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AU7098198A - 6,7-disubstituted-4-aminopyrido(2,3-d)pyrimidine compounds - Google Patents

6,7-disubstituted-4-aminopyrido(2,3-d)pyrimidine compounds Download PDF

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AU7098198A
AU7098198A AU70981/98A AU7098198A AU7098198A AU 7098198 A AU7098198 A AU 7098198A AU 70981/98 A AU70981/98 A AU 70981/98A AU 7098198 A AU7098198 A AU 7098198A AU 7098198 A AU7098198 A AU 7098198A
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phenyl
pyrido
amino
methyl
pyrimidine
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Shripad S. Bhagwat
Yu-Gui Gu
Chih-Hung Lee
Richard J. Perner
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Description

WO 98/46603 PCT/US98/04127 6.7-DISUBSTITUTED-4-AMINOPYRIDO[2.3-D1PYRIMIDINE COMPOUNDS Technical Field The present invention relates a method for inhibiting adenosine kinase by administering 6,7-disubstituted-4-aminopyrido[2,3-d]pyrimnidine compounds, to pharmaceutical compositions containing such compounds, as well as novel 6,7 5 disubstituted-4-aminopyrido[2,3-d]pyrimidine compounds. Background Of The Invention Adenosine kinase (ATP:adenosine 5'-phosphotransferase, EC 2.7.1.20) is a ubiquitous enzyme which catalyzes the phosphorylation of adenosine to AMP, using ATP, 10 preferentially, as the phosphate source. Adenosine kinase has broad tissue and species distribution, and has been isolated from yeast, a variety of mammalian sources and certain microorganisms. It has been found to be present in virtually every human tissue assayed including kidney, liver, brain, spleen, placenta and pancreas. Adenosine kinase is a key enzyme in the control of the cellular concentrations of adenosine. 15 Adenosine is a purine nucleoside that is an intermediate in the pathways of purine nucleotide degradation and salvage. Adenosine also has many important physiologic effects, many of which are mediated through the activation of specific ectocellular receptors, termed P 1 receptors (Burnstock, in Cell Membrane Receptors for Drugs and Hormones, 1978, (Bolis and Straub, eds.) Raven, New York, pp. 107-118; Fredholm, et al., 20 Pharmacol. Rev. 1994, 46: 143-156). In the central nervous system, adenosine inhibits the release of certain neurotransmitters (Corradetti, et al., Eur. J. Pharmacol. 1984, 104: 19-26), stabilizes membrane potential (Rudolphi, et al., Cerebrovasc. Brain Metab. Rev. 1992, 4: 346-360), functions as an endogenous anticonvulsant (Dragunow, Trends Pharmacol. Sci. 1986, 7: 25 128-130) and may have a role as an endogenous neuroprotective agent (Rudolphi, et al., Trends Pharmacol. Sci., 1992, 13: 439-445). Adenosine may play a role in several disorders of the central nervous system such as schizophrenia, anxiety, depression and Parkinson's disease. (Williams, M., in Psychopharmacology: The Fourth Generation of Progress; Bloom, Kupfer (eds.), Raven Press, New York, 1995, pp 643-655. 30 Adenosine has also been implicated in modulating transmission in pain pathways in the spinal cord (Sawynok, et al., Br. J. Pharmacol., 1986, 88: 923-930), and in mediating the analgesic effects of morphine (Sweeney, et al., J. Pharmacol. Exp. Ther. 1987, 243: 657-665). In the immune system, adenosine inhibits certain neutrophil functions and exhibits anti-inflammatory effects (Cronstein, J. Appl. Physiol. 1994, 76: 5-13). An AK WO 98/46603 PCT/US98/04127 inhibitor has been reported to decrease paw swelling in a model of adjuvant arthritis in rats (Firestein, et.al., Arthritis and Rheumatism, 1993, 36, S48. Adenosine also exerts a variety of effects on the cardiovascular system, including vasodilation, impairment of atrioventricular conduction and endogenous cardioprotection in 5 myocardial ischemia and reperfusion (Mullane and Williams, in Adenosine and Adenosine Receptors, 1990 (Williams, ed.) Humana Press, New Jersey, pp. 289-334). The widespread actions of adenosine also include effects on the renal, respiratory, gastrointestinal and reproductive systems, as well as on blood cells and adipocytes. Adenosine, via its Al receptor activation on adipocytes, plays a role in diabetes by inhibiting 10 lipolysis [Londos, et al., Proc. Natl. Acad. Sci. USA, 1980, 77, 2551. Endogenous adenosine release appears to have a role as a natural defense mechanism in various pathophysiologic conditions, including cerebral and myocardial ischemia, seizures, pain, inflammation and sepsis. While adenosine is normally present at low levels in the extracellular space, its release is locally enhanced at the site(s) of excessive cellular 15 activity, trauma or metabolic stress. Once in the extracellular space, adenosine activates specific extracellular receptors to elicit a variety of responses which tend to restore cellular function towards normal (Bruns, Nucleosides Nucleotides, 1991, 10: 931-943; Miller and Hsu, J. Neurotrauma, 1992, 9: S563-S577). Adenosine has a half-life measured in seconds in extracellular fluids (Moser, et al., Am. J. Physiol. 1989, 25: C799-C806), and 20 its endogenous actions are therefore highly localized. The inhibition of adenosine kinase can result in augmentation of the local adenosine concentrations at foci of tissue injury, further enhancing cytoprotection. This effect is likely to be most pronounced at tissue sites where trauma results in increased adenosine production, thereby minimizing systemic toxicities. 25 Pharmacologic compounds directed towards adenosine kinase inhibition provide potentially effective new therapies for disorders benefited by the site- and event-specific potentiation of adenosine. Disorders where such compounds may be useful include ischemic conditions such as cerebral ischemia, myocardial ischemia, angina, coronary artery bypass graft surgery (CABG), percutaneous transluminal angioplasty (PTCA), stroke, other 30 thrombotic and embolic conditions, and neurological disorders such as epilepsy, anxiety, schizophrenia, nociperception including pain perception, neuropathic pain, visceral pain, as well as inflammation, arthritis, immunosuppression, sepsis, diabetes and gastrointestinal disfunctions such as abnormal gastrointestinal motility. A number of compounds have been reported to inhibit adenosine kinase. The most 35 potent of these include 5'-amino-5'-deoxyadenosine (Miller, et al., J. Biol. Chem. 1979, 254: 2339-2345), 5-iodotubercidin (Wotring and Townsend, Cancer Res. 1979, 39: 3018 -2- WO 98/46603 PCT/US98/04127 3023) and 5'-deoxy-5-iodotubercidin (Davies, et al., Biochem. Pharmacol. 1984, 33: 347 355). Adenosine kinase is also responsible for the activation of many pharmacologically active nucleosides (Miller, et al., J. Biol. Chem. 1979, 254: 2339-2345), including 5 tubercidin, formycin, ribavirin, pyrazofurin and 6-(methylmercapto)purine riboside. These purine nucleoside analogs represent an important group of antimetabolites which possess cytotoxic, anticancer and antiviral properties. They serve as substrates for adenosine kinase and are phosphorylated by the enzyme to generate the active form. The loss of adenosine kinase activity has been implicated as a mechanism of cellular resistance to the 10 pharmacological effects of these nucleoside analogs (e.g. Bennett, et al., Mol. Pharmacol., 1966, 2: 432-443; Caldwell, et al., Can. J. Biochem., 1967, 45: 735-744; Suttle, et al., Europ. J. Cancer, 1981, 17: 43-51). Decreased cellular levels of adenosine kinase have also been associated with resistance to the toxic effects of 2'-deoxyadenosine (Hershfield and Kredich, Proc. Natl. Acad. Sci. USA, 1980, 77: 4292-4296). The accumulation of 15 deoxyadenosine triphosphate (dATP), derived from the phosphorylation of 2' deoxyadenosine, has been suggested as a toxic mechanism in the immune defect associated with inheritable adenosine deaminase deficiency (Kredich and Hershfield, in The Metabolic Basis of Inherited Diseases, 1989 (Scriver, et al., eds.), McGraw-Hill, New York, pp. 1045-1075). 20 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 hydroxypyrido[2,3-d]pyrimidines having antifolic acid activity. R. Sharma et al., (Indian J. 25 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-fluorophenyl)pyrido[2,3-d]pyrimidine and 4-amino-5-(4-chlorophenyl)-7-( 4 30 fluorophenyl)pyrido[2,3-d]pyrimidine compounds having antibacterial activity. L. Prakash et al., Pharmazie, 48: 221-222 (1993)) disclose 4-amino-5-phenyl-7-(4 aminophenyl)pyrido[2,3-d]pyrimidine, 4-amino-5-phenyl-7-(4-bromophenyl)pyrido[2,3 d]pyrimidine, 4-amino-5-(4-methoxyphenyl)-7-(4-aminophenyl)pyrido[2,3-d]pyrimidine, and 4-amino-5-(4-methoxyphenyl)-7-(4-bromophenyl)pyrido[2,3-d]pyrimidine compounds 35 having antifungal activity. P. Victory et al., Tetrahedron, 51: 10253-10258 (1995)) discloses the synthesis of 4-amino-5,7-diphenylpyrido[2,3-d]pyrimidine compounds from acyclic precursors. Bridges et al.(PCT application WO 95/19774, published July 27, 1995) -3- WO 98/46603 PCT/US98/04127 disclose various bicyclic heteroaromatic compounds as having utility for inhibiting tyrosine kinase of epidermal growth factors. Summary Of The Invention 5 The present invention provides for 6,7-disubstituted-4-aminopyrido[2,3 d]pyrirnidine compounds having utility as adenosine kinase inhibitors. In one aspect, the present invention provides novel compounds having the formula (I) R Na e , N R 2 H
R
3 together with the nitrogen atom to which they are attached to form a 5-to-7 membered ring optionally containing 1-3 additional heteroatoms selected from , N or S; 27,6 1N N 7 R4M 10 wherein R1 and R2 are independently H, loweralkyl, arylalkyl or acyl, or may be taken together with the nitrogen atom to which they are attached to formn a 5-to-7 membered ring optionally containing 1-3 additional heteroatoms selected from O, N or S;
R
3 and R 4 are independently selected from loweralkyl, loweralkenyl, loweralkynyl, 15 aryl, arylalkyl, heteroaryl, or a heterocyclic group and the dashed lines indicate a double bond is optionally present. The present invention also contemplates the pharmaceutically acceptable salts and amides of the compounds of Formula I, and the use thereof as provided below. In another aspect, the present invention provides a method for inhibiting adenosine 20 kinase by administering a compound of Formula (I). In particular, the method of inhibiting adenosine kinase comprises exposing an adenosine kinase to an effective inhibiting amount of a compound of Formula I of the present invention. Where the adenosine kinase is located in vivo, the compound is administered to the organism. 25 In another aspect, the present invention provides a pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula I above in combination with a pharmaceutically acceptable carrier. In 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. -4- WO 98/46603 PCT/US98/04127 In a preferred aspect, the present invention provides a method of treating cerebral ischemia, myocardial ischemia, angina, coronary artery bypass graft surgery, percutaneous transluminal angioplasty, stroke, thrombotic and embolic conditions, epilepsy, anxiety, schizophrenia, pain perception, neuropathic pain, visceral pain, arthritis, sepsis, diabetes 5 and abnormal gastrointestinal motility in a mammal in need of such treatment, comprising administering to the mammal a therapeutically effective amount of a compound of Formula I of the present invention. The present invention also contemplates the pharmaceutically acceptable salts and amides of compounds having Formula I, and their use for inhibiting adenosine kinase, in 10 pharmaceutical compositions and for administration to a mammal. In addition, the present invention relates to a compound of formula (II) R ' N, R2 H 4I. R3 3N 6 2K / N N R 4 wherein
R
1 and R 2 are independently H, loweralkyl, arylalkyl or acyl, or may be taken 15 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;
R
3 and R 4 are independently selected from loweralkyl, loweralkenyl, loweralkynyl, aryl, arylalkyl, heteroaryl, or a heterocyclic group. In another aspect, the present invention provides a process for the preparation of 20 compounds of formula II R " N, R 2 H 4. R3 N H \ 3 N
.
6 2 N N R 4 4 (II), wherein
R
1 and R 2 are hydrogen;
R
3 is loweralkyl, loweralkenyl, loweralkynyl, aryl, arylalkyl, heteroaryl, or a 25 heterocyclic group;
R
4 is aryl, heteroaryl, or a heterocyclic group; the method comprising (a) reacting 4,6-diamino-5-iodopyrimidine with an ethenylboronic acid derivative having the formula -5- WO 98/46603 PCT/US98/04127 (HO)2 - R 3 wherein R 3 is loweralkyl, loweralkenyl, loweralkynyl, aryl, arylalkyl, heterocyclic or heteroaryl or substituted versions thereof, in the presence of tetrakistriphenylphosphinepaladium(0) and an aqueous alkali metal base, and isolating a 5 first intermediate compound having the formula
NH
2 NL R3 N
NH
2 (b) reacting the first intermediate compound with an aldehyde compound having the formula R 4 -CHO, wherein R 4 is aryl, heteroaryl, or a heterocyclic group, under anhydrous conditions and with the removal of the water of reaction, and isolating the compound of 10 formula II. In another aspect, the present invention provides a process for the preparation of compounds of formula (II) RI" N R 2 N R3 N N R 4 (II), wherein 15 R 1 and R 2 are independently H, loweralkyl, arylalkyl or acyl, or may be 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, with the requirement that not both R 1 and R 2 may be hydrogen,
R
3 is loweralkyl, loweralkenyl, loweralkynyl, aryl, arylalkyl, heteroaryl, or a 20 heterocyclic group;
R
4 is aryl, heteroaryl, or a heterocyclic group; the method comprising (a) reacting a compound having the formula (II) RYN
R
2 N R3 N H 25 kN N R 4 (II), wherein -6- WO 98/46603 PCT/US98/04127
R
1 and R 2 are hydrogen;
R
3 is loweralkyl, loweralkenyl, loweralkynyl, aryl, arylalkyl, heteroaryl, or a heterocyclic group;
R
4 is aryl, heteroaryl, or a heterocyclic group; 5 with a compound selected from the group consisting of (i) an alkylating agent R 1 -Y, wherein R 1 is loweralkyl and Y is selected from the group consisting of a halide, a mesylate and a tosylate; (ii) an arylalkylating agent RI-loweralkyl-Y, wherein R 1 is arylalkyl and Y is 10 selected from the group consisting of a halide, a mesylate and a tosylate; (iii) an acyl compound R 1 -Z, wherein R 1 is an acyl group and Z is selected from the group consisting of an acid anhydride moiety, a halide or an acyl activating group; and isolating the desired compound; and (b) optionally, when it is desired that R 2 should not be hydrogen, treating the compound 15 from step (a) with a compound selected from the group consisting of (i) an alkylating agent R 2 -Y, wherein R 2 is loweralkyl and Y is selected from the group consisting of a halide, a mesylate and a tosylate; (ii) an arylalkylating agent R 2 -loweralkyl-Y, wherein R 2 is arylalkyl and Y is selected from the group consisting of a halide, a mesylate and a tosylate; 20 (iii) an acyl compound R 2 -Z, wherein R 2 is an acyl group and Z is selected from the group consisting of an acid anhydride moiety, a halide or an acyl activating group; and isolating the desired product. In another aspect, the present invention provides a process for the preparation of compounds of formula II R N, R 2 H N R 3 25 N N R 4 ~ I), wherein
