholine for the bis(2-methoxyethyl)amine thereof.
** prepared by treatment of 5-acetyl-2-chloro-pyridine with morpholine in refluxing ethanol.
Exam In a 282 4-amino-5-l3-bromophenyl)-7-~4-(lN-formvlamino)methy~ henylOvridof2 3-dlpyrimidine Sten 282a. 4-cvanoacetonhenone. acetal with 2 2-dimeth~r rolz, line g]xcol 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 NaHC03, water and brine, and dried over MgS04. The solvent was removed under vacuum to give the title compound (7.46 g).
step 282b. 4-(aminometh 1)~phenone acetal with 2 2-dime~lnro~,vlene g_lvcol 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 MgS04~10 H20, and the mixture was diluted with ether. The mixture was filtered, and the filtrate removed to give the title compound.
Step 282c. 1-(4-(BOC-~minomet~lvl~phenyllethanone The compound from Step 282b (1.18 g, 5 mmol) was dissolved in THF (20 mL), 1N HCl (20 mL) was added, and the mixture was stirred for 2 days. The volatiles were removed under vacuum, the residue was dissolved in THF (20 mL), and d-tibutyl dicarbonate (2.18 g, 10 mmol) was added. The mixture was stirred at room temperature s over a weekend. The solution was diluted with water, and the mixture was extracted with ether and ethyl acetate. The organic extracts were direct (MgS04), and the solvent was remove under vacuum to give the title compound.
Step 282d. 4-amino-5-(3-bromophenyl)-7-(4-(N-formvlaminolmethvllphenvl)pyridof2.3-l0 dlpvrimidine 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
15 (M+H) 434 ( 1 Br); IR (cm-1 ) 3440, 2700-3150, 1635, 1580, 1380.
Example 283 4-amino-5-(3-bromophenyl)-7-(4-( 1-(N-methylamino)-1-methylethyl)phenvl)pvridof 2.3-dlp~rimidine Step 283a. 4-(1-amino-1-methyleth, 1)~acetophenone CeCl3 ( 10 g, 34.9 mmol) was suspended in THF (60 mL), and the mixture was cooled to -78 °C. Methyl lithium ( 1.4 M, 2 mL) was added, and the mixture was 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 (MgS04), and the solvent was removed to give the title compound.
Step 283b. 4-(1-lN-BOC-amino)-1-methylethyl)acetophenone 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.

Steo 283c 4-amino-5-( 3-bromonhenvl)-7-(4-( 1-(N formvlamino) 1 methvlethvl)phenvl)~yridof2 3-dlpyrimidine Following the procedures of Example 244 Step c, except in step c substituting tit 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.
l0 Example 284 4-amino-5-(3-bromophenyl)-7-(4-(1-(N N-dimethylamino)-1-methvlethvl)phenvl)pvridof2 3-dlpvrimidine Step 284a. 4-(1-(dimethvlamino)-1-methvlethyl)acetonhenone The compound from Step 283a (1.18 g, 5 mmol) was dissolved in 5 mL formic acid, and 5 mL of formalin (37% ) was added. The mixture was heated at reflux for 4 hours, then cooled and neutralized with 2N Na3C03. The mixture was extracted with dichloromethane. The solution was dried .(MgS04), 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 Ex. Name R3 Reagent R4 Reagent Analytical Data No.
(for 5- (for 7-osition position) 285 4-amino-~-(3- l,l-dicyano-(3-1-(N-acetyl-5-mp (hydrochloride salt ) bromophenyl)-7-(N-(3- indolinyl)- >2~oc. 1R ~~mv>
3a4s.

acetyl-5- bromophenyl)prethanone 3loo-2soo. 1640.
l6os.

indoliny opene 144s, 1395.
1)pyrido[2,3- 1326.

_ t,luvts [M+H]-dJ dine m/z 460.

462.

286 4-amino-5-cyclohexyl-l, l-dicyano-3-1-(6-chloro-3-mp 240-242 c.
iit (cm-7-(6-chloro-3- cyclohexylethenepyridyl)- 1) 3s28, 3300, 3086, pyridyl)pyrido[2,3- ethanone 2936, 2853, 1645, d]pyrlmidine 1590, ls7s, 1s65,1350.
L~Ms Ht+H + m/z 340.

Examples 287-300 Following the procedures of Example 157, except substituting the appropriate - 5 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 Ex. Name R3 Reagent R4 Reagent Analytical Data No.
(for 5- (for 7-osition osition) 287 4-amino-5-(1-(2- l,l-dicyano-2-1-(6- >It (cm-1) 26oo-3soo, bromophenyl)ethyl)-7-methyl-(3-(2-dimethylamino-l6so, 1602, 1596, ls2o (6-dimethylamino-3-bromophenyl)pr3-pyridyl)- cm-1. Lltlvls (lvt+H)+

pyridyl)pyrido[2,3-opene ethanone m/z 449,4s1.

d 'dine 288 4-amino-5-(1-{2- l,l-dicyano-2-1-(6- mp (dihydrochloride salt) bromophenyl)ethyl)-7-methyl-(3-(2-morpholinyl-3-213-216 C. IR
(cm-1) (6-morpholinyl-3-bromophenyl)prpyridyl)- 24oo-3soo, 1660, 1600.

pyridyl)pyrido[2,3-opene ethanone Q~s fHt+Hl+
m/z 491&

d] 'dine 289 4-amino-5-{1-(2- 1,1-dicyano-2-1-(6-(N-methyl-mp 2s2-2s3c.
rn (omv) bromophenyl)ethyl)-7-methyl-(3-(2-N- 3sls. 3310, 3200-2800, (6-(N-methyl-N- bromophenyl)prfotmyl)amino)-16~s, lsgs, ls6o, ls4s, form 1 amino)-3- o ene 3 d 1) 1340. Lwvts Y ) P -PYr'i Y (Nt+t-~ m/z - 462, 464.

phenyl)pyrido[2,3- ethanone d] 'dine 290 4-amino-5-cyclohexyl-l,l-dicyano-3-1-(6- mp (dihydrocnloride salt) 7-(6-morpholinyl-3-cyclohexylethenemorpholinyl-3-tog-21o. ilt (cm-1) 3490, 3300, pyridyl)pyrido[2,3- pyrldyl)- 3050-3250.

1620, lsgo.
d]pynmldlne ethanone lsso, 1490.
LRMS M+H + m/z 391.

291 4-amino-5-((2- 1,1-dicyano-(3-1-(6- mp (dihydrochloride salt ) bromophenyl)methyl)-(2- morphoiinyl-3-201-204 c. Bt (cm-1) 7-(6-morpholinyl-3-bromophenyl)prpyridyl)- 2aso, isss isb~
iso2 , pyridyl)p opene ethanone , o[2,3- , d 1345 . LltMS
d~d (M+H]+

m/z 477, 479.
292 4-amino-5-{4- l,l-dicyano-3-1-(6- mp (dihydrochloride salt) tetrahydropyranyl)-7-(4- morpholinyl-3-213-216 c. nt (om-1) (6-morpholinyl-3-tetrahydropyranypyrldyl)- 3310, 3060, 29ss, 1587, pyridyl)pyrido[2,3-1}ethene ethanone lss9, lso6. l3so.

d] ding * LRMS [M+H]+ m/z 393.

293 4-amino-5-cyclohexyl-l,l-dicyano-3-1-(6- mp (dihydro~hloride salt) 7-(6-dimethylamino-3-cyclohexylethenedimethylamino-272-274 c. at (cm ~t) pyridyl)pyrido[2,3- 3-pyridyl)- 3s32.3294.3100.2930, 2853, 1606. 1586, d]pyrlmidine ethanone 1s60, 1522. 1387. LRMS

M+H + m/z 349.
294 4-amino-5-(1- 1,1-dicyano-3-1-(6- mp (free base):
2235-22s ethylpropyl)-7-(6-ethylpentene dimethylamino-c~ ~ (gym-1) 3480, dimethylamino-3- 3-pyridyl)- 3-3470. 2800-3000, 1630, 1610, 1s80, p ethanone is6s, yridyl)p o[2,3-d is20. LRMS [M+H]+
d~d m/z aa~~u 337.

295 4-amino-S- l , l -dicyano-3-1-(6- >R (om-~ ) 349s, 3320, cyclopentyl-7-(6-cyclopentylethenmorpholinyl-3-3080, 29so, 164s, 1600, morpholinyl-3- a p~dyl)_ lsoo, 1400, 13s0, 1240.

LRMS [M+H]' m/z pyridyl)pyrido[2,3- ethanone 377.

d] 'dine 296 4-amino-5-cyclohexyl-1,1-dicyano-3-1-(2-chloro-3-t>z (om-~) 33os, 3lss, 7-(2-chloro-3- cyclohexylethenepyridyl)- 2930, 28s5, 1590, 1610, 1s90, ls4s, 134s.
pyridyl)pyrido[2,3- ethanone Las [M+H]- m/z d]pyrlmldine 340, 342.

297 4-amino-5-(3,5- 1,1-dicyano-3-1-(6- nt (om-~) 3310, 3100, dimethylcyclohexyl}-(3,5- dimethylamino-29s0. 1605, 1590, l5ss, 7-(6-dimethylamino-3-dimethylcyclohe3-pyridyl)- 1390, l3so. LRMs pyridyl)pyndo[2,3-xyl)ethene ethanone [M+H]' m/z 377.

d] dine 298 4-amino-5-((N- l, l-dicyano-(3-1-(6- tlz (cm-1) 3s38, 3311, (benzyloxycarbonyl}-(4- morpholinyl-3-3032, 292s Z8s2, 4-piperidinyl)methyl)-(benzyloxycarbopyndyl)- lsgs, 1560. LltMs 7-(6-morpholinyl-3-nyl)piperidin-1-ethanone [M+H)+ m/z 540.

pyridyl)pyrido[2,3-yl)propene d] 'dine 299 4-amino-5-cyclohexyl-1,1-dicyano-3-1-(6-bromo-3-m.p. 2so-2s2 c, IR (cm-7-(6-bromo-3- cyclohexylethenepyridyl)- I) 3s30, 3298, 3093, pyridyl)pyrido[2,3- ethanone 2932.28s6.1645, lsg3, d]pyrimidine 1s69. 1543, 1461, 1346.

LRMS M+H + 384.
300 4-amino-5-cyclohexyl-l,l-dicyano-3-1-(3- 386.
m. p. 223-224 c. IR

7-(3- cyclohexylethenecyanophenyl)-(gym-1) 3s2s, 3298, cyanophenyl)pyrido[2, ethanone 307s, 2937, 223s.
164s.

1586, 1s48. 1567, 3-d]pynmidine 146.

LRMS [M+H]+ 332.

me ~,~-a~cyano-~-cyclonexyleulene was prepared according to the method of Moison, et al. (Tetrahedron (19$7), x: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 30I-305 were prepared. For Example 302 only, the 2o condensation solvent was DMSO instead of ethanol and dimethoxyethane.
Examples 301-305 Ex. blame R3 reagent reagent of Analytical N ste c Data o .

301 4-amino-5-(1-(2- 1,1-dicyano-(3-dimethylaminemp (dihydrochloride bromophenyl)ethyl)-7-{6-(2- sau ) >22oc.
IR

dimethylamino-3- bromophenyl)pr (gym-') 3soo-2400.

dazln 1 do 2,3- o ene 1640, 1610, PYn Y )PYn [ P 1580, 1370. LRMS
[M+H]' d] die m/z 450, 452.

302 4-amino-5-(3- 1',1'-dicyano-imidazole mp bromophenyl)-7-(6- (3-bromostyrenesodium salt (tetrahydrochloride imidazolyl-3- salt ) >24oc.
IR

pyridazinyl)pyrido[2,3- i64o~ ib~o X1590, d]pyrimidine 1560, 1415, 1370.

LRMS [M+H]' m/z 445, 447.

303 4-amino-5-(3- 1',1'-dicyano-azacycloheptanemp (dihydrochloride bromophenyl)-7-(6- (3-bromostyrene Salt ) >19oc.
IR

(azacycloheptanyl)-3- (cm'') 3435.

2400, 1635, pyridazinyl)pyrido[2 1610, , ls9o. lsso, d] 1440, rimidine py 1370. LRMS
[M+Hl' m/z 476, 478.

