AU7108398A - 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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AU7108398A
AU7108398A AU71083/98A AU7108398A AU7108398A AU 7108398 A AU7108398 A AU 7108398A AU 71083/98 A AU71083/98 A AU 71083/98A AU 7108398 A AU7108398 A AU 7108398A AU 7108398 A AU7108398 A AU 7108398A
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pyrido
amino
pyrimidine
bromophenyl
phenyl
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Shripad S. Bhagwat
Marlon D. Cowart
Anne Laure Grillot
Chih-Hung Lee
Jeffrey Mckie
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Abbott Laboratories
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    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • A—HUMAN NECESSITIES
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    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
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    • A—HUMAN NECESSITIES
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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
    • C07D471/04—Ortho-condensed systems

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Description

WO 98/46605 PCT/US98/07207 5,7-DISUBSTITUTED 4-AMINOPYRIDO[2,3-D]PYRIMIDINE COMPOUNDS AND THEIR USE AS ADENOSINE KINASE INHIBITORS Technical Field 5 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]pyrimnidine compounds. 10 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 15 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 20 effects, many of which are mediated through the activation of specific ectocellular receptors, termed P l receptors (Burnstock, in Cell Membrane Receptors for Drugs and Hormones, 1978, (Bolis and Straub, eds.) Raven, New York, pp. 107-118; Fredholm, et al., Pharmacol. Rev. 1994, 46: 143-156). In the central nervous system, adenosine inhibits the release of certain 25 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 30 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 35 the analgesic effects of morphine (Sweeney, et al., J. Pharmacol. Exp. Ther. 1987, 243: WO 98/46605 PCT/US98/07207 657-665). In the immune system, adenosine inhibits certain neutrophil functions and exhibits anti-inflammatory effects (Cronstein, J. Appl. Physiol. 1994, 76: 5-13). An AK inhibitor has been reported to decrease paw swelling in a model of adjuvant arthritis in rats (Firestein, et.al., Arthritis and Rheumatism, 1993, 36, S48. 5 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, 10 gastrointestinal and reproductive systems, as well as on blood cells and adipocytes. Adenosine, via its Al receptor activation on adipocytes, plays a role in diabetes by inhibiting lipolysis [Londos, et al., Proc. Natl. Acad. Sci. USA, 1980, 77, 2551. Endogenous adenosine release appears to have a role as a natural defense mechanism in various pathophysiologic conditions, including cerebral and myocardial ischemia, 15 seizures, pain, inflammation and sepsis. While adenosine is normally present at low levels in the extracellular space, its release is locally enhanced at the site(s) of excessive cellular activity, trauma or metabolic stress. Once in the extracellular space, adenosine activates specific extracellular receptors to elicit a variety of responses which tend to restore cellular function towards normal (Bruns, Nucleosides Nucleotides, 1991, 10: 931-943; Miller and 20 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 25 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 30 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 35 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, -2- WO 98/46605 PCT/US98/07207 254: 2339-2345), 5-iodotubercidin (Wotring and Townsend, Cancer Res. 1979, 39: 3018 3023) and 5'-deoxy-5-iodotubercidin (Davies, et al., Biochem. Pharmacol. 1984, 33: 347 355). Adenosine kinase is also responsible for the activation of many pharmacologically 5 active nucleosides (Miller, et al., J. Biol. Chem. 1979, 254: 2339-2345), including tubercidin, formycin, ribavirin, pyrazofurin and 6-(methylmercapto)purine riboside. These purine nucleoside analogs represent an important group of antimetabolites which possess cytotoxic, anticancer and antiviral properties. They serve as substrates for adenosine kinase and are phosphorylated by the enzyme to generate the active form. The loss of adenosine 10 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 15 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. 20 1045-1075). B.S. Hurlbert et al. (J. Med. Chem., 11: 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 25 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 30 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-amnino-5-phenyl-7-(4 aminophenyl)pyrido[2,3-d]pyrimidine, 4-amino-5-phenyl-7-(4-bromophenyl)pyrido[2,3 d]pyrimidine, 4 -amino-5-(4-methoxyphenyl)-7-(4-aminophenyl)pyrido[ 2 ,3-d]pyrimidine, 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 -3- WO 98/46605 PCT/US98/07207 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. 5 Summary Of The Invention The present invention provides for 5,7-disubstituted-4-aminopyrido[2,3 d]pyrinmidine compounds having utility as adenosine kinase inhibitors. In one aspect, the present invention provides a method of inhibiting adenosine kinase by administering a compound of formula (I) R N R 2 R 3N 6 3 N4 H 10 1
N
/
N
7
R
4 (I) wherein
R
1 and R 2 are independently selected from H, loweralkyl, C 1-C6alkoxyC 1 C6alkyl, arylC 1-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;
R
3 is selected from the group consisting of loweralkyl, loweralkenyl, loweralkynyl, cycloalkyl, aryl, arylalkyl, heteroaryl, heterocyclic group, heteroarylalkyl or heterocycloalkyl wherein the heteroaryl and heterocyclic groups are linked directly or indirectly by a ring carbon; 20 R 4 is selected from the group consisting of loweralkyl, loweralkenyl, loweralkynyl, cycloalkyl, aryl, arylalkyl, heteroaryl, heterocyclic group heteroarylalkyl or heterocycloalkyl; and a dashed line --- indicates that a double bond is optionally present provided that proper valencies are maintained. In particular, the method of inhibiting adenosine kinase comprises exposing an 25 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 30 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 -4- WO 98/46605 PCT/US98/07207 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 5 administering to the mammal a therapeutically effective amount of a compound of Formula I of the present invention. SThe 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) R IN.
R
2
R
3 4 I 3' N It " 1={4 102 N NI 7 R4 10 (I) wherein
R
1 and R 2 are independently selected from H, loweralkyl, C1-C6alkoxyC 1 C6alkyl, arylC 1 -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;
R
3 is selected from the group consisting of loweralkyl, loweralkenyl, loweralkynyl, cycloalkyl, aryl, arylalkyl, heteroaryl, heterocyclic group, heteroarylalkyl or heterocycloalkyl wherein the heteroaryl and heterocyclic groups are linked directly or indirectly by a ring carbon; 20 R 4 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-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; 30 (e) 4 -amino-5-phenyl-7-(4-amninophenyl)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 -5- WO 98/46605 PCT/US98/07207 (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. 5 In another aspect, the present invention provides a process for the preparation of adenosine kinase inhibiting compounds having the formula RI,
.R
2 R 4 I 3 / N R 4 , wherein
R
1 and R 2 are hydrogen, 10 the method comprising (a) contacting a ketone having the formula R 4
-CO-CH
3 , wherein R 4 is as defined above, with an aldehyde having the formula R 3 -CHO, wherein R 3 is as defined above and malononitrile in the presence of an ammonium salt under anhydrous conditions and isolating a first intermediate compound having the structure R3 NC 15
H
2 N N R (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. 20 Detailed Description of the Invention The present invention relates to 5,7-disubstituted-4-aminopyrido[2,3-d]pyrimidine compounds that are useful in inhibiting adenosine kinase, to pharmaceutical compositions containing such compounds, to a method of using such compounds for inhibiting adenosine 25 kinase, and to novel 5,7-disubstituted-4-aminopyrido[2,3-d]pyrimidine compounds. In one aspect, the present invention provides 5,7-disubstituted-4-aminopyrido[2,3 d]pyrimidine compounds that are adenosine kinase inhibitors. An adenosine kinase inhibitor of the present invention is a compound of the Formula I, shown above. As summarized above, the present invention relates to a method of inhibiting 30 adenosine kinase comprising administering a compound of formula I -6- WO 98/46605 PCT/US98/07207 RI. N
R
2 R N ,H 2 N N 7 R 21 N N R (I) wherein
R
1 and R 2 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 5 which they are attached to from a 5-7 membered ring optionally containing 1-2 additional heteroatoms selected from O, N or S;
R
3 and R 4 are independently selected from the group consisting of: Cl-C6alkyl, C2-C6alkenyl, 10 C2-C6alkynyl, C3-C8cycloalkyl, heteroarylCO-C6alkyl or substituted heteroarylCO-C6alkyl, optionally substituted cycloalkyl, arylCO-C6alkyl or substituted arylCO-C6alkyl, 15 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 20 halogen, oxo, CO2R 5 , cyanoC 1-C6alkyl, heteroarylCO-C6alkyl, heterocyclicCO-C6alkyl, C1-C6alkyloxy, C1-C6alkyloxyC1-C6alkyl, arylCO-C6alkyl, arylC 1-C6alkyloxy, R 5
R
6 NC(O), cyano, C2-C6alkenyl, C2-C6alkynyl, C1l-C6alkyl, C2-C6alkenyldialkylmalonyl, CF3, HO-, Cl C6alkyloxyC1-C6alkyloxy, C1-C6alkylSOn wherein n is 1-2, Cl 25 C6alkylthio, C1-C6alkylacryl, CF30, CF3, C1-C4alkylenedioxy, Cl C6alkylacryl, R 5
R
6
N(CO)NR
5 , N-formyl(heterocyclic), NO2, NR 5
R
6
CO
C6alkyl, (R 5 0)(R 6 0)-P(O)- CO-C6alkyl, wherein R 5 and R 6 are independently selected from H, C1-C6alkyl, HC(O), C l-C6alkyloxyC 1-C6alkyl, C 1-C6alkyloxy, C I 30 C6alkylC(O), CF3C(O), NR 7
R
8 C1-C6alkyl, phthalimidoC1 C6C(O), Cl1-C6alkylSOn where n is 1-2, CNC1-C6alkyl,
R
7
R
8
NC(O)NR
7 -, heteroaryl, NR 7
R
8
C
1 -C6alkylC(O), Cl C6alkyloxycarbamidoC 1-C6alkyl, -7- WO 98/46605 PCT/US98/07207 wherein R 7 and R 8 are independently selected from those variables identified for R 5 and R 6 or
R
5 and R 6 or R 7 and R 8 may join together with the nitrogen atom to which they are attached to form a 5-7 membered unsubstituted or 5 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 10 selected from a compound of formula II R INK
R
2 R3 N N R4 1 N (II) wherein R 1
-R
8 and n are as defined above. The present invention also relates to compounds of formula II with R 1
-R
8 and n as defined above with the proviso that the specific known compounds identified above for a compound of formula I are excluded. 15 In a preferred embodiment, an adenosine kinase inhibitor of the present invention is a compound of Formula (II) above, wherein R 4 is aryl or heteroaryl and substituted versions thereof. In a more preferred embodiment, an adenosine kinase inhibitor of the present invention is a compound of Formula (II) above, wherein R 4 is aryl or heteroaryl and 20 substituted versions thereof and R 3 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 R 4 is selected from the group consisting of: phenyl; thiophene-2-yl; 3-methyl-2-oxobenzoxazolin-6-yl; 2-(dimethylamino) 25 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 30 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 -8- WO 98/46605 PCT/US98/07207 (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 5 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 10 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)phenyl; 4-(5-pyrimidinyl)phenyl; 4-aminophenyl; 4-bromophenyl; 15 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-(dimethylanmino)ethyl)-N 20 formylamino)phenyl; 4-N-(3-methoxypropionyl)-N-isopropyl-an-iino)phenyl; 4-N-ethyl-N (2-methoxyethyl)amino)phenyl; 4-N-formylpiperazinylphenyl; 4-nitrophenyl; 4 piperidinylphenyl; 4-(3-pyridyl)phenyl; 4-pyrrolidinylphenyl; 4-t-butylacrylphenyl; 5 (dimethylamino)thiophene-2-yl; 5-amino-2-pyridyl; 5-dimethylamino-2-pyrazinyl; 3 dimethylaminopyridazin-6-yl; 5-dimethylamino-2-pyridyl; 5-pyrimidinylphenyl; 6-(N 25 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 kinase inhibitor of the present 30 invention is a compound of Formula (I) above, wherein R 3 is selected from the group consisting of: (thiophene-2-yl)methyl; (thiophene-3-yl)methyl; butyl; cycloheptyl; pentyl; thiophene-2-yl; 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; 35 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 -9- WO 98/46605 PCT/US98/07207 iodophenyl; 3 -bromo-5-methoxyphenyl; 3 -bromophenyl; 3-bromophenylmethyl; 3 carboxamidophenyl; 3-chlorophenyl; 3 -cyanophenyl; 3-diethylmalonylallylphenyl; 3 dimethylaminophenyl; 3-ethoxyphenyl; 3 -fluoro-5-trifluoromethylphenyl; 3-fluorophenyl; 3 hydroxyphenyl; 3-iodophenyl; 3 -methoxyethyoxyphenyl; 3-methoxyphenyl; 3 5 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 10 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. 15 Exemplary and preferred adenosine kinase inhibitor compounds of the invention utilized in the method recited herein include the compounds listed below wherein R 1 and R 2 in a compound of formula II are selected from H, the groups identified at the 5-position are included within R 3 and the groups identified at the 7-position are included within R 4 , R 5 R 8 are as described in the specific compound: 20 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 -dimethylanminophenyl)pyrido[2,3-d]pyrimidine; 4 -amino-5-( 4 -dimethylaminophenyl)-7-(4-methoxyphenyl)pyrido[2,3-d]pyrimidine; 25 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; 30 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 35 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; -10- WO 98/46605 PCTIUS98/07207 4 -arnino-5-(3,4-dimethoxyphenyl)-7-(4-dimethylam-inophenyl)pyido[2,3 dlpyrimaidine; 4 -anmino- 5 .(3.tbutylacrylphenyl)..7.(4-dim-ethylamidnophenyl)pyrido[2,3 dlpyrim-idine; 5 4 -amino..
5
.(
3 -methoxypheny1..7.(4.dimethyainopheny)pido[2,3d]pyrin-jdin; 4-amino..
5 .(3,5-dimethoxypheny1..7.(4-dimethylanminophenyl)pyrido[2,3-. dlpyrim-idine; 4 -amino- 5 -(3-diethylmalonyla11ylphenyl)..7.(4.dimethylan-inophenyl)pyrido[2,3. d]pyrimnidine; 10 4 -am-ino..
5 .(3..vinylpyridinylphenyl)..7-(4-dimethylan-inophenyl)pyrido[2,3-. dlpyrim-idine; 4 -an-ino- 5 -(3-trifluoromethylphenyl)-7(4dimethylaminophenyl)pyido[2,3 d]pyriniidine; 4 -am-ino- 5
-(
3 -carboxamidopheny).7-(4-dimethylan-inophenyl)pyrido[2,3 15 dlpyrin-lidine; 4 -amino- 5 -(3-cyanophenyl)-7-(4-dimethylanminophenyl)pyrido[12,3-dpyrimidine; 4 -amino- 5
-(
3 ..benzyloxypheny)-7-(4.dimethyaninopheny)pyrido[2,3d]pyfjn-ddne; 4 -amino..
5 .(3-methoxypheny7(4-methoxyphenyl)pyrido[2,3-d]pyrimdi 1 e; 4 -amidno-5-(3-bromopheny)-7-(4-butoxypheny)pyrido[2,3d]pfjmdine; 20 4 -amino-5-(3-(2-pyridyl)phenyl)-7.(4dimethylan-inophenyl)pyrido[2,3 d]pyrimidine; 4 -amino-5-(3-methylphenyl)-7- (4-dimethylamidnophenyl)pyrido[2,3-dlpyrin-idine; 4 -anino- 5 ..(3-chlorophenyl)..7-(4..dimethylanm±nophenyl)pyrido[2,3d]pyiidi 1 e; 4 -an-ino- 5
-(
3 .fluorophenyl)..7-(4-dimethylanminopheny1)pyrido[2,3-dlpyrimjdine; 25 4 -amiino- 5 -(3-bromopheny7(4-methoxyphenyl)pyrido[2,3-d]pyrimdine; 4 -amino- 5 -(3-methoxyphenyl)>7.(4-bromophenyl)pyrido [2,3-d]pyrimnidine; 4 -amnino-5-(3-bromophenyl)-7-phenylpyrido [2,3-dlpyrim-idine; 4-amino-5- ( 3 -bromophenyl)-7-(4-ethylphenyl)pyrido[2,3-dpyim-jdine; 4 -amino- 5 -(3-bromopheny)7(4-bromophenyl)pyrido[2,3-d]py.imidine; 30 4 ..am-ino..
5 .(3-bromophenyl).7.(4cyanophenyl)pyrido[2,3-d]py.riidin; 4 -amino- 5
-(
3 -bromopheny)7(4-hydroxyphenyl)pyrido[2,3-d]pyrimdine; 4 -amnino- 5
-(
3 .iodopheny)7(4-dimethylantinopheny)pyrido[2,3d]priidie; 4 -amino- 5
(
3 ethoxypheny>..7-(4-dimethylam-inopheny)pyrido[23d]pri-ldn; 4 -an-ino- 5
-(
3 -trifloromethyoxyphenyl)7(4-dimethylan-inophenyl)pyido[2,3 35 d]pyrim-idine; 4 -am-ino..
5 -(3,5.dichoropheny7(4dimethyaninopheny)pyrido[23d]p..jidne; WO 98/46605 PCT/US98/07207 4 -amino- 5 -(3-bromo4fluorophenyl)-7-(4-dimethylamiophenyl)pyrido[2,3. dlpyrimidine; 4 .-amiino-5-(3-hydroxyphenyl)-7-(4-dimethylam-inophenyl)pyrido [2,3-dlpyrnidine; 4 -am-ino-5-.(3-bromophenyl)-7-(4-(imidazol- 1-yl)phenyl)pyrido[2,3-d]pyrimidjne; 4-am-ino-5- (3-bromophenyl)-7- (4-chlorophenyl)pyrido[2,3-'d]pyrimidine; 4-mn--3boohnl--4iorplhnlprd[,-~yiiie 4-amino-5- ( 3 -bromophenyl)-7-(4-tifluorophenyl)pyrido[2,3-d]pyjrpiidine; 10 4-mn--3boohnl--4dehlaiohnlprd[,-~yi-iie 4 -aniino- 5
-(
3 -bromophenyl)-7-(3,4,5-timethoxyphenyl)pyrido[2,3d]py..jmidine; 4 -amino- 5 -(3-(3-methoxybenzyl)phenyl)-7-(4-dimethylaninophenyl)pyrido[2,3. dipyrimidine; 15 d~pyrimidine; 4 -amino-5-(3,4-methylenedioxyphenyl)-7-(4-dimethylamijnophenyl)pyrido[2,3 dlpyrim-idine; 4-amino-5- (3-bromophenyl)-7-(4-ethoxyphenyl)pyrido[2,3-d]pyim-idine; 4 -amino-5-(3-bromopheny1)-7-(2'-thiophene)pyrido[2,3-dlpyrimidine; 20 4 -am-ino-5-(3-bromophenyl)-7-(4-.fluorophenyl)pyrido [2,3-d]pyrimidine; 4 -amino-5-(3-dimethylanminopheny)-7-(4-dimethylaminophenyl)pyrido[2,3. d]pyrimidine; 4 -amino- 5 -phenyl-7-(4-dimethylaminophenyl)pyrido[2,3-d]pyrimidine; 4 -am-ino- 5 -(3, 4 ,5-trimethoxyphenyl)-7-(4-dimethylaminophenyl)pyirido[2,3 25 d]pyrimiddine; 4 -amino-5-(3-bromophenyl)-7-(4-nitrophenyl)pyrido[2,3-d]pyrin-idine; 4 -an-ino-5-(3-bromopheny1)-7-(4-iodophenyl)pyrido[2,3-d]pyrimjdine; 4-am-ino-.5-(3-bromophenyl)-7- (3 ,4-methylenedioxyphenyl)pyrido[2,3-d]pyrimidine; 4-am-ino-5-(thiophen-2-yl)-7- (4-morpholinylphenyl)pyrido [2,3-d]pyrimidine; 30 4-amino-5-(3 ,5-dimethoxyphenyl)-7-(thiophen-2-yle)pyrido [2,3-d]pyrimidine; 4-amino-.5-(3-bromophenyl)-7- (4-carboxam-idophenyl)pyrido[2,3-d]pyrimidine; 4 -an-dno-5-(3-bromophenyl)-7-(4-(2-methoxy)ethoxyphenyl)pyrido[2,3 dlpyrimaidine; 4 -amino- 5 -(3,5-dimethoxyphenyl)-7-(4-morpholinylphenyl)pyrido [2,3-dipyrim-idine; 35 4 -amidno-5-(3-trifluoromethylphenyl)-7-(thiophene-2-yl)pyrido [2 ,3-d] pyrimidine; 4 -amidno-5-(3-bromophenyl)-7-(4-amiinophenyl)pyrido [2,3-dlpyrim-idine; 4-amidno-5- (3-bromo-4-fluorophenyl)-7-(thiophene-2-yl)pyrido [2,3-dipyrimidine; -12- WO 98/46605 PCT/US98/07207 4-anino-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 5 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-dlpyrimidine; 10 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; 15 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; 20 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; 25 4-amino-5-(4-bromothiophene-2-yl)-7-(thiophene-2-yl)pyrido[2,3-d]pyrim-lidine; 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; 30 4-amino-5-(3,5-di(trifluoromethyl)phenyl)-7-(4-(dimethylamino)phenyl)pyrido[2,3 d]pyrimidine; 4-anino-5-(3,5-di(trifluoromethyl)phenyl)-7-(4-morpholinylphenyl)pyrido[2,3 d]pyrimidine; 4-amino-5-(3,5-dibromophenyl)-7-(4-(dimethylanino)phenyl)pyrido[2,3 35 d]pyrimidine; 4-amino-5-(3,5-dibromophenyl)-7-(4-morpholinylphenyl)pyrido[2,3-d]pyrimidine; -13- WO 98/46605 PCTIUS98/07207 4-an-ino-5-(4-bromothiophene-2-yl)-.7-(4-(4-methylpiperidinyl)phenyl)pyrido[2,3 d~pyrimidine; 4-arnno-5-(3,5-dibromophenyl)-7-(4-(dimethylamiino)phenyl)pyrido[2,3 dlpyrimidine; 5 4-amnino-5-(3-bromophenyl)-7-(3-(dimnethylamino)phenyl)pyrido [2,3-d]pyrimidine; 4-aniino-5-(3-bromophenyl)-7-(4-methylsulfonylphenyl)pyrido[2,3-dlpyrimidine; 4-am-ino-5-(3-bromophenyl)-7.-(3-methoxyphenyl)pyrido[2,3-d]pyrimidine; 4-arnino-5-(3-bromophenyl)-7-(4-(methylthio)phenyl)pyrido[2,3-d]pyrimidine; 4-amidno-5-(3-bromopheny1)-7-(3,4-dichlorophenyl)pyridoI2,3-d]pyrirnidine; 10 4-amnino-5-(3-bromophenyl)-7-(4-(N-methyl-N-formylan-ino)phenyl)pyrido[2,3 dlpyrimiddine; 4-anmino-.5-(3-bromophenyl)-7-(4-methylamiinophenyl)pyridol2,3-d]pyrirnidine; 4-am-ino-5-(3-brorno-4-fluorophenyl)-7-(4-methylsulfonylphenyl)pyrido [2,3 dlpyrimidine; 15 4-amidno-5-(3-bromophenyl)-7-(3-amiino-4-methoxyphenyl)pyridol2,3-d]pyrimidine; 4-am-ino-5-(3-bromophenyl)-7.-(3-bromo-4-(dimethylam-ino)phenyl)pyrido [2,3 dllpyrimidine; 4-amidno-5-(3-bromophenyl)-7-(3-methyl-4-(dimethylamino)phenyl)pyrido[2,3 d~pyrimidline; 20 4-amino-5-(3-bromophenyl)-7-(4- (N-methyl-N trifluoroacetylamino)phenyl)pyrido [2,3-dlpyrimiddine; 4-amidno-5- (3-bromophenyl)-7-(4-(dimethylamidno)-3-fiuorophenyl)pyrido[2,3 dlpyrimiddine; 4-amiino-5-(3-bromophenyl)-7-(4-(N-ethyl-N-formylarnino)phenyl)pyrido[2,3 25 d]pyrimidine; 4,4-bis(acetylan-iino)-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 dlpyrimiddine; 30 4-amino-5-(3-bromophenyl)-7-(4-(N-ethylamino)phenyl)pyrido[2,3-dlpyrimidine; 4-amino-5-(3-bromophenyl)-7-(4-(N-methyl-N-(2 methoxyethyl)amino)phenyl)pyrido[2,3-dlpyrimiddine; 4-amino-5-(3-bromophenyl)-7-(4-(N-isopropylamino)phenyl)pyrido [2,3 dilpyrimidine; 35 4-amino-5-(3-bromophenyl)-7-(4-N-ethyl-N-(2 methoxyethyl)am-ino)phenyl)pyrido[2,3-dlpyrimiddine; -14- WO 98/46605 PCT/US98/07207 4-amino-5-(3-bromophenyl)-7-(4-N-(3-methoxypropionyl)-N-isopropyl aniino)pheny1)pyridoI[2,3-dlpyimiddine; 4-amino-5-(3-bromophenyl)-7-(4-N-(2-(dimethylamino)ethyl)-N formylamino)phenyl)pyrido[2,3-d]pyrimiddine; 5 4-arnino-5-(3-bromophenyl)-7-(4-(N-(2 (dimethylamidno)ethyl)amino)phenyl)pyrido [2,3-dipyrimridine; 4-am-ino-5-(3-bromophenyl)-7- (4-(N-methyl-N-(2 cyano)ethylam-ino)phenyl)pyrido[2,3-d]pyrimiddine; 4-an-ino-5-(3-bromophenyl)-7-(4-(N-methyl-N-(3 10 methoxy)propionylamino)phenyl)pyrido[2,3-dlpyrim-idine; 4- amino- 5-(3-bromophenyl)-7 -(3-methyl-4-(N-formyl-N methylamidno)phenyl)pyrido[2,3-dlpyrimidine; 4-am-ino-5-(3-bromophenyl)-7-(3-methyl-4-(N-methylamino)phenyl)pyrido[ 2
,
3 dipyrimidine; 15 4-ami no-5-(3-bromophenyl)-7-(4-(4-methoxy-2-butyl)phenyl)pyrido[2,3 d]pyrimidine; 4-arniino-5- (3-bromophenyl)-7-(4- (N-methyl-N-(2-(N phthalimidyl)acetyl)amino)phenyl)pyrido[2,3-dlpyrimiddine; 4-amidno-5-(3-bromophenyl)-7- (3-methyl-4-(N-methyl-N 20 (trifluoroacetyl)amino)phenyl)pyrido[2,3-d]pyrimidine; 4-am-ino-5.-(3-bromophenyl)-7-(3-methyl-4-(N-acetyl-N methylam-ino)phenyl)pyrido[2,3-dlpyrimidine; 4-an-ino-5-(3-bromophenyl)-7-(6-dimethylam-ino-3-pyridinyl)pyrido[ 2
,
3 dilpyrimidine; 25 4-aniino-5-(3-cyanopheny1)-7-(4-methylsulfonylphenyl)pyrido[2,3-d]pyrin-idile; 4-amidno-5-(3-cyanophenyl)-7-(4-(N-methyl-N-formylamino)-phelyl)pyrido[ 2
,
3 d]pyrimidine; 4-anmino-5-(3-bromophenyl)-7-(6-(N-methyl-N-formylamino)-3 pyridinyl)pyrido[2,3-dlpyrimidine; 30 4-arnino-5- (3-bromophenyl)-7-(6-morpholinyl-3-pyridinyl)pyrido [2,3-dlpyrimidine; 4-amidno-5-(3-bromophenyl)-7-(6-(N-methyl-N-methoxyethylano)-3 pyridinyl)pyrido[2,3-dlpyrimidine; 4- amino- 5-(3 -bromophenyl)-7 -(6-pyrroliclinyl-3-pyridinyl)pyrido[2,3-dI pyrimidile; 4-am-ino-5-(3-bromophenyl)-7-(2- (dimethylamino)-5-pyrimidinyl)pyrido[2,3 3-5 dlpyrim-idine; 4-amino-5-(3-bromophenyl)-7-(2- (N-methoxyethyl-N-methyl amino)-5 pyrimnidinyl)pyrido[2,3-dlpyrirnidine; -15- WO 98/46605 PCT/US98/07207 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 dipyrimidine; 5 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 10 dlpyrimidine; 4-amino-5-(3-bromophenyl)-7-(2-pyridyl)pyrido[2,3-d]pyrimidine; 4-amino-5-(3-bromophenyl)-7-(3-pyridyl)pyrido[2,3-d]pyrimidine; 4-amino-5-(3-(thiophen-2-yl)phenyl)-7-(4-dimethylaminophenyl)pyrido[2,3 d]pyrimidine; 15 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; 20 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; 25 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; 30 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-anino-5-(2-(4-bromophenyl)ethyl)-7-(4-diethylaminophenyl)pyrido[2,3 d]pyrimidine; 35 4-amino-5-(butyl)-7-(4-dimethylaminophenyl)pyrido[2,3-dipyrimidine; 4-amino-5-(2-(3-cyanophenyl)methyl)-7-(4-dimethylaminophenyl)pyrido[2,3 d]pyrimidine; -16- WO 98/46605 PCT/US98/07207 4-amino-5-(2-(N-phenylmethoxycarbonyl)aminoethyl)-7-(4 dimethylaminophenyl)pyrido[2,3-dlpyimiidine; 4-am-ino-5-(cycloheptyl)-7-(4-dimethylaniinophenyl)pyridol2,3-d]pyrimidine; 4-amino-5-(2-(5-chloro-2-(thiophen-3-yl)phenylmethyl)-7-(4 5 dimethylam-inophenyl)pyrido[2,3-d]pyrimidine; 4-amino-5-(pentyl)-7-(4-diethylaniinophenyl)pyrido[2,3-d]pyrimidine; 4-amidno-5-hexyl-7-(4-diethylaminophenyl)pyrido [2,3-dipyrim-idine; 4-amino-5-(2-(3-bromophenyl)ethyl)-7- (4-diethylam-inophenyl)pyrido[2,3 dlpyrimidine; 10 4-am-ino-5-((2-bromophenyl)methyl)-7-(4-diethylamidnophenyl)pyrido[2,3 d~pyrimidine; 4-am-ino-5-cyclopropyl-7-(4-dimethylaminophenyl)pyrido[2,3-djpyrimidine; 4-amino-5-cyclohexyl-7-(4-dimnethylan-linophenyl)pyrido [2,3-dilpyrimidine; 4-amino-5-((2-bromo-5-.chlorophenyl)methyl)-7.-(4-diethylamidnophenyl)pyrido [2,3 15 d]pyrimidine; 4-amidno-5-methyl-7- (4-diethylaminophenyl)pyridol2,3-d]pyrimidine; 4-am-ino-5-(2,3-methylenedioxyphenyl)-7-(4-dimethylaminophenyl)pyrido [2,3 dlpyrimidinie; 4-amidno-5-(3-fluoro-5-trifluoromethylphenyl)-7-(4 20 dimethylamidnophenyl)pyrido[2,3-dlpyrimidine; 4-amino-5-(2-bromophenyl)-7-(4-dimethylaminophenyl)pyrido[2,3-dlpyrim-idine; 4-amino-5- (3 ,5-dimethylphenyl)-7-(4-dimethylaminophenyl)pyrido[2,3 d]pyriniidine; 4-amnino-5-(3,4-dichlorophenyl)-7-(4-dimethylaminophenyl)pyrido[2,3-d]pyrimidine; 25 4-amidno-5-(4-fluoro-3-trifluoromethylphenyl)-7-(4 dimethylaminophenyl)pyrido[2,3-dlpyrimiddine; 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 30 d]pyrimidine; 4-amidno-5- (3-bromo-.5-methoxyphenyl)-7-(4-piperidinylphenyl)pyrido [2,3 dlpyrim-idine; 4-amino-5-(3-bromo-5-methoxyphenyl)-7-(4-dimethylanminophenyl)pyrido[2,3 dilpyrimidine; 35 4-amino-5- (3-methylthiophenyl)-7- (4-dimethylaminophenyl)pyrido[2,3 dlpyrimidine; 4-amidno-5-(3-bromo-5-methoxyphenyl)-7- (thiophene-2-yl)pyrido [2,3-d]pyrimidine; -17- WO 98/46605 PCTIUS98/07207 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: 5 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 10 dlpyrimidine; 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; 15 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 20 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; 25 4-allylamino-5-(3-bromophenyl)-7-(4-dimethylaminophenyl) pyrido[2,3 d]pyrimidine; 4-(2-(N,N-dimethylanino)ethylamino)-5-(4-bromophenyl)-7-( 4 dimethylaminophenyl) pyrido[2,3-d]pyrimidine; 4-(4-(N,N-dimethylamino)butylamino)-5-(3-bromophenyl)-7-(4 30 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; 35 4-amino-5-(3-bromophenyl)-7-(5-amino-2-pyridyl)pyrido[2,3-dpyrimidine; 4-amino-5-(3-bromophenyl)-7-(5-dimethylamino-2-pyridyl)pyrido[2,3-d]pyrimidine; -18- WO 98/46605 PCT/US98/07207 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 5 yl)pyrido[2,3-d]pyrirmidine; 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; 10 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 15 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 dimethylanino)ethyl)amino)phenyl)pyrido[2,3-d]pyrimidine; 20 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; 25 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; 30 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 dipyrimidine; 4-amino-5-(1-(3-bromophenyl)ethyl)-7-(4-diethylaminophenyl)pyrido[2,3 35 d]pyrimidine; 4-amino-5-(4-dimethylan-inophenyl)-7-(4-bromophenyl)pyrido[2,3-d]pyrimidine; 4-amino- 5-(2-furanyl)-7-(4-(N-morpholinyl)phenyl)pyrido [2,3-d]pyrimidine; -19- WO 98/46605 PCT/US98/07207 4-amidno-5-(3-bromophenyl)-7-(2-dimethylaniino-5-pyrim-idinyl)pyrido[ 2 ,3 d]pyrimiddine; 4-amino-5-(3-bromophenyl)-7-(4-(ureido)phenyl)pyrido [2,3-d]pyrimidine; 4-amino-5-( 1 -phenylmetihyl-3-piperidinyl)-7-(4-diethylaminophenyl)pyrido[2,3 5 dllpyrirnidine; 4-amino-5-(3-bromophenyl)-7-(6-(3-methyl-5-isoxazolyl))-3 pyridinyl)pyrido[2,3-d]pyrimidine; 4- am-ino-5-(3-bromophenyl)-7-(6-chloro-3-pyridinyl)pyrido[2,3-d]pyrimidine; 4-am-ino-5-(3-bromophenyl)-7-(6-methoxy-3-pyridinyl)pyrido[2,3-d]pyrimidine; 10 4-am-ino-5-(3-bromophenyl)-7-(6-( 1,2,4-triazol-4-yl)-3-pyridinyl)pyridol2,3 dlpyrim-idine; 4-am-ino-5- (3-bromophenyl)-7-(2-morpholinyl-5-pyrimidinyl)pyrido [2,3 dilpyrim-idine; 4-amino-5-(2-thiazolyl)-7-(4-pyrrolidinylphenyl)-pyrido[2,3-d]pyrinidine; 15 4-amino-5-(3-bromophenyl)-7-(6-pyrazolyl-3-pyridinyl))-pyrido[2,3 d]pyrimidine; 4-am-ino-5-(3-bromophenyl)-7-(4-(l1-methyl-ureido)phenyl)-pyrido[2,3 dlpyrimiddine; 4-amino-5-(3-bromophenyl)-7-(4-(N-methyl-N-(2-pyrirnidinyl)amino)phenyl) 20 pyrido[2,3-d]pyrim-idine; 4-amidno-5-(3-bromophenyl)-7-(3-fluoro-4-(N-formyl-N-methylamino)phenyl) pyrido[2,3-d]pyrimidine-: 4-formnylamidno-5-(3-bromophenyl)-7-(3-fluoro-4-(N-formyl-N methylamino)phenyl)-pyrido [2,3-dlpyrim-idine; 25 4-am-ino-5-(3-bromophenyl)-7-(4-(N-methyl-N-methylsulfonylamino) phenyl)pyridolj2,3-d]pyrimidine; 4-ami no-5-(3-bromophenyl)-7-(6-(N-methyl-N-methylsulfonylam-ino)-3 pyridinyl)pyrido[2,3-d]pyrimidine; 4-arnino-5-(3-bromophenyl)-7-( 1 -methyl-5-indolinyl)pyrido[2,3-d]pyrimidine; 30 4-amidno-5-(3-bromophenyl)-7-( 1-methyl-5-benzimidazolyl)pyrido [2,3 dlpyrimidine; 4-am-ino-5-(3-bromophenyl)-7-(6-dimethylamiino-3-pyridazinyl)pyrido [2,3 dlpyrimiddine; 4- amino- 5- (3 bromop henyl)-7 -(6-morpholinyl- 3-pyridazinyl)pyrido [2,3 35 dllpyrimidine; 4- amino- 5- (3-bromophenyl) -7 -(6-pyrrolidinyl- 3-p yridazinyl)pyrido [2,3 d]pyrimidine; -20- WO 98/46605 PCT/US98/07207 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; 5 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 10 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; 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-(5-(N-formyl-N-methylamino)-2 pyridinyl)pyrido[2,3-d]pyrimidine; 4-an-ino-5-(3-bromophenyl)-7-(5-(2-propenyl)-2-pyridinyl)pyrido[ 2 ,3 20 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; 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 30 dlpyrimidine trihydrochloride; 4-amino-5-(3-bromophenyl)-7-(4-(aminomethyl)phenyl)pyrido[2,3-d]pyrimidine; 4-amino-5-(3-bromophenyl)-7-(2-bromo-4-(dimethylamino)phenyl)pyrido[2,3 dipyrimidine; 4-amino-5-(3-bromophenyl)-7-(4-(dimethylaminoethyl)phenyl)pyrido[2,3 35 d]pyrimiidine; 4-amino-5-(3-bromophenyl)-7-(4-(3-(dimethylamino)propynyl)phenyl)pyrido[2,3 dipyrimidine; -21- WO 98/46605 PCTIUS98/07207 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; 5 4-amino-5- (3-bromophenyl)-7 -(4- (3-(methoxypropynyl)pyrido[2,3-d]pyrimiddine; 4-amino-5-(3-bromophenyl)-7-(4-carboxyphenyl)pyrido[2,3-d]pyrimidine; 4-amno-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 10 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-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 20 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 25 dlpyrimidine; 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 dlpyrimidine; 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; -22- WO 98/46605 PCTIUS98/07207 4-arnino-5-cyclohexyl-7-(6-morpholinyl-3-pyridyl)pyrido [2,3-dlpyrimiddine; 4-amino-5-((2-bromopheny)methy)-7-(6-morphoiny-3-pyridyl)pyrido[ 2