R
1 and R 2 are independently H, loweralkyl, arylalkyl or acyl, or may be 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, with the proviso that not both 30 R 4 and R 5 are hydrogen;
R
3 is loweralkyl, loweralkenyl, loweralkynyl, aryl, arylalkyl, heteroaryl, or a heterocyclic group;
R
4 is aryl, heteroaryl, or a heterocyclic group; -7- WO 98/46603 PCT/US98/04127 the method comprising (a) reacting 6-amino-4-chloro-5-iodopyrimidine with an ethenylboronic acid derivative having the formula (HO)2B R3 wherein R 3 is loweralkyl, loweralkenyl, loweralkynyl, aryl, arylalkyl, heterocyclic or heteroaryl, in the presence of tetrakistriphenylphosphinepalladium(0) and an aqueous alkali metal base, and isolating a first intermediate compound having the formula CI N
R
3 N NH 2 10 (b) reacting the first intermediate compound with an aldehyde compound having the formula R 4 -CHO, wherein R 4 is aryl, heteroaryl, or a heterocyclic group, under anhydrous conditions and with the removal of the water of reaction, and isolating the second intermediate compound having the formula CI N R3 N N R 4 ; and 15 (c) treating the fourth intermediate compound with an amine compound having the formula
R
1
-NH-R
2 , wherein R 1 and R 2 are as described above, and isolating the desired product. Detailed Description of the Invention The present invention relates to 6,7-disubstituted-4-aminopyrido[2,3-d]pyrimidine 20 compounds that are useful in inhibiting adenosine kinase, to pharmaceutical compositions containing such compounds, to a method of using such compounds for inhibiting adenosine kinase, and to novel 6,7-disubstituted-4-aminopyrido[2,3-d]pyrimidine compounds. In one aspect, the present invention provides 6,7-disubstituted-4-aminopyrido[2,3 d]pyrimidine compounds that are adenosine kinase inhibitors. An adenosine kinase 25 inhibitor of the present invention is a compound of the Formula I or II, shown above. In a preferred embodiment, an adenosine kinase inhibitor of the present invention is a compound of Formula (I) or (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 30 invention is a compound of Formula (I) or (II) above, wherein R 4 is aryl or heteroaryl or -8- WO 98/46603 PCT/US98/04127 substituted versions thereof and R 3 is loweralkyl, aryl, arylalkyl or heteroaryl or substituted versions thereof. In an additional embodiment, the present invention relates to compounds of formula I and II as shown above wherein 5
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 which they are attached to from a 5-7 membered ring optionally containing 1-2 additional heteroatoms selected from O, N or S; 10 R 3 and R 4 are independently selected from the group consisting of: C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C8cycloalkyl, 15 heteroarylCO-C6alkyl or substituted heteroarylCO-C6alkyl, 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, cyanoC 1 -C6alkyl, heteroarylCO-C6alkyl, heterocyclicCo C6alkyl, C1-C6alkyloxy, C1-C6alkyloxyC1-C6alkyl, arylCO-C6alkyl, arylC1-C6alkyloxy, R 5
R
6 NC(O), cyano, C2-C6alkenyl, C2-C6alkynyl, 25 C 1-C6alkyl, C2-C6alkenyldialkylmalonyl, CF3, HO-, C 1-C6alkyloxyC l C6alkyloxy, Cl-C6alkylSOn wherein n is 1-2, C1-C6alkylthio, Cl C6alkylacryl, CF30, CF3, C 1-C4alkylenedioxy, C 1-C6alkylacryl,
R
5
R
6
N(CO)NR
5 , N-formyl(heterocyclic), NO2, NR 5
R
6 Co-C6alkyl, wherein R 5 and R 6 are independently selected from H, C1-C6alkyl, 30 HC(O), C1 -C6alkyloxyC 1 -C6alkyl, C 1-C6alkyloxy, C1 C6alkylC(O), CF3C(O), NR 7
R
8 C I-C6alkyl, phthalimidoC l C6C(O), Cl-C6alkylSOn where n is 1-2, CNCl-C6alkyl,
R
7
R
8
NC(O)NR
7 -, heteroaryl, NR 7
R
8 C I -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 -9- WO 98/46603 PCT/US98/04127
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 selected from O, N or S wherein the substituents are selected from 5 Cl1-C6alkyl and wherein, in the case of formula I, a dashed line --- indicates a double bond is optionally present. The present invention also includes those compounds having R 3 and R 4 independently selected from those groups shown below as 6-substituted groups and as 7-substituted groups. Exemplary and preferred compounds of the invention include: 10 4-amino-6-phenyl-7-(p-dimethylaminophenyl)pyrido[2,3-d]pyrimidine; 4-amino-6-(4-methylphenyl)-7-(4-(dimethylamino)phenyl)pyrido[2,3-d]pyrimidine; 4-amino-6-(4-(dimethylamino)phenyl)-7-(4-(dimethylamino)phenyl)pyrido[ 2
,
3 d]pyrimidine; 4-amino-6-(4-methylphenyl)-7-phenylpyrido[2,3-d]pyrimidine; 15 4-amino-6-(4-methylphenyl)-7-(4-bromophenyl)pyrido[2,3-d]pyrimidine; 4-amino-6-(4-(dimethylamino)phenyl)-7-(4-pyridinyl)pyrido[2,3-d]pyrimidine; 4-amino-6-(4-(dimethylamino)phenyl)-7-(4-bromophenyl)pyrido[2,3-d]pyrimidine; 4-amino-6- (4-methylphenyl)-7-(4-(5-pyrimidinyl)phenyl)pyrido[2,3-d]pyrimidine; 4-amino-6-(4-methylphenyl)-7-(4-(2-(2-pyridinyl)ethenyl)phenyl)pyrido[2,3 20 d]pyrimidine; 4-amino-6-(4-methylphenyl)-7-(3-pyridinyl)pyrido[2,3-d]pyrimidine; 4-amino-6-(4-methylphenyl)-7-(thiophen-3-yl)pyrido[2,3-d]pyrimidine; 4-amino-6-(4-methylphenyl)-7-(thiophen-2-yl)pyrido[2,3-d]pyrimidine; 4-amino-6-(4-methylphenyl)-7-(2-pyridinyl)pyrido[2,3-d]pyrimidine; 25 4-amino-6-(4-methylphenyl)-7-(3,4-methylenedioxyphenyl)pyrido[2,3 d]pyrimidine; 4-amino-6-butyl-7-(thiophen-2-yl)pyrido[2,3-d]pyrimidine; 4-amino-6-butyl-7-(thiophen-3-yl)pyrido[2,3-d]pyrimidine; 4-amino-6-(4-methylphenyl)-7-(5-bromothiophen-2-yl)pyrido[2,3-d]pyrimidine; 30 4-amino-6-(4-methylphenyl)-7-(5-methylthiophen-2-yl)pyrido[2,3-d]pyrimidine; 4-amino-6-(4-methylphenyl)-7-(4-(trifluoromethoxy)phenyl)pyrido[2,3 d]pyrimidine; 4-amino-6-(4-methylphenyl)-7-(3-phenoxyphenyl)pyrido[2,3-d]pyrimidine; 4-amino-6-(4-methylphenyl)-7-(5-nitrothiophen-2-yl)pyrido[2,3-d]pyrimidine; 35 4-amino-6-(4-methylphenyl)-7-(4-bromothiophen-2-yl)pyrido[2,3-d]pyrimidine; 4-amino-6-(4-methylphenyl)-7-(3-methylthiophen-2-yl)pyrido [2,3-d]pyrimidine; 4-amino-6-(4-methylphenyl)-7-(furan-2-yl)pyrido[2,3-d]pyrimidine; -10- WO 98/46603 PCTIUS98/04127 4-amidno-6-(4-methylphenyl)-7-(furan-3-.yl)pyrido[2,3-dlpyrimidine; 4-amidno-6-(4-rnethylphenyl)-7-(5-methyl-furan-2-yl)pyrido[2,3-d]pyrimidine; 4-arnino-6-(4-(2-propyl)phenyl)-7-(thiophen-2-yl)pyridol2,3-d]pyrimidine; 4-amino-6-.(4-(2-propyl)phenyl)-7-(5-nitrothiophen-2-yl)pyrido[2,3-d]pyrimidine; 5 4-amiino-6-(4-methylphenyl)-7-(5-nitrothiophen-2-yl)pyrido[2,3-d]pyrirnidine; 4-amidno-6-(4-(dimethylamino)phenyl)-7-(thiophen-2-yl)pyrido[2,3-dlpyrimidine; 4-amino-6-(3,4-dimethoxyphenyl)-7-(thiophen-2-yl)pyrido[2,3-d]pyrimidine; 4-amidno-6-(3,4-dimethoxyphenyl)-7-(5-nitrothiophen-2-yl)pyrido[2,3-d]pyrimidine; 4-amfino-6-.hexyl-7-(4-(dimethylamino)phenyl)pyrido[2,3-d]pyrimidine; 10 4-amidno-6-hexyl-7.-(thiophen-2-yl)pyrido[2,3-dlpyrimidine; 4-amidno-6-(2-methy1-2-propy1)-7-(thiophen-2-yl)pyrido[2,3-d~pyrimidine; 4-amidno-6-(4-(2-propyl)phenyl)-7-(4-(dimethylamino)phenyl)pyrido[2,3 dlpyrim-idine; 4-aniino-6-(4-propylphenyl)-7-(4-(dimethylamiino)phenyl)pyrido[2,3-d]pyrimidine; 15 4-amino-6-(3 ,4-dimethoxyphenyl)-7-.(4-(dimethylamino)phenyl)pyrido[2,3 dipyrimiline; 4-amino-6-(3-methoxyphenyl)-7-(4-(dimethylamino)phenyl)pyrido[2,3 dipyrimidine; 4-amino-6-(3-bromophenyl)-7-(4-(dimethylam-ino)phenyl)pyrido[2,3-dlpyrimidine; 20 4-amidno-6-(3-fluorophenyl)-7-(4-(dimethylan-ino)pheny1)pyrido[2,3-dlpyrifidile; 4-arnino-6-(3-trifluoromethylphenyl)-7-(4-(dimethylami no)phenyl)pyrido[2,3 d]pyrimidine; 4-amino-6-(3-chlorophenyl)-7-(4- (dimethylarnino)phenyl)pyrido[2,3-d] pyrimiddine; 4-amino-6-(3,5-dichlorophenyl)-7-(4-(dimethylamino)phenyl)pyrido[2,3 25 dllpyrimaidine; 4-amino-6-(3 ,4-methylenedioxyphenyl)-7-(4-(dimethylami no)phenyl)pyrido[2,3 d]pyrimidine; 4-amino-6-(3,4-methylenedioxyphenyl)-7- (thiophen-2-yl)pyrido[2,3-dlpyrirnidine; 4-amidno-6-(3-methoxycarbonylphenyl)-7-(4-(dimethylamino)phenyl)pyrido[2,3 30 dllpyrimidine; 4-amino-6-(3--(2-propyl)phenyl)--7-(4-(dimethylamino)phenyl)pyrido[2,3 d~pyrimidine; 4-amino-6- (4- (2-methyl-2-propyl)p hen yl)-7 -(4- (dimeth ylam-ino)phenyl)pyrido [2,3 dipyrimidine; 35 4-amino-6- (4-fluorophenyl)-7-(4-(dimethylamino)phenyl)pyrido[2,3-dlpyrimidine; 4-amidno-6-(4-methoxyphenyl)-7-(4-(dimethylamino)phenyl)pyrido [2,3 dilpyrimidine; WO 98/46603 PCT/US98/04127 4-amidno-6-(3-(phenylmethoxy)phenyl)-7-(4-(dimethylamino)phel)pyrido[2,3 d~pyrimidine; 4-amino-6-(4-chlorophenyl)-7-(4-(dimethylamidno)phenyl)pyrido[2,3-dlpyim-idine; 4-am-ino-6-(3-fluoro-4-methylphenyl)-7-(4- (dimethylam-ino)phenyl)pyrido[2,3 5 dlpyrimiddine; 4-amino-6-(3-fluoro-4-methylphenyl)-7-(thiophen-2-yl)pyrido[2,3-dlpyrirnidine; 4-am-ino-6-(3-phenylpropyl)-7-(4-methoxyphenyl)pyrido[2,3-dlpyrimidine; 4-amino-6- (3-phenylpropyl)-7-(4-(dimethylamino)phenyl)pyridol2,3-dlpyrimidine; 4-amino-6-(2-phenylethyl)-7.-(4-(dimethylamino)phenyl)pyrido[2,3-d]pyfrimidine; 10 4-amidno-6-(phenylmethyl)-7-(4- (dimethylamino)phenyl)pyrido[2,3-d]pyrimiddine; 4-amidno-6-(cyclohexylmethyl)-7-(4-(dimethylanino)phenyl)pyrido[2,3 dipyrimidine; 4-amino-6-butyl-7-(4-(dimethylamino)phenyl)pyrido[2,3-d]pyin-idile; 4-am-ino-6-pentyl-7-(4-(dimethylamino)phenyl)pyrido[2,3-d]pyritlidifle; 15 4-an-dno-6-(2-methylpropyl)-7-(4-(dimethylan-ino)phenyl)pyido[2,3-dlpyrim-idile; 4-amino-6-propyl-7-(4-(dimethylamidno)phenyl)pyrido[2,3-dlpyrimidile; 4-amino-6-(3-cyanopropyl)-7-(4-(dimethylamino)phenyl)pyrido[2,3-d]pyrimidile; 4-amino-6- (3-nitrophenyl)-7- (4- (dimethylainino)phenyl)pyridol2,3-dllpyrimidine; 4-amino-6-perityl-7 -(thiophen-2-yl)pyridoll2,3-djpyrimidine; 20 4-amidno-6-(3-carboxamiddopropyl)-7-(4-(dimethylamino)phelyl)pyrido [2,3 d]pyrim-idine; 4-amino-6- ((4-methoxyphenyl)methyl)-7-(thiophen-2-yl)pyrido [2,3-djpyrimidine; 4-amino-6-((3-bromophenyl)methyl)-7-(thiophen-2-yl)pyrido[2,3-dlpyrimidile; 4-amidno-6-((4-(2-propyl)phenyl)methyl)-7-(thiophen-2-yl)pyrido[2,3-d]pyrimidile; 25 4-amidno-6- ((4-methoxyphenyl)methyl)-7-(4-(2-propyl)phenyl)pyidol2,3 diipyrimiddine; 4-amino-6-((4-bromophenyl)methyl)-7 -(thiophen-2-yl)pyrido[2,3-d]pyrimidine; 4-amino-6-((3-fluorophenyl)methyl)-7-(thiophen-2-yl)pyrido[2,3-d]pyrimidile; 4-amino-6-((4-bromophenyl)methyl)-7-(thiazole-2-yl)pyrido [2,3-dipyrimidine; 30 4-amino-6-((3-methoxyphenyl)methyl)-7-(thiophen-2-yl)pyrido[2,3-dlpyfimidine; 4-amino-6-(phenylmethyl)-7-(thiophen-2-yl)pyido[2,3-dipyfinmidine, 4-amidno-6-((3-methoxyphenyl)methyl)-7-(4-(dimethylamino)phenyl)pyrido[2,3 d]pyrimidine; 4-amino-6-(4-methylphenyl)-7-(4-(trifluoromethyl)phenyl)pyrido[2,3-d]pyrimiddile; 35 4-amino-6-(4-methylphenyl)-7-(4-methylphenyl)pyrido[2,3-d]pyrimridine; 4-amidno-6-(4-methylphenyl)-7-(4-methoxyphenyl)pyrido [2,3-d] pyrim-idine; 4-amino-6- (4-methylphenyl)-7-(4-ethylphenyl)pyrido [2,3-dilpyrimidine; -12- WO 98/46603 PCT/US98/04127 4-amino-6-(4-methylphenyl)-7-(4-cyanophenyl)pyrido[2,3-d]pyrimidine; 4-amino-6-(4-methylphenyl)-7-(4-acetamidophenyl)pyrido[2,3-d]pyrimidine; 4-amino-6-(4-methylphenyl)-7-(4-phenoxyphenyl)pyrido[2,3-d]pyrimidine; 4-amino-6-(4-methylphenyl)-7-(4-nitrophenyl)pyrido[2,3-d]pyrimidine; 5 4-amino-6-(4-methylphenyl)-7-(4-fluorophenyl)pyrido[2,3-d]pyrimidine; 4-amino-6-(4-methylphenyl)-7-(4-chlorophenyl)pyrido[2,3-d]pyrimidine; 4-amino-6-(4-methylphenyl)-7-(4-aminophenyl)pyrido[2,3-d]pyrimidine; 4-amino-6-(4-methylphenyl)-7-(4-methylthiophenyl)pyrido[2,3-d]pyrimidine; 4-amino-6-(4-methylphenyl)-7-((4-phenyl)phenyl)pyrido[2,3-d]pyrimidine; 10 4-amino-6-(4-methylphenyl)-7-((4-phenylmethoxy)phenyl)pyrido[2,3-d]pyrimidine; 4-anmino-6-(4-methylphenyl)-7-((4-N,N-diethylamino)phenyl)pyrido[2,3 d]pyrimidine; 4-amino-6-(4-methylphenyl)-7-((4-2-phenylethenyl)phenyl)pyrido[2,3 d]pyrimidine; 15 4-amino-6-(4-methylphenyl)-7-(4-(2-methyl-2-propoxy)phenyl)pyrido[2,3 d]pyrimidine; 4-amino-6-(4-methylphenyl)-7-(3-chlorophenyl)pyrido[2,3-d]pyrinmidine; 4-amino-6-(4-methylphenyl)-7-(3,5-dimethoxyphenyl)pyrido[2,3-d]pyrimidine; 4-amino-6-(thiophen-2-yl)-7-(4-N,N-dimethylaminophenyl)pyrido[2,3 20 d]pyrimidine; 4-amino-6-(4-methylphenyl)-7-(benzofuran-2-yl)pyrido[2,3-d]pyrimidine; 4-amino-6-(thiophen-2-yl)-7-(thiophen-2-yl)pyrido[2,3-d]pyrimidine; 4-amino-6-(thiophen-2-yl)-7-(4-methoxyphenyl)pyrido[2,3-d]pyrinmidine; 4-amino-6-(4-bromophenyl)-7-(4-N,N-dimethylaminophenyl)pyrido[2,3 25 d]pyrimidine; 4-amino-6-(3-bromo-4-methoxyphenyl)-7-(4-N,N-dimethylaminophenyl) pyrido[2,3-d]pyrimidine; 4-amino-6-(3-bromo-4-methoxyphenyl)-7-(thiophen-2-yl)pyrido[2,3-d]pyrimidine; 4-amino-6-(4-methylphenyl)-7-(4-butoxyphenyl)pyrido[2,3-d]pyrimidine; 30 4-amino-6-(4-methylphenyl)-7-(3-methoxyphenyl)pyrido[2,3-d]pyrimidine; and 4-amino-6-(4-methylphenyl)-7-(3,5-dichlorophenyl)pyrido[2,3-d]pyrimidine. The present invention also includes those reduced versions of the compounds described above wherein the right side of the bicyclic ring may be reduced or partially reduced as shown in formula I via catalytic hydrogenation or other known reduction process 35 to form compounds as above wherein the 5,6 and/or the 7,8 double bond is absent or where there is a double bond between the 6 and 7 carbons. It is contemplated that the final -13- WO 98/46603 PCT/US98/04127 compounds shown above may be readily reduced and thus these compounds are within the scope of the invention. In addition, R 3 and R 4 may independently be selected fromphenyl; thiophen-2-yl; 1 methyl-2-oxobenzoxazolin-5-yl; 2-(dimethylamino)-5-pyrimidinyl; 2-(N-formyl-N-methyl 5 amino)-3-pyrimidinyl; 2-(N-(2-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-5-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 10 methylamino)phenyl; 3-methyl-4-(N-methyl-N-(trifluoroacetyl)amino)phenyl; 3-methyl-4 (N-methylamino)phenyl; 3-methyl-4-pyrrolidinylphenyl; 3-pyridyl; 3,4-dichlorophenyl; 3,4-methylenedioxyphenyl; 3,4,5-trimethoxyphenyl; 4-(acetylamino)phenyl; 4 (dimethylamino)-3-fluorophenyl; 4-(dimethylamino)phenyl; 4-(imidazol-1-yl)phenyl; 4 (methylthio)phenyl; 4-(morpholinyl)phenyl; 4-(N-(2-(dimethylamino)ethyl)amino)phenyl; 15 4-(N-(2-methoxyethyl)amino)phenyl; 4-(N-acetyl-N-methylamino)phenyl; 4-(N-ethyl-N formylamino)phenyl; 4-(N-ethylamino)phenyl; 4-(N-formyl-N-(2 methoxyethyl)amino)phenyl; 4-(N-isopropylamino)phenyl; 4-(N-methyl-N-((2 dimethylamino)ethyl)amino)phenyl; 4-(N-methyl-N-(2-(N phthalimidyl)acetyl)amino)phenyl; 4-(N-methyl-N-(2-cyano)ethylamino)phenyl; 4-(N 20 methyl-N-(2-methoxyethyl)amino)phenyl; 4-(N-methyl-N-(3 methoxy)propionylamino)phenyl; 4-(N-methyl-N-acetylamino)phenyl; 4-(N-methyl-N formylamino)phenyl; 4-(N-methyl-N-trifluoroacetylamino)phenyl; 4-(N morpholinyl)phenyl; 4-(thiophen-2-yl)phenyl; 4-(ureido)phenyl; 4-(2 (dimethylamino)acetylamino)phenyl; 4-(2-(2-methoxy)acetylamino)ethyl)amino)phenyl; 4 25 (2-methoxy)ethoxyphenyl; 4-(2-oxo-1-oxazolidinyl)phenyl; 4-(4-methoxy-2-butyl)phenyl; 4-(4-methylpiperidinyl)phenyl; 4-(5-pyrimidinyl)phenyl; 4-aminophenyl; 4-bromophenyl; 4-butoxyphenyl; 4-carboxamidophenyl; 4-chlorophenyl; 4-cyanophenyl; 4 diethylaminophenyl; 4-diethylmalonylallylphenyl); 4-dimethylaminophenyl; 4 ethoxyphenyl; 4-ethylphenyl; 4-fluorophenyl; 4-hydroxyphenyl; 4-imidazolylphenyl; 4 30 iodophenyl; 4-isopropylphenyl; 4-methoxyphenyl) 4-methylaminophenyl; 4 methylsulfonylphenyl; 4-morpholinylphenyl; 4-N-(2-(dimnethylamino)ethyl)-N formylamino)phenyl; 4-N-(3-methoxypropionyl)-N-isopropyl-amino)phenyl; 4-N-ethyl-N (2-methoxyethyl)amino)phenyl; 4-N-formylpiperidinylphenyl; 4-nitrophenyl; 4 piperidinylphenyl; 4-pyridylphenyl; 4-pyrrolidinylphenyl; 4-t-butylacrylphenyl; 5 35 (dimethylamino)thiophen-2-yl; 5-amino-2-pyridyl; 5-dimethylamino-2-pyrazinyl; 3 dimethylaminopyridazin-6-yl; 5-dimethylamino-2-pyridyl; 5-pyrimidinylphenyl; 6-(N methyl-N-formylamino)-3-pyridinyl; 6-(N-methyl-N-(2-methoxyethyl)amino)-3-pyridinyl; -14- WO 98/46603 PCT/US98/04127 6-(2-oxo-oxazolidinyl)-3-pyridinyl; 6-dimethylamino-3-pyridinyl; 6-imidazolyl-3-pyridinyl; 6-morpholinyl-3-pyridinyl; 6-pyrrolidinyl-3-pyridinyl; (2-propyl)-3-pyridinyl; and (4 formylamino)phenyl; (thiophen-2-yl)methyl; (thiophen-3-yl)methyl; butyl; cycloheptyl; pentyl; thiophen-2-yl; 1-(3-bromophenyl)ethyl; 2-(N-phenylmethoxycarbonyl)aminophenyl; 5 2-(3-bromophenyl)ethyl; 2-(3-cyanophenyl)methyl; 2-(4-bromophenyl)ethyl; 2-(5-chloro-2 (thiophen-3-yl)phenyl; 2-bromophenyl; 2-furanyl; 2-methylpropyl; 2-phenylethyl; phenylmethyl; 2,3-dimethoxyphenyl; 2,3-methylenedioxyphenyl; 3-(furan-2-yl)phenyl; 3 (thiophen-2-yl)phenyl; 3-(2-pyridyl)phenyl; 3-(3-methoxybenzyl)phenyl; 3 (amino)propynyl; 3-benzyloxyphenyl; 3-bromo-4-fluorophenyl; 3-bromo-5-iodophenyl; 3 10 bromo-5-methoxyphenyl; 3-bromophenyl; 3-bromophenylmethyl; 3-carboxamidophenyl; 3 chlorophenyl; 3-cyanophenyl; 3-diethylmalonylallylphenyl; 3-dimethylaminophenyl; 3 ethoxyphenyl; 3-fluoro-5-trifluoromethylphenyl; 3-fluorophenyl; 3-hydroxyphenyl; 3 iodophenyl; 3-methoxyethyoxyphenyl; 3-methoxyphenyl; 3-methylphenyl; 3 methylsulfonylphenyl; 3-methylthiophenyl; 3-t-butylacrylphenyl; 3-trifloromethyoxyphenyl; 15 3-trifluoromethylphenyl; 3-vinylpyridinylphenyl; 3,4-dichlorophenyl; 3,4-dimethoxyphenyl; 3,4-methylenedioxyphenyl; 3,4,5-trimethoxyphenyl; 3,5-di(trifluoromethyl)phenyl; 3,5 dibromophenyl; 3,5-dichlorophenyl; 3,5-dimethoxyphenyl; 3,5-dimethylphenyl; 4-(2 propyl)phenyl; 4-(2-propyl)oxyphenyl; 4-benzyloxyphenyl; 4-bromophenyl; 4 bromothiophen-2-yl; 4-butoxyphenyl; 4-dimethylaminophenyl; 4-fluoro-3 20 trifluoromethylphenyl; 4-methoxyphenyl; 4-neopentylphenyl; 4-phenoxyphenyl; 5 bromothiophen-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 or other groups as specified herein. 