304 4-amino-5-(3- 1', l'-dicyano-N-methyl-N-( mp (dihydrochloride bromophenyl)-7-(6-(N-(3-bromostyrenemethylethyl))amiSalt ) >21oc.
IR

methyl-N-(1- ne (mv> 3435, meth leth 1))amino)-3- 2400, 163s.
Y y 1610.

1590, 1550, pyridazinyl)pyrido[2,3- 1410, 1370. LRMS
[M+H]-d] 'dine m/z 450, 452.

305 4-amino-5-(1-(2- 1,1-dicyano-(3-morpholine Bt (cm-1) 3475, bromophenyl)ethyl)-7-(6-(2- 3313, 3100, l6so,' morphofinyl-3- bromophenyl)pr 1620, 1580, ls5s.

pyndazinyl)pyrido[2,3-opene lwvts iM+Hl+
z:c d] 'dine 492, 494.

Example 306 4-amino-S-cvclohexyl-7-l6-(4-acetylR~erazinyi~pyr~'dyl)~yridof7 3 dlpvri_mid~e A mixture of 679 mg (2 mlnol) 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, 3I 10, 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.
Ex. Name reagent Analytical Data No.

_ 307 4-amino-5- 1-acetyl-1,4- m.p. 169-171 c, llt (cm-cyclohexyl-7-(6-(4-diazacycloheptane1) 3535 3309, 3096, acetyl-1,4- 2930. 2854, 1638, 1605, 1587, 1s58, diazacycloheptanyl)- 1513.

Ltu~ts 1M+H]+446.

pyridyl)pylido[2,3-d] 'dine 308 4-amino-~- 1-methyl-1,4- l.tuv~s [M+H]+419.

cyclohexyl-7-(6-(4-diazacycloheptane methyl-1,4-diazacycloheptanyl)-pyridyl)pyrido[2,3-d] ' dine 309 4-amino-~- N-methyl-N-(2-(2-I.RMS [M+Hl+
441.

cyclohexyl-7-(6-(N-pyridyl)ethyl)amine methyl-N-(2-(2-pyridyl)ethyl)amino) pyridyl)pyrido[2>3-d] 'dine WO 98/46605 PCT/~JS98/07207 3101 4-amino-5- N,N-dimethyl, L~ttvts [ivi+Hl+
N'- a21.

cyclohexyl-7-(6-2-methyl-1,2-(N-{N',N'- ethylenediamine dimethylaminoethyl) -N-methylamino)-3-pyridyl)pyrido[2,3-d] 'dine 311 4-amino-5- azetidine LRMS [M+HI+
36i.

cyclohexyl-7-(6-azetidinyl-3-pyridyl)pyrido[2,3-d] 'dine 312 4-amino-5- N-methyl-N-(3- Litlvis [M+H]+
aa~.

cyclohexyl-7-{6-(3-pyrrolidinyl)acetami (N- de rnethylacetamido)pyr rolidinyl)pyridyl)pyr ido[2,3-d] 'dine 313 4-amino-5- pyrrolidine-2- LFtMS [M+H]+
419.

cyclohexyl-7-(6-(3-formamide (formamido)pyrrolid inyl)pyridyl)pyrido[

2,3-d ' midine 314 4-amino-5- 1-phenyl-1,38- t,xivts [M+H]+536.

cyclohexyl-7-(4-triazaspiro[4.5]deca oxo-1-phenyl-1,3,8-n-4-one triazaspiro[4.5[deca n-8-yl)pyrido[2,3-d 'dine 315 4-amino-5- 2- LxMS [M+H1+
a2o.

cyclohexyl-7-(6-(2-(methoxymethyl)pyr (methoxymethyl)pyrrolidine rolidin-1-yl)pyridyl)pyrido[2, 3-d] 'midine 316 4-amino-5- N- Liztvts llvt+HI+
a21.

cyclohexyl-7-(6-(N-(methoxyethyl)prop methoxyethyl-N-ylamine propylamino)pyridyl )pyrido[2,3-d] 'dine 317 4-amino-5- 2-(methylamino)-c.ltMS livt+HI*
a29.

cyclohexyl-7-(N-dimethylacetaldehyd methyl-N-(2,2- a dimethoxyethyl)ami no)pyrido[2,3-d] dine 318 4-amino-5- N-(4-piperidyl)-Ltuvts [M+H]*
433.

cyclohexyl-7-(6-(4-dimethylamine (dimethylamino)pipe ridinyl)pyridyl)pyrid 0[2,3-d] 'midine WO 98/46605 PCT/(TS98/07207 319 4-amino-S- piperidine-4- Ltt~tS [M+H)+
433.

cyclohexyl-7-(6-(4-formamide (aminocarbonyl))pip eridinyl)pyridyl)pyri do[2,3-d) 'midine 320 I 4-amino-~- N 1 N 1-diethyl-N3-LR~~ts (M+H)+
a t9.

cyclohexyl-7-(N-methyl-1,3-methyl-N-(3- propanediamine (diethylamino)propy 1)aminopyrid-3-yl)pyrido[2,3-d] 'dine 32 4-amino-5- N-methyl-(4- LRtvts fM+H)+
) 4ai.

cyclohexyl-7-(6-(N-pyridyl)ethylamine methyl-N-(4-pyridyl)ethylamino) pyrid-3-yl)pyrido[2,3-d] 'dine 322 4-amino-5- N-methyl-(3- LRMS (M+H)+ 42~.

cyclohexyl-7-(6-(N-pyridyl)methylamine methyl-N-(3-pyridylmethyl)amino )pyrid-3-yl)pyrido[2,3-d] 'dine Example 323 4-amino-5-fl-l2-bromophen 1 ethyl)-7-(1-methyl-5-indolyl)pyridof2 3 d]pyzimidine The procedures of Example 157 were followed, except substituting 1',1'-dicyano-bromostyrene for the R3 reagent and 1-( 1-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)+.
Exam )n a 324 4-amino-5-(1-(2-bromoDhenyl ethyl)-7-(1-methyl-2 3-dioxo 5 indolvl)nvridof2 3 dlpyrimidine The title compound was prepared from the compound of Example 323 by oxidation with Cr03 in sulfuric acid. IR (microscope) 3471, 1765, 1500 cm-l MS m/.
461(M+H)+.

Examines 325-326 Fflllowing the procedures of Example 157, except substituting the appropriate 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 Ex. Name R3 Reagent R4 Reagent Analytical Data No.
(for 5- (for 7-osition osition) 325 4-amino-5-(3- 1', I'-dicyano-3-1-(3-fluoro-4-(IR (microscope) 1- 3443, bromophenyl)-7-(3-bromostyrene morpholinyl)phe3~. 1639, 1606.
1584, fluoro-4-(I- nyl)-ethanone1520. 1362, 1245 cm-1;

morpholinyl)phenyl)p Ms miZ 4so (M+H)+.

yrido[2,3-d] 'dine 326 4-amino-5-{3- 1', l'-dicyano-3-1-(4-hydroxy-3-IR (K$r) 3461.
1623, bromophenyl)-7-{4-bromostyrene nitrophenyl)-1s79. ls4s, 1523.

hydroxy-3- ethanone ~m-1; Ms miz 43s nitrophenyl)pyrido[2,3 (M+H)+.

-d] 'dine 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 dichioroethane as the solvent in place of the ethanol solvent in Example 244 step c, the compound shown in the table below was prepared.
Ex. Name precursor Analytical N rea ent Data o .

327 4-amino-S-(3- 4-piperidinoneitt (microscope) bromophenyl)-7-(6-(4,4-ethylene ketal3091, 1602, 1580.

. ethylenedioxypiperidinyl)- 1558, 1512.
1353.

3-pyridyl)pyrido[2,3- 1236, 1103 cm' 1:

d] 'dine Ms m/z 519 (M+H)+.

Example 328 4-amino-5-l3-bromonhenvl)-7-(6-l4-oxopiperidinvl)-3-pvrid~rl,},~yridol2 3-dlpvrimidine Treating the compound of Example 327 with dilute HCI, 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 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 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.
Examlales 329-331 Ex. Name precursor Analytical No. rea ent Data -329 4-amino-5-(3- piperazine IR (I~r) 3489, 1674, bromophenyl)-7-(6-(4- ' formylpiperazinyl)-3- lso3, 1233, pyridyl)pyrido[2,3- cm-1: MS
m/z 491 d] dine (M+H)+.

330 4-amiri0-5-(3- 1- IR (microscope) bromophenyl)-7-(6-(4-methylpiperazine343x, 3osl, ls4o methylpiperazinyl)-3- cm-1: Ms mlz 4~~

pyridyl)pyrido[2,3- (M+H)+.

d) 'dine 331 4-amino-5-(3- thiomorpholineIR (KBr) 3486, 1602, bromophenyl)-7-(6- 1s81, ls6o.
lso2, thiomorpholinyl-3- 1228 cm-1;
MS m/z pyridyl)pyrido[2,3- 4~9 (M+H)+.

d) imidin Example 332 4-amino-5-(3-bromophenyl)-7-l6-l4 4-dioxothiomorphoiinyl)-,3-nyridy~~yridof2 3 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, 1122 cm-1; MS m/z 511(M+H)+.

Example 333 4-amino-5-(2-bromo~henvl)- -(6-mornholinvl-3-pvridyl)nvridof2 3-dlp'~midine Step 333a. 1'.1'-dicyano-2-bromostyrene The title compound was prepared by condensation of 2-bromobenzaldehyde with malononitrile and Mg0 in dichloromethane by the standard procedure of Broekhuis et al.
(Recl. J. R. Neth. Chem. Soe., 99: 6-12 (1980)).
Sten 333b. 5-acetvl-2-morpholin,~l, vridine The title compound was prepared by the reaction of 5-acetyl-2-chloropyridine with morpholine in refluxing ethanol.
yep 333c. 4-(2-bromonhenyl)-3-cyano-6-morpholin~pvtidine-2-amine The title compound was prepared by condensation of 1',1'-dicyano-2-bromostyrene with 5-acetyl-2-morpholinylpyridine 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 33~ 4-amino-5-l2-brom_ophenvl)-7-(6-mor~hoiinvl-3-pvridyl)pyridof2 3-2o dlpyrimidine A sample of 4-(2-bromophenyl)-3-cyano-6-morpholinylpyridine-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/CH2C12. IR (microscope) 3493, 1547, 1109cm-1; MS m/~ 464 (M+H)+.
Examules 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 Step a, and carrying the product forward as in procedures 333 Stepbs b-d, the compounds shown in the table below were prepared.

WO 98/46605 , PCT/US98/07207 Examples 334-336 Ex. Name precursor Analytical N aldehyde Data o .

rea ent 334 I 4-amino-~-(3-bromo-4-3-bromo-4- IR (microscope) methoxyphenyl)-7-(6-methoxybenzaldehyde3486, 1600, is7s, morpholinyl-3- 1562, 1500, 1260, pyridyl)pyrido[2,3- 1237 cm-1:
MS miz d] 'dine 493 (M+H)+.

