MXPA99009512A

MXPA99009512A - 5,6,7-trisubstituted-4-aminopyridol[2,3-d]pyrimidine compounds

Info

Publication number: MXPA99009512A
Application number: MXPA/A/1999/009512A
Authority: MX
Inventors: S Bhagwat Shripad; J Perner Richard; Gui Gu Yu
Original assignee: Abbott Laboratories
Priority date: 1997-04-16
Filing date: 1999-10-15
Publication date: 2000-07-01

Abstract

A compound having formula (II) wherein R1, R2, R3, R4 and R5 are defined, a method for inhibiting adenosine kinase by administering a compound thereof, a pharmaceutical composition comprising a therapeutically effective amount of a compound thereof above in combination with a pharmaceutically acceptable carrier, a method of treating cerebral ischemia, epilepsy, pain, nociperception, inflammation and sepsis in a mammal in need of such treatment, comprising administering to the mammal a therapeutically effective amount of a compound thereof, and methods for preparation thereof.

Description

COMPOUNDS OF 4-AMINOPlRID? R2.3-DlPIRIMlDINA 5.6.7-TRISUBSTITUIDOS This application is a conversion of the patent application of E.U.A. provisional provisional Series No. 60 / 043,252, filed on April 16, 1997.

Technical Field The present invention relates to a method for inhibiting adenosine kinase by administering 5,6,7-trisubstituted 4-aminopyridine [2,3-d] pyrimidine compounds, to pharmaceutical compositions containing said compounds, as well as to 4-aminopyrido [2, 3-d Ipyrimidine 5, 6, 7 -tri substituted compounds.

Background of the Invention The 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, preferably, as the source of phosphate. The adenosine kinase has a 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 virtually in every human tissue analyzed including kidney, liver, brain, spleen, placenta and pancreas. Adenosine kinase is a key enzyme in the control of adenosine cell concentrations.

Adenosine is a purine nucleoside that is an intermediate in the trajectories of the degradation and recovery of the purine nucleotide. Adenosine also has many important physiological effects, many of which are mediated through the activation of specific ectocellular receptors, termed P ^ receptors (Burnstock, in Cell Membrane Receptors for Drugs and Hormones, 1978, (Bolis and Straub, eds) Raven, New York, pp. 107-118; Fredholm, et al., Pharmacol., Rev. 1994, 46; 143-156). In the central nervous system, adenosine inhibits the release of certain neurotransmitters (Corradetti, et al., Eur. J. Pharmacol, 1984, 104: 19-26), stabilizes the membrane potential (Rudolphi, et al., Brain Metab. Rev., 4: 346-360), functions as an endogenous anticonvulsant (Dragunow, Trenos Pharmacol, Sci. 1986, 7: 128-130) and may have a role as an endogenous neuroprotective agent (Rudolphi, et al., Trends Pharmacol Sci. 1992, 13: 439-445). Adenosine can play an important role in various disorders of the central nervous system, such as schizophrenia, anxiety, depression and Parkinson's disease. (Williams, M., in Psychopharmacology: The Fourth Generation of Progress, Bloom, Kupfer (eds.), Raven Press, New York, 1995, pp. 643- 655.) Adenosine has also been involved in the modulation of transmission in trajectories of pain in the spinal cord (Sawynok, et al., Br. J. Pharmacol., 1986, 88: 923-930), and to mediate 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 inhibitor of AK reduces leg swelling in an auxiliary arthritis model in rats (Firestein, et al., Arthritis and Rheumatism, 1993, 36, S48) Adenosine also exerts a variety of effects on the cardiovascular system, including vasodilation, damage of atrioventricular conduction and endogenous cardioprotection in myocardial ischemia and reperfusion ( Mullane and Williams, in Adenosine and Adenosine Receptors, 1990 (Williams, ed.) Human Press, New Jersey, p. 289-334). The well-known actions of adenosine also include effects on the renal, respiratory, gastrointestinal and reproductive systems, as well as on blood cells and adipocytes. Adenosine, through its activation of the A1 receptor on adipocytes, plays an important role in diabetes by inhibiting lipolysis [Londos, et al., Proc. Nati Acad. Sci. USA, 1980, 77, 2551]. The release of endogenous adenosine seems to have a role as a natural defense mechanism in various pathophysiological conditions, including cerebral and myocardial ischemia, attacks, pain, inflammation and sepsis. Although adenosine is not present at low levels in the extracellular space, its release is locally enhanced at the site (s) of excess cellular activity, trauma or metabolic stress. Once in the extracellular space, adenosine activates specific extracellular receptors to produce a variety of responses, which tend to restore cellular function to normal (Bruns, Nucleosides Nucleotides, 1991 10: 931-943; Miller and Hsu, J. Neurotrauma, 1992, 9: S563-S577). Adenosine has a half-life measured in seconds in extracellular fluids (Moser, et al., Am. J. Physiol. 1989, 25: C799-C806), and its endogenous actions, therefore, are highly localized. Inhibition of adenosine kinase can result in increased local concentrations of adenosine at the site of tissue damage, further enhancing cytoprotection. This effect is probably the most pronounced in tissue sites where the trauma results in an increased production of adenosine, thus minimizing systemic toxicities. The pharmacological compounds directed towards the inhibition of adenosine kinase provide new potentially effective therapies for disorders benefited by the enhancement of adenosine-specific site and event. Disorders in which such compounds may be useful include ischemic conditions such as cerebral ischemia, myocardial ischemia, angina, graft surgery for coronary artery bypass (CABG), percutaneous transluminal angioplasty (PTCA), shock, other thrombotic and embolic conditions, and neurological disorders such as epilepsy, anxiety, schizophrenia, nociception including pain perception, neuropathic pain, visceral pain, as well as inflammation, arthritis, immunosuppression, sepsis, diabetes and gastrointestinal malfunctions, such as abnormal gastrointestinal motility. A number of compounds have been reported to inhibit the adenosine kinase. The most potent of these includes 5'-amino-5'-deoxyadenosine (Miller et al., J. Biol. Chem. 1979, 254: 2339-2345), 5-iodotubercidin (Wotring and Townsend, Cancer Res. 1979, 39 : 3018-3023) and 5'deoxy-5-iodotubercidin (Davies, et al., Biochem Pharmacol, 1984, 33: 347-355). The adenosine kinase is also responsible for the activation of many pharmacologically active nucleosides (Miller, et al., J. Biol. Chem. 1979, 254: 2339-2345), including tubercidin, formicin, ribavirin, pyrazofurin and riboside 6- (methylmercapto) purine. These purine nucleoside analogs represent an important group of antimetabolites, which possess cytotoxic, anti-cancer and antiviral properties. They serve as substrates for adenosine kinase and without phosphorylation through the enzyme to generate the active form. The loss of adenosine kinase activity has been implicated as a mechanism of cellular resistance to the pharmacological effects of these nucleoside analogues (eg, 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). Reduced cellular levels of adenosine kinase have been associated with resistance to the toxic effects of 2'-deoxyadenosine (Hershfield and Kredich, Proc Nati, Acad Sci USA, 1980, 77: 4292-4296). The accumulation of deoxyadenosine triphosphate (dATP), derived from the phosphorylation of 2'-deoxyadenosine, has been suggested as a toxic mechanism in the immune defect associated with inheritable adenosine deaminase deficiency (Kredich and Hershfield, in The Metabolic Basis of Inherited Diseases, 1989 (Scriver, et al., Eds.), McGraw-Hill, New York, pp. 1045-1075). B. S. Hurlbert et al. (J. Med. Chem. V 711-717 (1968)) describe various 2,4-diaminopyrido [2,3-d] pyrimidine compounds having use as antibacterial agents. RK Robins et al. (J. Amer. Chem. Soc, 80: 3449-3457 (1958)) describe methods for preparing a 2,4-dihydroxy-, 2,4-diamino-, 2-amino-4-number. -hydroxy-, and 2-mercapto-4-hydroxypyrido [2,3-d] pyrimidines having antifolic acid activity. R. Sharma et al. (Indian J. Chem., 31B: 719-720 (1992)) describe 4-amino-5- (4-chlorophenyl) -7- (4-nitrophenyl) pyrido [2,3-d] compounds ] pyrimidine and 4-amino-5- (4-methoxyphenyl) -7- (4-nitrophenyl) pyrido [2,3-d] pi rimidine having antibacterial activity. A. Gupta et al. (J. Indian Chem. Soc., 71_, 635-636 (1994)) describe compounds of 4-amino-5- (4-fluorophenyl) -7- (4-fluorophenyl) pyrido [2,3-d] pyrimidine and 4-amino-5- ( 4-chlorophenyl) -7- (4-fluorophenyl) pyrido [2,3-d] pyrimidine having antibacterial activity. L. Prakash et al., Pharmazie, 48: 221-222 (1993)) describe compounds of 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 having antifungal activity. P. Victory et al., Tetrahedron, 5J_, 10253-10258 (1995)) describe the synthesis of 4-amino-5,7-diphenyl-pyrido [2,3-d] pyrimidine compounds from acyclic precursors. Bridges et al. (PCT application WO 95/19774, published July 27, 1995) describe various bicyclic heteroaromatic compounds having utility for inhibiting tyrosine kinase from epidermal growth factors.

SUMMARY OF THE INVENTION The present invention provides 5,6,7-trisubstituted 4-aminopyrido [2,3-d] pyrimidine compounds having utility as adenosine kinase inhibitors. In one aspect, the present invention provides compounds having the formula (I): wherein: R1 and R2 independently are H, lower alkyl, arylalkyl or acyl, or can be taken together with the nitrogen atom to which they are attached to form a 5- to 7-membered ring optionally containing 1-3 additional heterogeneous atoms selected from N, O u S; R3, R4 and R5 independently are selected from lower alkyl, lower alkenyl, lower alkynyl, lower cycloalkyl, aryl, arylalkyl, heteroaryl or a heterocyclic group and dotted lines indicate that a double bond is optionally present.

The present invention also relates to a compound of the formula II: wherein: R1 and R2 independently are H, lower alkyl, arylalkyl or acyl, or can be taken together with the nitrogen atom to which they are attached to form a 5- to 7-membered ring optionally containing 1-3 heterogeneous atoms selected from N , O u S; Y R3, R4 and R5 independently are selected from lower alkyl, lower alkenyl, lower alkynyl, lower cycloalkyl, aryl, arylalkyl, heteroaryl or a heterocyclic group. In another aspect, the present invention provides a method for inhibiting adenosine kinase by administering a compound of formula (I) or (II). In particular, the method for inhibiting the adenosine kinase comprises exposing an adenosine kinase to an effective inhibitory amount of a compound of Formula I or II of the present invention. When the adenosine kinase is localized in vivo, the compound is administered to the organism. In another aspect, the present invention provides a pharmaceutical composition comprising a therapeutically effective amount of a compound of the Formula I or II above, in combination with a pharmaceutically acceptable carrier. In yet another aspect, the present invention provides a method for treating ischemia, neurological disorders, nociception, inflammation, immunosuppression, gastrointestinal disorders, diabetes and sepsis in a mammal in need of such treatment, which comprises administering to the mammal a therapeutically effective amount of a compound of Formula I or II of the present invention. In a preferred aspect, the present invention provides a method for treating cerebral ischemia, myocardial ischemia, angina, coronary artery bypass graft surgery, percutaneous transluminal angioplasty, shock, thrombotic and embolic conditions, epilepsy, anxiety, schizophrenia, perception of the pain, neuropathic pain, arthritis, sepsis, diabetes and abnormal gastrointestinal mobility in a mammal in need of such treatment, which comprises administering to the mammal a therapeutically effective amount of a compound of Formula I or II of the present invention. The present invention also contemplates the use of pharmaceutically acceptable salts and amides of the compounds of Formula I or II. In another aspect, the present invention provides a process for the preparation of a compound having the formula: wherein: R1 and R2 independently are H, lower alkyl, arylalkyl or acyl, or can be taken together with the nitrogen atom to which they are attached to form a 5- to 7-membered ring optionally containing 1-3 heterogeneous atoms selected from N , O u S; and R3 and R4 independently are selected from lower alkyl, lower alkenyl, lower alkynyl, lower cycloalkyl, aryl, arylalkyl, heteroaryl or a heterocyclic group; and R5 is selected from an aryl, heteroaryl or heterocyclic group; the method comprising: (a) reacting an aryl, heteroaryl or a heterocyclic bromide having the formula R5-Br, wherein R5 is as defined above, with a carboxylic acid derivative having the formula R4-CH2-CO- Y, wherein Y is OH or Cl, and R 4 is lower alkyl, lower alkenyl, lower alkynyl, aryl, arylalkyl, heteroaryl or a heterocyclic group, with N, O-dimethylhydroxylamine hydrochloride, 1- (3-dimethylaminopropyl) -3 -ethylcarbodiimide or 1-hydroxybenzotriazole hydrate and triethylamine, and isolating a first intermediate compound having the formula R5-CO-CH2-R4; (b) reacting the first intermediate compound having the formula R5-CO-CH2-R4, with an aldehyde having the formula R3-CHO, wherein R3 is as defined above, and malononitrile in the presence of an ammonium salt under anhydrous conditions, and isolate a second intermediate compound having the formula: (c) reacting the second intermediate compound with refluxing formamide for about 1 to about 24 hours, and isolating the compound of formula II. In still another aspect, the present invention provides a process for the preparation of compounds having the formula: wherein: R1 and R2 independently are H, lower alkyl, arylalkyl or acyl, or can be taken together with the nitrogen atom to which they are attached to form a 5- to 7-membered ring optionally containing 1-3 heterogeneous atoms selected from N , O u S; Y R3 and R4 independently are selected from lower alkyl, lower alkenyl, lower alkynyl, lower cycloalkyl, aryl, arylalkyl, heteroaryl or a heterocyclic group; and R5 is selected from an aryl, heteroaryl or heterocyclic group; provided that both R and R2 are not H, the method comprising: (a) reacting an aryl, heteroaryl or a heterocyclic bromide having the formula R5-Br with a carboxylic acid derivative having the formula R4-CH2CO-Y, wherein Y is OH or Cl, and R 4 is lower alkyl, lower alkenyl, lower alkynyl, arylalkyl, heteroaryl or a heterocyclic group, with N, O-dimethylhydroxylamine hydrochloride, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide or 1-hydroxybenzotriazole hydrate and triethylamine, and isolate a first intermediate compound having the formula R5-CO-R4; (b) reacting the first intermediate compound having the formula R5-CO-R4, with an aldehyde having the formula R3-CHO, wherein R3 is as defined above, and malononitrile in the presence of an ammonium salt under conditions anhydrous, and isolate a second intermediate compound that has the structure: (c) reacting the second intermediate compound with sulfuric acid and heating followed by treatment with triethyl orthoformate at reflux for about 1 to about 24 hours, and isolating a third intermediate compound having the structure: OH R3 N? R (d) treating the third intermediate compound with a chlorinating agent, and isolating a fourth intermediate product having the formula: Cl R3 N sA? -R4 with an amine compound having the formula R1-NH-R2, wherein R1 and R are as described above, and isolating the compound of the formula II. In still another aspect, the present invention provides a process for the preparation of compounds having the formula: wherein: R1 and R2 independently are H, lower alkyl, arylalkyl or acyl, or can be taken together with the nitrogen atom to which they are attached to form a 5- to 7-membered ring optionally containing 1-3 heterogeneous atoms selected from N , O u S; Y R3 and R4 independently are selected from lower alkyl, lower alkenyl, lower alkynyl, lower cycloalkyl, aryl, arylalkyl, heteroaryl or a heterocyclic group; and R5 is selected from an aryl, heteroaryl or heterocyclic group; the method comprising: (a) reacting an aryl, heteroaryl, or a heterocyclic bromide having the formula R5-Br with a carboxylic acid derivative having the formula R -CH2-CO-Y, wherein Y is OH or Cl , and R 4 is lower alkyl, lower alkenyl, lower alkynyl, aryl, arylalkyl, heteroaryl or a heterocyclic group, with N, O-dimethylhydroxylamine hydrochloride, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide or 1-hydroxybenzotriazole hydrate and triethylamine, and isolating a first intermediate compound having the formula R5-CO-CH2-R4; (b) treating the first intermediate compound having the formula R5-CO-CH2-R4, with a compound having the formula: wherein, R3 is as described above, refluxing in an alcoholic solvent and isolating a second intermediate product having the formula: (c) reacting the second intermediate compound with refluxing formamide for about 1 to about 24 hours, and isolating the desired product. In still another aspect, the present invention provides a process for the preparation of compounds having the formula: wherein: R1 and R2 independently are H, lower alkyl, arylalkyl or acyl, or can be taken together with the nitrogen atom to which they are attached to form a 5- to 7-membered ring optionally containing 1-3 heterogeneous atoms selected from N , O u S; Y R3 and R4 independently are selected from lower alkyl, lower alkenyl, lower alkynyl, lower cycloalkyl, aryl, arylalkyl, heteroaryl or a heterocyclic group; and R5 is selected from an aryl, heteroaryl or heterocyclic group, provided that both R1 and R2 are not hydrogen, the method comprising: (a) reacting an aryl, heteroaryl, or heterocyclic bromide having the formula R5-Br with a carboxylic acid derivative having the formula R 4 -CH 2 -CO-Y, wherein Y is OH or Cl, and R 4 is lower alkyl, lower alkenyl, lower alkynyl, aryl, arylalkyl, heteroaryl or a heterocyclic group, with N hydrochloride , O-dimethylhydroxylamine, 1- (3-dimethylaminopropyl) -3-ethylcarbodimide or hydrate of 1-hydroxybenzotriazole and triethylamine, and isolate a first intermediate compound having the formula R5-CO-CH2-R4; (b) treating the first intermediate compound having the formula R5-CO-CH2-R4, with a compound having the formula: NC X '^ CN where, R3 is as described above, reflux in an alcohol solvent and isolate a second intermediate product having the formula: (c) reacting the second intermediate compound with sulfuric acid and heating followed by treatment with triethyl orthoformate at reflux for about 1 to about 24 hours, and isolating a third intermediate compound having the structure: (d) treating the third intermediate compound with a chlorinating agent, and isolating a fourth intermediate product having the formula: Cl N? R4 (e) treating the fourth intermediate compound with an amine compound having the formula R1-NH- R2, wherein R1 and R2 are as described above, and isolate the compound of formula II. The present invention also relates to any of the above processes and an additional process step, which reduces or partially reduces the right lateral double bond (s) to partially saturated or fully saturated species as generically indicated by formula I. The preferred reduction method is through catalytic hydrogenation.