25 The term "acyl", as used herein, refers to a moiety attached by a carbonyl linkage, as for example, loweralkyl-carbonyl or aryl-carbonyl, wherein loweralkyl and aryl are as defined herein. Examples of acyl include, for example, acetyl, propionyl, hexanoyl, trifluoroacetyl, benzoyl, 4-methylbenzoyl, methoxyacetyl, pentanoyl, N Bocglycylimidazoyl, N-phthalimidylglycyl and the like or others as specified herein. 30 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 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 35 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-lowerlalkoxy, phenyl-loweralkenyl or -15- WO 98/46603 PCT/US98/04127 cycloalkyl-loweralkyl group. Examples of aryl radicals include, but are not limited to, 3 bromophenyl, 3-chlorophenyl, 4-chlorophenyl, 3-methoxyphenyl, 3-(2-propyl)phenyl, 3,4-dimethoxyphenyl, 3-trifluoromethylphenyl, 3-trifluoro-4-fluorophenyl, 4-(N-methyl N-methoxyl)ethylaminophenyl, 4-dimethylaminophenyl, 3-fluoro-4-methylphenyl, 4 5 methylphenyl, 4-cyanophenyl, 4-propylmethyl, 3,5-dichlorophenyl, 3,4 methylenedioxyphenyl, 3-cyanopropylphenyl, 4-ureidophenyl, 3-methylsulfonylphenyl, 3 carboxamidopropylphenyl or others as shown herein. The term "arylalkyl" refers to a loweralkyl radical having appended thereto an aryl group, as defined above, as for example benzyl and phenylethyl. 10 The term "aryloxy" refers to a aryl radical which is appended to the molecule via an ether linkage (i.e., through an oxygen atom), as for example phenoxy, naphthyloxy, 4 chlorophenoxy, 4-methylphenoxy, 3,5-dimethoxyphenoxy, 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, 15 cyclohexyl and cycloheptyl. Cycloalkyl is also described as C3-C8cycloalkyl. The term "cycloalkyl-loweralkyl" refers to a loweralkyl radical as defined below substituted with a cycloalkyl group as defined above by replacement of one hydrogen atom. Examples of cycloalkyl-loweralkyl include cyclopropylmethyl, cyclobutylethyl, cyclopentylmethyl, cyclohexylmethyl and cycloheptylbutyl, and the like. 20 The term "heteroaryl" refers to a monocyclic aromatic radical having from five to seven ring atoms of which one ring atom is nitrogen, oxygen or sulfur; zero, one or two ring atoms are additional heteroatoms independently selected from S, O and N; and the remaining ring atoms are carbon, the radical being joined to the rest of the molecule via any of the ring atoms. A heteroaryl group may be unsubstituted or substituted by independent 25 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 "heteroaryl "refers to a heteroaryl group substituted with one ureido, methylsulfonyl, pyrimidinyl, pyridinyl, pyridazinyl, 30 morpholinyl, phenyl-lowerlalkoxy, 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. Examples of heteroaryl include pyridinyl, pyrazinyl, pyrimidinyl, pyrrolyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, isoxazolyl, thiadiazolyl, oxadiazolyl, furanyl, thiophenyl, 5 35 methylthiophen-2-yl, 5-nitrothiophen-2-yl, 5-methylfuranyl, benzofuranyl, benzothiophenyl, and the like and others as shown herein. -16- WO 98/46603 PCT/US98/04127 The term "heterocyclic" refers to a saturated or unsaturated monocyclic ring system radical having from four to seven ring atoms of which one is nitrogen or oxygen; 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 5 atoms and being optionally substituted, either on a nitrogen or a carbon atom, by an additional radical selected from among aryl(loweralkyl), alkoxycarbonyl, loweralkyl, halo(loweralkyl), amino(loweralkyl), hydroxy-substituted loweralkyl, hydroxy, loweralkoxy, halogen, amino, loweralkylamino, and amino, (loweralkyl)amino or alkanoylamino of from one to eight carbon atoms in which the amino group may be further o10 substituted with alkanoyl of from one to eight carbons, an alpha-amino acid or a polypeptide. Examples of heterocyclic include pyrrolidine, tetrahydrofuran, dihydropyrrole, isoxazolidine, oxazolidine, tetrahydropyridine, piperidine, piperazine, morpholine, thiomorpholine, aziridine and azetidine and those additionally described herein. The term "heterocyclic-loweralkyl" refers to a loweralkyl radical as defined below 15 substituted with a heterocyclic-group as defined above by replacement of one hydrogen atom. Examples of cycloalkyl-loweralkyl include pyrrolidinylmethyl, piperidinylethyl, and the like. The term "loweralkyl", as used herein, refers to saturated, straight- or branched chain hydrocarbon radicals containing from one to six carbon atoms including, which may 20 be unsubstituted or substituted by independent replacement of one, two or three of the hydrogen atoms thereon with Cl, Br, F, I, cyano, carboxamido, hydroxy, loweralkoxy, amino, loweralkylamino, 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, methoxymethyl, 25 trifluoromethyl, 3-cyanopropyl, 3-carboxamidopropyl, 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 provided adjacent to aryl or heteroaryl or other generic group and represent or have the same meaning 30 as, for example, "arylalkyl"' or "heteroarylalkyl". The term "loweralkenyl", as used herein, refers to mono-unsaturated straight- or branched-chain hydrocarbon radicals containing from two to six carbon atoms including, but not limited to, vinyl, propenyl, n-butenyl, i-butenyl, n-pentenyl, and n-hexenyl. These variables are also recited as, for example, C2-C6alkenyl. 35 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, -17- WO 98/46603 PCT/US98/04127 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. 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 5 atoms including, but not limited to, ethynyl, propynyl, n-butynyl, n-pentynyl, and n hexynyl. This term is also described as C2-C6alkynyl. The term "mammal" has its ordinary meaning and includes human beings. In a further aspect of the present invention pharmaceutical compositions are disclosed which comprise a compound of the present invention in combination with a 10 pharmaceutically acceptable carrier. The present invention includes one or more compounds, as set forth above, formulated into compositions together with one or more non-toxic physiologically tolerable or acceptable diluents, carriers, adjuvants or vehicles that are collectively referred to herein as diluents, for parenteral injection, for oral administration in solid or liquid form, for rectal 15 or topical administration, or the like. As is well known in the art, a compound of the present invention can exist in a variety of forms including pharmaceutically-acceptable salts, amides and the like. Compositions may be prepared that will deliver the correct amount of a compound or compounds of the invention. The following dosages are thought to provide the optimal 20 therapy: iv infusions: 0.1- 250 nmol/kg/minute, preferably from 1-50 nmol/kg/minute; oral: 0.01-250 tMol/kg/day, preferably from about 0.1-50 Mol/kg/day; these oral molar dosage ranges correspond to 0.005-125 mg/kg/day, preferably 0.05-25 mg/kg/day. For treatment of acute disorders the preferred route of administration is intravenous; the preferred method of treating chronic disorders is orally by means of a tablet or sustained 25 release formulation. "Pharmaceutically-acceptable amide" refers to the pharmaceutically-acceptable, nontoxic amides of the compounds of the present invention which include amides formed with suitable organic acids or with amino acids, including short peptides consisting of from 1-to-6 amino acids joined by amide linkages which may be branched or linear, wherein the 30 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, 35 nontoxic, inorganic or organic acid addition salts of the compounds of the present invention, as described in greater detail below. -18- WO 98/46603 PCT/US98/04127 The term "substituted versions thereof" refers to those generic groups such as aryl or heteroaryl or heterocyclic which have substituents around the aryl, heteroaryl, heterocyclic or other genera variable at chemically appropriate positions and as designated or exemplified herein. 5 The compounds of the present invention can be used in the form of pharmaceutically-acceptable salts derived from inorganic or organic acids. These salts include, but are not limited to, the following: acetate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, flavianate, fumarate, 10 glucoheptonate, glycerophosphate, hemisulfate, heptonate, hexonoate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxy-ethanesulfonate, lactate, maleate, methanesulfonate, nicotinate, 2-naphthalenesulfonate, oxalate, palmoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, succinate, tartrate, thiocyanate, tosylate, and undecanoate. 15 Appropriate cationic salts are also readily prepared by conventional procedures such as treating an acid of Formula I with an appropriate amount of base, such as an alkali or alkaline earth metal hydroxide, e.g., sodium, potassium, lithium, calcium, or magnesium, or an organic base such as an amine, e.g., dibenzylethylenediamine, cyclohexylamine, dicyclohexylamine, triethylamine, piperidine, pyrrolidine, benzylamine, and the like, or a 20 quanternary ammonium hydroxide such as tetramethylammonium hydroxide and the like. Also, the basic nitrogen-containing groups can be quaternized with such agents as loweralkyl halides, such as methyl, ethyl, propyl, and butyl chlorides, bromides, and iodides; dialkyl sulfates; long chain halides such as decyl, lauryl, myristyl, and stearyl chlorides, bromides and iodides; arylalkyl halides like benzyl and phenethyl bromides, and 25 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 or II which contain a basic or acidic moiety by conventional methods, such as by reacting the free base or acid with stoichiometric amounts or with an excess of the desired salt forming inorganic acid or base in a suitable solvent or various combinations of solvents. 30 Further included within the scope of the present invention are pharmaceutical compositions comprising one or more of the compounds of formula (I) prepared and formulated in combination with one or more non-toxic pharmaceutically acceptable carriers compositions, in the manner described below. Compositions suitable for parenteral injection may comprise pharmaceutically 35 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 -19- WO 98/46603 PCT/US98/04127 include water, ethanol, polyols (propylene glycol, polyethylene glycol, glycerol, and the like), suitable mixtures thereof, vegetable oils (such as olive oil) and injectable organic esters such as ethyl oleate. Proper fluidity may be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of 5 dispersions, and by the use of surfactants. These compositions may also contain adjuvants such as preserving, wetting, emulsifying, and dispersing agents. Prevention of the action of microorganisms may be ensured by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, and the like. It may also be desirable to include isotonic 10 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 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 15 microspheres. They may be sterilized, for example, by filtration through a bacteria retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions, which may be dissolved in sterile water, or some other sterile injectable medium immediately before use. Solid dosage forms for oral administration may include capsules, tablets, pills, 20 powders, and granules. In such solid dosage forms, the active compound is admixed with at least one inert customary excipient (or carrier), such as sodium citrate or dicalcium phosphate, and additionally (a) fillers or extenders, as for example, starches, lactose, sucrose, glucose, mannitol and silicic acid; (b) binders, as for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and acacia; (c) 25 humectants, as for example, glycerol; (d) disintegrating agents, as for example, agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates and sodium carbonate; (e) solution retarders, as for example paraffin; (f) absorption accelerators, as for example, quaternary ammonium compounds; (g) wetting agents, as for example, cetyl alcohol and glycerol monostearate; (h) adsorbents, as for example, kaolin 30 and bentonite; and (i) lubricants, as for example, talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate or mixtures thereof. In the case of capsules, tablets and pills, the dosage forms may also comprise buffering agents. Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules, using such excipients as lactose or milk sugar, as well as high 35 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 -20- WO 98/46603 PCT/US98/04127 art. They may contain pacifying agents, and may also be of such composition that they release the active compound or compounds in a certain part of the intestinal tract in a delayed manner. Examples of embedding compositions which may be used are polymeric substances and waxes. 5 The active compounds may also be in micro-encapsulated form, if appropriate, with one or more of the above-mentioned excipients. Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups and elixirs. In addition to the active compounds, the liquid dosage forms may contain inert diluents commonly used in the art, o such as water or other solvents, solubilizing agents and emulsifiers, as for example, ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils, in particular, cottonseed oil, groundnut oil, corn germ oil, olive oil, castor oil and sesame oil, glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan or mixtures 5 of these substances, and the like. Besides such inert diluents, these liquid dosage forms may also include adjuvants, such as wetting agents, emulsifying and suspending agents, sweetening, flavoring and perfuming agents. Suspensions, in addition to the active compounds, may contain suspending agents, 0 as for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, or mixtures of these substances, and the like. Compositions for rectal or vaginal administrations are preferably suppositories which can be prepared by mixing the compounds of this invention with suitable non 5 irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax, which are solid at ordinary temperatures but liquid at body temperature and therefore, melt in the rectum or vaginal cavity and release the active component. Dosage forms for topical or transdermal administration of a compound of this invention further include ointments, pastes, creams, lotions, gels, powders, solutions, 0 sprays, inhalants or transdermal patches. Transdermal administration via a transdermal patch is a particularly effective and preferred dosage form of the present invention. The active component is admixed under sterile conditions with a pharmaceutically acceptable carrier and any needed preservative, buffers or propellants as may be required. It is known that some agents may require special handling in the preparation of transdermal patch 5 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 -21- WO 98/46603 PCT/US98/04127 require formulation with absorption-retarding agents or barriers. Ophthalmic formulations, eye ointments, powders and solutions are also contemplated as being within the scope of this invention. The present compounds may also be administered in the form of liposomes. As is 5 known in the art, liposomes are generally derived from phospholipids or other lipid substances. Liposomes are formed by mono- or multi-lamellar hydrated liquid crystals that are dispersed in an aqueous medium. Any non-toxic, physiologically acceptable and metabolizable lipid capable of forming liposomes may be used. The present compositions in liposome form may contain, in addition to the compounds of the present invention, 10 stabilizers, preservatives, excipients, and the like. The preferred lipids are the phospholipids and the phosphatidyl cholines (lecithins), both natural and synthetic. Methods to form liposomes are known in the art. See, for example, Prescott, Ed., Methods in Cell Biolovgy, Volume XIV, Academic Press, New York, N. Y., (1976), p 33 et seq. 15 Synthetic Methods The compounds and processes of the present invention will be better understood in connection with the following synthetic Schemes 1 and 2 which illustrate the methods by which the compounds of the invention may be prepared. The groups R 1 , R 2 , R 3 and R 4 are as defined above unless otherwise noted. 20 Scheme 1
NH
2
NH
2 N 1 (HO) RN
R
3 N NH 2 N NH 2 1 2 3
NH
2 R3 H
NH
2 N+ O" R4 N N NH 2 R N N R 3 4 5 In accordance with Scheme 1 are prepared compounds of Formula (II) wherein R 1 25 and R 2 are hydrogen. A starting material, 4 ,6-diamino-5-iodopyrimidine (1), is reacted with ethenylboronic acid derivatives (2), wherein R 3 is loweralkyl, loweralkenyl, -22- WO 98/46603 PCT/US98/04127 loweralkynyl, aryl, arylalkyl, heterocyclic or heteroaryl or substituted versions thereof, to prepare compound (3) in the presence of tetrakistriphenylphosphinepaUadium(0) or other suitable palladium(0) complexes, and aqueous alkali metal base, such as sodium or potassium hydroxide, for example, preferably buffered with an aqueous sodium or 5 potassium bicarbonate at reflux for about 8 to about 24 hours. Compound (1) may be prepared from 4,6-diaminopyridine by treatment with iodine in DMF at about 40 oC to about 50 oC for about 24 hours in the presence of potassium carbonate. Compounds of formula (2) may be prepared by reaction of an R 3 -substituted acetylene with catecholborane in a solvent such as THF. R 3 -substituted acetylenes may be prepared according to various 10 literature procedures, such as, for example, Van Hijfte et al., Tetrahedron Letters, 1989, 30: 3655; Tao et al., J. Org.Chem., 1990, 55: 63; and Rossi et al., Gazz. Chim. Ital., 1990, 120: 783-791. Compound (3) is then reacted with the aldehyde compound (4), wherein R 4 is aryl, heteroaryl, or a heterocyclic group, to prepare compound (5) in a suitable anhydrous 15 solvent, under Suzuki reaction conditions, such as diphenyl ether, 1,2,4-trichlorobenzene, toluene, or the like, in the presence of 4A molecular sieves to adsorb the water of reaction, at reflux for from about 2 to about 24 hours. Compounds (5) are compounds of Formula (II) wherein R 1 and R 2 are hydrogen. The compounds prepared according to Scheme 1 may be further treated with a suitable reducing agent such as hydrogen in the presence of a :0 catalyst or other reducing agent to form the 5,6 and/or 7,8 reduced versions of a compound of formula II. In addition, reduction can proceed to form single bonds at the 5,6 and 7,8 positions and a double bond between the 6, 7 carbons. In the former case(s), stereoisomers are formed and are included within the scope of the invention. These isomers may be isolated by conventional means. .5 Scheme 2 RI\ R 2
NH
2 NR2 R3 N::] R3 N \ \' N \ \~ II - I N N R 4 N N R 4 5 6 In accordance with Scheme 2, compounds of Formula (II) wherein one or both of 0 R 1 and R 2 are loweralkyl, arylalkyl or acyl, may be prepared by treatment of compound (5) with the appropriate reagent. To prepare compounds of formula (I) or (II) wherein R 1 and
R
2 are not both hydrogen atoms, it is possible to prepared the desired derivative from the -23- WO 98/46603 PCT/US98/04127 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 of a base such as triethylamine or potassium carbonate in a 5 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 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 10 the free amino group with the appropriate acid anhydride, an acyl halide such as acyl chloride, or an activated acyl group, such as an acyl cyanide, an acyl azide or a thiolester, 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 and R2 are taken together with the nitrogen atom to which they are attached to form a 5-to-7 membered ring optionally 15 containing an additional oxygen or nitrogen atom, the compound may be prepared by reacting a precursor compound having a halogen atom in place of the amino group at the 4 position with a 5-7 membered ring compound optionally containing an additional oxygen or nitrogen atom. Examples of such compounds include, but are not limited to, morpholine, piperidine, pyrrolidine, piperazine, thiomorpholine, and the like. Also, this alternate 20 procedure may be used to prepare alkyl substituted amino compounds, for example by reacting the chloro compound with a mono- or disubstituted amine, such as for example, diethylamine, allyl amine, dibutylamine. This reaction takes place readily in a solvent such as methylene chloride, for example, in the presence of a tertiary amine. The precursor compound having a halogen atom in place of the amino group at the 4-position may be 25 prepared by substitution of 6 -amino-4-chloro-5-iodopyrimidine for the 4,6-diamino-5 iodopyrimidine (compound (1) of Scheme 1) and carrying the product forward. Method of Inhibiting Kinase In yet another aspect of the present invention a method of inhibiting adenosine 30 kinase is disclosed. In accordance with this method, an adenosine kinase enzyme is exposed to an effective inhibiting amount of an adenosine kinase inhibitor compound of the present invention. Preferred such compounds for use in the method are the same as set forth above. Means for determining an effective inhibiting amount are well known in the art. 35 The adenosine kinase to be inhibited can be located in vitro, in situ or in vivo. Where the adenosine kinase is located in vitro, adenosine kinase'is contacted with the inhibitor compound, typically by adding the compound to an aqueous solution containing -24- WO 98/46603 PCT/US98/04127 the enzyme, radiolabeled substrate adenosine, magnesium chloride and ATP. The enzyme can exist in intact cells or in isolated subcellular fractions containing the enzyme. The enzyme is then maintained in the presence of the inhibitor for a period of time and under suitable physiological conditions. Means for determining maintenance times are well known 5 in the art and depend inter alia on the concentrations of enzyme and the physiological conditions. Suitable physiological conditions are those necessary to maintain adenosine kinase viability and include temperature, acidity, tonicity and the like. Inhibition of adenosine kinase can be performed, by example, according to standard procedures well known in the art (Yamada, et al., Comp. Biochem. Physiol. 1982, 71B: 367-372). 10 Where the adenosine kinase is located in situ or in vivo, is typically administered to a fluid perfusing the tissue containing the enzyme. That fluid can be a naturally occuring fluid such as blood or plasma or an artificial fluid such as saline, Ringer's solution and the like. A process of inhibiting adenosine kinase in vivo is particularly useful in mammals such as humans. Administering an inhibitor compound is typically accomplished by the parenteral 15 (e.g., intravenous injection or oral) administration of the compound. The amount administered is an effective inhibiting or therapeutic amount. By a "therapeutically-effective amount" of the compound of the invention is meant a sufficient amount of the compound to treat or mitigate adenosine kinase related disorders or those diseases or conditions which are ameliorated by adenosine kinase inhibition and 20 elevated levels of adenosine, at a reasonable benefit/risk ratio applicable to any medical treatment. It will be understood, however, that the total daily usage of the compounds and compositions of the present invention is to be decided by the attending physician within the scope of sound medical judgment. The specific therapeutically-effective dose level for any particular patient will depend upon a variety of factors including the disorder being treated 25 and the severity of the disorder; activity of the specific compound employed; the specific composition employed; the age, body weight, general health, gender and diet of the patient; the time of administration, route of administration, and rate of excretion of the specific compound employed; the duration of the treatment; drugs used in combination or coincidental with specific compound employed; and the like factors well known in the 30 medical arts and well within the capabilities of attending physicians. Compounds of the present invention inhibit adenosine kinase activity in vitro and in vivo. In vitro adenosine kinase activity can be measured using any of the standard procedures well known in the art. By way of example, cells containing adenosine kinase, such as IMR-32 human neuroblastoma cells, are cultured in the presence and absence of an 35 inhibitor. Inhibition is measured as the ability to inhibit phosphorylation of endogenous or 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 -25- WO 98/46603 PCT/US98/04127 inhibitors on adenosine Al and A2c receptor binding, adenosine deaminase activity and adenosine transport. Compounds of the present invention are effective in inhibiting adenosine kinase activity in vivo. Numerous animal models for studying adenosine kinase activity and the 5 affects of inhibiting such activity are well known in the art. By way of example, adenosine kinase inhibitors have been reported to protect rodents (e.g., mice and rats) from seizures induced by the subcutaneous administration of pentylenetetrazol (PTZ). Typically the rodents are injected with various doses of a given inhibitor followed at various times by the subcutaneous administration of from about 10 to about 500 milligrams per kilogram of PTZ. 10 The injected animals are then observed for the onset of seizures. The compounds of the invention were tested in vivo in the hot plate test of analgesia in mammals such as mice. For example, the compounds of examples 55, 103 and 104 in the procedure described directly below were tested thirty minutes after pretreatment with the drugs (30 pimol/kg i.p.) for latency to 10th jump (in seconds). The longer the number of 15 seconds, the more effective the drug at masking the pain felt from the hot plate. Compound 55 resulted in 132.86 seconds relative to the vehicle alone of 72.76+10.51 seconds. Compound 103 resulted in 103.29 seconds. Compound 104, when tested, resulted in an insignificant score of 62.44 seconds and will be retested in additional models of pain. Compounds of the invention are therefore potent pain relievers as well as adenosine kinase 20 inhibitors as demonstrated in this animal model and the additional assays described below. Mouse Hot Plate Assay Male CF1 mice (Charles River) of approximately 25-30 g body weight are pretreated with 25 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 30 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. 35 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)]. -26- WO 98/46603 PCT/US98/04127 Numerous inhibitor compounds of the present invention were tested in vitro and found to inhibit adenosine kinase activity. The results of some representative studies are shown below in Table 1 below. The data indicate that the compounds inhibit adenosine kinase. 5 Table 1 Inhibition of Adenosine Kinase by Representative Compounds of the Invention Compound of Example No. IC 50 (nM) 2 73 3 185 6 467 9 115 10 317 15 11 36 250 38 45 55 5 59 117 62 30 63 200 78 25 98 95 103 33 104 8 10 Method of Treating Cerebral Ischemia, Epilepsy, Nociperception (Nociception) (Pain), Inflammation including conditions such as Septic Shock due to Sepsis Infection In yet another aspect of the present invention a method of treating cerebral ischemia, epilepsy, nociperception or nociception, pain, inflammation including conditions such as 15 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. 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 20 growth rate (Jackson, et al., Br. J. Cancer, 1978, 37: 701-713). Adenosine kinase activity was also diminished in regenerating liver after partial hepatectomy in experimental animals (Jackson, et al., Br. J. Cancer, 1978, 37: 701-713). Erythrocyte Adenosine kinase activity was found to be diminished in patients with gout (Nishizawa, et al., Clin. Chim. Acta 1976, 67: 15-20). Lymphocyte adenosine kinase activity was decreased in patients infected with 25 the human immunodeficiency virus (HIV) exhibiting symptoms of AIDS, and increased in -27 0I IlTrI ITE CT==0- IDI II C ORI WO 98/46603 PCT/US98/04127 asymptomatic HIV-seropositive and HIV-seronegative high-risk subjects, compared to 5 normal healthy controls (Renouf, et al., Clin. Chem. 1989, 35: 1478-1481). It has been suggested that measurement of adenosine kinase activity may prove useful in monitoring the clinical progress of patients with HIV infection (Renouf, et al., Clin. Chem. 1989, 35: 1478-1481). Sepsis infection may lead to a systemic inflammatory syndrome (SIRS), characterized by an increase in cytokine production, neutrophil accumulation, hemodynamic 10 effects, and tissue damage or death. The ability of adenosine kinase inhibitor to elevate adenosine levels in tissues has been demonstrated to ameliorate syndrome symptoms, due to the know anti-inflammatory effects of adenosine. (Firestein, et al., J. of Immunology, 1994, pp. 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 15 adenosine or its analogs results in antinociception or antinociperception. (Swaynok, et al., Neuroscience, 1989, 32: No. 3, pp. 557-569). The compounds and processes of the present invention will be better understood in connection with the following Examples, which are intended as an illustration of and not a 20 limitation upon the scope of the invention. Example 1 4-amino-6-phenvl-7-(p-dimethylaminophenvyl)pyrido [2.3-d]pyrimidine 25 A sample of 4,6-diamino-5-(2-phenylethenyl)pyrimidine (150 mg) was suspended in 10 mL of phenylether with 1.2 eq of 4-(dimethylamino)benzaldehyde (the "R 4 " Reagent) and 1.5 g of 4A molecular sieves. The solution was heated to 170 oC for 4 hours, then cooled, and the solvent was removed. The residue was purified by column chromatography to give the title compound. IR (KBr) 3325, 1589, 1555, 1400, 1340, 1196, 819 cm- 1 ; MS 30 m/z 342 [M+H] + . The 4,6-diamino-5-(2-phenylethenyl)pyrimidine was prepared as follows: -28 Cl IETITI IT" CULIT IDI II 1 OR1 WO 98/46603 PCT/US98/04127 la. 5-iodo-4,6-diaminopyrimidine 4,6-Diaminopyrimidine hemisulfate monohydrate (26.13 g, 147.5 mmol, Aldrich) 5 and K 2