335 4-amino-S-(4- 4-bromobenzaldehyde11t (microscope) bromophenyl)-7-(6- 3497, 1532, moipholinyl-3- 1098cm-i;
MS m/z pyridyi)pyrido[2,3- 464 (M+H)+.

d) 'dine 336 4-amino-5-(3- 3-chlorobenzaldehydeIR (microscope) chlorophenyl)-7-(6- 3484, isoo, morpholinyl-3- 1o34cm-i:
MS (F~,s) pyridyl)pyrido[2,3- miz 587 (M+H)+.

d] 'dine Example 337 4-amino-5-f3-bromophenvl)-7-(5-chloro-6-morpholinyl-3-pyridyl)pyridof2 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-morpholinylpyridine, and substituting 5-acetyl-3-chloro-2-morpholinylpyridine for the 5-acetyl-2-morpholinylpyridine 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/~ 497 (M+H)+.
Example 338 4-amino-5-(3-bromophenyl)-7-(6-(N-oxidomorpholinyl)-3-pyrid3rI)pyridof2 3-dlpyrimidine 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-l3-bromophen_vl)-7-(6-(N-l2-h~yethoxveth~rl)amino)-3-~, '~dyl)pyridof2.3 dlgvrimidine Step 339a. 1'.1'-dicvano-3-bromostyrene The title compound was prepared by condensation of 3-bromobenzaldehyde with malononitrile and Mg0 in dichloromethane by the standard procedure of Broekhuis et al.
(Recl. J. R. Neth. Chem. Soc., 99: 6-12 (1980)).
Sten 339b. S-acetvl-2-(N-(2-ethox~yl)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-cyano-6-hl-(2-ethoxyeth~lamino~pvridine-2-amine t5 The title compound was prepared by condensation of I',1'-dicyano-2-bromostyrene with 5-acetyl-2-morpholinylpyridine 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-bromovhenyl,~-7-(6-(N-(2-ethoxyethvl)amino)-3-pvridvl)pvridof2,3-dlgyrimidine 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, 1120 cm-1; MS m/z 481 (M+H)+.
Example 340 4-amino-~-(3-bromophenyl)-7-(6-(N-(2-hydroxvethox3rethyl)-N-formylamino)-3 pyridvl)pyridof 2,3-dlpyrimidine This compound was isolated by chromatography as a product of the reaction described in Example 239 Step d. IR (microscope) 3306, 1679, 1596, 1577, 1548, 1493, 1352, 1125 cm-I; MS m/z 509 (M+H)+.

Example 341 4-amino-5-(3-bromophenyl)-7-(6-(N-l2-h droxyethoxyethvl)-3:gvridvl-N
oxide)gvridof2,3-dlQvrimidine 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-l; MS m/z 497 (M+H)+.
Example 342 4-amino-5-(3-bromophenvl)-7-(6-(3-hvdroxv)morpholinvl)-3-p ry-yl)pyridof2 3 d~pyrimidine 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, 1116 cm-l; MS m/z 478 (M+H)+.
Example 343 1-(5-(4-amino-5-(3-bromo~henyl)pyridof2 3-dlnvrimidin-7-yl)-2-~ 1~-'id~piperidine 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 5~6 (M+H)+.
Example 344 4-amino-5-f3-bromophenyl)-7-(6-(2-h dv rox,vlmoroholinvl)-3-pyridvl)pyridof2 3 dlpvrimidine 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. IR
(microscope) cm-1;
MS m/z 492 (M+CH30H-H20)+.
3o Example 345 4-amino-5-l3-bromonhenvl)-7-(4-methvlenvlnineridinvi)-3-nvridvl)pvridof2 3-dlnvrimidine 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-l;
MS
m/z 473 (M+H)+.

Examrle 346 4-amino-5-(3-brom~yl)-7-(4-hvdroxy-4-(~drox~et)~vl)p3ncridinvl)-3 wridvl)pvridof 2.3-dlpvrimidine The title compound was prepared from the compound of Example 345 by treatment with OsO~ 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-l; MS m/z 507 (M+H)+.
Example 347 4-amino-5-(3-bromophenyl)-7-(6-(4.4-ethylenedioxy~iperidin l~~,vridvl)pyridof dlpvrimidine Sten 347a. 1.1-dicyano-3-cyclohexvlethene 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.
Sten 347b. 2-acetvl-5-14,4-ethylenedioxypineridinvl)pyridine A sample of 2-acetyl-5-chloropyridine was treated in refluxing ethanol with 4-piperidinone ethylene ketal to give the title compound.
tep 347c. 4-amino-5-cvclohexvl-7-(6-(4 4-ethvlenedioxwineridinvll-3-p n~'dvl)pvridof2.3-dlgvrimidine 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-l;
MS m/z 447 (M+H)+.
Example 348 4-amino-5-cvclohexyl-7-(6-(4-oxo-pi eridinyl)-3~yridvl)pyridof2 3-dlgvrimidine 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-l; MS mlz 403 (M+H)+.

Example 349 4-amino-5-cvclohe~vl-7-l6-(4-methvlen~~ ridinvl)-3-g ry~'id",yl)nvridof2 3-dlgmirnidine 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-liminomethyl)amino-5-cvclohexyl-7-(6-dimethylamino-3-pvrid~~vridof2 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+H]+
m/z 376.

Claims (19)

WHAT IS CLAIMED IS:
1. A method for inhibiting adenosine kinase by administering a compound, or a pharmaceutically acceptable salt or amide thereof, having the formula wherein R1 and R2 are independently selected from H, loweralkyl, C1-C6alkoxyC1-C6alkyl, arylC1-C6alkyl, -C(O)C1-C6alkyl, -C(O)aryl, -C(O)heterocyclic or may join together with the nitrogen to which they are attached to form a 5-7 membered ring optionally containing 1-2 additional heteroatoms selected from O, N or S;
R3 is selected from the group consisting of loweralkyl, loweralkenyl, loweralkynyl, cycloalkyl, aryl, arylalkyl, heteroaryl, heterocyclic group, heteroarylalkyl or heterocycloalkyl wherein the heteroaryl and heterocyclic groups are linked directly or indirectly by a ring carbon;
R4 is selected from the group consisting of loweralkyl, loweralkenyl, loweralkynyl, cycloalkyl, aryl, arylalkyl, heteroaryl, heterocyclic group heteroarylalkyl or heterocycloalkyl; and a dashed line --- indicates that a double bond is optionally present provided that proper valencies are maintained, in vitro or to a mammal.
2. A method of inhibiting adenosine kinase according to Claim 1 comprising administering a compound of formula I
wherein R1 and R2 are independently selected from H, loweralkyl, arylC1-C6alkyl, -C(O)C1-C6alkyl, -C(O)aryl, -C(O)heterocyclic or may join together with the nitrogen to which they are attached to from a 5-7 membered ring optionally containing 1-2 additional heteroatoms selected from O, N or S;
R3 and R4 are independently selected from the group consisting of:

C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C8cycloalkyl.
heteroarylC0-C6alkyl or substituted heteroarylC0-C6alkyl, optionally substituted cycloalkyl, arylC0-C6alkyl or substituted arylC0-C6alkyl, heteroarylC2-C6alkenyl or substituted heteroarylC2-C6alkenyl, arylC2-C6alkenyl or substituted arylC2-C6alkenyl, heteroarylC2-C6alkynyl or substituted heteroarylC2-C6alkynyl, arylC2-C6alkynyl or substituted arylC2-C6alkynyl wherein the 1-4 heteroaryl or aryl substituents are independently selected from halogen, oxo, CO2R5, cyanoC1-C6alkyl, heteroarylC0-C6alkyl, heterocyclicC0-C6alkyl, C1-C6alkyloxy, C1-C6alkyloxyC1-C6alkyl, arylC0-C6alkyl, arylC1-C6alkyloxy, R5R6NC(O), cyano, C2-C6alkenyl, C2-C6alkynyl, C1-C6alkyl, C2-C6alkenyldialkylmalonyl, CF3, HO-, C1-C6alkyloxyC1-C6alkyloxy, C1-C6alkylSOn wherein n is 1-2, C1-C6alkylthio, C1-C6alkylacryl, CF3O, CF3, C1-C4alkylenedioxy, C1-C6alkylacryl, R5R6N(CO)NR5, N-formyl(heterocyclic), NO2, NR5R6C0-C6alkyl, (R5O)(R6O)-P(O)-C0-C6alkyl, wherein R5 and R6 are independently selected from H, C1-C6alkyl, HC(O), C1-C6alkyloxyC1-C6alkyl, C1-C6alkyloxy, C1-C6alkylC(O), CF3C(O), NR7R8C1-C6alkyl, phthalimidoC1-C6C(O), C1-C6alkylSOn where n is 1-2, CNC1-C6alkyl, R7R8NC(O)NR7-, heteroaryl, NR7R8C1-C6alkylC(O), C1-C6alkyloxycarbamidoC1-C6alkyl, wherein R7 and R8 are independently selected from those variables identified for R5 and R6 or R5 and R6 or R7 and R8 may join together with the nitrogen atom to which they are attached to form a 5-7 membered unsubstituted or substituted ring optionally containing 1-3 additional heteroatoms selected from O, N or S wherein the substituents are selected from C1-C6alkyl and a dashed line --- indicates a double bond is optionally present.
3. A method according to Claim 2 wherein the method of inhibiting adenosine kinase comprises administering a pharmaceutically effective amount of a compound of formula II
wherein R1-R8 and n are as defined above to a patient in need of treatment thereof.
4. A 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-(1-morpholinyl)-5-pyrimidinyl;
2-(1-pyrolidinyl)-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-1-yl)phenyl; 4-(methylthio)phenyl;
4-(morpholinyl)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-morpholinyl)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-morpholinylphenyl; 4-N-(2-(dimethylamino)ethyl)-N-formylamino)phenyl; 4-N-(3-methoxypropionyl)-N-isopropyl-amino)phenyl; 4-N-ethyl-N-(2-methoxyethyl)amino)phenyl; 4-N-formylpiperazinylphenyl) 4-nitrophenyl;
4-piperidinylphenyl; 4-(3-pyridyl)phenyl; 4-pyrolidinylphenyl; 4-t-butylacrylphenyl;
5-(dimethylamino)thiophene-2-yl; 5-amino-2-pyridyl; 5-dimethylamino-2-pyrazinyl;
3-dimethylaminopyridazin-6-yl; 5-dimethylamino-2-pyridyl; 5-pyrimidinylphenyl;

6-(N-methyl-N-formylamino)-3-pyridinyl; 6-(N-methyl-N-methoxyethylamino)-3-pyridinyl;
6-(2-oxo-3-oxazolidinyl)-3-pyridinyl; 6-dimethylamino-3-pyridinyl; 6-imidazolyl-3-pyridinyl;
6-morpholinyl-3-pyridinyl; 6-pyrrolidinyl-3-pyridinyl; 6-(2-propyl)-3-pyridinyl; and (4-formylamino)phenyl.
5. A method according to Claim 3 wherein R3 is selected from the group consisting of (thiophene-2-yl)methyl; (thiophene-3-yl)methyl; butyl;
cycloheptyl; pentyl;
thiophene-2-yl; 1-(3-bromophenyl)ethyl; 2-(N-phenylmethoxycarbonyl)aminophenyl;
2-(3-bromophenyl)ethyl; 2-(3-cyanophenyl)methyl; 2-(4-bromophenyl)ethyl; 2-(5-chloro-2-(thiophen-3-yl)phenyl; 2-bromophenyl; 2-furanyl; 2-methylpropyl; 2-phenylethyl;
phenylmethyl; 2,3-dimethoxyphenyl; 2,3-methylenedioxyphenyl; 3-(furan-2-yl)phenyl;
3-(thiophen-2-yl)phenyl; 3-(2-pyridyl)phenyl; 3-(3-methoxybenzyl)phenyl;
2-(3-aminopropynyl)phenylmethyl; 3-benzyloxyphenyl; 3-bromo-4-fluorophenyl; 3-bromo-5-iodophenyl; 3-bromo-5-methoxyphenyl; 3-bromophenyl; 3-bromophenyl)methyl;
3-carboxamidophenyl; 3-chlorophenyl; 3-cyanophenyl; 3-diethylmalonylallylphenyl;
3-dimethylaminophenyl; 3-ethoxyphenyl; 3-fluoro-5-trifluoromethylphenyl; 3-fluorophenyl;
3-hydroxyphenyl; 3-iodophenyl; 3-methoxyethyoxyphenyl; 3-methoxyphenyl;
3-methylphenyl; 3-methylsulfonylphenyl; 3-methylthiophenyl; 3-t-butylacrylphenyl;
3-trifloromethyoxyphenyl; 3-trifluoromethylphenyl; 3-vinylpyridinylphenyl;
3,4-dichlorophenyl; 3,4-dimethoxyphenyl; 3,4-methylenedioxyphenyl; 3,4,5-trimethoxyphenyl;
3,5-di(trifluoromethyl)phenyl; 3,5-dibromophenyl; 3,5-dichlorophenyl;
3,5-dimethoxyphenyl; 3,5-dimethylphenyl; 4-(2-propyl)phenyl; 4-(2-propyl)oxyphenyl;
4-benzyloxyphenyl; 4-bromophenyl; 4-bromothiophene-2-yl; 4-butoxyphenyl;
4-dimethylaminophenyl; 4-fluoro-3-trifluoromethylphenyl; 4-methoxyphenyl;
4-neopentylphenyl; 4-phenoxyphenyl; 5-bromothiophene-2-yl; 5-cyclohexyl; 5-cyclopropyl;
5-hexyl; 5-methyl; 5-phenyl; (2-bromo-5-chlorophenyl)methyl; (2-bromophenyl)methyl; and (5-chloro-2-(3-methoxyphenyl)phenyl)methyl.
6. A method according to Claim 1 wherein the compound is selected from:
4-amino-5-(4-dimethylaminophenyl)-7-(4-bromophenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(4-dimethylaminophenyl)-7-(4-dimethylaminophenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(4-methoxyphenyl)-7-(4-dimethylaminophenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(4-dimethylaminophenyl)-7-(4-methoxyphenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(4-(2-propyl)phenyl)-7-(4-methoxyphenyl)pyrido[2,3-d]pyrimidine;
4-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[2,3-d]pyrimidine;
4-amino-5-(4-benzyloxyphenyl)-7-(4-methoxyphenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(4-phenoxyphenyl)-7-(4-methoxyphenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(4-(2-propyl)phenyl)-7-(4-diethylmalonylallylphenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(4-(2-propyl)phenyl)-7-(4-t-butylacrylphenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(4-dimethylaminophenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3,4-dimethoxyphenyl)-7-(4-dimethylaminophenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-t-butylacrylphenyl)-7-(4-dimethylaminophenyl}pyrido[2,3-d]pyrimidine;
4-amino-5-(3-methoxyphenyl-7-(4-dimethylaminophenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3,5-dimethoxyphenyl-7-(4-dimethylaminophenyl)pyrido [2,3-d]pyrimidine;
4-amino-5-(3-diethylmalonylallylphenyl)-7-(4-dimethylaminophenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-vinylpyridinylphenyl)-7-(4-dimethylaminophenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-trifluoromethylphenyl)-7-(4-dimethylaminophenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-carboxamidophenyl)-7-(4-dimethylaminophenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-cyanophenyl)-7-(4-dimethylaminophenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-benzyloxyphenyl)-7-(4-dimethylaminophenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-methoxyphenyl)-7-(4-methoxyphenyl)pyrido[2,3-d]pyrimidine;