Detailed Description of the Invention The present invention relates to novel compounds of 4-aminopyrido [2,3-d] pyrimidine 5,6,7-trisubstituted of Formula (I) above, which are useful for inhibiting adenosine kinase, a method for inhibiting adenosine kinase with said compounds, to pharmaceutical compositions containing said compounds, to a method for using said compounds to inhibit adenosine kinase, and to novel compounds of 4-aminopyrido [2,3-djpyrimidine 5,6,7- trisubstituted The present invention relates to a compound of the formula I or II, as described above, wherein: R1 and R2 are independently selected from H, lower alkyl, arylalkyl of 1 to 6 carbon atoms, -C (O) alkyl from 1 to 6 carbon atoms, -C (O) aryl, -C (O) heterocyclic or can be attached together with the nitrogen to which they are attached to form a 5-7 membered ring optionally containing 1-2 additional heterogeneous atoms selected of O, N, or S; R3, R4 and R5 independently are selected from the group consisting of: alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms, alkynyl of 2 to 6 carbon atoms, cycloalkyl of 3 to 8 carbon atoms, heteroarylalkyl of 0 to 6 carbon atoms, or heteroarylalkyl of 0 to 6 carbon atoms substituted, arylalkyl of 0 to 6 carbon atoms or arylalkyl of 0 to 6 carbon atoms substituted, heteroarylalkenyl of 2 to 6 carbon atoms or heteroarylalkenyl of 2 to 6 carbon atoms substituted, to rilalq uen i lo of 2 to 6 carbon atoms or arylalkenyl of 2 to 6 carbon atoms substituted, heteroarylalkynyl of 2 to 6 carbon atoms or heteroarylalkynyl of 2 to 6 carbon atoms substituted, arylalkynyl of 2 to 6 carbon atoms or arylalkynyl of 2 to 6 carbon atoms substituted, wherein the 1-4 heteroaryl or aryl substituents are independently selected from: halogen, oxo, cyanoalkyl of 1 to 6 carbon atoms, heteroarylalkyl of 0 to 6 carbon atoms, alkyl of 0 to 6 carbon atoms heterocyclic, alkyloxy of 1 to 6 carbon atoms, alkyloxy of 1 to 6 carbon atoms-alkyl of 1 to 6 carbon atoms, arylalkyl of 0 to 6 carbon atoms, arylalkyloxy of 1 to 6 carbon atoms, R5R6NC (O), cyano, alkenyl of 2 to 6 carbon atoms, alkynyl of 2 to 6 carbon atoms, alkyl of 1 to 6 carbon atoms, alkenyldialkylmalonyl of 2 to 6 carbon atoms, CF 3, HO-, alkyloxy of 1 to 6 carbon atoms-alkyloxy of 1 to 6 carbon atoms, alkyl of 1 to 6 carbon atoms-SOn, where n is 1-2, alkyl C1 to 6 carbon atoms, alkylacryl of 1 to 6 carbon atoms, CF3O, CF3, alkylenedioxy of 1 to 4 carbon atoms, alkylacryl of 1 to 6 carbon atoms, R5R6N (CO) NR5, N-formyl ( heterocyclic), NO 2, NR 5 R 6 -alkyl of 0 to 6 carbon atoms, wherein R 5 and R 6 independently are selected from H, alkyl of 1 to 6 carbon atoms, HC (O), alkyloxy of 1 to 6 carbon atoms- alkyl of 1 to 6 carbon atoms, alkyloxy of 1 to 6 carbon atoms, alkyl of 1 to 6 carbon atoms-C (O), CF3C (O), NR7R8-alkyl of 1 to 6 carbon atoms, phthalimido- C (O) of 1 to 6 carbon atoms, alkyl of 1 to 6 carbon atoms-SOn, wherein n is 1-2, CN-alkyl of 1 to 6 carbon atoms, R7R8NC (O) NR7, heteroaryl, NR7R8-C 1-6 -alkyl (C) alkyl, C 1-6 -alkylcarbamido-C 1-6 -alkylcarbamido, wherein R 8 and R 9 independently are selected from those variables identified for R 6 and R 7 or R6 and R7 or R8 and R9 p they can be joined together with the nitrogen atom to which they are attached to form an unsubstituted or substituted 5-7 membered ring optionally containing 1-3 additional heterogeneous atoms selected from O, N or S, wherein the substituents are selected from 1 to 6 carbon atoms and where, in the case of formula I, a dotted line, ---, indicates that a double bond is optionally present. In a preferred embodiment of the present invention is a compound of the above Formula (I) or (II), wherein R5 is an aryl, arylalkyl, heteroaryl or a heterocyclic group or those other particular groups shown above, which are within each class. In a highly preferred embodiment of the present invention is a compound of the Formula (I) or (II) above, wherein R5 is selected from the group consisting of: 4- (dimethylamino) phenyl; 5-dimethylamino-2-pyridinyl; 5-methoxy-2-pyridinyl; 4-methoxyphenyl; 5-methylthiofen-2-yl; 4- (N-methyl-N- (2-methoxyethyl) amino) phenyl; v thiophen-2- In a preferred embodiment of the present invention there is found a compound of the above Formula (I) or (II), wherein R 4 is an aryl, arylalkyl, heteroaryl or heterocyclic group or those more particular groups shown above, which are inside each class. In a highly preferred embodiment of the present invention is found a compound of the above Formula (I) or (II), wherein R 4 is selected from the group consisting of: ethoxycarbonylmethyl; ethyl; 3-fluorophenyl; 3-fluoro-4-methylphenyl; 3,4-dimethoxyphenyl; 3-methoxyphenyl; 4-methoxyphenyl; pentyl; phenyl; 3- (2-propyl) phenyl; and 4- (2-propyl) phenyl.