CO
3 (30.58 g, 221.3 mmol) were suspended in water (400 mL). To this suspension was added a solution of iodine (41.19g, 162.3 mmol) in DMF (100 mL). The mixture was heated at 45 'C for 23 hours. After cooling, a 2 M solution of Na2S203 (15 mL) was added to quench the excess iodine. The white product was then collected, washed with water (3 x 20 mL) and dried under high vacuum to yield 33.1 g of the title compound (90%). 10 lb. 2-phenylethenylboronic acid (the "R 3 " Reagent) Phenylacetylene (5 mmol, Aldrich) was dissolved in 5 mL of dry THF and catecholborane (5 mL, IM in THF, Aldrich) was added dropwise at 0 oC. The solution was heated to reflux for 1.5 hours, and the solvent was removed under vacuum. The solution was quenched with IM HCI (10 mL), and this solution is taken directly to the next step. 15 Ic. 4,6-diamino-5-(2-phenvlethenvyl)pvrimidine To a solution of 5-iodo-4,6-diaminopyrimidine (1 mmol, from step 1 a above) in 50 mL of dioxane, 2-phenylethenylboronic acid (5 rmmol), 5% of Pd(PPh 3
)
4 , and 1M Na2CO3 (10 mL) were added. The reaction mixture was heated for 12 hours. The solvent was removed under vacuum, and the residue was diluted with water and extracted with CH2Cl2 20 (3 x 30 mL). The organic layer was concentrated under reduced pressure, and the residue was dried under high vacuum. The crude mixture was subjected to column chromatography (using 5% MeOH/CH 2 Cl 2 as eluant) to give the title compound. MS m/z: 213 (M+H) +. Examples 2-107 25 Following the procedures of Example 1, except substituting the reagents given in Table 1 below for the R 4 and R 3 Reagents of Example 1, the compounds of Examples 2-107 were prepared. Table 1 30 Examples 2-107 Ex. Name R 4 Reagent- R 3 Reagent- Data No. (7 position) (6-position) 2 4-amino-6-(4-methylphenyl)-7- 4-(dimethylamino)- 2-(4-methylphenyl)- IR (KBr) 3360, (4- benzaldehyde ethenyl-boronic acid 1660, 1600, 1185, (dimethylamino)phenyl)pyrido[ cm-1; MS m/z 356 2,3-d]pyrimidine [M+H]+. -29 0l ICTITI ITC CCT IDIII C or WO 98/46603 PCT/US98/04127 3 4-amino-6-(4- 4-(dimethylamino)- 2-(4- IR (microscope) (dimethylamino)phenyl)-7-(4- benzaldehyde dimethylaminophen 3325. 1608, 1589, (dimethylamino)phenyl)pyrido[ yl)-ethenyl-boronic 1560. 1520, 1400, 2,3-d]pyrimidine acid 1358. 1340, 1196, 818 cm- 1 ; MS m/z 385 [M+H] + . 4 4-amino-6-(4-methylphenyl)-7- benzaldehyde 2-(4-methylphenyl)- IR (microscope) phenylpyrido[2,3-d]pyrimidine ethenyl-boronic acid 3325, 1659, 1553, 1340, 1340, 821 cm- 1 ; MS m/z 313
[M+H]
+ . 5 4-amino-6-(4-methylphenyl)-7- 4- 2-(4-methylphenyl)- IR (microscope) (4-bromophenyl)pyrido[2,3- bromobenzaldehyde ethenyl-boronic acid 3325. 1600, 1553, d]pyrimidine 1340. 1340, 818 cm- 1 ; MS m/z 391
[M+H]
+ . 6 4-amino-6-(4- pyridine-4- 2-(4- IR (microscope) (dimethylamino)phenyl)-7-(4- carboxaldehyde dimethylaminophen 3320. 1608, 1560, pyridinyl)pyrido[2.3- yl)-ethenyl-boronic 1521. 1410. 1344. d]pyrimidine acid 818 cm- 1 ; MS m/z 343 [M+H] + . 7 4-amino-6-(4- 4- 2-(4- IR (microscope) (dimethylamino)phenyl)-7-(4- bromobenzaldehyde dimethylaminophen 3320, 1606, 1562, bromophenyl)pyrido[2,3- yl)-ethenyl-boronic 1547. 1520, 1340, d]pyrimidine acid 1010, 818 cm-1 MS m/z 420
[M+H]
+ . 8 4-amino-6-(4-methylphenyl)-7- 4-(5- 2-(4-methylphenyl)- IR 3360, 3160, (4-(5- pyrimidinyl)benzald ethenyl-boronic acid 1600. 1555, 1410, pyrimidinyl)phenyl)pyrido[2,3- ehyde 1345, 820; MS m/z d]pyrimidine 391 (M+H) + . 9 4-amino-6-(4-methylphenyl)-7- 4-(2-(2- 2-(4-methylphenyl)- IR 3400, 3320, (4-(2-(2- pyridinyl)ethenyl)be ethenyl-boronic acid 3160. 3040, 1595, pyridinyl)ethenyl)phenyl)pyrido nzaldehyde 1560. 1340; MS [2.3-d]pyrimidine m/z 416 (M+H) + . 1 0 4-amino-6-(4-methylphenyl)-7- 3- 2-(4-methylphenyl)- IR 3320, 3360, (3-pyridinyl)pyrido[2,3- pyridinecarboxaldeh ethenyl-boronic acid 3040, 1640, 1550, d]pyrimidine yde 1340. 815; MS m/z 314 (M+H) + . 11 4-amino-6-(4-methylphenyl)-7- 3- 2-(4-methylphenyl)- IR 3440. 3320, (thiophen-3-yl)pyrido[2,3- thiophenecarboxalde ethenyl-boronic acid 3160, 3100, 1600, d]pyrimidine hyde 1555, 1335; MS m/z 319 (M+H) + . 12 4-amino-6-(4-methylphenyl)-7- 2- 2-(4-methylphenyl)- IR 3460, 3360, (thiophen-2-yl)pyrido[2,3- thiophenecarboxalde ethenyl-boronic acid 3310, 3100, 1600, d]pyrimidine hyde 1555, 1425; MS m/z 319 (M+H) + . 13 4-amino-6-(4-methylphenyl)-7- 2- 2-(4-methylphenyl)- IR 3440, 3320, (2-pyridinyl)pyrido[2,3- pyridinecarboxaldeh ethenyl-boronic acid 3170, 1640, 1600, d]pyrimidine yde 1555, 1340; MS m/z 314 (M+H) + . -30 C l ICTITlI IT CICIT [DIR II C OR% WO 98/46603 PCT/US98/04127 1 4 4-amino-6-(4-methylphenyl)-7- 3,4- 2-(4-methylphenyl)- IR 3365, 3120, (3,4- Methylenedioxybenz ethenyl-boronic acid 1600, 1555, 1440, methylenedioxyphenyl)pyrido[2 aldehyde 1250, 1040; MS ,3-d]pyrimidine m/z 357 (M+H) + . 1 5 4-amino-6-butyl-7-(thiophen-2- 2- 1-hexenyl-boronic IR 3320, 3160, yl)pyrido[2,3-d]pyrimidine thiophenecarboxalde acid 2955, 2860, 1640, hyde 1560, 1335; MS m/z 285 (M+H) + . 1 6 4-amino-6-butyl-7-(thiophen-3- 3- 1-hexenyl-boronic IR 3300, 3070, yl)pyrido[2,3-d]pyrimidine thiophenecarboxalde acid 2950, 2850, 1600, hyde 1565, 1330; MS m/z 285 (M+H) + . 1 7 4-amino-6-(4-methylphenyl)-7- 5-bromothiophen-2- 2-(4-methylphenyl)- IR 3450, 3300, (5-bromothiophen-2- carboxaldehyde ethenyl-boronic acid 3100, 1640, 1600, yl)pyrido[2,3-d]pyrimidine 1555, 1425; MS m/z 397/399
(M+H)
+ . 1 8 4-amino-6-(4-methylphenyl)-7- 5-methylthiophen-2- 2-(4-methylphenyl)- IR 3460, 3380, (5-methylthiophen-2- carboxaldehyde ethenyl-boronic acid 3300, 3150, 1640, yl)pyrido[2,3-d]pyrimidine 1555, 1445; MS m/z 333 (M+H) + . 1 9 4-amino-6-(4-methylphenyl)-7- 4- 2-(4-methylphenyl)- IR 3440, 3320, (4- (trifluoromethyl)ben ethenyl-boronic acid 3180, 1555, 1490. (trifluoromethoxy)phenyl)pyrid zaldehyde 1340, 820; MS m/z o[2,3-d]pyrimidine 397 (M+H) + . 20 4-amino-6-(4-methylphenyl)-7- 3- 2-(4-methylphenyl)- IR 3400, 3180, (3-phenoxyphenyl)pyrido[2,3- phenoxybenzaldehyd ethenyl-boronic acid 3050, 1555, 1340, d]pyrimidine e 1255, 820; MS m/z 405 (M+H) + . 2 1 4-amino-6-(4-methylphenyl)-7- 5-nitro-thiophen-2- 2-(4-methylphenyl)- IR 3380, 3100, (5-nitrothiophen-2- carboxaldehyde ethenyl-boronic acid 1595, 1550, 1330, yl)pyrido[2,3-d]pyrimidine 1260, 815; MS m/z 364 (M+H) + . 22 4-amino-6-(4-methylphenyl)-7- 4-bromo-thiophen- 2-(4-methylphenyl)- IR 3320, 3100, (4-bromothiophen-2- 2-carboxaldehyde ethenyl-boronic acid 1595, 1555. 1415, yl)pyido[2,3-d]pyrimidine 1340, 820; MS m/z 397, 399 (M+H) + . 23 4-amino-6-(4-methylphenyl)-7- 3-methyl-thiophen- 2-(4-methylphenyl)- IR 3300, 3060, (3-methylthiophen-2- 2-carboxaldehyde ethenyl-boronic acid 1600, 1550, 1450, yl)pyrido[2,3-d]pyrimidine 1335, 820; MS m/z 333 (M+H) + . 24 4-amino-6-(4-methylphenyl)-7- furan-2- 2-(4-methylphenyl)- IR 3430, 3300, (furan-2-yl)pyrido[2,3- carboxaldehyde ethenyl-boronic acid 3170, 1630, 1560, d]pyrimidine 1450, 1340; MS m/z 303 (M+H) + . 25 4-amino-6-(4-methylphenyl)-7- furan-3- 2-(4-methylphenyl)- IR 3360, 3140, (furan-3-yl)pyrido[2,3- carboxaldehyde ethenyl-boronic acid 1655, 1605, 1555, d]pyrimidine 1340, 1165; MS m/z 303 (M+H) + . -31 C IDrCTIT ITE LIl~T IDI II C lor WO 98/46603 PCT/US98/04127 26 4-amino-6-(4-methylphenyl)-7- 5-methylfuran-2- 2-(4-methylphenyl)- IR 3440, 3180, (5-methyl-furan-2- carboxaldehyde ethenyl-boronic acid 1630, 1600, 1555, yl)pyrido[2,3-d]pyrimidine 1335, 820; MS m/z 317 (M+H) + . 27 4-amino-6-(4-(2- thiophen-2- 2-(4-(2- IR 3460, 3320, propyl)phenyl)-7-(thiophen-2- carboxaldehyde propyl)phenyl)- 3160, 2960, 1600, yl)pyrido[l2,3-d]pyrimidine ethenyl-boronic acid 1555, 1425; MS m/z 347 (M+H) + . 28 4-amino-6-(4-(2- 5-nitro-thiophen-2- 2-(4-(2- IR 3380, 3160, propyl)phenyl)-7-(5- carboxaldehyde propyl)phenyl)- 2960, 1635, 1600, nitrothiophen-2-yl)pyrido[2,3- ethenyl-boronic acid 1555, 1330; MS d]pyrimidine m/z 392 (M+H) + . 29 4-amino-6-(4-methylphenyl)-7- 5-nitro-thiophen-2- 2-(4-methylphenyl)- IR 3330, 3160, (5-nitrothiophen-2- carboxaldehyde ethenyl-boronic acid 1630, 1600, 1555, yl)pyrido[2,3-d]pyrimidine 1350, 810; MS m/z 348 (M+H) + . 30 4-amino-6-(4- thiophen-2- 2-(4- IR 3440, 3160, (dimethylamino)phenyl)-7- carboxaldehyde (dimethylamino)phe 1610, 1555, 1525, (thiophen-2-yl)pyrido[2,3- nyl)-ethenyl-boronic 1340, 820: MS m/z d]pyrimidine acid 348 (M+H) + . 3 1 4-amino-6-(3,4- thiophen-2- 2-(3,4- IR 3420. 3080. dimethoxyphenyl)-7-(thiophen- carboxaldehyde dimethoxyphenyl)- 1600, 1560, 1515, 2-yl)pyrido[2,3-d]pyrimidine ethenyl-boronic acid 1425, 1340; MS m/z 365 (M+H) + . 32 4-amino-6-(3,4- 5-nitro-thiophen-2- 2-(3,4- IR 3420, 2840. dimethoxyphenyl)-7-(5- carboxaldehyde dimethoxyphenyl)- 1600, 1555, 1515, nitrothiophen-2-yl)pyrido[2.3- ethenyl-boronic acid 1335, 1255; MS d]pyrimidine m/z 410 (M+H) + . 33 4-amino-6-hexyl-7-(4- 4-(dimethylamino)- 1-octenyl-boronic IR 3320, 3100, (dimethylamino)phenyl)pyrido[ benzaldehyde acid 2920, 2850, 1600, 2,3-d]pyrimidine 1560, 1335; MS m/z 350 (M+H) + . 34 4-amino-6-hexyl-7-(thiophen-2- thiophen-2- 1-octenyl-boronic IR 3320, 3160, yl)pyrido[2,3-d]pyrimidine carboxaldehyde acid 2920, 2840, 1600, 1560, 1425; MS m/z 313 (M+H) + . 35 4-amino-6-(2-methyl-2-propyl)- thiophen-2- 3,3-dimethyl-1- IR 3400, 3320, 7-(thiophen-2-yl)pyrido[2.3- carboxaldehyde butenyl-boronic acid 3180, IR 2960, d]pyrimidine 1640, 1565, 1335; MS m/z 285
(M+H)
+ . 36 4-amino-6-(4-(2- 4-(dimethylamino)- 2-(4-(2- IR 3600-3250, propyl)phenyl)-7-(4- benzaldehyde propyl)phenyl)- 2955, 1590, 1555, (dimethylamino)phenyl)pyrido[ ethenyl-boronic acid 1400, 1340, 1195, 2,3-d]pyrimidine 815; MS m/z 384
(M+H)
+ . -32 C1l RCTITI IT CIuCT IDI II 1 WO 98/46603 PCT/US98/04127 37 4-amnino-6-(4-propylphenyl)-7- 4-(dimethylamino)- 2-(4-propylphenyl)- IR 3520-3250. (4- benzaldehyde ethenyl-boronic acid 2960, 1590, 1555, (dimethylamino)phenyl)pyrido[ 1400, 1340, 1195, 2,3-d]pyrimidine 815; MS m/z 384
(M+H)
+ . 38 4-amino-6-(3,4- 4-(dimethylamino)- 2-(3,4- IR 3320, 3240 dimethoxyphenyl)-7-(4- benzaldehyde dimethoxyphenyl)- 2760, 1590, 1560, (dimethylamino)phenyl)pyrido[ ethenyl-boronic acid 1510, 1515, 1340, 2,3-d]pyrimidine 820; MS m/z 384
(M+H)
+ . 39 4-amino-6-(3-methoxyphenyl)- 4-(dimethylamino)- 2-(3- IR 3365, 3320, 7-(4- benzaldehyde methoxyphenyl)- 3250-2780, 1660, (dimethylamino)phenyl)pyrido[ ethenyl-boronic acid 1590, 1560. 1460, 2,3-d]pyrimidine 1400, 1200, 820; MS m/z 402
(M+H)
+ . 40 4-amino-6-(3-bromophenyl)-7- 4-(dimethylamino)- 2-(3-bromophenyl)- IR 3400-3250. (4- benzaldehyde ethenyl-boronic acid 3250-2840. 1660. (dimethylamino)phenyl)pyrido[ 1590, 1560, 1340. 2,3-d]pyrimidine 1200, 820; MS m/z 420
(M+H)
+ . 4 1 4-amino-6-(3-fluorophenyl)-7- 4-(dimethylamino)- 2-(3-fluorophenyl)- IR 3520-2800, (4- benzaldehyde ethenyl-boronic acid 1645, 1610, 1590, (dimethylamino)phenyl)pyrido[ 1560, 1525, 1400. 2,3-d]pyrimidine 1340, 1200, 820; MS m/z 360
(M+H)
+ . 42 4-amino-6-(3- 4-(dirinethylamino)- 2-(3- IR 3560, 3520, trifluoromethylphenyl)-7-(4- benzaldehyde trifluoromethylphen 3240-2840, 1660, (dimethylamino)phenyl)pyrido[ yl)-ethenyl-boronic 1590, 1560. 1400, 2,3-d]pyrimidine acid 1340, 1160, 1120, 810, 700; MS m/z 410
(M+H)
+ . 43 4-amino-6-(3-chlorophenyl)-7- 4-(dimethylamino)- 2-(3-chlorophenyl)- IR 3500-3280. (4- benzaldehyde ethenyl-boronic acid 3200-2840, 1660, (dimethylamino)phenyl)pyrido[ 1590, 1560, 1395, 2,3-d]pyrimidine 1370, 1340, 1200, 820; MS m/z 376
(M+H)
+ . 44 4-amino-6-(3,5- 4-(dimethylamino)- 2-(3,5- IR 3560-3280, dichlorophenyl)-7-(4- benzaldehyde dichlorophenyl)- 3240-3300, 1640, (dimethylamino)phenyl)pyrido[ ethenyl-boronic acid 1590, 1560, 1400, 2,3-d]pyrimidine 1365, 1340, 1195, 820, 800; MS m/z 411
(M+H)
+ . -33 lIlRRTITIITI .lIT (RIILE 2RI WO 98/46603 PCT/US98/04127 45 4-amino-6-(3,4- 4-(dimethylamino)- 2-(3,4- IR 3600-3280, methylenedioxyphenyl)-7-(4- benzaldehyde methylenedioxyphen 3240-3000, 1595, (dimethylamino)phenyl)pyrido[ yl)-ethenyl-boronic 1560, 1400, 1195, 2,3-d]pyrimidine acid 1040,815; MS mi/: 386(M+H) + . 46 4-amino-6-(3,4- thiophen-2- 2-(3,4- IR 3430, 3300, methylenedioxyphenyl)-7- carboxaldehyde methylenedioxyphen 3170, 1630, 1595, (thiophen-2-yl)pyrido[2,3- yl)-ethenyl-boronic 1575, 1450, 1425, d]pyrimidine acid 1035, 820; MS m/z 349
(M+H)
+ . 47 4-amino-6-(3- 4-(dimethylamino)- 2-(3- IR 3360. 3320, methoxycarbonylphenyl)-7-(4- benzaldehyde methoxycarbonylph 3200-3000, 1720, (dimethylamino)phenyl)pyrido[ enyl)-ethenyl- 1660, 1595, 1560, 2.3-d]pyrimidine boronic acid 1400. 1340, 1200, 820; MS m1z 400 1 (M+H) + . 48 4-amino-6-(3-(2- 4-(dimethylamino)- 2-(3-(2- IR 3500-3280, propyl)phenyl)-7-(4- benzaldehyde propyl)phenyl)- 3200-3000. 2960, (dimethylamino)phenyl)pyrido[ ethenyl-boronic acid 1590. 1555, 1395, 2.3-d]pyrimidine 1340. 1195; MS m/: 384(M+H)
+
. 49 4-amino-6-(4-(2-methyl-2- 4-(dimethylamino)- 2-(4-(2-methyl-2- IR 3520-3280, propyl)phenyl)-7-(4- benzaldehyde propyl)phenyl)- 3180, 2960, 1590, (dimethylamino)phenyl)pyrido[ ethenyl-boronic acid 1555, 1340, 1195, 2,3-d]pyrimidine 820; MS nm/l: 398
(M+H)
+ . 50 4-amino-6-(4-fluorophenyl)-7- 4-(dimethylamino)- 2-(4-fluorophenyl)- IR 3490, 3320, (4- benzaldehyde ethenyl-boronic acid 3200-3000, 1590, (dimethylamino)phenyl)pyrido[ 1555, 1400, 1340, 2.3-d]pyrimidine 1195, 820; MS m/z 360
(M+H)
+ . 5 1 4-amino-6-(4-methoxyphenyl)- 4-(dimethylamino)- 2-(4- IR 3370. 3320, 7-(4- benzaldehyde minethoxyphenyl)- 3200-3000, 1660, (dimethylamino)phenyl)pyrido[ ethenyl-boronic acid 1590, 1555, 1400, 2,3-d]pyrimidine 1340, 1250, 1195, 815; MS m/z 372