,
3 djpyrimidine; 4-am-ino-5-(4-tetrahydropyranyl)-7-(6-morpholinyl-3-pyridyl)pyrido [2,3 5 djpyrimidine; 4-amino-5-cyclohexyl-7-(6-dimethylamino-3-pyridyl)pyrido [2,3-d]pyrimidine; 4-amidno-5-( 1 -ethylpropyl)-7- (6-dimethylamidno-3-pyridyl)pyrido [2,3-dlpyrimiddine; 4-amidno-5-cyclopentyl-7-(6-morpholinyl-3-pyridyl)pyrido[2,3-d]pyfilmidile; 4-amino-5-cyclohexyl-7-(2-chloro-3-pyridyl)pyrido[2,3-d]pyri-lTidfe; 10 4-am-ino-5-(3,5-dimethylcyclohexyl)-7-(6-dimethylam-ino-3-pyridyl)pyrido [2,3 dipyrimiddine; 4-amino-5-((N-(benzyloxycarbonyl)-4-piperidinyl)methyl)-7-(6-morphohlyl- 3 pyridyl)pyrido[2,3-dlpyrimidine; 4-amidno-5-cyclohexyl-7- (6-bromo-3-pyridyl)pyrido[2,3-djpyrimiddifle; 15 4-amiino-5-cyclohexyl-7-(3-cyanophenyl)pyrido[2,3-d]pyim-idile; 4-amino-5- (1-(2-bromophenyl)ethyl)-7-(6-dimethylamino-3-pyridazilyl)pyrido [2,3 d]pyrimiddine; 4-amino-5-(3-bromophenyl)-7-(6-imidazolyl-3-pyridazinyl)pyido [2,3-d]pyrimidine; 4-amino-5-(3-bromophenyl)-7-(6- (azacycloheptanyl)-3-pyridazinyl)pyrido [2,3 20 dllpyimiidine; 4-amidno-5-(3-bromophenyl)-7-(6-(N-methyl-N-(l1-methylethyl))amino)-3 pyridazinyl)pyrido[2,3-d]pyrimidine; 4-amino-5-( 1-(2-bromophenyl)ethyl)-7-(6-morpholinyl-3-pyridazflyl)pyfldo[ 2
,
3 d]pyrim-idine; 25 4-anmino-5-cyclohexy1-7-(6-(4-acetylpiperaziny)-3-pyridyl)pyrido[2,3d]pyrin-lidle; 4-amino-5-cyclohexyl-7-(6-(4-acetyl- 1 ,4-diazacycloheptanyl)-3-pyridyl)pyrido[2,3 d]pyfimiddine; 4-amidno-5-cyclohexyl-7-(6-(4-methyl- 1 ,4-diazacycloheptanyl)-3 pyridyl)pyrido[2,3-dlpyriniidine; 30 4-amino-5-cyclohexyl-7-(6- (N-methyl-N-(2-(2-pyridyl)ethyl)arnino)-3 pyridyl)pyridoll2,3-dlpyrimidine; 4-am-ino-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-pyridy)pyrido[2,3-dlpyrimfidifle; 35 4-am-ino-5-cyclohexyl-7-(6-(3- (N-methylacetam-ido)pyrrolidinyl)pyridyl)pyrido[2,3 dlpyrimidine; -23- WO 98/46605 PCTIUS98/07207 4-amino-5-cyclohexyl-7-(6-(3-(formanddo)pyrolidilyl)pyfldyl)pyrido[ 2
,
3 d~pyrimidine; 4-amidno-5-cyclohexyl-7-(4-oxo- 1-phenyl- 1,3,8-triazaspiroll4.5[decan-8 yl)pyrido [2,3-d]pyrimidine; 5 4-an-ino-5-cyclohexyl-7-(6- (2-methoxymethyl)pyrrolidin- 1 -yl)pyridyl)pyrido [2,3 dlpyrimnidine; 4-amino-5-cyclohexyl-7-(6- (N-methoxyethyl-N-propylam-ino)pyridyl)pyridol 2 ,3 dilpyrimidine; 4-amino-5-cyclohexyl-7-(N-methyl-N- (2,2-dimethoxyethyl)amino)pyrido [2,3 10 d]pyrimidine; 4-anmino-5-cyclohexyl-7-(6-(4-(dimethylaio)piperidiyl)pyridyl)pyrido[ 2
,
3 dlpyrim-idine; 4-amino-5-cyclohexyl-7-(6-(4- (amidnocarbonyl))piperidinyl)pyridyl)pyrido [2,3 d]pyrirnidine; 15 4-amino-5-cyclohexyl-7-(N-methyl-N-(3-(diethylamo)propyI)amifopyrid- 3 yl)pyridoll2,3-dlpyrimidine; 4-amino-5-cyclohexyl-7-(6-(N-methyl-N-(4-pyridyl)ethylamilo)pyrid-3 yl)pyrido [2,3-dlpyrimidine; 4-amino-5-cyclohexyl-7-(6-(N-methyl-N-(3-pyridylmethylamflo)pyrid- 3 20 yl)pyrido[2,3-d]pyrimidine; 4-amino-5-( 1-(2-bromophenyl)ethyl)-7-(l1-methyl-5-indolyl)pyrido[2,3 dlpyrimidine; 4-amidno-5-(1- (2-bromophenyl)ethyl)-7-(l1-methyl-2,3-dioxo-5-indolyl)pyrido [2,3 dipyrimiddine; 25 4-amino-5-(3-bromophenyl)-7-(3-fluoro- 4 - (1-morpholinyl)phenyl)pyrido[2,3 dipyrimiddine; 4-amino-5-(3-bromopheny1)-7-(4-hydroxy-3-litrophel)pyrldo[2,3-dpyflidifle; 4-amino-5-(3-bromophenyl)-7-(6-(4,4-ethyleledioxypiperidflyl)-3 pyridyl)pyrido[2,3-dlpyrimidine; 30 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 dlpyimiddine; 4-amino-5-(3-bromophenyl)-7-(6-(4-methylpiperazilyl)-3-pyldyl)pyrido [2,3 35 dlpyrim-idine; 4-amidno-5-(3-bromophenyl)-7-(6-thiomorpholiyl-3-pyridyl)pyrdoII 2 ,3 dilpyimiddin; -24- WO 98/46605 PCT/US98/07207 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 5 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; 10 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]pyrimiidine; 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]pyrimnidin-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-amniino-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 30 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 -25- WO 98/46605 PCT/US98/07207 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 R 1 5 R 8 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; 10 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; 15 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; 20 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 25 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 30 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; 35 4-amino-5-(3-trifluoromethylphenyl)-7-(4-dimethylaminophenyl)pyrido[2,3 d]pyrimidine; -26- WO 98/46605 PCT/US98/07207 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; 5 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; 10 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]pyrinidine; 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; 15 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; 20 4-amino-5-(3-ethoxyphenyl)-7-(4-dimethylaminophenyl)pyrido[2,3-d]pyrimidine; 4-amino-5-(3-trifloromethyoxyphenyl)-7-(4-dimethylaminophenyl)pyrido[2,3 dipyrimidine; 4-amino-5-(3,5-dichlorophenyl)-7-(4-dimethylaminophenyl)pyrido[2,3-d]pyrimidine; 4-anino-5-(3-bromo-4-fluorophenyl)-7-(4-dimethylaminophenyl)pyrido[2,3 25 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; 30 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; 35 4-amino-5-(3-(3-methoxybenzyl)phenyl)-7-(4-dimethylaminophenyl)pyrido[2,3 d]pyrimidine; -27- WO 98/46605 PCT/US98/07207 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; 5 4-amino-5-(3-bromopheriyl)-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; 10 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]pyimidine; 15 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 20 d]pyrimidine; 4-amino-5-(3,5-dimethoxyphenyl)-7-(4-morpholinylphenyl)pyrido[2,3-d]pyfimidine; 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-anino-5-(3-bromo-4-fluorophenyl)-7-(thiophene-2-yl)pyrido [2,3-d]pyrimidine; 25 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-dpyrim-idine; 4-amino-5-(3,5-dimethoxyphenyl)-7-(4-(thiophene-2-yl)phenyl)pyrido[2,3 dipyrimidine; 30 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; 35 4-amino-5-(4-bromothiophene-2-yl)-7-(4-morpholinylphenyl)pyrido[ 2
,
3 d]pyrimidine; -28- WO 98/46605 PCTIUS98/07207 4-morpholinyl-5-(3-bromophenyl)-7-(4-dimethyaiinophelyl)pyrdoII 2
,
3 d~pyrimidine; 4-anmino-5-(5-bromothiophene-2-y)-7-(4-morpholiylphelyl)pyrdoII 2
,
3 d]pyrimidine; -5 4-amnino-5- (4-bromophenyl)-7-(4-dimethylalflophelyl)pyrido[ 2 ,3-dllpyrim-idine; 4-amino-5-(3-bromophenyl)-7-(4-(acetylamino)phelyl)pyrdo [2,3-dipyrimidine; 4-amino-5-(3-bromophenyl)-7 -(4-dimethylaminophenyl)pyrido [2,3-d]pyrimiddine; 4-amino-5- (3 ,5-dimethoxypheny1)-7-(5-pyimidinyphel)pyido[2,3-dpyfin-dile; 4-(4-fluorophenyl)amino)-5- (3-bromophenyl)-7- (4 10 dimethylaminophenyl)pyrido[2,3-d]pyrimiddile; 4-am-ino-5-(4-bromothiophene-2-yl)-7-(4-pyrrolidilylphelyl)pyrdo[ 2
,
3 d]pyrim-idine; 4-an-ino-5-(4-bromothiophene-2-y)-7-(thiophele-2-y)pyrido[2,3d]pyflfin-idfle; 4-amidno-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 dlpyrim-idine; 4-amnino-5- (3,5-di(trifluoromethy)pheny)-7-(4-(dimethyailo)phel)pyrido [2,3 d]pyrim-idine; 20 4-amidno-5-(3 ,5-di(trifluoromethyl)pheny)-7-(4-morphoflyphel)pyrido [2,3 dlpyrimiddine; 4-an-ino-5-(3,5-dibromophenyl)-7-(4-(dimethylaiino)phel)pyrido[ 2
,
3 dipyrimnidine; 4-am-ino-5-(3,5-dibromophenyl)-7- (4-morpholinylphenyl)pyrido[2,3-d]pytimidifle; 25 4-amino-5-(4-bromothiophene-2-yl)-7-(4-(4-methylpiperidiflyl)phelyl)pyrldo[ 2
,
3 dipyrimidine; 4-amidno-5-(3,5.dibromopheny)-7-(4-(dimethyamino)phelyl)pyrido[ 2
,
3 dlpyrimidine; 4-amino-5-(3-bromophenyl)-7-(3-(dimethylailo)phelyl)pyfldo [2,3-d]pyrimidine; 30 4-amidno-5- (3-bromophenyl)-7-(4-methylsulfonylphelyl)pyrido [2,3-d]pyrimiddine; 4- amino- 5- (3 -bromophenyl) -7 -(3 -methoxyphenyl)pyrido [2,3-d]pyrimidine; 4-amino-5-(3-bromophenyl)-7-(4-(methylthio)pheny1)pyrido[2,3-dlpyimfidile; 4-amino-5-(3-bromophenyl)-7-(3,4-dichlorophelyl)pyrido [2,3-dipyrimidine; 4-amino-5-(3-bromophenyl)-7-(4-(N-methy-N-formyaminfo)phel)pyrido[ 2 ,3 35 djpyrimiddine, 4-am-ino-5-(3-bromopheny)-7-(4-methyamiopheyl)pyrdo[2,3-d]pyriflhidine; -29- WO 98/46605 PCT/US98/07207 4-ntn--3boo4furpey)7-4mtysloypey~yio23 d~pyrimidine; 4-ndo5(-rmpey)7(-mn--mtoyhnlprd[,-lyiiie 4-am-ino-5- (3-bromopheny1)-7-(3-bromo-4-(dimethyaio)pheyl)pyrdoI 2
,
3 5 dlpyrim-idine; 4-amino-5-(3-bromophenyl)-7-(3-methy-4-(dimethyaniflo)phelyl)pyrido[ 2
,
3 dipyrimiddine; 4-an-ino-5-(3-bromophenyl)-7-(4-(N-methyl-N trifluoroacetylamino)phenyl)pyrido [2,3-dipyrirnidine; 10 4-amfino-5-(3-bromophenyl)-7- (4-(dimethylamino)-3-fluorophenyl)pyrido[2,3 dilpyrimidine; 4-ndo5(-rmpey)7(-Nehy--omlndopey~yio23 dipyrim-idine; 4,4-bis(acetylamino)-5- (3-bromophenyl)-7-(4-(N-methyl-N 15 acetylamino)phenyl)pyrido[2,3-dlpyrim-idine; 4-an-ino-5-(3-bromopheny1)-7-(4-(N-acety-N-methyanfiflo)phelyl)pyrido[ 2
,
3 dlpyrim-idine; 4-ndo5(-rmpey)7(-Nehlmn~hnlprd[,-lyiiie 4-amino-5-(3-bromophenyl)--7-(4-(N-methyl-N-( 2 20 methoxyethyl)arnino)phenyl)pyrido[2,3-dlpyrimidine; 4-amiino-5-(3-bromophenyl)-7-(4-(N-isopropyalllfo)phelyl)pyrido[ 2
,
3 d~pyrimidine; 4-amino-5-(3-bromophenyl)-7-(4-N-ethyl-N-( 2 methoxyethyl)amino)phenyl)pyrido[2,3-d]pyrimidine; 25 4-nin--3boohnl--4N-3mtoyrpoy)Niorpl amino)phenyl)pyrido[2,3-dlpyrimiddine; 4-arnno-5-(3-bromophenyl)-7-(4-N-(2-(dimethylailo)ethyl)-N formylarnino)phenyl)pyridoll2,3-d]pyrimidine; 4-amidno-5-(3-bromophenyl)-7-(4-(N-(2 30 (dimethylamino)ethyl)amidno)phenyl)pyrido[2,3-d]pyrimidile; 4-amino-5-(3-bromophenyl)-7-(4-(N-methyl-N-(2 cyano)ethylam-ino)phenyl)pyrido[2,3-dlpyrimidine; 4-am-ino-5-(3-bromophenyl)-7-(4-(N-methyl-N-(3 methoxy)propionylamino)phenyl)pyrido[2,3-d]pyrinudile; 35 4-amino-5-(3-bromophenyl)-7-(3-methyl-4-(N-formyl-N methylamino)phenyl)pyrido[2,3-dlpyrimidine; -30- WO 98/46605 PCT/US98/07207 4-amino-5-(3-bromophenyl)-7-(3-methyl-4-(N-methyla-lino)phenyl)pyrido[ 2 ,3 d]pyrimidine; 4-amino-5-(3-bromophenyl)-7-(4-(4-methoxy-2-butyl)phenyl)pyrido[2,3 dipyrimidine; 5 4-amino-5-(3-bromophenyl)-7-( 4 -(N-methyl-N-(2-(N phthalimidyl)acetyl)amino)phenyl)pyrido[2,3-d]pyfimidine; 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 10 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 15 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 20 pyridinyl)pyrido[2,3-d]pyrimidine; 4-amino-5-(3-bromophenyl)-7-(6-pyrrolidinyl-3-pyridinyl)pyrido [2,3-dpyrimidine; 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 25 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; 30 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 dipyrimidine; 4-amino-5-(3-bromophenyl)-7-(6-(2-oxo-3-oxazolidinyl)-3-pyridinyl)pyrido[2,3 35 d]pyrimidine; 4-amino-5-(3-bromophenyl)-7-(2-pyridyl)pyrido[2,3-dipyrimidine; 4-amino- 5-(3-bromophenyl)-7 -(3-pyridyl)pyrido [2,3-d]pyrinidine; -31- WO 98/46605 PCT/US98/07207 4-amino-5-(3-(thiophen-2-yl)phenyl)-7-(4-dimethylaminophenyl)pyrido[2,3 dipyrimidine; 4-amino-5-(3-(furan-2-yl)phenyl)-7-(4-dimethylaminophenyl)pyrido[2,3 d]pyrimidine; 5 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]pyrim-lidine; 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 10 djpyrimidine; 4-amino-5-(3-chlorophenyl)-7-(4-iodophenyl)pyrido [2,3-d]pyrimidine; 4-amino-5-(3-chlorophenyl)-7-(4-(thiophen-2-yl)phenyl)pyrido[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-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-anino-5-(2-phenylethyl)-7-(4-diethylaminophenyl)pyrido[2,3-d]pyrimidine; 4-amino-5-(2-methylpropyl)-7-(4-diethylaminophenyl)pyrido[2,3-dpyrimidine; 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-dlpyrimidine; 4-amino-5-(2-(3-cyanophenyl)methyl)-7-(4-dimethylaminophenyl)pyrido[2,3 25 dlpyrimidine; 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-aniino-5-((2-bromophenyl)methyl)-7-(4-diethylaminophenyl)pyrido[2,3 dlpyrimidine; 4-amino-5-cyclopropyl-7-(4-dimethylaminophenyl)pyrido[2,3-d]pyrimidine; -32- WO 98/46605 PCT/US98/07207 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; 5 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]pyrinidine; 10 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; 15 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 20 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; 25 4-anino-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; 30 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 35 d]pyrimidine; 4-trifluoroacetylamino-5-(3-bromophenyl)-7-(4-dimethylaminophenyl)pyrido[2,3 d]pyrimidine; -33- WO 98/46605 PCT/US98/07207 4 -pentanoylamino-5-(3-bromophenyl)-7-(4-dimnethylanminophenyl)pyrido[2,3 dilpyrimidine; 4 -benzoylamino-5-(3-bromophenyl)-7-(4-dimethylaniinophenyl)pyrido[2,3 dipyrimidine; 5 4- (N-B OC-glycyl)am-ino-5-(3-bromophenyl)-7-(4-dimethylaminophenyl)pyrido [2,3 dlpyrimiddine; 4- (N-.phthalim-idylglycyl)amino-5-(3-bromophenyl)-7-(4 dimethylam-inophenyl)pyrido [2,3-dlpyrim-idine; 4 -(ethoxycarbonyl)amino-5-(3-bromophenyl)-7-(4-dimethylanminphenyl)pyrido [2,3 10 dlpyrimidine; 4-(ethylaminocarbonyl)amino-5- (3-bromophenyl)-7-(4 dimethylarniinophenyl)pyrido[2,3-d]pyrimidine; 4 -allylam-ino-5-(3-bromophenyl)-7-(4-dimethylaminophenyl) pyrido[2,3 dlpyrimidine; 15 4- (2-(N,N-dimethylamino)ethylamino)-5-(4-bromophenyl)-7-(4 dimethylamidnophenyl) pyrido[2,3-d]pyrimidine; 4 -(4-(N,N-dimethylam-ino)butylamino)-5-(3-bromophenyl)-7-(4 dimethylaminophenyl) pyrido[2,3-dlpyrirnidine; 4 -(N-allyl-N-formylamino)-5-(4-dimethylarninophenyl)-7-(4 20 bromophenyl)pyrido[2,3-d]pyrirnidine; 4-diacetylamino-5-(p-dimethylaminophenyl)-7-(4 bromophenyl)pyrido[2,3-d]pyrirnidine; 4-amidno-5- (3-bromophenyl)-7-(5-aniino-2-pyridyl)pyrido[2,3-d]pyrimidine; 4 -am-ino-5-(3-bromophenyl)-7-(5-dimethylamino-2-pyridyl)pyrido[2,3-dlpyriniidine; 25 4-amino-5-(3-bromophenyl)-7-(5-dimethylam-ino-2 pyrazinyl)pyrido [2 ,3-d]pyrimidine; 4 -arnino-5-(3-bromophenyl)-7-(2-oxobenzoxazolin-6-yl)pyrido [2,3-d]pyrimidine; 4-amidno-5-(3-bromophenyl)-7-(l1-methyl-2-oxobenzoxazolin-6 yl)pyrido [2,3-d]pyrimidine; 30 4 -arnno-5-((5-chloro-2-(3-methoxyphenyl)phenyl)methyl)-7-(4 dimethylam-inophenyl)pyrido[2,3-d]pyrimidine; 4 -amnino-5-((thiophene-2-yl)methyl)-7-(4-diethylaminophenyl)pyrido [2,3 dilpyimidine; 4 -amiino-5-((thiophene-3-yl)methyl)-7-(4-diethylaminophenyl)pyrido[2,3 35 dlpyrin-iidine; 4-amino-5-((2-bromophenyl)methyl)-7 -(4-dimethylaminophenyl)pyrido[2,3 dilpyrimidine; -34- WO 98/46605 PCT/US98/07207 4-am-ino-5-(3-bromophenyl)-7-(4-(N-formyl-N-(2 methoxyethyl)amino)phenyl)pyrido[2,3-djpyrimidine; 4-amino-5-(3-bromophenyl)-7-(4-(N-(2-methoxyethyl)ami no)phenyl)pyrido[2,3 dlpyrimidine-, 5 4- amino- 5- (3- bromophenyl)-7- (4- (N-methyl-N-((2 dimethylamidno)ethyl)amidno)phenyl)pyrido[2,3-d]pyim-idine; 4-amino-5-(3-bromophenyl)-7-(4-(2 methoxy)acetylamnino)ethyl)amino)phenyl)pyrido [2,3-d]pyrim-idine; 4-am-ino-5-(3-bromophenyl)-7- ((4-formylam-ino)phenyl)pyrido [2,3-dlpyrimidine; 10 4-amino-5-(3-bromophenyl)-7-(4-(2-(dimethylamino)acetylarnino)phenyl)pyrido[2,3 dlpyrimidine; 4-am-ino-5-(3-bromophenyl)-7-(4- (2-oxo-3-oxazolidinyl)phenyl)pyrido [2,3 dlpyrimidine; 4- an-ino-5-(3-bromophenyl)-7-(6-(2-propyl)-3-pyridinyl)pyrido[2,3-dlpyrimidine; 15 4-am-ino-5-(3-bromophenyl)-7- (3-methyl-4-pyrrolidinylphenyl)pyrido[2,3 dipyrirnidine; 4-amino-5-(3-bromophenyl)-7-(6-imidazolyl-3-pyridinyl)pyrido[2,3-d]pyrimidine; 4-amiino-5-phenylmethyl-7-(4-diethylamiinophenyl)pyrido [2,3-d]pyrirnidine; 4-am-ino-5-(2-(3-am-inopropynyl)phenylmethyl)-7-(4-diethylaminophenyl)pyrido[2,3 20 dlpyrimidine; 4-am-ino-5-(1- (3-bromophenyl)ethyl)-7-(4-diethylaminophenyl)pyrido[2,3 dlpyrim-idine; 4-am-ino-5-(4-dirnethylaminophenyl)-7-(4-bromophenyl)pyrido[2,3-d]pyrimidine; 4- amino- 5- (2-furanyl)-7 -(4- (N-morpholinyl)phenyl)pyrido [2,3-d]pyimidine; 25 4-amino-5-(3-bromophenyl)-7-(2-dimethylamidno-5-pyrimidinyl)pyrido[2,3 d]pyrimidine; 4-am-ino-5- (3-bromophenyl)-7-(4-(ureido)phenyl)pyrido [2,3-d]pyrimidine; 4-amidno-5-( 1 -phenylmethyl-3-piperidinyl)-7-(4-diethylamidnophenyl)pyrido [2,3 dilpyrimidine; 30 4-amidno-5-(3-bromophenyl)-7-(6-(3-methyl-5-isoxazolyl))-3 pyridinyl)pyrido[2,3-dlpyrimidine; 4- amino- 5- (3-bromophenyl)-7 -(6-chloro-3-pyridinyl)pyrido [2,3 -dipyrim-idine; 4-am-ino-5- (3-bromophenyl)-7-(6-methoxy-3-pyridinyl)pyrido [2,3-d]pyrim-idine; 4- amino- 5 -(3-bromophenyl) -7- (6- (1 ,2,4-triazol-4- yl)- 3-p yridinyl)pyrido [2,3 35 d]pyrimidine; 4 -amidno-5-(3-bromophenyl)-7-(2-morpholinyl-5-pyrirn-dinyl)pyrido[2,3 dlpyrimidine; -35- WO 98/46605 PCT/US98/07207 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 5 d]pyrimidine: 4 -amino-5-(3-bromophenyl)-7-(4-(N-methyl-N-(2-pyrinidinyl)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; 10 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 15 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 20 d]pyrimidine; 4-amino-5-(3bromophenyl)-7-(6-morpholinyl-3-pyridazinyl)pyrido[2,3 dipyrimidine; 4 -amino-5-(3-bromophenyl)-7-(6-pyrrolidinyl-3-pyridazinyl)pyrido[2,3 dipyrimidine; 25 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 30 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 dipyrimidine; 35 4-amino-5-(3-bromophenyl)-7-(5-(1 -morpholinyl)-2-pyridinyl)pyrido[2,3 d]pyrimidine; -36- WO 98/46605 PCT/US98/07207 4-amidno-5-(3-bromophenyl)-7-(4-((dimethylamidno)methyl)-phenyl)pyrido [2,3 d]pyrimidine; 4- amino- 5- (3-bromophenyl)-7- (5- (4-hydroxy- 1 -piperidinyl)-2 pyridinvl)pyrido[2,3-d]pyrimidine; 5 4-amnino-5-(3-bromophenyl)-7-(5-(N-formnvl-N-methylamiino)-2 pyridinyl,-)pyrido72,3-d]pyrimidine; 4-amidno-5- (3-bromophenyl)-7-(5-(2-propenyl)-2-pyridinyl)pyrido[2,3 d~pyrimidine; 4-am-ino-5-(3-bromophenyl)-7-(3-(2-methoxyethyl)-2-oxo-6 10 benzoxazolyl)pyrido[2,3-d]pyrimidine; 4-amaino-5- (3-bromophenyl)-7-(4-( 1 -(N-formylamino)-ethyl)phenyl)pyrido [2,3 d]pyrimiddine; 4-(methylarnino)-5-(3-bromophenyl)-7-(4-dimethylaminophenyl)pyrido [2,3 dipyrimiddine hydrochloride; 15 4-(2-methoxyethylamino)-5-(3-bromophenyl)-7-(4 dimethylam-inophenyl)pyrido[2,3-dlpyrim-idine hydrochloride; 4-amidno-5-(3-bromophenyl)-7-(4-( 1-methyl-2-imidazolyl)phenyl)pyrido [2,3 dilpyrim-idine trihydrochioride; 4-amino-5--(3-bromophenyl)-7-(4- (aminomethyl)phenyl)pyrido [2,3-d]pyrimidine; 20 4-amidno-5-(3-bromophenyl)-7-(2-bromo-4-(dimethylamiino)phenyl)pyrido[2,3 dlpyrim-idine; 4-amino-5-(3-bromophenyl)-7-(4-(dim-ethylaminoethyl)phenyl)pyrido [2,3 d~pyrirnidine; 4-amidno-5- (3-bromophenyl)-7-(4-(3--(dimethylam-ino)propynyl)phenyl)pyrido[2,3 25 dllpyrirnidine; 4-amino-5-(3-bromophenyl)-7-(4- (3-amino-3-methylbutynyl)phenyI)pyrido[2,3 dipyrim-idine; 4-amidno-5-(3-bromophenyl)-7-(4-dimethylphosphonatophenyl)pyrido[2,3 d]pyrin-idine; 30 4-amidno-5- (3-bromophenyl)-7-(4- (3-(methoxypropynyl)pyrido[2,3-d]pyrirnidine; 4-amidno-5-(3-bromophenyl)-7-(4-carboxyphenyl)pyrido [2,3-d]pyrim-idine; 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-amidno-5-(3-bromophenyl)-7- (4-(2-(dimethylamino)ethyl)-3-oxo-2H-4H 35 pyrido[3 1.2-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]pyrim-idine; -37- WO 98/46605 PCT/US98/07207 4-amidno-5-(3-bromophenyl)-7-(4-methyl-3-oxo-2H-4H-benzo- 1 ,4-oxazin-7 yl)pyrido[2,3-d]pyrin-idine; 4-amino-5-(3-bromophenyl)-7-(2,2,4-trimethyl-3-oxo-2H-4H-benzo- 1 ,4-oxazin-7 yl)pyridoll2,3-d]pyrimidine; -5 4-am-ino-5-cyclohexyl-7-(4-(2-dimethylamino)ethyl)-2H-4H-benzo-3-oxo- 1.4 oxazin-7-yl)pyrido[2,3-d]pyrimidine; 4-arnino-5- (3-bromophenyl)-7- (5-( 1-methylethyl)-2-pyridyl)pyrido [2,3 dipyrimidine; 4-amino-5-(3-bromophenyl)-7-(5-piperidin- 1 -ylpyrid-2-yl)pyrido [2,3-d]pyrim-idine; 10 4-amino-5- (1-(4-bromophenyl)ethyl)-7-(6-morpholinylpyrid-3-yl)pyrido[2,3 dlpyrimidine; 4-arnino-5- (3-bromophenyl)-7- (4-((N-formylamino)methyl)phenyl)pyrido[2,3 dipyrim-idine; 4-amidno-5-(3-bromophenyl)-7-(4-( 1-methyl-i -(N-methylamino)ethyl)phenyl) 15 pyrido[2,3-d]pyrimiddine; 4-amidno-5- (3-bromophenyl)-7-(4-( 1-(dimethylamino)- 1 methylethyl)phenyl)pyrido[2,3-dlpyfrimidine; 4-amino-5-(3-bromophenyl)-7-(N-acetyl-5-indolinyl)pyrido [2,3-dlpyrim-idine;, 4-amnino-5-cyclohexyl-7-(6-chloro-3-pyridyl)pyrido[2,3-d]pyrimidine, 20 4-amidno-5-( 1-(2-bromophenyl)ethyl)-7-(6-diethylamino-3-pyridyl)pyrido[2,3 dlpyrimidine; 4-amino-5-(l1-(2-bromophenyl)ethyl)-7-(6-morpholinyi-3-pyridyl)pyrido [2,3 d]pyrimiddine; 4-am-ino-5-( 1-(2-bromophenyl)ethyl)-7-(4-(N-methyl-N-formnyl)amiino) 25 phenyl)pyrido[2,3-d]pyrimidine; 4-amino-5-cyclohexyl-7-(6-morpholinyl-3-pyridyl)pyrido[2,3-d]pyrin-idine; 4-amino-5-((2-bromophenyl)methyl)-7-(6-morpholinyl-3-pyridyl)pyrido [2,3 d~pyiimidine; 4-amino-5-(4-tetrahydropyranyl)-7-(6-morpholinyl-3-pyridyl)pyrido [2,3 30 dlpyfrmidine; 4-amino-5-cyclohexyl-7-(6-dimethylamiino-3-pyridyl)pyrido [2,3-d]pyrimiddine; 4-am-ino-5-( I -ethylpropyl)-7-(6-dimethylamino-3-pyridyl)pyrido[2,3-d]pyinidine; 4-amino-5-cyclopentyl-7-(6-morpholinyl-3-pyridyl)pyridol2,3-d]pyimiddine; 4-amino-5-cyclohexyl-7-(2-chloro-3-pyridyl)pyrido [2,3-dilpyrimiddine; 35 4-amino-5-(3,5-dimethylcyclohexyl)-7-(6-dimethylamiino-3-pyridyl)pyrido[2,3 dlpyrimiddine; -38- WO 98/46605 PCTIUS98/07207 4 -anmino- 5 -((N-(benzyloxycarbony1)-4-piperidinyl)methy)7(6morpholiny13. pyridyl)pyrido[2,3-d]pyrinmjdine;, 4 -an-ino- 5 -cyclohexyb7-(6-bromo-3pyridy)pyrido[2,3-d]pyjrin-dine; 4 -am-ino-5-cyclohexy1-7-(3-cyanophenyl)pyrido[2,3-djpy-imidine, 5 4-amiino-5-( 1-( 2 -bromophenyl)ethy)-7-(6-dimethyanino3pyridazinyl)pyrido[2,3 d]pyrimi dine, 4-amidno-5- ( 3 -bromophenyl)-7-.(6-imiddazolyl-3-pyridazinyl)pyrido [2,3-d]pyrimidine, 4-amino-5-(3-bromophenyl)-7-(6- (azacycloheptanyl)-3-pyridazinyl)pyrido [2,3 dlpyrimiddine; 10 4 -amino-5-(3-bromophenyl)-7-(6-(N-methybN-( 1-methylethyl))amidno)-3 pyridazinyl)pyrido[2,3-d]pyrimidine:, 4-amino-5-( 1-( 2 -bromophenyl)ethyl)-7-(6-morphoinyl-3pyridazinyl)pyrido[2,3 d]pyrimidine; 4-ndo5ccoey--6(-ctlieaznl--yiy~yio23dpfniie 15 4 -am-ino-5-cyclohexyl-7-(6-(4-acetyl. 1 , 4 -diazacycloheptanyl)-3-pyridyi)pyrido[2,3 d~pyrimidine; 4-arnino-5-cyclohexyl-7-(6- (4-methyl-i ,4-diazacycloheptanyl)-3 pyridyl)pyrido[2,3-dlpyrimidine; 4 -an-ino-5-cyclohexyl-7-(6-(N-methy[-N-(2-(2pyidyl)ethyl)aniino-3 20 pyridyl)pyrido[2,3-dlpyrimidine; 4 -amino-5-cyclohexyl-7-(6-2-(N- (N',N'-dimethylaminoethyl)-N-methylaniino)-3 pyridyl)pyrido[2,3-dlpyrirnidine; 4-nln--ylhxl7(-ztdnl3prdlprd[,-~yiiie 4-nio5ccoey--6(-Nmtylctmd yfldnlprdlprd[2,3 25 d]pyrimidine; 4 -amino-5-cyclohexyl-7-(6-(3- (formamiddo)pyrrolidinyl)pyridyl)pyrido [2,3 d~pyrimidine; 4-am-ino-5-cyclohexyl-7-(4-oxo- 1 -phenyl- 1 ,3,8-triazaspiro[4.5 [decan-8 yl)pyrido[2,3-dlpyrim-idine; 30 4 -an-iino- 5 -cyclohexyl-7-(6-(2-methoxymethyl)pyrrolidin- 1 -yl)pyridyl)pyrido[2,3 dipyrimidine; dlpyrimidine; 4 -anhino-5-cyclohexyl-7-(N-methylbN.(2,2-dimethoxyethyl)an-ino)pyrido [2,3 35 d]pyrimiddine; 4 -amino- 5 -cyclohexyl-7-(6-(4-(dimethylanno)piperidinyl)pyridyl)pyrido[2,3 d~pyrimidine; -39- WO 98/46605 PCT/US98/07207 4-amino-5-cyclohexyl-7-(6-(4- (am-inocarbonyl))piperidinyl)pyridyl)pyrido[2,3 dipyrimiddine; 4 -amino-5-cyclohexyl-7-(N-methyl-N-(3-(diethylarnino)propyl)aminopyrid-3.