In another preferred embodiment of the present invention is a compound of the above Formula (I) or (II), wherein R3 is an aryl, arylalkyl, heteroaryl or heterocyclic group or those very particular groups shown above, which are within of each class. In another highly preferred embodiment of the present invention is found a compound of the above Formula (I) or (II), wherein R3 is selected from the group consisting of: 3-bromophenyl; 3-bromo-4-fluorophenyl; 4-bromothiophen-2-yl; 3-chlorophenyl; 3,4-dimethoxyphenyl; 3-fluorophenyl; 3-fluoro-4-methylphenyl; 4- (2-propyl) phenyl; and 3-trifluoromethyl-4-fluo rophenyl. Illustrative and preferred compounds of the invention include: 4-amino-5- (3-bromo-4-fluorophenyl) -6-pentyl-7- (4- (dimethylamino) pyrido [2,3-d] pyrimidine; 4-amino-5- (3-bromo-4-fluorophenyl) -6-pentyl-7- (thiophen-2-yl) pyrido [2,3-d] pyrimidine; 4-amino-5- (3-bromophenyl) -6- (4-methoxyphenyl) -7- (4-methoxyphenyl) pyrido [2,3-d] pyrimidine; 4-amino-5- (3-bromophenyl) -6-ethyl-7- (thiophen-2-yl) pyrido [2,3-d] pyrimidine; 4-amino-5- (3-bro mofe nyl) -6-pentyl-7- (thiophen-2-yl) pyrido [2,3-d] pyrimidine; 4-amino-5- (3-bromophenyl) -6- (3,4-dimethoxyphenyl) -7- (thiophen-2-yl) pyrido [2,3-d] pyrimidine; 4-amino-5- (3-bromophenyl) -6- (4- (2-propyl) phenyl) -7- (4- (dimethylamino) phenyl) pyrido [2,3-d] pyrimidine; 4-amino-5- (3-bromophenyl) -6-ethoxycarbonylmethyl-7- (thiophen-2-yl) pyrido [2,3-d] pyrimidine; 4-amino-5- (3-bromophenyl) -6- (3-methoxyphenylmethyl) -7- (thiophen-2-yl) pyrido [2,3-d] pyrimidine; 4-amino-5- (3-bromophenyl) -6- (3,4-dimethoxyphenyl) -7- (4- (dimethylamino) phenyl) pyrido [2,3-d] pyrimidine; 4-amino-5- (4-bromothiophen-2-yl) -6- (3,4-dimethoxyphenyl) -7- (thiophen-2-yl) pyrido [2,3-d] pyrimidine; 4-amino-5- (3-chlorofenyl) + 6- (3,4-d-methoxyphenyl) -7- (thiophen-2-yl) pyrido [2,3-d] pyrimidine; 4-amino-5- (3-trifluoromethyl-4-fluorophenyl) -6- (3,4-dimethoxyphenyl) -7- (thiophen-2-yl) pyrido [2,3-d] pyrimidine; 4-amino-5- (3-chlorophenyl) -6- (3,4-dimethoxyphenyl) -7- (4- (dimethylamino) phenyl) pyrido [2,3-d] pyrimidine; 4-amino-5- (3-trif-1-chloromethyl-4-trifluoromethyl) -6- (3,4-di methoxyphenyl) -7- (4- (dimethylamino) phenyl) pyrido [2,3-d] ] pyrimidine; 4-amino-5- (3-chlorophenyl) -6- (3,4-dimethoxyphenyl) -7- (5-methylthiophen-2-yl) pyrido [2,3-d] pyrimidine; 4-amino-5- (4-bromothiophen-2-yl) -6- (3,4-dimethoxyphenyl) -7- (5-methylthiophen-2) -yl) pyrido [2,3-d] pyrimidine; 4-amino-5- (4-bromothiophen-2-yl) -6- (3,4-dimethoxyphenyl) -7- (4- (dimethylamino) phenyl) pyrido [2,3-d] pyrimidine; 4-amino-5- (4-bromothiophen-2-yl) -6- (3,4-dimethoxyphenyl) -7- (4- (N-methyl-N- (2-methoxyethyl) amino) phenyl) pyrido [ 2,3-d] pyrimidine; 4-amino-5-phenyl-6- (3,4-dimet oxy fe nil) -7- (4- (N-methyl-N- (2-methoxyethyl) amino) fe nyl) -5-phenylpyrido [2, 3-d] pyrimidine; 4-amino-5- (3-chlorophenyl) -6- (3,4-dimethoxyphenyl) -7- (4- (N-methyl-N- (2-methoxyethyl) amino) phenyl) pyrido [2,3- d] pyrimidine; 4-Amino-5-phenyl-6- (3,4-dimethoxyphenyl) -7- (5-methoxy-2-pyridinyl) pyrido [2,3-d] pyrimidine; 4-amino-5- (3-chlorophenyl) -6- (3,4-dimethoxyphenyl) -7- (5-methoxy-2-pyridinyl) p-irido [2,3-d] pyrimidine; 4-amino-5- (3-chlorophenyl) -6- (3,4-dimethoxyphenyl) -5- (5-dimethylamino-2-pyridinyl) pyrido [2,3-d) pyrimidine; 4-amino-5,6-bis (4- (2-propyl) phenyl-7- (4-dimethylaminophenyl) pyrido [2,3-d-pyrimidine; 4-amine-5,6-diphenyl-7- (4- ( N-methyl-N- (2-methoxyethyl) amino) phenyl) pyrido [2,3-d] pyrimidine; 4-amino-5,6-diphenyl-7- (4-dimethylaminophenyl) pyrido [2,3-d] pyrimidine; 4-amino-5,6-bis (3-fluorophenyl) -7- (4-dimethylaminophenyl) pyrido [2,3-d] pyrimidine; 4-amino-5,6-bis (3,4-dimethoxyphenyl) -7- (4-dimethylaminophenyl) pyrido [2,3-d] pyrimidine; 4-amino-5,6-bis (3-fluoro-4-methylphenyl) -7- (4-dimethylaminophenyl) pyrido [2,3-d] pyrimidine; 4-amino-5,6-bis (3-fluoro-4-methylphenyl) -7- (thiophen-2-yl) pyrido [2,3-d] pyrimidine; 4-amino-5,6-diphenyl-7- (thiophen-2-yl) pyrido [2,3-d] pyrimidine; 4-amino-5,6-diphenyl-7- (5-dimethylamino-2-pyridinyl) pyrido [2,3-d] pyrimidine; 4-amino-5-phenyl-6- (3,4-dimethoxyphenyl) -7- (5- (dimethylamino) pyridin-2-yl) pyrido [2,3-d] pyrimidine; 4-amino-5- (3-chlorophenyl) -6- (3,4-dimethoxyphenyl) -7- (5-N- (2-methoxyethyl) -N-methylamino) -2-pyridinyl) pyrido [2, 3-d] pyrimidine; 4-amino-5- (3-chlorophenyl) -6-phenyl-7- (5-dimethylamino-2-pyridinyl) pyrido [2,3-d] pyrimidine; 4-amino-5- (4-bromothiophen-2-yl) -6-phenyl-7- (5-dimethylamino-2-pyridinyl) pyrido [2,3-d] pyrimidine; 4-amino-5- (3-bromophenyl) -6-phenyl-7- (6-dimethylamino-3-pyridinyl) pyrido [2,3-d] pyrimidine 4-amino-5- (3-bromophenyl) -6- (4-fluorophenyl) -7- (6-morpholinyl-3-pyridinyl) pyrido [2,3-d] pyrimidine; 4-amino-5-phenyl-6-phenyl-7- (6-morpholinyl-3-pyridinyl) pyrido [2,3-d] pyrimidine; 4-amino-5- (3-bromophenyl) -6-phenyl-7- (6-morpholinyl-3-pyridinyl) pyrido [2,3-d] p i r i m i d a; 4-amino-5-phenyl-6-phenyl-7- (6- (N-methyl-N- (2-methoxyethyl) amino) -3-pyridinyl) pyrido [2,3-d] pyrimidine; 4-amino-5- (4-bromothienyl) -6-phenyl-7- (6- (N-methyl-N- (2-methoxyethyl) amino) -3-pyridinyl) pyrido [2,3-d] pyrimidine; 4-amino-5- (4-bromothienyl) -6-cyclopropyl-7- (6-dimethylamino-3-pyridinyl) p-irido [2,3-d] pyrimidine; 4-amino-5- (4-bromothienyl) -6- (4-fluorophenyl) -7- (6-morpholinyl-3-pyridinyl) p-irido [2,3-d] pyrimidine; 4-amino-5- (3-bromophenyl) -6-phenyl-7- (6-cyclopropylmethylamino-3-pyridinyl) pyrido [2,3-d] pyrimidine; 4-Amino-5-phenyl-6-phenyl-7- (6-cyclopropylmethylamino-3-pyridinyl) pyrido [2,3-d] pyrimidine; 4-amino-5- (3-bromophenyl) -6- (4-fluorophenyl) -7- (6-morpholinyl-3-pyridinyl) piido [2,3-d] pyrimidine; 4-amino-5- (3-chlorophenyl) -6-heptyl-7- (6-morpholinyl-3-pyridinyl) pyrido [2,3-d] pyrimidine; 4-amino-5-phenyl-6-phenylmethyl-7- (6-morpholinyl-3-pyridinyl) pyrido [2,3-d] pyrimidine; 4-amino-5- (4-bromothienyl) -6-heptyl-7- (6-morpholinyl-3-pyridinyl) pyrido [2,3-d] pyrimidine; 4-amino-5- (4-bromothienyl) -6- (1-methylethyl) -7- (6-morpholinyl-3-pyridinyl) pyrido [2,3-d] pyrimidine; 4-amino-5- (4-bromothienyl) -6-phenylmethyl-7- (6-morpholinyl-3-pyridinyl) pyrido [2,3-d] pyrimidine; 4-amino-5- (3-bromophenyl) -6-cyclohexyl-7- (6-dimethylamino-3-pyridinyl) pyrido [2,3-d] pyrimidine; and 4-amino-5- (3-bromophenyl) -6-pentyl-7- (6-dimethylamino-3-pyridinyl) pyrido [2,3-d] pyrimidine, and their pharmaceutically acceptable salts and amides. The partially saturated and fully saturated versions of the above compounds are also included within the scope of the method for inhibiting adenosine kinase in a patient in need of such treatment. The above compounds can be treated with hydrogen and a catalyst to form a compound of the formula I, wherein the double bonds on the right side are absent or there is a double bond between the carbons 5,6; carbon 6.7 or carbon 7, carbon 8. Groups R3, R4 and R5 can be independently selected from: phenyl; thiophen-2-yl; 1-methyl-2-oxobenzoxazolin-5-yl; 2- (dimethylamino) -5-pyrimidinyl; 2- (N-formyl-N-methylamino) -3-pyrimidinyl; 2- (N- (2-methoxyethyl) -N-methylamino) -5-pyrimidinyl; 5-dimethylamino-2-pyridinyl; 5- (N- (2-methoxyethyl) -N-methylamino) -2-pyridinyl; 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-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-fluoro-n-nyl; 4- (dimethylamino) phenyl; 4- (imidazol-1-yl) phenyl; 4- (methylthio) phenyl; 4- (morpholinyl) phenyl; 4- (N- (2- (dimethylamino) ethyl) -amino) phenyl; 4- (N- (2-methoxyethyl) amino) phenyl; 4- (N-acetyl-N-methylamino) phenyl; 4- (N-ethyl-N-formylamino) phenyl; 4- (N-ethylamino) phenyl; 4- (N-formyl-N- (2-methoxyethyl) amino) phenyl; 4- (N-isopropylamino) phenyl; 4- (N-methyl-N - ((2-dimethylamino) ethyl) amino) phenyl; 4- (N-methyl-N- (2- (N-phthalimidyl) acetyl) amino) phenyl; 4- (N-methyl-N- (2-cyano) ethylamino) phenyl; 4- (N-methyl-N- (2-methoxyethyl) amino) phenyl; 4- (N-methyl-N- (3-methoxy) propionylamino) phenyl; 4- (N-methyl-N-acetylamino) phenyl; 4- (N-methyl-N-formylamino) phenyl; 4- (N-methyl-N-trifluoroacetylamino) faith nile; 4- (N-morpholinyl) faith nyl; 4- (thio faith n-2-il) nil faith; 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; 4- (4-methylpiperidinyl) -phenyl; 4- (5-pyrimidinyl) phenyl; 4-aminophenyl; 4-bromophenyl; 4-butoxyphenyl; 4-carboxamidophenyl; 4-chlorophenyl; 4-cyanophenyl; 4-diethylaminophenyl; 4- (diethylmalonylalyl phenyl); 4-dimethylaminophenyl; 4-ethoxyphenyl; 4-ethyl-f-enyl; 4-fluorophenyl; 4-hydroxyphenyl; 4-imidazolylphenyl; 4-iodophenyl; 4- isopropylphenyl; 4-methoxyphenyl) 4-methylaminophenyl; 4-methylsulfonylphenyl; 4-morpholinyl phenyl; 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-dimethylaminopyridazin-6-yl; -dimethylamino-2-pyridyl; 5-pyrimidinylphenyl; 6- (N-methyl-N-formyl-amino) -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; pentyl; thiof en-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-methyl bromide 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; -bromo-4-fluorophenyl, 3-bromo-5-iodophenyl, 3-bromo-5-methoxyphenyl, 3-bromophenyl, 3-bromophenylmethyl 3-carboxamidophenyl; 3-chlorophenyl; 3-cyanophenyl; 3-diethylmalonylalyl phenyl; 3-dimethylaminophenyl; 3-ethoxyphenyl; 3-fluoro-5-trifluoromethylphenyl; 3-fluorophenyl; 3-hydroxyphenyl; 3-iodophenyl; 3-methoxyethioxyphenyl, 3-methoxyphenyl; 3-methylphenyl; 3-methylsulfonylphenyl; 3-methylthiophenyl; 3-t-butylacrylphenyl; 3-trifioromethioxyphenyl; 3-trif luoro methyl nyl; 3-vinylpyridinylphenyl; 3, 4-diclo rhephenyl; 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-trifluoromethylphenyl; 4-methoxyphenyl; 4-neopentylphenyl; 4-phenoxyphenyl; 5-bromothiophen-2-yl; cyclohexyl; cyclopropyl; hexyl; methyl; phenyl; (2-bromo-5-chlorophenyl) methyl; (2-bromophenyl) methyl; 6-cyclopropyl-methylamino-3-pyridinyl; and (5-chloro-2- (3-methoxyphenyl) phenyl) methyl. The term "acyl", as used herein, refers to a portion linked through a carbonyl bond, such as, for example, lower alkylcarbonyl or arylcarbonyl, wherein lower alkyl and aryl are as defined in the present. Examples of acyl include, for example, acetyl, propionyl, hexanoyl, trifluoroacetyl, benzoyl, 4-methylbenzoyl, methoxyacetyl, pentanoyl, N-Bocglycylamidozoyl, N-phthalimidylglycyl and the like or others as specified herein. The term "aryl" or "substituted aryl", as used herein, refers to a carbocyclic aromatic radical, which includes, for example, phenyl and 1- or 2-naphthyl, which may be unsubstituted or substituted respectively through the replacement of one, two or three of the hydrogen atoms with groups Cl, Br, F, I, cyano, carboxamido, hydroxy, lower alkoxy, lower alkyl, lower alkenyl, lower alkynyl, amino, lower alkylamino, di ( alq ui the lower-amino), N-lower alkyl-N-lower alkoxyamino, trifluoromethyl or methoxymethyl. In addition, the term "aryl" refers to a phenyl group substituted with a ureido, methylsulfonyl, pyrimidinyl, pyridinyl, pyridazinyl, morpholinyl, phenylalkoxy, phenylalkenyl or cycloalkyl-lower alkyl 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-methoxy) ethylaminophenyl, 4-dimethylaminophenyl, 3-fluoro-4-methylphenyl, 4-methylphenyl, 4-cyanophenyl, 4-propylmethyl, 3,5-dichlorophenyl, 3,4-methylenedioxyphenyl, 3 -cyanopropylphenyl, 4-ureidophenyl, 3-methylsulfonylphenyl, 3-carboxamidopropylphenyl, and others as shown herein. The term "arylalkyl" refers to a lower alkyl radical having an aryl group attached thereto, as defined above, such as benzyl and phenylethyl. The term "aryloxy" refers to an aryl radical, which is attached to the molecule via an ether linkage (ie, through an oxygen atom), such as 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, cyclohexyl and cycloheptyl. Cycloalkyl is also described as cycloalkyl of 3 to 8 carbon atoms. The term "cycloalkyl-lower alkyl" refers to a lower alkyl radical as defined below, substituted with a cycloalkyl group, as defined above, by the replacement of a hydrogen atom. Examples of cycloalkyl-lower alkyl include cyclopropylmethyl, cyclobutyl halide, cyclopentylmethyl, cyclohexylmethyl and cycloheptylbutyl, and the like. The term "heteroaryl" or "substituted heteroaryl" refers to a monocyclic aromatic radical having from 5 to 7 ring atoms, of which a ring atom is nitrogen, oxygen or sulfur; zero, one or two ring atoms are additional heterogeneous atoms independently selected from S, O and N; and the remaining ring atoms are carbon, the radical being attached to the rest of the molecule via any of the ring atoms. A heteroaryl group may be unsubstituted or substituted by the independent replacement of one, two or three of the hydrogen atoms thereon with Cl, Br, F, I, cyano, carboxamido, hydroxy, lower alkoxy, lower alkyl, groups. lower alkenyl, lower alkynyl, amino, lower alkylamino, di (lower alkylamino), N-lower alkyl-N-lower alkoxyamino, trifluoromethyl or methoxymethyl. In addition, the term "heteroaryl" refers to a heteroaryl group substituted with a ureido, methylsulfonyl, pyrimidinyl, pyridinyl, pyridazinyl, morpholinyl, phenyl-lower alkoxy, phenyl-lower alkenyl or cycloalkyl-lower alkyl group. In addition, a heteroaryl group can be substituted by replacing any of the 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-methylthiophen-2-yl, 5-nitrothiophen-2-yl, 5-methylfuranyl, benzofuranyl, benzothiophenyl, and the like and those additionally described herein. The term "heterocyclic" refers to a saturated or unsaturated monocyclic ring system radical having from 4 to 7 ring atoms of which one is nitrogen or oxygen; zero, one or two ring atoms are additional heterogeneous atoms independently selected from S, O and N; and the remainder is carbon, the radical being attached to the rest of the molecule via any of the ring atoms and being optionally substituted, either on a nitrogen or carbon atom, through an additional radical selected from ary I ( alko lower), alkoxycarbonyl, lower alkyl, halo (lower alkyl), amino (lower alkyl), lower alkyl substituted with hydroxy, hydroxy, lower alkoxy, halogen, amino, lower alkylamino and amino, (lower alkyl) amino or alkanoylamino of one to eight carbon atoms wherein the amino group can be further substituted with alkanoyl of 1 to 8 carbon atoms, 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-lower alkyl" refers to a lower alkyl radical as defined below substituted with a heterocyclic group as defined above, through the replacement of a hydrogen atom. Examples of cycloalkyl-lower alkyl include pyrrolidinylmethyl, piperidinylethyl, and the like. The term "lower alkyl", as used herein, refers to straight or branched chain saturated hydrocarbon radicals containing from 1 to 6 carbon atoms including, which may be unsubstituted or substituted by independent replacement of one, two or three of the hydrogen atoms therein with Cl, Br, F, I, cyano, carboxamido, hydroxy, lower alkoxy, amino, lower alkylamino, di (lower alkylamino) or N-lower alkyl-N- groups. lower alkoxyamino. Examples of lower alkyl include, but are not limited to, methyl, ethyl, propyl, isopropyl, n-butyl, tert-butyl, neopentyl, n-hexyl, hydroxyethyl, methoxymethyl, trifluoromethyl, 3-cyanopropyl, 3-carboxamidopropyl, and the like. . In certain cases, the "C 1 -C 6 alkyl" group is described and has a similar meaning as previously given for lower alkyl, but is more specifically presented. Also, the term "alkyl from 0 to carbon atoms" indicates the carbon atoms, which may be present in the alkyl chain including zero. These terms are also provided adjacent to aryl or heteroaryl or other generic group and represent or have the same meaning as, for example, "arylalkyl" or "heteroarylalkyl". The term "lower alkenyl", as used herein, refers to straight or branched chain mono-unsaturated hydrocarbon radicals containing from 2 to 6 carbon atoms including, but not limited to, vinyl, propenyl, n-butenyl , i-butenyl, n-pentenyl, and n-hexenyl. These variables are also presented as, for example, alkenyl of 2 to 6 carbon atoms. The term "lower alkoxy" refers to a lower alkyl radical, which is attached to the molecule via an ether linkage (ie, through an oxygen atom), such as, for example, methoxy, ethoxy, propoxy, 2- propoxy, 2-methyl-2-propoxy, tert-butoxy, pentyloxy, hexyloxy, isomeric forms thereof, and the like. This term is also described as alkyloxy of 1 to 6 carbon atoms. The term "lower alkynyl", as used herein, refers to straight or branched chain hydrocarbon radicals possessing an individual triple bond and containing from 2 to 6 carbon atoms including, but not limited to, ethinyl, propynyl , n-butynyl, n-pentynyl, and n-hexynyl. This term is also described as alkynyl of 2 to 6 carbon atoms. The term "mammal" has its ordinary meaning and includes human beings. In a further aspect of the present invention, pharmaceutical compositions are described which comprise a compound of the present invention in combination with a pharmaceutically acceptable carrier. The present invention includes one or more compounds, as set forth above, formulated in compositions together with one or more physiologically tolerable or acceptable non-toxic diluents, carriers, auxiliaries or vehicles, collectively referred to herein as diluents, for parenteral injection, for oral administration in solid or liquid form, for rectal or topical administration or the like. As is well known in the art, a compound of the present invention can exist in a variety of forms including pharmaceutically acceptable salts, amides, and the like. Compositions that will deliver the correct amount of a compound or compounds of the invention can be prepared. The following doses are believed to provide the optimal therapy: i.v infusions: 0.1-250 nmol / kg / minute, preferably 1-50 nmol / kg / minute; oral: 0.01-250 μmol / kg / day, preferably reference around 0.1-50 μmol / kg / day; These oral molar dose scales correspond to 0.005-125 mg / kg / day, preferably 0.05-25 mg / kg / day. For the treatment of acute disorders, the preferred route of administration is intravenous; The preferred method for treating chronic diseases is orally through a tablet or sustained release formulation. "Pharmaceutically acceptable amide" refers to the non-toxic, pharmaceutically acceptable amides of the present invention, which include amides formed with suitable organic acids or amino acids, including short peptides consisting of from 1 to 6 amino acids joined by amide bonds, which can be branched or linear, wherein the amino acids are independently selected 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, non-toxic, inorganic or organic acid addition salts of the compounds of the present invention, as described in greater detail below. The compounds of the present invention can be used in the form of pharmaceutically acceptable salts derived from inorganic or organic acids. These salts include, but are not limited to the following: acetate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, camphorate, camphor sulfonate, citrate, cyclopentanpropionate, digluconate, dodecyl sulfate, ethanesulfonate, flavianate, fumarate, glucoheptonate, glycerophosphate, hemisulfate, heptonate, hexonoate, hydrochloride, hydrobromide, iodhydrate, 2-hydroxy-ethanesulfonate, lactate, maleate, methanesulfonate, nicotinate, 2-naphthalenesulfonate, oxalate, palmate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, succinate, tartrate, thiocyanate, tosylate and undecanoate. Also suitable cationic salts are easily prepared by conventional methods such as treating an acid of Formula I or II with an appropriate amount of a base, such as an alkali metal or alkaline earth metal hydroxide, for example, sodium, potassium, lithium, calcium, or magnesium, or an organic base such as an amine, for example, dibenzylethylenediamine, cyclohexylamine, dicyclohexylamine, triethylamine, piperidine, pyrrolidine, benzylamine, and the like, or a quaternary ammonium hydroxide such as tetramethylammonium hydroxide and the like. Also, groups containing basic nitrogen can be quaternized with agents such as lower alkyl halides, such as methyl, ethyl, propyl and butyl chlorides, bromides and iodides; dialq or ilsu If atos; long chain halides such as decyl, lauryl, myristyl and stearyl chlorides, bromide and iodides; Arylalkyl halides such as benzyl and phenethyl bromides, and others. In this way, soluble or dispersible products are obtained in water or oil. The salts of the present invention can be synthesized from the compounds of Formula I or II, which contain a basic or acid portion through conventional methods, such as reacting the free base or acid with stoichiometric amounts or with a excess of the desired salt by forming an inorganic acid or base in a suitable solvent or various combinations of solvents. Also 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 pharmaceutically acceptable, non-toxic carrier compositions, as described below.

Compositions suitable for parenteral injection may comprise pharmaceutically acceptable, sterile solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Examples of suitable aqueous or non-aqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols (propylene glycol, polyethylene glycol, glycerol and the like), suitable mixtures thereof, vegetable oils (such as olive oil) and organic esters injectables such as ethyl oleate. An appropriate fluidity can be maintained, for example, through the use of a coating such as lecithin, through the maintenance of the required particle size in the case of dispersions, and through the use of surfactants. These compositions may also contain auxiliaries such as preservatives, humectants, emulsifiers and dispersants. The prevention of the action of microorganisms can be ensured through various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, and the like. It may also be desirable to include isotonic agents, for example, sugars, sodium chloride, and the like. Prolonged absorption of the injectable pharmaceutical form can be produced through the use of absorption retardation agents, for example, aluminum, monostearate and gelatin. If desired, and for a more effective distribution, the compounds can be incorporated into slow delivery or target delivery systems, such as polymer matrices, liposomes and microspheres. These can be sterilized, for example, by filtration through a bacteria retention filter, or by incorporating sterilization agents in the form of solid, sterile compositions, which can be dissolved in sterile water, or some other injectable, sterile medium. , immediately before use. Dosage forms for oral administration may include capsules, tablets, pills, powders, and granules. In said solid dosage forms, the active compound is mixed with at least one customary (or carrier) inert excipient, such as sodium citrate or dicalcium phosphate, and in addition, (a) fillers or extension agents, such as, for example, starches, lactose, sucrose, glucose, mannitol and silicic acid; (b) binders, such as, for example, carboxymethyl cellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose and acacia; (c) humectants, such as, for example, glycerol; (d) disintegrating agents, such as for example, agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates and sodium carbonate; (e) solution retarders, such as, for example, paraffin; (F) absorption accelerators, such as, for example, quaternary ammonium compounds; (g) wetting agents, such as, for example, cetyl alcohol and glycerol monostearate; (h) adsorbents, such as, for example, kaolin and bentonite; and (i) lubricants, such 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 can also comprise pH regulating agents. Solid compositions of a similar type can also be used as fillers in soft and hard filled gelatin capsules, using excipients such as lactose or milk sugar, as well as high molecular weight polyethylene glycols, and the like. Solid dosage forms such as tablets, dragees, capsules, pills and granules can be prepared with coatings and shells, such as enteric coatings and others well known in the art. These may contain opacifying 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 imbibition compositions, which can be used, are polymeric substances and waxes. The active compounds may also be in a micro-encapsulated form, if appropriate, with one more of the aforementioned excipients. Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups and elixirs. In addition to the active compounds, the liquid dosage forms may contain inert diluents commonly used in the art, such as water or other solvents, solubilization agents and emulsifiers, such as, for example, ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl, benzyl alcohol, benzyl benzoate, propylene glycol 1,3-butylene glycol, dimethylformamide, oils, in particular, cottonseed oil, ground walnut oil, corn germ oil, olive oil, castor oil and sesame oil, glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and sorbitan fatty acid esters or mixtures of these substances, and the like. In addition to said inert diluents, these liquid dosage forms may also include auxiliaries, such as wetting agents, emulsifying and suspending agents, sweetening, flavoring and perfume-providing agents. The suspensions, in addition to the active compounds, may contain suspending agents, such as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum tetrahydroxide, bentonite, agar-agar and tragacanth, or mixtures of these substances , and similar. Compositions for rectal or vaginal administration are preferably suppositories which can be prepared by mixing the compounds of this invention with suitable non-irritating excipients or carriers, such as cocoa butter, polyethylene glycol or a suppository of wax, which are solids 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 also include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants or transdermal patches. Transdermal administration via a transdermal patch is a particularly effective and preferred dosage form of the present invention. The active component is mixed under sterile conditions with a pharmaceutically acceptable carrier and any necessary preservatives, pH regulators, or propellants as required. It is known that some agents may require special handling in the preparation of transdermal patch formulations. For example, compounds that are volatile in nature may require mixing with special formulating agents or with special packaging materials to ensure an adequate supply of the dose. In addition, compounds that are very rapidly adsorbed through the skin may require formulation with delaying absorption agents or barriers. Also within the scope of the present invention are ophthalmic formulations, eye ointments, powders and solutions. The compounds of the present invention can also be administered in the form of liposomes. As is known in the art, liposomes are generally derived from phospholipids or other lipid substances. Liposomes are formed through mono- or multilamellar hydrated liquid crystals that are dispersed in an aqueous medium. Any non-toxic, physiologically acceptable and metabolizable lipid capable of forming liposomes can be used. The compositions herein in liposome form may contain, in addition to the compounds of the present invention, stabilizers, preservatives, excipients and the like. The preferred lipids are phospholipids and phosphatidylcholines (lecithins), both natural and synthetic. Methods for forming liposomes are known in the art. See, for example, Prescott, Ed., Methods in Cell Bioloqy, Volume XIV, Academic Press, New York, N. Y. (1976), p. 33 et seq.