(M+H)
+ . 52 4-amino-6-(3- 4-(dimethylamino)- 2-(3- IR 3360, 3320, (phenylmethoxy)phenyl)-7-(4- benzaldehyde (phenylmethoxy)phe 3200-3000, 1655, (dimethylamino)phenyl)pyrido[ nyl)-ethenyl-boronic 1590, 1560, 1400, 2,3-d]pyrimidine acid 1195, 820; MS m/z 448
(M+H)
+ . -34 QI IRQTITI IT= CUI=T (RIll 9R WO 98/46603 PCT/US98/04127 53 4-amino-6-(4-chlorophenyl)-7- 4-(dimethylamino)- 2-(4-chlorophenyl)- IR 3480-3320, (4- benzaldehyde ethenyl-boronic acid 3200-3020, 1590, (dimethylamino)phenyl)pyrido[ 1550, 1410, 1340. 2,3-d]pyrimidine 1195, 815; MS m/z 376
(M+H)
+ . 54 4-amino-6-(3-fluoro-4- 4-(dimethylamino)- 2-(3-fluoro-4- IR 3360, 3160 methylphenyl)-7-(4- benzaldehyde methylphenyl)- 3000, 1660, 1590, (dimethylamino)phenyl)pyrido[ ethenyl-boronic acid 1555, 1340, 1200, 2,3-d]pyrimidine 820; MS m/z 374
(M+H)
+ . 55 4-amino-6-(3-fluoro-4- thiophen-2- 2-(3-fluoro-4- IR 3600-3300, methylphenyl)-7-(thiophen-2- carboxaldehyde methylphenyl)- 3200, 3020. 1620, yl)pyrido[2,3-d]pyrimidine ethenyl-boronic acid 1415: MS m/z 337
(M+H)
+ . 5 6 4-amino-6-(3-phenylpropyl)-7- 4-methoxy- 5-phenyl-1- NMR (CDCI 3 ) 8 (4-methoxyphenyl)pyrido[2,3- benzaldehyde pentenyl-boronic 8.70 (s,1H), 8.06 d]pyrimidine acid (s .1H), 7.53 (d, J=9Hz, 2H), 7.22 (min. 3H), 7.06 (d, J=8Hz, 2H), 6.94 (d. J=9Hz, 2H), 6.19 (s, br, 2H), 3.88 (s, 3H), 2.88 (m, 2H), 2.57 (m, 2H), 1.88 (m, 2H); MS m/z 371
(M+H)
+ . 57 4-amino-6-(3-phenylpropyl)-7- 4-(dimethylamino)- 5-phenyl-1- NMR (CDC1 3 ) 8 (4- benzaldehyde pentenyl-boronic 8.73 (s, 1H), 7.88 (dimethylamino)phenyl)pyrido[ acid (s,1H), 7.58 (d, 2,3-d]pyrimidine J=8Hz, 2H), 7.22 (m, 3H). 7.10 (d, J=8Hz, 2H), 6.73 (d, J=9Hz. 2H), 5.78 (s, br, 2H), 3.04 (s, 6H), 2.96 (m, 2H), 2.61 (t, J=8Hz, 2H), 1.91 (m, 2H); MS m/z 384
(M+H)
+ . 58 4-amino-6-(2-phenylethyl)-7-(4- 4-(dimethylamino)- 4-phenyl-l1-butenyl- NMR (CDC1 3 ) 8 (dimethylamino)phenyl)pyrido[ benzaldehyde boronic acid 8.75 (s, 1H), 7.69 2,3-d]pyrimidine (s, 1H), 7.65 (m, 2H), 7.21 (m, 3H), 7.04 (m, 2H), 6.79 (m, 2H), 5.57 (s, br, 2H), 3.25 (m, 2H), 3.04 (s, 6H), 2.85 (m, 2H); MS m/z 370
(M+H)
+
. -35 QIIRTITIIT= C54=T (RII F 9RP WO 98/46603 PCT/US98/04127 59 4-amino-6-(phenvylmethyl)-7-(4- 4-(dimethylamino)- 3-phenyl-1- NMR (CDC13) 6 (dimethylamino)phenyl)pyrido[ benzaldehyde propenyl-boronic 8.74 (s, 1H). 7.74 2,3-d]pyrimidine acid (s, 1H), 7.65 (d, J=9Hz, 2H), 7.30 (m, 3H), 7.10 (m, 2H), 6.74 (d, J=9Hz, 2H), 5.64 (s, br, 2H), 4.29 (s, 2H), 3.02 (s, 6H); MS m/z 356
(M+H)
+ . 6 0 4-amino-6-(cyclohexylmethyl)- 4-(dimethylamino)- 3-cyclohexyl-1- NMR (CDCI 3 ) 6 7-(4- benzaldehyde propenyl-boronic 8.75 (s, 1H), 7.90 (dimethylamino)phenyl)pyrido[ acid (s, 1H), 7.59 (d, 2,3-d]pyrimidine J=9Hz, 2H), 6.76 (d, J=9Hz, 2H), 5.82 (s. br. 2H), 3.03 (s, 6H). 2.83 (d. J=7Hz, 2H), 1.70-1.40 (m, 6H), 1.07 (m. 3H-I), 0.83 (m, 2H); MS nm/z 362
(M+H)
+ . 6 1 4-amino-6-butyl-7-(4- 4-(dimethylanino)- 1-hexenyl-boronic NMR (CDCI 3 ) 6 (dimethylamino)phenyl)pyrido[ benzaldehyde acid 8.74 (s, 1H), 7.96 2,3-d]pyrimidine (s, 1H). 7.62 (d, J=9Hz, 2H). 6.77 (d, J=9Hz, 2H), 5.86 (s, 2H), 3.04 (s, 6H), 2.91 (m, 2H), 1.57 (m.2H), 1.32 (sextet, J=7Hz, 2H), 0.87 (t, J=7Hz, 3H); MS m/z 322
(M+H)
+ . 6 2 4-amino-6-pentyl-7-(4- 4-(dimethylamino)- 1-heptenyl-boronic NMR (DMSO-d 6 ) 5 (dimethylamino)phenyl)pyrido[ benzaldehyde acid 8.53 (s, 1H). 8.45 2,3-d]pyrimidine (s, 1H), 7.47 (d, J=8Hz, 2H), 6.82 (d, J=8Hz. 2H), 3.34 (s, 1H), 3.32 (s, IH), 2.99 (s, 6H), 2.81 (m, 2H), 1.58 (m, 2H), 1.23 (m, 4H), 0.82 (m, 3H); MS m/z 336
(M+H)
+ . -36 AlIRQTITIIT= U C T tll F RM WO 98/46603 PCT/US98/04127 63 4-amino-6-(2-methylpropyl)-7- 4-(dimethylamino)- 4-methyl-i- NMR (CDC1 3 ) 6 (4- benzaldehyde pentenyl-boronic 8.76 (s, 1H), 7.88 (dimethylamino)phenyl)pyrido[ acid (s, 1H), 7.61 (d, 2,3-d]pyrimidine J=9Hz, 2H), 6.77 (d, J=9Hz, 2H), 5.76 (s, br, 2H), 3.03 (s, 6H), 2.84 (d, J=7Hz, 2H), 1.78 (m, 1H), 0.78 (d, J=6Hz, 6H); MS m/z 322
(M+H)
+ . 64 4-amino-6-propyl-7-(4- 4-(dimethylamino)- 1-pentenyl-boronic NMR (DMSO-d 6 ) 8 (dimethylamino)phenyl)pyrido[ benzaldehyde acid 8.52 (s, 1H), 8.45 2,3-d]pyrimidine (s, 1H), 7.90 (s, br, 2H), 7.48 (d. J=8Hz, 2H), 6.82 (d, J=8Hz, 2H), 2.99 (s. 6H), 2.80 (m, 2H), 1.60 (sextet, J=7Hz, 2H), 0.85 (t, J=7Hz, 3H), MS m/z 308
(M+H)
+ . 65 4-amino-6-(3-cyanopropyl)-7- 4-(dimethylamino)- 5-cyano-1-pentenyl- NMR (DMSO-d 6 ) (4- benzaldehyde boronic acid 8.56 (s, 1H), 8.47 (dimethylamino)phenyl)pyrido[ (s, 1H), 7.94 (s, br, 2,3-d]pyrimidine 2H), 7.50 (d, J=9Hz, 2H). 6.83 (d, J=9Hz, 2H), 3.00 (s, 6H), 2.93 (m, 2H), 2.50 (m, 2H), 1.90 (m, 2H); MS m/z 333
(M+H)
+ . 6 6 4-amino-6-(3-nitrophenyl)-7-(4- 4-(dimethylamino)- 2-(3- IR (dimethylamino)phenyl)pyrido[ benzaldehyde nitrophenyl)ethenyl 3360,3100,1590,15 2,3-d]pyrimidine boronic acid 60 MS m/z 387
(M+H)
+ . 6 7 4-amino-6-pentyl-7-(thiophen- thiophen-2- 1-heptenyl-boronic ac idR 2-yl)pyrido[2,3-d]pyrimidine carboxaldehyde 3320,3100,1560,14 30 MS m/z 299
(M+H)
+ . 68 4-amino-6-(3- 4-(dimethylamino)- 5-cyano-1-pentenyl- IR carboxamidopropyl)-7-(4- benzaldehyde boronic acid 3325,3120,1660,15 (dimethylamino)phenyl)pyrido[ 95 2,3-d]pyrimidine MS m/z 351
(M+H)
+. 69 4-amino-6-((4- thiophen-2- 2-(4- IR methoxyphenyl)methyl)-7- carboxaldehyde methoxyphenyl)- 3360,3100,1605,15 (thiophen-2-yl)pyrido[2,3- propenyl boronic 65 d]pyrimidine acid MS m/z 349
(M+H)
+. -37 QIIRQTITI ITII= ClCT (RI ll F: 9R~ WO 98/46603 PCT/US98/04127 70 4-amino-6-((3- thiophen-2- 2-(3-bromophenyl)- IR bromophenyl)methyl)-7- carboxaldehyde propenyl boronic 3440,3120,1605,15 (thiophen-2-yl)pyrido[2,3- acid 65 d]pyrimidine MS ml: 397/399
(M+H)
+ . 7 1 4-amino-6-((4-(2- thiophen-2- 2-(4-(2- IR propyl)phenyl)methyl)-7- carboxaldehyde propyl)phenyl)- 3440.3080,1600,15 (thiophen-2-yl)pyrido[2,3- propenyl boronic 60 d]pyrimidine acid MS m/z 361 (M+H)+. 72 4-amino-6-((4- 4-isopropyl- 2-(4- IR methoxyphenyl)methyl)-7-(4- benzaldehyde methoxyphenyl)- 3360,3120,1565,15 (2-propyl)phenyl)pyrido[2,3- propenyl boronic 10 d]pyrimidine acid MS m/z 385
(M+H)
+ . 73 4-amino-6-((4- thiophen-2- 2-(4-bromophenyl)- IR bromophenyl)methyl)-7- carboxaldehyde propenyl boronic 3440.3160.1625,15 (thiophen-2-yl)pyrido[2,3- acid 60 d]pyrimidine MS mi: 397/399
(M+H)
+ . 74 4-amino-6-((3- thiophen-2- 2-(3-fluorophenyl)- IR fluorophenyl)methyl)-7- carboxaldehyde propenyl boronic 3320.3160,1600,15 (thiophen-2-yl)pyrido[2.3- acid 60 d]pyrimidine MS ml: 337
(M+H)
+ . 75 4-amino-6-((4- thiazole-2- 2-(4-bromophenyl)- IR bromophenyl)methyl)-7- carboxaldehyde propenyl boronic 3450.3100,1635,15 (thiazole-2-yl)pyrido[2,3- acid 60 d]pyrimidine MS nm/l: 398/400
(M+H)
+ . 7 6 4-amino-6-((3- thiophen-2- 2-(3- IR methoxyphenyl)methyl)-7- carboxaldehyde methoxyphenyl)- 3450.3150,1600,15 (thiophen-2-yl)pyrido[2,3- propenyl boronic 60 d]pyrimidine acid MS m/z 349
(M+H)
+ . 7 7 4-amino-6-(phenylmethyl)-7- thiophen-2- 2-phenyl-1-propenyl IR (thiophen-2-yl)pyrido[2,3- carboxaldehyde boronic acid 3390,3110.1605,15 d]pyrimidine 65 MS nim/l: 319
(M+H)
+ . 78 4-amino-6-((3- 4-(dimethylamino)- 2-(3- IR methoxyphenyl)methyl)-7-(4- benzaldehyde methoxyphenyl)- 3310,3080,1600,15 (dimethylamino)phenyl)pyrido[ propenyl boronic 65 2,3-d]pyrimidine acid MS m/z 386
(M+H)
+ . 79 4-amino-6-(4-methylphenyl)-7- 4-(trifluoromethyl)- 2-(4-methylphenyl)- IR (4- benzaldehyde ethenyl boronic acid 3230,1325,820;M (trifluoromethyl)phenyl)pyrido[ S m/z 381 2,3-d]pyrimidine (M+H)+. 80 4-amino-6-(4-methylphenyl)-7- 4-methyl- 2-(4-methylphenyl)- IR (4-methylphenyl)pyrido[2,3- benzaldehyde ethenyl boronic acid 3450,1449,1340,8 d]pyrimidine 20;MS m/z 327
(M+H)
+ . -38 Ql IRQTITI IT= QIEWT aIllI F 9A1 WO 98/46603 PCT/US98/04127 8 1 4-amino-6-(4-methylphenyl)-7- 4-methoxy- 2-(4-methylphenyl)- IR (4-methoxyphenyl)pyrido[2,3- benzaldehyde ethenyl boronic acid 3375,1600.820;M d]pyrimidine S m/z 343
(M+H)
+
. 82 4-amino-6-(4-methylphenyl)-7- 4-ethyl-benzaldehyde 2-(4-methylphenyl)- IR (4-ethylphenyl)pyrido[l2,3- ethenyl boronic acid 3340,1558,1340,8 d]pyrimidine 20;MS m/z 341
(M+H)
+ . 83 4-amino-6-(4-methylphenyl)-7- 4-cyano- 2-(4-methylphenyl)- IR (4-cyanophenyl)pyrido[2,3- benzaldehyde ethenyl boronic acid 3320,1560,820;M d]pyrimidine S m/z 338
(M+H)
+ . 84 4-amino-6-(4-methylphenyl)-7- 4-acetamido- 2-(4-methylphenyl)- IR (4-acetamidophenyl)pyrido[2,3- benzaldehyde ethenyl boronic acid 3325,1520.820;M d]pyrimidine S m/z 370
(M+H)
+ . 8 5 4-amino-6-(4-methylphenyl)-7- 4-phenoxy- 2-(4-methylphenyl)- IR (4-phenoxyphenyl)pyrido[2.3- benzaldehyde ethenyl boronic acid 3340,1550.1240,7 d]pyrimidine 50;MS m/z 405
(M+H)
+ . 8 6 4-amino-6-(4-methylphenyl)-7- 4-nitro-benzaldehyde 2-(4-methylphenyl)- IR (4-nitrophenyl)pyrido[2,3- ethenyl boronic acid 3390,1340,850;M d]pyrimidine S m/z 358
(M+H)
+
. 8 7 4-amino-6-(4-methylphenyl)-7- 4-fluoro- 2-(4-methylphenyl)- IR (4-fluorophenyl)pyrido[2,3- benzaldehyde ethenyl boronic acid 3320,1550,1340,8 d]pyrimidine 40;MS m/z 331
(M+H)
+ . 8 8 4-amino-6-(4-methylphenyl)-7- 4-chloro- 2-(4-methylphenyl)- IR (4-chlorophenyl)pyrido[2,3- benzaldehyde ethenyl boronic acid 3340,1550,1340.9 d]pyrimidine 10;MS m/z 347
(M+H)
+ . 89 4-amino-6-(4-methylphenyl)-7- 4-amino- 2-(4-methylphenyl)- IR (4-aminophenyl)pyrido[2,3- benzaldehyde ethenyl boronic acid 3325,1550,820;M d]pyrimidine S m/z 328
(M+H)
+ . 9 0 4-amino-6-(4-methylphenyl)-7- 4-methylthio- 2-(4-methylphenyl)- IR (4- benzaldehyde ethenyl boronic acid 3310,1560.1340,8 methylthiophenyl)pyrido[2,3- 19;MS m/z 359 d]pyrimidine (M+H)+. 9 1 4-amino-6-(4-methylphenyl)-7- 4-phenyl- 2-(4-methylphenyl)- IR ((4-phenyl)phenyl)pyrido[2,3- benzaldehyde ethenyl boronic acid 3345,1560,820;M d]pyrimidine S m/z 389
(M+H)
+ . 9 2 4-amino-6-(4-methylphenyl)-7- 4-phenylmethoxy- 2-(4-methylphenyl)- IR ((4- benzaldehyde ethenyl boronic acid 3400.1340,1245,7 phenylmethoxy)phenyl)pyrido[ 00;MS m/z 419 2,3-d]pyrimidine (M+H)+. 93 4-amino-6-(4-methylphenyl)-7- 4-(NN- 2-(4-methylphenyl)- IR ((4-N,N- diethylamino)- ethenyl boronic acid 3330,1550,1200,8 diethylamino)phenyl)pyrido[2,3 benzaldehyde 19;MS m/z 384 -d]pyrimidine (M+H)+. -39 I IRcTITrrl IT~ CLICCIT II II = 97M WO 98/46603 PCT/US98/04127 94 4-amino-6-(4-methylphenyl)-7- 4-(2-phenylethenyl)- 2-(4-methylphenyl)- IR ((4-2- benzaldehyde ethenyl boronic acid 3460,1600,1340,6 phenylethenyl)phenyl)pyrido[2, 90:MS m/z 415 3-d]pyrimidine (M+H)+. 95 4-amino-6-(4-methylphenyl)-7- 4-(2-methyl-2- 2-(4-methylphenyl)- IR (4-(2-methyl-2- propoxy)- ethenyl boronic acid 3315,1550,1160,9 propoxy)phenyl)pyrido[2,3- benzaldehyde 00;MS m/z 385 d]pyrimidine (M+H)+. 96 4-amino-6-(4-methylphenyl)-7- 3-chloro- 2-(4-methylphenyl)- IR (3-chlorophenyl)pyrido[2,3- benzaldehyde ethenyl boronic acid 3050,1555,1340, d]pyrimidine 825;MS m/z 347
(M+H)
+ . 97 4-amino-6-(4-methylphenyl)-7- 3,5-dimethoxy- 2-(4-methylphenyl)- IR 3430, 1600. (3,5- benzaldehyde ethenyl boronic acid 1200, 720;MS m/z dimethoxyphenyl)pyrido[2,3- 373 (M+H)
+
. d]pyrimidine 98 4-amino-6-(thiophen-2-yl)-7-(4- 4-(NN- 2-(thiophen-2-yl)- IR 3320,1590, N,N- dimethylamino)- ethenyl boronic acid 700;MS m/z 348 dimethylphenyl)pyrido[2,3- benzaldehyde (M+H)+. d]pyrimidine 9 9 4-amino-6-(4-methylphenyl)-7- benzofuran-2- 2-(4-methylphenyl)- IR 3310, 1640. (benzofuran-2-yl)pyrido[2,3- carboxaldehyde ethenyl boronic acid 750;MS m/z 353 d]pyrimidine (M+H)+. 100 4-amino-6-(thiophen-2-yl)-7- thiophen-2- 2-(thiophen-2-yl)- IR 3315, 1560, (thiophen-2-yl)pyrido[2,3- carboxaldehyde ethenyl boronic acid 1420, 700;MS mn/z d]pyrimidine 311 (M+H) + . 101 4-amino-6-(thiophen-2-yl)-7-(4- 4-methoxy- 2-(thiophen-2-yl)- IR 3400, 1560, methoxyphenyl)pyrido[2,3- benzaldehyde ethenyl boronic acid 1250, 835;MS m/z d]pyrimidine 335 (M+H) + . 102 4-amino-6-(4-bromophenyl)-7- 4-(NN- 2-(4-bromophenyl)- IR 3330, 1545, (4-N,N- dimethylamino)- ethenyl boronic acid 1190, 810;MS m/z dimethylphenyl)pyrido[2,3- benzaldehyde 420 (M+H) + . d]pyrimidine 103 4-amino-6-(3-bromo-4- 4-(NN- 2-(3-bromo-4- IR 3380. 1590. methoxyphenyl)-7-(4-NN- dimethylamino)- methoxy-phenyl)- 1200, 820;MS m/z dimethylphenyl)-pyrido[2.3- benzaldehyde ethenyl boronic acid 451. (M+H) + . d]pyrimidine 104 4-amino-6-(3-bromo-4- thiophen-2- 2-(3-bromo-4- IR 3400. 1550. methoxy-phenyl)-7-((thiophen- carboxaldehyde 3- methoxy-phenyl)- 1280, 715;MS m/z 2-yl)pyrido[2,3-d]pyrimidine ethenyl boronic acid 414 (M+H) + . 105 4-amino-6-(4-methylphenyl)-7- 4- 2-(4-methylphenyl)- na (4-butoxyphenyl)pyrido[2,3- butoxybenzaldehyde ethenyl boronic acid d]pyrimidine 106 4-amino-6-(4-methylphenyl)-7- 3- 2-(4-methylphenyl)- na (3-methoxyphenyl)pyrido[2,3- methoxybenzaldehyd ethenyl boronic acid d]pyrimidine e 107 4-amino-6-(4-methylphenyl)-7- 3,5-dichloro- 2-(4-methylphenyl)- na (3,5-dichlorophenyl)pyrido[2,3- benzaldehyde ethenyl boronic acid Sd]pyrimidine -40 I IRITrII IT= Q=F"T (RI I = 9OM

Claims (17)

1. A compound, and pharmaceutically acceptable salts and amides thereof, having the formula RI N- R2 H IK R3 3 NH 2 4 52 N N 7 R 4 5 (1) wherein R 1 and R 2 are independently H, loweralkyl, arylalkyl or acyl, or may be 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; 10 R 3 and R 4 are independently selected from loweralkyl, loweralkenyl, loweralkynyl, aryl, arylalkyl, heteroaryl, or a heterocyclic group and the dashed lines indicate a double bond is optionally present.
2. A compound according to Claim 1 wherein R 3 is selected from loweralkyl, loweralkenyl, loweralkynyl, aryl, arylalkyl, heteroaryl, or a heterocyclic group; and R 4 is selected from aryl, arylalkyl, heteroaryl, or a heterocyclic group. 5
3. A compound according to Claim 1 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 which they are attached to from a 5-7 membered ring optionally containing 1-2 additional 5 heteroatoms selected from O, N or S; R 3 and R 4 are independently selected from the group consisting of: C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, 10 C3-C8cycloalkyl, heteroarylCo-C6alkyl or substituted heteroarylCo-C6alkyl, arylCO-C6alkyl or substituted arylCo-C6alkyl, heteroarylC2-C6alkenyl or substituted heteroarylC2-C6alkenyl, arylC2-C6alkenyl or substituted arylC2-C6alkenyl, 15 heteroarylC2-C6alkynyl or substituted heteroarylC2-C6alkynyl, -41- WO 98/46603 PCT/US98/04127 arylC2-C6alkynyl or substituted arylC2-C6alkynyl wherein the 1-4 heteroaryl or aryl substituents are independently selected from halogen, cyanoCl1-C6alkyl, heteroaryl, heterocyclic, C1-C6alkyloxy, Cl C6alkyloxyC I -C6alkyl, arylC 1-C6alkyl, H2NC I -C6alkyl, arylC 1 20 C6alkyloxy, H2NC(O), cyano, C2-C6alkenyl, C2-C6alkynyl, C1-C6alkyl, C2-C6alkenyldialkylmalonyl, CF3, HO-, Cl -C6alkyloxyCl-C6alkyloxy, SOnC1-C6alkyl wherein n is 1-3, Cl1-C6alkylthio, C1-C6alkylacryl, CF30, CF3, Cl-C4alkylenedioxy, C1-C6alkylacryl, H2N(CO)NH, N formyl(heterocyclic), NO2, NR 5 R 6 CO-C6alkyl, 25 wherein R 5 and R 6 are independently selected from H, Cl1-C6alkyl, HC(O), C1-C6alkyloxyC 1-C6alkyl, C1-C6alkyloxy, C l C6alkylC(O), CF3C(O), NR 7 R 8 C 1-C6alkyl, phthalimidoC 1 C6C(O), CNC1-C6alkyl, H3NC(O)NH-, heteroaryl, NR 7 R 8 C1 C6alkylC(O), C 1-C6alkyloxycarbamidoC1-C6alkyl, 30 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 selected from O, N or S wherein the substituents are selected from 35 Cl1-C6alkyl.