4-amino-5-(3-bromophenyl)-7-(4-butoxyphenyl)pyrido(2,3-d]pyrimidine;
4-amino-5-(3-(2-pyridyl)phenyl)-7-(4-dimethylaminophenyl)pyrido[2,3-d]pyrimidine;
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[2,3-d]pyrimidine;
4-amino-5-(3-ethoxyphenyl)-7-(4-dimethylaminophenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-trifloromethyoxyphenyl)-7-(4-dimethylaminophenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3,5-dichlorophenyl)-7-(4-dimethylaminophenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromo-4-fluorophenyl)-7-(4-dimethylaminophenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-hydroxyphenyl)-7-(4-dimethylaminophenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(4-morpholinylphenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(4-piperidinylphenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(4-(imidazol-1-yl)phenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(4-chlorophenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(4-isopropylphenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(4-trifluorophenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(4-diethylaminophenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(3,4,5-trimethoxyphenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-(3-methoxybenzyl)phenyl)-7-(4-dimethylaminophenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-methoxyethyoxyphenyl)-7-(4-dimethylaminophenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3,4-methylenedioxyphenyl)-7-(4-dimethylaminophenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(4-ethoxyphenyl)pyrido[2,3-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-d]pyrimidine;
4-amino-5-phenyl-7-(4-dimethylaminophenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3,4,5-trimethoxyphenyl)-7-(4-dimethylaminophenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(4-nitrophenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(4-iodophenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(3,4-methylenedioxyphenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(thiophen-2-yl)-7-(4-morpholinylphenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3,5-dimethoxyphenyl)-7-(thiophen-2-yle)pyrido[2,3-d]pyrimidine;
4-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-d] pyrimidine;
4-amino-5-(3,5-dimethoxyphenyl)-7-(4-morpholinylphenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-trifluoromethylphenyl)-7-(thiophene-2-yl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(4-aminophenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromo-4-fluorophenyl)-7-(thiophene-2-yl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromo-4-fluorophenyl)-7-(2-furanyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3,5-dimethoxyphenyl)-7-(4-iodophenyl)pyrido[2,3-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[2,3-d]pyrimidine;
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-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(4-pyrrolidinylphenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(4-bromothiophene-)-7-(4-dimethylaminophenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(4-bromothiophene-2-yl)-7-(4-morpholinylphenyl)pyrido[2,3-d]pyrimidine;
4-morpholinyl-5-(3-bromophenyl)-7-(4-dimethylaminophenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(5-bromothiophene-2-yl)-7-(4-morpholinylphenyl)pyrido[2,3-d] pyrimidine;
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-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(4-dimethylaminophenyl)pyrido[2,3-d]pyrimidine;

4-amino-5-(3,5-dimethoxyphenyl)-7-(5-pyrimidinylphenyl)pyrido [2,3-d]pyrimidine;
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-d]pyrimidine;
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-d]pyrimidine;
4-amino-5-(3-bromo-5-iodophenyl)-7-(4-(dimethylamino)phenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3,5-di(trifluoromethyl)phenyl)-7-(4-(dimethylamino)phenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3,5-di(trifluoromethyl)phenyl)-7-(4-morpholinylphenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3,5-dibromophenyl)-7-(4-(dimethylamino)phenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3,5-dibromophenyl)-7-(4-morpholinylphenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(4-bromothiophene-2-yl)-7-(4-(4-methylpiperidinyl)phenyl)pyrido[2,3 d]pyrimidine;
4-amino-5-(3,5-dibromophenyl)-7-(4-(dimethylamino)phenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(3-(dimethylamino)phenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(4-methylsulfonylphenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(3-methoxyphenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(4-(methylthio)phenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(3,4-dichlorophenyi)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(4-(N-methyl-N-formylamino)phenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(4-methylaminophenyi)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromo-4-fluorophenyl)-7-(4-methylsulfonylphenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(3-amino-4-methoxyphenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(3-bromo-4-(dimethylamino)phenyl)pyrido[2,3-d]pyrimidine;
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-d]pyrimidine:
4-amino-5-(3-bromophenyl)-7-(4-(N-ethyl-N-formylamino)phenyl)pyrido[2,3-d]pyrimidine;
4,4-bis(acetylamino)-5-(3-bromophenyl)-7-(4-(N-methyl-N-acetylamino)phenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(4-(N-acetyl-N-methylamino)phenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(4-(N-ethylamino)phenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(4-(N-methyl-N-(2-methoxyethyl)amino)phenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(4-(N-isopropylamino)phenyl)pyrido[2,3-d]pyrimidine;
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-d]pyrimidine;
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[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-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-d)pyrimidine;
4-amino-5-(3-bromophenyl)-7-(6-dimethylamino-3-pyridinyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-cyanophenyl)-7-(4-methylsulfonylphenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-cyanophenyl)-7-(4-(N-methyl-N-formylamino)-phenyl)pyrido[2,3-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-morpholinyl-3-pyridinyl)pyrido[2,3-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[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(2-(dimethylamino)-5-pyrimidinyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(2-(N-methoxyethyl-N-methyl amino)-5-pyrimidinyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(2-(N-formyl-N-methyl amino)-5-pyrimidinyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(2-(N-methylamino)5-pyrimidinyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(2-(1-pyrrolidinyl)-5-pyrimidinyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(2-(1-morpholinyl)-5-pyrimidinyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(6-(2-oxo-3-oxazolidinyl)-3-pyridinyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(2-pyridyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(3-pyridyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-(thiophen-2-yl)phenyl)-7-(4-dimethylaminophenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-(furan-2-yl)phenyl)-7-(4-dimethylaminophenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-(3-methoxyphenyl)phenyl)-7-(4-dimethylaminophenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-phenyl-7-(4-dimethylaminophenyl)pyrido[2.3-d]pyrimidine;
4-amino-5-(3-chlorophenyl)-7-(4-(morpholinyl)phenyl)pyrido[2,3-d]pyrimidine;

4-amino-5-(3-bromo-4-fluorophenyl)-7-(4-(morpholinyl)phenyl)pyrido(2,3-d]pyrimidine;
4-amino-5-(3-chlorophenyl)-7-(4-iodophenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-chlorophenyl)-7-(4-(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-d]pyrimidine;
4-amino-5-(2-phenylethyl)-7-(4-diethylaminophenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(2-methylpropyl)-7-(4-diethylaminophenyl)pyrido[2,3-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[2,3-d]pyrimidine;
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-d]pyrimidine;
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-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-d]pyrimidine;
4-amino-5-hexyl-7-(4-diethylaminophenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(2-(3-bromophenyl)ethyl)-7-(4-diethylaminophenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-((2-bromophenyl)methyl)-7-(4-diethylaminophenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-cyclopropyl-7-(4-dimethylaminophenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-cyclohexyl-7-(4-dimethylaminophenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-((2-bromo-5-chlorophenyl)methyl)-7-(4-diethylaminophenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-methyl-7-(4-diethylaminophenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(2,3-methylenedioxyphenyl)-7-(4-dimethylaminophenyl)pyrido[2,3-d]pyrimidine;
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-d]pyrimidine;
4-amino-5-(3,5-dimethylphenyl)-7-(4-dimethylaminophenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3,4-dichlorophenyl)-7-(4-dimethylaminophenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(4-fluoro-3-trifluoromethylphenyl)-7-(4-dimethylaminophenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromo-5-methoxyphenyl)-7-(4-morpholinylphenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromo-5-methoxyphenyl)-7-(4-pyrrolidinylphenyl)pyrido[2,3-d] pyrimidine;
4-amino-5-(3-bromo-5-methoxyphenyl)-7-(4-piperidinylphenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromo-5-methoxyphenyl)-7-(4-dimethylaminophenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-methylthiophenyl)-7-(4-dimethylaminophenyl)pyrido[2,3-d]pyrimidine;
4-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-d]pyrimidine;
4-amino-5-(3-methylsulfonylphenyl)-7-(4-dimethylaminophenyl)pyrido[2,3-d]pyrimidine;
4-acetylamino-5-(3-bromophenyl)-7-(4-dimethylaminophenyl)pyrido[2,3-d]pyrimidine;
4-formylamino-5-(3-bromophenyl)-7-(4-dimethylaminophenyl)pyrido[2,3-d]pyrimidine;
4-(methoxyacetyl)amino-5-(3-bromophenyl)-7-(4-diethylaminophenyl)pyrido[2,3-d]pyrimidine;
4-trifluoroacetylamino-5-(3-bromophenyl)-7-(4-dimethylaminophenyl)pyrido[2,3-d]pyrimidine;
4-pentanoylamino-5-(3-bromophenyl)-7-(4-dimethylaminophenyl)pyrido[2,3-d]pyrimidine;
4-benzoylamino-5-(3-bromophenyl)-7-(4-dimethylaminophenyl)pyrido[2,3-d]pyrimidine;
4-(N-BOC-glycyl)amino-5-(3-bromophenyl)-7-(4-dimethylaminophenyl)pyrido[2,3-d]pyrimidine;
4-(N-phthalimidylglycyl)amino-5-(3-bromophenyl)-7-(4-dimethylaminophenyl)pyrido[2,3-d]pyrimidine;