Synthetic Methods The compounds and processes of the present invention will be better understood in conjunction with the following synthetic schemes, which illustrate the methods by which the compounds of the invention can be prepared. The groups R1, R2, R3, R4 and R5 are as defined above, unless what is continued is observed. The compounds of the present invention can be synthesized through the methods illustrated in Schemes 1-3.

SCHEME 1 R4-CH2-CO-Y + CH3-NH-O-CH3 3 ^ 5 (D According to Scheme 1, the 5,6,7-trisubstituted compounds, wherein R 5 and R 3 are aryl, heteroaryl or a heterocyclic group, and R 4 is lower alkyl, lower alkenyl, lower alkynyl, aryl, arylalkyl, heteroaryl or a Heterocyclic group, are prepared through a modification of a method of Kambe et al, Synthesis, 1980, 366-368. The N-methoxy-N-methylamide compounds (3) can be prepared from the appropriate carboxylic acid derivative (1, "reagent R4"), wherein Y is OH or Cl, and R4 is lower alkyl, lower alkenyl, alkynyl lower, aryl, arylalkyl, heteroaryl, or a heterocyclic group, through treatment with N, O-dimethylhydroxylamine hydrochloride (2) and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide (EDCI), t-butanol and triethylamine. The reaction can be carried out in methylene chloride, or a similar suitable solvent, such as for example, toluene or THF, at room temperature for about 8 to about 24 hours. The compound (3) is then reacted with compounds (4, "the reagent R4"), wherein R5 is substituted aryl, heteroaryl, or heterocyclic compounds to prepare the compound (5) according to the Nahm literature procedure and Weinreb (Tetrahedron Leff.1981, 22 .: 3815). The compounds (4) can be obtained commercially or can be easily prepared by standard methods in the art. The compound (5) is then reacted with an appropriately substituted aldehyde (6)., "Reagent R3"), wherein R3 is aryl, heteroaryl or a heterocyclic group, and malononitrile (7) by heating in the presence of ammonium acetate, or other suitable ammonium salt, such as, for example, ammonium propionate, iodide of ammonium, or the like, in a suitable solvent to produce the compound (8). Suitable solvents include ethanol, benzene, toluene, methylene chloride, DMF, THF, dioxane, and the like. The water of the reaction can be removed through the use of a Dean Stork apparatus or through other suitable means, such as 4Á molecular sieves. The reaction can be carried out from about 40 ° C to about 200 ° C, and preferably at the reflux temperature of the solvent, for about 1 hour to about 24 hours, preferably about 4 hours to 8 hours. The product (8) is preferably purified through chromatography after isolation from the reaction mixture. Suitable aldehyde starting materials (6) can be obtained commercially, or can be prepared easily, for example, through reductions of esters or acids with DIBAL or other suitable hydride reducing agent, or oxidation of alcohols under Swern, for example. Aliphatic aldehydes do not work effectively through this route. The ketone (5), however, can include R5 as alkyl groups. The compound (8) is then treated with excess formamide by refluxing. The formation of the product is verified through TLC, and when the reaction is complete (after about 1 to about 8 hours), the reaction mixture is cooled to room temperature. The desired pyrido [2,3-d] pyrimidine 5,6,7-trisubstituted product (I) is then removed by filtration and purified by column chromatography. This compound can then be reacted partially or completely through catalytic hydrogenation to the partially saturated or fully saturated version (s) (on the right side of the molecule) of the compounds shown in Scheme I or of the formula I. Within the Scope of the invention includes stereoisomers produced in the process or reduction step (s). The invention also includes those compounds wherein an individual bond is between positions 5,6 and 7,8 and a double bond is present among the 6,7 carbons. The stereoisomers can be isolated and purified by conventional means. In an alternative procedure, the compound (8) is treated by heating with formamidine acetate in ethoxyethanol or diglyme, followed by purification through flash chromatography. In another alternative procedure, the compound (8) and the ammonium sulfate are heated to reflux in triethyl orthoformate for about 1 to about 8 hours, but preferably about 2 hours. The reaction mixture is cooled and added to a mixture of ammonia in ethanol. The mixture is stirred for approximately 12 to 24 hours at 25 ° C, then refluxed for from one to 4 hours, and the solvent is removed under vacuum. The residue is purified by titration with chloroform / ethyl acetate, and the product can be converted to a hydrochloride salt through suspension in 3M HCl, followed by lyophilization. It is possible to prepare the desired compound of Formula (I), wherein R and R2 are not hydrogen atoms of the compound of Formula (I), wherein R1 and R2 are both hydrogen atoms. When R1 or R2 is lower alkyl, this can be achieved by reducing the free amino group with the appropriate alkylating reagent, such as an alkyl halide, an alkyl mesylate or an alkyl tosylate, for example, in the presence of a base such as triethylamine or potassium carbonate in a suitable solvent, such as, for example, methylene chloride or THF. When R1 or R2 is arylalkyl, this can be achieved by reaction of the free amino group with the appropriate arylalkyl halide., an alkyl mesylate or an alkyl tosylate, for example, in the presence of a base such as triethylamine or potassium carbonate in a suitable solvent, such as, for example, methylene chloride or THF. When R1 or R2 is acyl, this can be achieved by reaction of the free amino group with the appropriate acid anhydride, acyl chloride or an activated acyl group, in the presence of a base such as triethylamine or potassium carbonate in a suitable solvent, such as, for example, methylene chloride or THF. When R1 and R2 are taken together with the nitrogen atom to which they are attached to form a 5- to 7-membered ring optionally containing an additional oxygen or nitrogen atom, the compound can be prepared by reacting a precursor compound having an oxygen atom. halogen in place of the amino group in the 4-position with a 5-7 membered ring optionally containing an additional oxygen or nitrogen atom. The precursor compound having a halogen atom in place of the amino group in the 4-position can be prepared through substitution of treatment with sulfuric acid with heating, followed by treatment with triethyl orthoformate for treatment with formamide (cf. Scheme 1, wherein compound (8) is converted to compound (I)) followed by chlorination at the 4-position of the ring through treatment with phosphorous oxychloride or thionyl chloride. Also, this alternative procedure can be used to prepare amino compounds substituted with alkyl, for example, by reacting the chloro compound with a mono- or disubstituted amine, such as, for example, diethylamine, allylamine, dibutylamine. This reaction easily takes place in a solvent such as methylene chloride, for example, in the presence of a tertiary amine. Examples of possible rings, wherein R1 and R2 are taken together with the nitrogen atom to which they are attached to form a 5- to 7-membered ring optionally comprising an additional oxygen or nitrogen atom, include, but are not limited to, morpholine, piperidine, pyrrolidine, piperazine, thiomorpholine, and the like.

SCHEME 2 Scheme 2 illustrates an alternative method for preparing the compounds (8) of Scheme 1. Compounds (5), prepared as described above, are reacted with a dicyanalkene compound (10) by heating under reflux in an alcohol solvent, example, ethanol or n-butanol to give the compound (8). The dicyano compounds (10) can be prepared from the precursor aldehyde (6) through treatment with malononitrile in 1: 1 H 2 O: EtOH in the presence of a catalytic amount of glycine according to the method of Bastus (Tetrahedron Lett. 1963: 955).

SCHEME 3 Scheme 3 illustrates an alternative method for preparing compounds of Formula (I), wherein R 4 and R 3 are the same substituent. A bis-substituted acetylene derivative (11) is treated with catecoiborane in THF at reflux for about 8 to about 48 hours, then 4,6-diamino-5-iodo-pyrimidine (12), saturated aqueous sodium bicarbonate, hydroxide are added of 3N aqueous sodium and tetrakis (triphenylphosphine) palladium (0). The mixture was then heated to reflux for about 8 to about 48 hours to give the substituted pyrimidine compound (13). The compound (13) is then reacted with the appropriately substituted aldehyde compound (14) to give the desired compound of the Formula (I).

SCHEME 4 18 , cf Scheme 2 An alternative procedure for preparing compounds of the formula (5) is shown in Scheme 4. This procedure is particularly useful when it is desired to have a substituted aryl or a heteroaryl portion in the R5 position. A compound (15) containing the desired portion R4 can be reacted with an acyl halide of a halo-substituted compound (16), the ring of which for purposes of illustration only, is shown as a pyridyl ring (e.g. 2-halo-5-pyridine carboxylic acid), to give the compound (17). The compound (17) in turn is heated to the decarboxylate and gives the compound (18). Alternatively, compound (16) can be treated in a two-step procedure, first with N-methoxymethylamine HCl, then treating the intermediate with compound (19) under Grignard conditions to prepare compound (18). The compound (18) can then be reacted with an appropriate amine compound (20), wherein the compound (20) can be a heterocyclic compound, such as piperidine, pyrrolidine or morpholine, for example, or it can be a protected amine or substituted, that is, wherein R 'and R "are either substituents or amine protection groups, or R' and R" are taken together with the N atom to which they are attached to form a heterocyclic ring, in order to prepare the compound (5).

Method for Inhibiting Kinase In another aspect of the present invention, a method for inhibiting adenosine kinase is described. According to that process, an adenosine kinase enzyme is exposed to an effective inhibitory amount of an adenosine kinase inhibitor compound of the present invention. The preferred compounds for use in the method are the same as those set forth above. The means for determining an effective inhibitory amount are well known in the art. The adenosine kinase that is to be inhibited can be localized in vitro, in situ or in vivo. When the adenosine kinase is localized in vivo, the kinase adenosine is contacted with the inhibitor compound, typically by adding the compound to an aqueous solution containing the enzyme, radiolabelled 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 and under suitable physiological conditions. The means for determining maintenance are well known in the art and depend, among other things, on the concentrations of the enzyme and physiological conditions. The appropriate physiological conditions are those necessary to maintain the viability of the adenosine kinase and include temperature, acidity, tonicity and the like. Inhibition of adenosine kinase can be performed, for example, according to standard procedures well known in the art (Yamada et al., Comp .. Biochem. Physiol., 1982, 71B: 367-372). When the adenosine kinase is localized in situ or in vivo, a compound of the invention is typically administered to a fluid that perfuses the tissue containing the enzyme. That fluid can be a naturally occurring fluid such as blood or plasma or an artificial fluid such as saline, Ringer's solution, and the like. A method for inhibiting adenosine kinase in vivo is particularly useful in mammals, such as humans. Administration of an inhibitor compound is typically achieved through parenteral administration (e.g., intravenous or oral injection) of the compound. The amount administered is an effective inhibitory 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 disorders related to adenosine kinase, which broadly include those diseases, disorders or conditions that are benefited by the inhibition of adenosine kinase, at a reasonable risk / benefit ratio applicable to any medical treatment. However, it should be understood that the total daily use of the compounds and compositions of the present invention will be decided by the attending physician within the scope of the medical judgment. The therapeutically specific dose level for any particular patient will depend on a variety of factors, including the disorder being treated and the severity of the disorder; the activity of the specific compound employed; the specific composition employed; age, body weight, general health, gender and diet of the patient; the administration time, route of administration and the rate of excretion of the specific compound employed; the duration of the treatment; drugs used in combination or coinciding with the specific compound used; and similar factors well known in the medical field and within the capabilities of the physicians they serve. The compositions of the present invention inhibit the activity of adenosine kinase in vitro and in vivo. The in vitro activity of adenosine kinase can be measured using any of the standard procedures well known in the art. By way of example, cells containing adenosine kinase, such as human neuroblastoma IMR-32 cells, are cultured in the presence and absence of an inhibitor. Inhibition is measured as the ability to inhibit the phosphorylation of 1 C-adenosine endogenously or externally applied by these cells. The cells may be intact or separated. The specific character of the adenosine kinase inhibitory activity is determined by studying the effects of inhibitors on adenosine A1a and A2a receptor binding, adenosine deaminase activity and adenosine transport. The compounds of the present invention are effective in inhibiting the activity of adenosine kinase in vivo. Numerous animal models to study the activity of adenosine kinase and the effects to inhibit said activity are well known in the art. For example, it has been reported that adenosine kinase inhibitors protect rodents (eg, mice and rats) from attacks induced by the subcutaneous administration of pentylenetetrazole (PTZ). Typically, rodents are injected with several doses of a given inhibitor followed several times by subcutaneous administration of about 10 to about 50 milligrams per kilogram of PTZ. The animals injected later are observed for the beginning of attacks. The compounds of the invention were tested in vivo in the warm plate test of analgesia in mammals, such as mice. For example, the compounds of examples 19 and 27 in the procedure described directly below were tested 30 times after treatment with the drugs (30 μmol / kg i.p.) for a 10-step latency (in seconds). The larger the number of seconds, the more effective the drug is in masking the pain felt by the hot plate. Compound 19 resulted in 142.13 seconds in relation to the vehicle only of 72.76 + .10.51. Compound 27 yielded 154.86 seconds. The compounds of the invention, therefore, are potent pain relievers as demonstrated in this animal model.

Hot Plate Assay in Mice Male CFI mice (Charles River) weighing approximately 25-30 g were pretreated with 10 ml / kg of the test compounds, i.p. or p.o., in groups of 8 animals per dose. At the end of the pretreatment period, the mice were placed in an apparatus, Omnitech Electronics Automated 16 Animal Hot Guide Analgesia Monitor (Columbus, OH; Model AHP16AN) in individual plastic enclosures, 9.8 x 7.2 x 15.3 cm (I xwxh) on the upper part of a copper plate heated to 55 ° C. Infrared sensors located near the top of each enclosure recorded the light beam crosses that occur as the mice jump on the hot surface. The latency times for each jump are automatically recorded, and the latency in both the first jump and the tenth jump was used for data analysis. Mice that did not reach the criterion of 10 jumps in 180 seconds were immediately removed from the hot plate to avoid tissue damage, and were assigned the maximum value of 180 seconds as their latency at their tenth jump. Numerous other animal models of adenosine kinase activity have been described [see, for example, Davies, et al., Biochem. Pharmacol., 33: 347-355 (1984); Keil, et al., Eur. J. Pharmacol., 271: 37-46 (1994); Murria et al., Drug Development Res., 28: 410-415 (1993)]. Numerous inhibitor compounds of the present invention were tested in vitro and found to inhibit the activity of adenosine kinase. The results of some representative studies are shown in Table 1 below. The data indicate that the compounds inhibit adenosine kinase.

TABLE 1 Inhibition of Adenosine Kinase by the Representative Compounds of the Invention Method for treating cerebral ischemia, epilepsy, nociception (pain), inflammation including conditions such as septic shock due to sepsis infection. In yet another aspect of the present invention, a method is described for treating cerebral ischemia, epilepsy, nociception or nociception, inflammation including conditions such as septic shock due to infection by sepsis in a human or lower mammal, which comprises administering to the mammal a therapeutically effective amount of a compound. Alterations in adenosine kinase activity have been observed in certain disorders. It was found that the activity of adenosine kinase is reduced, in relation to normal liver, in a variety of rat hepatomas: the activity of the enzyme giving a negative correlation with a tumor growth regime (Jackson et al. Br. J. Cancer, 1978, 37: 701-713). Adenosine kinase activity was also decreased for liver regeneration after partial hepatectomy in experimental animals (Jackson et al., Br. J. Cancer, 1978, 37: 701-713). It was found that erythrocyte adenosine kinase activity can be decreased in patients with gout (Nishizawa et al., Clin.Chem. Acta 1976, 67: 15-20). The lymphocyte adenosine kinase activity was reduced in patients infected with the human immunodeficiency virus (HIV) exhibiting symptoms of AIDS, and was reported in high-risk HIV-seropositive and HIV-seronegative subjects, compared with health controls normal (Renouf et al., Clin.Chem. 1989, 35: 1478-1481). It has been suggested that the measurement of adenosine kinase activity may prove useful in verifying the clinical progress of HIV patients (Renouf et al., Clin.Chem. 1989, 35: 1478-1481). Infection by sepsis can lead to a systemic inflammatory syndrome (SIRS), characterized by an increase in cytosine production, neutrophil accumulation, hemodynamic effects and tissue damage or death. The ability of the adenosine kinase inhibitor to raise adenosine levels in tissues has been shown to mitigate the symptoms of the syndrome, due to the known anti-inflammatory effects of adenosine. (Firestien 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 shown that the administration of adenosine or its analogues results in antinociception or antinociception. (Swaynok et al., Neuroscience, 1989, 32: No. 3 pp. 557-569). The following examples illustrate preferred embodiments of the present invention and do not limit the specification and claims in any way.

EXAMPLE 1 4-Amino-5- (3-bromo-4-fluorophenyl) -6-pentyl-7- (4-dimethylamino) fe nil) pyridof2.3-d1-pyrimidine 4- (3-Bromo-4-fluorophenyl) -3-cyano-6- (dimethylaminophenyl) -5-pentyl-2-pyridinamine (951 mg, 1.98 mmol) in 2-ethoxyethanol was suspended followed by the addition of formamidine acetate (411 mg, 3.95 mmol). The reaction was heated at 130 ° C for two days, during which additional formamidine acetate (2-3 eq. Each) was added at various hour intervals. After this time, the reaction was cooled, concentrated in vacuo, and the residue was titrated with CH 2 Cl 2 and filtered. The filtrate was purified by flash chromatography (9% MeOH / CH2Cl2), which gave a red oil which was titrated with ethyl ether to yield the title compound as a yellow solid (174 mg, 17%). MS 508/510 (M + H) +; IR (cm-1) 3480, 2920, 1610, 1550, 820.