yl)pyrido [2,3-dipyrimidine; 5 4 -amino-5-cyclohexyl-7-(6-(N-methyl-N-(4-pyridyl)ethylanino)pyrid-3 yl)pyrido [2,3-dlpyrimidine; 4-amino-5-cyclohexyl-7-(6- (N-methyl-N-(3-pyridylmethylamino)pyrid-3 yl)pyrido [2,3-d]pyrim-idine; 4-amino-5-(l1-(2-bromophenyl)ethyl)-7- (1-methyl-5-indolyl)pyrido [2,3 10 d]pyrirnidine; 4-am-ino-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; 15 4-arnino-5- (3-bromophenyl)-7-(4-hydroxy-3-nitrophenyl)pyrido[2,3-d]pyrin-idine; 4-amino-5-(3-bromophenyl)-7- (6-(4,4-ethylenedioxypiperidinyl)-3 pyridyl)pyridoll2,3-d]pyrim-idine; 4-amidno-5-(3-bromophenyl)-7-(6- (4-oxopiperidinyl)-3-pyridyl)pyrido[2,3 d~pyrimidine; 20 4 -amiino-5-(3-bromophenyl)-7-(6-(4-formylpiperazinyl)-3-pyridyl)pyrido[2,3 dlpyrimidine; 4 -amino-5-(3-bromophenyl)-7-(6-(4-methylpiperazinyl)-3-pyridyl)pyrido [2,3 dlpyrimiddine; 4-am-ino-5- (3-bromophenyl)-7-(6-thiomorpholinyl-3-pyridyl)pyrido [2,3 25 dlpyrimiddin; 4-amino-5-(3-bromophenyl)-7-(6-(4,4-dioxothiomorpholinyl)-3-pyridyl)pyrido [2,3 d]pyrim-idine; 4 -anmino-5-(2-bromopheny)-7-(6-morpholinyl-3-pyidyl)pyrido[2,3-d]pyimidine; 4 -an-ino-5-(3-bromo-4-methoxyphenyl)-7-(6-morpholinyl-3-pyridyl)pyrido[2,3 30 dlpyrimidine; 4 -amino-5-(4-bromophenyl)-7-(6-morpholinyl-3-pyridyl)pyrido [2,3-d]pyriridine; 4-arnno-5-(3-chlorophenyl)-7- (6-morpholinyl-3-pyridyl)pyrido [2,3-d]pyrimidine; 4 -amino-5-(3-bromophenyl)-7-(5-chloro-6-morphotinyl-3-pyridyI)pyrido[2,3 dlpyrimidine; 35 4 -amino-5-(3-bromophenyl)-7-(6-(N-oxidomorpholinyl)-3-pyridyl)pyrido[2,3. d]pyrimidine; -40- WO 98/46605 PCT/US98/07207 4-amino-5-(3-bromophenyl)-7-(6-(N-(2-hydroxyethoxyethyl)an-mino)-3 pyridyl)pyrido[2,3-d]pyrinmidine; 4 -amino-5-(3-bromophenyl)-7-(6-(N-(2-hydroxyethoxyethyl)-N-formylamino)-3 pyridyl)pyrido[2,3-d]pyrimidine; 5 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) 10 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; 15 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; 20 4 -N-(iminomethyl)amino-5-cyclohexyl-7-(6-dimethylamino-3-pyridyl)pyrido[2,3 d]pyrimnidine; 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 R 3 group when it is selected from, for example, a substituted aryl group, is having at least one substituent at the meta position. The preferred substitution pattern on the R 4 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 30 recited as above wherein, in the case of R 3 selected from substituted aryl or heteroaryl groups and R 4 selected from substituted aryl or heteroaryl groups, the substiuents on the R 3 group are meta and the substituents on the R 4 group are para. In addition, the present invention encompasses pro-drugs of the above compounds which may be active in their own right or are metabolized or converted to the non pro-drug form as exemplified above. The 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. -41- WO 98/46605 PCT/US98/07207 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 5 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, 10 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 15 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 20 carboxamidopropylphenyl. The term "arylalkyl" refers to a loweralkyl radical having appended thereto an aryl group, as defined above, as for example benzyl and phenylethyl. The term "aryloxy" refers to a aryl radical which is appended to the molecule via an ether linkage (i.e., through an oxygen atom), as for example phenoxy, naphthyloxy, 4 25 chlorophenoxy, 4-methylphenoxy, 3,5-dimethoxypehenoxy, and the like. The term "cycloalkyl" refers to a cyclic saturated hydrocarbon radical having from 3 to 7 ring atoms. Examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl. Cycloalkyl is also described as C3-C8cycloalkyl. The term "cycloalkyl-loweralkyl" refers to a loweralkyl radical as defined below 30 substituted with a cycloalkyl group as defined above by replacement of one hydrogen atom. Examples of cycloalkyl-loweralkyl include cyclopropylmethyl, cyclobutylethyl, cyclopentylmethyl, cyclohexylmethyl and cycloheptylbutyl, and the like. The term "heteroaryl" or "substituted heteroaryl" refers to a monocyclic aromatic radical having from five to seven ring atoms of which one ring atom is nitrogen, oxygen or 35 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 -42- WO 98/46605 PCT/US98/07207 substituted by independent replacement of one, two or three of the hydrogen atoms thereon with Cl, Br, F, I, cyano, carboxamido, hydroxy, loweralkoxy, loweralkyl, loweralkenyl, loweralkynyl, amino, loweralkylamino, di(loweralkylamino), N-loweralkyl-N loweralkoxyamino, trifluoromethyl or methoxymethyl groups. In addition, the term 5 "heteroaryl " refers to a heteroaryl group substituted with one ureido, methylsulfonyl, pyrimidinyl, pyridinyl, pyridazinyl, morpholinyl, phenyl-loweralkoxy. phenyl-loweralkenyl or cycloalkyl-loweralkyl group. In addition a heteroaryl group may be substituted by replacement of any two adjacent hydrogen atoms with a grouping of atoms to form a fused benzene ring, e.g., benz derivatives such as indole, benzoxazole and the like. Examples of 10 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 15 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, 20 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, 25 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 cycloalkyl-loweralkyl include pyrrolidinylmethyl, piperidinylethyl, and 30 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, 35 amino, loweralkylamino, iminoloweralkylamino,di(loweralkylamino) or N-loweralkyl-N loweralkoxyamino groups. Examples of loweralkyl include, but are not limited to, methyl, ethyl, propyl, isopropyl, n-butyl, tert-butyl, neopentyl, n-hexyl, hydroxyethyl, -43- WO 98/46605 PCT/US98/07207 methoxymethyl, trifluoromethyl, 3-cyanopropyl, 3-carboxamnidopropyl, and the like. In certain cases, the group "C1-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 5 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 10 variables are also recited as, for example, C2-C6alkenyl. The term "loweralkoxy" refers to a loweralkyl radical which is appended to the molecule via an ether linkage (i.e., through an oxygen atom), as for example methoxy, ethoxy, propoxy, 2-propoxy, 2-methyl-2-propoxy, tert-butoxy, pentyloxy, hexyloxy, isomeric forms thereof and the like. This term is also described as C1-C6alkyloxy. 15 The term "loweralkynyl", as used herein, refers to straight- or branched-chain hydrocarbon radicals possessing a single triple bond and containing from two to six carbon atoms including, but not limited to, ethynyl, propynyl, n-butynyl, n-pentynyl, and n hexynyl. This term is also described as C2-C6alkynyl. The term "mammal" has its ordinary meaning and includes human beings. 20 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 25 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. 30 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 RMol/kg/day, preferably from about 0.1-50 tMol/kg/day; these oral molar dosage ranges correspond to 0.005-125 mg/kg/day, preferably 0.05-25 mg/kg/day. For treatment 35 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. -44- WO 98/46605 PCT/US98/07207 "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 5 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, 10 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, 15 benzenesulfonate, bisulfate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesuffonate, flavianate, fumarate, glucoheptonate, glycerophosphate, hemisulfate, heptonate, hexonoate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxy-ethanesulfonate, lactate, maleate, methanesulfonate, nicotinate, 2-naphthalenesulfonate, oxalate, palmoate, pectinate, persulfate, 3 20 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, 25 or an organic base such as an amine, e.g., dibenzylethylenediamine, cyclohexylamine, dicyclohexylamine, triethylamine, piperidine, pyrrolidine, benzylamine, and the like, or a quaternary ammonium hydroxide such as tetramethylammonium hydroxide and the like. Also, the basic nitrogen-containing groups can be quaternized with such agents as loweralkyl halides, such as methyl, ethyl, propyl, and butyl chlorides, bromides, and 30 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 35 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. -45- WO 98/46605 PCT/US98/07207 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. 5 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 10 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, 15 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 20 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 25 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 30 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 35 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 -46- WO 98/46605 PCT/US98/07207 (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 5 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 10 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, -47- WO 98/46605 PCT/US98/07207 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 5 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, 10 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 15 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 Biolovgy, 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. -48- WO 98/46605 PCT/US98/07207 Scheme 1
R
3 O CH3 O H NC
R
4 + R 3 + NC CN
H
2 N N R 4 1 2 3
R
3
NH
2
R
3 NC N N H NH 2
H
2 N N R 4 R4 3 (I) The compounds of the present invention may be synthesized by methods illustrated 5 in Schemes 1 and 2. In accordance with Scheme 1, the 5,7-disubstituted compounds wherein R 4 and R 3 are aryl, heteroaryl, or a heterocyclic group may be prepared by a modification of a method of Kambe et al., Synthesis, 1980, 366-368. An appropriately substituted acetophenone (1, the "R 4 Reagent"), wherein R 4 is aryl, heteroaryl, or a heterocyclic group, an appropriately substituted aldehyde (2, the "R 3 Reagent"), R 3 is aryl, 10 heteroaryl, or a heterocyclic group, and malononitrile are heated in the presence of ammonium acetate, or another suitable ammonium salt, such as for example, ammonium propionate, ammonium iodide, or the like, in an aprotic solvent to produce compound (3). The water of the reaction may removed by use of a Dean Stark apparatus or by another suitable means, such as 4 A molecular sieves. Suitable aprotic solvents include benzene, 15 toluene, methylene chloride, DMF, THF, dioxane, and the like. The reaction may be performed at from about 40 'C to about 200 oC, 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 20 malononitrile and isolating the resulting dicyano R 3 substituted alkene which is then reacted with the ketone (1) to form, upon addition of ammonium and cyclization, compound (3). Aliphatic aldehydes do not work effectively by this route. The ketone (1) may, however, include R 4 as alkyl groups. -49- WO 98/46605 PCT/US98/07207 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 5 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-d]pyrimidine product (I) is then removed by filtration and purified by column 10 chromatography. This compound may then be partially or fully reduced by catalytic hydrogenation to the partially saturated or fully saturated version(s) (on the right side of the molecule) of the compounds shown in Scheme 1 or of Formula I. Stereoisomers produced during these reduction steps are included within the scope of the invention. The present invention also contemplates reductions which produce single bonds between the 5,6 and 7,8 15 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 R 4 is preferrably an aryl, heteroaryl or heterocyclic group, and R 3 is loweralkyl, loweralkenyl, loweralkynyl, or an arylalkyl group. In addition, R 4 may be selected from those additional 20 groups listed in R 3 . Compound (4, the "R 3 Reagent") may be obtained commercially or prepared from the precursor ester (5) or alcohol (5) by suitable reactions. Compound (5) may be reduced with a suitable reducing agent, such as for example, diisobutylaluminum hydride or another similar alkylaluminum hydride, under conditions well known to the art. Compound (6) may 25 be oxidized to the aldehyde (4) Swern oxidation conditions, or other reactions known to those skilled in the art. The desired compound (4) is freshly prepared before its use in the reaction described below. Compound (9), the "R 4 Reagent")) may be prepared from the precursor alpha-bromo ketone (7) by a two-step procedure. Compound (7) is treated with triphenylphosphine in the 30 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 35 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 -50- WO 98/46605 PCT/US98/07207 heating in the presence of ammonium acetate as defined for Scheme 1 above to produce compound (11). Scheme 2
O
0 red'n O oxid'n R 3 R3 R34 R 3- CH2-OH
O-R
6 H 5 4 6 Br P(Ph) 3 ' Br P(Ph) 3 o1 o4 o
R
4
R
4 7 8 9
R
3 P(Ph)3 R3 O 0 O:H R4 O R 4 4 9 10
R
3
R
3 NC S+ NC~ CN : o R 4 4
H
2 N R 10 11 (I) 5 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 -51- WO 98/46605 PCT/US98/07207 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 5 chloroform/ethyl acetate, and the product may be converted to a hydrochloride salt by suspension in 3M HC1, followed by lyophilization. Scheme 3 R3 NC
R
3 O CH3 11Z R4+ NC CN R4 (1) 12 H 2 N (I) 10 Scheme 3 illustrates an alternate method for preparing the compounds (I) of the invention. Compounds (1), prepared as described above, are reacted with a dicyanoalkene compound (12) by heating with a suitable ammonium salt, such as for example, ammonium acetate, ammonium propionate, ammonium iodide, or the like, at reflux in an alcoholic or 15 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 20 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 Lett., 1963: 955), or alternately MgO in dichloromethane or a similar aprotic solvent (cf. Broekhuis, et al., Recl. J. R. Neth. Chem. Soc., 99: 6-12 (1980); Moison, et al. Tetrahedron (1987), 43:537-542). 25 To prepare compounds of formula (I) wherein R 1 and R 2 are not both hydrogen atoms, it is possible to prepared the desired derivative from the compound of Formula (I) wherein R 1 and R 2 are both hydrogen atoms. When R 1 or R 2 is loweralkyl this may be accomplished by reaction of the free amino group with the appropriate alkylating reagent, such as an alkyl halide, an alkyl mesylate or an alkyl tosylate, for example, in the presence 30 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 R 2 is arylalkyl this may be accomplished by reaction of the free amino group with the appropriate arylalkyl halide, an alkyl mesylate -52- WO 98/46605 PCT/US98/07207 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 R 2 is acyl this may be accomplished by reaction of the free amino group with the appropriate acid anhydride, acyl chloride or activated acyl group, in the presence of a 5 base such as triethylamine or potassium carbonate in a suitable solvent, such as for example, methylene chloride or THF. When R 1 and R 2 are taken together with the nitrogen atom to which they are attached to form a 5-to-7 membered ring optionally containing an additional oxygen or nitrogen atom, the compound may be prepared by reacting a precursor compound having a halogen atom in place of the amino group at the 4-position with a 5-7 membered 10 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, 15 dibutylamine. This reaction takes place readily in a solvent such as methylene chloride, for example, in the presence of a tertiary amine. The precursor compound having a halogen atom in place of the amino group at the 4-position may be prepared by substitution of triethyl orthoformate for the formamide followed by chlorination of the ring by treatment with phosphorous oxychloride or thionyl chloride in the presence of DMF in Scheme 1 wherein 20 compound (3) is converted to compound (I). Method of Inhibiting Kinase In yet another aspect of the present invention a process of inhibiting adenosine kinase is disclosed. In accordance with that process, an adenosine kinase enzyme is 25 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. 30 Where the adenosine kinase is located in vitro, adenosine kinase is contacted with the inhibitor compound, typically by adding the compound to an aqueous solution containing the enzyme, radiolabeled substrate adenosine, magnesium chloride and ATP. The enzyme can exist in intact cells or in isolated subcellular fractions containing the enzyme. The enzyme is then maintained in the presence of the inhibitor for a period of time and under 35 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 -53- WO 98/46605 PCT/US98/07207 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 5 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 10 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; 20 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 30 externally applied 14 C-adenosine by these cells. The cells can be intact or broken. The specificity of adenosine kinase inhibitory activity is determined by studying the effects of inhibitors on adenosine Al and A2oc 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 -54- WO 98/46605 PCT/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. 5 The compounds of the invention were tested in vivo in the hot plate test of analgesia in mammals such as mice. For example, the compounds of examples 6, 79, 104, 130, 133, 134, 137, 205, 246 and 256 in the procedure described directly below were tested thirty minutes after pretreatment with the drugs (30 ptmol/kg i.p.) for latency to 10th jump (in seconds). The longer the number of seconds, the more effective the drug at masking the 10 pain felt from the hot plate. Compound 6 resulted in 152 seconds relative to the vehicle alone of 72.8±10.5 seconds (average±standard deviation); compound 79 resulted in 143 seconds; compound 104 resulted in 180 seconds; compound 130 resulted in 158 seconds; compound 133 resulted in 131 seconds; compound 134 resulted in 137 seconds; compound 137 resulted in 159 seconds; compound 205 resulted in 158 seconds, compound 246 15 resulted in 160 seconds and compound 256 resulted in 143 seconds. Compounds of the invention are therefore potent pain relievers as demonstrated in this animal model. Mouse Hot Plate Assay Male CF1 mice (Charles River) of approximately 25-30 g body weight are pretreated 20 with 10 ml/kg of the test compounds, i.p. or p.o, in groups of 8 animals per dose. At the end of the pretreatment period, the mice are placed in an Omnitech Electronics Automated 16 Animal Hot Plate Analgesia Monitor (Columbus, OH; Model AHP16AN) in individual, 9.8 x 7.2 x 15.3 cm (1 x w x h) plastic enclosures on top of a copper plate warmed to 55 0 C. Infared sensors located near the top of each enclosure record beam crossings that occur as 25 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. 30 Numerous other animal models of adenosine kinase activity have been described [See, e.g., Davies,, et al., Biochem. Pharmacol., 33:347-355 (1984); Keil, et al., Eur. J. Pharmacol., 271:37-46 (1994); Murray, et al., Drug Development Res., 28:410-415 (1993)]. Compounds of the present invention were also tested in vitro . The results of some 35 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 -55- WO 98/46605 PCT/US98/07207 invention including compounds of formula I and II with the variables recited herein are also useful as screening tools or as comparative indicators of adenosine kinase inhibition activity relative to unknown inhibitors or potential inhibitors. 5 Table 1 Inhibition of Adenosine Kinase by Representative Compounds of the Invention Compound of Example No. IC50 (nM) 6 200 15 7 44 50 53 3 56 35 57 1 64 8 79 5 81 3 100 2 104 2 130 T 1 133 _ 2 137 5 147 150 150 150 170 1 175 300 177 25 201 3 205 3 208 4 246 5 247 3 256 1 270 20 272 >100 274 2 283 8 288 0.3 290 1 291 0.6 292 10 303 1 304 1 306 0.3 308 2 309 0.1 315 0.3 319 1 -56- WO 98/46605 PCT/US98/07207 327 1 330 5 333 2 336 8 337 4 338 4.5 347 3 Method of Treating Cerebral Ischemia, Epilepsy, Nociperception (Nociception) (Pain), Inflammation including conditions such as Septic Shock due to Sepsis Infection 5 In yet another aspect of the present invention a method of treating cerebral ischemia, epilepsy, nociperception or nociception, inflammation including conditions such as septic shock due to sepsis infection in a human or lower mammal is disclosed, comprising administering to the mammal a therapeutically effective amount of a compound of formula I with R 1
-R
8 as defined herein. The preferred compounds are those of formula II with the R 10 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 R 3 is a substituted aryl or heteroaryl moiety wherein the substituent (preferrably halogen) is at the meta position relative to the ring attachment and R 4 is a substituted heteroaryl or aryl moiety wherein the substituent is at the para position relative to the ring attachment. The 15 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 20 was also diminished in regenerating liver after partial hepatectomy in experimental animals (Jackson, et al., Br. J. Cancer, 1978, 37: 701-713). Erythrocyte Adenosine kinase activity was found to be diminished in patients with gout (Nishizawa, et al., Clin. Chim. Acta 1976, 67: 15-20). Lymphocyte adenosine kinase activity was decreased in patients infected with the human immunodeficiency virus (HIV) exhibiting symptoms of AIDS, and increased in 25 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), 30 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 -57- WO 98/46605 PCT/US98/07207 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., 5 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. 10 Example 1 4-amino-5-(p-dimethylaminophenvl)-7-(p-bromophenvyl)pvrido[2,3-d pvrimidine 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. 15 After about 3 hours, the reaction was complete as monitored by TLC, and the reaction mixture was cooled to room temperature. The product was allowed to precipitate, then recovered by filtration and washed with water. Additional product was recovered from the filtrate. The product was purified by column chromatography eluting with 10% MeOH/CH 2 Cl 2 to give the pure title compound. IR (KBr) 3503, 3398, 1731, 1658, 1510, 20 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 "R 4 reagent"), 4 dimethylaminobenzaldehyde (10 mmol, the "R 3 reagent"), malononitrile (10 mmol) and 25 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) + . 30 Examples 2-156 Following the procedures of Example 1, except substituting the appropriate reagents for R 4 and R 3 as indicated in Table 2 below, compounds of Examples 2-156 were prepared. -58- WO 98/46605 PCT/US98/07207 Table 2 Examples 2-156 E x. Name R 4 Reagent R 3 Reagent Analytical No. (for 7- (for 5- Data position) position 2 4-amino-5-(4- 1-(4- 4- IR (KBr) 3440, dimethylaminophenyl)-7- dimethylamino- dimethylamino- 1615, 1760, (4- phenyl)-ethanone benzaldehyde 1210cm-1; MS m/z dimethylaminophenyl)pyri 385 (M+H) + . do[2,3-d]pyrimidine; 3 4-amino-5-(4- 1-(4- 4- IR (KBr) 3330, methoxyphenyl)-7-(4- dimethylamino- methoxybenzalde 1600, 1640, 1780, dimethylaminophenyl)pyri phenyl)-ethanone hyde 1200cm- 1 ; MS m/z do[2,3-d]pyrimidine; 372(M+H)+. 4 4-amino-5-(4- 1-(4- 4- IR (KBr) 3660, dimethylaminophenyl)-7- methoxyphenyl)- dimethylamino- 1600, 1620, 1510, (4- ethanone benzaldehyde 1360, 1240 cm-1; methoxyphenyl)pyrido[2, MS m/z 372 3-d]pyrimidine; (M+H)+. 5 4-amino-5-(4- 1-(4- 4-isopropyl- IR (KBr) 3430, isopropylphenyl)-7-(4- methoxyphenyl)- benzaldehyde 3360, 1580, 1540 methoxyphenyl)pyrido[2, ethanone cm- 1 ; MS m/z 371 3-d]pyrimidine; (M+H)+. 6 4-amino-5-(4- 1-(4- 4-neopentyl- IR (KBr) 3480, neopentylphenyl)-7-(4- methoxyphenyl)- benzaldehyde 2960, 1580, 1510, methoxyphenyl)pyrido[2, ethanone 1240 cm - 1 ; MS m/z 3-d]pyrimidine; 399 (M+H) + . 7 4-amino-5-(4- 1-(4- 4- IR (KBr) butoxyphenyl)-7-(4- methoxyphenyl)- butoxybenzaldeh 3480,1600, 1580, methoxyphenyl)pyrido[2, ethanone yde 1510, 1240, 1180 3-d]pyrimidine; cm-1; MS m/z 401
(M+H)
+ . 8 4-amniino-5-(4- 1-(4- 4- IR (KBr) 3660, methoxyphenyl)-7-(4- bromophenyl)- methoxybenzalde 1600, 1680, 1520, bromophenyl)pyrido[2,3- ethanone hyde 1240cm- 1 ; MS m/z d]pyrimidine; 407(M+H)+. 9 4-amino-5-(4- 1-(4- 4-isopropoxy- IR (KBr) 3480, isopropoxyphenyl)-7-(4- methoxyphenyl)- benzaldehyde 2940, 1600, 1580, methoxyphenyl)pyrido[2, ethanone 1504 cm-1; MS m/z 3-d]pyrimidine; 386 (M+H) + . 10 4-amino-5-(4- 1-(4-N- 4-butoxy- IR (KBr) 3480, butoxyphenyl)-7-(4-N- formylpiperaziny benzaldehyde 2940, 1660, 1600, formylpiperazinylphenyl)p lphenyl)- 1580, 1510 cm-1; yrido[2,3-d]pyrimidine; ethanone MS m/z 483
(M+H)
+ . 11 4-amino-5-(4- 1-(4- 4-benzyloxy- IR (KBr) 3480, benzyloxyphenyl)-7-(4- methoxyphenyl)- benzaldehyde 3040, 1600, 1580, methoxyphenyl)pyrido[2, ethanone 1560 cm-1; MS m/z 3-d]pyrimidine; 435 (M+H) + . -59- WO 98/46605 PCT/US98/07207 12 4-anmino-5-(4- 1-(4- 4-phenoxy- IR (KBr) 3456, phenoxyphenyl)-7-(4- methoxyphenyl)- benzaldehyde 3053, 1580, 1558, methoxyphenyl)pyrido[2, ethanone 1247 cm-1; MS m/z 3-d]pyrimidine; 421 (M+H) + . 13 4-amino-5-(4- 1-(4-(3- 4-isopropyl- IR (KBr) 3480, isopropylphenyl)-7-(4- (diethylmalonyl) benzaldehyde 2980, 1735, 1580, diethylmalonylallylphenyl) allyl) phenyl)- 1555 cm- 1 ; MS m/z pyrido[2,3-d]pyrimidine; ethanone 539 (M+H) + . 14 4-amino-5-(4- 1-(4-t- 4-isopropyl- IR (KBr) 3471, isopropylphenyl)-7-(4-t- butylacrylphenyl benzaldehyde 2957, 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- dimethylaminoph benzaldehyde 1610, 1580, 1560, dimethylaminophenyl)pyri enyl)-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- dimethylaminoph benzaldehyde 1610, 1580, 1560, dimethylanminophenyl)pyri enyl)-ethanone 1510 cm-1; MS m/z do[2,3-d]pyrimidine; 402 (M+H) + . 17 4-amino-5-(3-t- 1-(4- 3-(3- IR (KBr) 3480, butylacrylphenyl)-7-(4- dimethylaminoph formylphenyl)acr 3400, 1700, 1610, dimethylaminophenyl)pyri enyl)-ethanone ylic acid t-butyl 1580, 1560 cm-l; do[2,3-d]pyrimidine; ester MS m/z 468
(M+H)
+ . 18 4-anmino-5-(3- 1-(4- 3-methoxy- IR (KBr) 3475, methoxyphenyl-7-(4- dimethylaminoph benzaldehyde 1610, 1580, 1560, dimethylanminophenyl)pyri enyl)-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- dimethylaminoph benzaldehyde 1637, 1600, 1572, dimethylaminophenyl)pyri enyl)-ethanone 1371, 1202 cm-; do[2,3-d]pyrimidine; MS m/z 402
(M+H)
+ . 20 4-amino-5-(3- 1-(4- 2-[2-(3- IR (KBr) 3480, diethylmalonylallylphenyl) dimethylaminoph formylphenyl)vi 1720, 1610, 1580, -7-(4- enyl)-ethanone nyl]malonic acid 1558, 1524,1360 dimethylaminophenyl)pyri diethyl ester cm- 1 ; MS m/z 540 do[2,3-d]pyrimidine; (M+H)+. 21 4-amino-5-(3- 1-(4- 3-vinylpyridinyl- IR (KBr) 3480, vinylpyridinylphenyl)-7- dimethylaminoph benzaldehyde 1610, 1580, 1560, (4- enyl)-ethanone 1513, 1360 cm- 1 ; dimethylaminophenyl)pyri MS m/z 385 do[2,3-d]pyrimidine; (M+H)+. 22 4-amino-5-(3- 1-(4- 3- IR (KBr) 3480, trifluoromethylphenyl)-7- dimethylaminoph trifluoromethyl- 1610, 1580, 1560, (4- enyl)-ethanone benzaldehyde 1360, 1200 cm- 1; dimethylaminophenyl)pyri MS m/z 410 do[2,3-d]pyrimidine; (M+H)+. -60- WO 98/46605 PCT/US98/07207 23 4-amino-5-(3- 1-(4- 3-amido- IR (KBr) 3480, carboxamidophenyl)-7-(4- dimethylaminoph benzaldehyde 1610, 1580, 1380, dimethylaminophenyl)pyri enyl)-ethanone 1200 cm-1; MS m/z do[2,3-d]pyrimidine; 446 (M+H) + . 24 4-amino-5-(3- 1-(4- 3-cyano- IR (KBr) 3460, cyanophenyl)-7-(4- dimethylaminoph benzaldehyde 3400, 2210. 1610. dimethylaminophenyl)pyri enyl)-ethanone 1580, 1554. 1360 do[2,3-d]pyrimidine; cm-1; MS m/z 367
(M+H)
+ . 25 4-amino-5-(3- 1-(4- 3-benzyloxy- IR (KBr) 3470, benzyloxyphenyl)-7-(4- dimethylaminoph benzaldehyde 1640, 1580, 1550, dimethylaminophenyl)pyri enyl)-ethanone 1515, 1357, 1250 do[2,3-d]pyrimidine; cm- 1 ; MS m/z 448
(M+H)
+ . 26 4-amino-5-(3- 1-(4- 3-methoxy- IR (KBr) 3470, methoxyphenyl)-7-(4- methoxyphenyl)- benzaldehyde 1640, 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)- benzaldehyde 1610, 1580, 1560, butoxyphenyl)pyrido[2,3- ethanone 1515, 1355, 1255, d]pyrimidine; 1240, 1180 cm-1; MS m/z 449
(M+H)
+ . 28 4-amino-5-(3-(2- 1-(4- 3-(2-pyridyl)- IR (microscope) pyridyl)phenyl)-7-(4- dimethylaminoph benzaldehyde 3476, 1609. 1580, dimethylanminophenyl)pyri enyl)-ethanone 1560, 1358 cm-1; do[2,3-d]pyrimidine; MS m/z 419
(M+H)
+ . 29 4-amino-5-(3- 1-(4- 3-methyl- IR (microscope) methylphenyl)-7-(4- dimethylaminoph benzaldehyde 3400, 1640,1600, dimethylaminophenyl)pyri enyl)-ethanone 1580, 1540cm-1; do[2,3-d]pyrimidine; MS m/z 356
(M+H)
+ . 30 4-amino-5-(3- 1-(4- 3-chloro- IR (microscope) chlorophenyl)-7-(4- dimethylaminoph benzaldehyde 3400, 1600, 1580, dimethylaminophenyl)pyri enyl)-ethanone 1540 cm- 1 ; MS m/z do[2,3-d]pyrimidine; 376 (M+H) +. 31 4-amino-5-(3- 1-(4- 3-fluoro- IR (microscope) fluorophenyl)-7-(4- dimethylaminoph benzaldehyde 3480, 1640, 1580, dimethylaminophenyl)pyri enyl)-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)- benzaldehyde 3485, 1607. 1575, methoxyphenyl)pyrido[2, ethanone 1550, 1515. 1350, 3-d]pyrimidine; 1255, 1240, 1180, 1030 cm-1: MS m/z 407 (M+H) + . -61- WO 98/46605 PCT/US98/07207 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 (KBr) 3480, bromophenyl)-7-phenyl ethanone benzaldehyde 1640, 1580, 1560, pyrido [2,3-d]pyrimnidine; 1480, 1350, 700 cm-1; MS m/z 377 (M+H)+. 35 4-amino-5-(3- 1-(4- 3-bromo- IR (microscope) bromophenyl)-7-(4- ethylphenyl)- benzaldehyde 3480, 1645, 1580 ethylphenyl)pyrido[2,3- ethanone (broad), 1490, 1380 d]pyrimidine; cm-1; MS m/z 405
(M+H)
+ . 36 4-anmino-5-(3- 1-(4- 3-bromo- IR (KBr) 3480, bromophenyl)-7-(4- bromophenyl)- benzaldehyde 1610, 1575, 1540, bromophenyl)pyrido[2,3- ethanone 1350 cm-1; MS m/z d]pyrimidine; 455 (M+H) + . 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 m/z 402 (M+H)
+
. 38 4-amino-5-(3- 1-(4- 3-bromo- IR (microscope) bromophenyl)-7-(4- hydroxyphenyl)- benzaldehyde 3481, 3060 (broad), hydroxyphenyl)pyrido[2,3 ethanone 1645, 1580, 1560, -d]pyrimidine; 1544, 1360, 1240 1155 cm- 1 ; MS m/z 393 (M+H)
+
. 39 4-amnino-5-(3- 1-(4- 3-iodo- IR (microscope) iodophenyl)-7-(4- dimethylaminoph benzaldehyde 3500, 3040, 1640, dimethylaminophenyl)pyri enyl)-ethanone 1600, 1580, 1560 do[2,3-d]pyrimidine; cm-1; MS m/z 468
(M+H)
+ . 40 4-amino-5-(3- 1-(4- 3-ethoxy- IR (microscope) ethoxyphenyl)-7-(4- dimethylaminoph benzaldehyde 3460, 3250, 1640, dimethylaminophenyl)pyri enyl)-ethanone 1600, 1580, 1560 do[2,3-d]pyrimidine; cm-1; MS m/z 386
(M+H)
+. 41 4-amino-5-(3- 1-(4- 3- IR (microscope) trifloromethyoxyphenyl)- dimethylaminoph trifluoromethoxy 3480, 1710, 1610, 7-(4- enyl)-ethanone -benzaldehyde 1580, 1560, 1540 dimethylaminophenyl)pyri cm- 1 ; MS m/z 426 do[2,3-d]pyrimidine; (M+H)+. 42 4-amino-5-(3,5- 1-(4- 3,5-dichloro- IR (microscope) dichlorophenyl)-7-(4- dimethylaminoph benzaldehyde 3500, 3040, 1640, dimethylaminophenyl)pyri enyl)-ethanone 1600, 1580, 1560 do[2,3-d]pyrimidine; cm-1; MS m/z 411
(M+H)
+. -62- WO 98/46605 PCT/US98/07207 43 4-amino-5-(3-bromo-4- 1-(4- 3-bromo-4- IR (microscope) fluorophenyl)-7-(4- dimethylaminoph fluoro- 3440, 3015, 1633, dimethylaminophenyl)pyri enyl)-ethanone benzaldehyde 1607, 1583 cm- 1 ; do[2,3-d]pyrimidine; MS m/z 438
(M+H)
+ . 44 4-amino-5-(3- 1-(4- 3-hydroxy- IR (microscope) hydroxyphenyl)-7-(4- dimethylaminoph benzaldehyde 3450, 1640, 1610, dimethylaminophenyl)pyri enyl)-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- morpholinylphen benzaldehyde 3483, 1607, 1578, morpholinylphenyl)pyrido yl)-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- IR (microscope) bromophenyl)-7-(4- piperidinylpheny benzaldehyde 3486, 1606, 1561, piperidinylphenyl)pyrido[ 1)-ethanone 1540, 1519, 1353, 2,3-d]pyrimnidine; 1231, 1199, 1128 cm- 1 ; MS m/z 460
(M+H)
+ . 47 4-amino-5-(3- 1-(4-(imidazol-1- 3-bromo- IR (KBr) 3481, bromophenyl)-7-(4- yl)phenyl)- benzaldehyde 1580, 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)- benzaldehyde 1635, 1580, 1560, chlorophenyl)pyrido[2,3- ethanone 1500, 1350, 1090 d]pyrimnidine; cm-1; MS m/z 411
(M+H)
+ . 49 4-amino-5-(3- 1-(4- 3-bromo- IR (KBr) 3484, bromophenyl)-7-(4- isopropylphenyl) benzaldehyde 1610, 1579, 1560, isopropylphenyl)pyrido[2, -ethanone 1550, 1483, 1357 3-d]pyrimrnidine; cm - 1 ; MS m/z 419
(M+H)
+ . 50 4-amino-5-(3- 1-(4- 3-bromo- IR (microscope) bromophenyl)-7-(4- trifluorophenyl)- benzaldehyde 3481, 3289, 1616, trifluorophenyl)pyrido[2,3 ethanone 1579, 1547, 1324, -d]pyrimidine; 1312, 1122, 1070 cm- 1 ; MS m/z 445
(M+H)
+ . 51 4-amino-5-(3- 1-(4- 3-bromo- IR (KBr) 3481, bromophenyl)-7-(4- diethylaminophe benzaldehyde 1607, 1578, 1561, diethylaminophenyl)pyrid nyl)-ethanone 1533, 1353, 1200, o[2,3-d]pyrimidine; 1155 cm- 1 ; MS m/z 448 (M+H) + . 52 4-amino-5-(3- 1-(3,4,5- 3-bromo- IR (KBr) 3485, bromophenyl)-7-(3,4,5- trimethoxypheny benzaldehyde 1579, 1548, 1507, trimethoxyphenyl)pyrido[ 1)-ethanone 1340, 1129 cm-1; 2,3-d]pyrimidine; MS m/z 467