4-(ethoxycarbonyl)amino-5-(3-bromophenyl)-7-(4-dimethylaminophenyl)pyrido[2,3-d]pyrimidine;
4-(ethylaminocarbonyl)amino-5-(3-bromophenyl)-7-(4-dimethylaminophenyl)pyrido[2,3-d]pyrimidine:
4-allylamino-5-(3-bromophenyl)-7-(4-dimethylaminophenyl) pyrido[2,3-d]pyrimidine;
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[2,3-d]pyrimidine;
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[2,3-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-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(1-methyl-2-oxobenzoxazolin-6-yl)pyrido[2,3-d]pyrimidine;
4-amino-5-((5-chloro-2-(3-methoxyphenyl)phenyl)methyl)-7-(4-dimethylaminophenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-((thiophene-2-yl)methyl)-7-(4-diethylaminophenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-((thiophene-3-yl)methyl)-7-(4-diethylaminophenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-((2-bromophenyl)methyl)-7-(4-dimethylaminophenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(4-(N-formyl-N-(2-methoxyethyl)amino)phenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(4-(N-(2-methoxyethyl)amino)phenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(4-(N-methyl-N-((2-dimethylamino)ethyl)amino)phenyl)pyrido[2,3-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[2,3-d]pyrimidine;
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-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(6-(2-propyl)-3-pyridinyl)pyrido[2,3-d]pyrimidine:
4-amino-5-(3-bromophenyl)-7-(3-methyl-4-pyrrolidinylphenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(6-imidazolyl-3-pyridinyl)pyrido[2,3-d]pyrimidine;
4-amino-5-phenylmethyl-7-(4-diethylaminophenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(2-(3-aminopropynyl)phenylmethyl)-7-(4-diethylaminophenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(1-(3-bromophenyl)ethyl)-7-(4-diethylaminophenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(4-dimethylaminophenyl)-7-(4-bromophenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(2-furanyl)-7-(4-(N-morpholinyl)phenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(2-dimethylamino-5-pyrimidinyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(4-(ureido)phenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(1-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[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-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(6-(1,2,4-triazol-4-yl)-3-pyridinyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(2-morpholinyl-5-pyrimidinyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(2-thiazolyl)-7-(4-pyrrolidinylphenyl)-pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(6-pyrazolyl-3-pyridinyl))-pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(4-(1-methyl-ureido)phenyl)-pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(4-(N-methyl-N-(2-pyrimidinyl)amino)phenyl)-pyrido[2,3-d]pyrimidine:

4-amino-5-(3-bromophenyl)-7-(3-fluoro-4-(N-formyl-N-methylamino)phenyl)-pyrido[2,3-d]pyrimidine;

4-formylamino-5-(3-bromophenyl)-7-(3-fluoro-4-(N-formyl-N-methylamino)phenyl)-pyrido[2,3-d]pyrimidine;

4-amino-5-(3-bromophenyl)-7-(4-(N-methyl-N-methylsulfonylamino)-phenyl)pyrido[2,3-d]pyrimidine;

4-amino-5-(3-bromophenyl)-7-(6-(N-methyl-N-methylsulfonylamino)-3-pyridinyl)pyrido[2,3-d]pyrimidine;

4-amino-5-(3-bromophenyl)-7-(1-methyl-5-indolinyl)pyrido[2,3-d]pyrimidine;

4-amino-5-(3-bromophenyl)-7-(1-methyl-5-benzimidazolyl)pyrido[2,3-d]pyrimidine;

4-amino-5-(3-bromophenyl)-7-(6-dimethylamino-3-pyridazinyl)pyrido[2,3-d]pyrimidine;

4-amino-5-(3-bromophenyl)-7-(6-morpholinyl-3-pyridazinyl)pyrido[2,3-d]pyrimidine;

4-amino-5-(3-bromophenyl)-7-(6-pyrrolidinyl-3-pyridazinyl)pyrido[2,3-d]pyrimidine;

4-amino-5-(3-bromophenyl)-7-(5-morpholinyl-2-pyrazinyl)pyrido[2,3-d]pyrimidine;

4-amino-5-(3-bromophenyl)-7-(5-(N-(2-methoxyethyl)-N-methylamino)-2-pyrazinyl)pyrido[2,3-d]pyrimidine;

4-amino-5-(3-bromophenyl)-7-(4-(morpholinylmethyl)-phenyl)pyrido[2,3-d]pyrimidine;

4-amino-5-(3-bromophenyl)-7-(5-(N,N-bis(2-methoxyethyl)amino)-2-pyridinyl)pyrido[2,3-d]pyrimidine;

4-amino-5-(3-bromophenyl)-7-(4-(imidazolylmethyl)-phenyl)pyrido[2,3-d]pyrimidine;

4-amino-5-(3-bromophenyl)-7-(5-(1-morpholinyl)-2-pyridinyl)pyrido[2,3-d]pyrimidine;

4-amino-5-(3-bromophenyl)-7-(4-((dimethylamino)methyl)-phenyl)pyrido[2,3-d]pyrimidine;

4-amino-5-(3-bromophenyl)-7-(5-(4-hydroxy-1-piperidinyl)-2-pyridinyl)pyrido[2,3-d]pyrimidine;

4-amino-5-(3-bromophenyl)-7-(5-(N-formyl-N-methylamino)-2-pyridinyl)pyrido[2,3-d]pyrimidine;

4-amino-5-(3-bromophenyl)-7-(5-(2-propenyl)-2-pyridinyl)pyrido[2,3-d]pyrimidine;

4-amino-5-(3-bromophenyl)-7-(3-(2-methoxyethyl)-2-oxo-6-benzoxazolyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(4-(1-(N-formylamino)-ethyl)phenyl)pyrido[2,3-d]pyrimidine;
4-(methylamino)-5-(3-bromophenyl)-7-(4-dimethylaminophenyl)pyrido[2,3-d]pyrimidine hydrochloride;
4-(2-methoxyethylamino)-5-(3-bromophenyl)-7-(4-dimethylaminophenyl)pyrido[2,3-d]pyrimidine hydrochloride;
4-amino-5-(3-bromophenyl)-7-(4-(1-methyl-2-imidazolyl)phenyl)pyrido[2,3-d]pyrimidine 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-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(4-(dimethylaminoethyl)phenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(4-(3-(dimethylamino)propynyl)phenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(4-(3-amino-3-methylbutynyl)phenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(4-dimethylphosphonatophenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(4-(3-(methoxypropynyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(4-carboxyphenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(4-methyl-3-oxo-2H-4H-pyrido[3,2-b]-1,4-oxazin-7-yl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(4-(2-(dimethylamino)ethyl)-3-oxo-2H-4H-pyrido[3,2-b]-1,4-oxazin-7-yl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(2,3-dihydro-3-(dimethylaminoethyl)-2-oxobenzoxazol-6-yl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(4-methyl-3-oxo-2H-4H-benzo-1,4-oxazin-7-yl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(2,2,4-trimethyl-3-oxo-2H-4H-benzo-1,4-oxazin-7-yl)pyrido[2,3-d]pyrimidine;
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-(1-methylethyl)-2-pyridyl)pyrido[2,3-d]pyrimidine;

4-amino-5-(3-bromophenyl)-7-(5-piperidin-1-ylpyrid-2-yl)pyrido[2,3-d]pyrimidine;
4-amino-5-(1-(4-bromophenyl)ethyl)-7-(6-morpholinylpyrid-3-yl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(4-((N-formylamino)methyl)phenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(4-(1-methyl-1-(N-methylamino)ethyl)phenyl)-pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(4-( 1-(dimethylamino)-1-methylethyl)phenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(N-acetyl-5-indolinyl)pyrido[2,3-d]pyrimidine;
4-amino-5-cyclohexyl-7-(6-chloro-3-pyridyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(1-(2-bromophenyl)ethyl)-7-(6-diethylamino-3-pyridyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(1-(2-bromophenyl)ethyl)-7-(6-morpholinyl-3-pyridyl)pyrido[2,3-d]pyrimidine:
4-amino-5-(1-(2-bromophenyl)ethyl)-7-(4-(N-methyl-N-formyl)amino)-phenyl)pyrido[2,3-d)pyrimidine;
4-amino-5-cyclohexyl-7-(6-morpholinyl-3-pyridyl)pyrido[2,3-d]pyrimidine;
4-amino-5-((2-bromophenyl)methyl)-7-(6-morpholinyl-3-pyridyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(4-tetrahydropyranyl)-7-(6-morpholinyl-3-pyridyl)pyrido[2,3-d]pyrimidine;
4-amino-5-cyclohexyl-7-(6-dimethylamino-3-pyridyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(1-ethylpropyl)-7-(6-dimethylamino-3-pyridyl)pyrido[2,3-d]pyrimidine;
4-amino-5-cyclopentyl-7-(6-morpholinyl-3-pyridyl)pyrido[2,3-d]pyrimidine:
4-amino-5-cyclohexyl-7-(2-chloro-3-pyridyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3,5-dimethylcyclohexyl)-7-(6-dimethylamino-3-pyridyl)pyrido [2,3-d]pyrimidine;
4-amino-5-((N-(benzyloxycarbonyl)-4-piperidinyl)methyl)-7-(b-morpholinyl-3-pyridyl)pyrido[2,3-d]pyrimidine;
4-amino-5-cyclohexyl-7-(6-bromo-3-pyridyl)pyrido[2,3-d]pyrimidine;
4-amino-5-cyclohexyl-7-(3-cyanophenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(1-(2-bromophenyl)ethyl)-7-(6-dimethylamino-3-pyridazinyl)pyrido[2,3-d]pyrimidine:
4-amino-5-(3-bromophenyl)-7-(6-imidazolyl-3-pyridazinyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(6-(azacycloheptanyl)-3-pyridazinyl)pyrido[2,3-d]pyrimidine;

4-amino-5-(3-bromophenyl)-7-(6-(N-methyl-N-(1-methylethyl))amino)-3-pyridazinyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(1-(2-bromophenyl)ethyl)-7-(6-morpholinyl-3-pyridazinyl)pyrido[2,3-d]pyrimidine;
4-amino-5-cyclohexyl-7-(6-(4-acetylpiperazinyl)-3-pyridyl)pyrido[2,3-d)pyrimidine;
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-1,4-diazacycloheptanyl)-3-pyridyl)pyrido[2,3-d]pyrimidine;
4-amino-5-cyclohexyl-7-(6-(N-methyl-N-(2-(2-pyridyl)ethyl)amino)-3-pyridyl)pyrido[2,3-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[2,3-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-d]pyrimidine;
4-amino-5-cyclohexyl-7-(4-oxo-1-phenyl-1,3,8-triazaspiro[4.5[decan-8-yl)pyrido[2,3-d]pyrimidine;
4-amino-5-cyclohexyl-7-(6-(2-methoxymethyl)pyrrolidin-1-yl)pyridyl)pyrido[2,3-d]pyrimidine;
4-amino-5-cyclohexyl-7-(6-(N-methoxyethyl-N-propylamino)pyridyl)pyrido[2,3-d]pyrimidine;
4-amino-5-cyclohexyl-7-(N-methyl-N-(2,2-dimethoxyethyl)amino)pyrido[2,3-d]pyrimidine;
4-amino-5-cyclohexyl-7-(6-(4-(dimethylamino)piperidinyl)pyridyl)pyrido[2,3-d]pyrimidine;
4-amino-5-cyclohexyl-7-(6-(4-(aminocarbonyl))piperidinyl)pyridyl)pyrido(2,3-d]pyrimidine;
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-d]pyrimidine;
4-amino-5-cyclohexyl-7-(6-(N-methyl-N-(3-pyridylmethylamino)pyrid-3-yl)pyrido[2,3-d]pyrimidine;

4-amino-5-(1-(2-bromophenyl)ethyl)-7-(1-methyl-5-indolyl)pyrido[2,3-d]pyrimidine:
4-amino-5-(1-(2-bromophenyl)ethyl)-7-(1-methyl-2,3-dioxo-5-indolyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(3-fluoro-4-(1-morpholinyl)phenyl)pyrido[2,3-d]pyrimidine;
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-pyridyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(6-(4-oxopiperidinyl)-3-pyridyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(6-(4-formylpiperazinyl)-3-pyridyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(6-(4-methylpiperazinyl)-3-pyridyl)pyrido[2,3-d]pyrimidine:
4-amino-5-(3-bromophenyl)-7-(6-thiomorpholinyl-3-pyridyl)pyrido[2,3-d]pyrimidin;
4-amino-5-(3-bromophenyl)-7-(6-(4,4-dioxothiomorpholinyl)-3-pyridyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(2-bromophenyl)-7-(6-morpholinyl-3-pyridyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromo-4-methoxyphenyl)-7-(6-morpholinyl-3-pyridyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(4-bromophenyl)-7-(6-morpholinyl-3-pyridyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-chlorophenyl)-7-(6-morpholinyl-3-pyridyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(5-chloro-6-morpholinyl-3-pyridyl)pyrido[2,3-d]pyrimidine;
4-amine-5-(3-bromophenyl)-7-(6-(N-oxidomorpholinyl)-3-pyridyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(6-(N-(2-hydroxyethoxyethyl)amino)-3-pyridyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(6-(N-(2-hydroxyethoxyethyl)-N-formylamino)-3-pyridyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(6-(N-(2-hydroxyethoxyethyl)-3-pyridyl-N-oxide)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(6-(3-hydroxy)morpholinyl)-3-pyridyl)pyrido[2,3-d]pyrimidine;