The 4-amino-5- (3-bromo-4-fluorophenyl) -6-pentyl-7- (4-dimethylamino) phenyl) pyrido [2,3-d] pyrimidine was prepared as follows: 1a. 1- (4-Dimethylaminophenyl) heptan-1-one was added dropwise triethylamine (19.6 g, 194 mmol) to a suspension of N, O-dimethylhydoxylamine hydrochloride (6.93 g, 71 mmol) in CH 2 Cl 2 at 0 ° C. Then heptanoyl chloride (9.60 g, 65 mmol) was added dropwise and the reaction was stirred for 1 hour. The crude product mixture was poured into water and the separated aqueous phase was extracted with CH2Cl2. The combined organic layers were washed with aqueous HCl, saturated NaHCO3, brine, dried (Na2SO4) and concentrated in vacuo to give 10 g (89%) of N-methyl-N-methoxyheptanamide as a yellow oil. N-Butyl lithium (2.5 M in hexanes, 51 mL, 127 mmol) was added dropwise to 4-bromo-N, N-dimethylaniline (23.1 g, 115 mmol, Aldrich Chemical Co.) in anhydrous THF at -78 ° C. C. After 10 minutes, a solution of N-methyl-N-methoxyheptanamide (10.0 g, 57.7 mmol) in 20 ml of THF was added dropwise through a cannula. The reaction was allowed to proceed for 1 hour, then quenched with 1N aqueous HCl and carefully emptied into saturated NaHCO3. The aqueous layer was extracted with ethyl ether, and the combined organic fraction was washed with water, brine, dried (MgSO4) and concentrated in vacuo. Flash chromatography (15% EtOAc / hexanes) yielded 1- (4-dimethylaminophenyl) heptan-1 -one as a yellow solid (6.49 g, 48%). MS 234 (M + H) +. 1 B. 4-Am i no - (3-brom or -4-f luorofenyl) -3-cyano-6- (d imeti lam i non-faith nyl) -5-pentyl-2-pyridinamine They were dissolved in 75 ml of benzene and were heated to reflux, 1- (4-dimethylaminophenyl) heptan-1 -one (2.15 g, 9.21 mmol), 3-bromo-4-fluorobenzaldehyde (1.87 g, 9.21 mmol, reagent R3), malononitrile (0.91 g, 13.8 mmoles) and NH4Oac (1.42 g, 18.4 mmoles). After three days, the crude reaction mixture was partitioned between EtOAc and H2O. The organic layer was washed with brine, dried over Na2SO4 and concentrated in vacuo. The residue was titrated with Et2O, and the resulting solid was collected through filtration yielding 1.25 g of the desired product as a yellow solid (28%): MS 444/446 (M + H) +.

EXAMPLES 2-10 Following the procedures of Example 1, except that by substituting the appropriate reagents required for R5, R4 and R3, as indicated in Table 2 below, optionally omitting the step of preparing the HCl salt, the compounds of Examples 2 were prepared -10 as described in Table 3 below.

C UAD RO 2 EJ EM PLOS 2-1 0 Ex. No. Reagent R (for Reagent R4 (for Reagent R3 (for Position 7) position 6) position 5) 2 2-bromot? Ofenohetanoyl chloride 3-bromo-4 fluorobenzaldehyde 3 1-bromo-4-4-methoxyphenol-3-bromobenzaldehyde chloride methoxybenzene acetyl 4 2 -bromotetreene butanoyl chloride 3-bromobenzaldehyde 2-bromot? Ofeno heptanoyl chloride 3-bromobenzaldehyde 6 2-bromot? Of? 3,4-d? Methox? Phen? L-3-bromobenzaldeh ido acetic acid 7 1-bromo-4- 4- (2-prop? L) phen? L-3-bromobenzaldehyde 1 (d? Met? Lam? No) benzene acetic 8 2-bromot? Ofeno ethyl succinyl chloride 3-bromobenzaldehyde 9 2-bromot? Ofeno acid 3- (3-methox? Phen? L) 3-bromobenzaldehyde propionic 10 1 -bromo-4- 3,4-d? Methox? Phen? L-3-bromobenzaldehyde acid 1 (d? Met? Lam? No) acetic ben C UAD RO 3 EJ EMP LOS 2 -1 0 Ex. Name Analytical Data No. 2 4-am? No-5- (3-bromo-4-fluorophen? L) -6- IR 3480, 2920, 1610, 1550, 820, pent? L-7- (t? Ofen-2-? L) p? R? Do [2,3- MS m / z 508/510 (M + H) + d] p? Pm? D? Na 3 4-am? No-5- (3-bromophen? L) -6- (4- IR 3480.3400.3070.1610.1550, MS methox? Fen? l) -7- (4- m / z 513 &515 (M + H) + methox? phen? l) p? r? do [2,3-d] p? rtm? d? na 4 4-am? no-5- (3-bromophen? l) -6-et? l-7- IR 3470.3390,3060,1550,1425, MS (t? ofen-2-? l) p? pdo [2,3- d] p? rim? d? na m / z 411 &413 (M + H) + 5 4-am? no-5- (3-bromophen? l) -6-pent? l-7- IR 3480.3300 , 3040.1550.1420, MS (t? Ofen-2-? L) p? R? Do [2,3-d] p? Pm? D? Na m / z 453 &455 (M + H) + 6 4-am? No-5- (3-bromophen? L) -6- (3,4-IR 3480.3390,3060,1545,1510, MS d? Methox? Phen?) -7- (t? Ofen -2- m / z 519 &521 (M + H) +? L) p? Pdo [2,3-d] p? R? M? D? Na 7 4-am? No-5- (3-bromophen 1) -6- (4- (2-IR 3470.3280,3060,1605.1540, MS prop?) fen? l) -7- (4 m / z 538 &540 (M + H) + (d? met? lam? no) fen? l) p? r? do [2,3-d] p? pm? d? na 8 4-am? no-5- (3-bromophen? l) hydrochloride -6- IR 3420 3060.1725.1600.1585, MS ethoxycarbon? Lmet? L-7- (t? Ofen-2-m / z 469 &471 (M + H) +? L) p? R? O [2,3 -d] p? r? m? d? na 9-ammo-5- (3-bromophen?) -6- (3- IR 3440,3040,1635,1600.1580, MS methox? fen? hydrochloride. lmet? l) -7- (t? ofer? -2- m / z 503 &505 (M + H) +? l) p? r? do [2,3-d] p? pm? d? na 10 4-amino-5- (3-bromopheryl) -6- (3,4-IR 3430,3020,1635,1600,1580, MS d? methox? phen?) -7- dihydrochloride ( 4- m / z 556 &558 (M + H) + (d? Met? Lam? R? O) fen? L) p? R? Do [2,3-d] p? R? M? D? Na EXAMPLE 11 4-Amino-5- (4-bromothiophen-2-yl) -6- (3,4-dimethoxy fe nyl) -7- (thio-fe-n-2-yl) pyrido 2,3-dlpyrimidine hydrochloride They were taken in 10 ml of diglyme and heated to 155 ° C, 3-cyano-4- (4-bromothiophen-2-yl) -5-pentyl-6- (thiophen-2-yl) -2-pyridinamine. (750 mg, 1.50 mmol) and formamidine acetate (312 mg, 3.00 mmol). Additional formamidine acetate (1 equivalent) was added at 90 minute intervals for a total of 6 hours, then heating was continued overnight. The cold reaction mixture was then partitioned between EtOAc and H2O. The organic layer was washed with brine, dried over Na2SO, and concentrated in vacuo. Vaporization chromatography (3.5% MeOH / CH 2 Cl 2) gave a brown residue, which was dissolved in a small amount of CH 2 Cl 2 followed by the addition of Et 2 O to precipitate the product (209 mg, 26%). This material was converted to the hydrochloride salt using 7M ethanolic HCl followed by precipitation with Et2O and filtration of the product. IR: 525/527: 3420, 2930, 1580, 1510, 820 cm 1; MS m / z 498 (M + H) +. 3-Cyano-4- (4-bromothiophen-2-yl) -5-pentyl-6- (thiophen-2-yl) -2-pyridinamine was prepared as follows: 11a. 2- (3,4-dimethoxyphenyl) -1- (thien-2-yl) ethanone Acid (3,4-dimethoxyphenyl) acetic acid (13.0 g, 66.4 mmol) was suspended in anhydrous CH2Cl2 followed by the addition of EDCI (15.3 g, 79.7 mmoles), HOBt (20.6 g, 152 mmol), triethylamine (8.06 g, 79.7 mmol) and N, O-dimethylhydroxylamine hydrochloride (6.48 g, 66.4 mmol). The reaction was stirred for 3 days at room temperature, after which the solvent was evaporated under reduced pressure. The residue was partitioned between EtOAc and water. The organic layer was washed with aqueous HCl, saturated NaHCO3, brine, dried (Na2SO) and concentrated in vacuo to give 10.5 g (66%) of N-methyl-N- (3,4-dimethoxyphenyl) acetamide as an oil pale brown. 2-Lithothiophene (1.0 M in THF, 33.0 ml, 33.0 mmol, Aldrich Chemical Co.) was added dropwise to N-methyl-N-methoxy- (3,4-dimethoxyphenyl) acetamide (5.26 g, 22.0 mmol) in THF anhydrous at -78 ° C. The reaction was allowed to proceed 90 minutes, then was diluted with 100 mL of Et2O and was poured into 1N aqueous HCl. The aqueous phase was extracted with Et2O and the combined organic fraction was washed with brine, dried (Na2SO4), and concentrated in vacuo. Flash chromatography (25% EtOAc / hexanes) yielded 2.91 g (50%) of 2- (3,4-dimethoxyphenyl) -1 - (thien-2-yl) ethanone as a brown oil. MS 263 (M + H) +, 280 (M + NH 4) +. 11b. 4-Bromo-2- (2,2-dicyanoethenyl) thiophene. 4-Bromo-2-thiophenecarboxaldehyde (6.92 g, 36.2 mmol) and malononitrile (2.39 g, 36.2 mmol) were dissolved in 100 ml of 1: 1.

EtOH: H2O. A small spatula of glycine was added and the reaction was stirred at room temperature for 30 minutes. The precipitated product was collected by suction filtration, washed with water, and dried under vacuum overnight. The result was 8.38 g (97%) of 4-bromo-2- (2,2-dicyanoethenyl) thiophene as a light green solid. MS 238/240 (M + H) +. 11c. 3-Cyano-4- (4-bromothiophen-2-yl) -5- (3,4-di methoxy-enyl) -6- (thiophene-2-yl) -2-pyridinamine 2- (3,4-dimethoxyphenyl) ) -1 - (thien-2-yl) ethanone (1.56 g, 5.95 mmoles), 4-bromo-2- (2,2-dicyanoethenyl) thiophene (1.71 g, 7.13 mmoles) and NH Oac (1.15 g, 14.9 mmoles) ) in n-BuOH (10 ml) and heated to reflux. After 24 hours, the reaction mixture was cooled, diluted with EtOAc and washed with water, brine, dried over Na2SO4 and concentrated in vacuo. Flash chromatography (40% EtOAc / hexanes) gave the desired product (0.76 g, 26%) as a dark yellow solid.

EXAMPLES 12-24 Following the procedures of Example 11, except that substituting the appropriate reagents required for R5, R4 and R3 as indicated in Table 4 below, the compounds of Examples 12-24 were prepared as described in Table 5 below.

C UAD RO 4 EJ E M P LOS 1 2 -24 Ex. Reagent Rs (for Reagent R4 (for Reagent R3 (for No. Position 7) position 6) position 5) 12 2-bromot? Ofenoic acid 3,4-d? Methox? -3-chlorobenzaldehyde phenylacetic 13 2-bromot 3,4-d? methox? -3-tr? fluoromet? l-4 phenylacetic acid fluorobenzaldehyde 14 1-bromo-4-acid 3,4-d? Methox? -3-chlorobenzaldehyde (d? Met? Lam? No) phenylacetic benzene 15 1-bromo-4-acid 3,4-d? Methox? -4 -fluoro-3 (d? met? lam? no) phenylacetic benzene tpfluoromethyl benzaldehyde 16 2-bromo-5-methy1-acid 3, -dimethoxy-3-chlorobenzaldehyde thiophene phenylacetic 17 2-bromo-5-methy1-acid 3,4-d-methoxy-4-bromo-2 thiophene phenylacetic thiophenecarboxaldehyde 18 1-bromo-4-acid 3 4-d? Methox? -4-bromo-2 (d? Met? Lam? No) benzene phenylacetic thiophenecarboxaldehyde 19 1-bromo-4- (N-meth? N-N-3,4-d? Methox? -4-bromo-2 (2-phenylacetic acid thiophenecarboxaldehyde methox? Et? L) am? No) benzene 1 -bromo- 4- (N-meth? N-N-3,4-d? Methox? -benzaldehyde (2-methox? Et? L) am? No) phenylacetic benzene 21 1 -bromo-4- (N-meth? N-acid) 3,4-d? Methox? -3-chlorobenzaldehyde (2-methoxyethylammo) phenylacetic benzene 22 5-bromo-2-acid 3 4-d? Methox? -benzaldehyde methoxypipdine phenylacetic acid 23 5-bromo-2-acid 3 4 -d? methox? -3-chlorobenzaldehyde methoxy pindine phenylacetic acid 24 5-bromo-2-acido 3 4-d? methox? -3-chlorobenzaldehyde dimethylaminopindine phenylacetic C OAD RO 5 EJ E M P LOS 1 2-24 Ex. Name Analytical Data No. 12 4-am? No-5- (3-chlorophen? L) -6- (3,4-IR 3440, 2940, 15401420, 1020 d? Methox? Phen?) Hydrochloride - 7- (t? Ofen-2-? L) p? R? Cm1 MS m / z 475 (M + H) + [2,3-d] p? R? M? D? Na 13 hydrochloride of 4- am? no-5- (3-tr? fluoromet? l-4-IR 34603060, 1600, 1510 1410 fluorophen?) -6- (3,4-d? methox? phen?) -7- 1140, MS m / z 527 (M + H) + (t? ofen-2-? l) p? r? do [2,3-d] p? r? m? d? na 14 4-ammonium dihydrochloride 5- (3-chlorophen? L) -6- (3,4-IR 34402940 1600 1570 1360 d? Methox? Phen?) -7- (4-1170, MS m / z 512 (M + H) + ( d? met? lam? no) fen? l) p? r? do [2,3- djpipmidine 15 4-am? no-5- (3-tpfluoromet? l-4-IR 3450, 3020, 1605, dihydrochloride, 1510, 1320, fluorophen?) -6- (3,4-d? Methox? Phen?) -7- (4-1140, MS m / z 564 (M + H) + (d? Met? Lam? no) phen? l) p? r? do [2,3-d] p? r? m? d? na 16 4-am? no-5- (3-chlorophen? l) -6- (3 hydrochloride , 4- IR 3440, 2920, 1600, 1570, 1440, d? Methox? Phen?) -7- (5-met? Lt? Ofen-2- 1360, MS m / z 489 (M + H) + 17 4-am? no-5- (4-bromot? ofen-2-? l) - IR 3420.2960, 1580 1440, 820, 6- (3,4-d? methox? phen?) -7 hydrochloride - (5-met? L t? ofen-2-MS m / z 539/541 (M + H) +? l) p? r? do [2,3-d] p? r? m? d? na 18 4-am? no-5- (4-bromot? ofen-2-? l) - IR 3420.2920, 1600.1380, 820, 6- (3,4-d? methox? phen?) -7- (4- MS m / z 562/564 (M + H) + (d? met? lam? no) fen? l) p? ndo [2, 3- d] p? R? M? D? Na 19 4-am? No-5- (4-bromot? Ofen-2-? L) hydrochloride - IR 3420.2920, 1600, 1380, 820, 6 - (3,4-d? Methox? Phen?) -7- (4- (N-meth? N- (2-MS m / z 606/608 (M + H) + methox? Et? L) am ? no) fen? l) p? r? do [2,3-d] p? r? m? d? na 20 4-am? no-5-phenol-6 (3,4-) hydrochloride d? methox? - IR 3420.2930.1630, 1600, 1570, phen?) -7- (4- (N-meth? N- (2- 1360, MS m / z 522 (M + H) + methox ? et? l) am? no) phen? l) -5-phen? lp? r? do [2,3-d] p? r? m? d? na 21 4-am? no-5- hydrochloride (3-chlorophen? L) -6- (3,4-IR 3440.2930, 160511570, 1355, d? Methox? Phen?) -7- (4- (N-meth? N- (2-1025, MS m / z 556 (M + H) + methox? Et? L) am? No) phen? L) p? R? Do [2,3- djpipmidine 22 4-am? No-5-phen? Hydrochloride -6- (3,4-d? Methox? - IR 3420 3000 1600, 1320, 1030, phen?) -7- (5-methox? -2-p? R? D? N? L) p? R [2,3- MS m / z 466 (M + H) + d] p? pm? d? na 23 4-am? no-5- (3-chlorophen? l) -6- (3 hydrochloride , 4- IR 3440, 3000, 1635, 1600, 1365, d? Methox? Phen?) -7- (5-methox? -2- MS m / z 500 (M + H) + p? R? D? n? l) p? r? do [2,3-d] p? r? m? d? na 24-hydrochloride 4-am? no-5- (3-chlorophen?) -6- (3,4 - IR 3435, 2950, 1645 , 1600, 1260, d? Methox? Phen?) -5- (5-d? Met? Lam? No-2- MSm / z513 (M + H) + p? R? D? N? L) p? r? do [2,3-d] p? pm? d? na EXAMPLE 25 4-Amino-5.6- (bis-4- (2-propyl) phenyl) -7- (4-dimethylaminophenyl) pyrido r2.3-dlpyrimidine A sample of 4,6-d? A? No-5- (1, 2-b? S (4- (2-prop? L) phen? L) ethen? L) pipmidine (745 mg, 2 mmol) is dissolved in 20 ml of 1,2,4-tpclorobenzene containing 4-d? met? lam? nobenzaldehyde (089 g, 6 mmol) and about 1 g of 4Á molecular sieves were added to the reaction mixture. The mixture was refluxed for 20 hours, cooled, and filtered through a pad of Celite. The filtrate was applied directly to a column of silica gel chromatography, which was eluted with 2.5% (19: 1 ethanohydroxide ammonium) in ethyl acetate to give the desired product (186 mg, 18.5% yield): IR 3460 , 2960, 1605, 1555, 1540, 1525, 1350, 820; MS m / z 502 (M + H) +. 4,6-Diamino-5- (1, 2-bis (4-isopropylphenyl) ethenyl) pyrimidine was prepared as follows: 25a 1,2-Bis (4- (2-propyl) phenyl) acetylene To a solution of 4-iodopropylbenzene (12.3 g, 50 mmol, Lancaster Chemical Co.) in 150 ml of triethylamine was added trimethylsilylacetylene (5.89 g, mmoles), dichlorobis (triphenylphosphine) palladium (II) (0.70 g, 1 mmol, Aldrich) and copper iodide (1) (1.5 g). The reaction was stirred at room temperature for 18 hours, diluted with hexanes and filtered. The filtrate was evaporated under reduced pressure to give crude 1- (4- (2-p ro pil) fe-nyl) -2-trimethylsilylacetylene. The crude 1- (4- (2-propyl) phenyl) -2-trimethylsilylacetylene was dissolved in 100 ml of methanol. An aqueous 1M potassium carbonate solution (25 ml) was added and the reaction was stirred at room temperature for 2 hours. The reaction mixture was then diluted with water and extracted with pentane. The organic layers were combined, dried with magnesium sulfate and evaporated under reduced pressure without heating to give crude 4- (2-propyl) phenylacetylene.