(M+H)
+ . -63- WO 98/46605 PCT/US98/07207 53 4-amino-5-(3-(3- 1-(4- 3-(3- IR (KBr) 3425, methoxybenzyl)phenyl)-7- dimethylaminoph methoxybenzyl)- 1613, 1580, 1558, (4- enyl)-ethanone benzaldehyde 1537 cm-1; MS m/z dimethylaminophenyl)pyri 478 (M+H) + . do[2,3-d]pyrimidine; 54 4-anmino-5-(3- 1-(4- 3- IR (KBr) 3469, methoxyethyoxyphenyl)- dimethylaminoph methoxyethoxy- 1610, 1580, 1560, 7-(4- enyl)-ethanone benzaldehyde 1357 cm- 1 ; MS m/z dimethylaminophenyl)pyri 416 (M+H) + . do[2,3-d]pyrimidine; 55 4-amino-5-(3,4- 1-(4- 3,4- IR (KBr) 3466, methylenedioxyphenyl)-7- dimethylaminoph methylenedioxy- 16245, 1579, 1560 (4- enyl)-ethanone benzaldehyde cm- 1 ; MS m/z 386 dimethylaminophenyl)pyri (M+H)+. do[2,3-d]pyrimidine; 56 4-amino-5-(3- 1-(4- 3-bromo- IR (KBr) 3480, bromophenyl)-7-(4- ethoxyphenyl)- benzaldehyde 1607, 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]pyrimidine; 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- dimethylaminoph dimethylamino- 1601. 1580, 1563, (4- enyl)-ethanone benzaldehyde 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 (KBr) 3400, dimethylaminophenyl)pyri dimethylaminoph 1600, 1580, 1560, do[2,3-d]pyrimidine; enyl)-ethanone 1530, 1200 cm- 1 ; MS m/z 342
(M+H)
+
. 61 4-amino-5-(3,4,5- 1-(4- 3,4,5- IR (KBr) 33460, trimethoxyphenyl)-7-(4- dimethylaminoph trimethoxy- 1607, 1578, dimethylamninophenyl)pyri enyl)-ethanone benzaldehyde 1127cm- 1 ; MS m/z do[2,3-d]pyrimidine; 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 L422 (M+H)
+
. -64- WO 98/46605 PCT/US98/07207 63 4-amino-5-(3- 1-(4- 3-bromo- IR (KBr) 3480, bromophenyl)-7-(4- iodophenyl)- benzaldehyde 1610, 1575, 1570, iodophenyl)pyrido[2,3- ethanone 1540, 1350, 1000 d]pyrimidine; cm'l; MS m/z 503
(M+H)
+ . 64 4-amino-5-(3- 1-(3,4- 3-bromo- IR (KBr) 3485, bromophenyl)-7-(3,4- methylenedioxyp benzaldehyde 1607, 1575, 1545, methylenedioxyphenyl)pyr henyl)-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- morpholinylphen carboxaldehyde 1607, 1580, 1560, morpholinylphenyl)pyrido yl)-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 benzaldehyde 1640, 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- IR (KBr) 3481, bromophenyl)-7-(4- carboxamidophe benzaldehyde 1674, 1611, 1577, carboxamidophenyl)pyrid nyl)-ethanone 1558, 1352 cm-1; o[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)ethoxy benzaldehyde 1607, 1580, 1560, methoxy)ethoxyphenyl)py phenyl)-ethanone 1515, 1357, 1260, rido[2,3-d]pyrimidine; 1235, 1180, 1113 cm- 1 ; MS m/z 451
(M+H)
+ . 69 4-amino-5-(3,5- 1-(4- 3,5-dimethoxy- IR (KBr) 3450, dimethoxyphenyl)-7-(4- morpholinylphen benzaldehyde 1608, 1580, 1555, morpholinylphenyl)pyrido yl)-ethanone 1541, 1230, 1210, [2,3-d]pyrimidine; 1160 cm- 1 ; MS m/z 444 (M+H) + . 70 4-amino-5-(3- 1-(thiophene-2- 3- IR (KBr) 3486, trifluoromethylphenyl)-7- yl)-ethanone trifluoromethyl- 1620, 1580, 1560, (thiophene-2-yl)pyrido benzaldehyde 1325, 1123cm- 1 ; [2,3-d]pyrimidine; MS m/z 373
(M+H)
+ . 71 4-amino-5-(3- 1-(4- 3-bromo- IR (KBr) 3450, bromophenyl)-7-(4- aminophenyl)- benzaldehyde 1632, 1605, 1580, aminophenyl)pyrido[2,3- ethanone 1365 cm - 1 ; MS m/z d]pyrimidine; 393 (M+H) + . 72 4-amino-5-(3-bromo-4- 1-(thiophene-2- 3-bromo-4- IR (KBr) 3480, fluorophenyl)-7- yl)-ethanone fluoro- 1640, 1580, 1560, (thiophene-2-yl)pyrido benzaldehyde 1500cm- 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- benzaldehyde 1500cm- 1 ; MS m/z d]pyrimidine; 385 (M+H) + . -65- WO 98/46605 PCT/US98/07207 74 4-amino-5-(3,5- 1-(4- 3,5-dimethoxy- IR (KBr) 3460, dimethoxyphenyl)-7-(4- iodophenyl)- benzaldehyde 1604, 1575, 1556, iodophenyl)pyrido[2,3- ethanone 1541, 1207, 1160 d]pyrimidine; cm'-1; MS m/z 485
(M+H)
+ . 75 4-amino-5-(3,5- 1-(4- 3,5-dimethoxy- IR (KBr) 3459. dimethoxyphenyl)-7-(4- imidazolylphenyl benzaldehyde 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-amnino-5-(3,5- 1-(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, 1159 pyridyl)phenyl)pyrido[2,3 cm-I; MS ml/z 436 -d]pyrinmidine; (M+H)+. 78 4-amino-5-(3- 1-(4-(4- 3-bromo- IR (KBr) 3475. bromophenyl)-7-(4-(4- methylpiperidiny benzaldehyde 1607, 1577, 1558, methylpiperidinyl)phenyl) 1)phenyl)- 1540, 1356, 1232 pyrido[2,3-d]pyrimidine; ethanone cm-1; MS m/: 475
(M+H)
+ . 79 4-amino-5-(3- 1-(4- 3-bromo- IR (KBr) 3486. bromophenyl)-7-(4- pyrrolidinylphen benzaldehyde 1608, 1577, 1560, pyrrolidinylphenyl)pyrido[ yl)-ethanone 1533, 1353, 1196 2,3-d]pyrimidine; cm-1; MS m/: 446
(M+H)
+. 80 4-amino-5-(4- 1-(4- 4- IR (KBr) 3327. bromothiophen-2-yl)-7-(4- dimethylaminoph bromothiophene- 1604, 1578, 1548, dimethylaminophenyl)pyri enyl)-ethanone 2- 1521, 1367, 1350, do[2.3-d]pyrimidine; carboxaldehyde 1202, 820 cm'-; MS m/z 426
(M+H)
+ . 81 4-amino-5-(4- 1-(4- 4- IR (KBr) 3460. bromothiophene-2-yl)-7- morpholinylphen bromothiophene- 1606, 1578, 1558, (4- yl)-ethanone 2- 1541, 1517, 1232, morpholinylphenyl)pyrido carboxaldehyde 824 cm- 1 ; MS m/z [2,3-d]pyrimidine; 468 (M+H) + . 82 4-morpholinyl-5-(3- 1-(4- 3-bromophenyl- IR (microscope) bromophenyl)-7-(4- dimethylaminoph benzaldehyde 3340, 1603, 1580, dimethylaminophenyl)pyri enyl)-ethanone 1540 cm-1; MS m/z do[2,3-d]pyrimidine; 490 (M+H) + . 83 4-amino-5-(5- 1-(4- 5- IR (KBr) 3460. bromothiophene-2-yl)-7- morpholinylphen bromothiophene- 1606, 1580, 1558, (4- yl)-ethanone 2-yl- 1541, 1517, 1233 morpholinylphenyl)pyrido benzaldehyde cm- 1 ; MS ml: 468 [2,3-d]pyrimidine; (M+H)+. -66- WO 98/46605 PCT/US98/07207 84 4-amino-5-(4- 1-(4- 4-bromo- IR (microscope) bromophenyl)-7-(4- dimethylaminoph benzaldehyde 3480, 3320, 1603, dimethylaminophenyl)pyri enyl)-ethanone 1580, 1540, 820 do[2,3-d]pyrimidine; cm'; MS m/z 420
(M+H)
+ . 85 4-amino-5-(3- 1-(4- 3-bromo- IR (microscope) bromophenyl)-7-(4- (acetylamino)phe benzaldehyde 3480 1600. 1580, (acetylamino)phenyl)pyrid nyl)-ethanone 1520cm- 1 : MS m/z o[2,3-d]pyrimidine; 434 (M+H) + . 86 4-amino-5-(3- 1-(4- 3-bromo- IR (microscope) bromophenyl)-7-(4- dimethylaminoph benzaldehyde 3300. 1606. 1600, dimethylaminophenyl)pyri enyl)-ethanone 1580, 1560 cm-1; do[2,3-d]pyrimidine; MS m/z 421
(M+H)
+ . 87 4-amino-5-(3,5- 1-(5- 3,5-dimethoxy- IR (microscope) dimethoxyphenyl)-7-(5- pyrimidinylphen benzaldehyde 3458. 1602, 1579, pyrimidinylphenyl)pyrido[ yl)-ethanone 1558, 1460, 1414, 2,3-d]pyrimidine; 1364. 1196, 1058 cm- 1 ; MS m/z 437
(M+H)
+ . 88 4-(4-fluorophenyl)amino)- 1-(4- 3-bromo- IR (KBr) 3410, 5-(3-bromophenyl)-7-(4- dimethylaminoph benzaldehyde 1605, 1570. 1525, dimethylamninophenyl)pyri enyl)-ethanone 1503 cm- 1 ; MS m/z do[2,3-d]pyrimidine; 514 (M+H) + . 89 4-amino-5-(4- 1-(4- 4- IR (KBr) 3470, bromothiophene-2-yl)-7- pyrrolidinylphen bromothiophene- 1609, 1577, 1555, (4- yl)-ethanone 2- 1520. 1409, 1386, pyrrolidinylphenyl)pyrido[ carboxaldehyde 1350. 1196. 821 2,3-d]pyrinmidine; cm- 1 ; MS m/z 452
(M+H)
+ . 90 4-anmino-5-(4- 1-(thiophene-2- 4- IR (KBr) 3308, bromothiophene-2-yl)-7- yl)-ethanone bromothiophene- 1606, 1578, 1543, (thiophene-2- 2- 1526, 1427, 1359 yl)pyrido[2,3- carboxaldehyde cm-1; MS m/z 389 d]pyrimidine; (M+H)+. 91 4-amino-5-(3- 1-(5- 3-bromo- IR (microscope) bromophenyl)-7-(5- (dimethylamino)t benzaldehyde 3490, 1581, 1556, (dimethylamino)thiophene hiophene-2-yl)- 1501, 1481, 1407, -2-yl)pyrido[2,3- ethanone 1373, 1072 cm-1; d]pyrimidine; 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)py phenyl)-ethanone 1364. 1350. 1200 rido[2,3-d]pyrimnidine; cm- 1: MS m/z 546
(M+H)
+ . 93 4-amino-5-(3,5- 1-(4- 3,5- IR (KBr) 3484, di(trifluoromethyl)phenyl) (dimethylamino) di(trifluoromethy 1607. 1580, 1554. -7-(4- phenyl)-ethanone 1-benzaldehyde 1386. 1280 cm-; (dimethylamino)phenyl)py MS m/z 478 rido[2,3-d]pyrimidine; (M+H)+. -67- WO 98/46605 PCT/US98/07207 94 4-anmino-5-(3,5- 1-(4- 3,5- IR (KBr) 3500, di(trifluoromethyl)phenyl) morpholinylphen di(trifluoromethy 1643, 1602, 1578, -7-(4- yl)-ethanone 1-benzaldehyde 1554, 1280 cm-1; morpholinylphenyl)pyrido MS m/z 520 [2,3-d]pyrimidine; (M+H)+. 95 4-amino-5-(3,5- 1-(4- 3,5-dibromo- IR (KBr) 3440, dibromophenyl)-7-(4- (dimethylamino) benzaldehyde 1608, 1570, 1559, (dimethylamino)phenyl)py phenyl)-ethanone 1536 cm- 1 ; MS m/z rido[2,3-d]pyrimidine; 475 (M+H) + . 96 4-amino-5-(3,5- 1-(4- 3,5-dibromo- IR (KBr) 3480, dibromophenyl)-7-(4- morpholinylphen benzaldehyde 1607, 1560, 1540, morpholinylphenyl)pyrido yl)-ethanone 1225 cm- 1 ; MS m/z [2,3-d]pyrimidine; 540 (M+H)+. 97 4-amino-5-(4- 1-(4-(4- 4- IR (KBr) 3460, bromothiophene-2-yl)-7- methylpiperidiny bromothiophene- 1608, 1576, 1557, (4-(4- 1)phenyl)- 2- 1540, 1513, 1384, methylpiperidinyl)phenyl) ethanone carboxaldehyde 1353, 1240, 823 pyrido[2,3-d]pyrimidine; cm- 1 ; MS m/z 481
(M+H)
+ . 98 4-amino-5-(3,5- 1-(4- 3,5-dibromo- IR (KBr) 3486, dibromophenyl)-7-(4- (dimethylamino) benzaldehyde 1608, 1570, 1559, (dimethylamnino)phenyl)py phenyl)-ethanone 1536, 1360, 1350, rido[2,3-d]pyrimidine; 1200, 823 cm-1; MS m/z 498
(M+H)
+ . 99 4-amino-5-(3- 1-(4- 3-bromo- IR (KBr) 3480, bromophenyl)-7-(3- (dimethylamino) benzaldehyde 1601, 1579, 1548, (dimethylamino)phenyl)py phenyl)-ethanone 1483, 1357 cm-1; rido[2,3-d]pyrimidine; MS m/z 420
(M+H)
+ . 100 4-amino-5-(3- 1-(4- 3-bromo- IR (KBr) 3486, bromophenyl)-7-(4- methylsulfonylp benzaldehyde 1600, 1580,1550, methylsulfonylphenyl)pyri henyl)-ethanone 1490 cm-1; MS m/z do[2,3-d]pyrimidine; 455 (M+H) +. 101 4-amino-5-(3- 1-(3- 3-bromo- IR (KBr) 3486, bromophenyl)-7-(3- methoxyphenyl)- benzaldehyde 1605, 1578, 1550, methoxyphenyl)pyrido[2, ethanone 1492, 1346, 1263 3-d]pyrimidine; cm-1; MS m/z 407
(M+H)
+ . 102 4-amino-5-(3- 1-(4- 3-bromo- IR (KBr) 3485, bromophenyl)-7-(4- (methylthio)phen benzaldehyde 1607, 1578, 1566, (methylthio)phenyl)pyrido yl)-ethanone 1538, 1350, 1094, [2,3-d]pyrimidine; 795 cm- 1 ; MS m/z 423 (M+H) + . 103 4-amino-5-(3- 1-(3,4- 3-bromo- IR (KBr) 3482, bromophenyl)-7-(3,4- dichlorophenyl)- benzaldehyde 1634, 1576, 1545, dichlorophenyl)pyrido[2,3 ethanone 1488, 1342 cm-1; -d]pyrimidine; MS m/: 445
(M+H)
+ . -68- WO 98/46605 PCT/US98/07207 104 4-amino-5-(3- 1-(4-(N-methyl- 3-bromo- IR (KBr) 3478, bromophenyl)-7-(4-(N- N- benzaldehyde 1672, 1639, 1603, methyl-N- formylamino)phe 1579, 1547, 841 formylamino)phenyl)pyrid nyl)-ethanone cm'l; MS m/z 434 o[2,3-d]pyrimidine: (M+H)+. 105 4-amino-5-(3- 1-(4- 3-bromo- IR (KBr) 3488. bromophenyl)-7-(4- methylaminophe benzaldehyde 1637, 1607, 1587, methylaminophenyl)pyrid nyl)-ethanone 1360 cm-1; MS m/z o[2,3-d]pyrimidine; 480 (M+H) +. 106 4-amino-5-(3-bromo-4- 1-(4- 3-bromo-4- IR (KBr) 3489, fluorophenyl)-7-(4- methylsulfonylp fluoro- 1578, 1560, 1496, methylsulfonylphenyl)pyri henyl)-ethanone benzaldehyde 1311. 1151, 775 do[2,3-d]pyrimnidine; cm-1: MS ml:/z 473
(M+H)
+ . 107 4-amino-5-(3- 1-(3-amino-4- 3-bromo- IR (microscope) bromophenyl)-7-(3- methoxyphenyl)- benzaldehyde 3431, 1629, 1606, amino-4- ethanone 1583, 1274 cm-l; methoxyphenyl)pyrido[2, MS mnz 422 3-d]pyrimidine; (M+H)+. 108 4-amino-5-(3- 1-(3-bromo-4- 3-bromo- IR (microscope) bromophenyl)-7-(3- (dimethylamino) benzaldehyde 3470. 1638, 1570, bromo-4- phenyl)-ethanone 1560. 1538, 1480, (dimethylamino)phenyl)py 1345 cm-1; MS m/z rido[2,3-d]pyrimidine; 498 (M+H) + . 109 4-amino-5-(3- 1-(3-bromo-4- 3-bromo- IR (microscope) bromophenyl)-7-(3- (dimethylamino) benzaldehyde 3438. 1640, 1605, methyl-4- phenyl)-ethanone 1580. 1555, 1368 (dimethylamino)phenyl)py cm- 1 ; MS ml/z 434 rido [2,3-d]pyrimidine; (M+H)+. 110 4-amino-5-(3- 1-(4-(N-methyl- 3-bromo- IR (KBr) 3443, bromophenyl)-7-(4-(N- N- benzaldehyde 1699. 1635, 1606, methyl-N- trifluoroacetylam 1201 cm-1; MS m/z trifluoroacetylamino)phen ino)phenyl)- 502 (M+H)+. yl)pyrido[2,3- ethanone d]pyrirmidine; 111 4-amino-5-(3- 1-(4- 3-bromo- IR (KBr) 3438, bromophenyl)-7-(4- (dimethylamino)- benzaldehyde 1638. 1592, 1365 (dimethylamino)-3- 3-fluorophenyl)- cm- 1: MS ml/z 438 fluorophenyl)pyrido[2,3- ethanone (M+H)+. d]pyrimidine; 112 4-amino-5-(3- 1-(4-(N-ethyl-N- 3-bromo- IR (KBr) 3477, bromophenyl)-7-(4-(N- formylamino)phe benzaldehyde 1672. 1604, 1580, ethyl-N- nyl)-ethanone 1562. 1353 cm-1; formylamino)phenyl)pyrid MS m,: 448 o[2,3-d]pyrimidine; (M+H)+. 113 4,4-bis(acetylamino)-5-(3- 1-(4-(N-methyl- 3-bromo- IR (KBr) 3434, bromophenyl)-7-(4-(N- N- benzaldehyde 1667. 1635, 1600, methyl-N- acetylamino)phe 1200 cm- 1 ; MS m/z acetylamino)phenyl)pyrido nyl)-ethanone 532 (M+H) +. [2.3-d]pyrimidine; -69- WO 98/46605 PCT/US98/07207 114 4-amino-5-(3- 1-(4-(N-acetyl- 3-bromo- IR (KBr) 3443, bromophenyl)-7-(4-(N- N- benzaldehyde 1667, 1635, 1600, acetyl-N- methylamino)phe 1200 cm-1; MS m/z methylamino)phenyl)pyrid nyl)-ethanone 532 (M+H) + . o[2,3-d]pyrimidine; 115 4-amino-5-(3- 1-(4-(N- 3-bromo- IR(KBr) 3441, bromophenyl)-7-(4-(N- ethylamino)phen benzaldehyde 1633, 1603, 1572, ethylamino)phenyl)pyrido[ yl)-ethanone 1368 cm- 1 ; MS mlz 2,3-d]pyrimidine; 420 (M+H) + . 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 m/z methoxyethyl)amino)phen ino)phenyl)- 464 (M+H) + . yl)pyrido[2,3- ethanone d]pyrimidine; 117 4-amiino-5-(3- 1-(-(N- 3-bromo- IR (KBr) 3430, bromophenyl)-7-(4-(N- isopropylamino) benzaldehyde 1632, 1600, 1578, isopropylamino)phenyl)py phenyl)-ethanone 1530, 1357 cm-; rido[2,3-d]pyrimnidine; 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, 1118 methoxyethyl)amino)phen ino)phenyl)- cm-1; MS m/z 506 yl)pyrido[2,3- ethanone (M+H)+. d]pyrimidine; 119 4-amino-5-(3- 1-(4-N-(3- 3-bromo- IR (KBr) 3201, bromophenyl)-7-(4-N-(3- methoxypropion benzaldehyde 1679, 1617, methoxypropionyl)-N- yl)-N-isopropyl- 1597,1576, 1539, isopropyl- anmino)phenyl)- 1177, 1117 cm-1; amino)phenyl)pyrido[2,3- ethanone MS m/z 521 d]pyrimidine; (M+H)+. 120 4-amino-5-(3- 1-(4-N-(2- 3-bromo- IR (KBr) 3475, bromophenyl)-7-(4-N-(2- (dimethylamino) benzaldehyde 1681, 1579, 1351, (dimethylamino)ethyl)-N- ethyl)-N- cm- 1 ; MS m/z 491 formylamino)phenyl)pyrid formylamino)phe (M+H)+. o[2,3-d]pyrimidine; nyl)-ethanone 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)anmi ethyl)amino)phe 1359 cm- 1 ; MS m/z no)phenyl)pyrido[2,3- nyl)-ethanone 463 (M+H) + . d]pyrimidine; 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, 1352 cyano)ethylamino)phenyl) o)phenyl)- cm- 1 ; MS m/l: 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, 1352 methoxy)propionylamino) ylamino)phenyl)- 1114 cm- 1 ; MS m/z phenyl)pyrido[2,3- ethanone 478 (M+H) + . d]pyrimidine; -70- WO 98/46605 PCT/US98/07207 124 4-amino-5-(3- 1-(3-methyl-4- 3-bromo- IR (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)pyrid nyl)-ethanone MS m/z 448 o [2,3-d]pyrinmidine; (M+H)+. 125 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 m/z methylamino)phenyl)pyrid nyl)-ethanone 420 (M+H) + . o[2,3-d]pyrimidine; 126 4-amino-5-(3- 1-(4-(4- 3-bromo- IR (microscope) bromophenyl)-7-(4-(4- methoxy-2- benzaldehyde 3473, 3063, 1710, methoxy-2- butyl)phenyl)- 1671, 1582,1564, butyl)phenyl)pyrido[2,3- ethanone 1352 cm- 1 ; MS m/z 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 m/z 463 phenyl)pyrido[2,3- -ethanone (M+H)+. d]pyrimidine; 128 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)phe mino)phenyl)- 1205, 1151 cm-1; nyl)pyrido[2,3- ethanone MS m/z 516 d]pyrimidine; (M+H)+. 129 4-amino-5-(3- 1-(3-methyl-4- 3-bromo- IR (KBr) 3484, bromophenyl)-7-(3- (N-acetyl-N- benzaldehyde 1663, 1607, methyl-4-(N-acetyl-N- methylamino)phe 1574,1547, 1354 methylamino)phenyl)pyrid nyl)-ethanone cm- 1 ; MS m/z 462 o[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]pyrimidine; (M+H)+. 131 4-amino-5-(3- 1-(4- 3-cyano- IR (KBr) 3479, cyanophenyl)-7-(4- methylsulfonylp benzaldehyde 1638, 1576,1559, methylsulfonylphenyl)pyri henyl)-ethanone 1303, 1147 cm- 1 ; do[2,3-d]pyrimidine; MS m/z 402
(M+H)
+ . 132 4-amino-5-(3- 1-(4-(N-methyl- 3- IR (KBr) 3418, cyanophenyl)-7-(4-(N- N-formylamino)- cyanobenzaldehy 2230, 1688, 1674, methyl-N-formylamino)- phenyl)-ethanone de 1584, 1554, 1114 phenyl)pyrido[2.3- cm- 1 ; MS m/z 381 d]pyrimidine; (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)+. -71- WO 98/46605 PCT/US98/07207 134 4-amino-5-(3- 1-(6- 3-bromo- IR (KBr) 3487, bromophenyl)-7-(6- morpholinyl-3- benzaldehyde 3396, 1601, 1580, morpholinyl-3- pyridinyl)- 1558, 1234cm- 1 ; pyridinyl)pyrido[2,3- ethanone MS m/z 463 d]pyrimidine; (M+H)+. 135 4-amino-5-(3- 1-(6-(N-methyl- 3-bromo- IR (KBr) 3476, bromophenyl)-7-(6-(N- N- benzaldehyde 3307, 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]pyrimidine; 136 4-amino-5-(3- 1-(6- 3-bromo- IR (KBr) 3487, bromophenyl)-7-(6- pyrrolidinyl-3- benzaldehyde 3396, 1601, 1580, pyrrolidinyl-3- pyridinyl)- 1558, 1234 cm-1; pyridinyl)pyrido[2,3- ethanone MS m/z 447 d]pyrimidine; (M+H)+. 137 4-amino-5-(3- 1-(2- 3-bromo- IR (microscope) bromophenyl)-7-(2- (dimethylamino)- benzaldehyde 3442 1640, 1604, (dimethylamino)-5- 5-pyrimidinyl)- 1577, 1536, 1408, pyrimidinyl)pyrido[2,3- ethanone 1367, 1348 cm-1; d]pyrimidine; MS m/z 422
(M+H)
+ . 138 4-amino-5-(3- 1-(2-(N- 3-bromo- IR (microscope) bromophenyl)-7-(2-(N- methoxyethyl-N- benzaldehyde 3439, 1640, 1606, methoxyethyl-N-methyl methyl amino)-5- 1587, 1556, 1537, amino)-5- pyrimidinyl)- 1374, 1347 cm- 1 ; pyrimidinyl)pyrido[2,3- ethanone MS m/z 466 d]pyrimidine; (M+H)+. 139 4-amino-5-(3- 1-(2-(N-formyl- 3-bromo- IR (microscope) bromophenyl)-7-(2-(N- N-methyl benzaldehyde 3472, 1687, 1583, formyl-N-methyl amino)- amino)-5- 1565, 1459, 1353, 5-pyrimidinyl)pyrido[2,3- pyrinmidinyl)- 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- benzaldehyde 3483, 1605, 1550, methylamino)5- pyrimidinyl)- 1346 cm-1; MS m/z pyrimidinyl)pyrido[2,3- ethanone 408 (M+H) + . d]pyrimidine; 141 4-amino-5-(3- 1-(2- 3-bromo- IR (KBr) 3468, bromophenyl)-7-(2-(1- pyrrolidinyl-5- benzaldehyde 1600, 1581, 1552, pyrrolidinyl)-5- pyrimnidinyl)- 1527, 1482, 1330 pyrimidinyl)pyrido[2,3- ethanone cm- 1 : MS m/z 448 d]pyrimidine; (M+H)+. 142 4-amino-5-(3- 1-(2- 3-bromo- IR (microscope)? bromophenyl)-7-(2-(1- morpholinyl-5- benzaldehyde cm- 1; MS m/z 463 morpholinyl)-5- pyrimidinyl)- (M+H)+. pyrimidinyl)pyrido[2,3- ethanone d]pyrimidine; -72- WO 98/46605 PCT/US98/07207 143 4-amino-5-(3- 1-(6-(2-oxo-3- 3-bromo- IR (microscope) bromophenyl)-7-(6-(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-5-(3- 1-(2-pyridyl)- 3-bromo- IR (microscope) bromophenyl)-7-(2- ethanone benzaldehyde 3427. 3017, 1601, pyridyl)pyrido[2,3- 783 cm- 1 ; MS m/z d]pyrimidine; 351/353 (M+H) + . 145 4-amino-5-(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- dimethylaminoph yl)-benzaldehyde 3482, 2922, 1578, dimethylaminophenyl)pyri enyl)-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- dimethylaminoph benzaldehyde 3479, 3104, 1559, dimethylaminophenyl)pyri enyl)-ethanone 1356 cm-1; MS m/z do[2,3-d]pyrimidine; 420/422 (M+H) + . 148 4-amino-5-(3-(3- 1-(4- 3-(3- IR (microscope) methoxyphenyl)phenyl)-7- dimethylaminoph methoxyphenyl)- 3477. 2924, 1579, (4- enyl)-ethanone benzaldehyde 1356 cm-1; MS m/z dimethylaminophenyl)pyri 420/422 (M+H) + . do[2,3-d]pyrimidine; 149 4-amino-5-phenyl-7-(4- 1-(4- benzaldehyde IR (microscope) dimethylaminophenyl)pyri dimethylaminoph 3477, 3298, 1580, do[2,3-d]pyrimidine; enyl)-ethanone 1355 cm-1; MS m/z 315 (M+H) + . 150 4-amino-5-(3- 1-(4- 3-chloro- IR (microscope) chlorophenyl)-7-(4- (morpholinyl)ph benzaldehyde 3480. 3056, 1579, (morpholinyl)phenyl)pyrid enyl)-ethanone 1356 cm-1; MS m/z o[2,3-d]pyrimidine; 391 (M+H) + . 151 4-amino-5-(3-bromo-4- 1-(4- 3-bromo-4- IR (microscope) fluorophenyl)-7-(4- (morpholinyl)ph fluoro- 3491, 3044, 1560, (morpholinyl)phenyl)pyrid enyl)-ethanone benzaldehyde 1230 cm-1; MS m/z o[2,3-d]pyrimidine; 453 (M+H) + . 152 4-amino-5-(3- 1-(4- 3-chloro- IR (microscope) chlorophenyl)-7-(4- iodophenyl)- benzaldehyde 3478, 3280, 1539, iodophenyl)pyrido[2,3- ethanone 1350 cm-1; MS m/z d]pyrimidine; 432 (M+H) + . 153 4-anmino-5-(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]pyrimidine; 154 4-amino-5-(3- 1-(4-(5- 3-chloro- IR (microscope) chlorophenyl)-7-(4-(5- pyrimidinyl)phen benzaldehyde 3477. 3040, 1578, pyrimidinyl)phenyl)pyrido yl)-ethanone 1351 cm-1; MS m/z [2,3-d]pyrimidine; 459 (M+H) + . -73- WO 98/46605 PCT/US98/07207 155 4-amrino-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]pyrimidine; 494/496 (M+H) + . 156 4-amino-5-(4- 1-(4- 4- IR(microscope) bromothiophene-2-yl)-7- methoxyphenyl)- bromothiophene- 3460. 3300, 2900 (4- ethanone 2- 3100, 1700, 1580, methoxyphenyl)pyrido[2, carboxaldehyde 1510 cm-1; MS m/z 3-d]pyrimidine; 413 (M+H) + . Example 157 4-amino-5-(3-bromophenyl)methyl-7-(4-(dimethylamino)phenvyl)pyrido r2,3-d]pyrimnidine hydrochloride 5 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 reflux for 2 hours. The reaction mixture was cooled and added to a mixture of 8 g of ammonia in 150 mL of ethanol. After 16 hours at 25 'C, the reaction 10 was heated at reflux for two hours, and the solvent was removed in vacuo. The residue was purified by chromatography, then converted to the hydrochloride salt by treatment with ether/HC1, 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: 15 step 157a: preparation of 3-bromophenylacetaldehyde (the "R 3 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 20 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 o-(triphenylphosphonium)-4-(dimethylamino)phenvlethan- 1-one 25 chloride Following the procedure of Fukui et al. (J. Org. Chem. 33: 3594-3507 (1968)), co bromo-(4-dimethylaminophenyl)ethan-1-one (the "R 4 reagent", CAS #37904-72-6; Chem. Abst. (1956), 864) was treated with triphenylphosphine in triethylamine and acetonitrile. The c(-bromo-(4-dimethylaminophenyl)ethan-1-one was prepared by bromination with 30 bromine in hydrobromic acid according to the method of Suzuki et al (J. Pharm. Soc. Japan, -74- WO 98/46605 PCT/US98/07207 (1955), 75:54. Removal of solvent and recrystallization from methanol/ethyl acetate/toluene gave the title product as a white powder. step 157c: preparation of 1-(4-(dimethvlamino)phenvl)-4-(3-bromophenyl)-but-2-en-1-one 5 20 g of (-(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 10 compound. The cis/trans mixture was taken to the next step without separation of the isomers. step 157d: preparation of 3-cvano-4-(3-bromophenvyl)methyl-6-(4 (dimethyl)aminophenvyl)pyridine-2-amine 15 A mixture of 1-(4-(dimethylamino)phenyl)-4-(3-bromophenyl)-but-2-en- 1-one chloride (3.85 g, from step c), ammonium acetate (2.6 g) and malononitrile (739 mg) in 3 mL of dimethoxyethane and 22 mL of ethanol was heated at 115 oC 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 20 compound. Examples 158-174 Following the procedures of Example 157, except substituting the appropriate reagents for the R 4 and R 3 reagents of Example 157 as indicated in Table 3 below, 25 compounds of Examples 158-174 were prepared. The treatment with aqueous HCI was omitted, and the free bases were obtained except as indicated. In Examples 167-174, the formamide or formamidine acetate (added periodically until the reaction was complete) treatment was replaced by treatment with triethyl orthoformate at reflux in the presence of a catalytic amount of ammonium sulfate, followed 30 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 oC for 1-8 hours. The reaction mixture was cooled to room temperatureand purified by chromatography, and the product was recrystallized if necessary (chloroform in methanol). 35 -75- WO 98/46605 PCT/US98/07207 Table 3 Examples 158-187 E x. Name R 4 Reagent R 3 Reagent Analytical Data No. (for 7- (for 5 position) position 158 4-amnino-5-(2- ' 1-(4- 3-phenyl- IR (KBr) 3340,3240 phenylethyl)-7-(4- diethylaminophe propionaldehyde 2800,1600,1580,1540; diethylaminophenyl)py nyl)-ethanone H. Res. MS m/z rido[2,3-d]pyrimidine 398.2343 (M+-H) + . 159 4-amino-5-(2- 1-(4- 3-methyl- IR (KBr) methylpropyl)-7-(4- diethylaminophe butanaldehyde 3550,3410,3320, 3240 diethylan-minophenyl)py nyl)-ethanone 2800,1605,1580,1560 rido[2,3-d]pyrimidine H. Res. MS m/z 350.2357 (M+H) + . 160 4-amino-5-(butyl)-7- 1-(4- pentanaldehyde IR (KBr) (4- diethylaminophe 3450,3300,3200 diethylaminophenyl)py nyl)-ethanone 2800,1660,1610,1580,1 rido[2,3-d]pyrimidine 540 H. Res. MS m/z 350.2354 (M+H) + . 161 4-amnino-5-(2-(4- 1-(4- 4-(4- IR (KBr) bromophenyl)ethyl)-7- diethylaminophe bromophenyl)- 3500,3300,3200 (4- nyl)-ethanone propionaldehyde 3000,1650,1615,1580 diethylaminophenyl)py H. Res. MS m/z rido[2,3-d]pyrimidine 478.1429 (M+H) + . 162 4-amino-5-(butyl)-7- * IR (KBr) (4- 3400,3350,3200 dimethylaminophenyl) 2900,1650,1620,1580,1 pyrido[2,3- 570 H. Res. MS m/z d]pyrinmidine 322.2032 (M+H) + . 163 4-amino-5-(2-(3- 1-(4- 3-cyanophenyl- IR (KBr) 2850 cyanophenyl)methyl)- dimethylaminoph acetaldehyde 3550,2220,1610,1580,1 7-(4- enyl)-ethanone 560,1540 MS m/z 381 dimethylaminophenyl)
(M+H)
+ . pyrido[2,3 d]pyrimidine 164 4-amino-5-(2-(N- 1-(4- 3-(N- IR (KBr) 3000 carbobenzyloxy)amino dimethylaminoph carbobenzyloxy) 3500,1710,1690,1650,1 ethyl)-7-(4- enyl)-ethanone - 590 H. Res. MS m/z dimethylaminophenyl) aminopropionald 443.2184 (M+H) + . pyrido[2,3- ehyde d]pyrimidine 165 4-amino-5- 1-(4- cycloheptane- IR (KBr) (cycloheptyl)-7-(4- dimethylaminoph carboxaldehyde 3500,3250,3100,2950,2 dimethylaminophenyl) enyl)-ethanone 850,1620,1575 H. Res. pyrido[2,3- MS m/z 362.2349 d]pyrimidine (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 m/z pyrido[2,3- 472.1363 (M+H) + . d]pyrimidine -76- WO 98/46605 PCT/US98/07207 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 m/z 364 (M+H)+; H. Res. MS m/z 364.2506
(M+H)
+ . 168 4-amino-5-hexyl-7-(4- 1-(4- heptanal IR (KBr) diethylamninophenyl)- diethylaminophe 3440,3310,3240 pyrido[2,3- nyl)-ethanone 2800,1580,1560,1540,1 d]pyrimidine 350; mp. 215-217; MS m/z 378 (M+H)+; H. Res. MS m/z 378.2654
(M+H)
+ . 169 4-amino-5-(2-(3- 1-(4- 3-(3- IR (KBr) 3640 bromophenyl)ethyl)-7- diethylaminophe bromophenyl)- 3240,3200 (4- nyl)-ethanone propionaldehyde 2800,1580,1555,1535,1 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+H) + . 170 4-amino-5-((2- 1-(4- 2-(2- IR (KBr) 3640 bromophenyl)methyl)- diethylaminophe bromophenyl)- 3240,3240 7-(4- nyl)-ethanone acetaldehyde 2800,1580,1555,1540,1 diethylanminophenyl)- 350; mp. 130-133; MS pyrido[2,3- m/z 462/464 (M+H)+; d]pyrimidine H. Res. MS m/z 462.1297 (M+H) + . 171 4-amino-5- 1-(4- cyclopropanecar IR (KBr) cyclopropyl-7-(4- dimethylaminoph boxaldehyde 3490,3290,3240 dimethylaminophenyl) enyl)-ethanone 2760,1610,1580,1540,1 -pyrido[2,3- 375; mp. 235-237; MS d]pyrimidine m/z 462/464 (M+H)+; 172 4-amino-5-cyclohexyl- 1-(4- cyclohexanecarb IR (KBr) 3640 7-(4- dimethylaminoph oxaldehyde 3000,2980 dimethylaminophenyl) enyl)-ethanone 2760,1610,1580,1540,1 -pyrido[2,3- 345; mp. 231-234; MS d]pyrimidine m/z 462/464 (M+H)+; 173 4-amino-5-((2-bromo- 1-(4- 2-(2-bromo-5- IR (KBr) 3460,3220 5- dimethylaminoph chlorophenyl)- 2760,1610,1575,1535,1 chlorophenyl)methyl)- enyl)-ethanone acetaldehyde 365; mp. 185-187; MS 7-(4- m/z 462/464 (M+H)+; diethylaminophenyl) pyrido[2,3 d]pyrimidine 174 4-amino-5-methyl-7- 1-(4- acetaldehyde IR (KBr) 3640 (4- dimethylamrninoph 3250,3250 diethylaminophenyl)- enyl)-ethanone 2760,1610,1585,1560,1 pyrido[2,3- 350: mp. 238-246: MS d]pyrimidine m/z 462/464 (M+H)+; * prepared from the compound of Example 157 by reaction with Pd(PPh 3
)
4 and zinc cyanide in DMF under Suzuki reaction conditions. -77- WO 98/46605 PCT/US98/07207 ** prepared from the compound of Example 173 by reaction with 2-thiopheneboronic acid, Pd(PPh 3
)
4 and aqueous sodium carbonate under Suzuki reaction conditions. Examples 175-188 5 Following the procedures of Example 1, except substituting the appropriate reagents for the R 4 and R 3 reagents of Example 1 as indicated in Table 4 below, compounds of Examples 175-188 were prepared. The treatment with aqueous HCI was omitted, and the free bases were obtained except as indicated. 10 Table 4 Examples 175-188 Ex. Name R 4 Reagent R 3 Reagent Analytical Data No. (for 7- (for 5 position) position 175 4-amino-5-(2,3- 1-(4- 2,3- IR (KBr) 3500 methylenedioxyphenyl dimethylaminoph methylenedioxy- 2500,1595,1580,1375; )-7-(4- enyl)-ethanone benzaldehyde mp. 290-305; dimethylaminophenyl) -pyrido[2,3 d]pyrimidine 176 4-amnino-5-(3-fluoro- 1-(4- 3-fluoro-5- IR (KBr) 3500,3440 5- dimethylaminoph trifluoromethyl- 3240,3200 trifluoromethylphenyl) enyl)-ethanone benzaldehyde 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 m/z d]pyrimidine 428.1509 (M+H) + . 177 4-amino-5-(2- 1-(4- 2-bromo- IR (KBr) 3480,3440 bromophenyl)-7-(4- dimethylaminoph benzaldehyde 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- 1-(4- 3,5-dimethyl- IR (KBr) 3480,3440 dimethylphenyl)-7-(4- dimethylaminoph benzaldehyde 3240,3200 dimethylaminophenyl) enyl)-ethanone 2800,1610,1575,1555,1 -pyrido[2,3- 535,1360; mp. 284-286; d]pyrimidine MS m/z 370 (M+H)+; H. Res. MS m/z 370.2036 (M+H)+. -78- WO 98/46605 PCT/US98/07207 179 4-amino-5-(3,4- 1-(4- 3,4-dichloro- IR (KBr) 3490,3440 dichlorophenyl)-7-(4- dimethylaminoph benzaldehyde 3240,3200 dimethylaminophenyl) enyl)-ethanone 2800,1610,1575,1560,1 -pyrido[2,3- 535,1355; mp. 288-291; d]pyrimidine MS m/z 410/412 (M+H)+: H. Res. MS m/z 410.0948 (M+H) + . 180 4-amino-5-(4-fluoro- 1-(4- 4-fluoro-3- . IR (KBr) 3500,3440 3- dimethylaminoph trifluoromethyl- 3240,3200 trifluoromethylphenyl) enyl)-ethanone benzaldehyde 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 ml/z 428.1487 (M+H) + . 181 4-amino-5-(3-bromo- 1-(4- 3-bromo-5- IR (KBr) 3470,3440 5-methoxyphenyl)-7- morpholinylphen methoxy- 3240,3200 (4- yl)-ethanone benzaldehyde 2800,1605,1580,1560; morpholinylphenyl)- mp. 257-260; MS m/z pyrido[2,3- 492/494 (M+H) + . d]pyrimidine 182 4-amino-5-(3-bromo- 1-(4- 3-bromo-5- IR (KBr) 3470,3440 5-methoxyphenyl)-7- pyrrolidinylphen methoxy- 3240,3200 (4- yl)-ethanone benzaldehyde 2800,1610,1580,1560,1 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- IR (KBr) 3470,3440 5-methoxyphenyl)-7- piperidinylpheny methoxy- 3240,3200-2800,1565; (4-piperidinylphenyl)- 1)-ethanone benzaldehyde mp. 224-244; MS m/z pyrido[2,3- 490/492 (M+H)+; d]pyrimidine 184 4-amino-5-(3-bromo- 1-(4- 3-bromo-5- IR (KBr) 3470,3420 5-methoxyphenyl)-7- dimethylaminoph methoxy- 3240,3200 (4- enyl)-ethanone benzaldehyde 2800,1610,1575,1555,1 dimethylaminophenyl) 535,1355: mp. 262-266; -pyrido[2,3- MS m/z 450/452 d]pyrimidine (M+H)+: H. Res. MS m/z 450.0944 (M+H) + . 185 4-amino-5-(3- 1-(4- 3-methylthio- IR (KBr) 3460,3420 methylthiophenyl)-7- dimethylaminoph benzaldehyde 3240,3200 (4- enyl)-ethanone 2800,1605,1575,1560,1 dimethylaminophenyl) 535,1355: mp. 184-220; -pyrido[2,3- MS m/z 388 (M+H)+; d]pyrimidine H. Res. MS m/z 388.1586 (M+H) + . -79- WO 98/46605 PCT/US98/07207 186 4-amino-5-(3-bromo- 1-(thiophene-2- 3-bromo-5- IR (KBr) 3470,3350 5-methoxyphenyl)-7- yl)-ethanone methoxy- 2200,1700,1640,1580,1 (thiophene-2-yl)- benzaldehyde 435,1365,1270; mp. pyrido[2,3- 246-249; MS m/z 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- dimethylaminoph benzaldehyde 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) dimethylaminoph methylsulfonyl- 2800,1610,1580,1555,1 -7-(4- enyl)-ethanone benzaldehyde 535,1355; mp. dimethylaminophenyl) 245-270; MS m/z 420 -pyrido[2,3- (M+H)+; H. Res. MS d]pyrimidine m/z 420.1493 (M+H) + . Example 189 4-acetylamino-5-(3-bromophenyl)-7-(4-dimethylaminophenyl)pyridor2,3-d]pyrimidine 5 A suspension of 4-amnino-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 (SiO 2 , EtOAc/hexanes) to 10 provide the title compound (0.23 g, 73% theoretical): IR (KBr) 3368, 3048, 1695, 1567; MS m/z 462/464 (M+H) + . Examples 190-198 Following the procedures of Example 189, except substituting the appropriate 15 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 20 E x. Name Acylating Analytical Data No. Reagent -80- WO 98/46605 PCT/US98/07207 190 4 -formylamino-5-(3- acetic anhydride and IR (KBr) 3382, 3047, bromophenyl)-7-(4- formic acid 1704, 1570; dimethylaminophenyl)- MS m/z 448/450 pyrido[2,3-d]pyrimidine-- 190 (M+H) +. 191 4-(methoxyacetyl)an-mino-5-(3- methoxyacetyl IR (KBr) 3344, 3044, bromophenyl)-7-(4- chloride 1731, 1561: MS m/z diethylaminophenyl)-pyrido[2,3- 492/494 (M+H) + . d]pyrimidine 192 4-trifluoroacetylamino-5-(3- trifluoroacetic IR (KBr) 3426, 3072, bromophenyl)-7-(4- anhydride 1610, 1578: MS m/z dimethylaminophenyl)- 516/518 (M+H) + . pyrido[2,3-d]pyrimidine 193 4-pentanoylamino-5-(3- pentanoyl chloride IR (KBr) 3408, 2954, bromophenyl)-7-(4- 1699, 1569; MS m/z dimethylaminophenyl)- 504/506 (M+H) +. pyrido[2,3-d]pyrimidine 194 4-benzoylamino-5-(3- benzoic anhydride IR (KBr) 3420, 3056, bromophenyl)-7-(4- 1606, 1583; MS m/z dimethylaminophenyl)- 524/526 (M+H) + . pyrido [2,3-d]pyrimidine 195 4-(N-BOC-glycyl)amino-5-(3- N-BOC-glycyl- IR (KBr) 3362, 2975, bromophenyl)-7-(4- imidazole 1719, 1570; MS m/z dimethylaminophenyl)- 577/579 (M+H) + . pyrido[2,3-d]pyrimidine 196 4-(N-phthalimidylglycyl)amnino-5- N-phthalimidyl- IR (KBr) 3408, 2927, (3-bromophenyl)-7-(4- glycyl-chloride 1719, 1570; MS m/z dimethylaminophenyl)- 607/609 (M+H) + . pyrido [2,3-d]pyrimidine 197 4-(ethoxycarbonyl)amino-5-(3- diethyl dicarbonate IR (KBr) 3405, 2987, bromophenyl)-7-(4- 1738, 1569; MS m/z dimethylaminophenyl)- 492/494 (M+H) + . pyrido[2,3-d]pyrimidine 198 4-(ethylaminocarbonyl)amino-5- ethyl isocyanate IR (KBr) 3405, 3053, (3-bromophenyl)-7-(4- 1701, 1548; MS m/z dimethylaminophenyl)- 491/493 (M+H) + . pyrido[2,3-d]pyrimidine Example 199 4 -allvlamino-5-(3-bromophenyl)-7-(4-dimethylaminophenyl) pyrido [2,3-d] pyrimidine 5 The product was prepared by treating a solution of 4-chloro-5-(p dimethylaminophenyl)-7-(p-bromophenyl)pyrido[2,3-d]pyrimidine in CH 2 Cl 2 -TEA with allylamine and heating the resulting mixture at reflux for 1 hour. The volatiles were removed under reduced pressure, and the residue was purified by flash chromatography (SiO 2 , EtOAc/hexanes) to provide the title compound IR (KBr) 3437, 1564, 1355, 1195; 10 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. -81- WO 98/46605 PCT/US98/07207 A sample of 4-(4-bromophenyl)-3-cyano-6-(4-(dimethylamino)phenyl)pyridine-2 amine (from Example 1, 5.0 g, 12.7 mmol) in 20 mL of H 2