4. A compound according to Claim 1 wherein R 3 and R 4 are independently selected from phenyl; thiophen-2-yl; 1-methyl-2 oxobenzoxazolin-5-yl; 2-(dimethylamino)-5-pyrimidinyl; 2-(N-formyl-N-methyl amino)-3 pyrimidinyl; 2-(N-(2-methoxyethyl)-N-methyl amino)-5-pyrimidinyl; 2-(N-methylamino)5 5 pyrimidinyl; 2-(1-morpholinyl)-5-pyrimidinyl; 2-(1-pyrrolidinyl)-5-pyrimidinyl; 2 dimethylamino-5-pyrimidinyl; 2-furanyl; 2-oxobenzoxazolin-5-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 10 (N-methylamino)phenyl; 3-methyl-4-pyrrolidinylphenyl; 3-pyridyl; 3,4-dichlorophenyl; 3,4-methylenedioxyphenyl; 3,4,5-trimethoxyphenyl; 4-(acetylamino)phenyl; 4 (dimethylamino)-3-fluorophenyl; 4-(dimethylamino)phenyl; 4-(imidazol-1-yl)phenyl; 4 (methylthio)phenyl; 4-(morpholinyl)phenyl; 4-(N-(2-(dimethylamino)ethyl)amino)phenyl; 4-(N-(2-methoxyethyl)amino)phenyl; 4-(N-acetyl-N-methylamino)phenyl; 4-(N-ethyl-N 15 formylamino)phenyl; 4-(N-ethylamino)phenyl; 4-(N-formyl-N-(2 methoxyethyl)amino)phenyl; 4-(N-isopropylamino)phenyl; 4-(N-methyl-N-((2 -42- WO 98/46603 PCT/US98/04127 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-(thiophen-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-1-oxazolidinyl)phenyl; 4-(4-methoxy-2-butyl)phenyl; 25 4-(4-methylpiperidinyl)phenyl; 4-(5-pyrimidinyl)phenyl; 4-aminophenyl; 4-bromophenyl; 4-butoxyphenyl; 4-carboxamidophenyl; 4-chlorophenyl; 4-cyanophenyl; 4 diethylaminophenyl; 4-diethylmalonylallylphenyl); 4-dimethylaminophenyl; 4 ethoxyphenyl; 4-ethylphenyl; 4-fluorophenyl; 4-hydroxyphenyl; 4-imidazolylphenyl; 4 iodophenyl; 4-isopropylphenyl; 4-methoxyphenyl) 4-methylaminophenyl; 4 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-formylpiperidinylphenyl; 4-nitrophenyl; 4 piperidinylphenyl; 4-pyridylphenyl; 4-pyrrolidinylphenyl; 4-t-butylacrylphenyl; 5 (dimethylamino)thiophen-2-yl; 5-amino-2-pyridyl; 5-dimethylamino-2-pyrazinyl; 3 35 dimethylaminopyridazin-6-yl; 5-dimethylamino-2-pyridyl; 5-pyrimidinylphenyl; 6-(N methyl-N-formylamino)-3-pyridinyl; 6-(N-methyl-N-(2-methoxyethyl)amino)-3-pyridinyl;
6-(2-oxo-oxazolidinyl)-3-pyridinyl; 6-dimethylamino-3-pyridinyl; 6-imidazolyl-3-pyridinyl; 6-morpholinyl-3-pyridinyl; 6-pyrrolidinyl-3-pyridinyl; (2-propyl)-3-pyridinyl; and (4 formylamino)phenyl; (thiophen-2-yl)methyl; (thiophen-3-yl)methyl; butyl; cycloheptyl; 40 pentyl; thiophen-2-yl; 1-(3-bromophenyl)ethyl; 2-(N-phenylmethoxycarbonyl)aminophenyl; 2-(3-bromophenyl)ethyl; 2-(3-cyanophenyl)methyl; 2-(4-bromophenyl)ethyl; 2-(5-chloro-2 (thiophen-3-yl)phenyl; 2-bromophenyl; 2-furanyl; 2-methylpropyl; 2-phenylethyl; phenylmethyl; 2,3-dimethoxyphenyl; 2,3-methylenedioxyphenyl; 3-(furan-2-yl)phenyl; 3 (thiophen-2-yl)phenyl; 3-(2-pyridyl)phenyl; 3-(3-methoxybenzyl)phenyl; 3 45 (amino)propynyl; 3-benzyloxyphenyl; 3-bromo-4-fluorophenyl; 3-bromo-5-iodophenyl; 3 bromo-5-methoxyphenyl; 3-bromophenyl; 3-bromophenylmethyl; 3-carboxamidophenyl; 3 chlorophenyl; 3-cyanophenyl; 3-diethylmalonylallylphenyl; 3-dimethylaminophenyl; 3 ethoxyphenyl; 3-fluoro-5-trifluoromethylphenyl; 3-fluorophenyl; 3-hydroxyphenyl; 3 iodophenyl; 3-methoxyethyoxyphenyl; 3-methoxyphenyl; 3-methylphenyl; 3 50 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 -43- WO 98/46603 PCT/US98/04127 propyl)phenyl; 4-(2-propyl)oxyphenyl; 4-benzyloxyphenyl; 4-bromophenyl; 4 55 bromothiophen-2-yl; 4-butoxyphenyl; 4-dimethylaminophenyl; 4-fluoro-3 trifluoromethylphenyl; 4-methoxyphenyl; 4-neopentylphenyl; 4-phenoxyphenyl; 5 bromothiophen-2-yl; 5-cyclohexyl; 5-cyclopropyl; 5-hexyl; 5-methyl; 5-phenyl; (2-bromo 5-chlorophenyl)methyl; (2-bromophenyl)methyl; and (5-chioro-2-(3 methoxyphenyl)phenyl)methyl. 60 5. A compound according to Claim 1 of the formula: RK ", R 2 H 4 R 3 3N 6 2N N R 4 wherein 5 R 1 and R 2 are independently H, loweralkyl, arylalkyl or acyl, or may be 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; R 3 and R 4 are independently selected from loweralkyl, loweralkenyl, loweralkynyl, aryl, arylalkyl, heteroaryl, or a heterocyclic group. 10 6. A compound according to Claim 5 wherein R 3 is selected from loweralkyl, loweralkenyl, loweralkynyl, aryl, arylalkyl, heteroaryl, or a heterocyclic group; and R 4 is selected from aryl, arylalkyl, heteroaryl, or a heterocyclic group. 5
7. A compound according to Claim 5 wherein R 1 and R 2 are independently selected from H, loweralkyl, arylC1-C6alkyl, -C(O)Cl-C6alkyl, -C(O)aryl, -C(O)heterocyclic or may join together with the nitrogen to which they are attached to from a 5-7 membered ring optionally containing 1-2 additional 5 heteroatoms selected from O, N or S; R 3 and R 4 are independently selected from the group consisting of: Cl -C6alkyl, C2-C6alkenyl, C2-C6alkynyl, 10 C3-C8cycloalkyl, heteroarylCO-C6alkyl or substituted heteroarylCO-C6alkyl, -44- WO 98/46603 PCT/US98/04127 arylCO-C6alkyl or substituted arylCO-C6alkyl, heteroarylC2-C6alkenyl or substituted heteroarylC2-C6alkenyl, arylC2-C6alkenyl or substituted arylC2-C6alkenyl, 15 heteroarylC2-C6alkynyl or substituted heteroarylC2-C6alkynyl, arylC2-C6alkcynyl or substituted arylC2-C6alkynyl wherein the 1-4 heteroaryl or aryl substituents are independently selected from halogen, oxo, cyanoCl-C6alkyl, heteroarylCO-C6alkyl, heterocyclicCo C6alkyl, Cl-C6alkyloxy, Cl-C6alkyloxyCl1-C6alkyl, arylCO-C6alkyl, 20 arylCl1-C6alkyloxy, R 5 R 6 NC(O), cyano, C2-C6alkenyl, C2-C6alkynyl, Ci1-C6alky l , C2-C6alkenyldialkylmalonyl, CF3, HO-, C1-C6alkyloxyC l C6alkyloxy, C1-C6alkylSOn wherein n is 1-2, C1-C6alkylthio, Cl C6alkylacryl, CF30, CF3, C1-C4alkylenedioxy, C1-C6alkylacryl, R 5 R 6 N(CO)NR 5 , N-formyl(heterocyclic), NO2, NR 5 R 6 CO-C6alkyl, 25 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 C 1-C6alkyl, phthalimidoC1 C6C(O), C1-C6alkylSOn where n is 1-2, CNCl-C6alkyl, R 7 R 8 NC(O)NR 7 -, heteroaryl, NR 7 R 8 Cl -C6alkylC(O), Cl 30 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 substituted ring optionally containing 1-3 35 additional heteroatoms selected from O, N or S wherein the substituents are selected from Cl -C6alkyl.
8. A compound according to Claim 5 wherein R 3 and R 4 are independently selected from phenyl; thiophen-2-yl; 1-methyl-2 oxobenzoxazolin-5-yl; 2-(dimethylamino)-5-pyrimidinyl; 2-(N-formyl-N-methyl amino)-3 pyrimidinyl; 2-(N-(2-methoxyethyl)-N-methyl amino)-5-pyrimidinyl; 2-(N-methylamino)5 5 pyrimidinyl; 2-( 1-morpholinyl)-5-pyrimidinyl; 2-(1-pyrrolidinyl)-5-pyrimidinyl; 2 dimethylamino-5-pyrimidinyl; 2-furanyl; 2-oxobenzoxazolin-5-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 10 (N-methylamino)phenyl; 3-methyl-4-pyrrolidinylphenyl; 3-pyridyl; 3,4-dichlorophenyl; 3,4-methylenedioxyphenyl; 3,4,5-trimethoxyphenyl; 4-(acetylamino)phenyl; 4 -45- WO 98/46603 PCTIUS98/04127 (dimethylaniino)-3-fluorophenyl; 4-(dimethylamnino)phenyl; 4-(imnidazol- 1-yl)phenyl; 4 (methylthio)phenyl; 4-(morpholinyl)phenyl; 4-(N-(2-(dimethylarnino)ethyl)amino)phenyl; 4-(N-(2-methoxyethyl)amino)phenyl; 4-(N-acetyl-N-methylamino)phenyl; 4-(N-ethyl-N 15 formylamidno)phenyl; 4-(N-ethylamino)phenyl; 4-(N-formvl-N-(2 methoxyethyl)arnino)phenyl; 4-(N-isopropylamnino)phenyl; 4-(N-methyl-N-((2 dimethylamino)ethyl)amino)phenyl; 4-(N-methyl-N-(2-(N phthalim-idyl)acetyl)amino)phenyl; 4-(N-methyl-N-(2-cyano)ethylamidno)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 formnylamino)phenyl; 4-(N-methyl-N-trifluoroacetylamino)phenyl; 4-(N morpholinyl)phenyl; 4-(thiophen-2-yl)phenyl; 4-(ureido)phenyl; 4-(2 (dirnethylamidno)acetylamidno)phenyl; 4 -( 2 -( 2 -methoxy)acetylam-ino)ethyl)arnino)phenyl; 4 (2-methoxy)ethoxyphenyl; 4-(2-oxo- 1 -oxazolidinyl)phenyl; 4-(4-methoxy-2-butyl)phenyl; 25 4-(4-methylpiperidinyl)phenyl; 4-(5-pyrimiddinyl)phenyl; 4-amninophenyl; 4-bromophenyl; 4-butoxyphenyl; 4-carboxamiddophenyl; 4-chiorophenyl; 4-cyanophenyl; 4 diethylam-inophenyl; 4-diethylmalonylallphenyl); 4-dimethylarninophenyl; 4 ethoxyphenyl; 4-ethyiphenyl; 4-fluorophenyl; 4-hydroxyphenyl; 4-im-idazolyiphenyl; 4 iodophenyl; 4-isopropyiphenyl; 4-methoxyphenyl) 4-methylaminophenyl; 4 30 methylsulfonyiphenyl; 4-morpholinyiphenyl; 4-N-(2-(dimethylamino)ethyl)-N formylamidno)phenyl; 4 -N-(3-methoxypropionyl)-N-isopropyl-amidno)phenyl; 4-N-ethyl-N (2-methoxyethyl)amidno)phenyl; 4-N-formylpiperidinylphenyl; 4-nitrophenyl; 4 piperidinyiphenyl; 4-pyridyiphenyl; 4-pyrrolidinyiphenyl; 4-t-butylacrylphenyl; 5 (dimethylam-ino)thiophen-2-yl; 5-ami no-2-pyridyl; 5-dimethylarnino-2-pyrazinyl; 3 35 dimethylaminopyridazin-6-yl; 5-dimethylamino-2-pyridyl; 5-pyrimiddinyiphenyl; 6-(N methyl-N-formylam-ino)-3-pyridinyl; 6-(N-methyl-N-(2--nethoxyethyl)amidno)-3-pyridinyl; 6-(2-oxo-oxazolidinyl)-3-pyridinyl; 6-dimethylamino-3-pyridinyl; 6-im-idazolyl-3-pyridinyl; 6-morpholinyl-3-pyridinyl; 6-pyrrolidinyl-3-pyridinyl; (2-propyl)-3-pyridinyl; and (4 formylamino)phenyl; (thiophen-2-yl)methyl; (thiophen-3-yl)methyl; butyl; cycloheptyl; 40 pentyl; thiophen-2-yl; 1 -(3-bromophenyl)ethyl; 2-(N-phenylmethox ycarbonyl)aminophenyl; 2-(3-bromophenyl)ethyl; 2-(3-cyanophenyl)methyl; 2-(4-bromophenyl)ethyl; 2-(5-chloro-2 (thiophen-3-yI)phenyl; 2-bromophenyl; 2-furanyl; 2-methyipropyl; 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; 3 45 (amino)propynyl; 3-benzyloxyphenyl; 3-bromo-4-fluorophenyl; 3-bromo-5-iodophenyl; 3 bromo-5-methoxyphenyl; 3-bromophenyl; 3-bromophenylmethyl; 3-carboxamaidophenvi: 3 chiorophenyl; 3-cyanophenyl; 3-diethylmalonylallyiphenyl; 3-dimethylaminophenyl; 3 ethoxyphenyl; 3-fluoro-5-trifluoromethylphenyl; 3-fluorophenyl; 3-hydroxyphenyl; 3 -46- WO 98/46603 PCT/US98/04127 iodophenyl; 3-methoxyethyoxyphenyl; 3-methoxyphenyl; 3-methylphenyl; 3 50 methylsulfonylphenyl; 3-methylthiophenyl; 3-t-butylacrylphenyl; 3-trifloromethyoxyphenyl; 3-trifluoromethylphenyl; 3-vinylpyridinylphenyl; 3,4-dichlorophenyl; 3,4-dimethoxyphenyl; 3,4-methylenedioxyphenyl; 3,4,5-trimethoxyphenyl; 3,5-di(trifluoromethyl)phenyl; 3,5 dibromophenyl; 3,5-dichlorophenyl; 3,5-dimethoxyphenyl; 3,5-dimethylphenyl; 4-(2 propyl)phenyl; 4-(2-propyl)oxyphenyl; 4-benzyloxyphenyl; 4-bromophenyl; 4 55 bromothiophen-2-yl; 4-butoxyphenyl; 4-dimethylaminophenyl; 4-fluoro-3 trifluoromethylphenyl; 4-methoxyphenyl; 4-neopentylphenyl; 4-phenoxyphenyl; 5 bromothiophen-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. 60
9. A compound according to Claim 5 wherein R 3 and R 4 are independently selected from: phenyl; 4-dimethylaminophenyl; 4-methylphenyl; 4-bromophenyl; 4 pyridinyl; (5-pyrimidinyl)phenyl; 2-(2-pyridinyl)ethenyl)phenyl; 3-pyridinyl; thiophen-3-yl; 2-pyridinyl; 3,4-methylenedioxyphenyl; butyl; 5-bromothiophen-2-yl; 5-methylthiophen-2 5 yl; 4-(trifluoromethoxy)phenyl; 3-phenoxyphenyl; 5-nitrothiophen-2-yl; 4-bromothiophen 2 -yl; 3-methylthiophen-2-yl; furan-2-yl; furan-3-yl; 5-methyl-furan-2-yl; 4-(2 propyl)phenyl; 3,4-dimethoxyphenyl; hexyl; 2-methyl-2-propyl; 4-(2-propyl)phenyl; 4 propylphenyl; 3-methoxyphenyl; 3-bromophenyl; 3-fluorophenyl; 3-trifluoromethylphenyl; 3-chlorophenyl; 3,5-dichlorophenyl; 3-methoxycarbonylphenyl; 3-(2-propyl)phenyl; 4-(2 10 methyl-2-propyl)phenyl; 4-fluorophenyl; 4-methoxyphenyl; 3-(phenylmethoxy)phenyl; 4 chlorophenyl; 3-fluoro-4-methylphenyl; 3-phenylpropyl; 4-methoxyphenyl; 3-phenylpropyl; 2-phenylethyl; phenylmethyl; cyclohexylmethyl; pentyl; 2-methylpropyl; propyl; 3 cyanopropyl; 3-nitrophenyl; 3-carboxamidopropyl; (4-methoxyphenyl)methyl; (3 bromophenyl)methyl; (4-(2-propyl)phenyl)methyl); (4-methoxyphenyl)methyl); (4 15 bromophenyl)methyl); (3-fluorophenyl)methyl; (4-bromophenyl)methyl; thiazole-2-yl; (3 methoxyphenyl)methyl; phenylmethyl; (3-methoxyphenyl)methyl; 4-methylphenyl; 4 (trifluoromethyl)phenyl; 4-ethylphenyl; 4-acetamidophenyl; 4-phenoxyphenyl; 4 nitrophenyl; 4-fluorophenyl; 4-chlorophenyl; 4-aminophenyl; 4-methylthiophenyl; (4 phenyl)phenyl; (4-phenylmethoxy)phenyl; (4-N,N-diethylamnino)phenyl; (4-2 20 phenylethenyl)phenyl; (2-methyl-2-propoxy)phenyl; 3-chlorophenyl; 3,5-dimethoxyphenyl; 4-N,N-dimethylphenyl; benzofuran-2-yl; 3-bromo-4-methoxyphenyl; 4-butoxyphenyl; 3 methoxyphenyl and 3,5-dichlorophenyl.