The crude 4- (2-propyl) phenylacetylene was dissolved in 100 ml of triethylamine. 4-iodopropylbenzene (12.3 g, 50 mmol), dichlorobis (triphenylphosphine) palladium (ll) (0.70 g, 1 mmol) and copper iodide (1) (1.5 g) were added. The reaction was stirred at room temperature during 2 days, it was heated to reflux for 1 hour, cooled, diluted with hexanes, and filtered. The filtrate was evaporated under reduced pressure. The residue was filtered through a pad of silica gel with hexanes, and the solvent was evaporated to give 11.40 g (87%) of 1,2-bis (4- (2-propyl) phenyl) acetylene. 25b. 4.6-Diamino-5- (1,2-bis (4-isopropylphenyl) ethenyl) pyrimidine 1,2-bis (4- (2-propyl) phenyl) acetylene (11.40 g, 43 mmol) was dissolved in 50 ml of THF , catecoiborane (1 M, 50 ml) in THF was added, and the mixture was heated to reflux for 30 hours. The mixture was cooled, after 4,6-diamino-5-iodo-pyrimidine, 30 μl of saturated aqueous sodium bicarbonate, 20 ml of 3N aqueous sodium hydroxide and 1.00 g (0.87 mmol) of tetrakis (triphenylphosphine) were added. palladium (0). The mixture was refluxed for 18 hours, cooled, diluted with water, then extracted with ethyl acetate. The organic layers were combined, dried with magnesium sulfate and the solvent was evaporated. The residue was chromatographed on silica gel with 2.5% to 5% (19: 1 ethanol: ammonium hydroxide) in ethyl acetate to give the desired product (4.53 g, 25% yield).

EXAMPLES 26-32 Following the procedures of Example 25, except that substituting the appropriate reagents required for R5, R4 and R3 as indicated in Table 6 below, the compounds of Examples 26-32 were prepared as described in Table 7 below. TABLE 6 EXAMPLES 26-32 Ex. Reagent R5 (for Reagents R4 - R3 (for No. position 7) positions 5 and 6) 26 4- (N- (2-methox? Et? L) -N ~ 1, 2-d fen? lacet? leno methylamino) benzaldehyde 27 4-d? met? lam? no- 1, 2-d? phen? lacet? leno benzaldehyde 28 4-d? met? lam? no- 1, 2-b? s (3-fluorophen? L) acet? Leno benzaldehyde 29 4-d? Met? Lam? No- 1, 2-b? S (34-d? Methox? Phen? L) acet? Leno benzaldehyde 30 4-d? Met ? lam? no- 1, 2-b? s (3-fluoro-4-benzaldehyde met? lfen? l) acet? leno 31 t? ofen-2- 1, 2-b? s (3-fluoro-4-carboxaldehyde met ? lfen? l) acet? leno 32 t? ofen-2- 12-d? fen? lacet? leno carboxaldehyde TABLE 7 EXAMPLES 27-32 Ex. Name Analytical Data No. 4-Am? No-5-phenyl? -6-phen? L-7- (4- (N-IR 3420, 3020, 1600, 1580 1365 Hydrochloride 26 met? N- (2-methox? Et? L) am? No) phen? L) p? Pdo MS m / z 462 (M + H) + 1 [2,3-d] p? R? M? d? n 27 4-am? no-5,6-d? phen? l-7- (4- IR 3410, 1635, 1600, 1580, 1360, d? met? la? nofen? l) d? r? do [2.3- 705cm1, MSm / z418 (M + H) + djpipmidine 28 4-am? no-5,6-b? s (3-fluorophen? l) -7- (4- IR 3450, 3060, 1605, 1540, 1345, d? Met? Nofen? L) p? R? Do [2.3-1200 cm \ MS m / z 454 (M + H) + djpinmidine 29 4-am? no-5,6-b? s (3,4-d? methox? - IR 3400, 3100-2800, 1630, 1600, phen?) -7- (4-d? met? lam? nofen? l) p? r? do [2,3- 1575, 1510, 1360, 1250, 1140 1020 djpyrimidine cm "1: MSm / z538 (M + H) + .30 4-amino-5,6-bis (3- fluoro-4-methyl-IR: 3330, 3100-2800, 1635, 1600, phenyl) -7- (4-methylmethoxyphenyl) pyrid [2,3- 1575, 1535, 1505, 1360, 1200 cm "1; djpyrimidine MS m / z 482 (M + H) +. 31 4-amino-5,6-bis (3-fluoro-4-methyl IR: 3330.3100-2800, 1635, 1580, phenol) -7- (thiophen-2-yl) pyrido hydrochloride [2,3- d] pyrimidine 1540, 1505, 1415, 1365, 1235 cm "1; MS m / z445 (M + H) +. 32 4-amino-5,6-diphenyl-7- (thiophen-2-IR: 3470.3390, 3050.1540, 1420 cm "1 il) pyrido [2,3-d] pyrimidine EXAMPLES 33-38 Following the procedures of Example 11, except that substituting the appropriate reagents required for R5, R4 and R3 as indicated in Table 8 below, the compounds of Examples 33-38 were prepared as described in Table 9 below.

TABLE 8 EXAMPLES 33-38 Ex. Reagent Rs (for Reagent R4 (for Reagent R3 (for No. 7 position) position 6) position 5) 33 5-bromo-2- phenylacetic acid benzaldehyde (dimethylamino) pyridine 34 5-bromo-2-acid 3.4 -dimethoxy-benzaldehyde (dimethylamino) pyridine phenylacetic acid 5-bromo-2- (N-methyl-N-acid 3,4-dimethoxy-3-chlorobenzaldehyde (methoxyethyl) amino) -phenylacetic pyridine 36 5-bromo-2- phenylacetic acid 3-chlorobenzaldehyde (dimethylamino) pyridine 37 5-bromo-2-phenylacetic acid 4-bromothiophen-2 (dimethylamino) pyridine carboxaldehyde 38 5-bromo-2-phenylacetic acid 3-bromobenzaldehyde (dimethylamino) pyridine TABLE 9 EXAMPLES 33- 38 Ex. Name Analytical Data No. 33 4-am? No-56-d? Phen? L-7- (5-d? Met? L-IR 3400.3040, 1640, 1565, 1365 am? No-2 hydrochloride -p? r? d? n? l) p? pdo [23-d] p? pm? d? na cm, MSm / z419 (M + H) + 34 hydrochloride of 4-am? no-5-phen? l-6- (3,4-d? methox? - IR 3420.2930, 1645, 1600 1255, fen? l) -7- (5- (d? met? lam? no) p? r? d? n -2-? L) p? R? Do MS m / z 479 (M + H) + [2,3-d] p? R? M? D? Na 35 4-ammo-5-dihydrochloride ( 3-chlorophen? L) -6- (3,4-IR 3040.2930, 1640, 1600, 1370, d? Methox? Phen?) -7- (5- (N- (2-methox? Et? L ) - MS m / z 557 (M + H) + N-met? Lam? No) -2-p? R? D? N? L) p? R? Do [2,3-d] p? R? m? d? na 4-am? no-5- (3-chlorophen? l) -6- IR 3420,3040, 1650, 1575, 1260 phenol-7- (5-d? met? lam) dichlorohydrate ? no-2-p? r? d? n? l) p? r? do [2,3-MS m / z 453 (M + H) + d] p? r? m? d? na 37 hydrochloride 4-am? No-5- (4-bromot? Ofen-2-? L) - IR 3400 3100, 1650.1355- -, MS m / z 6-phen? L-7- (5-d? Met? lam? no-2-p? r? d? n? l) p? r? do [2,3-503/505 (M + H) + djpinmidine 38 hydrochloride of 4-am? no-5- (3- bromophen? l) -6- IR 3450.3050 1650, 1575, MSm / z phenol-7- (5-d? met? lam? no-2-p? r? d? n? l) p? pdo [2,3- 497/4 99 (M + H) + d] p? Pm? D? Na EXAMPLE 39 4-Amino-5- (3-bromophenyl) -6- (4-fluorophenyl) -7- (6-morpholinyl-3-pyridinyl) pyrido 2,3-pyrimidine hydrochloride Step 39a. 1- (6-chloro-3-pyridyl) -2- (4-fluorophenyl) ethanone A solution of ethyl (p-fluorophenyl) acetate (12 1 g, 68 8 mmol, reagent R4) in 10 ml of THF was added dropwise to a solution of b? S (tr? Met? L? L) ammonia lithium (138 ml) in 150 ml of THF at -78 ° C. The reaction was stirred for 60 minutes. followed by the addition of 6-chloron-cotonol chloride (solid, reagent R5) in one portion. The reaction was stirred an additional 60 minutes, then quenched with a saturated ammonium chloride solution. The mixture was diluted with Et 2 O, was poured into water, and the aqueous phase was extracted with Et 2 O. The combined organic layers were washed with brine, dried (Na2SO) and concentrated in vacuo to 27.1 g of the crude product as a yellow solid. This material was dissolved in 200 ml of DMSO and 10 ml of H2O, and the solution was heated at 155 ° C for 3 hours. The reaction was then cooled, emptied to water, and the product extracted with Et2O. The Et2O layers were washed with water, brine, dried (MgSO4) and concentrated in vacuo. The product was purified by flash chromatography eluting with 30% EtOAc / hexanes to give 3.02 g (19%) of the title compound as a yellow solid: MS 250 (M + H) +.

Step 39b. 2- (4-fluorophenyl) -1 - (2-morpholinyl-5-pyridyl) ethanone The ketone compound from Step 39a (3.02 g, 12.1 mmol) and morpholine (4.30 ml, 48.4 mmol) were dissolved in 30 ml of ethanol absolute, and the mixture was heated to reflux for 18 hours. The volatiles were then removed under vacuum, and the residue was partitioned between Et2O and saturated NaHCO3. The Et2O layer was washed with brine, dried (Na2SO4) and concentrated in vacuo to give the title compound (3.42 g, 94%) as a yellow solid. MS: 301 (M + H) +.

Step 39c. 4-Amino-5- (3-bromophenyl) -6- (4-fluorophenyl) -7- (6-morpholinyl-3-pyridinyl) pyrido 2,3-dlpi rimidine hydrochloride Following the procedure of Example 11 step c, except that substituting the compound of Step 39b for the compound of Example 11 Step a, and replacing 3-bromobenzaldehyde for the 4-bromo-2-thiophenecarboxaldehyde of Example 11b, then carrying out the reaction of the product as in Example 1, the composed of the title. MS m / z (M + H) + 557; IR (crn 1) 3433, 3040, 1641, 1602, 1367.

EXAMPLES 40-47 Following the procedures of Example 39 and Example 11, except that by substituting the reagents shown below for reagents R3 and R4 and the reagent shown for the portion of position 7 for the morpholine of Example 39 Step b, the compounds shown in FIG. Table 10 below.

C UAD RO 1 0 EJ EM PLOS 40 -47 E¡. Position 5 Position 6 Reagent step 39b / No. position portion 7 40 benzaldehyde ethyl phenylacetate morpho na / 6-morpholine? -3-p? R? D? Na 41 3-bromobenzaldehyde ethyl phenylacetate morpholine / 6-morpholine? 3-p? R? D? Na 42 benzaldehyde ethyl phenylacetate N-met? N- (2 methox? Et? L) am? Na / 6- (N-met? N- (2-methox? Et? L) am? no) - 3-p? r? d? na 43 ethyl 4-bromo-2-phenylacetate N-met? lN- (2-thiophenecarboxaldehyde methox? et? l) am? na / 6- (N-met ? lN- (2 methox? et? l) am? no-3- pipdine 44 ethyl 4-bromo-2- 2-c? Clopropyl lactate dimethylamine / thiophenecarboxaldehyde 6-d? Met? Lam? No-3- pipdine 45 4-bromo-2- (4-fluorophen? L) acetate morpholyl / thiophenecarboxaidehyde ethyl 6-morpholine? -3-p? R? D? Na 46 3-bromobenzaldehyde ethyl phenylacetate cyclopropylmethylamine / 6- c? cloprop? lmet? lam? no-3-p? r? d? na 47 Benzaldehyde ethyl phenylacetate ethyl cyclopropylmethylamine / 6-cyclopropylmethylammo-3-p? R? D? Na An a litical data. E x em plos 40-47 Ej- Name Analytical Data No. 40 4-am? No-5-phen? L-6-phen? L-7- (6-morph? N? L-MS m / z hydrochloride (M + H) + 461, IR (cm ') 3-p? R? D? N? L) p? Ndo [2,3-d] p? R? M? D? Na 3431, 3050.1600, 1576.1245 41 4-am? No-5- (3-bromophenyl) -6-phen? L-7- (6-MS m / z (M + H) + 539, IR (cm 1) morphol? N hydrochloride l-3-p? r? d? n? l) p? r? do [2,3-3423,2855,1639,1600,1367 djpinmidina 42 hydrochloride of 4-am? no-5-phen? l- 6-phenol-7- (6- (N-met? N-MS m / z (M + H) + 463, IR (cm 1) (2-methox? Et? L) am? No) -3 -p? r? d? n? l) p? r? 3419,2932,1644,1580,1367 [2,3-d) p? r? m? d? na 43 4-ammonium hydrochloride 5- (4-bromot? In? L) -6-phen? L-7- MS m / z (M + H) + -547, IR (cm 1) (6- (N-meth? N- (2 -metox? et? l) am? no) -3- 3417.3053,2928,1643,1367 p? r? d? n? l) p? ndo [2,3-d] p? r? m? d ? n 4-am? no-5- hydrochloride (4-bromot? in? l) -6-c? clo- MS m / z (M + H) + 467, IR (cm 1) prop? l-7 - (6-d? Met? Lam? No-3-p? P? N? L) p? R? Do [2,3-3426,3001, 1649,1600,1373 djpirimidma 45 hydrochloride of 4-am? No -5- (4-bromot? In? L) -6- (4- MS m / z (M + H) + 563, IR (cm) fluorofen? L) -7- (6-mo) rfol? n? l-3- 3417.2969,1602,1571, 1367 p? r? d? n? l) p? r? do [2,3-d] p? r? m? d? na 46 hydrochloride of 4-am? no-5- (3-bromophen? l) -6-phen? l-7- MS m / z (M + H) + 523, IR (cm-1) (6-c? cloprop? lmet? lam? no-3-p? r? d? n? l) p? r? 3430,3000,1650,1630,1600 [2,3-d] p? r? m? d? na 47 hydrochloride of 4-am? no-5-phen? l-6-phen? l-7- (6- MS m / z (M + H) + 445, IR (cm 1) c? cloprop? lmet? lam? no- 3-p? R? D? N? L) p? R? D 3410.3000,1655,1600,1375 [2,3-d] p? R? M? D? Na EXAMPLE 48 252029.3 4-amino hydrochloride -5- (3-bromophenyl) -6-phenylmethyl-7- (6-morpholinyl-3-pyridinyl) pyridomide 2,3-d1pyrimidine Step 48a. 1- (6-chloro-3-pyridyl) -3-phenylpropanone A sample of 6-chloronicotinyl chloride (15.4 g, 87.4 mmol) was added to a mixture of N, O-dimethylhydroxylamine hydrochloride (9.38 g, 96.2 mmol) and triethylamine (36.6 mL, 262 mmol) in 200 mL of CH 2 Cl 2 cooled to 0 ° C. The reaction was stirred for 2 hours, then it was poured into water. The separated organic layer was washed with brine, dried (Na 2 SO 4) and concentrated in vacuo to give 14.6 g of the Weinreb amide intermediate as a light brown oil. A sample of the amide intermediate (4.09 g, 20.4 mmol) in 100 mL of THF was cooled to -78 ° C followed by the addition of phenylmagnesium chloride (30.6 mL, 30.6 mmol, 1 M in THF). The reaction was allowed to warm to room temperature and was stirred for 3 hours, after which it was quenched through 1N aqueous HCl. The mixture was partitioned between Et2O and saturated NaHCO3. The organic layer was washed with brine, dried (Na2SO4) and concentrated in vacuo. The crude product was purified by flash chromatography eluting with 30% EtOAc / hexanes to give 3.77 g (75%) of the desired product as a white solid. MS: 246 (M + H) +.

Step 48b. 1- (6-morpholinyl-3-pyridyl) -3-phenylpropanone Following the procedure of Example 39b, the compound from Step 48a was converted to the title compound.