SO
4 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 5 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 POCl 3 (15 mL) then 10 warmed at 100 oC for 2 hours. The POC1 3 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. 15 Example 200 4-(2-(N,N-dimethylamino)ethylamino)-5-(4-bromophenvyl)-7-(4-dimethylaminophenvyl) pvrido [2,3-d] pyrimidine trihydrochloride The product was prepared by treating a solution of 4-chloro-5-(p 20 dimethylaminophenyl)-7-(p-bromophenyl)pyrido[2,3-d]pyrimidine (prepared as in Example 199) in CH2Cl2-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 (SiO 2 , EtOAc/hexanes) to provide the title compound. The product was treated with excess 2M HCI (aq) followed by lyophilization to 25 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-dimethylamino)butvlamino)-5-(3-bromophenvl)-7-(4 30 dimethylaminophenyl) pyrido [2.3-d] pyrimidine tetrahydrochloride The product was prepared by treating a solution of 4-amino-5-(p dimethylaminophenyl)-7-(p-bromophenyl)pyrido[2,3-d]pyrimidine in CH 2 Cl 2 -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 35 purified by flash chromatography (SiO 2 , EtOAc/hexanes). The product was treated with excess 2M HCI (aq) followed by lyophilization to give the product as the -82- WO 98/46605 PCT/US98/07207 tetrahydrochloride salt; IR (KBr) 3439, 1567, 1356, 1196; MS m/z 519/521 (M+H)+. Example 202 5 4- (N-allvl-N-formvlamino)-5-(4-dimethylaminophenvyl)-7 (p-bromophenyl)pyridor2.3-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 0 C was treated with NaH (60% 10 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, 1193. 15 Example 203 4-diacetylamino-5-(4-dimethylaminophenvyl)-7-(p-bromophenyl) pyridor 2,3-dlpyrimidine This compound was isolated as a minor product from the reaction mixture of 20 Example 190 above: LRMS m/z 504/506. IR (cm') 2922, 1726, 1550, 1360, 1197. Example 204 4-amino-5-(3-bromophenyl)-7-(5-amino-2-pyridvl)pyrido[2,3-d]pyrimidine 25 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 30 (SiO 2 , EtOAc-CH 2 Cl 2 ). LRMS m/z 366/368. The intermediate was suspended in 15 mL of formamide, and the reaction mixture was heated at 180 oC for 4 hours. The solution was cooled to 25 C, 10 mL of 4M HCI (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 35 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: -83- WO 98/46605 PCT/US98/07207 204a. 5-amino-2-bromopyridine A solution of 2-bromo-5-nitropyridine (5.1 g, 25 mmol) in 50 mL of a 10:1 mixture of acetic acid and water was treated with iron powder (7.8 g, 140 mmol) in several portions over 20 minutes. After an additional 30 minutes the volatiles were removed under reduced 5 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%). 10 204b. 5-aminopyridine-2-ethanone A sample of 5-amino-2-bromopyridine (4.25 g, 24 mmol), PdC1 2 (PPh 3
)
2 (0.34 g, 2 mole%), Cul (0.09 g, 2 mole%), and trimethylsilylacetylene (3.0 g, 31 mmol) were dissolved in 100 mL of a 4:1 mixture of triethylamine and acetonitrile, and the reaction mixture was stirred 24 hours at 25 oC. The reaction mixture was concentrated, and the 15 residue was dissolved in 100 mL of a 10:1 mixture of acetone and water. Hg(O 2
CCF
3
)
2 (11.1 g, 26 mmol) and H 2
SO
4 (72 mmol) were added to the reaction mixture, and the solution was heated at reflux for 2 hours. The reaction mixture was cooled to 25 0 C and neutralized with saturated aqueous sodium carbonate. The aqueous layer was extracted with methylene chloride, then the combined organic layer was dried (Na 2
SO
4 ) and concentrated 20 in vacuo. Flash chromatography (SiO2, EtOAc-Hexanes) provided the title compound: LRMS m/z 137 (M = H+); IR (cm- 1 ) 3428, 1668, 1646, 1582, 1358, 1274. Example 205 4-amino-5-(3-bromophenvyl)-7-(5-dimethylamino-2-pyridvyl)pyrido[2.3-d]pyrimidine 25 trihydrochloride salt Following the procedure of Example 204, 5-dimethylaminopyridine-2 ethanone was reacted with bromobenzaldehyde, malononitrile, and ammonium acetate to give the title compound. The residue was triturated with excess HCl/ether, the 30 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: 35 205a..3-N,N-dimethylaminopyridine A solution of 3-aminopyridine (9.4 g, 0.10 mol) in a 1:1 mixture of formic acid (96%) and formaldehyde (37% aqueous solution) was heated at reflux for 18 hours. The volatiles were removed under reduced pressure and the residue was -84- WO 98/46605 PCT/US98/07207 neutralized with saturated aqueous NaHCO 3 . The aqueous layer was extracted with
CH
2 Cl 2 , then the combined organic layer was dried (Na 2
SO
4 ) and concentrated under reduced pressure. Flash chromatography (SiO2, EtOAc-Hexanes) provided the title compound: (11.1 g, 91%), LRMS m/z 123 (M + H+). 5 205b. 2-bromo-5-N, N-dimethylaminopyridine A solution of 3-NN-dimethylaminopyridine (5.88 g, 48.1 mmol) in 150 mL of CH2Cl2 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 10 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-dimethylamniinopyridine-2-ethanone Following the procedure of Example 203b, 2-bromo-5-N,N 15 dimethylaminopyridine, except converting the compound to the trihydrochloride salt by treatment with HCI/ether, was converted to the title compound: LRMS m/z 165; IR (cm-1) 3480, 1666, 1581, 1368, 1272. Example 206 20 4-amino-5-(3-bromophenyl)-7-(5-dimethylamino-2-pyrazinvyl) pyrido[2.3-dlpyrimidine hydrochloride Following the procedure of Example 204, 5-dimethylaminopyrazine-2 ethanone was reacted with bromobenzaldehyde, malononitrile, and ammonium acetate 25 to give the title compound. The residue was triturated with excess HCI/ether, the volatiles were removed under reduced pressure, and the title compound was dried under high vacuum: LRMS m/z 422/424. IR (cm 1 ) 3310, 1630, 1525, 1444, 1375. The 5-dimethylaminopyrazine-2-carboxaldehyde starting material was prepared as follows: 30 206a. 5-dimethylaminopvrazine-2-ethanone A solution of 5-hydroxypyrazine-2-carboxylic acid (4.0 g, 28.5 mmol) in 50 mL of thionyl chloride and 0.1 mL of DMF was heated at reflux for 8 hours. The volatiles were removed under reduced pressure, and the residue was dissolved in 20 35 mL of toluene. This solution was added to a solution of dimethyl malonate (4.75 g, 36 mmol), MgCl 2 (2.09 g, 22 mmol) and triethyl amine (7.08 g, 70 mmol) in 100 mL of toluene. The reaction mixture was stirred for 1 hour at 25 C, quenched by addition of water, and the product was extracted with methylene chloride. The solvent was -85- WO 98/46605 PCT/US98/07207 removed, the crude intermediate was dissolved in 25 mL of a 25:1 mixture of DMSO and water, and the resulting solution was warmed at 150 °C for 2 hours. The reaction was quenched by addition of water, and the product was extracted with methylene chloride to provide 2-acetyl-5-chloropyrazine (LRMS m/z 156). This intermediate was 5 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 10 4-amino-5-(3-bromophenvl)-7-(2-oxobenzoxazolin-6-vyl)1pyrido[2,3-d]pyrimidine Following the procedure of Example 204, 2-oxobenzoxazolin-6-ethanone was reacted with bromobenzaldehyde, malononitrile, and ammonium acetate to prepare the title compound: LRMS m/z 434/436; IR (cm') 3095, 1760, 1579, 1481, 1350. 15 The 2-oxobenzoxazolin-5-ethanonestarting material was prepared as follows: 207a. 2-oxobenzoxazolin-6-ethanone DMF (9 mL) was added dropwise to AlCl 3 (58.7 g, 440 mmol) over 20 minutes and the resulting suspension was stirred 15 minutes at 25 'C. Acetic 20 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/H 2 0. The resulting precipitate was collected by filtration and dried under vacuum to provide the title compound (6.4 g, 81%, LRMS m/z 177). 25 Example 208 4-amino-5-(3-bromophenvyl)-7-( 1 -methvl-2-oxobenzoxazolin-6-vl) pyvido [2,3-dIpyrimidine 30 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 (cmr') 3440, 1782, 1605, 1458, 1350. The 1-methyl-2-oxobenzoxazolin-5-ethanonestarting material was prepared as 35 follows: 208a. 1-methyl-2-oxobenzoxazolin-5-ethanone -86- WO 98/46605 PCT/US98/07207 A solution of 2-oxobenzoxazolin-5-ethanone (from Example 206a, 2.50 g, 14.1 mmol) in 20 mL of a 4:1 mixture of THF and DMF at 0 oC was treated with NaH (60 % dispersion, 0.8 g, 20 mmol) and the mixture was stirred 20 minutes at 0 0 C. Methyl iodide (3.97 g, 28 mmol) was added and the reaction mixture was warmed to 5 25 'C and stirred for 15 minutes. Saturated aqueous NaHCO 3 was added and the aqueous layer was extracted with CHCl. The desired product (2.55 g, 94%, LRMS m/z 191), was isolated following flash chromatography (SiO 2 , EtOAc-CH 2
C
2 ). Example 209 10 4 -amino-5-((5-chloro-2-(3-methoxvphenvl)phenyl)methyl)-7-(4 dimethylaminophenvl)pyrido[2,3-d]pyrimidine The title compound was prepared from the compound of Example 173 by reaction with 3-methoxyphenylboronic acid, Pd(PPh 3
)
4 and aqueous sodium carbonate under Suzuki reaction conditions. IR (KBr) 3550-3250,3240 15 2760,1580,1560,1540,1350; H. Res. MS m/z 496.1902 (M+H) + . Example 210 4 -amino-5-(( 2 -bromophenyl)methyl)-7-(4-dimethvlaminophenylv)pyrido2,3-d1primnidine Following the procedures of Example 157, except substituting 1-(4 20 dimethylaminophenyl)-ethanone for the R 4 reagent and 2-(2-bromophenyl) acetaldehyde for the R 3 reagent of Example 157, the title compound was prepared as shown in Table 6. Table 6 Ex. Name R 4 Reagent (for R 3 Reagent (for Analytical No. 7-position) 5-position Data 210 4-amino-5-((2- 1-(4- 2-(2- IR (KBr); MS bromophenyl)methyl)- dimethylaminophe bromophenyl)- m/z 434,436 7-(4- nyl)-ethanone acetaldehyde (M+H)+. dimethylaminophenyl) pyrido[2,3 d]pyrimidine 25 Example 211 4-amino-5-(2-((thiophene-2-vl)phenvyl)methyl)-7-(4-diethylaminophenvyl)pyrido r2,3 d1pyrimidine The title compound was prepared from the compound of Example 173 by reaction with 2-thiopheneboronic acid, Pd(PPh 3
)
4 and aqueous sodium carbonate 30 under Suzuki reaction conditions. IR (KBr) 3640-3240, 3240-2800, 1580, 1560, 1540, 1350; H. Res. MS m/z 466.2070 (M+H) + . -87- WO 98/46605 PCT/US98/07207 Example 212 4-amino-5-(2-((thiophene-3-vl)phenvyl)methyl)-7-(4-diethylaminophenvl)pyrido[2,3 d]1pyrimidine 5 The title compound was prepared from the compound of Example 173 by reaction with 3-thiopheneboronic acid, Pd(PPh 3
)
4 and aqueous sodium carbonate under Suzuki reaction conditions. IR (KBr) 3640-3240, 3240-2800, 1580, 1560, 1540, 1350; H. Res. MS m/z 466.2057 (M+H) + . 10 Examples 213-222 Following the procedures of Example 1, except substituting the appropriate reagents for R 4 and R 3 as indicated in Table 7 below, compounds of Examples 212-222 were prepared. 15 Table 7 Examples 213-222 Ex. Name R 4 Reagent (for R 3 Reagent (for Analytical No. 7-position) 5-position Data 213 4-amino-5-(3- 1-(4-(N-formyl-N- 3-bromo- IR (KBr) 3490, bromophenyl)-7-(4- (2- benzaldehyde 1689, 1120, 800 (N-formyl-N-(2- methoxy)ethylamin cm- 1 ; MS m/z methoxyethyl)amino)p o)phenyl)- 478/480 (M+H) + . henyl)pyrido[2,3- ethanone d]pyrimidine; 214 4-amino-5-(3- * IR (KBr) 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]pyrimidine; 215 4-amino-5-(3- 1-(4-(N-methyl-N- 3-bromo- IR (KBr) 3440, bromophenyl)-7-(4- ((2- benzaldehyde 1600, 1160, 810 (N-methyl-N-((2- dimethylamino)eth cm-1; MS m/z dimethylamino)ethyl)a yl)amino)phenyl)- 477/479 (M+H) + . mino)phenyl)pyrido[2, ethanone 3-d]pyrimidine; 216 4-anmino-5-(3- ** IR (KBr) 3480, bromophenyl)-7-(4-(2- 1520.710 cm- 1 ; methoxy)acetylamino) MS m/z 464,466 ethyl)amino)phenyl)py (M+H)+. rido[2,3-d]pyrimidine; -88- WO 98/46605 PCT/US98/07207 217 4-amino-5-(3- *** IR (KBr) 3475, bromophenyl)-7-((4- 1690, 1355, 800 formylamino)phenyl)p cm-1; MS m/z yrido[2,3- 420/422 (M+H) + . d]pyrimidine; 218 4-amnino-5-(3- **** IR (KBr) 3452, bromophenyl)-7-(4-(2- 1605, 1250, 590 (dimethylamino)acetyl cm- 1 ; MS m/z amino)phenyl)pyrido[ 477/479 (M+H)
+
. 2,3-d]pyrimidine; 219 4-amino-5-(3- 1-(4-(2-oxo-3- 3-bromo- IR (KBr) 3480, bromophenyl)-7-(4-(2- oxazolidinyl)pheny benzaldehyde 1750, 1400,700 oxo-3- 1)-ethanone cm- 1 ; MS m/z oxazolidinyl)phenyl)p 462/464 (M+H) + . yrido[2,3 d]pyrimidine; 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, 1282 pyridinyl)pyrido[2,3- cm-1:MS m/z 393 d]pyrimidine (M+H)+. trihydrochloride 221 4-amino-5-(3- 1-(3-methyl-4- 3-bromo- IR (KBr) 3440, bromophenyl)-7-(3- pyrrolidinylphenyl benzaldehyde 1640, 1607, 1586, methyl-4- )-ethanone 1370 cm- 1 ; MS m/z pyrrolidinylphenyl)pyr 433 (M+H) + . ido[2,3-d]pyrimidine dihydrochloride 222 4-amino-5-(3- 1-(6-imidazolyl-3- 3-bromo- IR (KBr) 3028, bromophenyl)-7-(6- pyridinyl)- benzaldehyde 1641, 1607, 1595, imidazolyl-3- ethanone 1375cm-1; MS m/z pyridinyl)pyrido[2,3- 417 (M+H) + . d]pyrimidine trihydrochloride *prepared by deformylation of Example 213 with dilute HCI 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. 5 ****prepared by acylation of Example 213 with the 2-(dimethylamino)acetyl chloride. Examples 223-225 Following the procedures of Example 157, except substituting the appropriate reagents for the R 4 and R 3 reagents of Example 157 as indicated in Table 8 below, 10 compounds of Examples 223-225 were prepared. -89- WO 98/46605 PCT/US98/07207 Table 8 Examples 223-225 E x. Name R 4 Reagent R 3 Reagent Analytical Data No. (for 7- (for 5 position) position 223 4-amino-5- 1-(4- 2-phenyl- IR (KBr) phenylmethyl-7-(4- diethylaminophe acetaldehyde 3450.3380,2850 diethylaminophenyl)py nyl)-ethanone 3200,1605,1580,1560,1 rido[2,3-d]pyrimidine 540; H. Res. MS ml/z 384.2176 (M+H) + . 224 4-amino-5-(2-(3- * IR (KBr) 2400 amninopropynyl)phenyl 3450,2050,2120,1650,1 methyl)-7-(4- 605,1540; MS m/z 437 diethylaminophenyl)py (M+H) + . rido[2,3-d]pyrimidine 225 4-amino-5-(1-(2- 1-(4- 2-(2- IR (KBr) 3520,3250 bromophenyl)ethyl)-7- dimethylaminoph bromophenyl)- 3500,2850 (4- enyl)-ethanone )propionaldehyd 3150,1605,1580,1560,1 dimethylaminophenyl) e 540; H. Res. MS miz pyrido[2,3- 448.1137 (M+H) +. d]pyrimidine *prepared from the compound of Example 170 by reaction with propargylamine, Cul and 5 Pd(PPh 3
)
4 under Suzuki reaction conditions. Examples 226-228 Following the procedures of Example 1, except substituting the appropriate reagents for R 4 and R 3 as indicated in Table 9 below, compounds of Examples 226-228 were 10 prepared. Table 9 Examples 226-228 Ex. Name R 4 Reagent (for R 3 Reagent (for Analytical No. 7-position) 5-position Data 226 4-amino-5-(4- 1-(4- 3-bromo- IR (KBr) 3456, dimethylaminophenyl) bromophenyl)- benzaldehyde 3053, 16600. 1556 -7-(4- ethanone cm- 1 ; MS ml:/z 420 bromophenyl)pyrido[2 (M+H)+. ,3-d]pyrimidine 227 4-amino-5-(2-furanyl)- 1-(4-(N- furan-2- IR (KBr) 3460, 7-(4-(N- morpholinyl)pheny carboxaldehyde 1600, 1580. 1457 morpholinyl)phenyl)- 1)ethanone cm- 1 ; MS m/: 374 pyrido[2,3- (M+H)+. d]pyrimidine -90- WO 98/46605 PCT/US98/07207 228 4-amino-5-(3- 1-(5-(2- 3-bromo- IR (KBr) 3442 bromophenyl)-7-(2- (dimethylamino)py benzaldehyde 1640, 1604, 1577, dimethylamino-5- rimidinyl))ethanon 1536, 1408, 1367, pyrimidinyl)pyrido[2, e 1348 cm- 1 ; MS m/z 3-d]pyrimidine ,422 (M+H) +. Example 229 4-amino-5-(3-bromophenvl)-7-(4-(ureido)phenvyl)pyridor2,3-d]pyrimnidine 5 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 (56 mg, 0.87 mmol), and the reaction mixture was stirred for 30 minutes at 25 'C. The solution was concentrated and the residue was suspended in aqueous NaHCO 3 . The crude product was collected by filtration, then purified by flash chromatography. The 10 product was dissolved in methanol and treated with excess 2M aqueous HC1 to provide the hydrochloride salt: LRMS m/z 435/437. IR (cm') 3442, 2212, 3186, 3059, 1681, 1582, 1525, 1358. Example 230 15 4-amino-5-(1-phenylmethyl-3-piperidinvyl)-7-(4-diethylaminophenyl)pyrido[2,3 dpyrijidine Following the procedures of Example 157, except substituting 1-(4-diethylamino phenyl)-ethanone for the R 4 reagent and 1-phenylmethylpiperidine-3-carboxaldehyde 20 (prepared as described by Gilligan et al., J. Med. Chem., 35:4344-4361 (1992)) for the R 3 reagent thereof, the title compound was prepared. The treatment with aqueous HCI was omitted, and the free base was obtained. IR (KBr) 3440, 3100-2800-1640, 1605, 1595, 1535 cm- 1 ; MS m/z 467 (M+H)+; mp 218-220 'C. 25 Examples 231-243 Following the procedures of Example 1, except substituting the appropriate reagents for R 4 and R 3 as indicated in Table 10 below, compounds of Examples 230-243 were prepared. In some cases, the treatment with aqueous HC1 was omitted, and the free bases were obtained. 30 -91- WO 98/46605 PCT/US98/07207 Table 10 Examples 231-243 E x. Name R 4 Reagent R 3 Reagent Analytical No. (for 7- (for 5- Data position) position 231 4-amino-5-(3- 1-(6-(3-methyl- 3-bromo- IR (KBr) 3484, 1635, bromophenyl)-7-(6-(3- 5-isoxazolyl))-3- benzaldehyde 1574, 1562, 1352 methyl-5-isoxazolyl))-3- pyridinyl)- cm-1; MS m/z 459 pyridinyl)pyrido[2,3- ethanone (M+H)
+
. d]pyrimidine; 232 4-amino-5-(3- 1-(6-chloro-3- 3-bromo- IR (KBr) 3478, 1608, bromophenyl)-7-(6- pyridinyl)- benzaldehyde 1574, 1542 cm-1; chloro-3- ethanone MS m/z 414 pyridinyl)pyrido[2,3- (M+H) +. d]pyrimidine; 233 4-amino-5-(3- 1-(6-methoxy-3- 3-bromo- IR (KBr) 3484, 1635, bromophenyl)-7-(6- pyridinyl)- benzaldehyde 1560, 1348 cm-1; methoxy-3- ethanone MS m/z 409 pyridinyl)pyrido[2,3- (M+H) . d]pyrimidine; 234 4-amino-5-(3- 1-(6-(1,2,4- 3-bromo- IR (KBr) 3494, 1612, bromophenyl)-7-(6- triazol-4-yl)-3- benzaldehyde 1579, 1467, 1359, (1,2,4-triazol-4-yl)-3- pyridinyl)- 1271, 1233 cm-1; pyridinyl)pyrido[2,3- ethanone MS m/z 445 d]pyrimidine; (M+H)
+
. 235 4-amino-5-(3- 1-(2- 3-bromo- IR (KBr) 3434, 1637, bromophenyl)-7-(2- morpholinyl-5- benzaldehyde 1608, 1585, 1335, morpholinyl-5- pyrimidinyl)- cm- 1 ; MS m/z 463 pyrimnidinyl)pyrido[2,3- ethanone (M+H)
+
. d]pyrimidine; 236 4-amino-5-(2-thiazolyl)-7- 1-(4- 2-thiazole- IR (KBr) 3400, 1637, (4-pyrrolidinylphenyl)- pyrrolidinylphen carboxaldehyde 1608. 1532, cm-1; pyrido[2,3-d]pyrimidine; yl)-ethanone MS m/z 376
(M+H)
+
. 237 4-amino-5-(3- 1-(6-pyrazolyl-3- 3-bromo- IR (KBr) 3474, 1580, bromophenyl)-7-(6- pyridinyl)- benzaldehyde 1562, 1492, 1395, pyrazolyl-3-pyridinyl))- ethanone cm-1; MS m/z 444 pyrido[2,3-d]pyrimidine; (M+H) + . 238 4-amino-5-(3- 1-(4-(1-methyl- 3-bromo- IR (KBr) 3400, 1665, bromophenyl)-7-(4-(1- ureido)phenyl)- benzaldehyde 1350 cm-1; MS m/z methyl-ureido)phenyl)- ethanone 450 (M+H) + pyrido[2,3-d]pyrimidine; 239 4-amino-5-(3- 1-(4-(N-methyl- 3-bromo- IR (KBr) 3475, 1578, bromophenyl)-7-(4-(N- N-(2- benzaldehyde 1553. 1482, 1396, methyl-N-(2- pyrirmidinyl)amin cm-1; MS m/z 484 pyrimidinyl)amino)phenyl o)phenyl)- (M+H) + . )-pyrido[2,3-d]pyrimidine; ethanone -92- WO 98/46605 PCT/US98/07207 240 4-amino-5-(3- 1-(3-fluoro-4- 3-bromo- IR (KBr) 3448, 1600, bromophenyl)-7-(3- (N- benzaldehyde 1525, 1476, cm-1; fluoro-4-(N-formyl-N- methylamino)phe MS m/z 484 methylamino)phenyl)- nyl)-ethanone (M+H) +. pyrido[2,3-d]pyrimidine; , 241 4-formylamino-5-(3- 1-(3-fluoro-4- 3-bromo- IR (KBr) 3465, 1607, bromophenyl)-7-(3- (N- benzaldehyde 1546, 1350, cm-1; fluoro-4-(N-formyl-N- methylamino)phe MS m/z 481 methylamino)phenyl)- nyl)-ethanone (M+H) +. pyrido[2,3-d]pyrimidine; * 242 4-amino-5-(3- 1-(4-(N-methyl- 3-bromo- IR (KBr) 3470, 1650, bromophenyl)-7-(4-(N- N- benzaldehyde 1570, 1338, cm-1; methyl-N- methylsulfonyl- MS m/z 484 methylsulfonylamino)- amino)phenyl)- (M+H) . phenyl)pyrido[2,3- ethanone d]pyrimidine; 243 4-amino-5-(3- 1-(6-(N-methyl- 3-bromo- IR (KBr) 3460, 1680, bromophenyl)-7-(6-(N- N- benzaldehyde 1580, 1330 cm-1; methyl-N- methylsulfonyl- MS m/z 485 methylsulfonylamino)-3- amino)-3- (M+H) + . pyridinyl)pyrido[2,3- pyridinyl) d]pyrimidine; ethanone * separated by chromatography from the same reaction mixture; formylation occurs during the cyclization step Example 244 5 4-amino-5-(3-bromophenvyl)-7-(1-methyl-5-indolinyl)pyrido[2,3-d]pyrimnidine 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 10 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/CH 2 Cl 2 and converted to the hydrochloride salt by treatment with ether/HC1. The salt was isolated and dried under 15 vacuum to give the title compound. LRMS m/z 432/434; IR (cmn - ) 3500, 3400, 3300, 3200-2800, 1610, 1580, 1560, 1540. The 4-(3-bromophenyl)-3-cyano-6-(1-methyl-5-indolyl)pyridine-2-amine starting material was prepared as follows: 20 244a. 5-bromo- 1-methylindoline -93- WO 98/46605 PCT/US98/07207 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 oC, the reaction was basified with aqueous NaOH and extracted with toluene. The organic phase was dried over MgSO 4 and concentrated to a powder under vacuum. This material was 5 purified by flash chromatography to give the title compound, 8.62 g (82 %): MS 212, 214 [M+H] + . 244b. 5-acetvl- 1-methylindoline A mixture of 5-bromo-1-methylindoline (8.6 g, 40.7 mmol), 10 trimethylsilylacetylene (12 mL), palladium bis-triphenylphosphine dichloride (600 mg), Cul (620 mg) and triethylamine (16 mL) in acetonitrile (20 mL) was heated at 75 'C for 3 days, then cooled and concentrated in vacuo. The residue was dissolved in 120 mL of 1:1 ethyl acetate/hexane, and the solids were removed by filtration. The solvent was removed and a sample of the residue (5 g) was dissolved in 90% aqueous 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 MgSO 4 and concentrated to an oil, which was purified by flash chromatography to give 850 mg of the title compound: MS 176 [M+H] +. 20 244c. 4-(3-bromophenvl)-3-cvano-6-( 1-methyl-5-indolinvyl)pyridine-2-amine Prepared by condensation of 1', l'-dicyano-3-bromostyrene (prepared by condensation of 3-bromobenzaldehyde with malononitrile in ethanol in the presence of a catalytic amount of glycine) and the 5-acetyl- 1-methylindoline (the R 4 reagent) with 25 ammonium acetate in ethanol. The reaction mixture was heated to reflux in a vessel fitted with a Dean-Stark apparatus. After 3.5 hours, the mixture was cooled, and the solvent was removed. The residue was purified by flash chromatography, eluting with methylene chloride, to give the title compound (588 mg, 30% yield; MS m/z 394
(M+H)
+ . 30 Example 245 4-amino-5-(3-bromophenv)-7-( 1-methyl-5-benzimidazolvl)pvyrido r2,3-d]pvrimidine tetrahydrochloride 35 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. II, 1978, 865) for the 4 -94- WO 98/46605 PCT/US98/07207 dimethylaminobenzaldehyde (the R 3 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 5 4-amino-5-(3-bromophenyl)-7-(6-dimethylamino-3-pyridazinyl)1pyridor[2,3-d]pyrimidine tetrahydrochloride 246a. 6-( 1-butoxvethenyl)-3-chloropyridazine 10 To a solution of 20 g (200 mmol) of butyl vinyl ether in 80 mL of THF at -78 oC 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 oC, 20 mL of methanol 15 was added, and the solution concentrated in vacuo. The residue was diluted with 400 mL of dioxane, and 20.9 g (140 mmol) of 3,6-dichloropyridazine, 2.31 g of Pd(PPh 3
)
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 20 dried over Na 2 SO4, concentrated in vacuo, and purified by flash chromatography to give 6.3 g (21%) of the title compound. MS {M + ]+213, 215. 246b. 1-(6-chloropyridazin-3-vl)ethanone A mixture 6.3 g of the compound from Step 246a in 40 mL of dimethoxyethane, 10 25 mL of water, and 4 mL of 12 M HCI was stirred for 20 minutes, then 125 mL of water was added, and the reaction was neutralized with 12 g of NaHCO 3 . The reaction was extracted with ethyl acetate, dried over Na2SO4, and concentrated in vacuo to give a yellow solid, 4.7 g. 30 246c. 1-(3-(6-(dimethylamino)pyridazin-3-vyl))ethanone (the R 4 reagent) 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 CH 2 Cl 2 and water. The organic phase was dried over CH 2 Cl 2 , and concentrated in vacuo to give the title 35 compound. -95- WO 98/46605 PCT/US98/07207 246d. 3 -acetyl- 6 -(dimethylamino)pyridazine The title compound was prepared by condensing 1,1-dicyano-(3-(3 bromophenyl)propene (the R 3 reagent) with the compound from Step 246c (the R 4 reagent) and ammonium acetate in ethanol according to the procedure of Example 157d. 246e. 4 -amino-5-(3-bromophenvyl)-7-(6-dimethvlamino-3-pxridazinvyl)pvridor2,3 d1pyrimidine tetrahvdrochloride The title compound was prepared from the compound of Step 246d according to the procedure of Example 157, except substituting formamide for the ammonium sulfate and 10 triethyl orthoformate thereof. Examples 247-248 Following the procedures of Example 246, except in step (c) substituting the appropriate reagents for methylamine as indicated in the Table 11A below, compounds of 15 Examples 247-248 were prepared. Table 11A Examples 247-248 Ex. Name reagent of Analytical N o. step c Data 247 4-amino-5- morpholine IR (KBr) 3600-3200, (3bromophenyl)-7-(6- 3000, 1630, 1605, morpholinyl-3- 1590, 1550 cm-1; pyridazinyl)pyrido[2,3- MS m/z 464/466, d]pyrimidine 464.0829 (M+H)+; dihydrochloride 248 4-amino-5-(3- pyrrolidine IR (KBr) 3600-3250, bromophenyl)-7-(6- 3100-2800, 1640, pyrrolidinyl-3- 1605, 1560 cm- 1 ; pyridazinyl)pyrido[2,3- MS m/z 448/450, d]pyrimidine (M+H)+; dihydrochloride 20 Examples 249-251 Following the procedures of Example 244, except in step (c) first substituting the appropriate reagent for R 4 as indicated in Table 11B below for the R 4 reagent of Example 244 step c, and secondly performing the condensation with ammonium acetate substituting dichloroethane as the solvent in place of the ethanol solvent in Example 244 step c, the 25 compounds of Examples 249-251 were prepared. In some cases, the hydrochloride salts were not prepared. -96- WO 98/46605 PCT/US98/07207 Table 11B Examples 249-260 Ex. Name R 4 Reagent Analytical No. (for 7- Data position) 249 4-amino-5-(3- 2-acetyl-5- IR (KBr) 3478, 3058, bromophenyl)-7-(5- morpholinyl- 1562. 1542. 1378. morpholinyl-2- pyrazine 1306 cm-1; MS m/z pyrazinyl)pyrido[2,3- 464/466, (M+H)*; d]pyrimidine dihydrochloride 250 4-amino-5-(3- 2-acetyl-5-(N-(2- IR (KBr) 3482, 3299, bromophenyl)-7-(5-(N-(2- methoxyethyl)- 3053, 1612, 1540, methoxyethyl)-N- N-methylamino)- 1310 cm-1; MS m/z methylamino)-2- pyrazine 466/468, (M+H)+; pyrazinyl)pyrido[2,3 d]pyrimidine dihydrochloride 251 4-amino-5-(3- 1-((4- IR (KBr) 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 hydrochloride 5 Example 252 4-amino-5-(3-bromophenvyl)-7-(5-(NN-bis(2-methoxyethyl)amino)-2-pyridinvyl)pyridor2.3 d1pyrimidine trihydrochloride Step 252a. 1-(5-bromo-2-pvridyl)ethanone, ethylene ketal 10 A solution of dibromopyridine (5.2 g, 21.95 mmol), tributyl(1-ethoxyvinyl)tin (9.11 g, 25.24 mmol), Pd2(dba)3 (0.7 g, 0.8 mmol), and (2-furyl)3P (0.37 g, 1.6 mmol) in 50 mL of toluene/THF (5:1) was warmed at reflux for 10 hours. The reaction mixture was concentrated, and the crude product was purified by elution through a short column of silica gel. The resulting enol-ether compound, ethylene glycol (2.79 g, 45 mmol), and p-toluene 15 sulfonic acid (0.1 g) were dissolved in 50 mL of toluene and the solution was warmed at reflux for 10 hours. The reaction mixture was quenched by the addition of saturated aqueous NaHCO3, and the aqueous layer was extracted with CH2Cl2. The combined organic layer was dried (Na2SO4), concentrated under reduced pressure, and the resulting crude product was purified by flash chromatography to provide the title compound (3.68 g, 20 79%). -97- WO 98/46605 PCT/US98/07207 Step 252b. 1-(5-(bis(2-methoxvethyl)amino)-2-pyridvyl)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 oC for 8 hours. The reaction mixture was quenched by the 5 addition of saturated aqueous NaHCO3 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 HCO (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 CH 2 Cl 2 . The combined organic layer was dried, concentrated under reduced pressure, and the crude 10 product was purified by flash chromatography to provide the title compound Step 252c. 4-amino-5-(3-bromophenvyl)-7-(5-(NN-bis(2-methoxvethyl)amino)-2 pyridinvyl)pyridoF[2,3-d]pyrimidine trihydrochloride Following the procedures of Example 244, except in step (c) first substituting the 15 reagent from Step 252b for the R 4 reagent of Example 244 step c, and secondly performing the condensation with ammonium acetate substituting dichloroethane as the solvent in place of the ethanol solvent in Example 244 step c, the free base of the title compound was prepared. The title compound was prepared from this by treatment with HCL in ether. IR (KBr) 3440, 1635, 1605, 1580, 1360 cm- 1 ; MS m/z 466/468, (M+H) +. 20 Examples 253-260 Following the procedures of Example 244, except in step (c) first substituting the appropriate reagent for R 4 as indicated in Table 11B below for the R 4 reagent of Example 244 step c, and secondly performing the condensation with ammonium acetate substituting 25 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. Ex. Name R 4 Reagent Analytical N o. (for 7- Data position) 253 4-amino-5-(3- 1-((4- IR (KBr) 3105, bromophenyl)-7-(4- acetylphenyl)- 1645. 1620. (imnidazolylmethyl)- methyl)imidazole 1570, 1350 phenyl)pyrido[2,3- cm-l: MS M: d]pyrimidine 466/468, trihydrochloride (M+H)+; -98- WO 98/46605 PCT/US98/07207 254 4 -arnino-5-(3- 1-(5- IR (KBr) 3297, 3081, bromophenyl)-7-(5-(1- morpholinyl-2- 1646, 1564, 1494, morpholinyl)-2- pyridyl)ethanone 1362 cm- 1 ; MS m/z pyridinyl)pyrido[2,3- * 463/465, (M+H)+; d]pyrimidine trihydrochloride 255 4-amino-5-(3- 1-(4- IR (KBr) 3308, 1645, bromophenyl)-7-(4- ((dimethylamino) 1590, 1560, 1375 ((dimethylamino)methyl)- methyl)phenyl)- cm-1; MS m/z phenyl)pyrido[2,3- ethanone 509/511, (M+H)+; d]pyrimidine dihydrochloride 256 4-amino-5-(3- 1-(5-(4- IR (KBr) 3000, 1650, bromophenyl)-7-(5-(4- hydroxypiperidin 1600, 1580, 1550, hydroxy-1-piperidinyl)-2- yl)-2- 1400 cm-1; MS m/z pyridinyl)pyrido[2,3- pyridyl)ethanone 477/479, (M+H)+; d]pyrimidine ** dihydrochloride 257 4-amino-5-(3- 5-acetyl-2- IR (KBr) 3477, 3060, bromophenyl)-7-(5-(N- pyridinemethana 1678, 1638, 1566, formyl-N-methylamino)- mine 1495, 1319 cm-1; 2-pyridinyl)pyrido[2,3- MS m/z 435/437, d]pyrimidine (M+H)+; dihydrochloride 258 4-amino-5-(3- 2-acetyl-5-(2- IR (KBr) 3085, 1562, bromophenyl)-7-(5-(2- propenyl)- 1485, 1357 cm-; propenyl)-2- pyridine MS m/z 418/420, pyridinyl)pyrido[2,3- (M+H)+; d]pyrimidine 259 4-amino-5-(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 hydrochloride 260 4-amino-5-(3- 4- IR (KBr) 3283, 3054, bromophenyl)-7-(4-(1-(N- acetylbenzeneeth 1678, 1631, 1547, formylamino)- anamine 1352 cm-1; MS m/z ethyl)phenyl)pyrido[2,3- 448/450, (M+H)+; d]pyrimidine * Prepared as in Ex. 252b, except substituting morpholine for the bis(2 methoxyethyl)amine thereof. ** Prepared as in Ex. 252b, except substituting 4-hydroxypiperidine for the bis(2-methoxyethyl)amine thereof. 5 Example 261 4-amino-5-(3-pyridyl)-7-(4-dimethylamino)phenvlpyrido[2,3-d]pyrimidine The compound was prepared by using the method generally described above in Scheme 3 and the associated examples using 1-(4-dimethylaminophenyl)ethanone as the R 4 10 reagent (7-position) and nicotinaldehyde as the R 3 reagent (5-position). IR (cm-1) 3305.8, 2922, 1606, 1578, 1535, 1360. MS (M+H) 342. -99- WO 98/46605 PCT/US98/07207 Example 262 4 -(methylamino)-5-(3-bromophenvl)-7-(4-dimethylaminophenvy)pvrido2,3-d1primidine hydrochloride 5 The title compound was prepared by using the method described in Example 200, except substituting methylamine for the 2-(dimethylamino)ethylamine thereof. MS (M+H), 478 (1Br); IR (cm-1) 3455, 3047, 2959, 1580, 1351, 1234. Example 263 10 4-(2-methoxvethylamino)-5-(3-bromophenyl)-7-(4 dimethylaminophenvl)pyrido2,3-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 (1Br); IR (cm-1) 3415, 2920, 1569, 1321, 1234. 15 Example 264 4-amino-5-(3-bromophenyl)-7-(4-(1-methyl-2-imidazolyl)phenvyl)pyridor[2,3-d]prirnmidine trihydrochloride 20 Step 264a. 1-(4-(1-Methylimidazol-2-vl)phenyl)ethanone A solution of N-methyl imidazole (0.90 g, 11.0 mmol) in 12 mL of THF at -78 oC 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, ZnC1 2 (20 mL, 1.0 M solution in Et 2 0, 20 mmol) was added, and the solution was warmed to 25 0 C. To this solution was added Pd(PPh 3