1-(5-(4-amino-5-(3-bromophenyl)pyrido[2,3-d]pyrimidin-7-yl)-2-pyridyl)-piperidine-4-phosphate, disodium salt;
4-amino-5-(3-bromophenyl)-7-(4-methylenylpiperidinyl)-3-pyridyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(4-hydroxy-4-(hydroxymethyl)piperidinyl)-3-pyridyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(6-(4,4-ethylenedioxypiperidinyl)-3-pyridyl)pyrido[2,3-d]pyrimidine;
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[2,3-d]pyrimidine;
4-N-(iminomethyl)amino-5-cyclohexyl-7-(6-dimethylamino-3-pyridyl)pyrido[2,3-d]pyrimidine.
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, or a pharmaceutically acceptable salt or amide thereof, of formula (I) wherein R1 and R2 are independently selected from H, loweralkyl, C1-C6alkoxyC1-C6alkyl, arylC1-C6alkyl, -C(O)C1-C6alkyl, -C(O)aryl, -C(O)heterocyclic or may join together with the nitrogen to which they are attached to form a 5-7 membered ring optionally containing 1-2 additional heteroatoms selected from O, N or S;
R3 is selected from the group consisting of loweralkyl, loweralkenyl, loweralkynyl, cycloalkyl, aryl, arylalkyl, heteroaryl, heterocyclic group, heteroarylalkyl or heterocycloalkyl wherein the heteroaryl and heterocyclic groups are linked directly or indirectly by a ring carbon;
R4 is selected from the group consisting of loweralkyl, loweralkenyl, loweralkynyl, cycloalkyl, aryl, arylalkyl, heteroaryl, heterocyclic group heteroarylalkyl or heterocycloalkyl; and a dashed line --- indicates that a double bond is optionally present provided that proper valencies are maintained;
with the proviso that the compound may not be selected from the group consisting of:
(a) 4-amino-5-(4-chlorophenyl)-7-(4-nitrophenyl)pyrido[2,3-d]pyrimidine;
(b) 4-amino-5-(4-methoxyphenyl)-7-(4-nitrophenyl)pyrido[2,3-d]pyrimidine;
(c) 4-amino-5-(4-fluorophenyl}-7-(4-fluorophenyl)pyrido[2,3-d]pyrimidine;
(d) 4-amino-5-(4-chlorophenyl)-7-(4-fluorophenyl)pyrido[2,3-d]pyrimidine;
(e) 4-amino-5-phenyl-7-(4-aminophenyl)pyrido[2,3-d]pyrimidine;
(f) 4-amino-5-phenyl-7-(4-bromophenyl)pyrido[2,3-d]pyrimidine;
(g) 4-amino-5-(4-methoxyphenyl)-7-(4-aminophenyl)pyrido[2,3-d]pyrimidine;
(h) 4-amino-5-(4-methoxyphenyl)-7-(4-bromophenyl)pyrido[2,3-d]pyrimidine; and (i) 4-amino-5,7-diphenylpyrido[2,3-d]pyrimidine.
11. A compound according to Claim 10 of formula II
wherein R1 and R2 are independently selected from H, loweralkyl, arylC1-C6alkyl, -C(O)C1-C6alkyl, -C(O)aryl, -C(O)heterocyclic or may join together with the nitrogen to which they are attached to from a 5-7 membered ring optionally containing 1-2 additional heteroatoms selected from O, N or S;
R3 and R4 are independently selected from the group consisting of:
C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C8cycloalkyl, heteroarylC0-C6alkyl or substituted heteroarylC0-C6alkyl, optionally substituted cycloalkyl, arylC0-C6alkyl or substituted arylC0-C6alkyl, heteroarylC2-C6alkenyl or substituted heteroarylC2-C6alkenyl, arylC2-C6alkenyl or substituted arylC2-C6alkenyl, heteroarylC2-C6alkynyl or substituted heteroarylC2-C6alkynyl, arylC2-C6alkynyl or substituted arylC2-C6alkynyl wherein the 1-4 heteroaryl or aryl substituents are independently selected from halogen, oxo, CO2R5, cyanoC1-C6alkyl, heteroarylC0-C6alkyl, heterocyclicC0-C6alkyl, C1-C6alkyloxy, C1-C6alkyloxyC1-C6alkyl, arylC0-C6alkyl, arylC1-C6alkyloxy, R5R6NC(O), cyano, C2-C6alkenyl, C2-C6alkynyl, C1-C6alkyl, C2-C6alkenyldialkylmalonyl, CF3, HO-, C1-C6alkyloxyC1-C6alkyloxy, C1-C6alkylSO n wherein n is 1-2, C1-C6alkylthio, C1-C6alkylacryl, CF3O, CF3, C1-C4alkylenedioxy, C1-C6alkylacryl, R5R6N(CO)NR5, N-formyl(heterocyclic), NO2, NR5R6C0-C6alkyl, (R5O)(R6O)-P(O)- C0-C6alkyl, wherein R5 and R6 are independently selected from H, C1-C6alkyl, HC(O), C1-C6alkyloxyC1-C6alkyl, C1-C6alkyloxy, C1-C6alkylC(O), CF3C(O), NR7R8C1-C6alkyl, phthalimidoC1-C6C(O), C1-C6alkylSO n where n is 1-2, CNC1-C6alkyl, R7R8NC(O)NR7-, heteroaryl, NR7R8C1-C6alkylC(O), C1-C6alkyloxycarbamidoC1-C6alkyl, wherein R7 and R8 are independently selected from those variables identified for R5 and R6 or R5 and R6 or R7 and R8 may join together with the nitrogen atom to which they are attached to form a 5-7 membered unsubstituted or substituted ring optionally containing 1-3 additional heteroatoms selected from O, N or S wherein the substituents are selected from C1-C6alkyl and with the proviso that the compound may not be selected from the group consisting of:
(a) 4-amino-5-(4-chlorophenyl)-7-(4-nitrophenyl)pyrido[2,3-d]pyrimidine;
(b) 4-amino-5-(4-methoxyphenyl)-7-(4-nitrophenyl)pyrido[2,3-d]pyrimidine;
(c) 4-amino-5-(4-fluorophenyl)-7-(4-fluorophenyl)pyrido[2,3-d]pyrimidine;
(d) 4-amino-5-(4-chlorophenyl)-7-(4-fluorophenyl)pyrido[2,3-d]pyrimidine;

(e) 4-amino-5-phenyl-7-(4-aminophenyl)pyrido[2,3-d]pyrimidine;
(f) 4-amino-5-phenyl-7-(4-bromophenyl)pyrido[2,3-d]pyrimidine;
(g) 4-amino-5-(4-methoxyphenyl)-7-(4-aminophenyl)pyrido[2,3-d]pyrimidine;
(h) 4-amino-5-(4-methoxyphenyl)-7-(4-bromophenyl)pyrido[2,3-d]pyrimidine; and (i) 4-amino-5,7-diphenylpyrido[2,3-d]pyrimidine.
12. A compound according to Claim 10, wherein R4 is selected from the group consisting of: phenyl; thiophene-2-yl; 3-methyl-2-oxobenzoxazolin-6-yl; 2-(dimethylamino)-5-pyrimidinyl; 2-(N-formyl-N-methyl amino)-5-pyrimidinyl; 2-(N-methoxyethyl-N-methyl amino)-5-pyrimidinyl; 2-(N-methylamino)5-pyrimidinyl; 2-(1-morpholinyl)-5-pyrimidinyl;
2-(1-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-1-yl)phenyl; 4-(methylthio)phenyl;
4-(morpholinyl)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-morpholinyl)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-morpholinylphenyl; 4-N-(2-(dimethylamino)ethyl)-N-formylamino)phenyl; 4-N-(3-methoxypropionyl)-N-isopropyl-amino)phenyl; 4-N-ethyl-N-(2-methoxyethyl)amino)phenyl; 4-N-formylpiperazinylphenyl) 4-nitrophenyl;
4-piperidinylphenyl; 4-(3-pyridyl)phenyl; 4-pyrrolidinylphenyl; 4-t-butylacrylphenyl;
5-(dimethylamino)thiophene-2-yl; 5-amino-2-pyridyl; 5-dimethylamino-2-pyrazinyl;
5-dimethylamino-2-pyridyl; 5-pyrimidinylphenyl; 6-(N-methyl-N-formylamino)-3-pyridinyl;
6-(N-methyl-N-methoxyethylamino)-3-pyridinyl; 6-(2-oxo-3-oxazolidinyl)-3-pyridinyl;
6-dimethylamino-3-pyridinyl; 6-imidazolyl-3-pyridinyl; 6-morpholinyl-3-pyridinyl;
6-pyrrolidinyl-3-pyridinyl; 6-(2-propyl)-3-pyridinyl; and (4-formylamino)phenyl.
13. A compound according to Claim 10, wherein R3 is selected from the group consisting of: (thiophene-2-yl)methyl; (thiophene-3-yl)methyl; butyl;
cycloheptyl; pentyl;
thiophene-2-yl; 1-(3-bromophenyl)ethyl; 2-(N-phenylmethoxycarbonyl)aminophenyl;
2-(3-bromophenyl)ethyl; 2-(3-cyanophenyl)methyl; 2-(4-bromophenyl)ethyl; 2-(5-chloro-2-(thiophen-3-yl)phenyl; 2-bromophenyl; 2-furanyl; 2-methylpropyl; 2-phenylethyl;
phenylmethyl; 2,3-dimethoxyphenyl; 2,3-methylenedioxyphenyl; 3-(furan-2-yl)phenyl;
3-(thiophen-2-yl)phenyl; 3-(2-pyridyl)phenyl; 3-(3-methoxybenzyl)phenyl;
2-(3-aminopropynyl)phenylmethyl; 3-benzyloxyphenyl; 3-bromo-4-fluorophenyl;
3-bromo-5-iodophenyl; 3-bromo-5-methoxyphenyl; 3-bromophenyl; 3-bromophenyl)methyl;
3-carboxamidophenyl; 3-chlorophenyl; 3-cyanophenyl; 3-diethylmalonylallylphenyl;
3-dimethylaminophenyl; 3-ethoxyphenyl; 3-fluoro-5-trifluoromethylphenyl; 3-fluorophenyl;
3-hydroxyphenyl; 3-iodophenyl; 3-methoxyethyoxyphenyl; 3-methoxyphenyl;
3-methylphenyl; 3-methylsulfonylphenyl; 3-methylthiophenyl; 3-t-butylacrylphenyl;
3-trifloromethyoxyphenyl; 3-trifluoromethylphenyl; 3-vinylpyridinylphenyl;
3,4-dichlorophenyl; 3,4-dimethoxyphenyl; 3,4-methylenedioxyphenyl; 3,4,5-trimethoxyphenyl;
3,5-di(trifluoromethyl)phenyl; 3,5-dibromophenyl; 3,5-dichlorophenyl;
3,5-dimethoxyphenyl; 3,5-dimethylphenyl; 4-(2-propyl)phenyl; 4-(2-propyl)oxyphenyl;
4-benzyloxyphenyl; 4-bromophenyl; 4-bromothiophene-2-yl; 4-butoxyphenyl;
4-dimethylaminophenyl; 4-fluoro-3-trifluoromethylphenyl; 4-methoxyphenyl;
4-neopentylphenyl; 4-phenoxyphenyl; 5-bromothiophene-2-yl; 5-cyclohexyl; 5-cyclopropyl;
5-hexyl; 5-methyl; 5-phenyl; (2-bromo-5-chlorophenyl)methyl; (2-bromophenyl)methyl; and (5-chloro-2-(3-methoxyphenyl)phenyl)methyl.
14. A compound according to Claim 10, or a pharmaceutically acceptable salt or amide thereof, which is 4-amino-5-(4-dimethylaminophenyl)-7-(4-bromophenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(4-dimethylaminophenyl)-7-(4-dimethylaminophenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(4-methoxyphenyl)-7-(4-dimethylaminophenyl)pyrido[2,3-d]pyrimidine;