Step 48c. 4-Amino-5- (3-bromophenyl) -6-phenylmethyl-7- (6-morpholyl nor l-3-pyridinium I) hydrochloride pyrido 2,3-pyrimidine Hydrochloride Following the procedure of Example 11 Step c, except substituting the compound of Step 48b for the compound of Example 11 Step a, and replacing 3-bromobenzaldehyde for the 4-bromo-2-thiophenecarboxaldehyde of Example 11b, then bringing the reaction product as in Example 11, the title compound was prepared . MS m / z (M + H) + 553; IR (cm "1) 3430, 3050, 1640, 1600, 1360.

EXAMPLE 49-55 Following the procedures of Example 48 and Example 11, except that by substituting the reagents shown below for reagents R3 and R4 and the reagent shown for the portion of position 7 for the morpholine of Example 48 Step b, the compounds shown in Table 11 below.

C UAD RO 1 1 EJ E M P LOS 49-55 Eg Position 5 Position 6 Reagent step 48b / No. portion position 7 49 3-chlorobenzaldehyde n-octyl morpholine / magnesium chloride 6-morpholine? -3-p? R? D? Na 50 benzaldehyde phenethyl morpholine / magnesium chloride 6-morpholine? -3-p? Pd? Na 51 4-bromo-2-n-octyl morpholine chloride / thiophenecarboxaldehyde magnesium 6-morpholine? -3-p? R? D? Na 52 4-bromo-2-isobutyl morfohna chloride / thiophenecarboxaldehyde magnesium 6-morpholine? -3-p? R? D? Na 53 4-bromo-2-phenethyl morpholine chloride / thiophenecarboxaldehyde magnesium 6-morpholine? -3-p? R? D? Na 54 3-bromobenzaldehyde cyclohexylmethyl dimethylamine / magnesium chloride 6-d? Meth? Lam? No-3 pindin 55 3-bromobenzaldehyde n-hexyl dimethylamine / magnesium chloride 6-d? Met? Lam? No-3- pindin An a litical data. Examples 49-55 Ex. Name Analytical Data No. 49 4-am? No-5- (3-chlorophen? L) -6-hept? L-7- MS m / z (M + H) + 517 hydrochloride , IR (cm p) (6-morfol? N? L-3-p? Pd? N? L) p? Pdo [2,3-3430,2940,1650,1600,1380 d] p? R? M? d? na 50 hydrochloride 4-am? no-5-phen? l-6-phen? lmet? l-7- (6- MS m / z (M + H) + 475, IR (cm 1) morphol? n? l-3-p? pd? n? l) p? r? do [2,3-3430,2850,1640,1600,1385 djpinmidine 51 hydrochloride of 4-am? no-5- (4-bromot? in? l) -6-hept? l-MS m / z (M + H) + 567, IR (cm 1) 7- (6-morpholine? -3-p? r? d? n? ) p? r? do [2,3-3420,2940,1625,1600,1380 djpirimidma 52 hydrochloride of 4-am? no-5- (4-bromot? in? l) -6- MS m / z (M + H) + 511, IR (cm 1) (1-met? Let? L) -7- (6-morph? N? L-3-p? R? D? N? L) p? R? Do [2 , 3-3410,3000,1650,1600.1250 djpipmidine 53 4-am? No-5- (4-bromot? In hydrochloride) -6-phen? L-MS m / z (M + H) + 559, IR (cm 1) met? L-7- (6-morpholine? -3-p? R? D? N? L) p? Pdo [2,3-3410,2890,1650,1600, 1380 djpinmidine 54 4-am? No-5- (3-bromophen?) -6-c? Clo-MS m / z (M + H) + 503, 505 (1 Br), hex? L-7 hydrochloride - (6-d? Met? Lam? No-3-p? R? D? N? L) p? R? Do [2, 3 IR (cm 1) 3432, 3047, 2945, 1560, djpipmidine 1465.1340 55 4-amino-5- (3-bromophenyl) -6-MS m / z (M + H) + 491 hydrochloride , 493 (1 Br), pent? L-7- (6-d? Met? Lam? No-3-p? R? D? N? L) p? Pdo [2,3-IR (cm) 3437, 3025, 2952, 1550, djpinmidina 1460,1320

Claims

1. - A compound or a pharmaceutically acceptable salt or amide thereof having the formula (I): wherein: R1 and R2 independently are H, lower alkyl, arylalkyl or acyl, or can be taken together with the nitrogen atom to which they are attached to form a 5- to 7-membered ring optionally containing 1-3 additional heterogeneous atoms selected from N, O u S; R3, R4 and R5 independently are selected from lower alkyl, lower alkenyl, lower alkynyl, lower cycloalkyl, aryl, arylalkyl, heteroaryl or a heterocyclic group and dotted lines indicate that a double bond is optionally present.

2. - A compound according to claim 1, wherein: R1 and R2 are independently selected from H, lower alkyl, arylalkyl of 1 to 6 carbon atoms, -C (O) alkyl of 1 to 6 carbon atoms, -C (O) aryl, -C (O) heterocyclic or they may be attached together with the nitrogen to which they are attached to form a 5-7 membered ring optionally containing 1-2 additional heterogeneous atoms selected from O, N, or S, R3, R4 and R5 independently are selected from the group consisting of alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms, alkiyl of 2 to 6 carbon atoms, cycloalkyl of 3 to 8 carbon atoms, heteroaplakyl of 0 to 6 carbon atoms, or heteroaplakyl of 0 to 6 carbon atoms substituted, aplakyl of 0 to 6 carbon atoms or aplakyl of 0 to 6 carbon atoms substituted, heteroaplalkenyl of 2 to 6 carbon atoms or heteroaplalkenyl of 2 to 6 carbon atoms substituted, aplaxkenyl d 2 to 6 carbon atoms or 2 to 2 6 substituted carbon atoms, heteroaplakkynyl of 2 to 6 carbon atoms or heteroaplalkymyl of 2 to 6 carbon atoms substituted, 2 to 6 carbon atoms or 2 to 6 substituted carbon-substituted aplakkynyl, wherein the 1-4 heterolayl or aplo substituents are independently selected from halogen, oxo, cyanoalkyl of 1 to 6 carbon atoms, heteroaplakyl of 0 to 6 carbon atoms, alkyl of 0 to 6 carbon atoms heterocyclic, alkyloxy of 1 to 6 carbon atoms, C 1 -C 6 -alkyloxy- C 1-6 -alkyl, C 0 -C 6 -lactalkyl, C 1 -C 6 -decylkyloxy, R 5 R 6 CN (O), cyano, alkenyl with 2 to 6 carbon atoms carbon, alkynyl of 2 to 6 carbon atoms, alkyl of 1 to 6 carbon atoms, alkenyldialkylmalonyl of 2 to 6 carbon atoms, CF3, HO-, alkyloxy of 1 to 6 carbon atoms-alkyloxy of 1 to 6 carbon atoms carbon, alkyl of 1 to 6 carbon atoms-SOn, as of n is 1-2, alkylthio of 1 to 6 carbon atoms, to which the number of 1 to 6 carbon atoms, CF3O, CF3, alkylenedioxy of 1 to 4 carbon atoms, alkyl acyl of 1 to 6 carbon atoms , R5R6N (CO) NR5, N-form? L (heterocyclic), NO2, NR5R6-alkyl of 0 to 6 carbon atoms, wherein R5 and R6 independently are selected from H, alkyl of 1 to 6 atoms carbon, HC (O), alkyloxy of 1 to 6 carbon atoms-alkyl of 1 to 6 carbon atoms, alkyloxy of 1 to 6 carbon atoms, alkyl of 1 to 6 carbon atoms-C (O), CF3C (O), NR7R8-alkyl of 1 to 6 carbon atoms, phthalamide-C (O) of 1 to 6 carbon atoms, alkyl of 1 to 6 carbon atoms-SOn, wherein n is 1-2, CN-alkyl of 1 to 6 carbon atoms, R7R8NC (O) NR7, heteropole, NR7R8-alkyl of 1 to 6 carbon atoms-C (O), alkyloxycarbamide of 1 to 6 carbon atoms - alkyl of 1 to 6 carbon atoms, wherein R8 and R9 independently are selected from those variables identified for R6 and R7 or R6 and R7 or R8 and R9 can be attached together with the nitrogen atom to which they are attached to form an unsubstituted or substituted 5-7 membered ring optionally containing 1-3 additional heterogeneous atoms selected from O, N or S, wherein the substituents are selected from alkyl of 1 to 6 carbon atoms.

3. - A compound of formula II: wherein: R1 and R2 independently are H, lower alkyl, arylalkyl or acyl, or can be taken together with the nitrogen atom to which they are attached to form a 5- to 7-membered ring optionally containing 1-3 heterogeneous atoms selected from N , O u S; Y R3, R4 and R5 independently are selected from lower alkyl, lower alkenyl, lower alkynyl, lower cycloalkyl, aryl, arylalkyl, heteroaryl or a heterocyclic group.

4. A compound according to claim 3, wherein: R1 and R2 are independently selected from H, lower alkyl, arylalkyl of 1 to 6 carbon atoms, -C (O) alkyl of 1 to 6 carbon atoms, -C (O) aryl, -C (O) heterocyclic or join together with the nitrogen to which they are attached to form a 5-7 membered ring optionally containing 1-2 additional heterogeneous atoms selected from O, N, or S; R3, R4 and R5 independently are selected from the group consisting of: alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms, alkynyl of 2 to 6 carbon atoms, cycloalkyl of 3 to 8 carbon atoms, heteroarylalkyl of 0 to 6 carbon atoms, or heteroarylalkyl of 0 to 6 carbon atoms substituted, arylalkyl of 0 to 6 carbon atoms or arylalkyl of 0 to 6 carbon atoms substituted, heteroarylalkenyl of 2 to 6 carbon atoms or heteroarylalkenyl of 2 to 6 carbon atoms substituted, arylalkenyl of 2 to 6 carbon atoms or arylalkenyl of 2 to 6 carbon atoms substituted, heteroarylalkynyl of 2 to 6 carbon atoms or heteroarylalkynyl of 2 to 6 carbon atoms substituted, arylalkynyl of 2 to 6 carbon atoms or arylalkynyl of 2 to 6 carbon atoms substituted, wherein the 1-4 heteroaryl or aryl substitueare independently selected from: halogen, oxo, cyanoalkyl of 1 to 6 carbon atoms carbon, heteroarylalkyl of 0 to 6 carbon atoms, alkyl of 0 to 6 heterocyclic carbon atoms, alkyloxy of 1 to 6 carbon atoms, alkyloxy of 1 to 6 carbon atoms-alkyl of 1 to 6 carbon atoms, arylalkyl of 0 to 6 carbon atoms, arylalkyloxy of 1 to 6 carbon atoms, R5R6NC (O), cyano, alkenyl of 2 to 6 carbon atoms, alkynyl of 2 to 6 carbon atoms, alkyl of 1 to 6 carbon atoms, alkenyldialkylmalonyl of 2 to 6 carbon atoms, CF3, HO-, alkyloxy of 1 to 6 carbon atoms-alkyloxy of 1 to 6 carbon atoms, alkyl of 1 to 6 carbon atoms-SOn, where n is 1-2 , alkylthio of 1 to 6 carbon atoms, alkylacryl of 1 to 6 carbon atoms, CF3O, CF3, alkylenedioxy of 1 to 4 carbon atoms, alkylacryl of 1 to 6 carbon atoms, R5R6N (CO) NR5, N-formyl (heterocyclic), NO 2, NR 5 R 6 -alkyl of 0 to 6 carbon atoms, wherein R 5 and R 6 independently are selected from H, alkyl of 1 to 6 carbon atoms , HC (O), alkyloxy of 1 to 6 carbon atoms-alkyl of 1 to 6 carbon atoms, alkyloxy of 1 to 6 carbon atoms, alkyl of 1 to 6 carbon atoms-C (O), CF3C (O ), NR7R8-alkyl of 1 to 6 carbon atoms, phthalimido-C (O) of 1 to 6 carbon atoms, alkyl of 1 to 6 carbon atoms-SOn, wherein n is 1-2, CN-alkyl of 1 to 6 carbon atoms, R7R8NC (O) NR7, heteroaryl, NR7R8-alkyl of 1 to 6 carbon atoms-C (O), alkyloxycarbamido of 1 to 6 carbon atoms- alkyl of 1 to 6 carbon atoms, in where R8 and R9 independently are selected from those variables identified for R6 and R7 or R6 and R7 or R8 and R9 can be attached together with the nitrogen atom to which they are attached to form an unsubstituted or substituted 5-7 membered ring optionally containing 1-3 additional heterogeneous atoms selected from O, N or S, wherein the substitueare selected from alkyl of 1 to 6 carbon atoms.

5. A compound according to claim 4, wherein R3, R4 and R5 are independently selected from: phenyl; thiof en-2-yl; 1-methyl-2-oxobenzoxazolin-5-yl; 2- (dimethylamino) -5-pyrimidinyl; 2- (N-formyl-N-methylamino) -3-pyrimidinyl; 2- (N- (2-methoxyethyl) -N-methylamino) -5-pyrimidinyl; 5-dimethylamino-2-pyridinyl; 5- (N- (2-methoxyethyl) -N-methylamino) -2-pyridinyl; 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-methylamino) phenyl; 3-methyl -4 - (N-methyl-N- (trifluoroacetyl) amino) phenyl; 3-methyl-4 (N-methylamino) phenyl; 3-methyl-4-pyrrolidinylphenyl; 3 -pi ri d i lo; 3,4-dichlorophenyl; 3,4-methylenedioxyphenyl; 3,4,5-trimethoxyphenyl; 4- (acetylamino) phenyl; 4- (dimethylamino) -3-fluorophenyl; 4- (dimethylamino) phenyl; 4- (imidazol-1-yl) phenyl; 4- (methylthio) phenyl; 4- (morpholinyl) phenyl; 4- (N- (2- (dimethylamino) ethyl) -amino) phenyl; 4- (N- (2-methoxyethyl) amino) phenyl; 4- (N-acetyl-N-methylamino) phenyl; 4- (N-ethyl-N-formylamino) phenyl; 4- (N-ethylamino) phenyl; 4- (N-formyl-N- (2-methoxyethyl) amino) phenyl; 4- (N-isopropylamino) phenyl; 4- (N-methyl-N - ((2-dimethylamino) ethyl) amino) phenyl; 4- (N-methyl-N- (2- (N-phthalimidyl) acetyl) amino) phenyl; 4- (N-methyl-N- (2-cyano) ethylamino) phenyl; 4- (N-methyl-N- (2-methoxyethyl) amino) phenyl; 4- (N-methyl-N- (3-methoxy) propionylamino) phenyl; 4- (N-methyl-N-acetylamino) phenyl; 4- (N-methyl-N-formylamino) phenyl; 4- (N-methyl-N-trifluoroacetylamino) phenyl; 4- (N-morpholinyl) phenyl; 4- (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; 4- (4-methylpiperidinyl) -phenyl; 4- (5-pyrimidinyl) phenyl; 4-aminophenyl; 4-bromophenyl; 4-butoxyphenyl; 4-carboxamidophenyl; 4-chlorophenyl; 4-cyanophenyl; 4-diethylaminophenyl; 4- (diethylmalonylalyl phenyl); 4-dimethylaminophenyl; 4-ethoxyphenyl; 4-ethylf in ilo; 4-fluorophenyl; 4-hydroxyphenyl; 4-imidazolylphenyl; 4-iodophenyl; 4- isopropylphenyl; 4-methoxyphenyl) 4-methylaminophenyl; 4-methylsulfonylphenyl; 4-morpholinyl phenyl; 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-dimethylaminopyridazin-6-yl; 5-dimethylamino-2-pyridyl; 5-pyrimidinylphenyl; 6- (N-methyl-N-formyl-amino) -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; pentyl; thiophen-2-yl; 1- (3-bromophenyl) ethyl; 2- (N-phenylmethoxycarbonyl) -aphenol; 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-f enileti lo; 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-bromo-5-methoxyphenyl; 3-bromophenyl; 3-bromophenylmethyl; 3-carboxamidophenyl; 3-chlorophenyl; 3-cyanophenyl; 3-diethylmalonylalyl phenyl; 3-dimethylaminophenyl; 3-ethoxyphenyl; 3-fluoro-5-trifluoromethylphenyl; 3-fluorophenyl; 3-hydroxyphenyl; 3-iodophenyl; 3-methoxyethioxyphenyl, 3-methoxyphenyl; 3-methylphenyl; 3-methylsulfonylphenyl; 3-methylthiophenyl; 3-t-butyl acri If enyl, 3-trifluoromethyloxyfine; 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-diclo rhephenyl; 3,5-dimethoxyphenyl; 3,5-dimethylphenyl; 4- (2-propyl) phenyl; 4- (2-propyl) oxyphenyl; 4-benzyloxyphenyl; 4-bromophenyl; 4-bromothiophen-2-ylo; 4-butoxyphenyl; 4-dimethylaminophenyl; 4-fluoro-3-trifluoromethylphenyl; 4-methoxyphenyl; 4-neopentylphenyl; 4-phenoxyphenyl; 5-bromothiophen-2-yl; cyclohexyl; cyclopropyl; hexyl; methyl; phenyl; (2-bromo-5-chlorophenyl) methyl; (2-bromophenyl) methyl; 6-cyclopropyl-methylamino-3-pyridinyl; and (5-chloro-2- (3-methoxyphenyl) phenyl) methyl.

6. A compound according to claim 5, wherein R5 is selected from the group consisting of: 4- (dimethylamino) phenyl; 5-dimethylamino-2-pyridinyl; 5-methoxy-2-pyridinyl; 4-methoxyphenyl; 5-methylthiophen-2-yl; 4- (N-methyl-N- (2-methoxyethyl) amino) phenyl; and thiophen-2-yl.