)
4 (70 mg, 0.06 mmol) 25 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 OC and quenched by the addition of saturated aqueous NaHCO 3 (10 mL). The aqueous layer was extracted with CH 2 Cl 2 , and the combined organic layer was concentrated under reduced 30 pressure. The residue was dissolved in 30 mL of THF, 15 mL of 3 M aqueous HCI was added, and the mixture was stirred for 2 hours at 25 oC. The solution was neutralized by the addition of saturated aqueous NaHCO 3 , and the aqueous layer was extracted with CH 2 Cl 2 . The combined organic layer was dried (MgSO 4 ) then concentrated under reduced pressure. The crude product was purified by flash chromatography to provide the title compound 35 (0.89 g, 64%). -100- WO 98/46605 PCT/US98/07207 Step 264b. 4-amino-5-(3-bromophenvl)-7-(4-(1-methyl-2-imidazolvl)phenyl)pyrido[2,3 d]pyrimidine trihydrochloride Following the procedures of Example 244, except in step (c) first substituting the R 4 reagent from Step 264a for the R 4 reagent of Example 244 step c, and secondly performing 5 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 (lBr); IR (cm-1) 3051, 2948, 1577, 1474, 1354. Examples 265-267 10 Following the procedures of Example 244, except in step (c) first substituting the appropriate reagent for R 4 as indicated in the Table below for the R 4 reagent of Example 244 step c, and secondly performing the condensation with ammonium acetate substituting dichloroethane as the solvent in place of the ethanol solvent in Example 244 step c, the compounds of Examples 264-285 were prepared. In Ex. 266, the hydrochloride salt was 15 not prepared. Ex. Name R 4 Reagent Analytical N o. (for 7.- Data position) 265 4-amino-5-(3- 1-(4- MS (M+H), 460; IR bromophenyl)-7-(4- (aminomethyl)ph (cm-1) 3024 2933, (aminomethyl)phenyl)pyri enyl)ethanone 1550, 1493, 1328 do[2,3-d]pyrimidine 266 4-amino-5-(3- 1-(2-bromo-4- MS (M+H), 500 (2 bromophenyl)-7-(2- (dimethylamino) Br); IR (cm-1) 3049, bromo-4- phenyl)ethanone 2949, 1536, 1468, (dimethylamino)phenyl)py 1320 rido[2,3-d]pyrimidine 267 4-amino-5-(3- 1-(4- MS (M+H), 448 (1 bromophenyl)-7-(4- (dimethylaminoet Br); IR (cm-1) 3420, (dimethylaminoethyl)phen hyl)phenyl)ethan 3, 298, 1635, 1610, 1590, 1435, yl)pyrido[2,3- one 1415 d]pyrimidine Example 268 20 4 -amino-5-(3-bromophenyl)v-7-(4-(3-(dimethylamino)propvnvyl)phenvl)pyridor2,3 d1pyrimidine A suspension of the compound of Example 63 (0.80 g, 1.59 mmol), PdCl 2 (PPh 3
)
2 , Cul, 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 -101- WO 98/46605 PCT/US98/07207 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 5 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. E x. Name Reagent Analytical N o. Data 269 4-amino-5-(3- 1,1-dimethyl- MS (M+H), 459 bromophenyl)-7-(4-(3- propargyl amine (1Br); IR (cm-1) amino-3- 3041, 2967, 1562, methylbutynyl)phenyl)pyri 1484, 1319 do[2,3-d]pyrimidine 270 4-amino-5-(3- dimethyl MS (M+H), 486 bromophenyl)-7-(4- phosphite (1Br); IR (cm-1) dimethylphosphonatophen 3105, 2912, 1625, yl)pyrido[2,3- 1437, 1350 d]pyrimidine 271 4-amino-5-(3- methyl propargyl MS (M+H), 446 bromophenyl)-7-(4-(3- ether (lBr); IR (cm-1) (methoxypropynyl)pyrido[ 3053, 2929, 1560, 2,3-d]pyrimidine 1484, 1352 10 Example 272 4-amino-5- (3-bromophenyl)-7-(4-carboxyphenvyl)pyrido[2,3-dlpyrimidine 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 HCI (aqueous) was heated at 60 oC for 8 hours. The mixture was lyophilized and the crude 15 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 20 4 -amino-5-(3-bromophenyl)-7-(4-methyl-3-oxo-2H-4H-pyridor3,2-b- 1,4 oxazinyl)pyrido[2,3-d]pyrimidine Step 273a. 7-acetyl-2H-pyridor3,2-bl-1,4-oxazin-3(4H)-one A solution of 2H-pyrido[3,2-b]-l,4-oxazin-3(4H)-one (9.8 g, 65.27 mmol, 25 Aldrich) in 120 mL of THF/MeOH (5:1) was treated with 0.4 mL of concentrated HC1 (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 -102- WO 98/46605 PCT/US98/07207 saturated aqueous NaHSO 3 . The aqueous layer was extracted with CH 2 Cl 2 and the combined organic layer was dried (Na 2 SO4), 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, 5 14 mmol), tributyl(1-ethoxyvinyl)tin (6.1 g, 17 mmol), Pd 2 (dba) 3 (0.5 g, 0.56 mmol), and (2-furyl) 3 P (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 HCI (aqueous) was added, and the mixture was stirred for 4 hours at 25 'C. The solution was neutralized by the addition of NaHCO 3 10 (aqueous), and the aqueous layer was extracted with CH 2 Cl 2 . The combined organic layer was dried (Na 2
SO
4 ), 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. 15 Step 273b. 7 -acetyl-4-methyl-2H-pvrido[3.2-bl-1,4-oxazin-3(4H)-one The compound from step 273 a was treated with methyl iodide and NaH in 1:1 THF/DMF for 6 hours at 0 oC to 25 oC. The reaction was quenched with aqueous sodium bicarbonate solution, the mixture was extracted with dichloromethane, and the resiue was 20 purified by chromatogaphy to give the title compound. MS (M+H), 407. Step 273c. 4 -amino-5-(3-bromophenvyl)-7-(4-methyl-3-oxo-2H-4H-pyidor3,2-bl]-1,4 oxazinvyl)pyrido[2,3-d]pyrimidine Following the procedure of Example 244 Step c, except first substituting 7-acetyl-4 25 methyl-2H-pyrido[3,2-b]-1,4-oxazin-3(4H)-one (the R 4 reagent) from Step 273b for the R 4 reagent of Example 244 Step c, and secondly performing the condensation with ammonium acetate substituting dichloroethane as the solvent in place of the ethanol solvent in Example 244 step c, the title compound was prepared. MS (M+H), 463 (1 Br); IR (cm-1) 3400, 3200-2800, 1700, 1640, 1605, 1590, 1395, 1380, 1345. 30 Example 274 4-amin-5-(3-brm hen)-7-(4-(2-(dimethylamino)ethyl)-3-oxo-2H-4H-pyrido [32-b] 1, 4 -oxazin-7-yl)pyridor2.3-dpyrimidine 35 Step 274a. 7 -acetyl-4-dimethylaminoethyl -2H-pyrido[3.2-b]-l 4 -oxazin-3(4H)-one -103- WO 98/46605 PCT/US98/07207 The compound from Example 273 Step a was treated with 2-chloro-(N,N dimethyl)ethylamine HC1 and K 2
CO
3 in aqueous acetone at reflux. The mixture was diluted with water and extracted with dichloromethane, and the residue was purified by chromatogaphy to give the title compound. 5 Step 274b. 4-amino-5-(3-bromophenvyl)-7-(4-(2-(dimethylamino)ethyl)-3-oxo-2H-4H pyridor3,2-bl- 1,4-oxazin-7-vl)pyrido[2,3-d]pyrimidine Following the procedures of Example 244 Step c, except in step c first substituting 7-acetyl-4-dimethylaminoethyl -2H-pyrido[3,2-b]-1,4-oxazin-3(4H)-one (the R 4 reagent, 10 from Step 273b) for the R 4 reagent of Example 244 Step c, and secondly performing the condensation with ammonium acetate substituting dichloroethane as the solvent in place of the ethanol solvent in Example 244 step c, the title compound was prepared. MS (M+H), 519 (1 Br); IR (cm-1) 3440, 1685, 1630, 1605, 1580, 1395 15 Example 275 4 -amino-5-(3-bromophenyl)-7-(2.3-dihydro-3-(dimethylaminoethyl)-2-oxobenzoxazol-6 vl)pyrido[2,3-d]pyrimidine Step 275a. 6-acetyl-2-benzoxazolinone 20 Following the procedures of Example 273 Step a, except substituting 2 benzoxazolinone (Aldrich) for the 2H-pyrido[3,2-b]-1,4-oxazin-3(4H)-one thereof, the title compound was prepared. Step 275b. 6-acetyl-3-(dimethylaminoethyl)-2-benzoxazolinone 25 The compound from Example 275 Step a was treated with 2-chloro-(N,N dimethyl)ethylamine HC1 and K 2
CO
3 in aqueous acetone at reflux. The mixture was diluted with water and extracted with dichloromethane, and the residue was purified by chromatogaphy to give the title compound. 30 Step 275c. 4 -amino-5-(3-bromophenvyl)-7-(2,3-dihydro-3-(dimethylaminoethyl)-2 oxobenzoxazol-6-yl)pyrido f2,3-d]pyrimidine Following the procedures of Example 244 Step c, except in step c first substituting the compound from Step 275a for the R 4 reagent of Example 244 Step c, and secondly performing the condensation with ammonium acetate substituting dichloroethane as the 35 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. -104- WO 98/46605 PCT/US98/07207 Example 276 4-amino-5-(3-bromophenyl)-7-(4-methvl-3-oxo-2H-4H-benzo- 1,4-oxazin-7-vl1pyrido[2,3 dpyrimidine 5 Step 276a. 6-acetyl-3-methyl-2-benzoxazolinone The compound from Example 275 Step a was treated with methyl iodide and NaH in 1:1 THF/DMF for 6 hours at 0 'C to 25 'C. The reaction was quenched with aqueous sodium bicarbonate solution, the mixture was extracted with dichloromethane, and the resiue was purified by chromatogaphy to give the title compound. 10 Step 276b. 1-(3-hydroxy-4-methylaminophenyl)-ethanone The compound from Step 276a (1.60 g, 8.37 mmol) was dissolved in acetone (70 mL) and treated with IM aqueous K 2
CO
3 solution (25 mL) with heating at reflux overnight. The mixture was neutralized with acid, then extracted with diethyl ether. The solvent was 15 dried (MgSO 4 ) 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 20 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)pyrido[2,3-d]pgrimidine 25 Following the procedures of Example 244 Step c, except in step c first substituting the compound from Step 276c for the R 4 reagent of Example 244 Step c, and secondly performing the condensation with ammonium acetate substituting dichloroethane as the solvent in place of the ethanol solvent in Example 244 step c, the title compound was prepared. MS (M+H), 462 (1 Br); IR (cm-1) 3500, 2800-3200, 1690, 1645, 1610, 1590, 30 1385, 1355. Example 277 4-amino-5- (3-bromophenvyl)-7-(2,2,4-trimethyl-3-oxo-2H-4H-benzo- 1,4-oxazin-7 v1)pyrido [2,3-dlpyrimidine 35 -105- WO 98/46605 PCT/US98/07207 Step 277a. 7-acetyl-2.2.4-trimethyl-2H-4H-benzo- 1.4-oxazin-3-one The compound from Step 276b (2.25 g, 9 mmol) was dissolved in DMSO and 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 5 was extracted with ether.ethyl acetate. The extract was dried (MgSO 4 ), the solvent was removed under vacuum, and the residue was purified by chromatography (silica gel) to give the title compound (1.33 g) MS (M+H), 234. Step 277b. 4-amino-5-(3-bromophenvl)-7-(2,2,4-trimethyl-3-oxo-2H-4H-benzo-1,4 10 oxazin-7-vl)pyrido[2.3-d]pyrimidine Following the procedures of Example 244 Step c, except in step c first substituting the compound from Step 277a for the R 4 reagent of Example 244 Step c, and secondly performing the condensation with ammonium acetate substituting dichloroethane as the solvent in place of the ethanol solvent in Example 244 step c, the title compound was 15 prepared. MS (M+H), 490 (1 Br); IR (cm-1) 3450, 2900-3100, 1680, 1645, 1610, 1515, 1385, 1365, 1165. Example 278 4-amino-5-cyclohexvl-7-(4-(2-dimethylamino)ethyl)-2H-4H-benzo-3-oxo- 1,4-oxazin-7 20 vl)pDyrido[2,3-d]pyrimidine Step 278a. 1-(3-hydroxv-4-(2-(dimethylamino)ethyl)phenvl)-ethanone A sample of 6-acetyl-3-(dimethylaminoethyl)-2-benzoxazolinone (from Example 275 Step b) was dissolved in acetone and treated with 1M aqueous K 2
CO
3 solution with heating 25 at reflux overnight. The mixture was neutralized with acid, then extracted with diethyl ether. The solvent was dried (MgSO4) and removed under vacuum to give the title compound. Step 278b. 7-acetyl-4-(dimethylamino)ethyl)-2H-4H-benzo-1,4-oxazin-3-one A sample of the compound from Step 278a (8.94 g, 32 mmol) was dissolved in 30 DMSO and treated with sodium ethoxide (32 mmol) and bromoacetic acid (5.34 g, 32 mmol) at room temperature for 2 days. The mixture was diluted with water then extracted with ether. The extract was dried (MgSO4), the solvent was removed under vacuum, and the residue was purified by chromatography (silica gel) to give the title compound (1.94 g). MS (M+H), 263. 35 -106- WO 98/46605 PCT/US98/07207 Step 278c. 4 -amino-5-cyclohexvl-7-(4-(dimethylamino)ethyl)-2H-4H-benzo-3-oxo-1,4 oxazin-7-vl)pyvridof2,3-d]pvrimidine 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. 5 (Tetrahedron (1987), 43:537-542) by treating cyclohexane carboxaldehyde with malononitrile in the presence of finely powdered magnesium oxide in dichloromethane) for the R3 reagent of Example 244 Step c, and substituting the compound from Step 278b for the R 4 reagent of Example 244 Step c, and also performing the condensation with ammonium acetate but also substituting dichloroethane as the solvent in place of the ethanol 10 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 -methvlethyl)-2-pvridvpl)vrido[2,3-d]pvrimidine 15 Step 279a. 1-(5-methvethvl-2-pyridvyl)ethanone A solution of 2-acetyl-5-bromopyridine (1.45 g, 7.9 mmol), 2-propenyltrimethyltin (1.77 g, 8.7 mmol), Pd 2 (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 20 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 H 2 . 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 H 2 . The reaction mixture was filtered and the resulting solution was concentrated under reduced pressure. The title 25 compound, 2, (1.04 g, 84%) was isolated following flash chromatography. Step 279b. 4-amino-5-(3-bromophenvl)-7-(5-(1-methvlethyl)-2-pvridyl)pyridor2,3 d1pyrimidine Following the procedures of Example 244 Step c, except in step c substituting the 30 compound from Step 279a for the R 4 reagent of Example 244 Step c, and performing the condensation with ammonium acetate and also substituting dichloroethane as the solvent in place of the ethanol solvent in Example 244 step c, the title compound was prepared. MS (M+H) 421 (lBr): IR (cm-1) 3489, 2940, 1545, 1482, 1357. 35 Examples 280-281 Following the procedures of Example 244 Step c, except in step c substituting the compound shown below for the R 4 reagent of Example 244 Step c, and performing the -107- WO 98/46605 PCT/US98/07207 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. Name R 4 Reagent Analytical N o. (for 7- Data position) 280 4-amino-5-(3- 1-(5-piperidinyl- MS (M+H), 460 bromophenyl)-7-(5- 2- (1Br); IR (cm-1) piperidin- 1 -ylpyrid-2- pyridyl)ethanone 3064, 2937, 1556, yl)pyrido[2,3- *1493, 1358 d]pyrimidine 281 4-amino-5-(1-(4- 1-(2- MS (M+H), 491 (1 bromophenyl)ethyl)-7-(6- morpholinyl-5- Br); IR (cm-1) 1585, morpholinylpyrid-3- pyridyl)ethanone 1555, 1505, 1240, yl)pyrido[2,3- **1110, 940 d]pyrimidine 5 * 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. 10 Example 282 4-amino-5-(3-bromophenyl)-7-(4-((N-formvlamino)methyl)phenyl)pyrido[2,3-d]pyrimidine Step 282a. 4-cvanoacetophenone. acetal with 2,2-dimethylpropylene glycol A sample of 4-cyanoacetophenone (4.35 g, 30 mmol) was dissolved in 150 mL of 15 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 20 aqueous NaHCO3, water and brine, and dried over MgSO4. The solvent was removed under vacuum to give the title compound (7.46 g). Step 282b. 4-(aminomethyllacetophenone. acetal with 2.2-dimethylpropylene glycol The compound from Step 282a (2.31 g, 10 mmol) was dissolved in ether (50 mL) 25 and stirred with lithium aluminum hydride (0.76 g, 20 mmol) at ambient temperature overnight. The reaction was quenched with MgSO4*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-aminomethyl)phenyl)ethanone -108- WO 98/46605 PCT/US98/07207 The compound from Step 282b (1.18 g, 5 mmol) was dissolved in THF (20 mL), IN HC1 (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 5 over a weekend. The solution was diluted with water, and the mixture was extracted with ether and ethyl acetate. The organic extracts were dired (MgSO4), and the solvent was remove under vacuum to give the title compound. Step 282d. 4-amino-5-(3-bromophenvl)-7-(4-(N-formvlamino)methyl)phenvyl)pyrido[2,3 10 dlpyrimidine Following the procedures of Example 244, except in step c substituting the compound from Step 282c for the R 4 reagent of Example 244 Step c, and performing the condensation with ammonium acetate but also substituting dichloroethane as the solvent in place of the ethanol solvent in Example 244 step c, the title compound was prepared. MS 15 (M+H) 434 (1 Br); IR (cm-1) 3440, 2700-3150, 1635, 1580, 1380. Example 283 4-amino-5-(3-bromophenvyl)-7-(4- (1-(N-methylamino)- 1-methylethyl)phenvyl)pyrido[2,3 d]pyrimidine 20 Step 283a. 4-(1-amino- -methylethyl)acetophenone CeCl 3 (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 25 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 (MgSO 4 ), and the solvent was removed to give the title compound. 30 Step 283b. 4-( 1-(N-BOC-amino)- 1-methylethyl)acetophenone The compound from Step 283a (2.32 g, 8.77 mmol) was treated sequentially with HC1 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. 35 -109- WO 98/46605 PCT/US98/07207 Step 283c. 4-amino-5-(3-bromophenvyl)-7-(4-(1-(N-formvlamino)- 1 methylethyl)phenyl)pyrido[2.3-dlpyrimidine Following the procedures of Example 244 Step c, except in step c substituting tle compound from Step 283b for the R 4 reagent of Example 244 Step c, and performing the 5 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. 10 Example 284 4-amino-5-(3-bromophenvyl)-7-(4-(1-(N,N-dimethylamino)- 1 methylethyl)phenvyl)pyrido[2,3-d]pyrimidine Step 284a. 4-(1-(dimethylamino)- 1-methylethyl)acetophenone 15 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 Na 3
CO
3 . The mixture was extracted with dichloromethane. The solution was dried (MgSO 4 ), 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, 20 1375. Examples 285-286 Following the procedures of Example 157, except substituting the 25 appropriate reagents for the R 3 and R 4 reagents of Example 157 as indicated in the Table below, compounds of Examples 285-286 were prepared. For Example 286, treatment with aqueous HCI was omitted, and the free base was obtained. 30 Examples 285-286 E x. Name R 3 Reagent R 4 Reagent Analytical Data No. (for 5- (for 7 position position) 285 4-amino-5-(3- 1,1-dicyano-(3- 1-(N-acetyl-5- mp (hydrochloride salt) bromophenyl)-7-(N- (3- indolinyl)- >270 0 c. IR (cm l ) 3445, acetyl-5- bromophenyl)pr ethanone 3100-2500. 1640, 1605, 1445, 1395. 1325. indolinyl)pyrido[2,3- opene LRMS [M+H]" m/z 460, d]pyrimidine 462. -110- WO 98/46605 PCT/US98/07207 286 4-amino-5-cyclohexyl- 1,1-dicyano-3- 1-(6-chloro-3- mp 240-242 'C. IR (cm 7-(6-chloro-3- cyclohexylethene pyridyl)- 1) 3528, 3300, 3086, pyridyl)pyrido[2,3- ethanone 2936, 2853, 1645, 1590, 1575, 1565,1350. LRMS d]pyrimidine [M+H]+ m/z 340. Examples 287-300 Following the procedures of Example 157, except substituting the appropriate R 3 5 and R 4 reagents as indicated in the Table below and replacing the formamide or formamidine acetate treatment with treatment with triethyl orthoformate at reflux in the presence of a catalytic amount of ammonium sulfate, followed by cooling to 25 'C and addition of excess ammonia in ethanol, compounds of Examples 287-300 were prepared.. After 24 hours, the precipitated amidine compound was filtered and washed with hexanes, then dried under 10 vacuum. The anmidine 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 HCI was omitted in some cases, and the free bases were obtained. 15 Examples 287-300 E x. Name R 3 Reagent R 4 Reagent Analytical Data No. (for 5- (for 7 position position) 287 4-amino-5-(1-(2- 1,1-dicyano-2- 1-(6- IR (cm-1) 2600-3500, bromophenyl)ethyl)-7- methyl-(3-(2- dimethylamino- 1650, 1602, 1596, 1520 (6-dimethylamino-3- bromophenyl)pr 3-pyridyl)- cm-1. LRMS [M+H]+ pyridyl)pyrido[2,3- opene ethanone d]pyrimidine 288 4-amino-5-(1-(2- 1,1-dicyano-2- 1-(6- mp (dihydrochloride salt) bromophenyl)ethyl)-7- methyl-(3-(2- morpholinyl-3- 213-216 'C. IR (cm-1) 2400-3500, 1660, 1600. (6-morpholinyl-3- bromophenyl)pr pyridyl)- 0LRMS [M+H,+ m/z 491& pyridyl)pyrido[2,3- opene ethanone 493. d]pyrimidine 289 4-amino-5-(1-(2- 1,1-dicyano-2- 1-(6-(N-methyl- mp 252-253°C. IR (cm t ) bromophenyl)ethyl)-7- methyl-(3-(2- N- 3515, 3310, 3200-2800, (6-(N-methyl-N- bromophenyl)pr formyl)amino)- 1675, 1585, 1560, 154m5, 1340. LRMS [M+H]* m/z formyl)amino)-3- opene 3-pyridyl)- 462, 464. phenyl)pyrido[2,3- ethanone d]pyrimidine 290 4-amino-5-cyclohexyl- 1,1-dicyano-3- 1-(6- mp (dihydrochloride salt) 7-(6-morpholinyl-3- cyclohexylethene morpholinyl-3- 208-210. IR (cm-1) pyridyl)pyrido[2,3- pyridyl)- 3490, 3300, 3050-3 2590, 1620, 1580, 1550, 1490. d]pyrimidine ethanone LRMS [M+H]+ m/z 391. -111- WO 98/46605 PCT/US98/07207 291 4-amino-5-((2- 1,1-dicyano-(3- 1-(6- mp (dihydrochloride salt) bromophenyl)methyl)- (2- morpholinyl-3- 201-204 'C. IR (cm-1) 3601, 3500, 3310, 2960, 7-(6-morpholinyl-3- bromophenyl)pr pyridyl)- 2850, 1585, 1561, 1502, pyridyl)pyrido[2,3- opene ethanone 1345 . LRMS [M+H]+ d]pyrimnidine m/z 477, 479. 292 4-amino-5-(4- 1,1-dicyano-3- 1-(6- mp (dihydrochloride salt) tetrahydropyranyl)-7- (4- morpholinyl-3- 213-216 'C. IR (cm-1) 3310, 3060, 2955, 1587, (6-morpholinyl-3- tetrahydropyrany pyridyl)- 1559, 506, 1350., pyridyl)pyrido[2,3- 1)ethene ethanone LRMS [M+H]+ m/z 393. d]pyrimidine * 293 4-amino-5-cyclohexyl- 1,1-dicyano-3- 1-(6- mp (dihydrochloride salt) 7-(6-dimethylamino-3- cyclohexylethene dimethylamino- 272-274 *C. IR (cm-1) pyridyl)pyrido[2,3- 3-pyridyl)- 353, 3294, 3100, 2930, d~pyimiine thaone2853, 1606, 1586, 1560, d]pyrimidine ethanone 1522, 1387. LRMS [M+H]+ m/z 349. 294 4-amino-5-(1- 1,1-dicyano-3- 1-(6- mp (free base): 223.5-225 ethylpropyl)-7-(6- ethylpentene dimethylamino- *C. IR (cm-1) 3480, dimethylamino-3- 3-pyridyl)- 3000-3470, 2800-3000, pyhdl~pyido2,3-ethaone1630, 1610, 1580, 1565, pyridyl)pyrido[2,3- ethanone 1520. LRMS [M+H]+ m/z d]pyrimidine 337. 295 4-amino-5- 1,1-dicyano-3- 1-(6- IR (cm') 3495, 3320, cyclopentyl-7-(6- cyclopentylethen morpholinyl-3- 3080, 2950, 1645, 1600, morpholinyl-3- e pyridyl)- 1500, 1400, 1350, 31240. pyridyl)pyrido[2,3- ethanone LRMS [M+H z 377. d]pyrimidine 296 4-amino-5-cyclohexyl- 1,1-dicyano-3- 1-(2-chloro-3- IR (cm ) 3305, 3155, 7-(2-chloro-3- cyclohexylethene pyridyl)- 2930, 2855, 1590, 1610, pyridyl)pyrido[2,3- ethanone 1590, 1545, 1345. d~pyrimidine LRMS [M+H] m/z 340, d]pyr de 342. 297 4-amino-5-(3,5- 1,1-dicyano-3- 1-(6- IR (cm - ) 3310, 3100, dimethylcyclohexyl)- (3,5- dimethylamino- 2950, 1605, 1590, 1555, 7-(6-dimethylamino-3- dimethylcyclohe 3-pyridyl)- 1390, 1350. LRMS pyridyl)pyrido[2,3- xyl)ethene ethanone [M+H /z 377. d]pyrimidine 298 4-amino-5-((N- 1,1-dicyano-(3- 1-(6- IR (cm-1) 3538, 3311, (benzyloxycarbonyl)- (4- morpholinyl-3- 3032, 2925, 2852, 1696, 4-piperidinyl)methyl)- (benzyloxycarbo pyridyl)- 1585, 1560. LRMS 7-(6-morpholinyl-3- nyl)piperidin-1- ethanone [M+H+ /z 54. pyridyl)pyrido[2,3- yl)propene d]pyrimidine 299 4-amino-5-cyclohexyl- 1,1-dicyano-3- 1-(6-bromo-3- m.p. 250-252 'C, IR (cm 7-(6-bromo-3- cyclohexylethene pyridyl)- 1) 3530, 3298, 3093, pyridyl)pyrido[2,3- ethanone 2932, 2856, 1645, 1583, d~pyrimidine 1569, 1543, 1461, 1346. d]pyn me LRMS [M+H]+ 384. 386. 300 4-amino-5-cyclohexyl- 1,1-dicyano-3- 1-(3- m. p. 223-224 oC. IR 7-(3- cyclohexylethene cyanophenyl)- (cm-1) 3528, 3298, cyanophenyl)pyrido[2, ethanone 3075, 2937, 2235. 1645, 1586, 1548, 1567, 1463. 3-d]pyrimidine LRMS [M+H]+ 332. * 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. -112- WO 98/46605 PCT/US98/07207 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; 5 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 10 (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). 15 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
R
4 reagent, and substituting the R 3 reagent shown below for the R 3 reagent of Example 246 step d, the compounds of Examples 301-305 were prepared. For Example 302 only, the 20 condensation solvent was DMSO instead of ethanol and dimethoxyethane. Examples 301-305 Ex. Name R 3 reagent reagent of Analytical N o. step c Data 301 4-amino-5-(1-(2- 1,1-dicyano-(3- dimethylamine mp (dihydrochloride bromophenyl)ethyl)-7-(6- (2- salt) >220°C. IR dimethylamino-3- bromophenyl)pr (cm') 3500 -2400, 1640, 1610, 1580, pyridazinyl)pyrido[2,3- opene 1370. LRMS [M+H] d]pyrimidine m/z 450, 452. 302 4-amino-5-(3- l',1 '-dicyano- imidazole mp bromophenyl)-7-(6- (3-bromostyrene sodium salt (tetrahydrochloride imidazolyl-3- salt) >240*C. IR pyridazinyl)pyrido[2,3- (cm') 3600-2400, pydazyl)pyrido[2,3 1640, 1610, 1590, d]pyrimidine 1560, 1415, 1370. LRMS [M+H]* m/z 445, 447. 303 4-amino-5-(3- 1', 1'-dicyano- azacycloheptane mp (dihydrochloride bromophenyl)-7-(6- (3-bromostyrene salt) >190 0 C. IR (azacycloheptanyl)-3- (cm-') 3435, 3100 .d . r.2400, 1635, 1610, pyridazinyl)pyrido[2,3- 1590, 1550, 1440, d]pyrimnidine 1370. LRMS [M+H] m/z 476, 478. 304 4-amino-5-(3- 1',1'-dicyano- N-methyl-N-(1- mp (dihydrochloride bromophenyl)-7-(6-(N- (3-bromostyrene methylethyl))ami salt) >210 0 C. IR methyl-N-(1- ne (cm) 3435, 3100 2400, 1635, 1610, methylethyl))amino)-3- 1590, 1550, 1410, pyridazinyl)pyrido[2,3- 1370. LRMS [M+H], d]pyrimidine m/z 450, 452. -113- WO 98/46605 PCT/US98/07207 305 4-amino-5-(1-(2- 1,1-dicyano-(3- morpholine IR (cm-1) 3475, bromophenyl)ethyl)-7-(6- (2- 3313, 3100, 1650, morpholinyl-3- bromophenyl)pr 1620,s 1580, 1555. LRMS [M+H]+ zt pyridazinyl)pyrido[2,3- opene 492, 494. dipyrimidine Example 306 4-amino-5-cyclohexvl-7-(6-(4-acetylpiperazinyl)-3-pyridyl)pyridor[2.3-d]pyrimidine 5 A mixture of 679 mg (2 mmol) of the compound from Example 298 and 1.28 g (10 mmol) of N-acetylpiperazine in 5 mL of DMSO was heated at 110 oC for 5 hours. On cooling a precipitate was deposited, which was collected and washed with 20% methanol and dried to give 647 mg of the product as orange flakes: IR (cm-1) 3522, 3306, 3110, 2925, 2854, 1670, 1650, 1586, 1506. LRMS [M+H]+ m/z 432. 10 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 15 chromatography. E x. Name reagent Analytical Data No. 307 4-amino-5- 1-acetyl-l,4- m.p. 169-171 °C, IR (cm cyclohexyl-7-(6-(4- diazacycloheptane 1) 3535, 3309, 3096, acetyl- 1,4- 2930, 2854, 1638. 1605, 1587, 1558, 1513. diazacycloheptanyl)- LRMS [M+H]+ 446. 3 pyridyl)pyrido[2,3 d]pyrimidine 308 4-amino-5- 1-methyl-1,4- LRMS [M+H] + 419. cyclohexyl-7-(6-(4- diazacycloheptane methyl- 1,4 diazacycloheptanyl) 3 pyridyl)pyrido[2,3 d]pyrimnidine 309 4-amino-5- N-methyl-N-(2-(2- LRMS [M+H] + 441. cyclohexyl-7-(6-(N- pyridyl)ethyl)amine methyl-N-(2-(2 pyridyl)ethyl)amino) -3 pyridyl)pyrido[2,3 d]pyrimidine -114- WO 98/46605 PCTIUS98/07207 3101 '4-anino-5- N,N-dimethyl, N'- LRMS [M+H]l 421. cyclohexyl-7-(6-2- methyl- 1,2 (N-(N',N'- ethylenediamine dimethylaminoethyl) -N-methylamino)-3 pyridyl)pyrido [2,3 dlpyriniidine _________ 311 4-amiino-5- azetidine LRMS [M+H]I 361. cyclohexyl-7-(6 azetidinyl-3 pyridyl)pyrido[2,3 dilpyrimiddine 312 4-amino-5- N-methyl-N-(3- LRMS [M+H]+ 447. cyclohexyl-7-(6-(3- pyrrolidinyl)acetami (N- de methylacetaniido)pyr rolidinyl)pyridyl)pyr idoII2,3 d]pyrim-idine_________ 313 4-amino-5- pyrrolidine-2- LRMS [M+H]l 419. cyclohexyl-7-(6-(3- formam-ide (formamiido)pyrrolid inyl)pyridyl)pyrido[ 2,3-d]pyrimidine __________________ 314 4-amino-5- 1-phenyl-1,38- LRMS [M+H]l 536. cyclohexyl-7-(4- triazaspirolj4.5]deca oxo-1-phenyl- 1,3,8- n-4-one triazaspirol4.5 [deca n-8-yl)pyrido[2,3 d~pyrimidine _________ 315 4-arnino-5- 2- LRMS [M+H]+ 420. cyclohexyl-7-(6-(2- (methoxymethyl)pyr (methoxymethyl)pyr rolidine rolidin-1 yl)pyridyl)pyrido [2, 3-dipyrim-idine 316 4-amidno-5- N- LRMS [M+H]+ 421. cyclohexyl-7-(6-(N- (methoxyethyl)prop methoxyethyl-N- ylam-ine propylaniino)pyridyl )pyrido[2,3 d]pyrimidine _________ 317 4-aniino-5- 2-(methylamino)- LRMS [M+H]+ 429. cyclohexyl-7-(N- dimethylacetaldehyd methyl-N-(2,2- e dimethoxyethyl)amni no)pyrido[2,3 dlpyrin-iidine _________ 318 4-amiino-5- N-(4-piperidyl)- LRMS [M+H]+ 433. cyclohexyl-7-(6-(4- dimethylamidne (dimethylarnino)pipe ridinyl)pyridyl)pyrid ____oI2,3-d]pyfimidine ___________________ -115- WO 98/46605 PCT/US98/07207 319 4 -amino-5- piperidine-4- LRMS [M+H] + 433. cyclohexyl-7-(6-(4- formamide (aminocarbonyl))pip eridinyl)pyridyl)pyri do[2,3-d]pyrimidine 320 4-amino-5- N 1 , N 1 -diethyl-N 3 - LRMS [M+H]* 449. cyclohexyl-7-(N- methyl-1,3 methyl-N-(3- propanediamine (diethylamino)propy 1)aminopyrid-3 yl)pyrido[2,3 d]pyrimidine 321 4-amino-5- N-methyl-(4- LRMS [M+H] + 441. cyclohexyl-7-(6-(N- pyridyl)ethylamine methyl-N-(4 pyridyl)ethylamino) pyrid-3 yl)pyrido[2,3 d]pyrimidine 322 4-amino-5- N-methyl-(3- LRMS [M+H]" 427. cyclohexyl-7-(6-(N- pyridyl)methylamine methyl-N-(3 pyridylmethyl)amino )pyrid-3 yl)pyrido[2,3 d]pyrimidine Example 323 4-amino-5-( 1-(2-bromophenyl)ethyl)-7-( -methyl-5-indoyl)pyridor2,3-dlpyvrimidine The procedures of Example 157 were followed, except substituting 1',1 l'-dicyano-3 5 bromostyrene for the R 3 reagent and 1-(1-methyl-5-indolyl)-ethanone for the R 4 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 10 aqueous HCI was omitted, and the free bases was obtained. IR (KBr) cm- 1 3500, 1578, 1500; MS m/z 431 (M+H) + . Example 324 4-amino-5-( 1 -(2-bromophenyl)ethyl)-7-( 1 -methyl-2,3-dioxo-5-indolvl)pyrido[2,3 15 d1pyrimidine The title compound was prepared from the compound of Example 323 by oxidation with CrO3 in sulfuric acid. IR (microscope) 3471, 1765, 1500 cm-1; MS m/z 461(M+H)+. -116- WO 98/46605 PCT/US98/07207 Examples 325-326 Following the procedures of Example 157, except substituting the appropriate R 3 and R 4 reagents as indicated in the Table below, compounds of Examples 325-326 were prepared. After 24 hours, the precipitated amidine compound was filtered and washed with 5 hexanes, then dried under vacuum. The amridine 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 HCI was omitted in some cases, and the free bases were obtained. 10 Examples 325-326 E x. Name R 3 Reagent R 4 Reagent Analytical Data No. (for 5- (for 7 position position) 325 4-amino-5-(3- 1',1 '-dicyano-3- 1-(3-fluoro-4-(1- IR (microscope) 3443, bromophenyl)-7-(3- bromostyrene morpholinyl)phe 3044, 1639, 1606, 1584, fluoro-4-(1- nyl)-ethanone 1520, 1362, 1245 cm-1; morpholinyl)phenyl)p MS m/z 480 (M+H)
+
. yrido[2,3 d]pyrimidine 326 4-amino-5-(3- l',l'-dicyano-3- 1-(4-hydroxy-3- IR (KBr) 3461, 1623, bromophenyl)-7-(4- bromostyrene nitrophenyl)- 1579. 1548, 1523, 1353 hydroxy-3- ethanone cm-1; MS m/z 438 nitrophenyl)pyrido[2,3 (M+H) +. -d]pyrimidine 15 Example 327 Following the procedures of Example 244 Step c, except in step c substituting the compound resulting from the reaction of 2-acetyl-5-chloropyridine in refluxing ethanol with the precursor reagent compound (4-piperidinone ethylene ketal) shown below for the R 4 reagent of Example 244 Step c, and substituting dichloroethane as the solvent in place of the 20 ethanol solvent in Example 244 step c, the compound shown in the table below was prepared. Ex. Name precursor Analytical No. reagent Data 327 4-amino-5-(3- 4-piperidinone IR (microscope) bromophenyl)-7-(6-(4,4- ethylene ketal 3091, 1602. 1580. ethylenedioxypiperidinyl)- 1558, 1512, 1353, 3-pyridyl)pyrido[2,3- 1236, 1103 cm'l; d]pyrimidine MS m/z 519 (M+H) + . -117- WO 98/46605 PCT/US98/07207 Example 328 4-amino-5-(3-bromophenyl)-7-(6-(4-oxo piperidinyvl)-3-pvridv )pvrido [2,3-dlpvrimidine Treating the compound of Example 327 with dilute HC1, the title compound was prepared. IR (microscope) 3438, 3051, 1645, 1605, 1558, 1450, 1371, 1240 cm- 1 ; MS 5 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 10 the precursor reagent compound shown below for the R 4 reagent of Example 244 Step c, and substituting dichloroethane as the solvent in place of the ethanol solvent in Example 244 step c, the compounds shown in the table below were prepared. Examples 329-331 15 Ex. Name precursor Analytical N o. reagent Data 329 4-amino-5-(3- piperazine IR (KBr) 3489, 1674, bromophenyl)-7-(6-(4- 1602, 1581, 1559, 1503, 1233, 1004 formylpiperazinyl)-3- 1503, 1233, 1004 pyridyl)pyrido[2,3- cm-1; MS m/z 491 d]pyrimnidine
(M+H)