10. A compound according to Claim 5 which is: 4-amino-6-phenyl-7-(4-dimethylaminophenyl)pyrido[2,3-d]pyrimidine; -47- WO 98/46603 PCTIUS98/04127 4-amino-6-(4-methylphenyl)-7-(4-(dimethylamino)phenyl)pyrido72,3-d]pyrimidine; 4-anmino-6-(4-(dimethylamino)phenyl)-7-(4-(dimethylamino)phenyl)pyrido[2,3 5 d]pyrimidine; 4-arnino-6-(4-methylphenyl)-7-phenylpyrido[2,3-d]pyimidine; 4-amino-6-(4-methylphenyl)-7-(4-bromophenyl)pyridol2,3-d]pyrirnidine; 4-amidno-6-(4-(dimethylamino)phenyl)-7-(4-pyridinyl)pyrido[2,3-dlpyrimiddine; 4-amino-6-(4-(dimethylamino)phenyl)-7-(4-bromophenyl)pyrido[2,3-d]pyimidine; 10 4-amidno-6-(4-methylphenyl)-7-(4-(5-pyrimidinyl)phenyl)pyrido[2,3-d]pyrimidine; 4-amidno-6-(4-methylphenyl)-7-(4-(2-(2-pyridinyl)ethenyl)phenyl)pyridol2,3. d]pyrimidine; 4-amidno-6-(4-methylphenyl)-7-(3-pyridinyl)pyrido[2,3-d]pyrimidine; 4-arnino-6-(4-methylphenyl)-7-(thiophen-3-yl)pyrido[2,3-d]pyrimidine; 15 4-amino-6-(4-methylphenyl)-7-(thiophen-2-yl)pyrido[2,3-d]pyrimidine; 4-amino-6-(4-methylphenyl)-7-(2-pyridinyl)pyrido[2,3-d]pyrimidine; 4-amidno-6-(4-methylphenyl)-7-(3,4-methylenedioxyphenyl)pyrido[2,3 dipyrimiddine; 4-arnno-6-butyl-7-(thiophen-2-yl)pyrido[2,3-d]pyrim-idine; 20 4-am-ino-6-butyl-7-(thiophen-3-yl)pyrido[2,3-d]pyrimidine; 4-amino-6-(4-methylphenyl)-7-(5-bromothiophen-2-yl)pyrido[2,3-dlpyrimidine; 4-amino-6-(4-methylphenyl)-7-(5-methylthiophen-2-yl)pyrido[2,3-dlpyrimiddine; 4-amino-6-(4-methylphenyl)-7-(4-(trifluorornethoxy)phenyl)pyrido[2,3 dipyrimidine; 25 4-amino-6-(4-methylphenyl)-7-(3-phenoxyphenyl)pyrido[2,3-d]pyrimidine; 4-amnino-6-(4-methylphenyl)-7-(5.-nitrothiophen-2-yl)pyrido[2,3-d]pyrimidine; 4-amidno-6-(4-methylphenyl)-7-(4-bromothiophen-2-yl)pyrido[2,3-d]pyrimidine; 4-amino-6-(4-methylphenyl)-7-(3-methylthiophen-2-yl)pyrido[2,3-dlpyrim-idine; 4-amino-6-(4-methylphenyl)-7-(furan-2-yl)pyrido [2,3-dlpyrimidine; 30 4-amino-6-(4-methylphenyl)-7-(furan-3-yl)pyrido[2,3-d]pyrimiddine; 4-amidno-6-(4-methylphenyl)-7-(5-methyl-furan-2-yl)pyrido[2,3-dlpyrimidine; 4-am-ino-6-(4-(2-propyl)phenyl)-7-(thiophen-2-yl)pyrido[2,3-d]pyrimidine; 4-ami no-6-(4- (2-propyl)phen yl)-7 -(5 -n itroth iophen -2- yl)pyri do [2,3-d] pyri mid ine; 4-amino-6-(4-methylphenyl)-7-(5-nitrothiophen-2-yl)pyrido[2,3-dlpyrimidine; 35 4-amino-6-(4-(dimethylamino)phenyl)-7-(thiophen-2-yl)pyrido[2,3-dlpyrimidine; 4-amino-6-(3 ,4-dimethoxyphenyl)-7-(thiophen-2-yl)pyrido[2,3-d]pyrimidine; 4-amino-6-(3,4-dimethoxyphenyl)-7-(5-nitrothiophen-2-yl)pyrido[2,3-dlpyrinidine; 4-amino-6-hexyl-7-( 4 -.(dimethylamiino)phenyl)pyrido[2,3-d]pyrim-idine; 4-amino-6-hexyl-7-(thiophen-2-yI)pyrido[2,3-d] pyrinidine; -48- WO 98/46603 PCTIUS98/04127 40 4-amino-6-(2-methyl-2-propyl)-7-(thiophen-2-yl)pyrido[2,3-dlpyrinidine; 4 -anmino- 6 -( 4 -(2-propyl)phenyl)-7-(4-(dimethylamino)phenyl)pyrido[2,3 dipyrimidine; 4-amino- 6 -( 4 -propylphenyl)-7-(4-(dimethylamino)phenyl)pyrido[2,3-d]pyrimidine; 4-amino-6- (3 , 4 -dimethoxyphenyl)-7.-(4-(dimethylamino)phenyl)pyrido[2,3 45 dlpyrimidine; 4-amidno-6-(3-methoxyphenyl)-7-(4-(dimethylamino)phenyl)pyrido[2,3 dlpyrimidine; 4-amino-6-(3-bromophenyl)-7-(4-(dimethylamino)phenyl)pyrido[2,3-d]pyrimidine; 4-amino-6-(3-fluorophenyl)-.7-(4-(dimethylan-ino)phenyl)pyrido[2,3-d]pyrirnidine; 50 4-amidno-6-(3-trifluoromethylphenyl)-7-(4-(dimethylamino)phenyl)pyrido[2,3 dlpyrimiddine; 4-amidno-6-(3-chlorophenyl)-7-(4- (dirnethylamidno)phenyl)pyrido [2,3-d]pyrim-idine; 4-amino-6-(3,5-dichlorophenyl)-7-(4-(dimethylamino)phenyl)pyrido[2,3 dilpyrimidine; 55 4-arnino-6-(3,4-methylenedioxyphenyl)-7-(4-(dimethylarnno)phenyl)pyrido [2,3 d]pyrimidine; 4-amino-6-(3,4-methylenedioxyphenyl)-7- (th iophen -2-yl)pyri do[2,3-d] pyri mid ine; 4-amino-6-(3-methoxycarbonylphenyl)-7-(4-(dimethylamino)phenyl)pyrido [2,3 d]pyrimidine; 60 4-amino-6-(3-(2-propyl)phenyl)-7-(4-(dimethylamino)phenyl)pyrido[2,3 dipyrimiddine; 4 -amino-6-(4-(2-methyl-2-propyl)phenyl)-7-(4-(dimethylamino)phenyl)pyrido [2,3 dlpyrimidine; 4 -am-ino-6-(4-fluorophenyl)-7-(4-(dimethylamidno)phenyl)pyrido[2,3-d]pyrimidine; 65 4 -amino-6-(4-methoxyphenyl)-7-(4-(dimethylamidno)phenyl)pyrido[2,3 d]pyrimidine; 4-amidno-6-(3-(phenylmethoxy)phenyl)-7-(4- (dimethylamino)phenyl)pyrido[2,3 dipyrimaidine; 4-am-ino-6-(4-chlorophenyl)-7-(4- (dimethylamidno)phenyl)pyrido[2,3-d]pyrimidine; 70 4 -amino- 6 -(3-fluoro- 4 -methylphenyl)-7-(4-(dimethylarmino)phenyl)pyrido[2,3 dipyrimidine; 4 -amino-6-(3-fluoro-4-methylphenyl)-7-(thiophen-2-yl)pyrido [2,3-d]pyrimidine; 4 -amino-6-(3-phenylpropyl)-7-(4-methoxyphenyl)pyrido[2,3-d]pyrimidine; 4 -amino-6-(3-phenylpropyl)-7-(4-(dimethylamino)phenyl)pyrido[2,3-d]pyrimidine; 75 4-amidno-6-(2-phenylethyl)-7-(4- (dimethylamidno)phenyl)pyrido[2,3-d]pyrimidine; 4-ntn--peymty)7(-dmtyaiopey~yio23dpfndie -49- WO 98/46603 PCT[US98/04127 4-amino-6-(cyclohexylmethyl)-7-(4-(dimethylaniino)phenyl)pyrido[2,3 d]pyrimidine; 4-amino-6-butyl-7-(4-(dimethylamidno)phenyl)pyrido[2,3-d]pyrimidine; 80 4-amino-6-pentyl-7-(4-(dimethylamino)phenyl)pyrido[2,3-d]pyrimidine; 4-aniino-6-(2-methylpropyl)-7-(4-(dimethylamino)phenyl)pyrido[2,3-dlpyriniidine; 4-amino-6-propyl-7-(4-(dimethylamino)phenyl)pyrido[2,3-d]pyrimidine; 4-amino-6-(3-cyanopropyl)-7-(4-(dimethylamino)phenyl)pyrido[2,3-d]pyrimidine; 4-amfino-6-(3-nitrophenyl)-7-(4-(dixnethylamino)phenyl)pyrido[2,3-dlpyrimidine; 85 4-am-ino-6-pentyl-7-(thiophen-2-yl)pyridol2,3-d]pyrirnidine; 4-.amino-6-(3-carboxamidopropyl).-7-(4-(dimethylam-ino)phenyl)pyrido[2,3 dipyrimidine; 4-anmino-6-((4-methoxyphenyl)methyl)-7-(thiophen-2-yl)pyrido[2,3-d]pyimidine; 4-amidno-6-((3-bromophenyl)methyl)-7-(thiophen-2-yl)pyrido[2,3-dlpyrimidine; 90 4-amino-6-((4-(2-propyl)pheny1)methyl)-7-(thiophen-2-y1)pyrido[2,3-d]pyfim-idinc-; 4-amidno-6-((4-methoxyphenyl)methyl)-7-(4-(2-propyl)phenyl)pyrido[2,3 dipyrimnidine; 4-amino-6.-((4-bromophenyl)methyl)-7-(thiophen-2-yl)pyrido[2,3-d]pyrimidine; 4-amino-6-((3-fluorophenyl)methyl)-7-(thiophen-2-yl)pyrido[2,3-dlpyrimidine; 95 4-aniino-6-((4-bromhophenyl)methyl)-7-(thiazole-2-yl)pyrido[2,3-d]pyrimidine; 4-amino-6-((3-methoxyphenyl)methyl)-7-(thiophen-2-yl)pyrido [2,3-d]pyrimidine; 4-amino-6-(phenylmethyl)-7-(thiophen-2-yl)pyrido[2,3-d]pyrimidine; 4-amino-6- ((3-methoxyphenyl)methyl)-7-(4-(dimethylamino)phenyl)pyrido[2,3 dipyrimidine; 1oo 4-amiino-6-(4-methylphenyl)-7-(4-(trifluoromethyl)phenyl)pyrido[2,3-d]pyrimidine; 4-arnno-6-(4-methylphenyl)-7-(4-methylphenyl)pyrido[2,3-d]pyrimidine; 4-am-ino-6-(4-methylphenyl)-7-(4-methoxyphenyl)pyrido[2,3-d]pyrimiddine; 4-amino-6-(4-methylphenyl)-7-(4-ethylphenyl)pyridol2,3-d]pyrimidine; 4-aniino-6-(4-methylphenyl)-7-(4-cyanophenyl)pyrido[2,3-d]pyrin-idine; 105 4-am-ino-6-(4-methylphenyl)-7-(4-acetarnidophenyl)pyrido[2,3-dlpyrimidine; 4-amidno-6-(4-methylphenyl)-7-(4-phenoxyphenyl)pyrido [2,3-dipyrimiidine; 4-amino-6-(4-methylphenyl)-7-(4-nitrophenyl)pyrido[2,3-d]pyfimidine; 4-amidno-6-(4-rnethylphenyl)-7-(4-fluorophenyl)pyrido[2,3-dlpyrimidine; 4-amino-6-(4-methylphenyl)-7-(4-chlorophenyl)pyrido[2,3-d] pyrim-idine; 110 4-amino- 6- (4-methylphenyl)-7-(4-aminop hen yl)pyrido [2,3-dI pyrimidine; 4-amidno-6-(4-methylphenyl)-7-(4-methylthiophenyl)pyrido [2,3-dipyrimidine; 4-amino-6-(4-methylphenyl)-7-((4-phenyl)phenyl)pyrido [2,3-dlpyrimidine; 4-an-ino-6-(4-methylphenyl)-7-((4-phenylmethoxy)phenyl)pyrido[2,3-d]pyrimidine; -50- WO 98/46603 PCT/US98/04127 4 -amino- 6 -( 4 -methylphenyl)-7-((4-N,N-diethylamino)phenyl)pyrido[2,3 115 d]pyrimidine; 4 -amino-6-(4-methylphenyl)-7-((4-2-phenylethenyl)phenyl)pyrido[2,3 d]pyrimidine; 4 -amino- 6 -( 4 -methylphenyl)-7-(4-(2-methyl-2-propoxy)phenyl)pyrido[2,3 d]pyrinmidine; 120 4-amino-6-(4-methylphenyl)-7-(3-chlorophenyl)pyrido[2,3-d]pyrimidine; 4 -amino- 6 -( 4 -methylphenyl)-7-(3,5-dimethoxyphenyl)pyrido[2,3-d]pyrimidine; 4 -amino-6-(thiophen-2-yl)-7-(4-N,N-dimethylphenyl)pyrido[2,3-d]pyrimidine; 4 -amino-6-(4-methylphenyl)-7-(benzofuran-2-yl)pyrido[2,3-d]pyrimidine; 4-amino-6-(thiophen-2-yl)-7-(thiophen-2-yl)pyrido[2,3-d]pyrimidine; 125 4 -amino-6-(thiophen-2-yl)-7-(4-methoxyphenyl)pyrido[2,3-d]pyrimidine; 4 -amino-6-(4-bromophenyl)-7-(4-N,N-dimethylphenyl)pyrido[2,3-d]pyrimidine; 4 -amino6-(3-bromo-4-methoxyphenyl)-7-(4-N,N-dimethylphenyl)-pyrido[2,3 d]pyrimidine; 4 -amino-6-(3-bromo-4-methoxyphenyl)-7-(thiophen-2-yl)pyrido[2,3-d]pyrimidine; 130 4 -amino-6-( 4 -methylphenyl)-7-(4-butoxyphenyl)pyrido[2,3-d]pyrimidine; 4 -amino-6-( 4 -methylphenyl)-7-(3-methoxyphenyl)pyrido[2,3-d]pyrimidine; or 4 -amino-6-(4-methylphenyl)-7-(3,5-dichlorophenyl)pyrido[2,3-d]pyrimidine.
11. A method of inhibiting adenosine kinase comprising exposing an adenosine kinase to an effective inhibiting amount of a compound according to Claim 1 or 5.
12. A pharmaceutical composition comprising a therapeutically effective amount of a compound according to Claim 1 or 5 in combination with a pharmaceutically acceptable carrier.
13. 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 -51- WO 98/46603 PCT/US98/04127
14. A method according to Claim 12 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, 5 sepsis, diabetes and abnormal gastrointestinal motility.
15. A process for the preparation of a compound having the formula R " N R2 H N R3 N N R 4 wherein R 1 and R 2 are hydrogen, 5 R 3 is loweralkyl, loweralkenyl, loweralkynyl, aryl, arylalkyl, heteroaryl, or a heterocyclic group or substituted versions thereof; R 4 is aryl, heteroaryl, or a heterocyclic group or substituted versions thereof; the method comprising 10 (a) reacting 4,6-diamino-5-iodopyrimidine with an ethenylboronic acid derivative having the formula (HO)2B R 3 wherein R 3 is loweralkyl, loweralkenyl, loweralkynyl, aryl, arylalkyl or heteroaryl or heterocyclic or substituted versions thereof, in the presence of 15 tetrakistriphenylphosphinepalladium(0) and an aqueous alkali metal base, and isolating a first intermediate compound having the formula NH 2 N R3 N NH 2 (b) reacting the first intermediate compound with an aldehyde compound having the formula R 4 -CHO, wherein R 4 is aryl, heteroaryl, or a heterocyclic group or substituted 20 versions thereof, under anhydrous conditions and with the removal of the water of reaction, and isolating the compound of formula II. -52- WO 98/46603 PCT/US98/04127
16. A process for the preparation of a compound having the formula R' NR 2 H N H N N R 4 (, wherein R 1 and R 2 are independently H, loweralkyl, arylalkyl or acyl, or may be taken 5 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, with the requirement that not both R 1 and R 2 may be hydrogen; R 3 is loweralkyl, loweralkenyl, loweralkynyl, aryl, arylalkyl, heteroaryl, or a heterocyclic group or substituted versions thereof; 10 R 4 is aryl, heteroaryl, or a heterocyclic group or substituted versions thereof; the method comprising (a) reacting a compound having the formula R 1 N. N R2 H N \ R 3 N N R 4 wherein 15 R 1 and R 2 are hydrogen; R 3 is loweralkyl, loweralkenyl, loweralkynyl, aryl, arylalkyl, heteroaryl, or a heterocyclic group or substituted versions thereof; R 4 is aryl, heteroaryl, or a heterocyclic group or substituted versions thereof; 20 with a compound selected from the group consisting of (i) an alkylating agent R 1 -Y, wherein R 1 is loweralkyl and Y is selected from the group consisting of a halide, a mesylate and a tosylate; (ii) an arylalkylating agent R 1 -loweralkyl-Y, wherein R 1 is arylalkyl and Y is selected from the group consisting of a halide, a mesylate and a tosylate; 25 (iii) an acyl compound R 1 -Z, wherein R 1 is an acyl group and Z is selected from the group consisting of an acid anhydride moiety, a halide or an acyl activating group; and isolating the desired compound; and (b) optionally, when it is desired that R 2 should not be hydrogen, treating the compound from step (a) with a compound selected from the group consisting of -53- WO 98/46603 PCT/US98/04127 30 (i) an alkylating agent R 2 -Y, wherein R 2 is loweralkyl and Y is selected from the group consisting of a halide, a mesylate and a tosylate; (ii) an arylalkylating agent R 2 -loweralkyl-Y, wherein R 2 is arylalkyl and Y is selected from the group consisting of a halide, a mesylate and a tosylate; (iii) an acyl compound R 2 -Z, wherein R 2 is an acyl group and Z is selected from the 35 group consisting of an acid anhydride moiety, a halide or an acyl activating group; and isolating the compound of formula II.
17. A process for the preparation of a compound having the formula R'-11. N'R 2 R N R H N N R 4 i), wherein R 1 and R 2 are independently H, loweralkyl, arylalkyl or acyl, or may be taken 5 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, with the proviso that not both R 1 and R 2 are hydrogen; R 3 is loweralkyl, loweralkenyl, loweralkynyl, aryl, arylalkyl, heteroaryl, or a heterocyclic group or substituted versions thereof; 10 R 4 is aryl, heteroaryl, or a heterocyclic group or substituted versions thereof; the method comprising (a) reacting 6-amino-4-chloro-5-iodopyrimidine with an ethenylboronic acid derivative having the formula (HO) 2 B R3 15 wherein R 3 is loweralkyl, loweralkenyl, loweralkynyl, aryl, arylalkyl or heteroaryl, or heterocyclic or substituted versions thereof in the presence of tetrakistriphenylphosphinepaladium(0) and an aqueous alkali metal base, and isolating a first intermediate compound having the formula CI N - \ N NH 2 20 (b) reacting the first intermediate compound with an aldehyde compound having the formula R 4 -CHO, wherein R 4 is aryl, heteroaryl, or a heterocyclic group or substituted -54- WO 98/46603 PCT/US98/04127 versions thereof, under anhydrous conditions and with the removal of the water of reaction, and isolating the second intermediate compound having the formula CI N N R 4 ; and 25 (c) treating the fourth intermediate compound with an amine compound having the formula R 1 -NH-R 2 , wherein R 1 and R 2 are as described above, and isolating the compound of formula II.
18. A compound of the formula: X N N R 4 wherein X is selected from halogen or OH and R 3 and R 4 are as defined above. -55-
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