4-amino-5-(4-dimethylaminophenyl)-7-(4-methoxyphenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(4-(2-propyl)phenyl)-7-(4-methoxyphenyl)pyrido[2,3-d]pyrimidine;
4-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[2,3-d]pyrimidine;
4-amino-5-(4-benzyloxyphenyl)-7-(4-methoxyphenyl)pyrido[2.3-d]pyrimidine;
4-amino-5-(4-phenoxyphenyl)-7-(4-methoxyphenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(4-(2-propyl)phenyl)-7-(4-diethylmalonylallylphenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(4-(2-propyl)phenyl)-7-(4-t-butylacrylphenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(4-dimethylaminophenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3,4-dimethoxyphenyl)-7-(4-dimethylaminophenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-t-butylacrylphenyl)-7-(4-dimethylaminophenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-methoxyphenyl-7-(4-dimethylaminophenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3,5-dimethoxyphenyl-7-(4-dimethylaminophenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-diethylmalonylallylphenyl)-7-(4-dimethylaminophenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-vinylpyridinylphenyl)-7-(4-dimethylaminophenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-trifluoromethylphenyl)-7-(4-dimethylaminophenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-carboxamidophenyl)-7-(4-dimethylaminophenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-cyanophenyl)-7-(4-dimethylaminophenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-benzyloxyphenyl)-7-(4-dimethylaminophenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-methoxyphenyl)-7-(4-methoxyphenyl)pyrido[2.3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(4-butoxyphenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-(2-pyridyl)phenyl)-7-(4-dimethylaminophenyl)pyrido[2,3-d]pyrimidine;
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[2,3-d]pyrimidine;
4-amino-5-(3-ethoxyphenyl)-7-(4-dimethylaminophenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-trifloromethyoxyphenyl)-7-(4-dimethylaminophenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3,5-dichlorophenyl)-7-(4-dimethylaminophenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromo-4-fluorophenyl)-7-(4-dimethylaminophenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-hydroxyphenyl)-7-(4-dimethylaminophenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(4-morpholinylphenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(4-piperidinylphenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(4-(imidazol-1-yl)phenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(4-chlorophenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(4-isopropylphenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(4-trifluorophenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(4-diethylaminophenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(3,4,5-trimethoxyphenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-(3-methoxybenzyl)phenyl)-7-(4-dimethylaminophenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-methoxyethyoxyphenyl)-7-(4-dimethylaminophenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3,4-methylenedioxyphenyl)-7-(4-dimethylaminophenyl)pyrido[2,3-d]Pyrimidine;
4-amino-5-(3-bromophenyl)-7-(4-ethoxyphenyl)pyrido[2,3-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-d]pyrimidine;
4-amino-5-phenyl-7-(4-dimethylaminophenyl)pyrido[2,3-d]pyrimidine;

4-amino-5-(3,4,5-trimethoxyphenyl)-7-(4-dimethylaminophenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(4-nitrophenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(4-iodophenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(3,4-methylenedioxyphenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(thiophen-2-yl)-7-(4-morpholinylphenyl)pyrido [2,3-d]pyrimidine;
4-amino-5-(3,5-dimethoxyphenyl)-7-(thiophen-2-yle)pyrido [2,3-d]pyrimidine;
4-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-d]pyrimidine;
4-amino-5-(3,5-dimethoxyphenyl)-7-(4-morpholinylphenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-trifluoromethylphenyl)-7-(thiophene-2-yl)pyrido [2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(4-aminophenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromo-4-fluorophenyl)-7-(thiophene-2-yl)pyrido [2,3-d]pyrimidine;
4-amino-5-(3-bromo-4-fluorophenyl)-7-(2-furanyl)pyrido [2,3-d]pyrimidine;
4-amino-5-(3,5-dimethoxyphenyl)-7-(4-iodophenyl)pyrido[2,3-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[2,3-d]pyrimidine;
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-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(4-pyrrolidinylphenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(4-bromothiophene-)-7-(4-dimethylaminophenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(4-bromothiophene-2-yl)-7-(4-morpholinylphenyl)pyrido[2,3-d]pyrimidine;
4-morpholinyl-5-(3-bromophenyl)-7-(4-dimethylaminophenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(5-bromothiophene-2-yl)-7-(4-morpholinylphenyl)pyrido[2,3-d]pyrimidine;
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-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(4-dimethylaminophenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3,5-dimethoxyphenyl)-7-(5-pyrimidinylphenyl)pyrido[2,3-d]pyrimidine;
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-d]pyrimidine;
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-d]pyrimidine;
4-amino-5-(3-bromo-5-iodophenyl)-7-(4-(dimethylamino)phenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3,5-di(trifluoromethyl)phenyl)-7-(4-(dimethylamino)phenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3,5-di(trifluoromethyl)phenyl)-7-(4-morpholinylphenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3,5-dibromophenyl)-7-(4-(dimethylamino)phenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3,5-dibromophenyl)-7-(4-morpholinylphenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(4-bromothiophene-2-yl)-7-(4-(4-methylpiperidinyl)phenyl)pyrido[2,3 d]pyrimidine;
4-amino-5-(3,5-dibromophenyl)-7-(4-(dimethylamino)phenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(3-(dimethylamino)phenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(4-methylsulfonylphenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(3-methoxyphenyl)pyrido[2,3-d)pyrimidine;
4-amino-5-(3-bromophenyl)-7-(4-(methylthio)phenyl)pyrido[2,3-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[2,3-d]pyrimidine;
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-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(3-amino-4-methoxyphenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(3-bromo-4-(dimethylamino)phenyl)pyrido[2,3-d]pyrimidine;
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-d]pyrimidine;

4-amino-5-(3-bromophenyl)-7-(4-(N-ethyl-N-formylamino)phenyl)pyrido[2,3-d]pyrimidine;
4,4-bis(acetylamino)-5-(3-bromophenyl)-7-(4-(N-methyl-N-acetylamino)phenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(4-(N-acetyl-N-methylamino)phenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(4-(N-ethylamino)phenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(4-(N-methyl-N-(2-methoxyethyl)amino)phenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(4-(N-isopropylamino)phenyl)pyrido[2,3-d]pyrimidine;
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-d]pyrimidine;
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[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-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-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(6-dimethylamino-3-pyridinyl)pyrido[2,3-d]pyrimidine;

4-amino-5-(3-cyanophenyl)-7-(4-methylsulfonylphenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-cyanophenyl)-7-(4-(N-methyl-N-formylamino)-phenyl)pyrido[2,3 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-morpholinyl-3-pyridinyl)pyrido[2,3-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[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(2-(dimethylamino)-5-pyrimidinyl)pyrido[2,3-d)pyrimidine;
4-amino-5-(3-bromophenyl)-7-(2-(N-methoxyethyl-N-methyl amino)-5-pyrimidinyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(2-(N-formyl-N-methyl amino)-5-pyrimidinyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(2-(N-methylamino)5-pyrimidinyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(2-(1-pyrrolidinyl)-5-pyrimidinyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(2-(1-morpholinyl)-5-pyrimidinyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(6-(2-oxo-3-oxazolidinyl)-3-pyridinyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(2-pyridyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(3-pyridyl)pyrido [2,3-d]pyrimidine;
4-amino-5-(3-(thiophen-2-yl)phenyl)-7-(4-dimethylaminophenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-(furan-2-yl)phenyl)-7-(4-dimethylaminophenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-(3-methoxyphenyl)phenyl)-7-(4-dimethylaminophenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-phenyl-7-(4-dimethylaminophenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-chlorophenyl)-7-(4-(morpholinyl)phenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromo-4-fluorophenyl)-7-(4-(morpholinyl)phenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-chlorophenyl)-7-(4-iodophenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-chlorophenyl)-7-(4-(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-d]pyrimidine;
4-amino-5-(2-phenylethyl)-7-(4-diethylaminophenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(2-methylpropyl)-7-(4-diethylaminophenyl)pyrido[2,3-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[2,3-d]pyrimidine;
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-d]pyrimidine;
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-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-d]pyrimidine;
4-amino-5-hexyl-7-(4-diethylaminophenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(2-(3-bromophenyl)ethyl)-7-(4-diethylaminophenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-((2-bromophenyl)methyl)-7-(4-diethylaminophenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-cyclopropyl-7-(4-dimethylaminophenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-cyclohexyl-7-(4-dimethylaminophenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-((2-bromo-5-chlorophenyl)methyl)-7-(4-diethylaminophenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-methyl-7-(4-diethylaminophenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(2,3-methylenedioxyphenyl)-7-(4-dimethylaminophenyl)pyrido[2,3-d]pyrimidine;
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-d]pyrimidine;
4-amino-5-(3,5-dimethylphenyl)-7-(4-dimethylaminophenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3,4-dichlorophenyl)-7-(4-dimethylaminophenyl)pyrido[2,3-d]pyrimidine;

4-amino-5-(4-fluoro-3-trifluoromethylphenyl)-7-(4-dimethylaminophenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromo-5-methoxyphenyl)-7-(4-morpholinylphenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromo-5-methoxyphenyl)-7-(4-pyrrolidinylphenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromo-5-methoxyphenyl)-7-(4-piperidinylphenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromo-5-methoxyphenyl)-7-(4-dimethylaminophenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-methylthiophenyl)-7-(4-dimethylaminophenyl)pyrido[2,3-d]pyrimidine;
4-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-d]pyrimidine;
4-amino-5-(3-methylsulfonylphenyl)-7-(4-dimethylaminophenyl)pyrido[2,3-d]pyrimidine;
4-acetylamino-5-(3-bromophenyl)-7-(4-dimethylaminophenyl)pyrido[2,3-d]pyrimidine;
4-formylamino-5-(3-bromophenyl)-7-(4-dimethylaminophenyl)pyrido[2,3-d]pyrimidine;
4-(methoxyacetyl)amino-5-(3-bromophenyl)-7-(4-diethylaminophenyl)pyrido[2,3-d]pyrimidine;
4-trifluoroacetylamino-5-(3-bromophenyl)-7-(4-dimethylaminophenyl)pyrido[2,3-d]pyrimidine;
4-pentanoylamino-5-(3-bromophenyl)-7-(4-dimethylaminophenyl)pyrido[2,3-d]pyrimidine;
4-benzoylamino-5-(3-bromophenyl)-7-(4-dimethylaminophenyl)pyrido[2,3-d]pyrimidine;
4-(N-BOC-glycyl)amino-5-(3-bromophenyl)-7-(4-dimethylaminophenyl)pyrido[2,3-d]pyrimidine;
4-(N-phthalimidylglycyl)amino-5-(3-bromophenyl)-7-(4-dimethylaminophenyl)pyrido[2,3-d]pyrimidine;
4-(ethoxycarbonyl)amino-5-(3-bromophenyl)-7-(4-dimethylaminophenyl)pyrido[2,3-d]pyrimidine;
4-(ethylaminocarbonyl)amino-5-(3-bromophenyl)-7-(4-dimethylaminophenyl)pyrido[2,3-d]pyrimidine;

4-allylamino-5-(3-bromophenyl)-7-(4-dimethylaminophenyl)pyrido[2,3-d]pyrimidine:
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[2,3-d]pyrimidine;
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[2,3-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-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(1-methyl-2-oxobenzoxazolin-6-yl)pyrido[2,3-d]pyrimidine;
4-amino-5-((5-chloro-2-(3-methoxyphenyl)phenyl)methyl)-7-(4-dimethylaminophenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-((thiophene-2-yl)methyl)-7-(4-diethylaminophenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-((thiophene-3-yl)methyl)-7-(4-diethylaminophenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-((2-bromophenyl)methyl)-7-(4-dimethylaminophenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(4-(N-formyl-N-(2-methoxyethyl)amino)phenyl)pyrido(2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(4-(N-(2-methoxyethyl)amino)phenyl)pyrido(2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(4-(N-methyl-N-((2-dimethylamino)ethyl)amino)phenyl)pyrido[2,3-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[2,3-d]pyrimidine;
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-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(6-(2-propyl)-3-pyridinyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(3-methyl-4-pyrrolidinylphenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(6-imidazolyl-3-pyridinyl)pyrido[2,3-d]pyrimidine;
4-amino-5-phenylmethyl-7-(4-diethylaminophenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(2-(3-aminopropynyl)phenylmethyl)-7-(4-diethylaminophenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(1-(3-bromophenyl)ethyl)-7-(4-diethylaminophenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(4-dimethylaminophenyl)-7-(4-bromophenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(2-furanyl)-7-(4-(N-morpholinyl)phenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(2-dimethylamino-5-pyrimidinyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(4-(ureido)phenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(1-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[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-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(6-(1,2,4-triazol-4-yl)-3-pyridinyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(2-morpholinyl-5-pyrimidinyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(2-thiazolyl)-7-(4-pyrrolidinylphenyl)-pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(6-pyrazolyl-3-pyridinyl))-pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(4-(1-methyl-ureido)phenyl)-pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(4-(N-methyl-N-(2-pyrimidinyl)amino)phenyl)-pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(3-fluoro-4-(N-formyl-N-methylamino)phenyl)-pyrido[2,3-d]pyrimidine;
4-formylamino-5-(3-bromophenyl)-7-(3-fluoro-4-(N-formyl-N-methylamino)phenyl)-pyrido[2,3-d]pyrimidine;