+. 330 4-amino-5-(3- 1- IR (microscope) bromophenyl)-7-(6-(4- methylpiperazine 3438, 3051, 1540 methylpiperazinyl)-3- cm-1; MS m/z 477 pyridyl)pyrido[2,3- (M+H) +. d]pyrimidine 331 4-amino-5-(3- thiomorpholine IR (KBr) 3486, 1602, bromophenyl)-7-(6- 1581, 1560, 1502, thiomorpholinyl-3- 1228 cm-1; MS m/z pyridyl)pyrido[2,3- 479 (M+H) + . d]pyrimidin Example 332 4-amino-5-(3-bromophenyl)-7-(6-(4,4-dioxothiomorpholinvyl)-3-pvridvl)pyrido[2,3 dlpyrimidine 20 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) + . -118- WO 98/46605 PCT/US98/07207 Example 333 4-amino-5-( 2 -bromophenvyl)-7-(6-morpholinvl-3-pvridyl)pyridor2,3-d]pyrimidine Step 333a. 1',1'-dicyano-2-bromostvrene 5 The title compound was prepared by condensation of 2-bromobenzaldehyde with malononitrile and MgO in dichloromethane by the standard procedure of Broekhuis et al. (Recl. J. R. Neth. Chem. Soc., 99: 6-12 (1980)). Step 333b. 5-acetyl-2-morpholinvlpyridine 10 The title compound was prepared by the reaction of 5-acetyl-2-chloropyridine with morpholine in refluxing ethanol. Step 333c. 4-(2-bromophenvl)-3-cvano-6-morpholinvlpyridine-2-amine The title compound was prepared by condensation of 1', 1'-dicyano-2-bromostyrene 15 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 333d. 4 -amino-5-(2-bromophenvyl)-7-(6-morpholinvl-3-pyridvl)pyridor2.3 20 d]pyrimidine 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 25 extracted from the filtrate. The product was purified by column chromatography eluting with 10% MeOH/CH 2 Cl 2 . IR (microscope) 3493, 1547, 1109cm- 1 ; MS m/z 464 (M+H) + . Examples 334-336 Following the procedures of Example 333, except in Step a substituting the 30 precursor aldehyde reagent shown below for the 2-bromobenzaldehyde of Example 333 Step a, and carrying the product forward as in procedures 333 Stepbs b-d, the compounds shown in the table below were prepared. -119- WO 98/46605 PCT/US98/07207 Examples 334-336 Ex. Name precursor Analytical N o. aldehyde Data reagent 334 4-amino-5-(3-bromo-4- 3-bromo-4- IR (microscope) methoxyphenyl)-7-(6- methoxybenzaldehyde 3486, 1600, 1575, morpholinyl-3- 1562, 1500, 1260, pyridyl)pyrido[2,3- 1237 cm-1; MS m/z d]pyrimidine 493 (M+H)*. 335 4-amino-5-(4- 4-bromobenzaldehyde IR (microscope) bromophenyl)-7-(6- 3497, 1532, morpholinyl-3- 1098cm- 1 ; MS m/z pyridyl)pyrido[2,3- 464 (M+H) + . d]pyrimidine 336 4-amino-5-(3- 3-chlorobenzaldehyde IR (microscope) chlorophenyl)-7-(6- 3484, 1500, morpholinyl-3- 1034cm- 1 ; MS (FAB) pyridyl)pyrido[2,3- m/z 587 (M+H)*. d]pyrimidine Example 337 5 4-amino-5-(3-bromophenyl)-7-(5-chloro-6-morphoinyl-3-pyridvl)pyrido[2,3-d]pyrimidine 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 10 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/z 497 (M+H) + . Example 338 15 4-amino-5-(3-bromophenvl)-7-(6-(N-oxidomorpholinyl)-3-pyridyl)pyrido[2,3-d]pyrimidine The title compound was prepared by treating the compound of Example 134 with hydrogen peroxide in acetic acid according to standard procedures. IR (microscope) 3486, 1579, 1552, 1353, 1121, 1020 cm-1; MS m/z 479 (M+H) + . -120- WO 98/46605 PCT/US98/07207 Example 339 4-amino-5-(3-bromophenyl)-7-(6-(N-(2-hydroxvethoxvethyl)amino)-3-pvridyl)pridorf2,3 dlpvrimidine 5 Step 339a. 1'.1'-dicvano-3-bromostvrene The title compound was prepared by condensation of 3-bromobenzaldehyde with malononitrile and MgO in dichloromethane by the standard procedure of Broekhuis et al. (Recl. J. R. Neth. Chem. Soc., 99: 6-12 (1980)). 10 Step 339b. 5-acetyvl-2-(N-(2-ethoxvethyl)amino)pvridine The title compound was prepared by the reaction of 5-acetyl-2-chloropyridine with 2-ethoxyethylamine in refluxing ethanol. Step 339c. 4-(3-bromophenvl)-3-cvano-6-(N-(2-ethoxvethyl)amino)pvridine-2-amine 15 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. 20 Step 339d. 4-amnino-5-(2-bromophenvyl)-7-(6-(N-(2-ethoxvethyl)amino)-3 pyridvyl)pvrido[2,3-d]pyrimidine A sample of the compound from Step 239d was treated according to the procedure of Example 233d to give the title compound. IR (microscope) 3301, 1610, 1579, 1543, 1346, 1304, 1120 cm-1; MS m/z 481 (M+H) + . 25 Example 340 4-amino-5-(3-bromophenvyl)-7-(6-(N-(2-hydroxvethoxvethyl)-N-formylamino)-3 pyridvyl)pyrido[2.3-dlpvrimidine This compound was isolated by chromatography as a product of the reaction 30 described in Example 239 Step d. IR (microscope) 3306, 1679, 1596, 1577, 1548, 1493, 1352, 1125 cm- 1 ; MS m/z 509 (M+H) + . -121- WO 98/46605 PCT/US98/07207 Example 341 4-amino-5-(3-bromophenvl)-7-(6-(N-(2-hydroxvethoxvethyl)-3-pyridyl-N oxide)pVgrido r2,3-d]pyrimidine The title compound was prepared by treating the compound of Example 341 with 5 hydrogen peroxide in acetic acid according to standard procedures. IR (microscope) 3296, 1628, 1560, 1411, 1353 cm- 1 ; MS m/z 497 (M+H) + . Example 342 4-amino-5-(3-bromophenyl)-7-(6-(3-hydroxy)morpholinvyl)-3-pyridvl)pyrido[23 10 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- 1 ; MS m/z 478 (M+H) + . 15 Example 343 1-(5-(4-amino-5-(3-bromophenvyl)pyrido[2,3-d]pyrimidin-7-vl)-2-pyridv1)-piperidine-4 phosphate, disodium salt The title compound was prepared from the compound of Example 342 by treatment with POC1 3 , and subsequent workup acccording to standard procedures. IR (microscope) 20 3498, 1500, 1444 cm- 1 ; MS m/z 556 (M+H) + . Example 344 4-amino-5-(3-bromophenvyl)-7-(6-(2-hydroxy)morpholinvl)-3-pyridvl)pyrido r2,3 d]pyrimidine 25 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+CH3OH-H20) + . 30 Example 345 4-amino-5-(3-bromophenvl)-7-(4-methylenvlpiperidinvl)-3-pyridvyl)prido r2,3-d]1pyrimidine 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 35 chromatography. IR (microscope) 3055, 1602, 1559, 1508, 1440, 1344, 1174 cm- 1 ; MS m/z 473 (M+H) + . -122- WO 98/46605 PCT/US98/07207 Example 346 4-amino-5-(3-bromophenvl)-7-(4-hvdroxy-4-(hydroxymethyl)piperidinyl)-3 pyridvyl)prido[2.3-dlpyrimidine The title compound was prepared from the compound of Example 345 by treatment 5 with OsO4 in DMSO at room temperature. After quenching, the title compound was extracted, then purified by chromatography. IR (microscope) 3304, 1603, 1580, 1557, 1509, 1352, 1241 cm- 1 ; MS m/z 507 (M+H) + . Example 347 10 4-amino-5-(3-bromophenvyl)-7-(6-(4.4-ethylenedioxvpiperidinvyl)-3-pyridvyl)pyrido[2,3 d]pvrimidine Step 347a. 1,1-dicvano-3-cyclohexvlethene The 1,1 -dicyano-3-cyclohexylethene was prepared according to the method of 15 Moison, et al. (Tetrahedron (1987), 43:537-542) by treating cyclohexane carboxaldehyde with malononitrile in the presence of finely powdered magnesium oxide in dichloromethane. Step 347b. 2-acetyl-5-(4,4-ethylenedioxvpiperidinvl)pyridine A sample of 2-acetyl-5-chloropyridine was treated in refluxing ethanol with 4 20 piperidinone ethylene ketal to give the title compound. Step 347c. 4-amino-5-cyclohexyl-7-(6-(4,4-ethylenedioxvpiperidinvyl)-3 pyridyl)pvrido [2.3-d1pyrimidine Following the procedures of example 339 Step c, except substituting the compounds 25 from Step 347a and 347b for the compounds of Steps 339a and 339b, and carrying the product forward according to the procedure of example 339 Step d, the title compound was prepared. IR (microscope) 2929, 1604, 1585, 1557, 1514, 1426, 1344, 1238, 1106 cm- 1 ; MS m/z 447 (M+H) + . 30 Example 348 4-amino-5-cyclohexvl-7-(6-(4-oxo-piperidinvl)-3-pyridvyl)pyrido r2,3-dlpyrimidine The title compound was prepared from the compound of Example 347 by treatment with dilute HC1 in ethanol. The title compound was purified by chromatography. IR (microscope) 2928, 1715, 1603, 1585, 1559, 1507, 1344, 1226 cm-1; MS m/z 403 35 (M+H) + . -123- WO 98/46605 PCT/US98/07207 Example 349 4 -amino-5-cclohexv1-7-(6-(4-methylenv1piperidinvl)-3-pyridv1)pyridor[23-dluv-imrnidine 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 5 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) + . 10 Example 350 4 -N-(iminomethyl)amino-5-cyclohexvl-7-(6-dimethylamino-3-pyridvl)pvrido[2.3 d]pynimijdine 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]+ 15 m/z 376. -124-

Claims (19)

1. A method for inhibiting adenosine kinase by administering a compound, or a pharmaceutically acceptable salt or amide thereof, having the formula R N-. R 2 R N RH 4 1 N N " 7 R 4 5 1 N (I) wherein R 1 and R 2 are independently selected from H, loweralkyl, C1-C6alkoxyC1 C6alkyl, arylC 1 -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 10 containing 1-2 additional heteroatoms selected from O, N or S; R 3 is selected from the group consisting of loweralkyl, loweralkenyl, loweralkynyl, cycloalkyl, aryl, arylalkyl, heteroaryl, heterocyclic group, heteroarylalkyl or heterocycloalkyl wherein the heteroaryl and heterocyclic groups are linked directly or indirectly by a ring carbon; 15 R 4 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 R N R 2 R 3N 6 3 4 I 2N/NN"7 R 4 wherein 5 R 1 and R 2 are independently selected from H, loweralkyl, arylCl -C6alkyl, C(0)C1-C6alkyl, -C(0)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; R 3 and R 4 are independently selected from the group consisting of: -125- WO 98/46605 PCT/US98/07207 10 C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C8cycloalkyl, heteroarylCO-C6alkyl or substituted heteroarylCO-C6alkyl, 15 optionally substituted cycloalkyl, arylCO-C6alkyl or substituted arylCO-C6alkyl, heteroarylC2-C6alkenyl or substituted heteroarylC2-C6alkenyl, arylC2-C6alkenyl or substituted arylC2-C6alkenyl, heteroarylC2-C6alkynyl or substituted heteroarylC2-C6alkynyl, 20 arylC2-C6alkynyl or substituted arylC2-C6alkynyl wherein the 1-4 heteroaryl or aryl substituents are independently selected from halogen, oxo, CO2R 5 , cyanoC1-C6alkyl, heteroarylCO-C6alkyl, heterocyclicCO-C6alkyl, Cl-C6alkyloxy, C1-C6alkyloxyC1-C6alkyl, arylCO-C6alkyl, arylC1-C6alkyloxy, R 5 R 6 NC(O), cyano, C2-C6alkenyl, 25 C2-C6alkynyl, C1-C6alkyl, C2-C6alkenyldialkylmalonyl, CF3, HO-, Cl C6alkyloxyC1-C6alkyloxy, C1-C6alkylSOn wherein n is 1-2, C1 C6alkylthio, C1-C6alkylacryl, CF30, CF3, C1-C4alkylenedioxy, Cl C6alkylacryl, R 5 R 6 N(CO)NR 5 , N-formyl(heterocyclic), NO2, NR 5 R 6 CO C6alkyl, (R 5 0)(R 6 0)-P(O)-C0-C6alkyl, 30 wherein R 5 and R 6 are independently selected from H, C1-C6alkyl, HC(O), C1-C6alkyloxyC1-C6alkyl, C1-C6alkyloxy, Cl C6alkylC(O), CF3C(O), NR 7 R 8 C1-C6alkyl, phthalimidoC1 C6C(O), C 1-C6alkylSOn where n is 1-2, CNC1-C6alkyl, R 7 R 8 NC(O)NR 7 -, heteroaryl, NR 7 R 8 C 1-C6alkylC(O), Cl 35 C6alkyloxycarbamidoC 1-C6alkyl, wherein R 7 and R 8 are independently selected from those variables identified for R 5 and R 6 or R 5 and R 6 or R 7 and R 8 may join together with the nitrogen atom to which they are attached to form a 5-7 membered unsubstituted or 40 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. -126- WO 98/46605 PCT/US98/07207
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 R I-N R 2 R 3 (4 H 5 wherein R 1 -R 8 and n are as defined above to a patient in need of treatment thereof.
4. A method according to Claim 3 wherein R 4 is selected from the group consisting of: phenyl; thiophene-2-yl; 3-methyl-2-oxobenzoxazolin-6-yl; 2-(dimethylamino)
5-pyrimidinyl; 2-(N-formyl-N-methyl amino)-5-pyrimidinyl; 2-(N-methoxyethyl-N-methyl amino)-5-pyrimidinyl; 2-(N-methylamino)5-pyrimidinyl; 2-(1-morpholinyl)-5-pyrimidinyl; 5 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 10 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 15 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 20 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 25 ( 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 -127- WO 98/46605 PCT/US98/07207 ethoxyphenyl; 4-ethylphenyl; 4-fluorophenyl; 4-hydroxyphenyl; 4-imidazolylphenyl; 4 iodophenyl; 4 -isopropylphenyl; 4-methoxyphenyl; 4-methylaminophenyl; 4 30 methylsulfonylphenyl; 4-morpholinylphenyl; 4-N-(2-(dimethylamino)ethyl)-N formylamino)phenyl; 4-N-(3-methoxypropionyl)-N-isopropyl-amino)phenyl; 4-N-ethyl-N (2-methoxyethyl)amino)phenyl; 4-N-formylpiperazinylphenyl) 4-nitrophenyl; 4 piperidinylphenyl; 4-(3-pyridyl)phenyl; 4-pyrrolidinylphenyl; 4-t-butylacrylphenyl; 5 (dimethylamino)thiophene-2-yl; 5-amino-2-pyridyl; 5-dimethylamino-2-pyrazinyl; 3 35 dimethylaminopyridazin-6-yl; 5-dimethylamino-2-pyridyl; 5-pyrimnidinylphenyl; 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. 40 5. A method according to Claim 3 wherein R 3 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 5 (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 10 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 15 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 20 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. -128- WO 98/46605 PCT/US98/07207 6. A method according to Claim I 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; 5 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; 10 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; 15 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; 20 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; 25 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 30 d]pyrimidine; 4-amino-5-(3-trifluoromethylphenyl)-7-(4-dimethylaminophenyl)pyrido[2,3 dipyrimidine; 4 -amino-5-(3-carboxamidophenyl)-7-(4-dimethylaminophenyl)pyrido[2,3 dipyrimidine; 35 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; -129- WO 98/46605 PCT/US98/07207 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 40 d]pyrimidine; 4 -amino-5-(3-methylphenyl)-7-(4-dimethylaminophenyl)pyrido[2,3-d]pyrim-lidine; 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; 45 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]pyrinidine; 4 -amino-5-(3-bromophenyl)-7-(4-bromophenyl)pyrido[2,3-d]pyriniidine; 4 -amino-5-(3-bromophenyl)-7-(4-cyanophenyl)pyrido[2,3-d]pyrimidine; 50 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 dipyrimidine; 55 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; 60 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; 65 4 -amino-5-(3-bromophenyl)-7-(4-diethylaniinophenyl)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-dimethylaninophenyl)pyrido[2,3 70 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; -130- WO 98/46605 PCT/US98/07207 75 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 -anino-5-phenyl-7-(4-dimethylaminophenyl)pyrido[2,3-d]pyrimidine; 4 -amino-5-(3,4,5-trimethoxyphenyl)-7-(4-dimethylaminophenyl)pyrido[2,3 80 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; 85 4-amino-5- (3,5-dimethoxyphenyl)-7-(thiophen-2-yle)pyrido [2,3-d]pyrimidine; 4-amino-5-(3-bromophenyl)-7-(4-carboxamidophenyl)pyrido[2,3-d]pyrimidine; 4-amino-5-(3-bromophenyl)-7-(4-(2-methoxy)ethoxyphenyl)pyrido[2,3 d]pyrirnidine; 4-anino-5-(3,5-dimethoxyphenyl)-7-(4-morpholinylphenyl)pyrido[2,3-d]pyrimidine; 90 4 -amino-5-(3-trifluoromethylphenyl)-7-(thiophene-2-yl)pyrido [2,3-d]pyrinidine; 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-dipyrimidine; 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; 95 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 dipyrimidine; 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[2,3 100 dipyrimidine; 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 dipyrimidine; 105 4 -morpholinyl-5-(3-bromophenyl)-7-(4-dimethylaminophenyl)pyrido[2,3 dipyrinidine; 4-amino-5-(5-bromothiophene-2-yl)-7-(4-morpholinylphenyl)pyrido[2,3 dipyrimidine; 4-amino-5-( 4 -bromophenyl)-7-(4-dimethylaminophenyl)pyrido[2,3-d]pyrimidine; 110 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; -131- WO 98/46605 PCT/US98/07207 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]pyrinidine; 115 4 -amino-5-(4-bromothiophene-2-yl)-7-(4-pyrrolidinylphenyl)pyrido[2,3 dipyrimidine; 4-amino-5-(4-bromothiophene-2-yl)-7-(thiophene-2-yl)pyrido[2,3-dipyrinidine; 4-amino-5-(3-bromophenyl)-7-(5-(dimethylamino)thiophene-2-yl)pyrido[2,3 d]pyrimidine; 120 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[2,3 125 d]pyrimidine; 4 -amino-5-(3,5-dibromophenyl)-7-(4-(dimethylamino)phenyl)pyrido[2,3 dipyrimidine; 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[2,3 130 d]pyrimidine; 4 -amino-5-(3,5-dibromophenyl)-7-(4-(dimethylamino)phenyl)pyrido[2,3 d]pyriniidine; 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; 135 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 dlpyrimidine; 140 4-amino-5-(3-bromophenyl)-7-(4-methylaminophenyl)pyrido[2,3-dlpyrimidine; 4 -amino-5-(3-bromo-4-fluorophenyl)-7-(4-methylsulfonylphenyl)pyrido[2,3 d]pyrimidine; 4-amino-5-(3-bromophenyl)-7-(3-amino-4-methoxyphenyl)pyrido[2,3-dlpyrimidine; 4 -amino-5-(3-bromophenyl)-7-(3-bromo-4-(dimethylamino)phenyl)pyrido[2,3 145 d]pyrimidine; 4-amino-5-(3-bromophenyl)-7-(3-methyl-4-(dimethylamino)phenyl)pyrido[2,3 dipyrimidine; -132- WO 98/46605 PCT/US98/07207 4-amino-5-(3-bromophenyl)-7-(4-(N-methyl-N trifluoroacetylamino)phenyl)pyrido[2,3-d]pyrimidine; 150 4-amino-5-(3-bromophenyl)-7-(4-(dimethylamino)-3-fluorophenyl)pyrido[2,3 dipyrimidine; 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 155 acetylamino)phenyl)pyrido[2,3-d]pyrimidine; 4-amino-5-(3-bromophenyl)-7-(4-(N-acetyl-N-methylanino)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-(2 160 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)anino)phenyl)pyrido[2,3-d]pyrimidine; 165 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-(2 170 (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-anino-5-(3-bromophenyl)-7-(4-(N-methyl-N-(3 methoxy)propionylamino)phenyl)pyrido[2,3-d]pyrimidine; 175 4-amino-5-(3-bromophenyl)-7-(3-methyl-4-(N-formyl-N methylamino)phenyl)pyrido[2,3-d]pyrimidine; 4-amino-5-(3-bromophenyl)-7-(3-methyl-4-(N-methylanino)phenyl)pyrido[2,3 d]pyrimidine; 4 -amino-5-(3-bromophenyl)-7-(4-(4-methoxy-2-butyl)phenyl)pyrido [2,3 180 d]pyrimidine; 4-aniino-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; -133- WO 98/46605 PCT/US98/07207 185 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; 190 4-amino-5-(3-cyanophenyl)-7-(4-(N-methyl-N-formylamino)-phenyl)pyrido[2,3 dlpyrimidine; 4-amino-5-(3-bromophenyl)-7-(6-(N-methyl-N-formylamino)-3 pyridinyl)pyrido[2,3-d]pyrimidine; 4- amino-5-(3-bromophenyl)-7-(6-morpholinyl-3-pyridinyl)pyrido[2,3-d]pyrimidine; 195 4-anino-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 dipyrimidine; 200 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[2,3 205 d]pyrimidine; 4-amino-5-(3-bromophenyl)-7-(2-(1-pyrrolidinyl)-5-pyrimidinyl)pyrido[2,3 dipyrimidine; 4-amino-5-(3-bromophenyl)-7-(2-(1 -morpholinyl)-5-pyrimidinyl)pyrido[2,3 dlpyrimidine; 210 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[2,3 215 d]pyrinidine; 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; 220 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; -134- WO 98/46605 PCT/US98/07207 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-dpyrimidine; 225 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]pyrinidine; 4- amino-5-(3-bromo-4-fluorophenyl)-7- (4-iodophenyl)pyrido[2,3-d]pyrimidine; 4 -amino-5-(4-bromothiophene-2-yl)-7-(4-methoxyphenyl)pyrido[2,3-d]pyrimidine; 4-amino-5-(3-bromophenyl)methyl-7-(4-(dimethylamino)phenyl)pyrido[2,3 230 d]pyrimidine; 4-anino-5-(2-phenylethyl)-7-(4-diethylaminophenyl)pyrido[2,3-d]pyrinidine; 4-amino-5-(2-methylpropyl)-7-(4-diethylaminophenyl)pyrido[2,3-d]pyrin-idine; 4 -amino-5-(butyl)-7-(4-diethylaminophenyl)pyrido[2,3-d]pyrimidine; 4 -amino-5-(2-(4-bromophenyl)ethyl)-7-(4-diethylaminophenyl)pyrido[2,3 235 d]pyrimidine; 4- amino-5-(butyl)-7-(4-dimethylaminophenyl)pyrido[2,3-d]pyrimidine; 4 -amino-5-(2-(3-cyanophenyl)methyl)-7-(4-dimethylaninophenyl)pyrido[2,3 d]pyrimidine; 4-amino-5-(2-(N-phenylmethoxycarbonyl)aninoethyl)-7-(4 240 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; 245 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 dipyrimidine; 4 -amino-5-((2-bromophenyl)methyl)-7-(4-diethylaniinophenyl)pyrido[2,3 d]pyrimidine; 250 4 -amino-5-cyclopropyl-7-(4-dimethylaminophenyl)pyrido[2,3-d]pyrimidine; 4 -amino-5-cyclohexyl-7-(4-dimethylaninophenyl)pyrido[2,3-d]pyrinidine; 4 -amino-5-((2-bromo-5-chlorophenyl)methyl)-7-(4-diethylaminophenyl)pyrido[2,3 d]pyrimidine; 4 -amino-5-methyl-7-(4-diethylaninophenyl)pyrido[2,3-d]pyrimidine; 255 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; -135- WO 98/46605 PCTIUS98/07207 4 -amino- 5 -(2-bromophenyl)-7-(4-dimethylaminophenyl)pyrido[2,3-d]pyrimidine; 260 4-amino-5-(3,5-dimethylphenyl)-7-(4-dimethylaminophenyl)pyrido[2,3 dipyrimidine; 4 -amino-5-(3,4-dichlorophenyl)-7-(4-dimethylaminophenyl)pyrido[2,3-d]pyrimidine; 4 -amino-5-(4-fluoro-3-trifluoromethylphenyl)-7-(4 dinethylaminophenyl)pyrido[2,3-d]pyrimidine; 265 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[2,3 270 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; 275 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; 280 4 -acetylamino-5-(3-bromophenyl)-7-(4-dimethylaninophenyl)pyrido[2,3 d]pyrimidine; 4-formylamino-5-(3-bromophenyl)-7-(4-dimethylaminophenyl)pyrido[2,3 dlpyrimidine; 4-(methoxyacetyl)amino-5-(3-bromophenyl)-7-(4-diethylaminophenyl)pyrido[2,3 285 d]pyrimidine; 4 -trifluoroacetylanino-5-(3-bromophenyl)-7-(4-dimethylaminophenyl)pyrido[2,3 dipyrinidine; 4 -pentanoylamino-5-(3-bromophenyl)-7-(4-dimethylaminophenyl)pyrido[2,3 d]pyrimidine; 290 4-benzoylamino-5-(3-bromophenyl)-7-(4-dimethylaminophenyl)pyrido[2,3 dipyrimidine; 4-(N-BOC-glycyl)amino-5-(3-bromophenyl)-7-(4-dimethylaminophenyl)pyrido[2,3 d]pyrimidine; 4-(N-phthalimidylglycyl)amino-5-(3-bromophenyl)-7-(4 295 dimethylaninophenyl)pyrido[2,3-d]pyrimidine; -136- WO 98/46605 PCTIUS98/07207 4 -(ethoxycarbonyl)amino-5-(3-bromophenyl)-7-(4-dimethylaminophenyl)pyrido[2,3 d]pyrimidine; 4-(ethylaninocarbonyl)amino-5-(3-bromophenyl)-7-(4 dimethylaminophenyl)pyrido[2,3-d]pyrimidine; 300 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-(4 305 dimethylaminophenyl) pyrido[2,3-d]pyrimidine; 4-(N-allyl-N-formylamino)-5-(4-dimethylaninophenyl)-7-(4 bromophenyl)pyrido[2,3-d]pyrimidine; 4-diacetylamino-5-(p-dimethylaminophenyl)-7-(4 bromophenyl)pyrido[2,3-d]pyrimidine; 310 4-amino-5-(3-bromophenyl)-7-(5-anino-2-pyridyl)pyrido[2,3-d]pyrimidine; 4 -anino-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; 315 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-anino-5-((thiophene-2-yl)methyl)-7-(4-diethylaminophenyl)pyrido[2,3 320 d]pyrimidine; 4 -anino-5-((thiophene-3-yl)methyl)-7-(4-diethylaninophenyl)pyrido[2,3 d]pyrimidine; 4 -amino-5-((2-bromophenyl)methyl)-7-(4-dimethylaninophenyl)pyrido[2,3 dipyrimidine; 325 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-((2 330 dimethylamino)ethyl)anmino)phenyl)pyrido[2,3-d]pyrimidine; 4-amino-5-(3-bromophenyl)-7-(4-(2 methoxy)acetylamino)ethyl)amino)phenyl)pyrido[2,3-d]pyrimidine; -137- WO 98/46605 PCTIUS98/07207 4 -arnino- 5 -(3-.bromophenyl)-7-((4-formylamino)phenyl)pyrido[2,3-d]pyrimidine; 4-arnino-5-(3-bromophenyl)-7- (4-(2-(dimethylamfino)acetylamino)phenyl)pyrido[2,3 335 d]pyrimidine; 4 -amidno-5-(3-bromophenyl)-7-(4-(2-oxo-3-oxazolidinyl)phenyl)pyrido[2,3 d]pyrimidine; 4 -an-lno-5-(3-bromophenyl)-7-(6-(2-propyl)-3-pyridinyl)pyido[2,3dlpyin-idine 4-aniiino-5- (3-bromophenyl)-7-(3-methyl-4-pyrrolidinylphenyl)pyrido[2,3 340 dipyrirnidine; 4 -armino-5-(3-bromophenyl)-7-(6-imidazolyl-3-pyridinyl)pyrido[2,3-d]pyrin-dine; 4 -amino-5-phenylmethyl-7-(4-diethylamidnophenyl)pyrido[2,3-d]pyim-idine; 4 -amino-5-(2-(3-am-inopropyny)phenylmethy)-7-(4-diethylaniinophenyl)pyrido[2,3. dipyrimidine; 345 4-an-ino-5-(l1-(3-bromophenyl)ethyl)-7-(4-diethylaminophenyl)pyrido[2,3 dipyrim-idine; 4 -amino-5-(4-dimethylaminophenyl)-7-(4-bromophenyl)pyrido[2,3-dlpyrrnidine; 4 -amino- 5- (2-furanyl)-7-(4-(N-morpholinyl)phenyl)pyrido [2,3-d]pyrimidine; 4 -amaino-5-(3-bromophenyl)-7-(2-dimethylamino-5-pyrimidinyl)pyrido[2,3 350 dllpyrimidine; 4-am-ino-5- (3-bromophenyl)-7-(4-(ureido)phenyl)pyrido[12,3-d]pyrimidine; 4-amino-5-( 1-phenylmethyl-3-piperidinyl)-7-(4-diethylarninopheny)pyrido [2,3 dlpyrirnidine; 4 -amidno-5-(3-bromophenyl)-7-(6-(3-methyl-5-isoxazolyl))-3 355 pyridinyl)pyrido[2,3-dlpyfimidine; 4- amino- 5- (3-bromophenyl)-7- (6-chloro-3-pyridinyl)pyrido [2,3 -d]pyrir-nidine; 4-am-ino-5- (3-bromophenyl)-7-(6-methoxy-3-pyridinyl)pyrido [2,3-d]pyrirnidine; 4- amino- 5-(3-bromophenyl)-7 -(6- (1 ,2,4-triazol-4-yl)- 3-pyridinyl)pyrido [2,3 dipyrimidine; 360 4-arnino-5- (3-bromophenyl)-7-(2-morpholinyl-5-pyrimidinyl)pyrido [2,3 dlpyrimidine; 4 -am-ino-5-(2-thiazolyl)-7-(4-pyrrolidinylphenyl)-pyrido [2,3-d]pyrim-idine:, 4 -armino-5-(3-bromophenyl)-7-(6-pyrazolyl-3-pyridinyl))-pyrido[2,3 dlpyrimidine; 365 4-amidno-5-(3-bromophenyl)-7-(4-(l1-methyl-ureido)phenyl)-pyrido[2,3 dlpyrim-idine; 4 -amino-5-(3-bromophenyl)-7-(4-(N-methyl-N-(2-pyriniidinyl)an-ino)phenyl) pyrido[2,3-d]pyfimidine: -138- WO 98/46605 PCT/US98/07207 4 -amino- 5 -( 3 -bromophenyl)-7-(3-fluoro-4-(N-formyl-Nmethylaino)phenyl). 370 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 -amidno-5-(3-bromophenyl)-7- (4-(N-methyl-N-methylsulfonylan-ino) phenyl)pyrido[2,3-dlpyrimidine; 375 4 -anno-5-(3-bromophenyl)7(6-(NmethylN-methysufonylantjno-3 pyridinyl)pyrido[2,3-dlpyrimidine; 4 -amnno-5-(3-bromophenyl>7-(l1-methyl-5-indolinyl)pyrido[2,3-d]pyrimidine; 4 -amino-5-.(3-bromophenyl)-7-( 1-methyl-5-benzimiddazolyl)pyrido[2,3 d]pyrim-idine; 380 4 -amino-5-(3-bromophenyl)-7-(6-dimethylanino-3-pyridazinyI)pyrido[2,3 d~pyrimidine; 4-amino-5- (3 bromophenyl)-7-(6-morpholinyl-3-pyridazinyl)pyrido[2,3 d~pyrimidine; 4-amidno-5- ( 3 -bromophenyl)-7-(6-pyrrolidinyl-3-pyridazinyl)pyrido[2,3 385 dlpyrimidine; 4 -amino- 5- (3-bromophenyl) -7-(5-morphoinyl-2-pyrazinyl)pyrido [2,3 dipyrimidine; 4 -amino-5-(3-bromophenyl)-7- (5-(N-(2-methoxyethyl)-N-methylarnino)-2 pyrazinyl)pyrido [2,3-dipyrimidine;, 390 4 -am-ino-5-(3-bromophenyl)-7-(4-(morpholinylmethyl)-phenyl)pyrido [2,3 d~pyriniidine; 4 -aino-5-(3-bromopheny)>7-(5(N,N-bis(2-methoxyethyl)an-lno)>2 pyridinyl)pyrido[2,3-dlpyrimidine; 4 -amidno-5-(3-bromophenyl)-7-(4-(in-idazolylmethyl)-phenyl)pyrido[2,3 395 d~pyrimidine; 4 -amino-5-(3-bromophenyl)-7-(5-( 1-morpholinyl)-2-pyridinyl)pyrido [2,3 dilpyrimidine; 4 -anmino- 5 -(3-bromopheny)-7-(4-((dimethylan-ino)methyl)>pheny)pyrido[2,3. d~pyrimidine; 400 4- amino- 5- (3 -bromophenyl) -7 -(5- (4-hydroxy- 1 -piperidinyl)-2 pyridinyl.)pyrido[2, 3-dipyrimidine-. 4 -am-ino-5-(3-bromophenyl)-7-(5-(N-formyl-N-methylam-ino)-2 pyridinyl)pyrido[2. 3-d] pyrimi dine:, 4-amidno-5- ( 3 -bromophenyI)-7-(5-(2-propeny1-2-pyridiniy1)pyrido [2,3 405 d]pyrim-idine; -139- WO 98/46605 PCT/US98/07207 4 -anhino- 5 -( 3 -bromopheny1)-7-(3-(2-methoxyethyl>2-oxo-6 benzoxazolyl)pyrido[2,3-d]pyrimidine; 4 -amidno-5-(3-bromophenyl)-7-(4-( 1-(N-formylaniino)-ethyl)phenyl)pyrido [2,3-. d]pyrimidine; 410 4 -(methylamino)-5-(3-bromopheny7(4dimethylaminophenyl)pyrido[2,3 dilpyrimidine hydrochloride; 4 -( 2 -methoxyethylan-ino)-5-(3-bromophenyl)>7-(4 dimethylam-inophenyl)pyrido[2,3-d]pyrimidine hydrochloride; 4 -amino-5-(3-bromophenyl)-7-(4-( 1-methyl-2-imidazolyl)phenyl)pyrido [2,3 415 dlpyrimiddine trihydrochioride; 4 -amidno-5-(3-bromophenyl)-7-(4- (aminomethyl)phenyl)pyrido[2,3-dlpyrimidine; 4 -amino- 5 -(3-bromophenyl)-7-(2-bromo-4-(dimethylan-io)phenyl)pyrido[2,3 d]pyrim-idine; 4 -amino-5-(3-bromopheny)-7-(4-(dimethylaniinoethyl)phenyl)pyrido[2,3. 420 d]pyrimiddine; 4 -amidno-5-(3-bromophenyl)-7- ( 4 -(3-(dimethylamino)propynyl)phenyl)pyrido [2,3 dlpyrimidine; 4 -amino-5-(3-bromophenyl)-7-(4-(3-amno-3methylbutynyl)phenyl)pyido[2,3 d~pyrimidine; 425 4-amino-5- (3-bromophenyl)-7-(4-dimethylphosphonatophenyl)pyrido [2,3 d~pyriniidine; 4-amino-5- (3-bromophenyl)-7-(4- (3-(methoxypropynyl)pyrido[2,3-d]pyrimnidine; 4 -an-ino-5-(3-bromopheny1)-7-(4-carboxyphenyl)pyrido[2,3-d]pyrin-idine; 4 -amino-5-(3-bromophenyl)-7-(4-methyl-3-oxo2H4Hpyrido[3,2-b]- 1 ,4-oxazin 430 7 -yl)pyrido[2,3-d]pyrimidine; 4 -an-ino-5-(3-bromophenyl)-7-(4-(2-(dimethyan-o)ethy3oxo2H-4H pyrido[3,2-b]- 1 ,4-oxazin-7-y1)pyrido[2,3-dlpyrimidine; 4 -amino-5-(3-bromophenyl)-7-(2,3-dihydro-3(dimethylam-jnoethyl>2 oxobenzoxazol-6-yl)pyrido[2,3-dlpyrimidine; 435 4 -amino-5-(3-bromophenyl)-7- (4-methyl-3-oxo-2H-4H-benzo- 1 ,4-oxazin-7 yl)pyrido [2,3-d]pyrimidine; 4 -amiino- 5 -(3-bromophenyl)-7-(2,2,4-trimethyl3oxo2H-4Hbenzo- 1 ,4-oxazin-7 yl)pyrido [2,3-dipyrimidine; 4-amino-5-cyclohexyl-7-(4- (2-dimethylamino)ethyl)-2H-4H-benzo-3-oxo- 1,4 440 oxazin-7-yl)pyrido[2,3-dlpyin-iidine; 4 -amino-5-(3-bromophenyl)-7-(5-( 1-methylethyl)-2-pyridyl)pyrido[2,3 dipyrim-idine; -140- WO 98/46605 PCTIUS98/07207 4-amino-5-(3-bromophenyl)-7-(5-piperidin- 1 -ylpyrid-2-yl)pyrido[2,3-d]pyrirnidine; 4-amino-5-( 1-(4-bromophenyl)ethyl)-7-(6-morpholinylpyrid-3-yl)pyrido[2,3 445 d]pyrimidine; 4-amfino-5-(3-bromophenyl)-7-(4-((N-formylarnino)methyl)phenyl)pyrido[2,3 dipyrim-idine; 4-amidno-5-(3-bromophenyl)-7-(4-( 1-methyl-i 1-(N-methylam-ino)ethyl)phenyl) pyridor2,3-d]pyrfrnidine,; 450 4-arnino-5-(3-bromophenyl)-7-(4-(1-(dimethylamidno)-1I methylethyl)phenyl)pyrido[2,3-d]pyrimidine; 4-amino-5-(3-bromophenyl)-7- (N-acetyl-5-indolinyl)pyridol2,3-d]pyrimidine 4-amino-5-cyclohexyl-7-(6-chloro-3-pyridyl)pyrido[2,3-d]pyrimiddine; 4-ami no-5-(1- (2-bromophenyl)ethyl)-7-(6-diethylamidno-3-pyridyl)pyrido[2,3 455 d]pyrim-idine; 4-am-ino-5- (1-(2-bromophenyl)ethyl)-7-(6-morpholinyl-3-pyridyl)pyrido [2,3 dip yim-idine; 4-amidno-5-( 1-(2-bromophenyl)ethyl)-7-(4-(N-methyl-N-fomnyl)anino) phenyl)pyrido [2,3-dlpyfimidine; 460 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 dlpyfrmidine; 4-amino-5- (4-tetrahydropyranyl)-7-(6-morpholinyl-3-pyridyl)pyrido[2,3 dlpyrimidine, 465 4-arnino-5-cyclohexyl-7-(6-dimethylamino-3-pyridyl)pyrido [2,3-d]pyrimidine; 4-amidno-5-( 1-ethylpropyl)-7-(6-dimethylam-ino-3-pyridyl)pyrido[2,3-d]pyrimiidine; 4 -amidno-5-cyclopentyl-7-(6-morpholinyl-3-pyridyl)pyrido[2,3-d]pyinidine, 4-amnino-5-cyclohexyl-7-(2-chloro-3-pyridyl)pyrido[2,3-d]pyrimiddine; 4-amino-5-(3 ,5-dimethylcyclohexyl)-7-(6-dimethylamino-3-pyridyl)pyrido [2,3 470 dipyrimidine; 4 -am-ino-5-((N-(benzyloxycarbonyl)-4-piperidinyl)methyl)-7- (6-morpholinyl-3 pyridyl)pyrido[2,3-dlpyrimidine; 4 -amino-5-cyclohexyl-7-(6-bromo-3-pyridyl)pyrido[2,3-d]pyrimiddine; 4 -amino-5-cyclohexyl-7-(3-cyanophenyl)pyrido [2,3-d]pyrimidine; 475 4-amino-5-( 1-(2-bromophenyl)ethyl)-7-(6-dimethylami no-3-pyridazinyl)pyrido [2,3 dip yrim-idine; 4 -amino-5-(3-bromophenyl)-7-(6-imidazolyl-3-pyridazinyl)pyrido[2,3-dlpyrimidine; 4-amidno-5-(3-bromophenyl)-7-(6- (azacycloheptanyl)-3-pyridazinyl)pyrido[2 ,3 dipyfrmidine; -141- WO 98/46605 PCTIUS98/07207 480 4 -amino-5-(3-bromophenyl)-7-(6-(N-methyl-N-(1-methylethyl))amino)-3 pyridazinyl)pyrido[2,3-d]pyrimidine; 4-anino-5-(1-(2-bromophenyl)ethyl)-7-(6-morpholinyl-3-pyridazinyl)pyrido[2,3 dipyrimidine; 4-amino-5-cyclohexyl-7-(6-(4-acetylpiperazinyl)-3-pyridyl)pyrido[2,3-d]pyrimidine; 485 4-amino-5-cyclohexyl-7-(6-(4-acetyl- 1,4-diazacycloheptanyl)-3-pyridyl)pyrido[2,3 dlpyrimidine; 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)-3 490 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]pyrinidine; 4 -amino-5-cyclohexyl-7-(6-(3-(N-methylacetamido)pyrrolidinyl)pyridyl)pyrido[2,3 495 d]pyrimidine; 4 -anino-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; 500 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[2,3 505 d]pyrimidine; 4 -amino-5-cyclohexyl-7-(6-(4-(dimethylamino)piperidinyl)pyridyl)pyrido[2,3 dipyrimidine; 4 -amino-5-cyclohexyl-7-(6-(4-(aminocarbonyl))piperidinyl)pyridyl)pyrido[2,3 d]pyrimidine; 510 4 -amino-5-cyclohexyl-7-(N-methyl-N-(3-(diethylamino)propyl)aminopyrid-3 yl)pyrido[2,3-d]pyrimidine; 4 -an-ino-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-3 515 yl)pyrido[2,3-d]pyrimidine; -142- WO 98/46605 PCT1US98/07207 4-amino-5-( 1-(2-bromophenyl)ethyl)-7-(l1-methyl-5-indolyl)pyrido[2,3 dipyrim-idine; 4-amino-5-( 1-(2-bromophenyl)ethyl)-7-( 1-methyl-2,3-dioxo-5-indolyl)pyrido[2,3. dilpyimidine; 520 4 -ami no-5-(3-bromophenyl)-7-(3-fluoro-4- (1 -morpholinyl)phenyl)pyrido [2,3 dlpyrimidine; 4-am-ino-5- ( 3 -bromophenyl)-7-(4-hydroxy-3-nitrophenyl)pyrido[2,3-dlpyrim-idine; 4-arnino-5-(3- bromophenyl)-7-(6-(4,4-ethylenedioxypiperidinyl)-3. pyridyl)pyrido[2,3-dlpyrimidine; 525 4-am-ino-5-(3- bromophenyl)-7-(6- (4-oxopiperidinyl)-3-pyridyl)pyrido [2,3 dipyrimiddine; 4 -aiino-5-(3-bromophenyl)-7-(6-(4-fonrmylpiperazinyl)-3-pyridyl)pyrido [2,3 d]pyrimidine; 4-amino-5-(3- bromophenyl)-7-(6-(4-methylpiperazinyl)-3-pyridyl)pyrido[2,3 530 dlpyrimiddine; 4-amidno- 5- (3-bromophenyl)-7-(6-thiomorpholinyl-3-pyridyl)pyrido [2,3 dipyrim-idin; 4-am-ino-5- (3-bromophenyl)-7-(6-(4,4-dioxothiomorpholunyl)-3..pyridyl)pyiido[2,3 d~pyrimidine; 535 4-mn--2boohnl--6mrhlnl3prdlprd[,-~yiiie 4 -an-ino-5-(3-bromo-4-methoxyphenyl)-7-(6-morpholinyp3-pyridyl)pyrido[2,3 dlpyrim-idine; 4 -amino-5-(4-bromopheny)-7-(6-morpholiny13-pyridyl)pyrido[2,3-dlpyimidne; 4 -amino-5-(3-chlorophenyl)-7-(6-morpholinyb3-pyridyl)pyrido[2,3-d]py-imiiine; 540 4 -an-ino-5-(3-bromophenyl)-7-(5-chloro-6-morpholinyl3pyridyl)pyrido[2,3 dlpyrimidine; 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)arnino)-3 545 pyridyl)pyrido[2,3-d]pyrimidine; 4-mn--3boohnl--6(-2hyrxehxehl--omlnln)3 pyridyl)pyrido[2,3-d]pyrirn-idine; 4-amidno-5-(3-bromophenyl)-7-(6- (N-(2-hydroxyethoxyethyl)-3-pyridyl-N oxide)pyrido[2,3-d]pyriniidine; 550 4 -arfino-5-(3-bromophenyl)-7-(6-(3-hydroxy)morpholiny)-3pyridyl)pyrido[2,3 dlpyrimaidine; -143- WO 98/46605 PCT/US98/07207 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[2,3 555 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; 560 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-dimethylamnino-3-pyridyl)pyrido[2,3 d]pyrimidine. 565
7. A pharmaceutical composition comprising a therapeutically effective amount of a compound according to Claim 1 in combination with a pharmaceutically acceptable carrier.