7. A compound according to claim 5, wherein R4 is selected from the group consisting of: ethoxycarbonylmethyl; ethyl; 3-fluorophenyl; 3-fluoro-4-methylphenyl; 3,4-dimethoxyphenyl; 3-methoxyphenyl; 4-methoxyphenyl; pentyl; phenyl; 3- (2-propi l) f eni lo; and 4- (2-propyl) phenyl.

8. A compound according to claim 5, wherein R3 is selected from the group consisting of: 3-bromophenyl; 3-bromo-4-fluorophenyl; 4-bromothiophen-2-yl; 3-chlorophenyl; 3,4-dimethoxyphenyl; 3-fluorophenyl; 3-fluoro-4-methoxyphenyl; 4- (2-propyl) phenyl; and 3-trifluoromethyl-4-fluorophenyl.

9. A compound according to claim 1, which is: 4-amino-5- (3-bromo-4-fluorophenyl) -6-pentyl-7- (4- (dimethylamino) pyrido) [2,3-d] pyrimidine; 4-amino-5- (3-bromo-4-fluorophenyl) -6-pentyl-7- (thiophen-2-yl) pyrido [2,3-d] pyrimidine; 4-amino-5- (3-bromophenyl) -6- (4-methoxyphenyl) -7- (4-methoxyphenyl) pyrido [2,3-d] pyrimidine; 4-amino-5- (3-bromophenyl) -6-ethyl-7- (thiophen-2-yl) pyrido [2,3-d] pyrimidine; 4-amino-5- (3-b ro mofe nyl) -6-pentyl-7- (thiophen-2-yl) pyrido [2,3-d] pyrimidine; 4-amino-5- (3-bromophenyl) -6- (3,4-dimethoxyphenyl) -7- (thiophen-2-yl) pyrido [2,3-d] pyrimidine; 4-amino-5- (3-bromophenyl) -6- (4- (2-propyl) phenyl) -7- (4- (dimethylamino) phenyl) pyrido [2,3-d] pyrimidine; 4-amino-5- (3-bromophenyl) -6-ethoxycarbonylmethyl-7- (thiophen-2-yl) pyrido [2,3-d] pyrimidine; 4-amino-5- (3-bromophenyl) -6- (3-methoxyphenylmethyl) -7- (thiophen-2-yl) pyrido [2,3-d] pyrimidine; 4-amino-5- (3-bromophenyl) -6- (3,4-dimethoxyphenyl) -7- (4- (dimethylamino) phenyl) pyrido [2,3-d] pyrimidine; 4-amino-5- (4-bromothiophen-2-yl) -6- (3,4-dimethoxyphenyl) -7- (thiophen-2-yl) pyrido [2,3-d] pyrimidine; 4-amino-5- (3-chlorophenyl) -6- (3,4-dimethoxyphenyl) -7- (thiophen-2-yl) pyrido [2,3-d] pyrimidine; 4-Amino-5- (3-trifluoromethyl) -4-f-lorofenyl) -6- (3, 4-di methoxy-enyl) -7- (thiophen-2-yl) -pyrido [2,3-d] ] pyrimidine; 4-amino-5- (3-chlorophenyl) -6- (3,4-dimethoxyphenyl) -7- (4- (dimethylamino) phenyl) pyrido [2,3-d] pyrimidine; 4-amino-5- (3-trifluoromethyl-4-fluorophenyl) -6- (3,4-dimethoxyphenyl) -7- (4- (dimethylamino) phenyl) pyrido [2,3-d] pyrimidine; 4-amino-5- (3-chlorophenyl) -6- (3,4-dimethoxyphenyl) -7- (5-methylthiophen-2-yl) pyrido [2,3-d] pyrimidine; 4-amino-5- (4-bromothiophen-2-yl) -6- (3,4-dimethoxyphenyl) -7- (5-methylthiophen-2) -yl) pyrido [2,3-d] pyrimidine; 4-am i non-5- (4-bromothiophen-2-yl) -6- (3,4-di methoxy-en-1) -7- (4- (dimethylamino) n-nyl) pyrido [2,3-d] pyrimidine; 4-amino-5- (4-bromothiophen-2-yl) -6- (3,4-dimethoxyphenyl) -7- (4- (N-methyl-N- ( 2-methoxyethyl) amino) phenyl) pyrido [2,3-d] pyrimidine; 4-amino-5-phenyl-6- (3,4-dimethoxyphenyl) -7- (4- (N-methyl-N- (2-methoxyethyl) amino) phenyl) -5-phenylpyrido [2,3-d] pyrimidine; 4-amino-5- (3-chlorophenyl) -6- (3,4-dimethoxyphenyl) -7- (4- (N-methyl-N- (2-methoxyethyl) amino) phenyl) pyrido [2,3- d] pyrimidine; 4-Amino-5-phenyl-6- (3,4-dimethoxyphenyl) -7- (5-methoxy-2-pyridinyl) pyrid [2,3-d] pyrimidine; 4-amino-5- (3-chlorophenyl) -6- (3,4-dimethoxyphenyl) -7- (5-methoxy-2-pyridinyl) p-irido [2,3-d] pyrimidine; 4-amino-5- (3-chlorophenyl) -6- (3,4-dimethoxyphenyl) -5- (5-dimethylamino-2-pyridinyl) pyrido [2,3-d] pyrimidine; 4-amino-5,6-bis (4- (2-pro-pil) phenyl-7- (4-dimethyl-aminophenyl) pi-or [2,3-d] pyrimidine; 4-amino-5,6- diphenyl-7- (4- (N-methyl-N- (2-methoxyethyl) amine) phenyl) pyrido [2,3-d] pyrimidine; 4-amino-5,6-diphenyl-7- (4-dimethylaminophenyl) pyrido [2, 3-d] pi rimidine; 4-amino-5,6-bis (3-fluorophenyl) -7- (4-dimethylaminophenyl) pyrido [2,3-d] pyrimidine; 4-amino-5,6-bis (3,4-dimethoxyphenyl) -7- (4-dimethylaminophenyl) pyrido [2,3-d-pyrimidine; 4-amino-5,6-bis (3-fluoro-4-methylphenyl) -7- (4-dimethylaminophenyl) pyrido [2,3-d] pyrimidine; 4-amino-5,6-bis (3-fluoro-4-methylphenyl) -7- (thiophen-2-yl) pyrido [2,3-d] pyrimidine; 4-amino-5,6-d ifeni l-7- (thiophen-2-yl) pyrido [2,3-d] pyrimidine; 4-amino-5,6-diphenyl-7- (5-dimethylamino-2-pyridinyl) pyrido [2,3-d] pyrimidine; 4-amino-5-phenyl-6- (3,4-dimethoxyphenyl) -7- (5- (dimethylamino) pyridin-2-yl) pyrido [2,3-d] pyrimidine; 4-amino-5- (3-chlorophenyl) -6- (3,4-dimethoxyphenyl) -7- (5-N- (2-methoxyethyl) -N-methylamino) -2-pyridinylpyrid [2, 3-d] pyrimidine; 4-amino-5- (3-chlorophenyl) -6-phenyl-7- (5-dimethylamino-2-pyridinyl) pyrid [2,3-d] pyrimidine; 4-amino-5- (4-bromothiophen-2-yl) -6-phenyl-7- (5-dimethylamino-2-pyridinyl) pyrido [2,3-d] pyrimidine; 4-amino-5- (3-bromophenyl) -6-phenyl-7- (6-dimethylamino-3-pyridinyl) pyrido [2,3-d] pyrimidine 4-amino-5- (3-bromophenyl) -6- (4-fluorophenyl) -7- (6-morpholinyl-3-pyridinyl) pyrido [2,3-d] pyrimidine; 4-amino-5-phenyl-6-phenyl-7- (6-morpholinyl-3-pyridinyl) pyrido [2,3-d] pyrimidine; 4-amino-5- (3-bromophenyl) -6-phenyl-7- (6-morpholinyl-3-pyridinyl) pyrido [2,3-d-pyrimidine; 4-amino-5-phenyl-6-phenyl-7- (6- (N-methyl-N- (2-methoxyethyl) amino) -3-pyridinyl) pyrido [2,3-d] pyrimidine; 4-amino-5- (4-bromothienyl) -6-phenyl-7- (6- (N-methyl-N- (2-methoxyethyl) amino) -3-pyridinyl) pyrido [2,3-d] pyrimidine; 4-amino-5- (4-bromothienyl) -6-cyclopropyl-7- (6-dimethylamino-3-pyridinyl) p-irido [2,3-d] pyrimidine; 4-amino-5- (4-bromothienyl) -6- (4-fluorophenyl) -7- (6-morpholinyl-3-pyridinyl) p-irido [2,3-d] pyrimidine; 4-amino-5- (3-bromophenyl) -6-phenyl-7- (6-cyclopropylmethylamino-3-pyridinyl) pyrido [2,3-d] pyrimidine; 4-amino-5-phenyl-6-phenyl-7- (6-cyclopropylmethylamino-3-pyridinyl) pyrido [2,3-d] pyrimidine; 4-amino-5- (3-bromophenyl) -6- (4-fluorophenyl) -7- (6-morpholinyl-3-pyridinyl) piido [2,3-d] pyrimidine; 4-amino-5- (3-chlorophenyl) -6-heptyl-7- (6-morpholinyl-3-pyridinyl) pyrid [2,3-d] pyrimidine; 4-amino-5-phenyl-6-phenylmethyl-7- (6-morpholinyl-3-pyridinyl) pyrido [2,3-d] pyrimidine; 4-amino-5- (4-bromothienyl) -6-heptyl-7- (6-morpholinyl-3-pyridinyl) pyrido [2,3-d] pyrimidine; 4-amino-5- (4-bromothienyl) -6- (1-methylethyl) -7- (6-morpholinyl-3-pyridinyl) pyrido [2,3-d] pyrimidine; 4-amino-5- (4-bromothienyl) -6-phenylmethyl-7- (6-morpholinyl-3-pyridinyl) pyrido [2,3-d] pyrimidine; 4-amino-5- (3-bromophenyl) -6-cyclohexyl-7- (6-dimethylamino-3-pyridinyl) pyrido [2,3-d] pyrimidine; or 4-amino-5- (3-bromophenyl) -6-pentyl-7- (6-dimethylamino-3-pyridinyl) pyrido [2,3-d] pyrimidine.

10. A method for inhibiting adenosine kinase by administering a compound according to claim 1 or 3.

11. A pharmaceutical composition comprising a therapeutically effective amount of a compound according to claim 1 or 3, in combination with a pharmaceutically acceptable vehicle.

12. A method for treating ischemia, neurological disorders, nociperception, inflammation, immunosuppression, gastrointestinal malfunction, diabetes and sepsis in a mammal in need of such treatment, which comprises administering to the mammal a therapeutically effective amount of a compound according to with claim 1 or 3.

13. 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, shock, thrombotic and embolic conditions, epilepsy, anxiety, schizophrenia, pain perception, neuropathic pain, visceral pain, arthritis, sepsis, diabetes and abnormal gastrointestinal mobility.

14. A process for the preparation of a compound having the formula: wherein: R1 and R2 independently are H, lower alkyl, arylalkyl or acyl, or can be taken together with the nitrogen atom to which they are attached to form a 5-7 membered ring optionally containing 1-3 heterogeneous atoms selected from N , O u S; and R3 and R4 independently are selected from lower alkyl, lower alkenyl, lower alkynyl, lower cycloalkyl, aryl, arylalkyl, heteroaryl or a heterocyclic group; and R5 is selected from an aryl, heteroaryl or heterocyclic group; the method comprising: (a) reacting an aryl, heteroaryl or a heterocyclic bromide having the formula R5-Br, wherein R5 is as defined above, with a carboxylic acid derivative having the formula R4-CH2-CO- Y, wherein Y is OH or Cl, and R 4 is lower alkyl, lower alkenyl, lower alkynyl, aryl, arylalkyl, heteroaryl or a heterocyclic group, with N, O-dimethylhydroxylamine hydrochloride, 1- (3-dimethylaminopropyl) -3 -ethylcarbodiimide or hydrate of 1-hydroxybenzotriazole and triethylamine, and isolate a first intermediate compound having the formula R5-CO-CH2-R4; (b) reacting the first intermediate compound having the formula R5-CO-CH2-R4, with an aldehyde having the formula R3-CHO, wherein R3 is as defined above, and malononitrile in the presence of an ammonium salt under anhydrous conditions, and isolate a second intermediate compound having the formula: (c) reacting the second intermediate compound with refluxing formamide for about 1 to about 24 hours, and isolating the compound of formula II.

15. A process for the preparation of compounds having the formula: where: R1 and R2 independently are H, lower alkyl, arylalkyl or acyl, or can be taken together with the nitrogen atom to which they are attached to form a 5- to 7-membered ring optionally containing 1-3 heterogeneous atoms selected from N, O or S; and R3 and R4 independently are selected from lower alkyl, lower alkenyl, lower alkynyl, aryl, arylalkyl, heteroaryl or a heterocyclic group; and R5 is selected from an aryl, heteroaryl or heterocyclic group; provided that both R1 and R2 are not H, the method comprising: (a) reacting an aryl, heteroaryl or a heterocyclic bromide having the formula R5-Br, wherein R5 is as defined above, with a carboxylic acid derivative having the formula R 4 -CH 2 -CO-Y, wherein Y is OH or Cl, and R 4 is lower alkyl, lower alkenyl, lower alkynyl, aryl, arylalkyl, heteroaryl or a heterocyclic group, with N, O-dimethylhydroxylamine hydrochloride , 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide or hydrate of 1-hydroxybenzotriazole and triethylamine, and isolate a first intermediate compound having the formula R5-CO-CH2-R4; (b) reacting the first intermediate compound having the formula R5-CO-CH2-R4, with an aldehyde having the formula R3-CHO, wherein R3 is as defined above, and malononitrile in the presence of an ammonium salt under anhydrous conditions, and isolate a second intermediate compound having the formula: (c) reacting the second intermediate compound with sulfuric acid and heating followed by treatment with triethyl orthoformate at reflux for about 1 to about 24 hours, and isolating a third intermediate compound having the structure: OH R3 NA? 4 (d) treating the third intermediate compound with a chlorinating agent, and isolating a fourth intermediate product having the formula: with an amine compound having the formula R1-NH-R2, wherein R1 and R2 are as described above, and isolating the compound of the formula II.

16. A process for the preparation of compounds having the formula: wherein: R1 and R2 independently are H, lower alkyl, arylalkyl or acyl, or can be taken together with the nitrogen atom to which they are attached to form a 5- to 7-membered ring optionally containing 1-3 heterogeneous atoms selected from N , O u S; Y R3 and R4 independently are selected from lower alkyl, lower alkenyl, lower alkynyl, aryl, arylalkyl, heteroaryl or a heterocyclic group; and R5 is selected from an aryl, heteroaryl or heterocyclic group; the method comprising: (a) reacting an aryl, heteroaryl, or a heterocyclic bromide having the formula R5-Br with a carboxylic acid derivative having the formula R4-CH2-CO-Y, wherein Y is OH or Cl , and R 4 is lower alkyl, lower alkenyl, lower alkynyl, aryl, arylalkyl, heteroaryl or a heterocyclic group, with N, O-dimethylhydroxylamine hydrochloride, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide or 1-hydroxybenzotriazole hydrate and triethylamine, and isolating a first intermediate compound having the formula R5-CO-CH2-R4; (b) treating the first intermediate compound having the formula R5-CO-CH2-R4, with a compound having the formula: wherein, R3 is as described above, refluxing in an alcoholic solvent and isolating a second intermediate product having the formula: (c) reacting the second intermediate compound with refluxing formamide for about 1 to about 24 hours, and isolating the compound of formula II. 17 - A process for the preparation of compounds having the formula: (II)) wherein: R1 and R2 independently are H, lower alkyl, arylalkyl or acyl, or they may be taken together with the nitrogen atom to which they are attached to form a 5-7 membered ring optionally containing 1-3 atoms heterogeneous selected from N, O or S; and R3 and R4 independently are selected from lower alkyl, lower alkenyl, lower alkynyl, aryl, arylalkyl, heteroaryl or a heterocyclic group; and R5 is selected from an aryl, heteroaryl or heterocyclic group; so long as both R1 and R2 are not H, the method comprising: (a) reacting an aryl, heteroaryl, or a heterocyclic bromide having the formula R5-Br with a carboxylic acid derivative having the formula R4-CH2-CO -Y, where Y is OH or Cl, and R4 is lower alkyl, lower alkenyl, lower alkynyl, aryl, arylalkyl, heteroaryl or a heterocyclic group, with N, O-dimethylhydroxylamine hydrochloride, 1- (3-dimethylaminopropyl) - 3-ethylcarbodiimide or 1-hydroxybenzotriazole hydrate and triethylamine, and isolating a first intermediate compound having the formula R5-CO-CH2-R4; (b) treating the first intermediate compound having the formula R5-CO-CH2-R4, with a compound having the formula: wherein, R3 is as described above, refluxing in an alcoholic solvent and isolating a second intermediate product having the formula: (c) reacting the second intermediate compound with sulfuric acid and heating followed by treatment with triethyl orthoformate at reflux for about 1 to about 24 hours, and isolating a third intermediate compound having the structure: (d) treating the third intermediate compound with a chlorinating agent, and isolating a fourth intermediate product having the formula: (e) treating the fourth intermediate compound with an amine compound having the formula R1-NH-R2, wherein R1 and R2 are as described above, and isolating the compound of the formula II. 18.- A compound of the formula: wherein R3-R5 are as defined in claim 1 and X is selected from OH or halogen. 19. A method for using a compound of the formula III according to claim 17 as an intermediate for producing a compound of the formula II according to claim 2, said method comprises: (a) reacting the compound of the formula III with an amine or substituted amine of the formula NR1R2, wherein R1 and R2 are as defined above, under appropriate conditions, to form a compound of the formula II according to claim 1.