4-amino-5-(3-bromophenyl)-7-(4-(N-methyl-N-methylsulfonylamino)-phenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(6-(N-methyl-N-methylsulfonylamino)-3-pyridinyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(1-methyl-5-indolinyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(1-methyl-5-benzimidazolyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(6-dimethylamino-3-pyridazinyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3bromophenyl)-7-(6-morpholinyl-3-pyridazinyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(6-pyrrolidinyl-3-pyridazinyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(5-morpholinyl-2-pyrazinyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(5-(N-(2-methoxyethyl)-N-methylamino)-2-pyrazinyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(4-(morpholinylmethyl)-phenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(5-(N,N-bis(2-methoxyethyl)amino)-2-pyridinyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(4-(imidazolylmethyl)-phenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(5-(1-morpholinyl)-2-pyridinyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(4-((dimethylamino)methyl)-phenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(5-(4-hydroxy-1-piperidinyl)-2-pyridinyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(5-(N-formyl-N-methylamino)-2-pyridinyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(5-(2-propenyl)-2-pyridinyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(3-(2-methoxyethyl)-2-oxo-6-benzoxazolyl)pyrido[2,3-d]pyrimidine:
4-amino-5-(3-bromophenyl)-7-(4-(1-(N-formylamino)-ethyl)phenyl)pyrido[2,3-d]pyrimidine;

4-(methylamino)-5-(3-bromophenyl)-7-(4-dimethylaminophenyl)pyrido[2,3-d]pyrimidine hydrochloride;
4-(2-methoxyethylamino)-5-(3-bromophenyl)-7-(4-dimethylaminophenyl)pyrido[2,3-d]pyrimidine hydrochloride;
4-amino-5-(3-bromophenyl)-7-(4-(1-methyl-2-imidazolyl)phenyl)pyrido[2,3-d]pyrimidine 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-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(4-(dimethylaminoethyl)phenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(4-(3-(dimethylamino)propynyl)phenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(4-(3-amino-3-methylbutynyl)phenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(4-dimethylphosphonatophenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(4-(3-(methoxypropynyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(4-carboxyphenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(4-methyl-3-oxo-2H-4H-pyrido[3,2-b]-1,4-oxazin-7-yl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(4-(2-(dimethylamino)ethyl)-3-oxo-2H-4H-pyrido[3,2-b]-1,4-oxazin-7-yl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(2,3-dihydro-3-(dimethylaminoethyl)-2-oxobenzoxazol-6-yl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(4-methyl-3-oxo-2H-4H-benzo-1,4-oxazin-7-yl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(2,2,4-trimethyl-3-oxo-2H-4H-benzo-1,4-oxazin-7-yl)pyrido[2,3-d]pyrimidine;
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-(1-methylethyl)-2-pyridyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(5-piperidin-1-ylpyrid-2-yl)pyrido[2,3-d]pyrimidine;
4-amino-5-(1-(4-bromophenyl)ethyl)-7-(6-morpholinylpyrid-3-yl)pyrido[2,3-d]pyrimidine;

4-amino-5-(3-bromophenyl)-7-(4-((N-formylamino)methyl)phenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(4-(1-methyl-1-(N-methylamino)ethyl)phenyl)-pyrido[2.3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(4-(1-(dimethylamino)-1-methylethyl)phenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(N-acetyl-5-indolinyl)pyrido[2,3-d]pyrimidine:
4-amino-5-cyclohexyl-7-(6-chloro-3-pyridyl)pyrido[2,3-d]pyrimidine:
4-amino-5-(1-(2-bromophenyl)ethyl)-7-(6-diethylamino-3-pyridyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(1-(2-bromophenyl)ethyl)-7-(6-morpholinyl-3-pyridyl)pyrido[2,3-d]pyrimidine:
4-amino-5-(1-(2-bromophenyl)ethyl)-7-(4-(N-methyl-N-formyl)amino)-phenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-cyclohexyl-7-(6-morpholinyl-3-pyridyl)pyrido[2,3-d]pyrimidine;
4-amino-5-((2-bromophenyl)methyl)-7-(6-morpholinyl-3-pyridyl)pyrido[2,3-d]pyrimidine:
4-amino-5-(4-tetrahydropyranyl)-7-(6-morpholinyl-3-pyridyl)pyrido[2,3-d]pyrimidine:
4-amino-5-cyclohexyl-7-(6-dimethylamino-3-pyridyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(1-ethylpropyl)-7-(6-dimethylamino-3-pyridyl)pyrido[2,3-d]pyrimidine;
4-amino-5-cyclopentyl-7-(6-morpholinyl-3-pyridyl)pyrido[2,3-d]pyrimidine;
4-amino-5-cyclohexyl-7-(2-chloro-3-pyridyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3,5-dimethylcyclohexyl)-7-(6-dimethylamino-3-pyridyl)pyrido[2,3-d]pyrimidine;
4-amino-5-((N-(benzyloxycarbonyl)-4-piperidinyl)methyl)-7-(6-morpholinyl-3-pyridyl)pyrido[2,3-d]pyrimidine:
4-amino-5-cyclohexyl-7-(6-bromo-3-pyridyl)pyrido[2,3-d]pyrimidine;
4-amino-5-cyclohexyl-7-(3-cyanophenyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(1-(2-bromophenyl)ethyl)-7-(6-dimethylamino-3-pyridazinyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(6-imidazolyl-3-pyridazinyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(6-(azacycloheptanyl)-3-pyridazinyl)pyrido[2,3-d]pyrimidine:
4-amino-5-(3-bromophenyl)-7-(6-(N-methyl-N-(1-methylethyl))amino)-3-pyridazinyl)pyrido[2,3-d]pyrimidine;

4-amino-5-(1-(2-bromophenyl)ethyl)-7-(6-morpholinyl-3-pyridazinyl)pyrido[2,3-d]pyrimidine;
4-amino-5-cyclohexyl-7-(6-(4-acetylpiperazinyl)-3-pyridyl)pyrido[2,3-d]pyrimidine;
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-1,4-diazacycloheptanyl)-3-pyridyl)pyrido[2,3-d]pyrimidine;
4-amino-5-cyclohexyl-7-(6-(N-methyl-N-(2-(2-pyridyl)ethyl)amino)-3-pyridyl)pyrido[2,3-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[2,3-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-d]pyrimidine;
4-amino-5-cyclohexyl-7-(4-oxo-1-phenyl-1,3,8-triazaspiro[4.5[decan-8-yl)pyrido[2,3-d]pyrimidine;
4-amino-5-cyclohexyl-7-(6-(2-methoxymethyl)pyrrolidin-1-yl)pyridyl)pyrido[2,3-d]pyrimidine;
4-amino-5-cyclohexyl-7-(6-(N-methoxyethyl-N-propylamino)pyridyl)pyrido[2,3-d]pyrimidine;
4-amino-5-cyclohexyl-7-(N-methyl-N-(2,2-dimethoxyethyl)amino)pyrido[2,3-d]pyrimidine;
4-amino-5-cyclohexyl-7-(6-(4-(dimethylamino)piperidinyl)pyridyl)pyrido[2,3-d]pyrimidine;
4-amino-5-cyclohexyl-7-(6-(4-(aminocarbonyl))piperidinyl)pyridyl)pyrido[2,3-d]pyrimidine;
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-d]pyrimidine;
4-amino-5-cyclohexyl-7-(6-(N-methyl-N-(3-pyridylmethylamino)pyrid-3-yl)pyrido[2,3-d]pyrimidine;
4-amino-5-(1-(2-bromophenyl)ethyl)-7-(1-methyl-5-indolyl)pyrido[2,3-d]pyrimidine:

4-amino-5-(1-(2-bromophenyl)ethyl)-7-(1-methyl-2,3-dioxo-5-indolyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(3-fluoro-4-(1-morpholinyl)phenyl)pyrido[2,3-d]pyrimidine;
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-pyridyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(6-(4-oxopiperidinyl)-3-pyridyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(6-(4-formylpiperazinyl)-3-pyridyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(6-(4-methylpiperazinyl)-3-pyridyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(6-thiomorpholinyl-3-pyridyl)pyrido[2,3-d]pyrimidin;
4-amino-5-(3-bromophenyl)-7-(6-(4,4-dioxothiomorpholinyl)-3-pyridyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(2-bromophenyl)-7-(6-morpholinyl-3-pyridyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromo-4-methoxyphenyl)-7-(6-morpholinyl-3-pyridyl)pyrido[2,3 d]pyrimidine;
4-amino-5-(4-bromophenyl)-7-(6-morpholinyl-3-pyridyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-chlorophenyl)-7-(6-morpholinyl-3-pyridyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(5-chloro-6-morpholinyl-3-pyridyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(6-(N-oxidomorpholinyl)-3-pyridyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(6-(N-(2-hydroxyethoxyethyl)amino)-3-pyridyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(6-(N-(2-hydroxyethoxyethyl)-N-formylamino)-3-pyridyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(6-(N-(2-hydroxyethoxyethyl)-3-pyridyl-N-oxide)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(6-(3-hydroxy)morpholinyl)-3-pyridyl)pyrido[2,3-d]pyrimidine;
1-(5-(4-amino-5-(3-bromophenyl)pyrido[2,3-d]pyrimidin-7-yl)-2-pyridyl)-piperidine-4-phosphate, disodium salt;

4-amino-5-(3-bromophenyl)-7-(4-methylenylpiperidinyl)-3-pyridyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(4-hydroxy-4-(hydroxymethyl)piperidinyl)-3-pyridyl)pyrido[2,3-d]pyrimidine;
4-amino-5-(3-bromophenyl)-7-(6-(4,4-ethylenedioxypiperidinyl)-3-pyridyl)pyrido[2,3-d]pyrimidine;
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[2,3-d]pyrimidine;
4-N-(iminomethyl)amino-5-cyclohexyl-7-(6-dimethylamino-3-pyridyl)pyrido[2,3-d]pyrimidine.
15. A pharmaceutical composition comprising a compound according to Claim and a pharmaceutically acceptable carrier.
16. A compound of formula III
wherein X is selected from -OH or halogen and R3 and R4 are as defined above and a dashed line---indicates a double bond is optionally present.
17. A compound according to Claim 16 wherein said compound is an intermediate in a process to produce a compound according to Claim 10 or 11.
18. A process for the preparation of an adenosine kinase inhibiting compound having the formula wherein R1 and R2 are hydrogen, 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 (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 (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 wherein R1 and R2 are hydrogen, the method comprising (a) reacting a ketone having the formula R4-CO-CH3, wherein R4 is as defined above, with an dicyanoalkene compound having the formula R3-CH=C(CN)2, wherein R3 is as defined above by heating at reflux and isolating a first intermediate compound having the structure (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 (c) optionally reducing the compound from step (b) to form a partially reduced or fully reduced right side of formula I by catalytic hydrogenation.
CA002286909A 1997-04-16 1998-04-14 5,7-disubstituted 4-aminopyrido¬2,3-d|pyrimidine compounds and their use as adenosine kinase inhibitors Abandoned CA2286909A1 (en)

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ATE305303T1 (en) 2001-02-12 2005-10-15 Hoffmann La Roche 6-SUBSTITUTED PYRIDOPYRIMIDINES
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