8. A method of 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. 5
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, 5 diabetes and abnormal gastrointestinal motility:
10. A compound, or a pharmaceutically acceptable salt or amide thereof, of formula (I) R "N R 2 R 3 3 N 6H 2U 4 N N 7 R 4 wherein -144- WO 98/46605 PCT/US98/07207 5 R 1 and R 2 are independently selected from H, loweralkyl, C1-C6akoxyC1 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 0. N or S; R 3 is selected from the group consisting of loweralkyl, loweralkenyl, loweralkynyl, 10 cycloalkyl, aryl, arylalkyl, heteroaryl, heterocyclic group, heteroarylalkyl or heterocycloalkyl wherein the heteroaryl and heterocyclic groups are linked directly or indirectly by a ring carbon; R 4 is selected from the group consisting of loweralkyl, loweralkenyl, loweralkynyl, cycloalkyl, aryl, arylalkyl, heteroaryl, heterocyclic group heteroarylalkyl or 15 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; 20 (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; 25 (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 R -. N. R 2 R3 4I 3 N N R4 (II) wherein R 1 and R 2 are independently selected from H, loweralkyl, arylC 1-C6alkyl, 5 C(O)C1-C6alkyl, -C(0)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; R 3 and R 4 are independently selected from the group consisting of: C 1-C6alkyl, -145- WO 98/46605 PCT/US98/07207 10 C2-C6alkenyl, C2-C6alkynyl, C3-C8cycloalkyl, heteroarylCO-C6alkyl or substituted heteroarylCO-C6alkyl, optionally substituted cycloalkyl, 15 arylCO-C6alkyl or substituted arylCO-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 20 substituents are independently selected from halogen, oxo, CO2R 5 , cyanoC 1-C6alkyl, heteroarylCO-C6alkyl, heterocyclicCO-C6alkyl, C1-C6alkyloxy, Cl1-C6alkyloxyC 1-C6alkyl, arylCO-C6alkyl, arylC 1-C6alkyloxy, R 5 R 6 NC(O), cyano, C2-C6alkenyl, C2-C6alkynyl, C1-C6alkyl, C2-C6alkenyldialkylmalonyl, CF3, HO-, Cl 25 C6alkyloxyCl-C6alkyloxy, C1-C6alkylSOn wherein n is 1-2, C1 C6alkylthio, C1-C6alkylacryl, CF30, CF3, C1-C4alkylenedioxy, Cl C6alkylacryl, R 5 R 6 N(CO)NR 5 , N-formyl(heterocyclic), NO2, NR 5 R 6 CO C6alkyl, (R 5 0)(R 6 0)-P(O)- CO-C6alkyl, wherein R 5 and R 6 are independently selected from H, CI-C6alkyl, 30 HC(O), Cl1-C6alkyloxyC 1-C6alkyl, C1-C6alkyloxy, C1 C6alkylC(O), CF3C(O), NR 7 R 8 C1-C6alkyl, phthalimidoC1 C6C(O), C1-C6alkylSOn where n is 1-2, CNC1-C6alkyl, R 7 R 8 NC(O)NR 7 -, heteroaryl, NR 7 R 8 C 1-C6alkylC(O), Cl C6alkyloxycarbamidoC 1-C6alkyl, 35 wherein R 7 and R 8 are independently selected from those variables identified for R 5 and R 6 or R 5 and R 6 or R 7 and R 8 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 40 selected from O, N or S wherein the substituents are selected from C 1-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; 45 (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; -146- WO 98/46605 PCT/US98/07207 (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; 50 (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 R 4 is selected from the group consisting of: phenyl; thiophene-2-yl; 3-methyl-2-oxobenzoxazolin-6-yl; 2-(dimethylamino) 5-pyrimidinyl; 2-(N-formyl-N-methyl amino)-5-pyrimidinyl; 2-(N-methoxyethyl-N-methyl amino)-5-pyrimidinyl; 2-(N-methylamino)5-pyrimidinyl; 2-(1-morpholinyl)-5-pyrimidinyl; 5 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 10 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 15 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 20 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 25 (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 30 methylsulfonylphenyl; 4-morpholinylphienyl; 4-N-(2-(dimethylamino)ethyi)-N formylamino)phenyl; 4-N-(3-methoxypropionyl)-N-isopropyl-amino)phenyl; 4-N-ethyl-N -147- WO 98/46605 PCT/US98/07207 (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 35 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 R 3 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 5 (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 10 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 15 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 20 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 5 d]pyrimidine; 4-amino-5-(4-methoxyphenyl)-7-(4-dimethylaminophenyl)pyrido[2,3-d]pyrimidine; -148- WO 98/46605 PCTIUS98/07207 4-amino-5-(4-dimethylaminophenyl)-7-(4-methoxyphenyl)pyrido[2,3-d]pyrin-idine; 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; 10 4-amino-5-(4-butyloxyphenyl)-7-(4-methoxyphenyl)pyrido[2.3-dlpyrimidine; 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; 15 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; 20 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 dipyrimidine; 4-amino-5-(3-t-butylacrylphenyl)-7-(4-dimethylaminophenyl)pyrido[2,3 d]pyrimidine; 25 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; 30 4-amino-5-(3-vinylpyridinylphenyl)-7-(4-dimethylaminophenyl)pyrido[2,3 d]pyrimidine; 4-amino-5-(3-trifluoromethylphenyl)-7-(4-dimethylaminophenyl)pyrido[2,3 dipyrimidine; 4-amino-5-(3-carboxamidophenyl)-7-(4-dimethylaminophenyl)pyrido[2,3 35 d]pyrimidine; 4-anino-5-(3-cyanophenyl)-7-(4-dimethylaminophenyl)pyrido[2,3-d]pyrimidine; 4-anino-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; 40 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; -149- WO 98/46605 PCT/US98/07207 4-amino-5-(3-fluorophenyl)-7-(4-dimethylaminophenyl)pyrido[2,3-d]pyrinidine; 45 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; 50 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-anino-5-(3-trifloromethyoxyphenyl)-7-(4-dimethylaminophenyl)pyrido[2,3 55 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; 60 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; 65 4-anino-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; 70 4-amino-5-(3-methoxyethyoxyphenyl)-7-(4-dimethylaminophenyl)pyrido[2,3 d]pyrimidine; 4-amino-5-(3,4-methylenedioxyphenyl)-7-(4-dimethylaninophenyl)pyrido[2,3 d]pyrimidine; 4-amino-5- (3-bromophenyl)-7-(4-ethoxyphenyl)pyrido [2,3-d]pyrimidine; 75 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]pyrinidine; 4-amino-5-(3-dimethylaminophenyl)-7-(4-dimethylaminophenyl)pyrido[2,3 d]pyrimidine; 4-amino-5-phenyl-7-(4-dimethylaminophenyl)pyrido[2,3-dlpyrimidine; -150- WO 98/46605 PCT/US98/07207 80 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-djpyrimidine; 4 -am-ino-5-(3-bromophenyl)-7-(4-iodophenyl)pyrido[2,3-d]pyiidine; 4 -an-ino-' 5 -( 3 -bromoph-enyl)-7-(3,4-methylenedioxyphenyl)pyrido[2,3-dlpyrimidine, 85 4-am-ino-5-(thiophen-2-yl)-7- (4-morpholinylphenyl)pyrido [2,3-d]pyrimiddine; 4 -amidno-5-(3,5-dimethoxyphenyl)-7-(thiophen-2-yle)pyrido [2,3-dlpyrirnidine; 4 -amino -5 -(3- bromophenyl)-7- (4-carboxamidophenyl)pyido [2,3-dlpyrimsddine; 4-amino-5-(3-bromophenyl)- 7-(4- (2-methoxy)ethoxyphenyl)pyrido[2,3 dipyrimidine; 90 4-am-ino-5- (3 ,5-dimethoxypheny1)-7-(4-morpholinypheny)pyrido[2,3-dlpyrimidine; 4 -anino-5-(3-trifluoromethylphenyl)-7- (thiophene-2-yl)pyrido [2,3-dlpyrimidine; 4 -amino-5-(3-bromophenyl)-7-.(4-aminophenyl)pyrido[2,3-d]pyriidine; 4-am-ino-5- (3-bromo-4-fluorophenyl)-7-(thiophene-2-yl)pyrido [2,3-d]pyrimidine; 4 -am-ino-5-(3-bromo-4-fluorophenyl)-7-(2-furanyl)pyrido [2,3-d]pyrim-idine; 95 4 -amino-5-(3,5-dimethoxyphenyl)-7-(4-iodophenyl)pyrido[2,3-d]pyrjmidine; 4 -amino-5-(3,5-dimethoxyphenyl)-7-(4-im-idazolylphenyl)pyrido[2,3-dpyjmidine; 4-arniino-5-(3 ,5-dimethoxyphenyl)-7-(4- (thiophene-2-yl)phenyl)pyrido[2,3 dlpyrim-idine; 4 -am-ino-5-(3,5-dimethoxyphenyl)-7-(4- (3-pyridyl)phenyl)pyrido[2,3-d]pyrimidine; 100 4 -amino- 5- (3-bromophenyl) -7-(4- (4-methylpiperidinyl)phenyl)pyrido [2,3 dlpyrimidine; 4 -.am-ino-5-(3-bromophenyl)-7-(4-pyrrolidinylphenyl)pyrido[2,3-d]pyimsddine; 4 -amino-5-(4-bromothiophene-)-7-(4-dimethylaminophenyl)pyrido[2,3-d]pyimidine; 4 -amino-5-(4-bromothiophene-2-yl)-7-(4-morpholinylphenyl)pyrido[2,3 105 d]pyrim-idine; 4 -morpholinyl-5-(3-bromophenyl)-7-(4-dimethylanophenyl)pyrido [2,3 dlpyrin-iidine; 4 -amino-5-(5-bromothiophene-2-y)-7-(4-morpholinylphenyl)pyrido[2,3 dlpyrimiddine; 110 4 -amino-5-(4-bromophenyl)-7-(4-dimethylan-inophenyl)pyrido[2,3-d]pyrimidine; 4 -amino- 5 -(3-bromophenyl)-7-(4-(acetylamino)phenyl)pyrido[2,3-d]pyimidine; 4-rio5(-rmpey)7(-iehlndohnlprd[,-~yiiie 4-am-ino-5-(3 .5-dirnethoxyphenyl)-7- (5-pyrimidinylphenyl)pyrido[2,3-djpyrimidine; 4 -( 4 -fluorophenyl)amino)-5-(3-bromophenyl)-7- (4 115 dimethyiamidnophenyl)pyrido[2,3-d]pyin-dine; -151- WO 98/46605 PCTIUS98/07207 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[2,3 120 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-(dimethylanino)phenyl)pyrido[2,3 dipyrimidine; 125 4-amino-5-(3, 5 -di(trifluoromethyl)phenyl)-7-(4-morpholinylphenyl)pyrido[2,3 d]pyrimidine; 4 -amino-5-(3,5-dibromophenyl)-7-(4-(dimethylan-jno)phenyl)pyrido[2,3 d]pyrimidine; 4 -amino-5-(3,5-dibromophenyl)-7-(4-morpholinylphenyl)pyrido[2,3-d]pyrimidine; 130 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 dlpyrimidine; 4 -anino-5-(3-bromophenyl)-7-(3-(dimethylamino)phenyl)pyrido[2,3-d]pyrimidine; 135 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[2,3 140 d]pyrimidine; 4 -amino- 5 -( 3 -bromophenyl)-7-(4-methylaminophenyl)pyrido[2,3-dlpyrinidine; 4 -amino-5-(3-bromo-4-fluorophenyl)-7-(4-methylsulfonylphenyl)pyrido[2,3 d]pyrimidine; 4 -amino- 5 -(3-bromophenyl)-7-(3-anino-4-methoxyphenyl)pyrido[2,3-d]pyrim-dine; 145 4-anino-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 150 trifluoroacetylamino)phenyl)pyrido[2,3-d]pyrimridine; 4-amino-5-(3-bromophenyl)-7-( 4 -(dimethylamino)-3-fluorophenyl)pyrido[2,3 d]pyrimidine; -152- WO 98/46605 PCTIUS98/07207 4 -amino-5-(3-bromophenyl)-7-(4-(N-ethyl-N-formylamino)phenyl)pyrido[2,3 d]pyrimidine; 155 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-ethylan-hno)phenyl)pyrido[2,3-d]pyrimidine; 160 4-anino-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-(2 165 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; 170 4-amino-5-(3-bromophenyl)-7-(4-(N-(2 (dimethylamino)ethyl)amino)phenyl)pyrido[2,3-d]pyrinidine; 4-amino-5-(3-bromophenyl)-7-(4-(N-methyl-N-(2 cyano)ethylamino)phenyl)pyrido[2,3-d]pyrimidine; 4 -amino-5-(3-bromophenyl)-7-(4-(N-methyl-N-(3 175 methoxy)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; 180 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 185 (trifluoroacetyl)amino)phenyl)pyrido[2,3-d]pyrimidine; 4 -armino-5-(3-bromophenyl)-7-(3-methyl-4-(N-acetyl-N methylamino)phenyl)pyrido[2,3-d]pyrimidine; 4-amino-5-(3-bromophenyl)-7-(6-dimethylarmino-3-pyridinyl)pyrido[2,3 d]pyrimidine; -153- WO 98/46605 PCT/US98/07207 190 4 -amino-5-(3-cyanophenyl)-7-(4-methylsulfonylphenyl)pyrido[2,3-d]pyrimidine; 4-amino-5-(3-cyanophenyl)-7-(4-(N-methyl-N-formylanino)-phenyl)pyrido[2,3 d]pyrimidine; 4-anino-5-(3-bromophenyl)-7-(6-(N-methyl-N-formylamino)-3 pyridinyl)pyrido[2,3-d]pyrimidine; 195 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[2,3 200 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; 205 4-amino-5-(3-bromophenyl)-7-(2-(N-methylamino)5-pyrimidinyl)pyrido[2,3 d]pyriniidine; 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[2,3 210 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; 215 4-amino-5-(3-(thiophen-2-yl)phenyl)-7-(4-dimethylaminophenyl)pyrido[2,3 dipyrimidine; 4-anino-5-(3-(furan-2-yl)phenyl)-7-(4-dimethylaminophenyl)pyrido[2,3 d]pyrimidine; 4-anino-5-(3-(3-methoxyphenyl)phenyl)-7-(4-dimethylaminophenyl)pyrido[2,3 220 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]pyrimildine; 4-amino-5-(3-bromo-4-fluorophenyl)-7-(4-(morpholinyl)phenyl)pyrido[2,3 d]pyrimidine; 225 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; -154- WO 98/46605 PCT/US98/07207 4 -amino-5-(3-chlorophenyl)-7-(4-(5-pyrimidinyl)phenyl)pyrido[2,3-d]pyrinidine; 4 -amino-5-(3-bromo-4-fluorophenyl)-7-(4-iodophenyl)pyrido [2,3-dlpyrimidine; 4 -amino-5-(4-bromothiophene-2-yl)-7-(4-methoxyphenyl)pyrido[2,3-dlpyrimidine; 230 4-amino-5-(3-bromophenyl)methyl-7-(4- (dimethylamino)phenyl)pyrido[2,3 dlpyrim-idine; 4-amino-5- (2-phenylethyl)-7-(4-diethylami nophenyl)pyrido[2,3-dlpyrimidine; 4-arnino-5- (2-methylpropyl)-7-(4-diethylaminophenyl)pyrido[2,3-dlpyrimidine; 4 -an-ino-5-(butyl)-7-(4-diethylaminophenyl)pyrido[2,3-d]pyrimiddine; 235 4-amino.-5-(2- (4-bromophenyl)ethyl)-7- (4-diethylamlinophenyl)pyrido[2,3 d]pyrimiddine; 4-an-ino-5-(butyl)-7-(4-dimnethylaminophenyl)pyrido[2,3-dlpyrimidine; 4 -aniio-5-(2-(3-cyanophenyl)methyl)-7-(4-dimethylamidnophenyl)pyrido[2,3 dlpyrimidine; 240 4 -an-ino-5-(2-(N-phenylmethoxycarbony1)am-inoethyl)-7-(4 dimnethylam-inophenyl)pyrido[2,3-d]pyrimidine; 4-arnino-5-(cycloheptyl)-7-(4-dimethylamiinophenyl)pyrido [2,3-d]pyrim-idine; 4-am-ino-5-(2-(5-chloro-2-(thiophen-3-yl)phenylmethyl)-7-(4 dimethylaminophenyl)pyrido [2,3-dlpyrimidine; 245 4-amidno-5-(pentyl)-7-(4-diethylaminophenyl)pyrido[2,3-dlpyrimidine; 4 -amino-5-hexyl-7-(4-diethylaminophenyl)pyrido [2,3-d]pyrimidine; 4-amino-5-(2- (3-bromophenyl)ethyl)-7-(4-diethylamfinophenyl)pyrido[2,3 d~pyrimidine; 4-amino-5-((2-bromophenyl)methyl)-7-(4-diethylarninophenyl)pyrido[2,3 250 dlpyrirnidine; 4 -am-ino-5-cyclopropyl-7-(4-dimethylaminophenyl)pyrido[2,3-d]pyrimidine; 4 -amidno-5-cyclohexyl-7-(4-dimethylarniinophenyl)pyrido[2,3-d]pyrimidine; 4 -amidno-5-((2-bromo-5-chlorophenyl)methyl)-7-(4-diethylaminophenyl)pyrido[2,3 dipyrimiddine; 255 4-amiino-5-methyl-7- (4-diethylamiinophenyl)pyrido[2,3-d]pyrimidine; 4 -amidno-5-(2,3-methylenedioxyphenyl)-7-(4-dimethylaminophenyl)pyrido [2,3 dllpyrin-idine; 4-amino-5-(3-fluoro-5-trifluoromethylphenyl)-7-(4 dimethylaminophenyl)pyrido[2,3-d]pyrimidine; 260 4 -amidno-5-(2-bromophenyl)-7-(4-dimethylaminophenyl)pyrido [2,3-dipyrimidine; 4-am-ino-5- (3 ,5-dimethylphenyl)-7-(4-dimethylaminophenyl)pyrido[2,3 dlpyrimidine; 4-am-ino-5 -(3,4-dichlorophenyl)-7-(4-dimethylaminophenyl)pyrido [2,3-dilpyrimidine; -155- WO 98/46605 PCTIUS98/07207 4-amino-5-(4-fluoro-3-trifluoromethylphenyl)-7-(4 265 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 dlpyrimidine; 270 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 dipyrimidine; 4-amino-5-(3-methylthiophenyl)-7-(4-dimethylaminophenyl)pyrido[2,3 275 d]pyrimidine; 4 -amino-5-(3-bromo-5-methoxyphenyl)-7-(thiophene-2-yl)pyrido[2,3-dlpyrimidine; 4-amino-5-(2,3-dimethoxyphenyl)-7-(4-dimethylaminophenyl)pyrido[2,3 d]pyrimidine; 4 -amino-5-(3-methylsulfonylphenyl)-7-(4-dimethylaminophenyl)pyrido[2,3 280 d]pyrimidine; 4 -acetylamino-5-(3-bromophenyl)-7-(4-dimethylaninophenyl)pyrido[2,3 dipyrimidine; 4 -formylamino-5-(3-bromophenyl)-7-(4-dimethylaminophenyl)pyrido[2,3 d]pyrimidine; 285 4-(methoxyacetyl)amino-5-(3-bromophenyl)-7-(4-diethylarninophenyl)pyrido[2,3 dipyrimidine; 4 -trifluoroacetylamino-5-(3-bromophenyl)-7-(4-dimethylaminophenyl)pyrido[2,3 d]pyrimidine; 4 -pentanoylamino-5-(3-bromophenyl)-7-(4-dimethylaninophenyl)pyrido[2,3 290 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; 295 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-(4 300 dimethylaminophenyl)pyrido[2,3-d]pyrinidine; -156- WO 98/46605 PCT/US98/07207 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; 305 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-(4 310 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; 315 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]pyrinidine; 4-amino-5-((5-chloro-2-(3-methoxyphenyl)phenyl)methyl)-7-(4 dimethylaminophenyl)pyrido[2,3-d]pyrimidine; 320 4-anino-5-((thiophene-2-yl)methyl)-7-(4-diethylaminophenyl)pyrido[2,3 dlpyrimidine; 4-amino-5-((thiophene-3-yl)methyl)-7-(4-diethylaminophenyl)pyrido[2,3 d]pyrimidine; 4-amino-5-((2-bromophenyl)methyl)-7-(4-dimethylaminophenyl)pyrido[2,3 325 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; 330 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; 335 4-amino-5-(3-bromophenyl)-7-(4-(2-(dimethylamino)acetylamino)phenyl)pyrido[2,3 d]pyrimidine; -157- WO 98/46605 PCTIUS98/07207 4-amidno-5-(3-bromophenyl)-7-(4-(2-oxo-3-oxazolidinyl)phenyl)pyrido[2,3 d]pyrin-idine; 4-amidno-5-(3-bromophenyl)-7-(6-(2-propyl)-3-pyridinyl)pyidol2,3-d]pyrim-idine; 340 4- amino- 5-(3 -bromophenyl)-7- (3 -methyl-4-pyrrolidinylphenyl)pyrido [2,3 d]pyrim-idine; 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]pyrimlidine; 4-amidno-5-(2-(3-aminopropynyl)phenylmethyl)-7-(4-diethylamidnophenyl)pyrido[2,3 345 d]pyrimiddine; 4-arnino-5-(1- (3-bromophenyl)ethyl)-7-(4-diethylaminophenyl)pyrido[2,3 dlpyrimidine; 4-arnino-5-.(4-dimethylamiinophenyl)-7-(4-bromophenyl)pyrido [2,3-d]pyrimidine; 4-an-ino-5-(2-furanyl)-7-(4-(N-morpholinyl)phenyl)pyrido[2,3-d]pyrimidine; 350 4-amino-5-(3-bromophenyl)-7-(2-dimethylamino-5-pyrimidinyl)pyrido[2,3 dlpyrimiddine; 4-amino-5- (3-bromophenyl)-7-(4-(ureido)phenyl)pyrido [2,3-d]pyrimiddine; 4-am-ino-5- (1 -phenylmethyl-3-piperidinyl)-7-(4-diethylam-inophenyl)pyrido[2,3 d~pyrimidine; 355 4-amidno-5-(3-bromophenyl)-7-(6-(3-methyl-5-isoxazolyl))-3 pyidinyl)pyrido[2,3-d]pyfimidine; 4-amidno-5- (3-bromophenyl)-7-(6-chloro-3-pyridinyl)pyrido [2,3-dlpyrim-idine; 4-arnino-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[2,3 360 dlpyrim-idine; 4-amino-5-(3-bromophenyl)-7-(2-morpholinyl-5-pyrimidinyl)pyrido[2,3 dilpyrimiddine; 4-anino--5-(2-thiazolyl)-7-(4-pyrrolidinylphenyl)-pyrido [2,3-dilpyrimidine; 4-aniino-5-(3-bromophenyl)-7-(6-pyrazolyl-3-pyridinyl))-pyrido [2,3 365 d]pyrintidine; 4-amidno-5-(3-bromophenyl)-7-(4-( 1 -methyl-ureido)phenyl)-pyrido [2,3 dlpyrim-idine; 4-amino-5-(3-bromophenyl)-7- (4-(N-methyl-N-(2-pyiidinyl)amino)phenyl) pyrido[2-,3-d]pyfimidine; 370 4-amino-5-(3-bromophenyl)-7- (3-fluoro-4-(N-formyl-N-methylamidno)phenyl) pyrido[2.3-d]pyrimidine-: 4-formnylam-ino-5-(3-bromophenyl)-7-(3-fluoro-4-(N-formyl-N methylamino)phenyl)-pyrido [2,3-d]pyrimidine; -158- WO 98/46605 PCTIUS98/07207 4-amino-5-(3-bromophenyl)-7-(4-(N-methyl-N-methylsulfonylamino) 375 phenyl)pyrido[2,3-dlpyrimiddine; 4-arnino-5-(3-bromophenyl)-7-(6-(N-methyl-N-methylsulfonylamino)-3 pyridinyl)pyrido[2,3-dlpyrimidine; 4-amino-5-(3-bromophenyl)-7-( 1 -methyl-5-indolinyl)pyrido[2,3-dlpyrim-idine; 4-amidno-5-(3-bromophenyl)-7-( 1-methyl-5-benzimidazolyl)pyridol2,3 380 d~pyrimidine; 4-amino-5-(3-bromophenyl)-7-(6-dimethylamino-3-pyridazinyl)pyrido[2,3 dipyrimidine; 4-amino-5- (3bromophenyl)-7-(6-morpholinyl-3-pyridazinyl)pyrido [2,3 d]pyrimiddine; 385 4-am-ino-5-(3-bromophenyl)-7-(6-pyrrolidinyl-3-pyridazinyl)pyrido[2,3 d]pyrim-idine; 4- amino- 5- (3-bromophenyl)-7-(5-morpholinyl-2-pyrazinl)pyrido [2,3 d~pyrimidine; 4-amidno-5-(3-bromophenyl)-7-(5-(N-(2-methoxyethyl)-N-methylamino)-2 390 pyrazinyl)pyrido[2,3-d]pyrimidine; 4- amino- 5- (3-bromophenyl)-7 -(4-(morpholinylmethyl)-phenyl)pyrido [2,3 d]pyrim-idine; 4-amino-5-(3-bromophenyl)-7-(5-(N,N-bis(2-methoxyethyl)amino)-2 pyridinyl)pyrido[2,3-d]pyrimidine; 395 4-amidno-5-(3-bromophenyl)-7- (4-(imiddazolvlmethyl)-phenyl)pyrido[2,3 dlpyrimidine; 4-amidno-5-(3-bromophenyl)-7-(5-( 1 -morpholinyl)-2-pyridinyl)pyrido[2,3 dipyrimidine; 4-amino-5-(3-.bromophenyl)-7-(4-((dimethylamidno)methyl)-phenyl)pyrido [2,3 400 dlpyrimidine; 4-amidno-5-(3-bromophenyl)-7-(5-(4-hydroxy- 1 -piperidinyl)-2 pyridinyl)pyrido[2,3-dlpyrimiddine; 4-am-ino-5-(3-bromophenyl)-7- (5-(N-formyl-N-methylamino)-2 pyridinyl)pyrido [2,3-d]pyrimidine; 405 4-amino-5- (3-bromophenyl)-7-( 5-(2-propenyl )-2-pyridinyl)pyrido[2,3 dlpyrimidine; 4-amino-5-(3-bromophenyl)-7-(3-(2-methoxvethyl)-2-oxo-6 benzoxazolyl)pyrido [2,3-d] pyrimidine:, 4-amidno-5- (3-bromophenyl)-7 -(4-(I 1-(N-formylamiino)-ethyl)phenyl)pyrido [2,3 410 djpyrirnidine; -159- WO 98/46605 PCT/US98/07207 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; 415 4-amino-5-(3-bromophenyl)-7-(4-(1-methyl-2-imidazolyl)phenyl)pyrido[2,3 dipyrimidine 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; 420 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[2,3 425 d]pyrimidine; 4-amino-5-(3-bromophenyl)-7-(4-dimethylphosphonatophenyl)pyrido[2,3 dipyrimidine; 4-amino-5-(3-bromophenyl)-7-(4-(3-(methoxypropynyl)pyrido[2,3-d]pyrimidine; 4-amino-5-(3-bromophenyl)-7-(4-carboxyphenyl)pyrido[2,3-d]pyrimidine; 430 4-amino-5-(3-bromophenyl)-7-(4-methyl-3-oxo-2H-4H-pyrido[3,2-b]- 1,4-oxazin 7-yl)pyrido[2,3-d]pyrimidine; 4-amino-5-(3-bromophenyl)-7-(4-(2-(dimethylanino)ethyl)-3-oxo-2H-4H pyrido[3,2-b]- 1,4-oxazin-7-yl)pyrido[2,3-d]pyrimidine; 4-anino-5-(3-bromophenyl)-7-(2,3-dihydro-3-(dimethylaminoethyl)-2 435 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; 440 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; 445 4-amino-5-(1-(4-bromophenyl)ethyl)-7-(6-morpholinylpyrid-3-yl)pyrido[2,3 dlpyrimidine; -160- WO 98/46605 PCTIUS98/07207 4-amino-5-(3-bromophenyl)-7-(4-((N-formylam-ino)methyl)phenyl)pyrido[2,3 d~pyrimidine; 4-amino-5-(3-bromophenyl)-7-(4-( 1-methyl- I -(N-methylam-ino)ethyl)phenyl) 450 pyrido[2.3-d]pyimidine; 4-amino-5-(3-bromophenyl)-7-(4-(I -(dimethylamino)- 1 methylethyl)phenyl)pyrido[2,3-d]pyrimidine; 4-amidno-5-(3-bromophenyl)-7-(N-acetyl-5-indolinyl)pyrido[2,3-d]pyimiddine; 4-amino-5-cyclohexyl-7-(6-chloro-3-pyridyl)pyrido [2,3-d]pyrin-idine: 455 4-amino-5-( 1-(2-bromophenyl)ethyl)-7-(6-diethylamino-3-pyridyl)pyrido[2,3 d]pyrim-idine; 4-amino-5-(l1-(2-bromophenyl)ethyl)-7-(6-morpholinyl-3-pyridyl)pyrido[2,3 dlpyrim-die, I4-amino-5-(l1-(2-bromophenyl)ethyl)-7-(4-(N-methyl-N-formyl)anmino) 460 phenyl)pyrido[2,3-dlpyrimidine; 4-amidno-5-cyclohexyl-7-(6-morpholinyl-3-pyridyl)pyrido [2,3-dilpyrimidine; 4-am-ino-5-((2-bromophenyl)methyl)-7- (6-morpholinyl-3-pyridyl)pyrido[2,3 dlpyrimidine: 4-am-ino-5-(4-tetrahydropyranyl)-7-(6-morpholinyl-3-pyridyl)pyrido[2,3 465 dlpyrimicline; 4-amino-5-cyclohexyl-7-(6-dimethylamino-3-pyridyl)pyrido [2,3-d]pyrimidine; 4-am-ino-5-( 1-ethylpropyl)-7-(6-dimethylam-ino-3-pyridyl)pyrido[2,3-djpyrimidine; 4-amino-5-cyclopentyl-7-(6-morpholinyl-3-pyridyl)pyrido[2,3-d]pyrim-idine; 4-amino-5-cyclohexyl-7-(2-chloro-3-pyridyl)pyrido[2,3-dlpyrimidine; 470 4-amino-5-(3 ,5-dimethylcyclohexyl)-7-(6-dimethylani ino-3-pyridyl)pyrido[2,3 dipyrimiddine; 4-amino-5-((N-(benzyloxycarbonyl)-4-piperidinyl)methyl)-7- (6-morpholinyl-3 pyridyl)pyrido[2,3-dlpyrimidine; 4-amino-5-cyclohexyl-7-(6-bromo-3-pyridyl)pyrido[2,3-d]pyrimidine; 475 4-amino-5-cyclohexyl-7-(3-cyanophenyl)pyrido[2,3-d]pyrimiddine; 4-amidno-5-(l1-(2-bromophenyl)ethyl)-7-(6-dimethylamino-3-pyridazinyl)pyrido [2,3 dlpyfiu-idine, 4-amino-5- (3-bromophenyl)-7-(6-imiddazolyl-3-pyridazinyl)pyrido [2,3-dipyrimidine; 4-amino-5-(3-bromophenyl)-7-(6-(azacycloheptanyl)-3-pyridazinyl)pyrido[2,3 48 0 dlpyrirnidine: 4-amidno-5-(3-bromophenyl)-7-(6-(N-methyl-N-( 1-methylethyl))amino)-3 pyridazinyl)pyrido[2,3-d]pyrimidine; -16 1- WO 98/46605 PCTIUS98/07207 4-amino-5-(1-(2-bromophenyl)ethyl)-7-(6-morpholinyl-3-pyridazinyl)pyrido[2,3 d]pyrimidine; 485 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; 490 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-aniino-5-cyclohexyl-7-(6-azetidinyl-3-pyridyl)pyrido[2,3-d]pyrimidine; 495 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]pyrinidine; 4-amino-5-cyclohexyl-7-(4-oxo- 1-phenyl- 1,3,8-triazaspiro[4.5[decan-8 500 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 dipyrimidine; 505 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[2,3 510 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; 515 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 dipyrimidine: -162- WO 98/46605 PCT/US98/07207 4-amino-5-(1-(2-bromophenyl)ethyl)-7-(1 -methyl-2,3-dioxo-5-indolyl)pyrido[2,3 520 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)-3 525 pyridyl)pyrido[2,3-d]pyriniidine; 4-amino-5-(3-bromophenyl)-7-(6-(4-oxopiperidinyl)-3-pyridyl)pyrido[2,3 dipyrimidine; 4-amino-5-(3-bromophenyl)-7-(6-(4-formylpiperazinyl)-3-pyridyl)pyrido[2,3 d]pyrimidine; 530 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[2,3 535 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; 540 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; 545 4 -amino-5-(3-bromophenyl)-7-(6-(N-(2-hydroxyethoxyethyl)amino)-3 pyridyl)pyrido[2,3-d]pyrimidine; 4-amino-5-(3-bromophenyl)-7-(6-(N-(2-hydroxyethoxyethyl)-N-formylamino)-3 pyridyl)pyrido[2,3-d]pyrimidine; 4-amino-5-(3-bromophenyl)-7-(6-(N-(2-hydroxyethoxyethyl)-3-pyridyl-N 550 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; -163- WO 98/46605 PCT/US98/07207 555 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)-3 560 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[2,3 565 d]pyrimidine.
15. A pharmaceutical composition comprising a compound according to Claim 10 and a pharmaceutically acceptable carrier.
16. A compound of formula El X R 3 32 6 H 2N N 7' R 4 wherein X is selected from -OH or halogen and R 3 and R 4 are as defined above and a dashed line---indicates a double bond is optionally present. 5
17. A compound according to Claim 16 wherein said compound is an intermediate in a process to produce a compound according to Claim 10 or 11.
18. A process for the preparation of an adenosine kinase inhibiting compound having the formula R lN-, R 3 2 R 4 I 3N 4 214 "N - ' N 7 - R 4 1 N N 7R, (I) wherein R 1 and R 2 are hydrogen, the method comprising 5 (a) reacting a ketone having the formula R 4 -CO-CH 3 , wherein R 4 is as defined above, with an aldehyde having the formula R 3 -CHO, wherein R 3 is as defined above and malononitrile -164- WO 98/46605 PCT/US98/07207 in the presence of an ammonium salt under anhydrous conditions and isolating a first intermediate compound having the structure R a NC K4 H 2 N N R 4 10 (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 15 reduced right side of formula I by catalytic hydrogenation.
19. A process for the preparation of an adenosine kinase inhibiting compound having the formula R 1 N- R 2 R 3 3N R 6 34 3N N R 1 N N 7R, (I) wherein R 1 and R 2 are hydrogen, the method comprising 5 (a) reacting a ketone having the formula R 4 -CO-CH 3 , wherein R 4 is as defined above, with an dicyanoalkene compound having the formula R 3 -CH=C(CN)2, wherein R 3 is as defined above by heating at reflux and isolating a first intermediate compound having the structure R3 NC H 2 N N R 4 (b) reacting the first intermediate compound with formamide at reflux for from about 1 to 10 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. -165-
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